bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical features and prognostic factors in adults with brain abscess
Authors: Bodilsen Jacob , Duerlund Lærke Storgaard , Mariager Theis , Brandt Christian Thomas , Petersen Pelle Trier , Larsen Lykke , Hansen Birgitte Rønde , Omland Lars Haukali , Tetens Malte Mose , Wiese Lothar , Jørgensen Rasmus Langelund , Leth Steffen , Nielsen Henrik ,   the DASGIB study group, Storgaard Merete , Larsen Lykke , Hansen Birgitte Rønde , Andersen Christian Østergaard , Wiese Lothar , Brandt Christian Thomas , Helweg-Larsen Jannik , von Lüttichau Hans Rudolf , Nielsen Henrik , Bodilsen Jacob
Published: August 2022

Studies on brain abscess are hampered by single-centre design with limited sample size and incomplete follow-up. Thus, robust analyses on clinical prognostic factors remain scarce.

This Danish nationwide, population-based cohort study included clinical details of all adults (≥18 years) diagnosed with brain abscess in the Danish National Patient Registry from 2007 through 2014 and the prospective clinical database of the Danish Study Group of Infections of the Brain covering all Danish departments of infectious diseases from 2015 through 2020. All patients were followed for 6 months after discharge. Prognostic factors for mortality at 6 months after discharge were examined by adjusted modified Poisson regression to compute relative risks with 95% confidence intervals (CI).

Among 485 identified cases, the median age was 59 years [interquartile range (IQR 48–67)] and 167 (34%) were female. The incidence of brain abscess increased from 0.4 in 2007 to 0.8 per 100 000 adults in 2020. Immuno-compromise was prevalent in 192/485 (40%) and the clinical presentation was predominated by neurological deficits 396/485 (82%), headache 270/411 (66%), and fever 208/382 (54%). The median time from admission until first brain imaging was 4.8 h (IQR 1.4–27). Underlying conditions included dental infections 91/485 (19%) and ear, nose and throat infections 67/485 (14%), and the most frequent pathogens were oral cavity bacteria (59%), Staphylococcus aureus (6%), and Enterobacteriaceae (3%). Neurosurgical interventions comprised aspiration 356/485 (73%) or excision 7/485 (1%) and was preceded by antibiotics in 377/459 (82%). Fatal outcome increased from 29/485 (6%) at discharge to 56/485 (12%) 6 months thereafter. Adjusted relative risks for mortality at 6 months after discharge was 3.48 (95% CI 1.92–6.34) for intraventricular rupture, 2.84 (95% CI 1.45–5.56) for immunocompromise, 2.18 (95% CI 1.21–3.91) for age >65 years, 1.81 (95% CI 1.00–3.28) for abscess diameter >3 cm, and 0.31 (95% CI 0.16–0.61) for oral cavity bacteria as causative pathogen. Sex, neurosurgical treatment, antibiotics before neurosurgery, and corticosteroids were not associated with mortality.

This study suggests that prevention of rupture of brain abscess is crucial. Yet, antibiotics may be withheld until neurosurgery, if planned within a reasonable time period (e.g. 24 h), in some clinically stable patients. Adjunctive corticosteroids for symptomatic perifocal brain oedema was not associated with increased mortality.
Effect of empagliflozin on circulating proteomics in heart failure: mechanistic insights into the EMPEROR programme
Authors: Zannad Faiez , Ferreira João Pedro , Butler Javed , Filippatos Gerasimos , Januzzi James L , Sumin Mikhail , Zwick Matthias , Saadati Maral , Pocock Stuart J , Sattar Naveed , Anker Stefan D , Packer Milton
Published: August 2022

Aims

Sodium-glucose co-transporter 2 (SGLT2) inhibitors improve cardiovascular outcomes in diverse patient populations, but their mechanism of action requires further study. The aim is to explore the effect of empagliflozin on the circulating levels of intracellular proteins in patients with heart failure, using large-scale proteomics.

Methods and results

Over 1250 circulating proteins were measured at baseline, Week 12, and Week 52 in 1134 patients from EMPEROR-Reduced and EMPEROR-Preserved, using the Olink® Explore 1536 platform. Statistical and bioinformatical analyses identified differentially expressed proteins (empagliflozin vs. placebo), which were then linked to demonstrated biological actions in the heart and kidneys. At Week 12, 32 of 1283 proteins fulfilled our threshold for being differentially expressed, i.e. their levels were changed by ≥10% with a false discovery rate <1% (empagliflozin vs. placebo). Among these, nine proteins demonstrated the largest treatment effect of empagliflozin: insulin-like growth factor-binding protein 1, transferrin receptor protein 1, carbonic anhydrase 2, erythropoietin, protein-glutamine gamma-glutamyltransferase 2, thymosin beta-10, U-type mitochondrial creatine kinase, insulin-like growth factor-binding protein 4, and adipocyte fatty acid-binding protein 4. The changes of the proteins from baseline to Week 52 were generally concordant with the changes from the baseline to Week 12, except empagliflozin reduced levels of kidney injury molecule-1 by ≥10% at Week 52, but not at Week 12. The most common biological action of differentially expressed proteins appeared to be the promotion of autophagic flux in the heart, kidney or endothelium, a feature of 6 proteins. Other effects of differentially expressed proteins on the heart included the reduction of oxidative stress, inhibition of inflammation and fibrosis, and the enhancement of mitochondrial health and energy, repair, and regenerative capacity. The actions of differentially expressed proteins in the kidney involved promotion of autophagy, integrity and regeneration, suppression of renal inflammation and fibrosis, and modulation of renal tubular sodium reabsorption.

