bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of quasi-periodic and steep-spectrum timing noise on the measurement of pulsar timing parameters
Authors: Keith Michael J , Niţu Iuliana C
Published: June 2023

Timing noise in pulsars is often modelled with a Fourier-basis Gaussian process that follows a power law with periodic boundary conditions on the observation time, Tspan. However the actual noise processes can extend well below 1/Tspan, and many pulsars are known to exhibit quasi-periodic timing noise. In this paper we investigate several adaptions that try to account for these differences between the observed behaviour and the simple power-law model. Firstly, we propose to include an additional term that models the quasi-periodic spin-down variations known to be present in many pulsars. Secondly, we show that a Fourier basis of 1/2Tspan can be more suited for estimating long term timing parameters such as the spin frequency second derivative (F2), and is required when the exponent of the power spectrum is greater than ∼4. We also implement a Bayesian version of the generalised least squares ‘Cholesky’ method which has different limitations at low frequency, but find that there is little advantage over Fourier-basis methods. We apply our quasi-periodic spin down model to a sample of pulsars with known spin-down variations and show that this improves parameter estimation of F2 and proper motion for the most pathological cases, but in general the results are consistent with a power-law model. The models are all made available through the run_enterprise software package.
Dynamically coupled kinetic chemistry in brown dwarf atmospheres – I. Performing global scale kinetic modelling
Authors: Lee Elspeth K H , Tan Xianyu , Tsai Shang-Min
Published: June 2023

The atmospheres of brown dwarfs have been long observed to exhibit a multitude of non-equilibrium chemical signatures and spectral variability across the L, T, and Y spectral types. We aim to investigate the link between the large-scale 3D atmospheric dynamics and time-dependent chemistry in the brown dwarf regime, and to assess its impact on spectral variability. We couple the miniature kinetic chemistry module ‘mini-chem’ to the Exo-FMS general circulation model (GCM). We then perform a series of idealized brown dwarf regime atmospheric models to investigate the dynamical 3D chemical structures produced by our simulations. The GCM output is post-processed using a 3D radiative transfer model to investigate hemisphere-dependent spectral signatures and rotational variability. Our results show the expected strong non-equilibrium chemical behaviour brought on by vertical mixing and global spatial variations due to zonal flows. Chemical species are generally globally homogenized, showing variations of ±10 per cent or less, dependent on pressure level, and follow the dynamical structures present in the atmosphere. However, we find localized storm regions and eddies can show higher contrasts, up to ±100 per cent, in mixing ratio compared to the background global mean. This initial study represents another step in understanding the connection between 3D atmospheric flows in brown dwarfs and their rich chemical inventories.
Astrophysical cloaking of a naked singularity
Authors: Vieira Ronaldo S S , Kluźniak Włodek
Published: June 2023

A massive naked singularity would be cloaked by accreted matter, and thus may appear to a distant observer as an opaque (quasi-)spherical surface of a fluid, not unlike that of a star or planet. We present here analytical solutions for levitating atmospheres around a wide class of spherically symmetric naked singularities. Such an atmosphere can be constructed in every spacetime which possesses a zero-gravity radius and which is a solution of a (modified-)gravity theory possessing the usual conservation laws for matter. Its density peaks at the zero-gravity radius and the atmospheric fluid is supported against infall onto the singularity by gravity alone. In an astrophysical context, an opaque atmosphere would be formed in a very short time by accretion of ambient matter onto the singularity—in a millisecond for an X-ray binary, in a thousand seconds for a singularity traversing interstellar space, and a thousand years for a singularity that is the central engine of an AGN.
Carbon–oxygen ultra-massive white dwarfs in general relativity
Authors: Althaus Leandro G , Córsico Alejandro H , Camisassa María E , Torres Santiago , Gil-Pons Pilar , Rebassa-Mansergas Alberto , Raddi Roberto
Published: June 2023

We employ the La Plata stellar evolution code, lpcode, to compute the first set of constant rest-mass carbon–oxygen ultra-massive white dwarf evolutionary sequences for masses higher than 1.29 M⊙ that fully take into account the effects of general relativity on their structural and evolutionary properties. In addition, we employ the lp-pul pulsation code to compute adiabatic g-mode Newtonian pulsations on our fully relativistic equilibrium white dwarf models. We find that carbon–oxygen white dwarfs more massive than 1.382 M⊙ become gravitationally unstable with respect to general relativity effects, being this limit higher than the 1.369 M⊙ we found for oxygen–neon white dwarfs. As the stellar mass approaches the limiting mass value, the stellar radius becomes substantially smaller compared with the Newtonian models. Also, the thermo-mechanical and evolutionary properties of the most massive white dwarfs are strongly affected by general relativity effects. We also provide magnitudes for our cooling sequences in different passbands. Finally, we explore for the first time the pulsational properties of relativistic ultra-massive white dwarfs and find that the period spacings and oscillation kinetic energies are strongly affected in the case of most massive white dwarfs. We conclude that the general relativity effects should be taken into account for an accurate assessment of the structural, evolutionary, and pulsational properties of white dwarfs with masses above ∼1.30 M⊙.
CN and CO features: key indicators of red giant evolutionary phase in moderate-resolution X-shooter spectra
Authors: Banks Kirsten A , Ho Chantel Y Y , Martell Sarah L , Buder Sven , Stello Dennis , Sharma Sanjib , Priest James , Gonneau Anaïs , Hawkins Keith
Published: June 2023

