bluuebunny/crossref_metadata_2025 huggingface dataset:
No Evidence that Selection on Synonymous Codon Usage Affects Patterns of Protein Evolution in Bacteria
Authors: Moutinho Ana Filipa , Eyre-Walker Adam
Published: December 2023

Bias in synonymous codon usage has been reported across all kingdoms of life. Evidence suggests that codon usage bias is often driven by selective pressures, typically for translational efficiency. These selective pressures have been shown to depress the rate at which synonymous sites evolve. We hypothesize that selection on synonymous codon use could also slow the rate of protein evolution if a non-synonymous mutation changes the codon from being preferred to unpreferred. We test this hypothesis by looking at patterns of protein evolution using polymorphism and substitution data in two bacterial species, Escherichia coli and Streptococcus pneumoniae. We find no evidence that non-synonymous mutations that change a codon from being unpreferred to preferred are more common than the opposite. Overall, selection on codon bias seems to have little influence over non-synonymous polymorphism or substitution patterns.
Variational Bayesian experimental design for geophysical applications: seismic source location, amplitude versus offset inversion, and estimating CO2 saturations in a subsurface reservoir
Authors: Strutz Dominik , Curtis Andrew
Published: December 2023

In geophysical surveys or experiments, recorded data are used to constrain properties of the planetary subsurface, oceans, atmosphere or cryosphere. How the experimental data are collected significantly influences which parameters can be resolved and how much confidence can be placed in the results. Bayesian experimental design methods characterize, quantify and maximize expected information post-experiment—an optimization problem. Typical design parameters that can be optimized are source and/or sensor types and locations, and the choice of modelling or data processing methods to be applied to the data. These may all be optimized subject to various physical and cost constraints. This paper introduces variational design methods, and discusses their benefits and limitations in the context of geophysical applications. Variational methods have recently come to prominence due to their importance in machine-learning applications. They can be used to design experiments that best resolve either all model parameters, or the answer to specific questions about the system to be interrogated. The methods are tested in three schematic geophysical applications: (i) estimating a source location given arrival times of radiating energy at sensor locations, (ii) estimating the contrast in seismic velocity across a stratal interface given measurements of the amplitudes of seismic wavefield reflections from that interface, and (iii) designing a survey to best constrain CO2 saturation in a subsurface storage scenario. Variational methods allow the value of expected information from an experiment to be calculated and optimized simultaneously, which results in substantial savings in computational cost. In the context of designing a survey to best constrain CO2 saturation in a subsurface storage scenario, we show that optimal designs may change substantially depending on the particular questions of interest. We also show that one method, so-called DN design, can be effective at substantially lower computational cost than other methods. Overall, this work demonstrates that optimal design methods could be used more widely in Geophysics, as they are in other scientifically advanced fields.
Chlamydia trachomatis T3SS Effector CT622 Induces Proinflammatory Cytokines Through TLR2/TLR4-Mediated MAPK/NF-κB Pathways in THP-1 Cells
Authors: Lei Wenbo , Wen Yating , Yang Yewei , Liu Shuangquan , Li Zhongyu
Published: December 2023

Background

The pathogenesis of Chlamydia trachomatis is associated with the induction of the host inflammatory response; however, the precise underlying molecular mechanisms remain poorly understood.

Methods

CT622, a T3SS effector protein, has an important role in the pathogenesis of C trachomatis; however, whether CT622 can induce a host inflammatory response is not understood. Our findings demonstrate that CT622 induces the expression of interleukins 6 and 8 (IL-6 and IL-8). Mechanistically, these effects involve the activation of the MAPK/NF-κB signaling pathways (mitogen-activated protein kinase/nuclear factor κB).

Results

Interestingly, we demonstrated that the suppression of toll-like receptor 4 using small interfering RNA markedly reduced the phosphorylation of ERK, p38, JNK, and IκBα, concomitant with a significant decrease in IL-6 and IL-8 secretion. Conversely, disruption of toll-like receptor 2 abrogated the CT622-induced upregulation of IL-8 and activation of ERK, whereas IL-6 expression and p38, JNK, and IκBα phosphorylation were unaffected.

Conclusions

Taken together, these results indicate that CT622 contributes to the inflammatory response through the toll-like receptor 2/4–mediated MAPK/NF-κB pathways, which provides insight into the molecular pathology of C trachomatis infection.
Thermostability optimization of the aspartate/alanine exchange transporter from Tetragenococcus halophilus
Authors: Kunii Kota , Yamanaka Takashi , Miyamoto Akari , Nanatani Kei , Abe Keietsu
Published: December 2023

Aspartate/alanine exchange transporter (AspT) is a secondary transporter isolated from the lactic acid bacterium Tetragenococcus halophilus D10 strain. This transporter cooperates with aspartate decarboxylase to produce proton-motive force through decarboxylative phosphorylation. A method that successfully analyzes the AspT mechanism could serve as a prototype for elucidating the substrate transport mechanism of other exchange transporters; therefore, the purpose of this study was to search for conditions that improve the thermal stability of AspT for 3D structure analysis. We used the fluorescence size-exclusion chromatography-based thermostability assay to evaluate conditions that contribute to AspT stability. We found that the AspT thermostability was enhanced at pH 5.0 to 6.0 and in the presence of Na+ and Li+. Pyridoxal phosphate, a coenzyme of aspartate decarboxylase, also had a thermostabilizing effect on AspT. Under the conditions obtained from these results, it was possible to increase the temperature at which 50% of dimer AspT remained by 14°C. We expect these conditions to provide useful information for future structural analysis of AspT.
Precision dosing of venlafaxine during pregnancy: a pharmacokinetics modelling approach
Authors: Alenezi Mona , Badhan Raj K S
Published: December 2023

Objectives

Venlafaxine exposure through gestation is affected by the longitudinal changes in maternal physiology. Confounding treatment is also the impact of CYP2D6 polymorphisms affecting plasma concentrations of venlafaxine.