Conclusions

Changes in circulating protein levels in patients with heart failure are consistent with the findings of experimental studies that have shown that the effects of SGLT2 inhibitors are likely related to actions on the heart and kidney to promote autophagic flux, nutrient deprivation signalling and transmembrane sodium transport.
‘Replace uncertainty with information’: shared decision-making and decision quality surrounding catheter ablation for atrial fibrillation
Authors: Reading Turchioe Meghan , Mangal Sabrina , Ancker Jessica S , Gwyn Jaslynn , Varosy Paul , Slotwiner David
Published: August 2022

Aims

As a first step in developing a decision aid to support shared decision-making (SDM) for patients with atrial fibrillation (AF) to evaluate treatment options for rhythm and symptom control, we aimed to measure decision quality and describe decision-making processes among patients and clinicians involved in decision-making around catheter ablation for AF.

Methods and results

We conducted a cross-sectional, mixed-methods study guided by an SDM model outlining decision antecedents, processes, and outcomes. Patients and clinicians completed semi-structured interviews about decision-making around ablation, feelings of decision conflict and regret, and preferences for the content, delivery, and format of a hypothetical decision aid for ablation. Patients also completed surveys about AF symptoms and aspects of decision quality. Fifteen patients (mean age 71.1 ± 8.6 years; 27% female) and five clinicians were recruited. For most patients, decisional conflict and regret were low, but they also reported low levels of information and agency in the decision-making process. Most clinicians report routinely providing patients with information and encouraging engagement during consultations. Patients reported preferences for an interactive, web-based decision aid that clearly presents evidence regarding outcomes using data, visualizations, videos, and personalized risk assessments, and is available in multiple languages.

Conclusion

Disconnects between clinician efforts to provide information and bolster agency and patient experiences of decision-making suggest decision aids may be needed to improve decision quality in practice. Reported experiences with current decision-making practices and preferences for decision aid content, format, and delivery can support the user-centred design and development of a decision aid.
Human gut bifidobacteria inhibit the growth of the opportunistic fungal pathogenCandida albicans
Authors: Ricci Liviana , Mackie Joanna , Donachie Gillian E , Chapuis Ambre , Mezerová Kristýna , Lenardon Megan D , Brown Alistair J P , Duncan Sylvia H , Walker Alan W
Published: August 2022

The human gut microbiota protects the host from invading pathogens and the overgrowth of indigenous opportunistic species via a process called colonization resistance. Here, we investigated the antagonistic activity of human gut bacteria towards Candida albicans, an opportunistic fungal pathogen that can cause severe infections in susceptible individuals. Coculture batch incubations of C. albicans in the presence of faecal microbiota from six healthy individuals revealed varying levels of inhibitory activity against C. albicans. 16S rRNA gene amplicon profiling of these faecal coculture bacterial communities showed that the Bifidobacteriaceae family, and Bifidobacterium adolescentis in particular, were most correlated with antagonistic activity against C. albicans. Follow-up mechanistic studies performed under anaerobic conditions confirmed that culture supernatants of Bifidobacterium species, particularly B. adolescentis, inhibited C. albicans in vitro. Fermentation acids (FA), including acetate and lactate, present in the bifidobacterial supernatants were important contributors to inhibitory activity. However, increasing the pH of both bacterial supernatants and mixtures of FA reduced their anti-Candida effects, indicating a combinatorial effect of prevailing pH and FA. This work, therefore, demonstrates potential mechanisms underpinning gut microbiome-mediated colonization resistance against C. albicans, and identifies particularly inhibitory components such as bifidobacteria and FA as targets for further study.
Nano-RNases: oligo- or dinucleases?
Authors: Lee Vincent T , Sondermann Holger , Winkler Wade C
Published: August 2022

Diribonucleotides arise from two sources: turnover of RNA transcripts (rRNA, tRNA, mRNA, and others) and linearization of cyclic-di-nucleotide signaling molecules. In both cases, there appears to be a requirement for a dedicated set of enzymes that will cleave these diribonucleotides into mononucleotides. The first enzyme discovered to mediate this activity is oligoribonuclease (Orn) from Escherichia coli. In addition to being the enzyme that cleaves dinucleotides and potentially other short oligoribonucleotides, Orn is also the only known exoribonuclease enzyme that is essential for E. coli, suggesting that removal of the shortest RNAs is an essential cellular function. Organisms naturally lacking the orn gene encode other nanoRNases (nrn) that can complement the conditional E. coli orn mutant. This review covers the history and recent advances in our understanding of these enzymes and their substrates. In particular, we focus on (i) the sources of diribonucleotides; (ii) the discovery of exoribonucleases; (iii) the structural features of Orn, NrnA/NrnB, and NrnC; (iv) the enzymatic activity of these enzymes against diribonucleotides versus other substrates; (v) the known physiological consequences of accumulation of linear dinucleotides; and (vi) outstanding biological questions for diribonucleotides and diribonucleases.
Genome-wide polymorphism and genic selection in feral and domesticated lineages of Cannabis sativa
Authors: Woods Patrick , Price Nicholas , Matthews Paul , McKay John K
Published: August 2022

