bluuebunny/crossref_metadata_2025 huggingface dataset:
Simple numerical X-ray polarization models of reflecting axially symmetric structures around accreting compact objects
Authors: Podgorný J , Dovčiak M , Marin F
Published: April 2024

We present a series of numerical models suitable for X-ray polarimetry of accreting systems. First, we provide a spectropolarimetric routine that integrates reflection from inner optically thick walls of a geometrical torus of arbitrary size viewed under general inclination. In the studied example, the equatorial torus is illuminated by a central isotropic source of X-ray power-law emission, representing a hot corona. Nearly neutral reprocessing inside the walls is precomputed by Monte Carlo code stokes that incorporates both line and continuum processes, including multiple scatterings and absorption. We created a new xspec model, called xsstokes, which in this version enables efficient X-ray polarimetric fitting of the torus parameters, observer’s inclination and primary emission properties, interpolating for arbitrary state of primary polarization. Comparison of the results to a Monte Carlo simulation allowing partial transparency shows that the no-transparency condition may induce different polarization by tens of per cent. Allowing partial transparency leads to lower/higher polarization fraction, if the resulting polarization orientation is perpendicular/parallel to the rotation axis. We provide another version of xsstokes that is suitable for approximating nearly neutral reflection from a distant optically thick disc of small geometrical thickness. It assumes local illumination averaged for a selected range of incident angles, representing a toy model of a diffuse corona of various physical extent. Assessing both xsstokes variants, we conclude that the resulting polarization can be tens of per cent and perpendicularly/parallelly oriented towards the rotation axis, if the reflecting medium is rather vertically/equatorially distributed with respect to a compact central source.
Astrometric weak lensing with Gaia DR3 and future catalogues: searches for dark matter substructure
Authors: Mondino Cristina , Tsantilas Andreas , Taki Anna-Maria , Van Tilburg Ken , Weiner Neal
Published: April 2024

Small-scale dark matter structures lighter than a billion solar masses are an important probe of primordial density fluctuations and dark matter microphysics. Due to their lack of starlight emission, their only guaranteed signatures are gravitational in nature. We report on results of a search for astrometric weak lensing by compact dark matter subhaloes in the Milky Way with Gaia DR3 data. Using a matched-filter analysis to look for correlated imprints of time-domain lensing on the proper motions of background stars in the Magellanic Clouds, we exclude order-unity substructure fractions in haloes with masses Ml between 107 and $10^9 \, {\rm M}_\odot$ and sizes of one parsec or smaller. We forecast that a similar approach based on proper accelerations across the entire sky with data from Gaia DR4 may be sensitive to substructure fractions of fl ≳ 10−3 in the much lower mass range of $10 \, {\rm M}_\odot \lesssim M_l \lesssim 3 \times 10^3 \, {\rm M}_\odot$. We further propose an analogous technique for stacked star–star lensing events in the regime of large impact parameters. Our first implementation is not yet sufficiently sensitive but serves as a useful diagnostic and calibration tool; future data releases should enable average stellar mass measurements using this stacking method.1
Purple is the new green: biopigments and spectra of Earth-like purple worlds
Authors: Coelho Lígia Fonseca , Kaltenegger Lisa , Zinder Stephen , Philpot William , Price Taylor L , Hamilton Trinity L
Published: April 2024

With more than 5500 detected exoplanets, the search for life is entering a new era. Using life on Earth as our guide, we look beyond green landscapes to expand our ability to detect signs of surface life on other worlds. While oxygenic photosynthesis gives rise to modern green landscapes, bacteriochlorophyll-based anoxygenic phototrophs can also colour their habitats and could dominate a much wider range of environments on Earth-like exoplanets. Here, we characterize the reflectance spectra of a collection of purple sulfur and purple non-sulfur bacteria from a variety of anoxic and oxic environments. We present models for Earth-like planets where purple bacteria dominate the surface and show the impact of their signatures on the reflectance spectra of terrestrial exoplanets. Our research provides a new resource to guide the detection of purple bacteria and improves our chances of detecting life on exoplanets with upcoming telescopes. Our biological pigment data base for purple bacteria and the high-resolution spectra of Earth-like planets, including ocean worlds, snowball planets, frozen worlds, and Earth analogues, are available online, providing a tool for modellers and observers to train retrieval algorithms, optimize search strategies, and inform models of Earth-like planets, where purple is the new green.
Observation uncertainty effects on the precision of interior planetary parameters
Authors: Plotnykov Mykhaylo , Valencia Diana
Published: April 2024

Determining compositions of low-mass exoplanets is essential in understanding their origins. The certainty by which masses and radius are measured affects our ability to discern planets that are rocky or volatile rich. In this study, we aim to determine sound observational strategies to avoid diminishing returns. We quantify how uncertainties in mass, radius, and model assumptions propagate into errors in inferred compositions of rocky and water planets. For a target error in a planet’s iron-mass fraction or water content, we calculate the corresponding required accuracies in radius and mass. For instance, a rocky planet with a known radius error of 2 per cent (corresponding to TESS detection best errors) demands mass precision to be at 5–11 per cent to attain an 8 wt% precision in iron-mass fraction, regardless of mass. Similarly, a water world of equal radius precision requires 9–20 per cent mass precision to confine the water content within a 10 wt% margin. Lighter planets are more difficult to constrain, especially water-rich versus water-poor worlds. Studying Earth as an exoplanet, we find an ∼±5 point ’error floor’ in iron-mass fraction and ∼±7 in core-mass fraction from our lack of knowledge on mineralogy. The results presented here can quickly guide observing strategies to maximize insights into small exoplanet compositions while avoiding overobserving.
On data set tensions and signatures of new cosmological physics
Authors: Cortês Marina , Liddle Andrew R
Published: April 2024

