bluuebunny/crossref_metadata_2025 huggingface dataset:
Discovering research articles containing evolutionary timetrees by machine learning
Authors: Stanojevic Marija , Andjelkovic Jovan , Kasprowicz Adrienne , Huuki Louise A , Chao Jennifer , Hedges S Blair , Kumar Sudhir , Obradovic Zoran
Published: January 2023

Motivation

Timetrees depict evolutionary relationships between species and the geological times of their divergence. Hundreds of research articles containing timetrees are published in scientific journals every year. The TimeTree (TT) project has been manually locating, curating and synthesizing timetrees from these articles for almost two decades into a TimeTree of Life, delivered through a unique, user-friendly web interface (timetree.org). The manual process of finding articles containing timetrees is becoming increasingly expensive and time-consuming. So, we have explored the effectiveness of text-mining approaches and developed optimizations to find research articles containing timetrees automatically.

Results

We have developed an optimized machine learning system to determine if a research article contains an evolutionary timetree appropriate for inclusion in the TT resource. We found that BERT classification fine-tuned on whole-text articles achieved an F1 score of 0.67, which we increased to 0.88 by text-mining article excerpts surrounding the mentioning of figures. The new method is implemented in the TimeTreeFinder (TTF) tool, which automatically processes millions of articles to discover timetree-containing articles. We estimate that the TTF tool would produce twice as many timetree-containing articles as those discovered manually, whose inclusion in the TT database would potentially double the knowledge accessible to a wider community. Manual inspection showed that the precision on out-of-distribution recently published articles is 87%. This automation will speed up the collection and curation of timetrees with much lower human and time costs.

Availability and implementation

https://github.com/marija-stanojevic/time-tree-classification.

Supplementary information

Supplementary data are available at Bioinformatics online.
Shared and distinct patterns of dynamic functional connectivity variability of thalamo-cortical circuit in bipolar depression and major depressive disorder
Authors: Lu Fengmei , Chen Yanchi , Cui Qian , Guo Yuanhong , Pang Yajing , Luo Wei , Yu Yue , Chen Jiajia , Gao Jingjing , Sheng Wei , Tang Qin , Zeng Yuhong , Jiang Kexing , Gao Qing , He Zongling , Chen Huafu
Published: January 2023

Evidence has indicated abnormalities of thalamo-cortical functional connectivity (FC) in bipolar disorder during a depressive episode (BDD) and major depressive disorder (MDD). However, the dynamic FC (dFC) within this system is poorly understood. We explored the thalamo-cortical dFC pattern by dividing thalamus into 16 subregions and combining with a sliding-window approach. Correlation analysis was performed between altered dFC variability and clinical data. Classification analysis with a linear support vector machine model was conducted. Compared with healthy controls (HCs), both patients revealed increased dFC variability between thalamus subregions with hippocampus (HIP), angular gyrus and caudate, and only BDD showed increased dFC variability of the thalamus with superior frontal gyrus (SFG), HIP, insula, middle cingulate gyrus, and postcentral gyrus. Compared with MDD and HCs, only BDD exhibited enhanced dFC variability of the thalamus with SFG and superior temporal gyrus. Furthermore, the number of depressive episodes in MDD was significantly positively associated with altered dFC variability. Finally, the disrupted dFC variability could distinguish BDD from MDD with 83.44% classification accuracy. BDD and MDD shared common disrupted dFC variability in the thalamo-limbic and striatal-thalamic circuitries, whereas BDD exhibited more extensive and broader aberrant dFC variability, which may facilitate distinguish between these 2 mood disorders.
Initial Supplementary Dose of Dolutegravir in Second-Line Antiretroviral Therapy: A Noncomparative, Double-Blind, Randomized Placebo-Controlled Trial
Authors: Zhao Ying , Griesel Rulan , Omar Zaayid , Simmons Bryony , Hill Andrew , van Zyl Gert , Keene Claire , Maartens Gary , Meintjes Graeme
Published: January 2023

Background

Dolutegravir concentrations are reduced by efavirenz induction effect necessitating twice-daily dolutegravir dosing when coadministered. Efavirenz induction persists for several weeks after stopping, which could potentially select for dolutegravir resistance if switching occurred with unsuppressed human immunodeficiency virus type 1 (HIV-1) RNA levels and standard dolutegravir dosing. We evaluated the need for a lead-in supplementary dolutegravir dose in adults failing first-line tenofovir-emtricitabine-efavirenz (TEE).

Methods

We conducted a randomized, double-blind, placebo-controlled, phase 2 trial in Khayelitsha, South Africa. Eligible patients had virologic failure (2 consecutive HIV-1 RNA ≥1000 copies/mL) on first-line TEE. Participants were randomly assigned (1:1) to switch to tenofovir-lamivudine-dolutegravir (TLD) with a supplementary 50 mg dolutegravir dose or placebo taken 12 hours later for 14 days. Primary outcome was proportion with HIV-1 RNA <50 copies/mL at week 24. This study was not powered to compare arms.

Results

One hundred thirty participants were randomized (65 to each arm). Median baseline HIV-1 RNA was 4.0 log10 copies/mL and 76% had baseline resistance to both tenofovir and lamivudine. One participant died and 2 were lost to follow-up. At week 24, 55 of 64 (86% [95% confidence interval {CI}: 75%–93%]) in the supplementary dolutegravir arm and 53 of 65 (82% [95% CI: 70%–90%]) in the placebo arm had HIV-1 RNA <50 copies/mL. Grade 3 or 4 adverse events were similar in frequency between arms. None of 6 participants (3 in each arm) eligible for resistance testing by 24 weeks developed dolutegravir resistance.