A comprehensive understanding of the degree to which genomic variation is maintained by selection vs. drift and gene flow is lacking in many important species such as Cannabis sativa, one of the oldest known crops to be cultivated by humans worldwide. We generated whole genome resequencing data across diverse samples of feralized (escaped domesticated lineages) and domesticated lineages of C. sativa. We performed analyses to examine population structure, and genome-wide scans for FST, balancing selection, and positive selection. Our analyses identified evidence for subpopulation structure and further supported the Asian origin hypothesis of this species. Feral plants sourced from the United States exhibited broad regions on chromosomes 4 and 10 with high F¯ST, which may indicate chromosomal inversions maintained at high frequency in this subpopulation. Both our balancing and positive selection analyses identified loci that may reflect differential selection for traits favored by natural selection and artificial selection in feral vs. domesticated subpopulations. In the US feral subpopulation, we found 6 loci related to stress response under balancing selection and 1 gene involved in disease resistance under positive selection, suggesting local adaptation to new climates and biotic interactions. In the marijuana subpopulation, we identified the gene SMALLER TRICHOMES WITH VARIABLE BRANCHES 2 to be under positive selection, which suggests artificial selection for increased tetrahydrocannabinol yield. Overall, the data generated and results obtained from our study help to form a better understanding of the evolutionary history in C. sativa.
Functional genomic assays to annotate enhancer–promoter interactions genome wide
Authors: Leung Alden King-Yung , Yao Li , Yu Haiyuan
Published: August 2022

Enhancers are pivotal for regulating gene transcription that occurs at promoters. Identification of the interacting enhancer–promoter pairs and understanding the mechanisms behind how they interact and how enhancers modulate transcription can provide fundamental insight into gene regulatory networks. Recently, advances in high-throughput methods in three major areas—chromosome conformation capture assay, such as Hi-C to study basic chromatin architecture, ectopic reporter experiments such as self-transcribing active regulatory region sequencing (STARR-seq) to quantify promoter and enhancer activity, and endogenous perturbations such as clustered regularly interspaced short palindromic repeat interference (CRISPRi) to identify enhancer–promoter compatibility—have further our knowledge about transcription. In this review, we will discuss the major method developments and key findings from these assays.
Basic principles of cardiothoracic surgery training: a position paper by the European Association for Cardiothoracic Surgery Residents Committee
Authors: Zientara Alicja , Hussein Nabil , Bond Chris , Jacob Kirolos A , Naruka Vinci , Doerr Fabian , Nägele Felix , Pölzl Leo , Eid Maroua , Jarral Omar , Cerqueira Rui , Haunschild Josephina , Sádaba J Rafael , Gollmann-Tepeköylü Can
Published: August 2022

OBJECTIVES

Across Europe there are significant variations in the fundamental structure and content of cardiothoracic surgery (CTS) training programmes. Previous efforts have been made to introduce a Unified European Training System, which outlined the fundamentals of the ideal programme and supported a paradigm shift from an apprenticeship to a competency-based model. This article’s goal was to define key structural, administrative and executive details of such a programme to lay the foundations for the standardization of cardiothoracic surgical training across Europe.

METHODS

The European Association for Cardiothoracic Surgery Residents Committee had previously conducted a residents’ training survey across Europe in 2020. Training curricula from the twelve most represented countries across Europe were either searched online or obtained from the countries’ national trainee representative and reviewed by the committee. Information was collated and placed into one of the following categories to develop the position paper: (i) selection of eligible candidates, (ii) guidance for an outcome-based syllabus, (iii) documentation and evaluation of training progress, (iv) mandatory rotations and training courses, (v) number of independent or assisted cases and (vi) requirements and quality assurance of teachers.

RESULTS

An independent professional body should promote an outcome-based syllabus and take responsibility for the training programme’s quality assurance. Trainees should be selected on merit by an open and transparent process. Training should be delivered within a defined period and supervised by an appointed training committee to ensure its implementation. This committee should review the trainees progression regularly, provide feedback and offer trainees the opportunity to experience various training environments and trainers. A common electronic portal be used by trainees to record their agreed objectives and to evidence their completion. Trainees should regularly attend specialty-relevant courses and conferences to promote professional and academic development. The end of training is reached when the formal requirements of the training programme are met and the trainee is able to perform at the level expected of a day-1 independent surgeon.

CONCLUSIONS

This article defines the key structural, administrative, and executive principles for CTS training. Programmes are encouraged to review and modify their training curricula, if necessary, to ensure the delivery of high-quality, standardized, outcome-orientated CTS training across Europe.
Trimethoprim-associated hyperkalaemia: a systematic review and meta-analysis
Authors: Faré Pietro B , Memoli Erica , Treglia Giorgio , Bianchetti Mario G , Milani Gregorio P , Marchisio Paola , Lava Sebastiano A G , Janett Simone
Published: August 2022

Introduction

Trimethoprim is structurally similar to potassium-sparing diuretics and may induce hyperkalaemia. The prevalence and the factors that predispose to trimethoprim-associated hyperkalaemia have never been extensively addressed.

Methods

A literature search with no date or language limits was carried out using the National Library of Medicine, Embase and Web of Science in March and repeated during August 2021. The principles underlying the Economic and Social Research Council guidance on the conduct of synthesis and the PRISMA guidelines were employed. For the analysis, we retained reports including ≥10 subjects on treatment with trimethoprim, which addressed the possible occurrence of hyperkalaemia.

Results

Eighteen reports were retained for the final analysis. The pooled prevalence of potassium value >5.0 mmol/L, >5.5 mmol/L and >6.0 mmol/L or symptomatic, was, respectively, 22%, 10% and 0.2%. The analysis disclosed that the risk of trimethoprim-associated hyperkalaemia is dose-related and enhanced by drugs with known hyperkalaemic potential including potassium-sparing diuretics, renin–angiotensin–aldosterone system inhibitors, β-blockers and non-steroidal anti-inflammatory agents. Poor kidney function also increased the tendency towards hyperkalaemia. The time to onset of hyperkalaemia was generally 1 week or less after starting trimethoprim.