Can new cosmic physics be uncovered through tensions amongst data sets? Tensions in parameter determinations amongst different types of cosmological observation, especially the ‘Hubble tension’ between probes of the expansion rate, have been invoked as possible indicators of new physics, requiring extension of the ΛCDM paradigm to resolve. Within a fully Bayesian framework, we show that the standard tension metric gives only part of the updating of model probabilities, supplying a data co-dependence term that must be combined with the Bayes factors of individual data sets. This shows that, on its own, a reduction of data set tension under an extension to ΛCDM is insufficient to demonstrate that the extended model is favoured. Any analysis that claims evidence for new physics solely on the basis of alleviating data set tensions should be considered incomplete and suspect. We describe the implications of our results for the interpretation of the Hubble tension.
DNA sequence data, multispecies coalescent and morphometrics shed new light on the systematics of Iberian islamiinae springsnails (Caenogastropoda: Hydrobiidae)
Authors: Delicado Diana , Miller Jonathan P , García-Guerrero Fernando , Arconada Beatriz , Ramos Marian A
Published: April 2024

Multilocus phylogenies have shown that soft-part anatomy alone is insufficient for the systematics of valvatiform- and trochiform-shelled springsnails of the subfamily Islamiinae (family Hydrobiidae) due to morphological similarities between taxa that are not closely related. However, a solid knowledge of their systematics and species boundaries is crucial to conserve this highly imperilled group. Here, we inferred molecular phylogenies based on two mitochondrial and two nuclear gene fragments from representatives of three morphological species of the Iberian genus Iberhoratia and performed multispecies coalescent and shell variation analyses (geometric morphometrics) to reevaluate their taxonomic status. The resulting phylogenetic analyses, which included homologous sequences of 15 other valvatiform-shelled hydrobiid species endemic to the Iberian Peninsula, depicted the topotypical specimens of I. aurorae and I. gatoa elisai distantly related to one another and the type species I. morenoi. Considering their high genetic divergence and morphological differences from other hydrobiid taxa, we have placed the former two species in the new genera Beatrix n. gen. and Actenidia n. gen. The multispecies coalescent delimitation method DELINEATE, a novel approach to the taxonomy of the Hydrobiidae, and shell morphometric data suggested two species within the ‘I. gatoa elisai’ clade. Based on morphological and molecular evidence, we recognized this clade as Actenidia, a new genus comprising the species A. elisai n. gen., n. comb. and A. baetica n. gen., n. sp. Our results underscore the importance of using multiple lines of evidence to delimitate species of Islamiinae and interpret their systematics. We also discuss the implications of our findings for conserving I. gatoa.
Activity reconstitution of Kre33 and Tan1 reveals a molecular ruler mechanism in eukaryotic tRNA acetylation
Authors: Ma Chun-Rui , Liu Na , Li Hong , Xu Hong , Zhou Xiao-Long
Published: April 2024

RNA acetylation is a universal post-transcriptional modification that occurs in various RNAs. Transfer RNA (tRNA) acetylation is found at position 34 (ac4C34) in bacterial tRNAMet and position 12 (ac4C12) in eukaryotic tRNASer and tRNALeu. The biochemical mechanism, structural basis and functional significance of ac4C34 are well understood; however, despite being discovered in the 1960s and identification of Kre33/NAT10 and Tan1/THUMPD1 as modifying apparatuses, ac4C12 modification activity has never been reconstituted for nearly six decades. Here, we successfully reconstituted the ac4C12 modification activity of yeast Kre33 and Tan1. Biogenesis of ac4C12 is primarily dependent on a minimal set of elements, including a canonical acceptor stem, the presence of the 11CCG13 motif and correct D-arm orientation, indicating a molecular ruler mechanism. A single A13G mutation conferred ac4C12 modification to multiple non-substrate tRNAs. Moreover, we were able to introduce ac4C modifications into small RNAs. ac4C12 modification contributed little to tRNA melting temperature and aminoacylation in vitro and in vivo. Collectively, our results realize in vitro activity reconstitution, delineate tRNA substrate selection mechanism for ac4C12 biogenesis and develop a valuable system for preparing acetylated tRNAs as well as non-tRNA RNA species, which will advance the functional interpretation of the acetylation in RNA structures and functions.
Cdc13 exhibits dynamic DNA strand exchange in the presence of telomeric DNA
Authors: Nickens David G , Feng Zhitong , Shen Jiangchuan , Gray Spencer J , Simmons Robert H , Niu Hengyao , Bochman Matthew L
Published: April 2024