Data-driven analysis methods can help to infer physical properties of red giant stars where ‘gold-standard’ asteroseismic data are not available. The study of optical and infrared spectra of red giant stars with data-driven analyses has revealed that differences in oscillation frequencies and their separations are imprinted in said spectra. This makes it possible to confidently differentiate core helium burning red clump (RC) stars from those that are still on their first ascent of the red giant branch (RGB). We extend these studies to a tenfold larger wavelength range of 0.33–2.5 µm with the moderate-resolution VLT/X-shooter spectrograph. Our analysis of 49 stars with asteroseismic data from the K2 mission confirms that CN, CO, and CH features are indeed the primary carriers of spectroscopic information on the evolutionary stages of red giant stars. We report 215 informative features for differentiating the RC from the RGB within the range of 0.33–2.5 µm. This makes it possible for existing and future spectroscopic surveys to optimize their wavelength regions to deliver both a large variety of elemental abundances and reliable age estimates of luminous red giant stars.
Characterizing asteroid (152830) Dinkinesh in preparation for the encounter with the NASA Lucy mission: a photometric study
Authors: Mottola Stefano , Denk Tilmann , Marchi Simone , Binzel Richard P , Noll Keith S , Spencer John R , Levison Harold F
Published: June 2023

Main Belt asteroid (152830) Dinkinesh will be the first fly-by target of the Lucy mission on 2023 November 1, during its cruise to the Trojan clouds. We report our photometric time series observations of this target performed on 14 nights over nearly three months during the 2022-23 apparition with the 1.23-m telescope at Calar Alto, Spain, aimed at determining its rotation and photometric properties. We find that Dinkinesh is a slow rotator (Psyn = 52.67 ± 0.04 h) with a moderately large light-curve amplitude (A = 0.39 ± 0.02), which implies an axial ratio a/b ≳ 1.43. Its photometric parameters in the HG-system are HR = 17.17 ± 0.04 and GR = 0.378 ± 0.035 with a colour index $\rm {V \!-\! R}$  = 0.455 ± 0.025. A fit to the IAU $\rm {H,G_1,G_2}$ system results in $H_{\rm R-(H,G_1,G_2)}$  = 17.17 ± 0.14; G1  = 0.37 ± 0.17 and G2  = 0.43 ± 0.04. Assuming that Dinkinesh’s albedo lies within ±2σ of the average value for small S-class asteroids, its spherical surface-equivalent diameter is between 0.66 and 1.36 km.
Varstrometry selected radio-loud candidates of dual and off-nucleus quasars at sub-kpc scales
Authors: Wang Hao-Chen , Wang Jun-Xian , Gu Min-Feng , Liao Mai
Published: June 2023

Dual super massive black holes (SMBHs) at sub-kpc to kpc scales, the product of galaxy mergers, are progenitors of eventually coalescing binary SMBHs. If both or one of the dual SMBHs are accreting, they may appear as dual AGNs or off-nucleus AGNs. Studying such systems is essential to learn the dynamical evolution of binary SMBHs as well as the process of galaxy merging. Recently a novel astrometry-based method named varstrometry has been put forward to search for dual SMBHs at high redshift, as the unsynchronized flux variability of dual AGNs (or off-nucleus AGNs) will cause astrometric jitters detectable by Gaia without spatially resolving them. Based on Gaia varstrometry, we select a rare sample of five radio loud quasars with clear Gaia astrometric jitters. With e-MERLIN observations, we have revealed a single compact radio source for each of them. Remarkably all but one exhibit clear Gaia-radio offsets of ∼9–60 mas. The observed Gaia jitters appear consistent with the expected values. These detected Gaia-radio offsets suggest these candidate dual SMBHs may have projected separations as small as ∼0.01–0.1 arcsec (∼0.1 kpc, depending on the optical flux ratio of two SMBHs). Meanwhile, this work highlights the remarkably high efficiency of Gaia varstrometry selection of jittering sources.
Cytoplasmic Polyadenylation Is an Ancestral Hallmark of Early Development in Animals
Authors: Rouhana Labib , Edgar Allison , Hugosson Fredrik , Dountcheva Valeria , Martindale Mark Q , Ryan Joseph F
Published: June 2023

Differential regulation of gene expression has produced the astonishing diversity of life on Earth. Understanding the origin and evolution of mechanistic innovations for control of gene expression is therefore integral to evolutionary and developmental biology. Cytoplasmic polyadenylation is the biochemical extension of polyadenosine at the 3′-end of cytoplasmic mRNAs. This process regulates the translation of specific maternal transcripts and is mediated by the Cytoplasmic Polyadenylation Element-Binding Protein family (CPEBs). Genes that code for CPEBs are amongst a very few that are present in animals but missing in nonanimal lineages. Whether cytoplasmic polyadenylation is present in non-bilaterian animals (i.e., sponges, ctenophores, placozoans, and cnidarians) remains unknown. We have conducted phylogenetic analyses of CPEBs, and our results show that CPEB1 and CPEB2 subfamilies originated in the animal stem lineage. Our assessment of expression in the sea anemone, Nematostella vectensis (Cnidaria), and the comb jelly, Mnemiopsis leidyi (Ctenophora), demonstrates that maternal expression of CPEB1 and the catalytic subunit of the cytoplasmic polyadenylation machinery (GLD2) is an ancient feature that is conserved across animals. Furthermore, our measurements of poly(A)-tail elongation reveal that key targets of cytoplasmic polyadenylation are shared between vertebrates, cnidarians, and ctenophores, indicating that this mechanism orchestrates a regulatory network that is conserved throughout animal evolution. We postulate that cytoplasmic polyadenylation through CPEBs was a fundamental innovation that contributed to animal evolution from unicellular life.
Body-Plan Reorganization in a Sponge Correlates with Microbiome Change
Authors: Vargas Sergio , Leiva Laura , Eitel Michael , Curdt Franziska , Rohde Sven , Arnold Christopher , Nickel Michael , Schupp Peter , Orsi William D , Adamska Maja , Wörheide Gert
Published: June 2023