Methods

A pharmacokinetic modelling approach was employed to assess variations in maternal and foetal cord venlafaxine levels throughout gestation and to identify appropriate doses to maintain venlafaxine levels within the therapeutic range.

Key findings

Throughout gestation, there was a significant decrease in simulated venlafaxine trough plasma concentrations in both extensive metaboliser (EM) and ultra-rapid metaboliser (UM) phenotypes. Approximately 70%–87% of EM and UM phenotypes exhibited trough venlafaxine plasma concentrations below the therapeutic level (<25 ng/ml), which increased to 96% at week 30. While for poor metabolizer (PM) phenotypes, the percentage was approximately 4%.

Conclusion

The standard daily dose of 75 mg required adjustment for all phenotypes examined during gestation. A daily dose of 37.5–112.5 mg is appropriate for PM throughout pregnancy. For EM, a dose of 225 mg daily in the first trimester, 262.5 mg daily in the second trimester, and 375 mg daily in the third trimester is suggested to be optimal. For UM, a dose of 375 mg daily throughout gestation is suggested to be optimal.
Particle acceleration by sub-proton cyclotron frequency spectrum of dispersive Alfven waves in inhomogeneous solar coronal plasmas
Authors: Tsiklauri D
Published: December 2023

The problem of explaining observed soft X-ray fluxes during solar flares, which invokes acceleration of large fraction of electrons, if the acceleration takes places at the solar coronal loop-top, can potentially be solved by postulating that flare at loop-top creates dispersive Alfven waves (DAWs) which propagate towards the foot-points. As DAWs move in progressively denser parts of the loop (due to gravitational stratification) the large fraction of electrons is no longer needed. Here, we extend our previous results by considering f−1 frequency spectrum of DAWs and add He++ ions using fully kinetic particle-in-cell (PIC) simulations. We consider cases when transverse density gradient is in the range 4–40c/ωpe and DAW driving frequency is 0.3–0.6ωcp. We find that (i) The frequency spectrum case does not affect electron acceleration fraction in the like-to-like cases, but few times larger percentage of He++ heating is seen due to ion cyclotron resonance; (ii) In cases when counter propagating DAWs collide multiple-times, much larger electron and ion acceleration fractions are found, but the process is intermittent in time. This is because intensive heating (temperature increase) makes the-above-thermal-fraction smaller; Also more isotropic velocity distributions are seen; (iii) Development of kink oscillations occurs when DAWs collide; (iv) Scaling of the magnetic fluctuations power spectrum steepening in the higher-density regions is seen, due to wave refraction. Our PIC runs produce much steeper slopes than the orginal spectrum, indicating that the electron-scale physics has a notable effect on DAW spectrum evolution.
Comparing indirect methods for black hole masses in AGN: the good, the bad, and the ugly
Authors: Gliozzi M , Williams J K , Akylas A , Papadakis I E , Shuvo O I , Halavatkar A , Alt A
Published: December 2023

The black hole mass MBH is crucial in constraining the growth of supermassive black holes within their host galaxies. Since direct measurements of MBH with dynamical methods are restricted to a limited number of nearly quiescent nearby galaxies and a small minority of active galactic nuclei (AGN), we must rely on indirect methods. In this work, we utilize an unbiased, volume-limited, hard X-ray selected sample of AGN to compare the reliability of some commonly used indirect methods, emphasizing those that can be applied to obscured AGN. Based on a subsample of AGN with MBH determined via dynamical methods, our study suggests that X-ray-based techniques, such as the scaling method and the one based on the variability measured through the excess variance, are in good agreement with the dynamical methods. On the other hand, the M–σ⋆ correlation based on inactive galaxies tends to systematically overestimate MBH, regardless of the level of obscuration. We provide a correcting factor that produces an acceptable agreement with dynamical values and can be used to quickly correct the MBH computed with this method. We also derive an alternative M–σ⋆ correlation based on this unbiased sample of AGN with a slope considerably shallower than the ones obtained using inactive galaxies, suggesting that the latter may not be appropriate to compute the MBH in AGN. Finally, we find that no quick fix can be applied to correct the MBH obtained from the fundamental plane of black hole activity, casting doubts on the reliability of this method.
Evolution of eccentric stellar discs around supermassive black holes: the complex disc disruption dynamics and the milliparsec stars
Authors: Rantala Antti , Naab Thorsten
Published: December 2023