Telomerase is the enzyme that lengthens telomeres and is tightly regulated by a variety of means to maintain genome integrity. Several DNA helicases function at telomeres, and we previously found that the Saccharomyces cerevisiae helicases Hrq1 and Pif1 directly regulate telomerase. To extend these findings, we are investigating the interplay between helicases, single-stranded DNA (ssDNA) binding proteins (ssBPs), and telomerase. The yeast ssBPs Cdc13 and RPA differentially affect Hrq1 and Pif1 helicase activity, and experiments to measure helicase disruption of Cdc13/ssDNA complexes instead revealed that Cdc13 can exchange between substrates. Although other ssBPs display dynamic binding, this was unexpected with Cdc13 due to the reported in vitro stability of the Cdc13/telomeric ssDNA complex. We found that the DNA exchange by Cdc13 occurs rapidly at physiological temperatures, requires telomeric repeat sequence DNA, and is affected by ssDNA length. Cdc13 truncations revealed that the low-affinity binding site (OB1), which is distal from the high-affinity binding site (OB3), is required for this intermolecular dynamic DNA exchange (DDE). We hypothesize that DDE by Cdc13 is the basis for how Cdc13 ‘moves’ at telomeres to alternate between modes where it regulates telomerase activity and assists in telomere replication.
Growth-regulated co-occupancy of Mediator and Lsm3 at intronic ribosomal protein genes
Authors: Abdel-Fattah Wael R , Carlsson Mattias , Hu Guo-Zhen , Singh Ajeet , Vergara Alexander , Aslam Rameen , Ronne Hans , Björklund Stefan
Published: April 2024

Mediator is a well-known transcriptional co-regulator and serves as an adaptor between gene-specific regulatory proteins and RNA polymerase II. Studies on the chromatin-bound form of Mediator revealed interactions with additional protein complexes involved in various transcription-related processes, such as the Lsm2–8 complex that is part of the spliceosomal U6 small nuclear ribonucleoprotein complex. Here, we employ Chromatin Immunoprecipitation sequencing (ChIP-seq) of chromatin associated with the Lsm3 protein and the Med1 or Med15 Mediator subunits. We identify 86 genes co-occupied by both Lsm3 and Mediator, of which 73 were intron-containing ribosomal protein genes. In logarithmically growing cells, Mediator primarily binds to their promoter regions but also shows a second, less pronounced occupancy at their 3′-exons. During the late exponential phase, we observe a near-complete transition of Mediator from these promoters to a position in their 3′-ends, overlapping the Lsm3 binding sites ∼250 bp downstream of their last intron–exon boundaries. Using an unbiased RNA sequencing approach, we show that transition of Mediator from promoters to the last exon of these genes correlates to reduction of both their messenger RNA levels and splicing ratios, indicating that the Mediator and Lsm complexes cooperate to control growth-regulated expression of intron-containing ribosomal protein genes at the levels of transcription and splicing.
Interactive Tree of Life (iTOL) v6: recent updates to the phylogenetic tree display and annotation tool
Authors: Letunic Ivica , Bork Peer
Published: April 2024

The Interactive Tree Of Life (https://itol.embl.de) is an online tool for the management, display, annotation and manipulation of phylogenetic and other trees. It is freely available and open to everyone. iTOL version 6 introduces a modernized and completely rewritten user interface, together with numerous new features. A new dataset type has been introduced (colored/labeled ranges), greatly upgrading the functionality of the previous simple colored range annotation function. Additional annotation options have been implemented for several existing dataset types. Dataset template files now support simple assignment of annotations to multiple tree nodes through substring matching, including full regular expression support. Node metadata handling has been greatly extended with novel display and exporting options, and it can now be edited interactively or bulk updated through annotation files. Tree labels can be displayed using multiple simultaneous font styles, with precise positioning, sizing and styling of each individual label part. Various bulk label editing functions have been implemented, simplifying large scale changes of all tree node labels. iTOL’s automatic taxonomy assignment functions now support trees based on the Genome Taxonomy Database (GTDB), in addition to the NCBI taxonomy. The functionality of the optional user account pages has been expanded, simplifying the management, navigation and sharing of projects and trees. iTOL currently handles more than one and a half million trees from >130 000 individual user accounts.
Deep carbon recycling viewed from global plate tectonics
Authors: Zhang Maoliang , Xu Sheng , Sano Yuji
Published: April 2024

Plate tectonics plays an essential role in the redistribution of life-essential volatile elements between Earth's interior and surface, whereby our planet has been well tuned to maintain enduring habitability over much of its history. Here we present an overview of deep carbon recycling in the regime of modern plate tectonics, with a special focus on convergent plate margins for assessing global carbon mass balance. The up-to-date flux compilation implies an approximate balance between deep carbon outflux and subduction carbon influx within uncertainty but remarkably limited return of carbon to convecting mantle. If correct, carbon would gradually accumulate in the lithosphere over time by (i) massive subsurface carbon storage occurring primarily in continental lithosphere from convergent margins to continental interior and (ii) persistent surface carbon sinks to seafloors sustained by high-flux deep CO2 emissions to the atmosphere. Further assessment of global carbon mass balance requires updates on fluxes of subduction-driven carbon recycling paths and reduction in uncertainty of deep carbon outflux. From a global plate tectonics point of view, we particularly emphasize that continental reworking is an important mechanism for remobilizing geologically sequestered carbon in continental crust and sub-continental lithospheric mantle. In light of recent advances, future research is suggested to focus on a better understanding of the reservoirs, fluxes, mechanisms, and climatic effects of deep carbon recycling following an integrated methodology of observation, experiment, and numerical modeling, with the aim of decoding the self-regulating Earth system and its habitability from the deep carbon recycling perspective.
Semiconductor fibers for textile integrated electronic systems
Authors: Zheng Yuanyuan , Wang Zhen , Chen Peining , Peng Huisheng
Published: April 2024