Conclusions

Our findings do not support the need for initial dolutegravir dose adjustment in patients switching to TLD who failed first-line TEE.

Clinical Trials Registration

NCT03991013.
Drosophila postembryonic nervous system development: a model for the endocrine control of development
Authors: Truman James W , Riddiford Lynn M
Published: January 2023

During postembryonic life, hormones, including ecdysteroids, juvenile hormones, insulin-like peptides, and activin/TGFβ ligands act to transform the larval nervous system into an adult version, which is a fine-grained mosaic of recycled larval neurons and adult-specific neurons. Hormones provide both instructional signals that make cells competent to undergo developmental change and timing cues to evoke these changes across the nervous system. While touching on all the above hormones, our emphasis is on the ecdysteroids, ecdysone and 20-hydroxyecdysone (20E). These are the prime movers of insect molting and metamorphosis and are involved in all phases of nervous system development, including neurogenesis, pruning, arbor outgrowth, and cell death. Ecdysteroids appear as a series of steroid peaks that coordinate the larval molts and the different phases of metamorphosis. Each peak directs a stereotyped cascade of transcription factor expression. The cascade components then direct temporal programs of effector gene expression, but the latter vary markedly according to tissue and life stage. The neurons read the ecdysteroid titer through various isoforms of the ecdysone receptor, a nuclear hormone receptor. For example, at metamorphosis the pruning of larval neurons is mediated through the B isoforms, which have strong activation functions, whereas subsequent outgrowth is mediated through the A isoform through which ecdysteroids play a permissive role to allow local tissue interactions to direct outgrowth. The major circulating ecdysteroid can also change through development. During adult development ecdysone promotes early adult patterning and differentiation while its metabolite, 20E, later evokes terminal adult differentiation.
Geodetic modelling of the 2022Mw 6.6 Menyuan earthquake: insight into the strain-partitioned northern Qilian Shan fault system and implications for regional tectonics and seismic hazards
Authors: Zhang Yingfeng , Chen Jie , Gong Wenyu , Han Nana , Liu Yunhua , Shan Xinjian
Published: January 2023

Strain partitioning between strike-slip faults in mountains and thrust faults in the foreland is a typical mountain building process to accommodate oblique plate convergence. Studying the geometry and movement of such strain-partitioned fault systems is key to understanding the mountain building process and related seismic hazards. The 2022 Mw 6.6 Menyuan earthquake is the largest strike-slip earthquake to have ruptured the northern Qilian Shan fault system in the modern geodetic era. We combined satellite and field observations to determine the fault geometry and coseismic slip distribution in the Menyuan earthquake, and link the distribution of coseismic slip with the pattern of interseismic strain accumulation within the northern Qilian Shan from our geodetic slip model. We find that the Menyuan earthquake ruptured a 25 km-long section of the left-lateral Longlongling Fault between the surface and 7 km depth. The maximum slip was 4 m at 3–4 km depth. Damage to a high-speed railway tunnel recorded a fault offset of 2.7 m at a depth of 200 m compared to 2.5–3.0 m on the surface, suggesting that dispersion of the rupture through unconsolidated shallow sediments was limited, at least at the tunnel site. We also determined the pattern of interseismic deformation prior to the earthquake using Interferometric Synthetic Aperture Radar and Global Navigation Satellite System data. We found the interseismic geodetic data can be explained by the oblique movement of a low-angle décollement beneath the Qilian Shan rather than a strain partitioning fault system. We suggested that the strike-slip faults and foreland thrusts are separated by a creeping décollement, which would act as a barrier to stop the cascading rupture of the strike-slip and thrust fault.
Vaccine Effectiveness Against 12-Month Incident and Persistent Anal Human Papillomavirus Infection Among Gay, Bisexual, and Other Men Who Have Sex With Men
Authors: Chambers Catharine , Deeks Shelley L , Sutradhar Rinku , Cox Joseph , de Pokomandy Alexandra , Grennan Troy , Hart Trevor A , Lambert Gilles , Moore David M , Grace Daniel , Grewal Ramandip , Jollimore Jody , Lachowsky Nathan , Nisenbaum Rosane , Ogilvie Gina , Sauvageau Chantal , Tan Darrell H S , Coutlée François , Burchell Ann N
Published: January 2023

Background

Real-world evidence of human papillomavirus (HPV) vaccine effectiveness (VE) against longitudinal outcomes is lacking among gay, bisexual, and other men who have sex with men (GBM). We compared 12-month incidence and persistence of anal HPV infection between vaccinated and unvaccinated GBM.

Methods

We recruited GBM aged 16–30 years in Montreal, Toronto, and Vancouver, Canada, from 2017 to 2019. Participants were followed over a median of 12 months (interquartile range, 12–13 months). Participants self-reported HPV vaccination and self-collected anal specimens for HPV DNA testing. We calculated prevalence ratios (PR) for 12-month cumulative incidence and persistence with ≥1 quadrivalent vaccine type (HPV 6/11/16/18) between vaccinated (≥1 dose at baseline) and unvaccinated participants using a propensity score-weighted, modified Poisson regression.

Results

Among 248 participants, 109 (44.0%) were vaccinated at baseline, of whom 62.6% received 3 doses. PRs for HPV 6/11/16/18 were 0.56 (95% confidence interval [CI], .24–1.31) for cumulative incidence and 0.53 (95% CI, .25–1.14) for persistence. PRs were 0.23 (95% CI, .05–1.03) and 0.08 (95% CI, .01–.59) for incidence and persistence, respectively, among participants who received their first dose at age ≤23 years and 0.15 (95% CI, .03–.68) and 0.12 (95% CI, .03–.54) among participants who were sexually active for ≤5 years before vaccination.