Mounting evidence suggests that animals and their associated bacteria interact via intricate molecular mechanisms, and it is hypothesized that disturbances to the microbiome influence animal development. Here, we show that the loss of a key photosymbiont (i.e., bleaching) upon shading correlates with a stark body-plan reorganization in the common aquarium cyanosponge Lendenfeldia chondrodes. The morphological changes observed in shaded sponges include the development of a thread-like morphology that contrasts with the flattened, foliose morphology of control specimens. The microanatomy of shaded sponges markedly differed from that of control sponges, with shaded specimens lacking a well-developed cortex and choanosome. Also, the palisade of polyvacuolar gland-like cells typical in control specimens was absent in shaded sponges. The morphological changes observed in shaded specimens are coupled with broad transcriptomic changes and include the modulation of signaling pathways involved in animal morphogenesis and immune response, such as the Wnt, transforming growth factor β (TGF-β), and TLR–ILR pathways. This study provides a genetic, physiological, and morphological assessment of the effect of microbiome changes on sponge postembryonic development and homeostasis. The correlated response of the sponge host to the collapse of the population of symbiotic cyanobacteria provides evidence for a coupling between the sponge transcriptomic state and the state of its microbiome. This coupling suggests that the ability of animals to interact with their microbiomes and respond to microbiome perturbations has deep evolutionary origins in this group.
IL-18 receptor-α signalling pathway contributes to autoantibody-induced arthritis via neutrophil recruitment and mast cell activation
Authors: Kaieda Shinjiro , Kinoshita Takashi , Chiba Asako , Miyake Sachiko , Hoshino Tomoaki
Published: June 2023

Objectives

The interleukin (IL)-18 signalling pathway is involved in animal models of collagen-induced arthritis, but the role of this pathway in autoantibody-induced arthritis is poorly understood. An autoantibody-induced arthritis model, K/BxN serum transfer arthritis, reflects the effector phase of arthritis and is important in innate immunity including neutrophils and mast cells. This study aimed to investigate the role of the IL-18 signalling pathway in autoantibody-induced arthritis using IL-18 receptor (IL-18R) α-deficient mice.

Methods

K/BxN serum transfer arthritis was induced in IL-18Rα−/− and wild-type B6 (controls) mice. The severity of arthritis was graded, and histological and immunohistochemical examinations were performed on paraffin-embedded ankle sections. Total Ribonucleic acid (RNA) isolated from mouse ankle joints was analysed by real-time reverse transcriptase–polymerase chain reaction.

Results

IL-18 Rα−/− mice had significantly lower arthritis clinical scores, neutrophil infiltration, and numbers of activated, degranulated mast cells in the arthritic synovium than in controls. IL-1β, which is indispensable for the progression of arthritis, was significantly downregulated in inflamed ankle tissue in IL-18 Rα−/− mice.

Conclusions

IL-18/IL-18Rα signalling contributes to the development of autoantibody-induced arthritis by enhancing synovial tissue expression of IL-1β and inducing neutrophil recruitment and mast cell activation. Therefore, inhibition of the IL-18Rα signalling pathway might be a new therapeutic strategy for rheumatoid arthritis.
Safety and effectiveness of sarilumab in Japanese patients with rheumatoid arthritis refractory to previous treatments: An interim analysis of a post-marketing surveillance
Authors: Kameda Hideto , Tasaka Sadatomo , Takahashi Toshiya , Suzuki Katsuhisa , Soeda Naoki , Tanaka Yoshiya
Published: June 2023

Objectives

An interim analysis of post-marketing surveillance data to assess the safety and effectiveness of sarilumab in Japanese patients with rheumatoid arthritis refractory to previous treatment.

Methods

The interim analysis included patients who initiated sarilumab therapy between June 2018 and January 2021. The primary objective of this surveillance was safety.

Results

In total, 1036 patients were enrolled and registered by 12 January 2021 (interim cut-off date). Of these, 678 were included in the safety analysis [75.4% female; mean age (± standard deviation) 65.8 ± 13.0 years]. Adverse drug reactions, defined as adverse events classified as possibly or probably related to sarilumab, were reported in 170 patients (incidence: 25.1%), with white blood cell count decreased (4.4%) and neutrophil count decreased (1.6%) most frequently reported. Serious haematologic disorders (3.4%) and serious infections (including tuberculosis) (2.5%) were the most frequently reported priority surveillance items. No malignant tumour was reported. An absolute neutrophil count (ANC) below the minimum standard value did not increase the incidence of serious infections.