Conclusions

The present analysis documents the hyperkalaemic potential of trimethoprim, a widely prescribed drug that was introduced more than 50 years ago. Clinicians must recognize patients at risk of trimethoprim-associated hyperkalaemia.
Binding of temocillin to plasma proteins in vitro and in vivo: the importance of plasma protein levels in different populations and of co-medications
Authors: Ngougni Pokem Perrin , Matzneller Peter , Vervaeke Steven , Wittebole Xavier , Goeman Lieven , Coessens Marie , Cottone Eleonora , Capron Arnaud , Wulkersdorfer Beatrix , Wallemacq Pierre , Mouton Johan W , Muller Anouk E , Zeitlinger Markus , Laterre Pierre François , Tulkens Paul M , Van Bambeke Françoise
Published: August 2022

Background

Temocillin plasma protein binding (PPB) in healthy individuals is reported to be ∼85% but had not been studied in patients.

Objectives

To obtain normative data on temocillin PPB in patients in relation to infection and impact of co-medications widely used in ICU.

Methods

Plasma was obtained from healthy individuals (Group #1), non-ICU patients with UTI (Group #2), ICU patients with suspected/confirmed ventriculitis (Group #3) or with sepsis/septic shock (Group #4). Total and unbound temocillin concentrations were measured in spiked samples from temocillin-naive donors (in vitro) or in plasma from temocillin-treated subjects (in vivo). The impact of diluting plasma, using pharmaceutical albumin, or adding drugs potentially competing for PPB was tested in spiked samples. Data were analysed using a modified Hill–Langmuir equation taking ligand depletion into account.

Results

Temocillin PPB was saturable in all groups, both in vitro and in vivo. Maximal binding capacity (Bmax) was 1.2–2-fold lower in patients. At 20 and 200 mg/L (total concentrations), the unbound fraction reached 12%–29%, 23%–42% and 32%–52% in Groups #2, #3, #4. The unbound fraction was inversely correlated with albumin and C-reactive protein concentrations. Binding to albumin was 2–3-fold lower than in plasma and non-saturable. Drugs with high PPB but active at lower molar concentrations than temocillin caused minimal displacement, while fluconazole (low PPB but similar plasma concentrations to temocillin) increased up to 2-fold its unbound fraction.

Conclusions

Temocillin PPB is saturable, 2–4-fold lowered in infected patients in relation to disease severity (ICU admission, hypoalbuminaemia, inflammation) and only partially reproducible with albumin. Competition with other drugs must be considered for therapeutic concentrations to be meaningful.
Interruptive Electronic Alerts for Choosing Wisely Recommendations: A Cluster Randomized Controlled Trial
Authors: Ho Vy T , Aikens Rachael C , Tso Geoffrey , Heidenreich Paul A , Sharp Christopher , Asch Steven M , Chen Jonathan H , Shah Neil K
Published: August 2022

Objective

To assess the efficacy of interruptive electronic alerts in improving adherence to the American Board of Internal Medicine’s Choosing Wisely recommendations to reduce unnecessary laboratory testing.

Materials and methods

We administered 5 cluster randomized controlled trials simultaneously, using electronic medical record alerts regarding prostate-specific antigen (PSA) testing, acute sinusitis treatment, vitamin D testing, carotid artery ultrasound screening, and human papillomavirus testing. For each alert, we assigned 5 outpatient clinics to an interruptive alert and 5 were observed as a control. Primary and secondary outcomes were the number of postalert orders per 100 patients at each clinic and number of triggered alerts divided by orders, respectively. Post hoc analysis evaluated whether physicians experiencing interruptive alerts reduced their alert-triggering behaviors.

Results

Median postalert orders per 100 patients did not differ significantly between treatment and control groups; absolute median differences ranging from 0.04 to 0.40 for PSA testing. Median alerts per 100 orders did not differ significantly between treatment and control groups; absolute median differences ranged from 0.004 to 0.03. In post hoc analysis, providers receiving alerts regarding PSA testing in men were significantly less likely to trigger additional PSA alerts than those in the control sites (Incidence Rate Ratio 0.12, 95% CI [0.03–0.52]).

Discussion

Interruptive point-of-care alerts did not yield detectable changes in the overall rate of undesired orders or the order-to-alert ratio between active and silent sites. Complementary behavioral or educational interventions are likely needed to improve efforts to curb medical overuse.

Conclusion

Implementation of interruptive alerts at the time of ordering was not associated with improved adherence to 5 Choosing Wisely guidelines.

Trial Registration

NCT02709772
Accuracy of ICD-10-CM encounter diagnoses from health records for identifying self-harm events
Authors: Simon Gregory E , Shortreed Susan M , Boggs Jennifer M , Clarke Gregory N , Rossom Rebecca C , Richards Julie E , Beck Arne , Ahmedani Brian K , Coleman Karen J , Bhakta Bhumi , Stewart Christine C , Sterling Stacy , Schoenbaum Michael , Coley R Yates , Stone Marc , Mosholder Andrew D , Yaseen Zimri S
Published: August 2022

Objective

Assess the accuracy of ICD-10-CM coding of self-harm injuries and poisonings to identify self-harm events.