Conclusions

Findings support national recommendations for HPV vaccination at younger ages or soon after sexual debut.
BNT162b2 Effectiveness Against Delta and Omicron Variants of Severe Acute Respiratory Syndrome Coronavirus 2 in Adolescents Aged 12–17 Years, by Dosing Interval and Duration
Authors: Ionescu Iulia G , Skowronski Danuta M , Sauvageau Chantal , Chuang Erica , Ouakki Manale , Kim Shinhye , De Serres Gaston
Published: January 2023

Background

Two- and 3-dose BNT162b2 vaccine effectiveness (VE) against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, including Delta and Omicron variants, was assessed among adolescents in Canada, where first and second doses were spaced longer than the manufacturer-specified 3-week interval.

Methods

Test-negative design estimated VE against laboratory-confirmed SARS-CoV-2 infection ≥14 days after vaccination among 12–17-year-olds in Quebec and British Columbia, Canada, between 5 September 2021 and 30 April 2022 (epidemiological weeks 36–17). VE was explored by the interval between first and second doses, time since the second dose, and with a third dose.

Results

The VE against Delta was ≥90% until at least 5 months after the second dose. The VE against Omicron decreased from about 65%–75% at 2–3 weeks to ≤50% by the third month after vaccination, restored to approximately 65% by a third dose. Although confidence intervals overlapped, VE against Omicron was about 5%–7% higher (absolute) when first and second doses were spaced ≥8 versus 3–4 weeks apart.

Conclusions

In adolescents, 2 BNT162b2 doses provided strong and sustained protection against Delta but reduced and rapidly waning VE against Omicron. A longer interval between first and second doses and a third dose marginally improved Omicron protection.
Antioxidant, antibacterial, and antileishmanial potential ofMicromeria nervosaextracts and molecular mechanism of action of the bioactive compound
Authors: Kefi Sarra , Essid Rym , Papetti Adele , Abid Ghassen , Bouslama Lamjed , Aouani Ezzedine , Tabbene Olfa , Limam Ferid
Published: January 2023

Aims

This study aimed to determine the antibacterial and antileishmanial potential of Micromeria nervosa extracts. The identification of the antileishmanial compound and the study of its molecular mechanism of action have also been undertaken.

Methods and results

Ethanol extract showed high polyphenol content and diethyl ether extract exhibited high DPPH scavenging and low beta-carotene bleaching activity (IC50 = 13.04 ± 0.99 and 200.18 ± 3.32 μg mL−1, respectively). However, diethyl ether extract displayed high antibacterial activity against Gram-positive strains including methicillin-resistant Staphylococcus aureus (MIC = 31.25 μg mL−1), Staph. aureus ATCC6538 (MIC = 62.5 μg mL−1), and Listeria monocytogenes ATCC 19115 (MIC = 125 μg mL−1), as well as high antileishmanial activity against the promastigote forms of L. infantum and L. major (IC50 = 11.45 and 14.53 μg mL−1, respectively). The active compound was purified using bioassay-guided fractionation and thin layer chromatography, and identified as ursolic acid using high-performance liquid chromatography coupled with a photodiode array and mass spectrometry. The purified compound was strongly inhibitory against the promastigote and amastigote forms of L. infantum and L. major (IC50 = 5.87 and 6.95 μg mL−1 versus 9.56 and 10. 68 μg mL−1, respectively) without overt cytotoxicity against Raw 264.7 macrophage cells (SI = 13.53 and 11.43, respectively). The commercial compound (ursolic acid) showed similar activity against amastigotes and promastigotes forms of L. infantum and L. major. Moreover, its molecular mode of action against leishmaniasis seems to involve the expression of the ODC and SPS genes involved in thiol pathway.

Conclusion

Extracts of M. nervosa can be considered as a potential alternative to antimicrobial and antileishmanial drugs.
A tale of two concepts: differential temporal predictions of habitual and compulsive social media use concerning connection overload and sleep quality
Authors: Koban Kevin , Stevic Anja , Matthes Jörg
Published: January 2023

Given how strongly social media is permeating young people’s everyday lives, many of them have formed strong habits that, under specific circumstances, can spiral out of control and bring harmful experiences. Unlike in extant literature where habitual and compulsive behaviors are often conflated, we report findings from a two-wave panel study examining the individual predictive value of both habitual and compulsive social media use on connection overload (i.e., information and communication overload) and sleep quality. Longitudinal structural equation modeling reveals that only compulsive social media use is related to enhanced feelings of connection overload and to poorer sleep, whereas habitual social media use had no significant associations with either indicator over time. These differential findings highlight a conceptual imperative for future approaches to further clarify the nature of people’s media habits to prevent spurious (and potentially overpathologizing) conclusions.
Tissue injury and leukocyte changes in post-acute sequelae of SARS-CoV-2: review of 2833 post-acute patient outcomes per immune dysregulation and microbial translocation in long COVID
Authors: Islam Md Sahidul , Wang Zhaoxiong , Abdel-Mohsen Mohamed , Chen Xin , Montaner Luis J
Published: January 2023