Conclusions

Sarilumab was well tolerated, and no new safety signals were noted in this analysis. There was no difference in the frequency of serious infections between patients with an ANC below or above normal.
DDMut: predicting effects of mutations on protein stability using deep learning
Authors: Zhou Yunzhuo , Pan Qisheng , Pires Douglas E V , Rodrigues Carlos H M , Ascher David B
Published: June 2023

Understanding the effects of mutations on protein stability is crucial for variant interpretation and prioritisation, protein engineering, and biotechnology. Despite significant efforts, community assessments of predictive tools have highlighted ongoing limitations, including computational time, low predictive power, and biased predictions towards destabilising mutations. To fill this gap, we developed DDMut, a fast and accurate siamese network to predict changes in Gibbs Free Energy upon single and multiple point mutations, leveraging both forward and hypothetical reverse mutations to account for model anti-symmetry. Deep learning models were built by integrating graph-based representations of the localised 3D environment, with convolutional layers and transformer encoders. This combination better captured the distance patterns between atoms by extracting both short-range and long-range interactions. DDMut achieved Pearson's correlations of up to 0.70 (RMSE: 1.37 kcal/mol) on single point mutations, and 0.70 (RMSE: 1.84 kcal/mol) on double/triple mutants, outperforming most available methods across non-redundant blind test sets. Importantly, DDMut was highly scalable and demonstrated anti-symmetric performance on both destabilising and stabilising mutations. We believe DDMut will be a useful platform to better understand the functional consequences of mutations, and guide rational protein engineering. DDMut is freely available as a web server and API at https://biosig.lab.uq.edu.au/ddmut.
Sordarin bound eEF2 unlocks spontaneous forward and reverse translocation on CrPV IRES
Authors: Ou Zheren , Petrov Alexey
Published: June 2023

The Intergenic Region Internal Ribosome Entry Sites (IGR IRESs) of Discistroviridae promote protein synthesis without initiation factors, with IRES translocation by elongation factor 2 (eEF2) being the first factor-catalysed reaction. Here, we developed a system that allows for the observation of intersubunit conformation of eukaryotic ribosomes at the single-molecule level by labeling rRNA. We used it to follow translation initiation and subsequent translocation of the cricket paralysis virus IRES (CrPV IRES). We observed that pre-translocation 80S–IRES ribosomes spontaneously exchanged between non-rotated and semi-rotated conformations, but predominantly occupied a semi-rotated conformation. In the presence of eEF2, ribosomes underwent forward and reverse translocation. Both reactions were eEF2 concentration dependent, indicating that eEF2 promoted both forward and reverse translocation. The antifungal, sordarin, stabilizes eEF2 on the ribosome after GTP hydrolysis in an extended conformation. 80S–CrPV IRES–eEF2-sordarin complexes underwent multiple rounds of forward and reverse translocations per eEF2 binding event. In the presence of sordarin, neither GTP hydrolysis nor a phosphate release were required for IRES translocation. Together, these results suggest that in the presence of sordarin, eEF2 promotes the mid and late stages of CrPV IRES translocation by unlocking ribosomal movements, with mid and late stages of translocation being thermally driven.
DNA mismatch repair in cancer immunotherapy
Authors: Guan Junhong , Li Guo-Min
Published: June 2023

Tumors defective in DNA mismatch repair (dMMR) exhibit microsatellite instability (MSI). Currently, patients with dMMR tumors are benefitted from anti-PD-1/PDL1-based immune checkpoint inhibitor (ICI) therapy. Over the past several years, great progress has been made in understanding the mechanisms by which dMMR tumors respond to ICI, including the identification of mutator phenotype-generated neoantigens, cytosolic DNA-mediated activation of the cGAS-STING pathway, type-I interferon signaling and high tumor-infiltration of lymphocytes in dMMR tumors. Although ICI therapy shows great clinical benefits, ∼50% of dMMR tumors are eventually not responsive. Here we review the discovery, development and molecular basis of dMMR-mediated immunotherapy, as well as tumor resistant problems and potential therapeutic interventions to overcome the resistance.
Short-chain fatty acids and insulin sensitivity: a systematic review and meta-analysis
Authors: Pham Nhan H T , Joglekar Mugdha V , Wong Wilson K M , Nassif Najah T , Simpson Ann M , Hardikar Anandwardhan A
Published: June 2023

Context

There is substantial evidence that reduced short-chain fatty acids (SCFAs) in the gut are associated with obesity and type 2 diabetes, although findings from clinical interventions that can increase SCFAs are inconsistent.

Objective

This systematic review and meta-analysis aimed to assess the effect of SCFA interventions on fasting glucose, fasting insulin, and homeostatic model assessment of insulin resistance (HOMA-IR).

Data Sources

Relevant articles published up to July 28, 2022, were extracted from PubMed and Embase using the MeSH (Medical Subject Headings) terms of the defined keywords [(short-chain fatty acids) AND (obesity OR diabetes OR insulin sensitivity)] and their synonyms. Data analyses were performed independently by two researchers who used the Cochrane meta-analysis checklist and the PRISMA guidelines.

Data Extraction

Clinical studies and trials that measured SCFAs and reported glucose homeostasis parameters were included in the analysis. Standardized mean differences (SMDs) with 95%CIs were calculated using a random-effects model in the data extraction tool Review Manager version 5.4 (RevMan 5.4). The risk-of-bias assessment was performed following the Cochrane checklist for randomized and crossover studies.

Data Analysis

In total, 6040 nonduplicate studies were identified, 23 of which met the defined criteria, reported fasting insulin, fasting glucose, or HOMA-IR values, and reported change in SCFA concentrations post intervention. Meta-analyses of these studies indicated that fasting insulin concentrations were significantly reduced (overall effect: SMD = −0.15; 95%CI = −0.29 to −0.01, P = 0.04) in treatment groups, relative to placebo groups, at the end of the intervention. Studies with a confirmed increase in SCFAs at the end of intervention also had a significant effect on lowering fasting insulin (P = 0.008). Elevated levels of SCFAs, compared with baseline levels, were associated with beneficial effects on HOMA-IR (P < 0.00001). There was no significant change in fasting glucose concentrations.