The near-room temperature resistance transition in the Lu-H-N compound is repeatedly reproduced, which is clarified to originate from a metal-to-semiconductor/insulator transition rather than superconductivity.
Up with Categories, Down with Sets; Out with Categories, In with Sets!
Authors: Kirby Jonathan
Published: April 2024

Practical approaches to the notions of subsets and extension sets are compared, coming from broadly set-theoretic and category-theoretic traditions of mathematics. I argue that the set-theoretic approach is the most practical for ‘looking down’ or ‘in’ at subsets and the category-theoretic approach is the most practical for ‘looking up’ or ‘out’ at extensions, and suggest some guiding principles for using these approaches without recourse to either category theory or axiomatic set theory.
A 10-year analysis of application and match rates for pain medicine training in the United States
Authors: Silvestre Jason , Nagpal Ameet
Published: April 2024

Objective

We analyzed application and match rates for pain medicine training in the United States and hypothesized that there would be (1) greater growth in the number of training positions than applicants, (2) higher match rates among US allopathic graduates relative to non-US allopathic graduates, and (3) greater number of unfilled training positions over time.

Design

Retrospective, cross-sectional study of all applicants for pain medicine training in the United States.

Method

National Resident Matching Program data were obtained over a ten-year period (2014-2023). Match rates and applicant-to-position ratios were calculated and compared over time with linear regression. Comparisons were made with chi-square tests.

Results

Growth in the number of annual training positions (261-377, 44% increase) exceeded growth in the number of interested applicants (398-415, 4% increase) (P < .001). Annual applicant-to-training position ratios decreased (1.5-1.1, P < .001). The representation of US allopathic graduates among incoming pain medicine fellows decreased over the study period (73%-58%, P < .001) while US osteopathic graduates increased (9%-28%, P < .001).

Match rates increased for both US allopathic graduates (71%-91%, P < .001) and non-US allopathic graduates (51%-81%, P < .001). From 2018 to 2023, US allopathic graduates (79%) had higher match rates than US osteopathic graduates (60%, P < .001) and international medical graduates (57%, P < .001). More available annual training positions went unfilled over the study period (2%-5%, P = .006).

Conclusions

Stagnant annual applicant volume and increasing number of available training positions have led to increasing match rates for pain medicine fellowship training. Fewer US allopathic graduates are pursuing pain medicine training. The increasing percentage of unfilled training positions warrants ongoing surveillance.
Validation of three health literacy screening questions compared with S-TOFHLA in a low-income diverse English- and Spanish-Speaking population
Authors: Kincaid Hope , Coyne Cathy A , Hamadani Roya , Friel Timothy
Published: April 2024

Background

Clinicians need a tool to gauge patients’ ability to understand health conditions and treatment options. The Short-form Test of Functional Health Literacy in Adults (S-TOFHLA) is the gold standard for this, but its length is prohibitive for use in clinical settings. This study seeks to validate a novel three-item question set for predicting health literacy.

Methods

This cross-sectional study utilized an in-person questionnaire alongside the S-TOFHLA. The sample included 2027 English- and Spanish-speaking adults (≥18 years) recruited from primary care practices serving a low-income eastern Pennsylvania community. Most patients (57.7%) identified as Hispanic. Diagnostic accuracy of each question and aggregated scores were assessed against the validated survey by calculating the area under the receiver operating characteristic (AUROC) curve.

Results

Questions in the ‘Problems Learning’ and ‘Help Reading’ domains (AUROC 0.66 for each) performed better than the ‘Confident Forms’ question (AUROC 0.64). Summing all three scores resulted in an even higher AUROC curve (0.71). Cronbach’s alpha of the combined items was 0.696.

Conclusions

Study results suggest that any of the three questions are viable options for screening health literacy levels of diverse patients in primary care clinical settings. However, they perform better as a summed score than when used individually.
Do investors care about biodiversity?
Authors: Garel Alexandre , Romec Arthur , Sautner Zacharias , Wagner Alexander F
Published: April 2024

This article introduces a new measure of a firm’s negative impact on biodiversity, the corporate biodiversity footprint (CBF), and studies whether it is priced in an international sample of stocks. On average, the CBF does not explain the cross-section of returns between 2019 and 2022. However, a biodiversity footprint premium (higher returns for firms with larger footprints) began emerging in October 2021 after the Kunming Declaration, which capped the first part of the UN Biodiversity Conference (COP15). Consistent with this finding, stocks with large footprints lost value in the days after the Kunming Declaration. The launch of the Taskforce on Nature-related Financial Disclosures (TNFD) in June 2021 had a similar effect. These results indicate that investors have started to require a risk premium upon the prospect of, and uncertainty about, future regulation or litigation to preserve biodiversity.
Long-term Changes in Personal Recovery and Quality of Life Among Patients With Schizophrenia Spectrum Disorders and Different Durations of Illness: A Meta-analysis
Authors: de Winter Lars , Jelsma Auke , Vermeulen Jentien M , van Weeghel Jaap , Hasson-Ohayon Ilanit , Mulder Cornelis L , Boonstra Nynke , Veling Wim , de Haan Lieuwe
Published: April 2024

Background and Hypothesis

In schizophrenia spectrum disorders (SSD) personal recovery and subjective quality of life (S-QOL) are crucial and show conceptual overlap. There is limited knowledge about how these outcomes change over time. Therefore, we investigated changes in personal recovery or S-QOL for patients with SSD. We specifically focused on the influence of the patients’ durations of illness (DOI) on changes in personal recovery and S-QOL.