A significant number of persons with coronavirus disease 2019 (COVID-19) experience persistent, recurrent, or new symptoms several months after the acute stage of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. This phenomenon, termed post-acute sequelae of SARS-CoV-2 (PASC) or long COVID, is associated with high viral titers during acute infection, a persistently hyperactivated immune system, tissue injury by NETosis-induced micro-thrombofibrosis (NETinjury), microbial translocation, complement deposition, fibrotic macrophages, the presence of autoantibodies, and lymphopenic immune environments. Here, we review the current literature on the immunological imbalances that occur during PASC. Specifically, we focus on data supporting common immunopathogenesis and tissue injury mechanisms shared across this highly heterogenous disorder, including NETosis, coagulopathy, and fibrosis. Mechanisms include changes in leukocyte subsets/functions, fibroblast activation, cytokine imbalances, lower cortisol, autoantibodies, co-pathogen reactivation, and residual immune activation driven by persistent viral antigens and/or microbial translocation. Taken together, we develop the premise that SARS-CoV-2 infection results in PASC as a consequence of acute and/or persistent single or multiple organ injury mediated by PASC determinants to include the degree of host responses (inflammation, NETinjury), residual viral antigen (persistent antigen), and exogenous factors (microbial translocation). Determinants of PASC may be amplified by comorbidities, age, and sex.
Mapping the interplay between NK cells and HIV: therapeutic implications
Authors: Anderko Renee R , Mailliard Robbie B
Published: January 2023

Although highly effective at durably suppressing plasma HIV-1 viremia, combination antiretroviral therapy (ART) treatment regimens do not eradicate the virus, which persists in long-lived CD4+ T cells. This latent viral reservoir serves as a source of plasma viral rebound following treatment interruption, thus requiring lifelong adherence to ART. Additionally, challenges remain related not only to access to therapy but also to a higher prevalence of comorbidities with an inflammatory etiology in treated HIV-1+ individuals, underscoring the need to explore therapeutic alternatives that achieve sustained virologic remission in the absence of ART. Natural killer (NK) cells are uniquely positioned to positively impact antiviral immunity, in part due to the pleiotropic nature of their effector functions, including the acquisition of memory-like features, and, therefore, hold great promise for transforming HIV-1 therapeutic modalities. In addition to defining the ability of NK cells to contribute to HIV-1 control, this review provides a basic immunologic understanding of the impact of HIV-1 infection and ART on the phenotypic and functional character of NK cells. We further delineate the qualities of “memory” NK cell populations, as well as the impact of HCMV on their induction and subsequent expansion in HIV-1 infection. We conclude by highlighting promising avenues for optimizing NK cell responses to improve HIV-1 control and effect a functional cure, including blockade of inhibitory NK receptors, TLR agonists to promote latency reversal and NK cell activation, CAR NK cells, BiKEs/TriKEs, and the role of HIV-1-specific bNAbs in NK cell–mediated ADCC activity against HIV-1-infected cells.
Peli1 deletion in macrophages attenuates myocardial ischemia/reperfusion injury by suppressing M1 polarization
Authors: Chen Hao , Hou Yuxing , Zhai Yali , Yang Jie , Que Linli , Liu Jichun , Lu Linming , Ha Tuanzhu , Li Chuanfu , Xu Yong , Li Jiantao , Li Yuehua
Published: January 2023

The polarization of macrophages to the M1 or M2 phenotype has a pivotal role in inflammatory response following myocardial ischemia/reperfusion injury. Peli1, an E3 ubiquitin ligase, is closely associated with inflammation and autoimmunity as an important regulatory protein in the Toll-like receptor signaling pathway. We aimed to explore the function of Peli1 in macrophage polarization under myocardial ischemia/reperfusion injury and elucidate the possible mechanisms. We show here that Peli1 is upregulated in peripheral blood mononuclear cells from patients with myocardial ischemia/reperfusion, which is correlated with myocardial injury and cardiac dysfunction. We also found that the proportion of M1 macrophages was reduced and myocardial infarct size was decreased, paralleling improvement of cardiac function in mice with Peli1 deletion in hematopoietic cells or macrophages. Macrophage Peli1 deletion lessened M1 polarization and reduced the migratory ability in vitro. Mechanistically, Peli1 contributed to M1 polarization by promoting K63-linked ubiquitination and nuclear translocation of IRF5. Moreover, Peli1 deficiency in macrophages reduced the apoptosis of cardiomyocytes in vivo and in vitro. Together, our study demonstrates that Peli1 deficiency in macrophages suppresses macrophage M1 polarization and alleviates myocardial ischemia/reperfusion injury by inhibiting the nuclear translocation of IRF5, which may serve as a potential intervention target for myocardial ischemia/reperfusion injury.
RNA splicing factors in normal hematopoiesis and hematologic malignancies: novel therapeutic targets and strategies
Authors: Li Zhenzhen , He Zhongzheng , Wang Jihan , Kong Guangyao
Published: January 2023