Conclusion

Increased postintervention levels of SCFAs are associated with lower fasting insulin concentrations, offering a beneficial effect on insulin sensitivity.

Systematic Review Registration

PROSPERO registration number CRD42021257248.
Comparing 7-Day Versus 6–8-Day Penicillin Treatment Intervals Among Pregnant People With Syphilis of Late or Unknown Duration: No Difference Found in Incidence of Congenital Syphilis
Authors: Johnson Kelly A , Burghardt Nicole O , Snyder Robert E , Plotzker Rosalyn E , Imp Brandon M , Murphy Ryan , Jacobson Kathleen , Tang Eric C
Published: June 2023

Background

Guidelines recommend that pregnant patients with syphilis of late/unknown duration be treated with benzathine penicillin G, dosed as 3 weekly intramuscular injections (BPGx3) given ideally at strict 7-day intervals. Given limited pharmacokinetic data, it is unknown whether more flexible BPG treatment intervals might be effective in preventing congenital syphilis (CS).

Methods

We used California surveillance data to identify birthing parent/infant dyads wherein the pregnant parent had syphilis of late/unknown duration between January 1, 2016 – June 30, 2019. We divided the dyads into 3 groups based on prenatal treatment: (1) BPGx3 at strict 7-day intervals, (2) BPGx3 at 6-8 day intervals, and (3) no/inadequate treatment. We then compared CS incidence among infants in each group.

Results

We analyzed 1,092 parent/infant dyads: 607 (55.6%) in the 7-day treatment group, 70 (6.4%) in the 6–8 day treatment group, and 415 (38.0%) in the no/inadequate treatment group. The incidence proportion of infants meeting CS criteria in each group was, respectively, 5.6%, 5.7%, and 36.9%. Compared with BPGx3 at 7-day intervals, the odds of CS were 1.0 [95% CI 0.4–3.0] in the 6–8 day group and 9.8 [95% CI 6.6–14.7] in the no/inadequate treatment group.

Conclusions

Prenatal BPGx3 at 6–8 days was no more likely to lead to CS in infants than 7-days. These findings hint that 6-8-day intervals might be adequate to prevent CS among pregnant people with syphilis of late/unknown duration. Consequently, it is possible that CS evaluation beyond an RPR at delivery may be unnecessary in asymptomatic infants whose parents received BPGx3 at 6–8 days.
Propensity-Score Matched Analysis of the Effectiveness of Baricitinib in Patients With Coronavirus Disease 2019 (COVID-19) Using Nationwide Real-World Data: An Observational Matched Cohort Study From the Japan COVID-19 Task Force
Authors: Tanaka Hiromu , Chubachi Shotaro , Namkoong Ho , Sato Yasunori , Asakura Takanori , Lee Ho , Azekawa Shuhei , Otake Shiro , Nakagawara Kensuke , Fukushima Takahiro , Watase Mayuko , Sakurai Kaori , Kusumoto Tatsuya , Kondo Yasushi , Masaki Katsunori , Kamata Hirofumi , Ishii Makoto , Kaneko Yuko , Hasegawa Naoki , Ueda Soichiro , Sasaki Mamoru , Izumo Takehiro , Inomata Minoru , Miyazawa Naoki , Kimura Yasuhiro , Suzuki Yusuke , Harada Norihiro , Ichikawa Masako , Takata Tohru , Ishikura Hiroyasu , Yoshiyama Takashi , Kokuto Hiroyuki , Murakami Koji , Sano Hirohito , Ueda Tetsuya , Kuwahara Naota , Fujiwara Akiko , Ogura Takashi , Inoue Takashi , Asami Takahiro , Mutoh Yoshikazu , Nakachi Ichiro , Baba Rie , Nishi Koichi , Tani Mayuko , Kagyo Junko , Hashiguchi Mizuha , Oguma Tsuyoshi , Asano Koichiro , Nishikawa Masanori , Watanabe Hiroki , Okada Yukinori , Koike Ryuji , Kitagawa Yuko , Kimura Akinori , Imoto Seiya , Miyano Satoru , Ogawa Seishi , Kanai Takanori , Fukunaga Koichi
Published: June 2023

Background

To determine the effectiveness of baricitinib in patients with coronavirus disease 2019 (COVID-19), investigate whether baricitinib prevents the need for invasive mechanical ventilation and identify patient subgroups that would benefit from baricitinib.

Methods

This observational matched-cohort study was conducted by the Japan COVID-19 Task Force, a nationwide multicenter consortium. Patients with COVID-19 aged ≥18 years were identified from 70 hospitals in Japan. Among patients with confirmed COVID-19 from February 2020 to September 2021, those receiving baricitinib were propensity-score matched with controls.

Results

Among 3309 patients, 144 propensity score-matched pairs were identified. Thirteen (9.0%) patients in the baricitinib group and 27 (18.8%) in the control group required invasive mechanical ventilation during the disease course (odds ratio, 0.43). Although the baricitinib group had more severe disease, there were no significant differences in the intensive care unit admission rates (odds ratio, 1.16) and mortality rates (odds ratio, 0.74) between groups. In subgroup analyses, baricitinib was associated with a significant reduction in the need for invasive mechanical ventilation in patients requiring oxygen support (odds ratio, 0.28), with rapid shadow spread on chest radiography (odds ratio, 0.11), or treated with remdesivir (odds ratio, 0.27), systemic corticosteroids (odds ratio, 0.31), or anticoagulants (odds ratio, 0.17).