Materials and Methods

In 7 integrated health systems, records data identified patients reporting frequent suicidal ideation. Records then identified subsequent ICD-10-CM injury and poisoning codes indicating self-harm as well as selected codes in 3 categories where uncoded self-harm events might be found: injuries and poisonings coded as undetermined intent, those coded accidental, and injuries with no coding of intent. For injury and poisoning encounters with diagnoses in those 4 groups, relevant clinical text was extracted from records and assessed by a blinded panel regarding documentation of self-harm intent.

Results

Diagnostic codes selected for review include all codes for self-harm, 43 codes for undetermined intent, 26 codes for accidental intent, and 46 codes for injuries without coding of intent. Clinical text was available for review for 285 events originally coded as self-harm, 85 coded as undetermined intent, 302 coded as accidents, and 438 injury events with no coding of intent. Blinded review of full-text clinical records found documentation of self-harm intent in 254 (89.1%) of those originally coded as self-harm, 24 (28.2%) of those coded as undetermined, 24 (7.9%) of those coded as accidental, and 48 (11.0%) of those without coding of intent.

Conclusions

Among patients at high risk, nearly 90% of injuries and poisonings with ICD-10-CM coding of self-harm have documentation of self-harm intent. Reliance on ICD-10-CM coding of intent to identify self-harm would fail to include a small proportion of true self-harm events.
Incidence of invasive fungal infections in patients with hematological malignancies receiving ibrutinib therapy in south-east Austria
Authors: Egger Matthias , Gornicec Max , Wölfler Albert , Lembeck Anna Lena , Tinchon Christoph , Maderdonner Manuela , Prattes Juergen
Published: August 2022

Since the broad implementation of ibrutinib therapy, an increasing number of studies have been reported on invasive fungal infections (IFI) associated with ibrutinib administration. We conducted a retrospective cohort study in three hospitals in south-east Austria in order to assess the local epidemiology of ibrutinib associated IFIs. A total of 113 patients with underlying hematological malignancy were included in the study. During the study period, a single IFI episode was observed, which corresponds to an IFI incidence of 2.3 cases per 100 person years (95% CI: 0.12–11.47). IFIs during ibrutinib therapy seem to be a rare event in case of absent additional risk factors for IFIs.
The short ionizing photon mean free path at z = 6 in Cosmic Dawn III, a new fully coupled radiation-hydrodynamical simulation of the Epoch of Reionization
Authors: Lewis Joseph S W , Ocvirk Pierre , Sorce Jenny G , Dubois Yohan , Aubert Dominique , Conaboy Luke , Shapiro Paul R , Dawoodbhoy Taha , Teyssier Romain , Yepes Gustavo , Gottlöber Stefan , Rasera Yann , Ahn Kyungjin , Iliev Ilian T , Park Hyunbae , Thélie Émilie
Published: August 2022

Recent determinations of the mean free path of ionizing photons (mfp) in the intergalactic medium (IGM) at z = 6 are lower than many theoretical predictions. In order to gain insight, we investigate the evolution of the mfp in our new massive fully coupled radiation-hydrodynamics cosmological simulation of reionization: Cosmic Dawn III (CoDa III). CoDa III’s scale ($\rm 94^3 \, cMpc^3$) and resolution ($\rm 8192^3$ grid) make it particularly suitable to study the IGM during reionization. The simulation was performed with ramses-cudaton on Summit, and used 13 1072 processors coupled to 24 576 GPUs, making it the largest reionization simulation, and largest ever ramses simulation. A superior agreement with global constraints on reionization is obtained in CoDa III over Cosmic Dawn II (CoDa II), especially for the evolution of the neutral hydrogen fraction and the cosmic photoionization rate, thanks to an improved calibration, later end of reionization (z = 5.6), and higher spatial resolution. Analysing the mfp, we find that CoDa III reproduces the most recent observations very well, from z = 6 to z = 4.6. We show that the distribution of the mfp in CoDa III is bimodal, with short (neutral) and long (ionized) mfp modes, due to the patchiness of reionization and the coexistence of neutral versus ionized regions during reionization. The neutral mode peaks at sub-kpc to kpc scales of mfp, while the ionized mode peak evolves from 0.1 Mpc h−1 at z = 7 to ∼10 Mpc h−1 at z = 5.2. Computing the mfp as the average of the ionized mode provides the best match to the recent observational determinations. The distribution reduces to a single neutral (ionized) mode at z > 13 (z < 5).
Modelling the host galaxies of binary compact object mergers with observational scaling relations
Authors: Santoliquido Filippo , Mapelli Michela , Artale M Celeste , Boco Lumen
Published: August 2022

The merger rate density evolution of binary compact objects and the properties of their host galaxies carry crucial information to understand the sources of gravitational waves. Here, we present galaxy$\mathcal {R}$ate, a new code that estimates the merger rate density of binary compact objects and the properties of their host galaxies, based on observational scaling relations. We generate our synthetic galaxies according to the galaxy stellar mass function. We estimate the metallicity according to both the mass–metallicity relation (MZR) and the fundamental metallicity relation (FMR). Also, we take into account galaxy–galaxy mergers and the evolution of the galaxy properties from the formation to the merger of the binary compact object. We find that the merger rate density changes dramatically depending on the choice of the star-forming galaxy main sequence, especially in the case of binary black holes (BBHs) and black hole neutron star systems (BHNSs). The slope of the merger rate density of BBHs and BHNSs is steeper if we assume the MZR with respect to the FMR, because the latter predicts a shallower decrease of metallicity with redshift. In contrast, binary neutron stars (BNSs) are only mildly affected by both the galaxy main sequence and metallicity relation. Overall, BBHs and BHNSs tend to form in low-mass metal-poor galaxies and merge in high-mass metal-rich galaxies, while BNSs form and merge in massive galaxies. We predict that passive galaxies host at least ∼5–10 per cent, ∼15–25 per cent, and ∼15–35 per cent of all BNS, BHNS, and BBH mergers in the local Universe.
A deep, multi-epoch Chandra HETG study of the ionized outflow from NGC 4051
Authors: Ogorzalek A , King A L , Allen S W , Raymond J C , Wilkins D R
Published: August 2022