We study the 10 Myr evolution of parsec-scale stellar discs with initial masses of Mdisc = 1.0–$7.5 \times 10^4\, \mathrm{M}_\odot$ and eccentricities einit = 0.1–0.9 around supermassive black holes (SMBHs). Our disc models are embedded in a spherical background potential and have top-heavy single and binary star initial mass functions (IMF) with slopes of 0.25–1.7. The systems are evolved with the N-body code BIFROST, including post-Newtonian (PN) equations of motion and simplified stellar evolution. All discs are unstable and evolve on Myr time-scales towards similar eccentricity distributions peaking at e⋆ ∼ 0.3–0.4. Models with high einit also develop a very eccentric (e⋆ ≳ 0.9) stellar population. For higher disc masses Mdisc ≳ 3 × 104 M⊙, the disc disruption dynamics is more complex than the standard secular eccentric disc instability with opposite precession directions at different disc radii – a precession direction instability. We present an analytical model describing this behaviour. A milliparsec population of N ∼ 10–100 stars forms around the SMBH in all models. For low einit, stars migrate inward while for einit ≳ 0.6 stars are captured by the Hills mechanism. Without PN, after 6 Myr, the captured stars have a sub-thermal eccentricity distribution. We show that including PN effects prevents this thermalization by suppressing resonant relaxation effects and cannot be ignored. The number of tidally disrupted stars is similar or larger than the number of milliparsec stars. None of the simulated models can simultaneously reproduce the kinematic and stellar population properties of the Milky Way centre clockwise disc and the S-cluster.
OGHReS: star formation in the outer galaxy (ℓ = 250°–280°)
Authors: Urquhart J S , König C , Colombo D , Karska A , Wyrowski F , Menten K M , Moore T J T , Brand J , Elia D , Giannetti A , Leurini S , Figueira M , Lee M -Y , Dumke M
Published: December 2023

We have used data from the Outer Galaxy High-Resolution Survey (OGHReS) to refine the velocities, distances, and physical properties of a large sample of 3584 clumps detected in far-infrared/submillimetre emission in the Hi-GAL survey located in the ℓ = 250°–280° region of the Galactic plane. Using 12CO and 13CO spectra, we have determined reliable velocities to 3412 clumps (95 per cent of the sample). In comparison to the velocities from the Hi-GAL catalogue, we find good agreement for 80 per cent of the sample (within 5 km s−1). Using the higher resolution and sensitivity of OGHReS has allowed us to correct the velocity for 632 clumps and provide velocities for 687 clumps for which no velocity had been previously allocated. The velocities are used with a rotation curve to refine the distances to the clumps and to calculate the clumps’ properties using a distance-dependent gas-to-dust ratio. We have determined reliable physical parameters for 3200 outer Galaxy dense clumps (∼90 per cent of the Hi-GAL sources in the region). We find a trend of decreasing luminosity-to-mass ratio with increasing Galactocentric distance, suggesting the star formation efficiency is lower in the outer Galaxy or that it is resulting in more lower mass stars than in the inner Galaxy. We also find a similar surface density for protostellar clumps located in the inner and outer Galaxy, revealing that the surface density requirements for star formation are the same across the Galactic disc.
Light curve and hardness tests for millilensing in GRB 081122A, GRB 081126A, GRB 110517B, and GRB 210812A
Authors: Mukherjee Oindabi , Nemiroff Robert
Published: December 2023

Analyses are given on four recent gravitational millilensing claims on gamma-ray bursts (GRBs): GRB 081122A, GRB 081126A, GRB 110517B, and GRB 210812A. Two tests, a light curve similarity test and a hardness similarity test, compare different temporal sections of a single GRB to see if they are statistically similar. The hardness similarity test shows that the ratio between the second and the first emission episodes in each energy channel differed from the same ratio averaged over all energy channels at above 90 per cent confidence level in GRB 081122A. Additionally, the light curve similarity test applied to GRB 081122A, GRB 081126A, and GRB 110517B separately indicated a high likelihood that the two emission episodes in each GRB were not from the same parent emission episode. This conclusion was reached with confidence levels of 4.8σ for GRB 081122A, 3.08σ for GRB 081126A, and 8.45σ for GRB 110517B. However, these tests did not detect a significant difference between the pulses of GRB 210812A. Consequently, our results suggest that while GRB 210812A could not be conclusively ruled out, the other three GRBs do not show clear evidence of millilensing.
Lyricist as Analyst: Rhyme Scheme as Music-Setting in the Great American Songbook
Authors: Lawrence John Y
Published: December 2023

Although most songwriting teams in the Great American Songbook wrote music first and lyrics second, most studies of music-text interaction in this repertoire still evince a lyrics-first mindset, in which the music is viewed as text-setting. In this article, I propose the opposite approach: considering lyrics as a form of music-setting, in which the lyricist’s superimposition of a verbal form (the rhyme scheme) upon the composer’s pre-existing musical form counts as an act of analysis. I examine in turn: (1) the most common phrase structures and their associated rhyme schemes in songs from 1919 to 1943; (2) Lorenz Hart’s negotiation of the unusual XYYZ phrase structure that Richard Rodgers frequently employed; and (3) special cases where the lyricist contests the composer’s form and the effect that this can have on performers’ choices.
BG4 antibody can recognize telomeric G-quadruplexes harboring destabilizing base modifications and lesions
Authors: Johnson Samuel A , Paul Tapas , Sanford Samantha L , Schnable Brittani L , Detwiler Ariana C , Thosar Sanjana A , Van Houten Bennett , Myong Sua , Opresko Patricia L
Published: December 2023