Study Design

We included 46 studies investigating longitudinal changes in quantitative assessments of personal recovery or S-QOL for patients with SSD. Outcomes were categorized in overall personal recovery, overall S-QOL connectedness, hope and optimism, identity, meaning in life, and empowerment. We evaluated effect sizes of change between baseline and follow-up assessments. We also evaluated potential moderating effects, including DOI on these changes in outcomes.

Study Results

We found small improvements of overall personal recovery and S-QOL, but marginal or no improvement over time in the other more specific outcome domains. Patients without a schizophrenia diagnosis, a younger age, and more recent publications positively influenced these changes. We found no significant influence of DOI on the changes in any outcome domain.

Conclusions

Improvement in personal recovery or S-QOL of people with SSD is modest at best. However, these studies did not fully capture the personal narratives or nonlinear process of recovery of an individual. Future research should focus on how to shift from a clinical to more person-oriented approach in clinical practice to support patients in improving their personal process of recovery.

Review protocol registration

CRD42022377100.
A review of soybean processing byproducts and their use in swine and poultry diets
Authors: Gaffield Katelyn N , Goodband Robert D , DeRouchey Joel M , Tokach Mike D , Woodworth Jason C , Denny Gordon , Gebhardt Jordan T
Published: April 2024

Due to its importance in animal feed, soybean meal has been extensively studied to optimize its use in livestock diets. Despite extensive research, the industry has not fully characterized specific areas of soybean processing such as the inclusion of soybean byproducts added back to soybean meal during processing. Soybean processing byproducts can encompass a large variety of materials including weeds and foreign material, soybean hulls, gums, soapstocks, lecithins, spent bleaching clays, and deodorizer distillates. Despite the potential for being added back to soybean meal when a crushing plant is integrated with an oil refinery, there is currently limited information on the composition of many of these soybean processing byproducts and their subsequent effects on soybean meal quality and animal performance. Therefore, there may be opportunities for a new area of research focused on soybean processing byproducts and their optimal use within the livestock feed industry. This review summarizes the current information on soybean byproducts with a focus on identifying the areas with the greatest potential for future research in swine and poultry nutrition.
Evaluation of a Novel Fungicidal Extract from Blue Spruce, Picea pungens
Authors: Guo Yonghong , Zhou Bin , Pooler Margaret
Published: April 2024

Aqueous extracts from 22 species of evergreen plants and 32 accessions of spruce ( Picea A. Dietr.) were screened using an in vitro assay to determine their antifungal activity against Calonectria henricotiae, one of the causal agents of boxwood blight. Most of the evergreen species and all the spruce accessions showed significant antifungal activity ( P < 0.05); in particular, the extract from one accession of Picea pungens Engelm. had significant effective fungistatic and fungicidal activity ( P < 0.05), both in vitro and when tested on detached boxwood leaves and whole boxwood plants. The extraction process was simple, consisting of autoclaving fresh leaves in water, and, once extracted, the active compound was stable in aqueous solution and when lyophilized and reconstituted. Further investigations will focus on the potential of this extract as an alternative to traditional fungicides for use in a wide range of crops and in diverse applications, from controlling fungal infections in the landscape to preventing postharvest losses in fruit and vegetable crops.
Dawn of CAR-T cell therapy in autoimmune diseases
Authors: Liu Yuxin , Dong Minghao , Chu Yunhui , Zhou Luoqi , You Yunfan , Pang Xiaowei , Yang Sheng , Zhang Luyang , Chen Lian , Zhu Lifang , Xiao Jun , Wang Wei , Qin Chuan , Tian Daishi
Published: April 2024

Chimeric antigen receptor (CAR)-T cell therapy has achieved remarkable success in the treatment of hematological malignancies. Based on the immunomodulatory capability of CAR-T cells, efforts have turned toward exploring their potential in treating autoimmune diseases. Bibliometric analysis of 210 records from 128 academic journals published by 372 institutions in 40 countries/regions indicates a growing number of publications on CAR-T therapy for autoimmune diseases, covering a range of subtypes such as systemic lupus erythematosus, multiple sclerosis, among others. CAR-T therapy holds promise in mitigating several shortcomings, including the indiscriminate suppression of the immune system by traditional immunosuppressants, and non-sustaining therapeutic levels of monoclonal antibodies due to inherent pharmacokinetic constraints. By persisting and proliferatingin vivo, CAR-T cells can offer a tailored and precise therapeutics. This paper reviewed preclinical experiments and clinical trials involving CAR-T and CAR-related therapies in various autoimmune diseases, incorporating innovations well-studied in the field of hematological tumors, aiming to explore a safe and effective therapeutic option for relapsed/refractory autoimmune diseases.
Integrated analysis of single-cell and bulk RNA sequencing to construct a CD8 + T cell-related immune gene signature in pancreatic cancer
Authors: Liu Yuzhi , Xu Fei , Jiang Anyi , Ding Jie , Li Chungao , Quan Ming
Published: April 2024

Background:

Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant tumor that responds poorly to immunotherapy. The pivotal influence of CD8 + T-cell infiltration on immunotherapy has been documented in various solid tumors. However, the specific contribution of CD8 + T cell-associated immune genes (TIGs) to the tumor immune microenvironment remains unclear.