Actively accreting supermassive black holes significantly impact the evolution of their host galaxies, truncating further star formation by expelling large fractions of gas with wide-angle outflows. The X-ray band is key to understanding how these black hole winds affect their environment, as the outflows have high temperatures (∼105–8 K). We have developed a Bayesian framework for characterizing active galactic nucleus outflows with an improved ability to explore parameter space and perform robust model selection. We applied this framework to a new 700 ks and an archival 315 ks Chandra High Energy Transmission Gratings observation of the Seyfert galaxy NGC 4051. We have detected six absorbers intrinsic to NGC 4051. These wind components span velocities from 400 to 30 000 km s−1. We have determined that the most statistically significant wind component is purely collisionally ionized, which is the first detection of such an absorber. This wind has T ≈ 107 K and v ≈ 880 km s−1 and remains remarkably stable between the two epochs. Other slow components also remain stable across time. Fast outflow components change their properties between 2008 and 2016, suggesting either physical changes or clouds moving in and out of the line of sight. For one of the fast components, we obtain one of the tightest wind density measurements to date, log n/(cm−3) = 13.0$^{+0.01}_{-0.02}$, and determine that it is located at ∼240 gravitational radii. The estimated total outflow power surpasses 5 per cent of the bolometric luminosity (albeit with large uncertainties) making it important in the context of galaxy–black hole interactions.
Long-term photometric monitoring and spectroscopy of the white dwarf pulsar AR Scorpii
Authors: Pelisoli Ingrid , Marsh T R , Parsons S G , Aungwerojwit A , Ashley R P , Breedt E , Brown A J , Dhillon V S , Dyer M J , Green M J , Kerry P , Littlefair S P , Sahman D I , Shahbaz T , Wild J F , Chakpor A , Lakhom R
Published: August 2022

AR Scorpii (AR Sco) is the only radio-pulsing white dwarf known to date. It shows a broad-band spectrum extending from radio to X-rays whose luminosity cannot be explained by thermal emission from the system components alone, and is instead explained through synchrotron emission powered by the spin-down of the white dwarf. We analysed NTT/ULTRACAM, TNT/ULTRASPEC, and GTC/HiPERCAM high-speed photometric data for AR Sco spanning almost seven years and obtained a precise estimate of the spin frequency derivative, now confirmed with 50-σ significance. Using archival photometry, we show that the spin-down rate of $P/\dot{P} = 5.6 \times 10^6$ yr has remained constant since 2005. As well as employing the method of pulse-arrival time fitting used for previous estimates, we also found a consistent value via traditional Fourier analysis for the first time. In addition, we obtained optical time-resolved spectra with WHT/ISIS and VLT/X-shooter. We performed modulated Doppler tomography for the first time for the system finding evidence of emission modulated on the orbital period. We have also estimated the projected rotational velocity of the M-dwarf as a function of orbital period and found that it must be close to Roche lobe filling. Our findings provide further constraints for modelling this unique system.
MeerKAT radio observations of the neutron star low-mass X-ray binary Cen X–4 at low accretion rates
Authors: van den Eijnden J , Fender R , Miller-Jones J C A , Russell T D , Saikia P , Sivakoff G R , Carotenuto F
Published: August 2022

Centaurus X–4 (Cen X–4) is a relatively nearby neutron star low-mass X-ray binary that showed outbursts in 1969 and 1979, but has not shown a full outburst since. Due to its proximity and sustained period of quiescence, it is a prime target to study the coupling between accretion and jet ejection in quiescent neutron star low-mass X-ray binaries. Here, we present four MeerKAT radio observations at 1.3 GHz of Cen X–4, combined with NICER and Swift X-ray monitoring. During the first and most sensitive observation, Cen X–4 was in a fully quiescent X-ray state. The three later and shorter observations targeted a brief period of faint X-ray activity in 2021 January, which has been referred to as a ‘mis-fired’ outburst. Cen X–4 is not detected in any of the four MeerKAT observations. We place these radio non-detections on the X-ray–radio luminosity diagram, improving the constraints on the correlation between the two luminosities from earlier quiescent radio studies. We confirm that Cen X–4 is radio fainter than the transitional millisecond pulsar PSR J1023+0038 at the same X-ray luminosity. We discuss the radio behaviour of accreting neutron stars at low X-ray luminosity more generally and finally comment on future observing campaigns.
Radiative hydrodynamical simulations of super-Eddington accretion flow in tidal disruption event: the origin of optical/UV emission
Authors: Bu De-Fu , Qiao Erlin , Yang Xiao-Hong , Liu Jifeng , Chen Zhiwei , Wu Yongxin
Published: August 2022