RNA splicing, a crucial transesterification-based process by which noncoding regions are removed from premature RNA to create mature mRNA, regulates various cellular functions, such as proliferation, survival, and differentiation. Clinical and functional studies over the past 10 y have confirmed that mutations in RNA splicing factors are among the most recurrent genetic abnormalities in hematologic neoplasms, including myeloid malignancies, chronic lymphocytic leukemia, mantle cell lymphoma, and clonal hematopoiesis. These findings indicate an important role for splicing factor mutations in the development of clonal hematopoietic disorders. Mutations in core or accessory components of the RNA spliceosome complex alter splicing sites in a manner of change of function. These changes can result in the dysregulation of cancer-associated gene expression and the generation of novel mRNA transcripts, some of which are not only critical to disease development but may be also serving as potential therapeutic targets. Furthermore, multiple studies have revealed that hematopoietic cells bearing mutations in splicing factors depend on the expression of the residual wild-type allele for survival, and these cells are more sensitive to reduced expression of wild-type splicing factors or chemical perturbations of the splicing machinery. These findings suggest a promising possibility for developing novel therapeutic opportunities in tumor cells based on mutations in splicing factors. Here, we combine current knowledge of the mechanistic and functional effects of frequently mutated splicing factors in normal hematopoiesis and the effects of their mutations in hematologic malignancies. Moreover, we discuss the development of potential therapeutic opportunities based on these mutations.
Colonization, Density, and Antibiotic Resistance of Streptococcus pneumoniae, Haemophilus Influenzae, and Moraxella catarrhalis among PCV13-Vaccinated Infants in the First Six Months of Life in Rochester, New York: A Cohort Study
Authors: Kaur Ravinder , Pichichero Michael
Published: January 2023

Background

Streptococcus pneumoniae (Spn), Haemophilus influenzae (Hflu), and Moraxella catarrhalis (Mcat) nasopharyngeal colonization precedes disease pathogenesis and varies among settings and countries. We sought to assess colonization prevalence, density, Spn serotypes, and antibiotic resistance in children in the first 6 months of life in pediatric primary care settings.

Methods

Prospective cohort study in Rochester, NY during 2018–2020. Nasopharyngeal swabs were collected from 101 children at age 1, 2, and 3 weeks, then 1, 2, 4, 6, 9, 12, 15, 18, and 24 months. Spn serotypes were determined by Quellung. Oxacillin resistance for Spn and β-lactamase production by Hflu and Mcat was tested. All children received PCV13 vaccine according to U.S. recommended schedule.

Results

Spn, Hflu, and Mcat colonization was detected in only 5% of infants before age 2 months old. Cumulative prevalence was 34% for Spn, 10% for Hflu, and 53% for Mcat in children ≤6 months of age. Nasopharyngeal bacterial density of Spn, Hflu, and Mcat (x = 2.71 log) in children ≤6 months of age was lower than at 7–24 months of age (x = 3.15 log, p < 0.0001). Predominant serotypes detected ≤6 months of age were 23B (16.7%), 22F (12.9%), 15B/C (11%), and 16F (9.2%). In total, 14.8% of Spn isolates were oxacillin resistant and 66.7% of Hflu isolates were β-lactamase producing.

Conclusion

Spn, Hflu, and Mcat nasopharyngeal colonization was uncommon and of low density among children ≤6 months old, especially among children <2 months of age. Non-PCV13 serotypes predominated and a different serotype distribution was observed in ≤6-month olds compared to 7- to 24-month olds.
The Extragalactic Serendipitous Swift Survey (ExSeSS) – I. Survey definition and measurements of the X-ray number counts
Authors: Delaney Jack N , Aird James , Evans Phil A , Barlow-Hall Cassandra , Osborne Julian P , Watson Michael G
Published: January 2023

We present the Extragalactic Serendipitous Swift Survey (ExSeSS), providing a new well-defined sample constructed from the observations performed using the Swift X-ray Telescope. The ExSeSS sample consists of 79 342 sources detected in the medium (1–2 keV), hard (2–10 keV), or total (0.3–10 keV) energy bands, covering 2086.6 deg2 of sky across a flux range of f0.3–10 keV ∼ 10−15 − 10−10 erg s−1 cm−2. Using the new ExSeSS sample we present measurements of the differential number counts of X-ray sources as a function of 2–10 keV flux that trace the population of Active Galactic Nuclei (AGNs) in a previously unexplored regime. We find that taking the line-of-sight absorption column density into account has an effect on the differential number count measurements and is vital to obtain agreement with previous results. In the hard band, we obtain a good agreement between the ExSeSS measurements and previous, higher energy data from NuSTAR and Swift/BAT when taking into account the varying column density of the ExSeSS sample as well as the X-ray spectral parameters of each of the samples we are comparing to. We also find discrepancies between the ExSeSS measurements and AGN population synthesis models, indicating a change in the properties of the AGN population over this flux range that is not fully described by current models at these energies, hinting at a larger, moderately obscured population at low redshifts (z ≲ 0.2) that the models are not currently taking into account.
Letter to the Editor: Double-counting due to inadequate statistics leads to false-positive findings in “Effects of creatine supplementation on memory in healthy individuals: a systematic review and meta-analysis of randomized controlled trials”
Authors: Eckert Igor , Pascher Eric
Published: January 2023

Prokopidis et al have conducted a meta-analysis of randomized, placebo-controlled clinical trials to assess the effects of oral creatine supplementation on memory performance of healthy individuals. However, concerns were raised regarding the validity of their statistical analyses, which may have led to misleading conclusions. In this letter, we describe the statistical issue at hand and its potential implications.
Inhibitory effect of baricitinib on microglia and STAT3 in a region with a weak blood–brain barrier in a mouse model of rheumatoid arthritis
Authors: Matsushita Takayuki , Otani Kazuhiro , Yoshiga Masayuki , Hirano Masashi , Noda Kentaro , Kurosaka Daitaro
Published: January 2023

Objectives

In patients with RA, baricitinib not only improves arthritis symptom severity, but also patients’ neuropsychological symptoms, such as depression and fatigue. However, the cellular mechanisms through which baricitinib can affect neural activity is unexplored. While the blood–brain barrier (BBB) permeability of this drug remains unclear, Janus kinase inhibitors (JAKi) might reach the area postrema, which is a unique brain region with a weak BBB function. Our recent study demonstrated microglial activation during experimental arthritis in the area postrema. Therefore, we sought to assess the effect of baricitinib on microglia in the area postrema using the CIA mouse model.