Methods:

We obtained CD8 + T cell-related immune genes from the INNATE and IMMPORT databases. Univariate analysis and lasso regression analysis were utilized to screen hub TIGs and develop a prognostic signature, the TIGs score. This score was used to evaluate prognosis, immunocyte infiltration, cancer-associated signaling pathways, and the potential responsiveness of immunotherapy. The transcriptomic data and single-cell data from the GSE183795 and GE212966 datasets are employed to validate the reliability of the findings.

Results:

Our findings suggest that patients with low TIGs scores have stronger immune effector functions and immune checkpoint activation, resulting in a more favorable response to PD-L1 inhibitors. TIGs scores were significantly correlated with various molecular characteristics and clinical outcomes, such as tumor mutation burden, multiple tumor-associated pathways, and chemotherapeutic drug sensitivity. PSME2 was identified as a potential prognostic biomarker for predicting survival in patients with PDAC.

Conclusions:

This study elucidates the intricate regulatory mechanisms of TIGs within the tumor immune microenvironment of pancreatic cancer. Our findings strongly suggest that the TIGs score is a robust prognostic marker for prognosis and immunotherapy responsiveness. Additionally, targeting PSME2 may offer a novel avenue for enhancing the effectiveness of immunotherapy in pancreatic cancer.
Potentially Modifiable Dementia Risk Factors in Canada: An Analysis of Canadian Longitudinal Study on Aging with a Multi-Country Comparison
Authors: Son Surim , Speechley Mark , Zou Guangyong , Kivipelto Miia , Mangialasche Francesca , Feldman Howard , Chertkow Howard , Belleville Sylvie , Nygaard Haakon , Hachinski Vladimir , Pieruccini-Faria F , Montero-Odasso Manuel
Published: April 2024

BACKGROUND

Previous estimates suggested that up to 40% of dementia cases worldwide are associated with modifiable risk factors, however, these estimates are not known in Canada. Furthermore, sleep disturbance, an emerging factor, has not been incorporated into the life-course model of dementia prevention.

Objective

To estimate the population impact of 12 modifiable risk factors in Canadian adults including sleep disturbance, by sex and age groups, and to compare with other countries.

Design

Cross-sectional analysis of Canadian Longitudinal Study on Aging Baseline data

Setting

Community

Participants

30,097 adults aged 45 years and older.

Measurements

Prevalence and Population Attributable Fraction (PAF) of less education, hearing loss, traumatic brain injury, hypertension, excessive alcohol, obesity, smoking, depression, social isolation, physical inactivity, diabetes, and sleep disturbance.

Results

The risk factors with the largest PAF were later life physical inactivity (10.2%; 95% CI, 6.8% to 13%), midlife hearing loss (6.5%; 3.7% to 9.3%), midlife obesity (6.4; 4.1% to 7.7%), and midlife hypertension (6.2%; 2.7% to 9.3%). The PAF of later life sleep disturbance was 3.0% (95% CI, 1.8% to 3.8%). The 12 risk factors accounted for 51.9% (32.2% to 68.0%) of dementia among men and 52.4% (32.5% to 68.7%) among women. Overall, the combined PAF of all risk factors was 49.2% (31.1% to 64.9%), and it increased with age.

Conclusion

Nearly up to 50% of dementia cases in Canada could be prevented by modifying the 12 risk factors across the lifespan. Canadian risk reduction strategies should prioritize targeting physical inactivity, hearing loss, obesity, and hypertension.
Personalized CZA-ATM dosing against an XDRE. coliin liver transplant patients; the application of thein vitrohollow fibre infection model (HFIM)
Authors: Sadouki Zahra , Wey Emmanuel Q. , Iype Sateesh , Nasralla David , Potts Jonathan , Spiro Mike , Williams Alan , McHugh Timothy D. , Kloprogge Frank
Published: April 2024

Background & aims

An extensively-drug resistant (XDR) NDM and OXA-48 producingE. colicontributing to repeat episodes of biliary sepsis was isolated from the blood stream of a 45-55 year-old male with a background of IgG4 related sclerosing cholangitis. The patient was awaiting orthotopic liver transplant (OLT). There is no standardized antibiotic prophylaxis regimen however in line with the Infectious Diseases Society of America (IDSA) guidance an antibiotic prophylactic regimen of Ceftazidime-Avibactam (CZA) 2.5g TDS with Aztreonam (ATM) 2g TDS IV was proposed.

Methods

To inform the individualised pharmacodynamic outcome likelihood prior to prophylaxis dosing the hollow fibre infection model (HFIM) was applied to simulate thein vivoantibiotic exposures of the CZA-ATM regimen. The HFIM was inoculated with ∼10 x 105bacterial CFU/mL of the XDRE. colistrain and CFUs/mL were measured for a total of 120 hours to determine thein vitroPK/PD killing dynamics.