BG4 is a single-chain variable fragment antibody shown to bind various G-quadruplex (GQ) topologies with high affinity and specificity, and to detect GQ in cells, including GQ structures formed within telomeric TTAGGG repeats. Here, we used ELISA and single-molecule pull-down (SiMPull) detection to test how various lengths and GQ destabilizing base modifications in telomeric DNA constructs alter BG4 binding. We observed high-affinity BG4 binding to telomeric GQ independent of telomere length, although three telomeric repeat constructs that cannot form stable intramolecular GQ showed reduced affinity. A single guanine substitution with 8-aza-7-deaza-G, T, A, or C reduced affinity to varying degrees depending on the location and base type, whereas two G substitutions in the telomeric construct dramatically reduced or abolished binding. Substitution with damaged bases 8-oxoguanine and O6-methylguanine failed to prevent BG4 binding although affinity was reduced depending on lesion location. SiMPull combined with FRET revealed that BG4 binding promotes folding of telomeric GQ harboring a G to T substitution or 8-oxoguanine. Atomic force microscopy revealed that BG4 binds telomeric GQ with a 1:1 stoichiometry. Collectively, our data suggest that BG4 can recognize partially folded telomeric GQ structures and promote telomeric GQ stability.
The disordered N-terminal tail of SARS-CoV-2 Nucleocapsid protein forms a dynamic complex with RNA
Authors: Cubuk Jasmine , Alston Jhullian J , Incicco J Jeremías , Holehouse Alex S , Hall Kathleen B , Stuchell-Brereton Melissa D , Soranno Andrea
Published: December 2023

The SARS-CoV-2 Nucleocapsid (N) protein is responsible for condensation of the viral genome. Characterizing the mechanisms controlling nucleic acid binding is a key step in understanding how condensation is realized. Here, we focus on the role of the RNA binding domain (RBD) and its flanking disordered N-terminal domain (NTD) tail, using single-molecule Förster Resonance Energy Transfer and coarse-grained simulations. We quantified contact site size and binding affinity for nucleic acids and concomitant conformational changes occurring in the disordered region. We found that the disordered NTD increases the affinity of the RBD for RNA by about 50-fold. Binding of both nonspecific and specific RNA results in a modulation of the tail configurations, which respond in an RNA length-dependent manner. Not only does the disordered NTD increase affinity for RNA, but mutations that occur in the Omicron variant modulate the interactions, indicating a functional role of the disordered tail. Finally, we found that the NTD-RBD preferentially interacts with single-stranded RNA and that the resulting protein:RNA complexes are flexible and dynamic. We speculate that this mechanism of interaction enables the Nucleocapsid protein to search the viral genome for and bind to high-affinity motifs.
Cluster-based prognostication in glioblastoma: Unveiling heterogeneity based on diffusion and perfusion similarities
Authors: Foltyn-Dumitru Martha , Kessler Tobias , Sahm Felix , Wick Wolfgang , Heiland Sabine , Bendszus Martin , Vollmuth Philipp , Schell Marianne
Published: December 2023

Background

While the association between diffusion and perfusion magnetic resonance imaging (MRI) and survival in glioblastoma is established, prognostic models for patients are lacking. This study employed clustering of functional imaging to identify distinct functional phenotypes in untreated glioblastomas, assessing their prognostic significance for overall survival.

Methods

A total of 289 patients with glioblastoma who underwent preoperative multimodal MR imaging were included. Mean values of apparent diffusion coefficient normalized relative cerebral blood volume and relative cerebral blood flow were calculated for different tumor compartments and the entire tumor. Distinct imaging patterns were identified using partition around medoids (PAM) clustering on the training dataset, and their ability to predict overall survival was assessed. Additionally, tree-based machine-learning models were trained to ascertain the significance of features pertaining to cluster membership.

Results

Using the training dataset (231/289) we identified 2 stable imaging phenotypes through PAM clustering with significantly different overall survival (OS). Validation in an independent test set revealed a high-risk group with a median OS of 10.2 months and a low-risk group with a median OS of 26.6 months (P = 0.012). Patients in the low-risk cluster had high diffusion and low perfusion values throughout, while the high-risk cluster displayed the reverse pattern. Including cluster membership in all multivariate Cox regression analyses improved performance (P ≤ 0.004 each).

Conclusions

Our research demonstrates that data-driven clustering can identify clinically relevant, distinct imaging phenotypes, highlighting the potential role of diffusion, and perfusion MRI in predicting survival rates of glioblastoma patients.
Exploring the multifaceted role of NRF2 in brain physiology and cancer: A comprehensive review
Authors: Moubarak Maya M , Pagano Zottola Antonio C , Larrieu Claire M , Cuvellier Sylvain , Daubon Thomas , Martin Océane C B
Published: December 2023

Chronic oxidative stress plays a critical role in the development of brain malignancies due to the high rate of brain oxygen utilization and concomitant production of reactive oxygen species. The nuclear factor-erythroid-2-related factor 2 (NRF2), a master regulator of antioxidant signaling, is a key factor in regulating brain physiology and the development of age-related neurodegenerative diseases. Also, NRF2 is known to exert a protective antioxidant effect against the onset of oxidative stress-induced diseases, including cancer, along with its pro-oncogenic activities through regulating various signaling pathways and downstream target genes. In glioblastoma (GB), grade 4 glioma, tumor resistance, and recurrence are caused by the glioblastoma stem cell population constituting a small bulk of the tumor core. The persistence and self-renewal capacity of these cell populations is enhanced by NRF2 expression in GB tissues. This review outlines NRF2’s dual involvement in cancer and highlights its regulatory role in human brain physiology and diseases, in addition to the development of primary brain tumors and therapeutic potential, with a focus on GB.
The RALF signaling pathway regulates cell wall integrity during pollen tube growth in maize
Authors: Zhou Liang-Zi , Wang Lele , Chen Xia , Ge Zengxiang , Mergner Julia , Li Xingli , Küster Bernhard , Längst Gernot , Qu Li-Jia , Dresselhaus Thomas
Published: December 2023