Methods

Microglia number and morphology in the area postrema were assessed by immunostaining for ionized calcium-binding adaptor molecule-1 (Iba-1). Data were collected on post-immunization day 35 (early phase) and 84 (late phase), and compared between baricitinib- and vehicle-treated mice. The effect on signal transducers and activators of transcription (STAT3) in the area postrema was also immunohistochemically examined. Behavioural outcomes were assessed by examining feeding behaviours and sucrose preference tests.

Results

In the early phase, activated microglial levels in the area postrema were decreased by baricitinib, accompanied by the inhibition of phosphorylated-STAT3 and recovery of food intake and sucrose preference. On the other hand, baricitinib did not affect microglial morphology in the late phase.

Conclusion

Our results demonstrate that baricitinib can affect brain cells, specifically microglia, in the brain region with a weak BBB and mitigate aberrant behaviours during autoimmune arthritis, pointing to the potential therapeutic effect of JAKi on brain pathologies underpinning RA.
Mitochondrial DNA: a novel indicator of active inflammation in ANCA-associated vasculitides
Authors: Giaglis Stavros , Daoudlarian Douglas , Thiel Jens , Rizzi Marta , Kyburz Diego , Venhoff Nils , Walker Ulrich A
Published: January 2023

Objectives

ANCA-associated vasculitis (AAV) includes granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA). ANCA triggers neutrophil extracellular trap formation, which releases either mitochondrial (mt) DNA or nuclear DNA (n) DNA, contributing to inflammation. Our aim was to prospectively examine the extent and nature of circulating DNA in AAV and the clinical utility of DNA quantification.

Methods

DNA was isolated from platelet-free plasma of consecutive GPA and MPA patients and healthy controls (HCs). mtDNA and nDNA copy numbers were quantified by PCR. Clinical data, including the BVAS, were collected.

Results

Ninety-two HCs (median age 51 years, 58.7% female) and 101 AAV patients (80 GPA, 21 MPA, median age 64 years, 50.5% female, BVAS range: 0–30) were included. Median mtDNA copies were 13-fold higher in patients with AAV than in HCs; nDNA concentrations did not differ. Patients with active AAV (BVAS > 0) had 4-fold higher median mtDNA copies than patients in remission (P = 0.03). mtDNA, unlike nDNA, correlated with BVAS (r = 0.30, P = 0.002) and was associated with AAV activity at multivariable analysis. Receiver operating characteristic curve analysis indicated that mtDNA quantification differentiates patients with active AAV (BVAS > 0) from HCs with 96.1% sensitivity and 98.9% specificity (area under the curve 0.99). In 27 AAV patients with follow-up, mtDNA changes but not CRP or ANCA-titres correlated with BVAS changes (r = 0.56, P = 0.002).

Conclusions

mtDNA, unlike nDNA, is elevated in the plasma of AAV patients and may contribute to systemic inflammation. mtDNA could be superior to established biomarkers in the laboratory monitoring of AAV activity.
Impact of Phylogenetic Tree Completeness and Mis-specification of Sampling Fractions on Trait Dependent Diversification Models
Authors: Mynard Poppy , Algar Adam C , Lancaster Lesley T , Bocedi Greta , Fahri Fahri , Gubry-Rangin Cécile , Lupiyaningdyah Pungki , Nangoy Meis , Osborne Owen G , Papadopulos Alexander S T , Sudiana I Made , Juliandi Berry , Travis Justin M J , Herrera-Alsina Leonel
Published: January 2023

Understanding the origins of diversity and the factors that drive some clades to be more diverse than others are important issues in evolutionary biology. Sophisticated SSE (state-dependent speciation and extinction) models provide insights into the association between diversification rates and the evolution of a trait. The empirical data used in SSE models and other methods is normally imperfect, yet little is known about how this can affect these models. Here, we evaluate the impact of common phylogenetic issues on inferences drawn from SSE models. Using simulated phylogenetic trees and trait information, we fitted SSE models to determine the effects of sampling fraction (phylogenetic tree completeness) and sampling fraction mis-specification on model selection and parameter estimation (speciation, extinction, and transition rates) under two sampling regimes (random and taxonomically biased). As expected, we found that both model selection and parameter estimate accuracies are reduced at lower sampling fractions (i.e., low tree completeness). Furthermore, when sampling of the tree is imbalanced across sub-clades and tree completeness is ≤ 60%, rates of false positives increase and parameter estimates are less accurate, compared to when sampling is random. Thus, when applying SSE methods to empirical datasets, there are increased risks of false inferences of trait dependent diversification when some sub-clades are heavily under-sampled. Mis-specifying the sampling fraction severely affected the accuracy of parameter estimates: parameter values were over-estimated when the sampling fraction was specified as lower than its true value, and under-estimated when the sampling fraction was specified as higher than its true value. Our results suggest that it is better to cautiously under-estimate sampling efforts, as false positives increased when the sampling fraction was over-estimated. We encourage SSE studies where the sampling fraction can be reasonably estimated and provide recommended best practices for SSE modeling. [Trait dependent diversification; SSE models; phylogenetic tree completeness; sampling fraction.]
Population Pharmacokinetic Analysis of Drug–Drug Interactions Between Perampanel and Carbamazepine Using Enzyme Induction Model in Epileptic Patients
Authors: Fujita Yuito , Murai Mariko , Muraki Shota , Suetsugu Kimitaka , Tsuchiya Yuichi , Hirota Takeshi , Matsunaga Naoya , Ieiri Ichiro
Published: January 2023

Background:

Perampanel (PER) is an oral antiepileptic drug and its concomitant use with carbamazepine (CBZ) leads to decreased PER concentrations. However, the magnitude of its influence may vary, depending on the dynamics of the enzyme induction properties of CBZ. This study aimed to develop a population pharmacokinetic (PPK) model considering the dynamics of enzyme induction and evaluate the effect of CBZ on PER pharmacokinetics.