Conclusions

Baricitinib is effective at preventing the need for invasive mechanical ventilation in patients with COVID-19.
Less Irradiation to Lymphocyte-Related Organs Reduced the Risk of G4 Lymphopenia in Esophageal Cancer: Re-Analysis of Prospective Trials
Authors: Tseng Ihsuan , Li Fangfang , Ai Dashan , Chen Yun , Xu Yang , Yu Lu , Hao Shengnan , Zhu Hongcheng , Deng Jiaying , Liu Qi , Pan Fan , Su Fengtao , Zhao Kuaile
Published: June 2023

Background

This study aimed to explore the relationship between irradiation of lymphocyte-related organs at risk (LOARs) and lymphopenia during definitive concurrent chemoradiotherapy (dCCRT) for esophageal squamous cell carcinoma (ESCC).

Materials and Methods

Cases of ESCC patients who received dCCRT from 2 prospective clinical trials were identified. To find its correlation with survival outcomes, grades of absolute lymphocyte counts (ALCs) nadir during radiotherapy were recorded following COX analysis. Associations of lymphocytes at nadir and dosimetric parameters including relative volumes of spleen and bone marrow receiving 0.5, 1, 2, 3, 5, 10, 20, 30, and 50Gy (V0.5, V1, V2, V3, V5, V10, V20, V30, and V50), and effective dose to circulating immune cells (EDIC) were examined by logistic risk regression analysis. The cutoffs of dosimetric parameters were determined by the receiver operating characteristic curve (ROC).

Results

A total of 556 patients were included. The incidences of grades 0, 1, 2, 3, and 4 (G4) lymphopenia during dCCRT were 0.2%, 0.5%, 9.7%, 59.7%, and 29.8%, respectively. Their median overall survival (OS) and progression-free survival (PFS) time were 50.2 and 24.3 months, respectively; the incidence of local recurrence and distant metastasis were 36.6% and 31.8%, respectively. Patients once suffering from G4 nadir during radiotherapy had unfavorable OS (HR, 1.28; P = .044) and a higher incidence of distant metastasis (HR, 1.52; P = .013). Furthermore, patients with EDIC ≤8.3Gy plus spleen V0.5 ≤11.1% and bone marrow V10 ≤33.2% were strongly associated with lower risk of G4 nadir (OR, 0.41; P = .004), better OS (HR, 0.71; P = .011) and lower risk of distant metastasis (HR, 0.56; P = .002).

Conclusions

Smaller relative volumes of spleen V0.5 and bone marrow V10 plus lower EDIC were jointly prone to reduce the incidence of G4 nadir during definitive concurrent chemoradiotherapy. This modified therapeutic strategy could be a significant prognostic factor for survival outcomes in ESCC.
The Value of Pharmaceutical Industry-Sponsored Patient Registries in Oncology Clinical Research
Authors: Flick E Dawn , Terebelo Howard R , Fish Susan , Kitali Amani , Mahajan Vrinda , Nifenecker Melissa , Sullivan Kristen , Thaler Paul , Ussery Sarah , Grinblatt David L
Published: June 2023

In May 2019, the US Food and Drug Administration (FDA) released the Framework for FDA’s Real-World Evidence (RWE) Program, a draft guidance to evaluate the potential use of real-world data in facilitating regulatory decisions. As a result, pharmaceutical companies and medical communities see patient registries, which are large, prospective, noninterventional cohort studies, as becoming increasingly important in providing evidence of treatment effectiveness and safety in clinical practice. Patient registries are designed to collect longitudinal clinical data on a broad population to address critical medical questions over time. With their large sample sizes and broad inclusion criteria, patient registries are often used to generate RWE in the general and underrepresented patient populations that are less likely to be studied in controlled clinical trials. Here, we describe the value of industry-sponsored patient registries in oncology/hematology settings to healthcare stakeholders, in drug development, and in fostering scientific collaboration.
Impact of Volumetric Dosimetry on the Projected Cost of Radiation-Related Late Effects Screening After Childhood Cancer: A Real-World Cohort Analysis
Authors: Cohen-Cutler Sally , Kaplan Cameron , Olch Arthur , Wong Kenneth , Malvar Jemily , Constine Louis S , Freyer David R
Published: June 2023

Background

Screening guidelines for childhood cancer survivors treated with radiation currently rely on broad anatomic irradiated regions (IR) to determine risk for late effects. However, contemporary radiotherapy techniques use volumetric dosimetry (VD) to define organ-specific exposure, which supports more specific screening recommendations that could be less costly.

Patients and Methods

This was a cross-sectional study of 132 patients treated with irradiation at Children’s Hospital Los Angeles from 2000 to 2016. For 5 key organs (cochlea, breast, heart, lung, and colon), radiation exposure was determined retrospectively using both IR and VD methods. Under each method, Children’s Oncology Group Long-Term Follow-Up Guidelines were used to identify organs flagged for screening and recommended screening tests. Projected screening costs incurred under each method were computed through age 65 using insurance claims data.