Autocrine signaling pathways regulated by RAPID ALKALINIZATION FACTORs (RALFs) control cell wall integrity during pollen tube germination and growth in Arabidopsis (Arabidopsis thaliana). To investigate the role of pollen-specific RALFs in another plant species, we combined gene expression data with phylogenetic and biochemical studies to identify candidate orthologs in maize (Zea mays). We show that Clade IB ZmRALF2/3 mutations, but not Clade III ZmRALF1/5 mutations, cause cell wall instability in the sub-apical region of the growing pollen tube. ZmRALF2/3 are mainly located in the cell wall and are partially able to complement the pollen germination defect of their Arabidopsis orthologs AtRALF4/19. Mutations in ZmRALF2/3 compromise pectin distribution patterns leading to altered cell wall organization and thickness culminating in pollen tube burst. Clade IB, but not Clade III ZmRALFs, strongly interact as ligands with the pollen-specific Catharanthus roseus RLK1-like (CrRLK1L) receptor kinases Z. mays FERONIA-like (ZmFERL) 4/7/9, LORELEI-like glycosylphosphatidylinositol-anchor (LLG) proteins Z. mays LLG 1 and 2 (ZmLLG1/2), and Z. mays pollen extension-like (PEX) cell wall proteins ZmPEX2/4. Notably, ZmFERL4 outcompetes ZmLLG2 and ZmPEX2 outcompetes ZmFERL4 for ZmRALF2 binding. Based on these data, we suggest that Clade IB RALFs act in a dual role as cell wall components and extracellular sensors to regulate cell wall integrity and thickness during pollen tube growth in maize and probably other plants.
IntraCranial pressure prediction AlgoRithm using machinE learning (I-CARE): Training and Validation Study
Authors: Fong Nicholas , Feng Jean , Hubbard Alan , Dang Lauren Eyler , Pirracchio Romain
Published: December 2023

OBJECTIVES:

Elevated intracranial pressure (ICP) is a potentially devastating complication of neurologic injury. Developing an ICP prediction algorithm to help the clinician adjust treatments and potentially prevent elevated ICP episodes.

DESIGN:

Retrospective study.

SETTING:

Three hundred thirty-five ICUs at 208 hospitals in the United States.

SUBJECTS:

Adults patients from the electronic ICU (eICU) Collaborative Research Database was used to train an ensemble machine learning model to predict the ICP 30 minutes in the future. Predictive performance was evaluated using a left-out test dataset and externally evaluated on the Medical Information Mart for Intensive Care-III (MIMIC-III) Matched Waveform Database.

INTERVENTIONS:

None.

MEASUREMENTS AND MAIN RESULTS:

Predictors included age, assigned sex, laboratories, medications and infusions, input/output, Glasgow Coma Scale (GCS) components, and time-series vitals (heart rate, ICP, mean arterial pressure, respiratory rate, and temperature). Each patient ICU stay was divided into successive 95-minute timeblocks. For each timeblock, the model was trained on nontime-varying covariates as well as on 12 observations of time-varying covariates at 5-minute intervals and asked to predict the 5-minute median ICP 30 minutes after the last observed ICP value. Data from 931 patients with ICP monitoring in the eICU dataset were extracted (46,207 timeblocks). The root mean squared error was 4.51 mm Hg in the eICU test set and 3.56 mm Hg in the MIMIC-III dataset. The most important variables driving ICP prediction were previous ICP history, patients’ temperature, weight, serum creatinine, age, GCS, and hemodynamic parameters.

CONCLUSIONS:

IntraCranial pressure prediction AlgoRithm using machinE learning, an ensemble machine learning model, trained to predict the ICP of a patient 30 minutes in the future based on baseline characteristics and vitals data from the past hour showed promising predictive performance including in an external validation dataset.
ACR–ARS Practice Parameter for Radiation Oncology
Authors: Lo Simon , Chao Samuel , Harris Eleanor , Knisely Jonathan , Luh Join Y. , Mohindra Pranshu , Quang Tony S. , Ye Jason , Small William , Schechter Naomi R.
Published: December 2023

Aim/Objectives/Background:

This practice parameter was revised collaboratively by the American College of Radiology (ACR), and the American Radium Society. This practice parameter provides updated reference literature regarding radiation oncology practice and its key personnel.

Methods:

This practice parameter was developed according to the process described under the heading The Process for Developing ACR Practice Parameters and Technical Standards on the ACR website (https://www.acr.org/Clinical-Resources/Practice-Parameters-and-Technical-Standards) by the Committee on Practice Parameters—Radiation Oncology of the ACR Commission on Radiation Oncology in collaboration with the American Radium Society.

Results:

This practice parameter provides a comprehensive update to the reference literature regarding radiation oncology practice in general. The overall roles of the radiation oncologist, the Qualified Medical Physicist, and other specialized personnel involved in the delivery of external-beam radiation therapy are discussed. The use of radiation therapy requires detailed attention to equipment, patient and personnel safety, equipment maintenance and quality assurance, and continuing staff education. Because the practice of radiation oncology occurs in a variety of clinical environments, the judgment of a qualified radiation oncologist should be used to apply these practice parameters to individual practices. Radiation oncologists should follow the guiding principle of limiting radiation exposure to patients and personnel while accomplishing therapeutic goals.