Results

A 4-log reduction in CFU/mL in the first ten hours of the regimen exposure was observed however the killing dynamics were slow and six eight-hourly infusions were required to reduce bacterial cells to below the limit of quantification. Thus, the HFIM supported the use of the regimen for infection clearance however highlighted the need for several infusions. Standard local practise is to administer prophylaxis antibiotics at induction of OLT however the HFIM provided data to rationalise earlier dosing therefore the patient was dosed at 24 hours prior to their OLT induction. The patient was subsequently discharged 8 days after surgery.

Conclusions

The HFIM provides a dynamic culture solution for informing individualised medicine by testing antibiotic combinations and exposures against the bacterial isolates cultured from the patient’s infection.
Partnering for Progress: Lessons Learned from a Mental Health Assessment for Youth Living with HIV in India through Community-Based Participatory Research
Authors: Sannigrahi Siddhaparna , Seenappa Babu , Laxmikanth Prashant , Reddy Suhas , Filian Kacie , Raj Michael Babu , Ganapathi Lakshmi , Shet Anita
Published: April 2024

YLHIV face diverse mental health challenges necessitating interventions informed by their lived experiences. Failure to do so can perpetuate a self-reinforcing cycle of misaligned and ineffective support, further exacerbating existing vulnerabilities. This study directly addresses this gap by using a community-based participatory research (CBPR) approach to empower Youth Living with HIV (YLHIV) in India to address their mental health challenges. YLHIV actively participated in adapting and implementing a culturally responsive mental health screening program. The study, incorporating CBPR principles at every step aimed to identify practical methods for integrating YLHIV voices in research, and showcase the value of YLHIV participation in co-creating and implementing impactful interventions. Six youth investigators aged 18-24, born with HIV and residing in southern Indian states underwent certification in human subjects’ protection and training in mental health screening and survey administration techniques. They actively shaped the research process by culturally adapting standardized mental health screening tools (PHQ-9, GAD-7) through iterative discussions with experts, drawing on their own perspectives. Following field assessments of the mental health screening tools among their peers, they documented their reflections in surveys and written essays. Youth investigators’ involvement improved the research process by optimizing tools, combating stigma, and facilitating reliable data collection. Beyond data collection, the youth investigators’ participation significantly boosted their own knowledge, self-confidence, and research skills. This study serves as an illustrative model of CBPR in mental health research among YLHIV, highlighting the importance of interactive training, continuous feedback mechanisms, and respectful youth engagement in fostering impactful research that can inform tailored sustainable interventions.
Data rectification to account for delays in reporting disease incidence with an application to forecasting COVID-19 cases
Authors: Abdulhameed Yunus A. , Roberts Samuel , Aguilar Jacob B. , Kercheville James , Gutierrez Juan B.
Published: April 2024

Effective monitoring of infectious disease incidence remains a major challenge to public health. Difficulties in estimating the trends in disease incidence arise mainly from the time delay between case diagnosis and the reporting of cases to public health databases. However, predictive models usually assume that public data sets faithfully reflect the state of disease transmission. In this paper, we study the effect of delayed case reporting by comparing data reported by the Johns Hopkins Coronavirus Resource Center (CRC) with that of the raw clinical data collected from the San Antonio Metro Health District (SAMHD), San Antonio, Texas. An insight on the subtle effect that such reporting errors potentially have on predictive modeling is presented. We use an exponential distribution model for the regression analysis of the reporting delay. The proposed model for correcting reporting delays was applied to our recently developed SEYAR (Susceptible, Exposed, Symptomatic, Asymptomatic, Recovered) dynamical model for COVID-19 transmission dynamics. Employing data from SAMHD, we demonstrate that the forecasting ability of the SEYAR model is substantially improved when the rectified reporting obtained from our proposed model is utilized. The methods and findings demonstrated in this work have ample applicability in the forecasting of infectious disease outbreaks. Our findings suggest that failure to consider reporting delays in surveillance data can significantly alter forecasts.
Deep generative AI models analyzing circulating orphan non-coding RNAs enable accurate detection of early-stage non-small cell lung cancer
Authors: Karimzadeh Mehran , Momen-Roknabadi Amir , Cavazos Taylor B. , Fang Yuqi , Chen Nae-Chyun , Multhaup Michael , Yen Jennifer , Ku Jeremy , Wang Jieyang , Zhao Xuan , Murzynowski Philip , Wang Kathleen , Hanna Rose , Huang Alice , Corti Diana , Nguyen Dang , Lam Ti , Kilinc Seda , Arensdorf Patrick , Chau Kimberly H. , Hartwig Anna , Fish Lisa , Li Helen , Behsaz Babak , Elemento Olivier , Zou James , Hormozdiari Fereydoun , Alipanahi Babak , Goodarzi Hani
Published: April 2024