One of the most prominent problems of optical/ultraviolet (UV) tidal disruption events (TDEs) is the origin of their optical/UV emission. It has been proposed that the soft X-rays produced by the stellar debris accretion disc can be reprocessed into optical/UV photons by a surrounding optically thick envelope or outflow. However, there is still no detailed models for this mechanism. In this paper, by performing hydrodynamic simulations with radiative transfer, we calculate the optical/UV emission of the circularized stellar debris accretion flow/outflow system. We find that the optical/UV photons can be generated by reprocessing the emission of the accretion flow in the optically thick outflows. The model can well interpret the observed emission properties of optical/UV TDEs, including the emission radius, the radiation temperature, and the blackbody luminosity, as well as the evolution of these quantities with time, providing a strong theoretical basis for understanding the origin of optical/UV TDEs.
Internally controlled RNA sequencing comparisons using nucleoside recoding chemistry
Authors: Courvan Meaghan C S , Niederer Rachel O , Vock Isaac W , Kiefer Lea , Gilbert Wendy V , Simon Matthew D
Published: August 2022

Quantitative comparisons of RNA levels from different samples can lead to new biological understanding if they are able to distinguish biological variation from variable sample preparation. These challenges are pronounced in comparisons that require complex biochemical manipulations (e.g. isolating polysomes to study translation). Here, we present Transcript Regulation Identified by Labeling with Nucleoside Analogues in Cell Culture (TILAC), an internally controlled approach for quantitative comparisons of RNA content. TILAC uses two metabolic labels, 4-thiouridine (s4U) and 6-thioguanosine (s6G), to differentially label RNAs in cells, allowing experimental and control samples to be pooled prior to downstream biochemical manipulations. TILAC leverages nucleoside recoding chemistry to generate characteristic sequencing signatures for each label and uses statistical modeling to compare the abundance of RNA transcripts between samples. We verified the performance of TILAC in transcriptome-scale experiments involving RNA polymerase II inhibition and heat shock. We then applied TILAC to quantify changes in mRNA association with actively translating ribosomes during sodium arsenite stress and discovered a set of transcripts that are translationally upregulated, including MCM2 and DDX5. TILAC is broadly applicable to uncover differences between samples leading to improved biological insights.
Processing oxidatively damaged bases at DNA strand breaks by APE1
Authors: Whitaker Amy M , Stark Wesley J , Freudenthal Bret D
Published: August 2022

Reactive oxygen species attack the structure of DNA, thus altering its base-pairing properties. Consequently, oxidative stress-associated DNA lesions are a major source of the mutation load that gives rise to cancer and other diseases. Base excision repair (BER) is the pathway primarily tasked with repairing DNA base damage, with apurinic/apyrimidinic endonuclease (APE1) having both AP-endonuclease and 3′ to 5′ exonuclease (exo) DNA cleavage functions. The lesion 8-oxo-7,8-dihydroguanine (8-oxoG) can enter the genome as either a product of direct damage to the DNA, or through polymerase insertion at the 3′-end of a DNA strand during replication or repair. Importantly, 3′-8-oxoG impairs the ligation step of BER and therefore must be removed by the exo activity of a surrogate enzyme to prevent double stranded breaks and cell death. In the present study, we use X-ray crystallography to characterize the exo activity of APE1 on 3′-8-oxoG substrates. These structures support a unified APE1 exo mechanism that differs from its more canonical AP-endonuclease activity. In addition, through complementation of the structural data with enzyme kinetics and binding studies employing both wild-type and rationally designed APE1 mutants, we were able to identify and characterize unique protein: DNA contacts that specifically mediate 8-oxoG removal by APE1.
The toxin–antitoxin RNA guards of CRISPR-Cas evolved high specificity through repeat degeneration
Authors: Cheng Feiyue , Wu Aici , Liu Chao , Cao Xifeng , Wang Rui , Shu Xian , Wang Lingyun , Zhang Yihan , Xiang Hua , Li Ming
Published: August 2022

Recent discovery of ectopic repeats (outside CRISPR arrays) provided unprecedented insights into the nondefense roles of CRISPR-Cas. A striking example is the addiction module CreTA (CRISPR-regulated toxin–antitoxins), where one or two (in most cases) ectopic repeats produce CRISPR-resembling antitoxic (CreA) RNAs that direct the CRISPR effector Cascade to transcriptionally repress a toxic RNA (CreT). Here, we demonstrated that CreTA repeats are extensively degenerated in sequence, with the first repeat (ψR1) being more diverged than the second one (ψR2). As a result, such addiction modules become highly specific to their physically-linked CRISPR-Cas loci, and in most cases, CreA could not harness a heterologous CRISPR-Cas to suppress its cognate toxin. We further disclosed that this specificity primarily derives from the degeneration of ψR1, and could generally be altered by modifying this repeat element. We also showed that the degenerated repeats of CreTA were insusceptible to recombination and thus more stable compared to a typical CRISPR array, which could be exploited to develop highly stable CRISPR-based tools. These data illustrated that repeat degeneration (a common feature of ectopic repeats) improves the stability and specificity of CreTA in protecting CRISPR-Cas, which could have contributed to the widespread occurrence and deep diversification of CRISPR systems.
Rbp95 binds to 25S rRNA helix H95 and cooperates with the Npa1 complex during early pre-60S particle maturation
Authors: Bhutada Priya , Favre Sébastien , Jaafar Mariam , Hafner Jutta , Liesinger Laura , Unterweger Stefan , Bischof Karin , Darnhofer Barbara , Siva Sankar Devanarayanan , Rechberger Gerald , Abou Merhi Raghida , Lebaron Simon , Birner-Gruenberger Ruth , Kressler Dieter , Henras Anthony K , Pertschy Brigitte
Published: August 2022