Methods:

We retrospectively collected data on patient background, laboratory tests, and prescribed drugs from electronic medical records. We developed 2 PPK models incorporating the effect of CBZ-mediated enzyme induction to describe time–concentration profiles of PER using the following different approaches: (1) treating the concomitant use of CBZ as a categorical covariate (empirical PPK model) and (2) incorporating the time-course of changes in the amount of enzyme by CBZ-mediated induction (semimechanistic PPK model). The bias and precision of the predictions were investigated by calculating the mean error, mean absolute error, and root mean squared error.

Results:

A total of 133 PER concentrations from 64 patients were available for PPK modelling. PPK analyses showed that the co-administration of CBZ increased the clearance of PER. Goodness-of-fit plots indicated a favorable description of the observed data and low bias. The mean error, mean absolute error, and root mean square error values based on the semimechanistic model were smaller than those obtained using the empirical PPK model for predicting PER concentrations in patients with CBZ.

Conclusions:

We developed 2 PPK models to describe PER pharmacokinetics based on different approaches, using electronic medical record data. Our PPK models support the use of PER in clinical practice.
Hepatocyte-to-cholangiocyte conversion occurs through transdifferentiation independently of proliferation in zebrafish
Authors: Lee Seung-Hoon , So Juhoon , Shin Donghun
Published: January 2023

Background and aims:

Injury to biliary epithelial cells (BECs) lining the hepatic bile ducts leads to cholestatic liver diseases. Upon severe biliary damage, hepatocytes can convert to BECs, thereby contributing to liver recovery. Given a potential of augmenting this hepatocyte-to-BEC conversion as a therapeutic option for cholestatic liver diseases, it will be important to thoroughly understand the cellular and molecular mechanisms of the conversion process.

Approach and results:

Towards this aim, we have established a zebrafish model for hepatocyte-to-BEC conversion by employing Tg(fabp10a:CFP-NTR) zebrafish with a temporal inhibition of Notch signaling during regeneration. Cre/loxP-mediated permanent and H2B-mCherry-mediated short-term lineage tracing revealed that in the model, all BECs originate from hepatocytes. During the conversion, BEC markers are sequentially induced in the order of Sox9b, Yap/Taz, Notch activity/epcam, and Alcama/krt18; the expression of the hepatocyte marker Bhmt disappears between the Sox9b and Yap/Taz induction. Importantly, live time-lapse imaging unambiguously revealed transdifferentiation of hepatocytes into BECs: hepatocytes convert to BECs without transitioning through a proliferative intermediate state. In addition, using compounds and transgenic and mutant lines that modulate Notch and Yap signaling, we found that both Notch and Yap signaling are required for the conversion even in Notch- and Yap-overactivating settings.

Conclusions:

Hepatocyte-to-BEC conversion occurs through transdifferentiation independently of proliferation, and Notch and Yap signaling control the process in parallel with a mutually positive interaction. The new zebrafish model will further contribute to a thorough understanding of the mechanisms of the conversion process.
Conventional type 1 dendritic cells protect against gut barrier disruption via maintaining Akkermansia muciniphila in alcoholic steatohepatitis
Authors: Hao Liuyi , Zhong Wei , Woo Jongmin , Wei Xiaoyuan , Ma Hao , Dong Haibo , Guo Wei , Sun Xinguo , Yue Ruichao , Zhao Jiangchao , Zhang Qibin , Zhou Zhanxiang
Published: January 2023

Background and Aims:

Alcohol-perturbed gut immune homeostasis is associated with the development of alcoholic liver disease (ALD). However, the role of intestinal dendritic cells (DCs) in ALD progression is still unknown. This study aimed to investigate the cellular and molecular mechanisms through which intestinal DCs respond to alcohol exposure and contribute to the pathogenesis of ALD.

Approach and Results:

After 8 weeks of alcohol consumption, the number of basic leucine zipper transcription factor ATF-like 3 (Batf3)-dependent conventional type 1 DCs (cDC1s) was dramatically decreased in the intestine but not the liver. cDC1 deficient Batf3 knockout mice along with wild-type mice were subjected to chronic-binge ethanol feeding to determine the role of intestinal cDC1s reduction in ALD. cDC1s deficiency exacerbated alcohol-induced gut barrier disruption, bacterial endotoxin translocation into the circulation, and liver injury. Adoptive transfer of cDC1s to alcohol-fed mice ameliorated alcohol-mediated gut barrier dysfunction and liver injury. Further studies revealed that intestinal cDC1s serve as a positive regulator of Akkermansia muciniphila (A. muciniphila). Oral administration of A. muciniphila markedly reversed alcoholic steatohepatitis in mice. Mechanistic studies revealed that cDC1s depletion exacerbated alcohol-downregulated intestinal antimicrobial peptides which play a crucial role in maintaining A. muciniphila abundance, by disrupting the IL-12-interferon gamma signaling pathway. Lastly, we identified that intestinal cDC1s were required for the protective role of Lactobacillus reuteri in alcoholic steatohepatitis.