Liquid biopsies have the potential to revolutionize cancer care through non-invasive early detection of tumors, when the disease can be more effectively managed and cured. Developing a robust liquid biopsy test requires collecting high-dimensional data from a large number of blood samples across heterogeneous groups of patients. We propose that the generative capability of variational auto-encoders enables learning a robust and generalizable signature of blood-based biomarkers that capture true biological signals while removing spurious confounders (e.g., library size, zero-inflation, and batch effects). In this study, we analyzed orphan non-coding RNAs (oncRNAs) from serum samples of 1,050 individuals diagnosed with non-small cell lung cancer (NSCLC) at various stages, as well as sex-, age-, and BMI-matched controls to evaluate the potential use of deep generative models. We demonstrated that our multi-task generative AI model, Orion, surpassed commonly used methods in both overall performance and generalizability to held-out datasets. Orion achieved an overall sensitivity of 92% (95% CI: 85%–97%) at 90% specificity for cancer detection across all stages, outperforming the sensitivity of other methods such as support vector machine (SVM) classifier, ElasticNet, or XGBoost on held-out validation datasets by more than ∼30%.
Discovering mechanisms underlying medical AI prediction of protected attributes
Authors: Gadgil Soham , DeGrave Alex J. , Daneshjou Roxana , Lee Su-In
Published: April 2024

Recent advances in Artificial Intelligence (AI) have started disrupting the healthcare industry, especially medical imaging, and AI devices are increasingly being deployed into clinical practice. Such classifiers have previously demonstrated the ability to discern a range of protected demographic attributes (like race, age, sex) from medical images with unexpectedly high performance, a sensitive task which is difficult even for trained physicians. Focusing on the task of predicting sex from dermoscopic images of skin lesions, we are successfully able to train high-performing classifiers achieving a ROC-AUC score of ∼0.78. We highlight how incorrect use of these demographic shortcuts can have a detrimental effect on the performance of a clinically relevant downstream task like disease diagnosis under a domain shift. Further, we employ various explainable AI (XAI) techniques to identify specific signals which can be leveraged to predict sex. Finally, we introduce a technique to quantify how much a signal contributes to the classification performance. Using this technique and the signals identified, we are able to explain ∼44% of the total performance. This analysis not only underscores the importance of cautious AI application in healthcare but also opens avenues for improving the transparency and reliability of AI-driven diagnostic tools.
Protocol for the development and validation of a Rheumatoid Arthritis PredIction moDel using primary care health records (RAPID)
Authors: Hammond Ben , Baranskaya Aliaksandra , Adderley Nicola , Zemedikun Dawit , d’Elia Alexander , Falahee Marie , Mallen Christian , Insch Elspeth , Chandan Joht Singh , Nirantharakumar Krishnarajah , Snell Kym , Raza Karim
Published: April 2024

Background

Rheumatoid Arthritis (RA) is a chronic rheumatological condition which causes inflammation of both the joint lining and extra-articular sites. It affects around 1% of the UK population and, if not properly treated, can lead joint damage, disability, and significant socioeconomic burden. The risk of long-term damage is reduced if treatment is started in an early disease stage with treatment in the first 3 months being associated with significantly improved clinical outcomes. However, treatment is often delayed due to long referral waits and challenges in identifying early RA in primary care. We plan to use large primary care datasets to develop and validate an RA risk prediction model for use in primary care, with the aim to provide an additional mechanism for early diagnosis and referral for treatment.

Methods

We identified candidate predictors from literature review, expert clinical opinion, and patient research partner input. Using coded primary care data held in Clinical Practice Research Datalink (CPRD) Aurum, we will use a time to event Cox proportional hazards model to develop a 1-year risk prediction model for RA. This will be validated first in CPRD GOLD and then independently in the Secure Anonymised Information Linkage dataset. We will also conduct a sensitivity analysis for the same model at 2–5-year risk, with a secondary outcome of RA and initiation of a disease modifying drug, and with the addition of laboratory test results as candidate predictors.

Discussion

The resulting risk prediction model may provide an additional mechanism to distinguish early RA in primary care and reduce treatment delays through earlier referral.
Consensus Guideline for the Management of Malignant Gastrointestinal Obstruction in Patients with Peritoneal Surface Malignancies
Authors:   PSM Writing Group,   PSM Consortium Group, Turaga Kiran K.
Published: April 2024

Background

Malignant gastrointestinal obstruction (MGIO), a frequent complication of peritoneal surface malignancies (PSM), often portends a poor prognosis. The lack of high-quality evidence on optimal management strategies necessitated a national consensus to address this clinical problem.

Methods

A clinical management pathway was designed through a Delphi consensus process with national experts in peritoneal disease. Two rounds of voting were conducted to assess agreement levels with pathway blocks. Supporting evidence regarding procedural interventions for MGIO underwent evaluation via a rapid literature review.

Results

Of 111 participants responding in the first round, 90 (81%) responded in the second round. Over 90% consensus was achieved in 4/6 and 6/6 pathway blocks during rounds I and II, respectively. Encouraging a multidisciplinary approach, the pathway emphasized early palliative care assessments and iterative goals of care evaluation throughout treatment. Management was delineated based on obstruction acuity, and selection criteria for palliative-intent surgical interventions and stenting were elucidated. Studies demonstrated limited benefits for such interventions in patients with multifocal obstructions, poor performance status, and high-grade and/or high-burden PSMs. In these cases, a recommendation for supportive care or upper GI decompression tube placement was favored. The overall level of evidence was generally low-moderate in existing literature.

Conclusion

Given limited evidence, the consensus-driven pathway provides crucial clinical guidance for practitioners dealing with MGIO in PSM patients. There is a need for high-quality prospective evidence in this domain.