Results

Median age at the end of treatment was 10.6 years (range, 1.4-20.4). Brain tumor was the most common diagnosis (45%) and head/brain the most common irradiated region (61%). For all 5 organs, use of VD rather than IR resulted in fewer recommended screening tests. This led to average cumulative estimated savings of $3769 (P = .099), with significant savings in patients with CNS tumors (P = .012). Among patients with savings, average savings were $9620 per patient (P = .016) and significantly more likely for females than males (P = .027).

Conclusion

Use of VD to enhance precision of guideline-based screening for radiation-related late effects permits fewer recommended screening tests and generates cost-savings.
Exocrine Pancreatic Insufficiency Induced by Immune Checkpoint Inhibitors
Authors: Satish Deepika , Lin I-Hsin , Flory James , Gerdes Hans , Postow Michael A , Faleck David M
Published: June 2023

Background

Scant data describe exocrine pancreatic insufficiency (EPI) secondary to immune checkpoint inhibitor (ICI) use. The goal of this study is to describe the incidence, risk factors, and clinical characteristics of patients with ICI-related EPI.

Patients and Methods

A single center, retrospective case-control study was performed of all ICI-treated patients at Memorial Sloan Kettering Cancer Center between January 2011 and July 2020. ICI-related EPI patients had steatorrhea with or without abdominal discomfort or weight loss, started pancrelipase after initiation of ICI, and demonstrated symptomatic improvement with pancrelipase. Controls were matched 2:1 by age, race, sex, cancer type, and year of ICI start.

Results

Of 12 905 ICI-treated patients, 23 patients developed ICI-related EPI and were matched to 46 controls. The incidence rate of EPI was 1.18 cases per 1000 person-years and the median onset of EPI was 390 days after the first dose of ICI. All 23 (100%) EPI cases had steatorrhea that improved with pancrelipase, 12 (52.2%) had weight loss, and 9 (39.1%) had abdominal discomfort; none had changes of chronic pancreatitis on imaging. Nine (39%) EPI patients had episodes of clinical acute pancreatitis preceding the onset of EPI, compared to 1 (2%) control (OR 18.0 (2.5-789.0), P < .001). Finally, the EPI group exhibited higher proportions of new or worsening hyperglycemia after ICI exposure compared with the control group (9 (39.1%) vs. 3 (6.5%), P < .01).

Conclusion

ICI-related EPI is a rare but clinically significant event that should be considered in patients with late onset diarrhea after ICI treatment and often is associated with development of hyperglycemia and diabetes.
Gene-based drug therapy in children
Authors: Rassekh S Rod , Rieder Michael , ‘t Jong Geert
Published: June 2023

The past two decades have seen enormous advancements in medical knowledge around the role of genetic factors of variability, both in human disease and drug response. This knowledge is increasingly being translated into guidelines that inform drug dosing, monitoring for efficacy and safety, and determining the suitability of specific agents to treat patients. Health Canada and the U.S. Food and Drug Administration have recommended using genetic information to guide dosing for more than 20 drugs. There are no current, comprehensive paediatric guidelines to assist health care professionals in the use of genetics to inform medication dosing, safety, and efficacy in children, and such guidance is urgently needed. This statement helps to guide clinician understanding of the role of pharmacogenetics and how to use this information when prescribing medications in paediatrics.
Urgent call for guidance supporting gene-based drug dosing in children and adolescents
Authors: Scodellaro Sierra , Cohn Ronald D , Cohn Iris
Published: June 2023

In the past decade, there have been tremendous advancements in the field of genomics that have led to significant progress in redefining the concept of precision medicine. Pharmacogenetics (PGx) is one of the most promising areas of precision medicine and is the ‘low hanging fruit’ of this individualized approach to medication dosing and selection. Although a variety of regulatory health agencies and professional consortia have established PGx clinical practice guidelines, implementation has been slow given numerous barriers faced by health care professionals. Many lack the training needed to interpret PGx and there are no paediatric specific guidelines. As the field of PGx continues to grow, an emphasis on collaborative inter-professional education, coupled with ongoing efforts to increase accessibility to advancing testing technology are necessary to translate this branch of precision medicine from the bench to the bedside.
Rethinking Political Polarization
Authors: Schedler Andreas
Published: June 2023

The comparative study of political polarization has been central to current debates on the global crisis of democracy. It has been built on uncertain conceptual foundations, though. Established uses of the concept lack a distinctive semantic core as multiple meanings compete against each other. On the basis of a broad reading of the comparative literature, I seek to circumscribe the use and reconstruct the core of political polarization as an instance of extraordinary democratic conflict. In a first step, I delineate the basic parameters of debate by distinguishing between cluster-analytic and conflict-analytic approaches and by specifying the generic type of political conflict that characterizes the polarization of democratic polities. In a second step, I argue for political intolerance as the defining trait of both ideological and social polarization. In a final step, I introduce a third, democratic dimension into the debate: the breakdown of basic democratic trust that leads actors to view their adversaries as “enemies of democracy.” Such perceptions spell the end of democratic consolidation. When played among “democratic enemies,” democracy stops being “the only game in town.”
The current existence of ChatGPT in education: a double-edged sword?
Authors: Situmorang Dominikus David Biondi , Salim Rose Mini Agoes , Ifdil Ifdil , Liza Ledya Oktavia , Rusandi M Arli , Hayati Isnaria Rizki , Amalia Rizki , Muhandaz Ramon , Fitriani Arbania
Published: June 2023

The authors in this article would like to invite related parties to carry out updates in the world of education, that the existence of ChatGPT can provide new enthusiasm for all of us to improve in a better direction.
Causal associations and genetic overlap between COVID-19 and intelligence
Authors: Cao Hongbao , Baranova Ancha , Song Yuqing , Chen Jian-Huan , Zhang Fuquan
Published: June 2023

Objective

COVID-19 might cause neuroinflammation in the brain, which could decrease neurocognitive function. We aimed to evaluate the causal associations and genetic overlap between COVID-19 and intelligence.