Conclusions:

This study demonstrated that cDC1s protect alcohol-induced liver injury by maintaining A. muciniphila abundance in mice. Targeting cDC1s may serve as a promising therapeutic approach for treating ALD.
Primary prophylaxis for spontaneous bacterial peritonitis is linked to antibiotic resistance in the Veterans Health Administration
Authors: Badal Bryan D. , Silvey Scott , Dragilev Lyuba , O’Leary Jacqueline G. , Morgan Timothy R. , Cheung Ramsey , Patel Arpan , Rogal Shari , Patton Heather , Nobbe Anna , Jakab Sofia S. , Liu Jinze , Patel Nilang , Bajaj Jasmohan S.
Published: January 2023

Spontaneous bacterial peritonitis (SBP) is a major cause of mortality. Although SBP primary prophylaxis (SBPPr) with fluoroquinolones and trimethoprim-sulfamethoxazole (TMP-SMX) is often used, resistance could reduce its benefit.

Aim:

Analyze peritoneal fluid resistance patterns in patients with a first SBP episode with/without SBPPr using the Veterans Health Administration corporate data warehouse and to evaluate national antibiograms. Corporate data warehouse data were extracted using validated International Classification of Disease-9/10 codes, culture, resistance data, and outcomes of 7553 patients who developed their first inpatient SBP between 2009 and 2019 and compared between those with/without SBPPr. Escherichia coli (E. coli) and Klebsiella pneumoniae (K. pneumoniae) sensitivity to ciprofloxacin and TMP-SMX was calculated using 2021 Veterans Health Administration antibiogram data from all states. The most common isolates were E. coli, K. pneumoniae, and Staphylococcus species. Veterans taking ciprofloxacin SBBPr had higher fluoroquinolone resistance (34% vs 14% no SBPPr, p<0.0001); those taking TMP-SMX had higher TMP-SMX resistance (40% vs 14%, p<0.0001). SBPPr patients showed higher culture positivity, greater length of stay, higher second SBP, and higher probability of liver transplant rates versus no SBPPr. Multivariable models showed SBBPr to be the only variable associated with gram-negative resistance, and SBPPr was associated with a trend toward longer length of stay.E. coli ciprofloxacin sensitivity rates were 50%–87% and 43%–92% for TMP-SMX. K. pneumoniae ciprofloxacin sensitivity was 76%–100% and 72%–100% for TMP-SMX.

Conclusion:

Among patients who developed their first SBP episode, there was a higher prevalence of antibiotic resistance in those on SBPPr, with a high rate of fluoroquinolone resistance across the Veterans Health Administration sites.
An American Board of Surgery Pilot of Video Assessment of Surgeon Technical Performance in Surgery
Authors: Pryor Aurora D. , Lendvay Thomas , Jones Andrew , Ibáñez Beatriz , Pugh Carla
Published: January 2023

Objective:

The American Board of Surgery (ABS) sought to investigate the suitability of video-based assessment (VBA) as an adjunct to certification for assessing technical skills.

Background:

Board certification is based on the successful completion of a residency program coupled with knowledge and reasoning assessments. VBA is a new modality for evaluating operative skills that have been shown to correlate with patient outcomes after surgery.

Methods:

Diplomates of the ABS were initially assessed for background knowledge and interest in VBA. Surgeons were then solicited to participate in the pilot. Three commercially available VBA platforms were identified and used for the pilot assessment. All participants served as reviewers and reviewees for videos. After the interaction, participants were surveyed regarding their experiences and recommendations to the ABS.

Results:

To the initial survey, 4853/25,715 diplomates responded. The majority were neither familiar with VBA, nor the tools used for operative assessments. Two hundred seventy-four surgeons actively engaged in the subsequent pilot. One hundred sixty-nine surgeons completed the postpilot survey. Most participants found the process straightforward. Of the participants, 74% felt that the feedback would help their surgical practice. The majority (81%) remain interested in VBA for continuing medical education credits. Using VBA in continuous certification could improve surgeon skills felt by 70%. Two-thirds of participants felt VBA could help identify and remediate underperforming surgeons. Identified barriers to VBA included limitations for open surgery, privacy issues, and technical concerns.

Conclusions:

VBA is promising as an adjunct to the current board certification process and should be further considered by the ABS.
Obsessive-compulsive symptoms in the schizophrenia-spectrum: current developments in psychopathology research
Authors: Rasmussen Andreas Rosén , Raballo Andrea
Published: January 2023

Purpose of review

Schizophrenia-spectrum disorders (SSD) frequently involve symptoms that usually are ascribed to nonpsychotic disorder spectra, such as obsessive-compulsive symptoms (OCS). These symptoms can cause differential diagnostic challenges, particularly in early illness stages, and must be considered in treatment planning. In this review, we provide an overview of recent literature within the field of OCS in SSD, with a focus on psychopathology research.

Recent findings

OCS are seen in approximately a quarter of patients with SSD or at-risk mental state of psychosis. They are associated with more severe clinical features and specific temporal patterns of OCS may be linked with different clinical trajectories. However, the current definitions of OCS have been criticized for their overinclusive nature, which is a limiting step for differential diagnosis and more precise prognostic stratification. Specific phenomenological features, including a link with experiential anomalies (disorders of basic self), have been suggested to provide clinically relevant distinctions.

The presence of OCS in SSD is associated with more severe clinical features and invites a higher clinical attention and perspectival monitoring. Some findings suggest that more fine-grained psychopathological distinctions might be a viable clinical and research strategy to advance the field in the direction of precision psychiatry.