Conclusions:

This practice parameter can be used as an effective tool to guide radiation oncology practice by successfully incorporating the close interaction and coordination among radiation oncologists, medical physicists, dosimetrists, nurses, and radiation therapists.
COVID-19 pandemic re-shaped the global dispersal of seasonal influenza viruses
Authors: Chen Zhiyuan , Tsui Joseph L.-H. , Gutierrez Bernardo , Moreno Simon Busch , Plessis Louis du , Deng Xiaowei , Cai Jun , Bajaj Sumali , Suchard Marc A. , Pybus Oliver G. , Lemey Philippe , Kraemer Moritz U. G. , Yu Hongjie
Published: December 2023

Understanding how the global dispersal patterns of seasonal influenza viruses were perturbed during and after the COVID-19 pandemic is needed to inform influenza intervention and vaccination strategies in the post-pandemic period. Although global human mobility has been identified as a key driver of influenza dispersal1, alongside climatic and evolutionary factors2,3, the impact of international travel restrictions on global influenza transmission and recovery remains unknown. Here we combine molecular, epidemiological, climatic, and international travel data within a phylodynamic framework to show that, despite human mobility remaining the principal driver of global influenza virus dissemination, the pandemic’s onset led to a shift in the international population structure and migration network of seasonal influenza lineages. We find that South Asia and Africa played important roles as exporters and phylogenetic trunk locations of influenza in 2020 and 2021, and we highlight the association between population movement, antigenic drift and persistence during the intensive non-pharmaceutical interventions (NPIs) phase. The influenza B/Yamagata lineage disappeared in a context of reduced relative genetic diversity, moderate lineage turnover, and lower positive selection pressure. Our results demonstrate that mobility perturbations reshaped the global dispersal dynamics of influenza viruses, with potential implications for vaccine design and genomic surveillance programmes. As the risk of future pandemics persists, our study provides an opportunity to assess the impact of NPIs during the pandemic on respiratory infectious diseases beyond the interplay between SARS-CoV-2 and influenza viruses.
The gender gap in the relationship between Metabolic Syndrome and Restrictive Ventilatory Defect
Authors: Chu Ya-Chun , Yang Chi-Chiang , Chen Shaw-Ji , Cheng Pei-Ling , Wu Mei-Chuan , Wu Hsin-Hung , Lai Jerry Cheng-Yen
Published: December 2023

Background

Given the fundamental physiological differences between the sexes, this study aimed to investigate the effect of metabolic syndrome on ventilatory defects stratified by sex.

Methods

We conducted a nationwide, pooled, cross-sectional study. Data of 45,788 participants (men, n=15,859; women, n=29,929) aged 30 years or more were obtained from the Taiwan Biobank. Age-sex adjusted and multivariate logistic regression models were used to estimate the risk of developing impaired pulmonary function (restrictive or obstructive ventilatory defect) in individuals with or without metabolic syndromes. Separate models were also used to estimate for the risk of metabolic syndrome scores and the risk of individual metabolic abnormalities on the risk of restrictive ventilatory defect.

Results

The overall prevalence of metabolic syndrome was estimated to be 15.9% in Taiwan, much higher in men than in women (18.6% versus 14.4%). Significant association was observed on the effect of metabolic syndromes on the risk of restrictive ventilatory defect. The risk of developing restrictive ventilator defect was 35% higher in participants with metabolic syndromes (odds ratio, 1.35; 95% confidence interval, 1.26-1.45) than those without metabolic syndromes. Elevated blood pressure and triglycerides abnormality were important predictors of restrictive ventilator defect.

Sex-stratified subgroup analyses of the individual metabolic abnormalities indicated that men with abdominal obesity and women with dysglycemia were more likely to develop restrictive ventilatory defect.

Conclusion

Our study evidences suggested that metabolic syndromes were important predictors of impaired pulmonary function and increased risk of developing restrictive ventilatory defects, and its risk increased with increasing numbers of metabolic abnormalities.
Causal association between serum bilirubin and ischemic stroke: Multivariable Mendelian Randomization
Authors: Shin Jong Won , Jung Keum Ji , Kimm Heejin , Jee Sun Ha
Published: December 2023

BACKGROUND

Past studies have mainly focused on total bilirubin levels, and have not clearly distinguished between direct and indirect bilirubin, a subgroup of bilirubin. In this study, the differences between these subgroups were clearly examined, and the causal association with ischemic stroke was examined in more detail.

METHODS

Utilizing Two sample Multivariable Mendelian randomization (MVMR) analyses, summary data for bilirubin were extracted from the KCPS-II (Korean Cancer Prevention Study-II; n=159,844) and the KoGES (Korean Genome and Epidemiology Study; n=72,299), while ischemic stroke data were derived from the BBJ (Bio Bank Japan; n=201,800).

RESULTS

The crude two-sample MR analysis revealed a significant negative association between total bilirubin and ischemic stroke in KoGES data (odds ratio [OR], 0.86; 95% confidence interval [CI], 0.75-0.98). Subsequent bivariable MR analyses, controlling for lipid profile, also showed significant results. In KCPS-II data, direct bilirubin showed significance in both crude (0.65, 0.43-0.97) and bivariable analyses, while indirect bilirubin demonstrated significant associations in MVMR analyses (0.76, 0.59-0.98), emphasizing its role in mitigating the risk of ischemic stroke.