Eukaryotic ribosome synthesis involves more than 200 assembly factors, which promote ribosomal RNA (rRNA) processing, modification and folding, and assembly of ribosomal proteins. The formation and maturation of the earliest pre-60S particles requires structural remodeling by the Npa1 complex, but is otherwise still poorly understood. Here, we introduce Rbp95 (Ycr016w), a constituent of early pre-60S particles, as a novel ribosome assembly factor. We show that Rbp95 is both genetically and physically linked to most Npa1 complex members and to ribosomal protein Rpl3. We demonstrate that Rbp95 is an RNA-binding protein containing two independent RNA-interacting domains. In vivo, Rbp95 associates with helix H95 in the 3′ region of the 25S rRNA, in close proximity to the binding sites of Npa1 and Rpl3. Additionally, Rbp95 interacts with several snoRNAs. The absence of Rbp95 results in alterations in the protein composition of early pre-60S particles. Moreover, combined mutation of Rbp95 and Npa1 complex members leads to a delay in the maturation of early pre-60S particles. We propose that Rbp95 acts together with the Npa1 complex during early pre-60S maturation, potentially by promoting pre-rRNA folding events within pre-60S particles.
Association of single and serial measures of serum phosphorus with adverse outcomes in patients on peritoneal dialysis: results from the international PDOPPS
Authors: Lopes Marcelo Barreto , Karaboyas Angelo , Zhao Junhui , Johnson David W , Kanjanabuch Talerngsak , Wilkie Martin , Nitta Kosaku , Kawanishi Hideki , Perl Jeffrey , Pisoni Ronald L ,   The PDOPPS Steering Committee, Johnson David , Perl Jeffrey , Sanabria Mauricio , Kawanishi Hideki , Kim Yong-Lim , Kanjanabuch Talerngsak , Davies Simon , Pisoni Ronald , Robinson Bruce , Shen Jenny
Published: August 2022

Background

While high serum phosphorus levels have been related to adverse outcomes in hemodialysis patients, further investigation is warranted in persons receiving peritoneal dialysis (PD).

Methods

Longitudinal data (2014–17) from the Peritoneal Dialysis Outcomes and Practice Patterns Study (PDOPPS), a prospective cohort study, were used to examine associations of serum phosphorus with all-cause mortality and major adverse cardiovascular events via Cox regression adjusted for confounders. Serum phosphorus levels were parameterized by four methods: (i) baseline serum phosphorus; (ii) mean 6-month serum phosphorus; (iii) number of months with serum phosphorus >4.5 mg/dL; and (iv) mean area-under-the-curve of 6-month serum phosphorus control.

Results

The study included 5847 PD patients from seven countries; 9% of patients had baseline serum phosphorus <3.5 mg/dL, 24% had serum phosphorus ≥3.5 to ≤4.5 mg/dL, 30% had serum phosphorus >4.5 to <5.5 mg/dL, 20% had serum phosphorus ≥5.5 to <6.5 mg/dL, and 17% had serum phosphorus ≥6.5 mg/dL. Compared with patients with baseline serum phosphorus ≥3.5 to ≤4.5 mg/dL, the adjusted all-cause mortality hazard ratio (HR) was 1.19 (0.92,1.53) for patients with baseline serum phosphorus ≥5.5 to <6.5 mg/dL and HR was 1.53 (1.14,2.05) for serum phosphorus ≥6.5 mg/dL. Associations between serum phosphorus measurements over 6 months and clinical outcomes were even stronger than for a single measurement.

Conclusions

Serum phosphorus >5.5 mg/dL was highly prevalent (37%) in PD patients, and higher serum phosphorus levels were a strong predictor of morbidity and death, particularly when considering serial phosphorus measurements. This highlights the need for improved treatment strategies in this population. Serial serum phosphorus measurements should be considered when assessing patients’ risks of adverse outcomes.
Model-based orbital-scale precipitation δ18O variations and distinct mechanisms in Asian monsoon and arid regions
Authors: Liu Xiaodong , Xie Xiaoxun , Guo Zhengtang , Yin Zhi-Yong , Chen Guangshan
Published: August 2022

The past Asian precipitation δ18O (δ18Op) records from stalagmites and other deposits have shown significant orbital-scale variations, but their climatic implications and regional differences are still not fully understood. This study, as the first attempt of a 300-kyr transient stable isotope-enabled simulation, investigated the characteristics and mechanisms of the orbital-scale δ18Op variations in three representative regions of Asia: arid Central Asia (CA), monsoonal South Asia (SA) and monsoonal East Asia (EA). The modelling results showed that the variations in the CA, SA and EA annual δ18Op exhibited significant but asynchronous 23-kyr precession cycles. Further analyses revealed that although the precession-induced insolation variation was the ultimate cause of the δ18Op variation in all three regions, the dominant mechanisms and the involved physical processes were distinct among them. For the CA region, the rainy-season (November–March) temperature effect and water vapour transport by the westerly circulation were identified as the key precession-scale processes linking the October–February boreal mid-latitude insolation to the rainy-season or annual δ18Op. In the SA region, the rainy-season (June–September) precipitation amount effect and upstream depletion of the monsoonal water vapour δ18O served as the main mechanisms linking the rainy-season or annual δ18Op to the April–July insolation variation at the precession scale. For the EA region, however, the precession-scale annual δ18Op was mainly controlled by the late-monsoon (August–September) and pre-monsoon (April–May) water vapour transport patterns, which were driven by the July–August insolation and the global ice volume, respectively. These results suggest that the climatic implications of the orbital-scale Asia δ18Op variations are sensitive to their geographic locations as determined by the combined effects of insolation and regional circulation patterns associated with the respective rainy seasons. This study provides new insights into understanding the regional differences and formation mechanisms of the Asian orbital-scale δ18Op variations.