Methods

We performed Mendelian randomization (MR) analyses to assess potential associations between three COVID-19 outcomes and intelligence (N = 269 867). The COVID phenotypes included severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (N = 2 501 486), hospitalized COVID-19 (N = 1 965 329) and critical COVID-19 (N = 743 167). Genome-wide risk genes were compared between the genome-wide association study (GWAS) datasets on hospitalized COVID-19 and intelligence. In addition, functional pathways were constructed to explore molecular connections between COVID-19 and intelligence.

Results

The MR analyses indicated that genetic liabilities to SARS-CoV-2 infection (odds ratio [OR]: 0.965, 95% confidence interval [CI]: 0.939–0.993) and critical COVID-19 (OR: 0.989, 95% CI: 0.979–0.999) confer causal effects on intelligence. There was suggestive evidence supporting the causal effect of hospitalized COVID-19 on intelligence (OR: 0.988, 95% CI: 0.972–1.003). Hospitalized COVID-19 and intelligence share 10 risk genes within 2 genomic loci, including MAPT and WNT3. Enrichment analysis showed that these genes are functionally connected within distinct subnetworks of 30 phenotypes linked to cognitive decline. The functional pathway revealed that COVID-19-driven pathological changes within the brain and multiple peripheral systems may lead to cognitive impairment.

Conclusions

Our study suggests that COVID-19 may exert a detrimental effect on intelligence. The tau protein and Wnt signaling may mediate the influence of COVID-19 on intelligence.
Realization of regularity coefficients for flows
Authors: Barreira Luis , Valls Claudia
Published: June 2023

We establish sharp relations between several regularity coefficients for flows generated by non-autonomous differential equations. We verify that these relations are sharp by showing that all possible values of the regularity coefficients satisfying these relations are attained by some linear equation with bounded piecewise-continuous coefficient matrix. In addition, we introduce two new regularity coefficients and we obtain sharp relations between these and other coefficients.
Development of a computed tomography calcium scoring technique for assessing calcinosis distribution, pattern and burden in dermatomyositis
Authors: Cervantes Briana A , Gowda Prateek , Rider Lisa G , Miller Frederick W , Chen Marcus Y , Schiffenbauer Adam
Published: June 2023

Objectives

To utilize whole-body CT imaging and calcium scoring techniques as tools for calcinosis assessment in a prospective cohort of patients with adult and juvenile dermatomyositis (DM and JDM, respectively).

Methods

Thirty-one patients (14 DM and 17 JDM) who fulfilled Bohan and Peter Classification criteria as probable or definite DM, the EULAR-ACR criteria for definite DM, and with calcinosis identified by physical examination or prior imaging studies were included. Non-contrast whole-body CT scans were obtained using low-dose radiation procedures. Scans were read qualitatively and quantitated. We calculated the sensitivity and specificity of calcinosis detection of physician physical exam against CT. We quantified calcinosis burden using the Agatston scoring technique.

Results

We identified five distinct calcinosis patterns: Clustered, Disjoint, Interfascial, Confluent and Fluid-filled. Novel locations of calcinosis were observed, including the cardiac tissue, pelvic and shoulder bursa, and the spermatic cord. Quantitative measures using Agatston scoring for calcinosis were used in regional distributions across the body. Physician physical exams had a sensitivity of 59% and a specificity of 90% compared with CT detection. A higher calcium score correlated with higher Physician Global Damage, Calcinosis Severity scores, and disease duration.

Conclusion

Whole-body CT scans and the Agatston scoring metric define distinct calcinosis patterns and provide novel insights relating to calcinosis in DM and JDM patients. Physicians’ physical examinations underrepresented the presence of calcium. Calcium scoring of CT scans correlated with clinical measures, which suggests that this method may be used to assess calcinosis and follow its progression.
Organizing family philanthropy: mobilizing resources and setting up governance for impact
Authors: Eichenberger Etienne , Smulowitz Malgorzata , Vogel Peter
Published: June 2023

Based on their research and experience, the authors find that “best practice” philanthropists adopt a pragmatic and rigorous approach to organizing their philanthropy. That is, they tend to run their philanthropic organizations as efficiently and effectively as possible, with clear structures, roles and responsibilities, as well as goals. The total resources and engagement of a family and wider network determine the setup and governance of one’s giving. In this article, the authors show how philanthropic families can organize their resources and governance to achieve the desired impact across generations. The authors conclude that mobilizing resources and structuring governance in a harmonized and holistic way helps philanthropists to achieve their desired impact.
The Knowledge Intensification of Agriculture
Authors: Vincelli Paul
Published: June 2023

Federal funding for agricultural sciences was initiated with the passage of the Morrill Act in 1862. Since then, the need for science-based information to support our knowledge-intensive agricultural and food systems has grown substantially, and continues to grow, in all farm and food systems. Transformative developments in the disciplines of plant microbiology and plant pathology have led to an increased pace in research and application of knowledge in soil ecosystems and phytobiomes, precision agriculture, and more sophisticated tools for the manipulation of plant genetics. Appropriate federal support remains critical to our robust farming and food systems.

[Formula: see text] Copyright © 2023 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license .