CONCLUSIONS

Our study establishes a causal association between genetically determined levels of serum bilirubin (total, direct, and indirect) and a reduced risk of ischemic stroke in an Asian population. Notably, the protective effect was predominantly associated with indirect bilirubin. The findings highlight the significance of considering bilirubin subgroup in understanding the mechanisms underlying endogenous antioxidants and its impact on ischemic stroke.
Healthcare utilisation in people with long COVID: an OpenSAFELY cohort study
Authors: Lin Liang-Yu , Henderson Alasdair D , Carlile Oliver , Dillingham Iain , Butler-Cole Ben FC , Marks Michael , Briggs Andrew , Jit Mark , Tomlinson Laurie A , Bates Chris , Parry John , Bacon Sebastian CJ , Goldacre Ben , Mehrkar Amir , MacKenna Brian ,   The OpenSAFELY Collaborative, Eggo Rosalind M , Herrett Emily
Published: December 2023

Background

Long COVID, characterised by various symptoms and complications, potentially increases healthcare utilisation and costs. However, its impact on the NHS remains to be determined.

Objective

This study aims to assess the healthcare utilisation of individuals with long COVID.

Methods

With the approval of NHS England, we conducted a matched cohort study using primary and secondary care data via OpenSAFELY, a platform for analysing anonymous electronic health records. The long COVID exposure group, defined by diagnostic codes, was matched with five comparators without long COVID between Nov 2020 and Jan 2023. We compared their total healthcare utilisation from GP consultations, prescriptions, hospital admissions, A&E visits, and outpatient appointments. Healthcare utilisation and costs were evaluated using a two-part model adjusting for covariates. Using a difference-in-difference model, we also compared healthcare utilisation after long COVID with pre-pandemic records.

Results

We identified 52,988 individuals with a long COVID diagnosis, matched to 264,867 comparators without a diagnosis. In the 12 months post-diagnosis, there was strong evidence that those with long COVID were more likely to use healthcare resources (OR: 8.07, 95% CI: 7.54 – 8.64), and have 49% more healthcare utilisation (RR: 1.49, 95% CI: 1.47 – 1.50). Our model estimated that the long COVID group had 30 healthcare visits per year (predicted mean: 29.23, 95% CI: 28.58 - 29.92), compared to 16 in the comparator group (predicted mean visits: 16.04, 95% CI: 15.73 - 16.36). Individuals with long COVID were more likely to have non-zero healthcare expenditures (OR = 7.47, 95% CI = 7.02 – 7.95), with costs being 43% higher than the comparator group (cost ratio = 1.43, 95% CI: 1.38 – 1.49). The long COVID group costs approximately £2,500 per person per year (predicted mean cost: £2,562.50, 95% CI: £2,335.60 - £2,819.22), and the comparator group costs £1,500 (predicted mean cost: £1,527.43, 95% CI: £1,404.33 - 1,664.45.) Historically, individuals with long COVID utilised healthcare resources more frequently, but their average healthcare utilisation increased more after being diagnosed with long COVID, compared to the comparator group.

Conclusion

Long COVID increases healthcare utilisation and costs. Public health policies should allocate more resources towards preventing, treating, and supporting individuals with long COVID.
Exclusive Enteral Nutrition Initiates Individual Protective Microbiome Changes to Induce Remission in Pediatric Crohn’s Disease
Authors: Häcker Deborah , Siebert Kolja , Smith Byron J , Köhler Nikolai , Riva Alessandra , Mahapatra Aritra , Heimes Helena , Nie Jiatong , Metwaly Amira , Hölz Hannes , Manz Quirin , De Zen Federica , Heetmeyer Jeannine , Socas Katharina , Le Thi Giang , Meng Chen , Kleigrewe Karin , Pauling Josch K , Neuhaus Klaus , List Markus , Pollard Katherine S , Schwerd Tobias , Haller Dirk
Published: December 2023

Exclusive enteral nutrition (EEN) is the first-line therapy for pediatric Crohn’s disease (CD), but protective mechanisms remain unknown. We established a prospective pediatric cohort to characterize the function of fecal microbiota and metabolite changes of treatment-naïve CD patients in response to EEN. Integrated multi-omics analysis identified network clusters from individually variable microbiome profiles, withLachnospiraceaeand medium chain fatty acids as protective features. Bioorthogonal non-canonical amino acid tagging selectively identified bacterial species in response to medium chain fatty acids. Metagenomic analysis identified high strain-level dynamics in response to EEN. Functional changes of diet-exposed fecal microbiota were further validated in a combined approach using gut chemostat cultures and microbiota transfer into germ-freeIl10-deficient mice. Dietary model conditions induced individual patient-specific strain signatures to prevent or cause IBD-like inflammation in gnotobiotic mice. Hence, we provide evidence that EEN therapy operates through explicit functional changes of temporally and individually variable microbiome profiles.
Assessing the Impact of Dental Malocclusion on the Body’s Postural Balance: Correlation between Angle Class, Pelvic Balance, and Center of Foot Pressure
Authors: Akensous Imad , Karkouri Samia , Iziki Chaimae , Rerhrhaye Wiam , Abdelkoui Anissa
Published: December 2023

Background

The purpose of this study was to determine the association between pelvic and center foot pressure (CoP) imbalances and angle class II or III malocclusions.

Methods

Our study is a prospective, descriptive, and analytic study conducted on two groups: a test group of 53 patients who present malocclusion class II or III compared with 53 controls matched for age and gender. The evaluation of the center of foot pressure (CoP) and the confidence ellipse area (mm2) were performed by stabilometric platefrom using bipodal test in two occlusal conditions, in maximum intercuspation (MI) and with a cotton roll (CR), with and without visual cue. A pelvic level device was used to perform the pelvic balance examination. Statistical analysis used the chi-square test, the McNemar test, and the Pearson test.

Results

In the case group, the bipodal test was poor (outside reference values) in MI open eyes, MI closed eyes, CR open eyes, and CR closed eyes in 47.2%, 62.3%, 58.5%, and 64.2%, respectively, vs 54.7%, 43.4%, 34.0%, and 67.9%, respectively, of controls (p <0.05). None subjects in the control group were diagnosed with pelvic imbalance, against five patients (9.4%) in the case group (p <0.05). Pelvic imbalance was noted in two patients in class II and only one patient in class III. For Class II, the bipodal test results were poor in MI open eyes, MI closed eyes, CR open eyes, and CR closed eyes conditions with percentages of 54.2%, 66.7%, 70.8%, and 58.3%, respectively (p <0.05). In Class III, results were generally good in MI open eyes (80%), but mostly poor in MIP and CR closed eyes (90%).

Conclusion

There was a significant difference in pelvic imbalance between the case group and the control group. Angle Classes II and III had no significant correlation with pelvic tilt. The stabilometric examinations have shown that Angle class II influences the CoP displacement and the confidence ellipse area in MI open eyes conditions. This finding supports the hypothesis that dental malocclusion can have an effect on the postural system.
Drivers and barriers to promoting self-care in individuals living with multimorbidity: a cross-sectional online survey of health and care professionals
Authors: Barber Susan , Hayhoe Benedict , Richardson Sonia , Norton John , Karki Manisha , El-Osta Austen
Published: December 2023

Objective

Investigate knowledge, attitudes, and perceptions of health and care professionals (H&CPs) in England concerning drivers and barriers for promoting self-care in service-users with multimorbidity.

Design

A cross-sectional online survey of the health and care workforce.

Setting

Health and social care workforce.

Participants

Eighty-eight health and social care professionals in England.

Methods

A cross-sectional online survey administered via Imperial College Qualtrics platform. Questions were asked about perceived drivers and barriers to promoting self-care in individuals with multimorbidity, including mental health.

Results

Extant barriers associated with service-users ability and opportunity to self-care were feelings of loneliness and social isolation (18.9%; n=61), mobility and access issues (14%; n=45). Strategies deployed by H&CPs to support self-care were social prescribing (17.9%; n=59), helping service-users to monitor their symptoms (15.2%; n=50), referring to recognised programmes to support self-management (13.9%; n=46), knowledge and understanding about the benefits of self-care (91.8%; n=67), the purposes of prescribed medicines (83.3%; n=60), and support for self-care (91.7%; n=66) were considered key drivers of successful self-management and to engagement between service-users and service providers. Service providers’ reported gaps in their knowledge including how to improve practical interactions to sustain health seeking behaviours by service-users (30.6%; n=49), health coaching (21.9%; n=35), improved understanding about effective self-care interventions (21.3%; n=34) and improving self-care in relation to medicines use (20%; n=32). Most respondents (92.2%; n=71) reported that the COVID-19 pandemic had highlighted the need for self-care, and (42.7%; n=32) agreed that the pandemic had a positive impact on their ability to promote self-care among service-users.

Conclusions

Self-care is important for service-users who live with multimorbidity. H&CPs are in a unique position to influence lifestyle choices and health-seeking self-care behaviours. Raising awareness about the importance of self-care, health literacy, knowledge, understanding and skills among service-users and providers is key to improving supported self-care.
Regional-specific calibration enables application of bioinformatic evidence for clinical classification of 5’ cis-regulatory variants in Mendelian disease
Authors: Villani Rehan M. , McKenzie Maddison E. , Davidson Aimee L. , Spurdle Amanda B.
Published: December 2023

To date, clinical genetic testing and approaches to classify genetic variants in Mendelian disease genes have focused heavily on exonic coding and intronic gene regions. This multi-step study was undertaken to provide an evidence base for selecting and applying bioinformatic approaches for use in clinical classification of 5’ cis-regulatory region variants. Curated datasets of rare clinically reported disease-causing 5’ cis-regulatory region variants, and variants from matched genomic regions in population controls, were used to calibrate six bioinformatic tools as predictors of variant pathogenicity. Likelihood ratio estimates were aligned to code weights following ClinGen recommendations for application of the American College of Medical Genetics (ACMG)/American Society of Molecular Pathology (AMP) classification scheme. Considering code assignment across all reference dataset variants, performance was best for CADD (81.2%) and REMM (81.5%). Optimized thresholds provided moderate evidence towards pathogenicity (CADD, REMM), and moderate (CADD) or supporting (REMM) evidence against pathogenicity. Both sensitivity and specificity of prediction were improved when further categorizing variants based on location in an EPDnew-defined promoter region. Combining predictions (CADD, REMM, and location in a promoter region) increased specificity at the expense of sensitivity. Importantly, the optimal CADD thresholds for assigning ACMG/AMP codes PP3 (≥10) and BP4 (≤8) were vastly different to recommendations for protein-coding variants (PP3 ≥ 25.3; BP4 ≤22.7); CADD <22.7 would incorrectly assign BP4 for >90% of reported disease-causing cis-regulatory region variants. Our results demonstrate the need to consider a tiered approach and tailored score thresholds to optimize bioinformatic impact prediction for clinical classification of cis-regulatory region variants.