bluuebunny/crossref_metadata_2025_split huggingface dataset:
Common variation in a long non-coding RNA gene modulates variation of circulating TGF-β2 levels in metastatic colorectal cancer patients (Alliance)
Authors: Quintanilha Julia C.F. , Sibley Alexander B. , Liu Yingmiao , Niedzwiecki Donna , Halabi Susan , Rogers Layne , O’Neil Bert , Kindler Hedy , Kelly William , Venook Alan , McLeod Howard L. , Ratain Mark J. , Nixon Andrew B. , Innocenti Federico , Owzar Kouros 
Published: December 2023

AbstractBackgroundHerein, we report results from a genome-wide study conducted to identify protein quantitative trait loci (pQTL) for circulating angiogenic and inflammatory protein markers in patients with metastatic colorectal cancer (mCRC).The study was conducted using genotype, protein marker, and baseline clinical and demographic data from CALGB/SWOG 80405 (Alliance), a randomized phase III study designed to assess outcomes of adding VEGF or EGFR inhibitors to systemic chemotherapy in mCRC patients. Germline DNA derived from blood was genotyped on whole-genome array platforms. The abundance of protein markers was quantified using a multiplex enzyme-linked immunosorbent assay from plasma derived from peripheral venous blood collected at baseline. A robust rank-based method was used to assess the statistical significance of each variant and protein pair against a strict genome-wide level. A given pQTL was tested for validation in two external datasets of prostate (CALGB 90401) and pancreatic cancer (CALGB 80303) patients. Bioinformatics analyses were conducted to further establish biological bases for these findings.ResultsThe final analysis was carried out based on data from 540,021 common typed genetic variants and 23 protein markers from 869 genetically estimated European patients with mCRC. Correcting for multiple testing, the analysis discovered a novelcis-pQTL inLINC02869, a long non-coding RNA gene, for circulating TGF-β2 levels (rs11118119; AAF = 0.11;P-value < 1.4e-14). This finding was validated in a cohort of 538 prostate cancer patients from CALGB 90401 (AAF = 0.10,P-value < 3.3e-25). The analysis also validated acis-pQTL we had previously reported for VEGF-A in advanced pancreatic cancer, and additionally identifiedtrans-pQTLs for VEGF-R3, andcis-pQTLs for CD73.ConclusionsThis study has provided evidence of a novelcisgermline genetic variant that regulates circulating TGF-β2 levels in plasma of patients with advanced mCRC and prostate cancer. Moreover, the validation of previously identified pQTLs for VEGF-A, CD73, and VEGF-R3, potentiates the validity of these associations.
Associations of infections and vaccines with Alzheimer’s disease point to a major role of compromised immunity rather than specific pathogen in AD
Authors: Ukraintseva Svetlana , Yashkin Arseniy P. , Akushevich Igor , Arbeev Konstantin , Duan Hongzhe , Gorbunova Galina , Stallard Eric , Yashin Anatoliy 
Published: December 2023

ABSTRACTINTRODUCTIONDiverse pathogens (viral, bacterial, fungal) have been linked to Alzheimer’s disease (AD) indicating a possibility that the culprit may be compromised immunity rather than particular microbe. If true, then vaccines with broad beneficial effects on immunity might be protective against AD.METHODSWe estimated associations of common adult infections, including herpes simplex, zoster (shingles), pneumonia, and recurrent mycoses, as well as vaccinations against shingles and pneumonia, with the risk of AD in a pseudorandomized sample of the Health and Retirement Study.RESULTSShingles, pneumonia, and mycoses diagnosed between ages 65-75, were all associated with higher risk of AD later in life, by 16%-42%. Pneumococcal and shingles vaccines received between ages 65-75 both lowered the risk of AD, by 15%-21%.DISCUSSIONOur results support the idea that the connection between AD and infections involves compromised immunity rather than specific pathogen. We discuss mechanisms by which the declining immune surveillance may promote AD, and the role of biological aging in it. Repurposing of vaccines with broad beneficial effects on immunity could be a reasonable approach to AD prevention. Pneumococcal and zoster vaccines are promising candidates for such repurposing.
Acoustic enrichment of heterogenous circulating tumor cells and clusters from patients with metastatic prostate cancer
Authors: Magnusson Cecilia , Augustsson Per , Undvall Anand Eva , Lenshof Andreas , Josefsson Andreas , Welén Karin , Bjartell Anders , Ceder Yvonne , Lilja Hans , Laurell Thomas 
Published: December 2023

BackgroundThere are important unmet clinical needs to develop cell enrichment technologies to enable unbiased label-free isolation of both single cell and clusters of circulating tumor cells (CTCs) manifesting heterogeneous lineage specificity. Here, we report a pilot study based on microfluidic acoustophoresis enrichment of CTCs using the CellSearch CTC assay as a reference modality.MethodsAcoustophoresis uses an ultrasonic standing wave field to separate cells based on biomechanical properties (size, density, and compressibility) resulting in inherently label-free and epitope-independent cell enrichment. Following red blood cell lysis and paraformaldehyde fixation, 6 mL of whole blood from 12 patients with metastatic prostate cancer and 20 healthy controls were processed with acoustophoresis and subsequent image cytometry.ResultsAcoustophoresis enabled enrichment and characterization of phenotypic CTCs (EpCAM+, Cytokeratin+, DAPI+, CD45-/CD66b-) in all patients with metastatic prostate cancer and detected CTC-clusters composed of only CTCs or heterogenous aggregates of CTCs clustered with various types of white blood cells in 9 out of 12 patients. By contrast, CellSearch did not detect any CTC-clusters, but detected comparable numbers of phenotypic CTCs as acoustophoresis, with trends of finding higher number of CTCs using acoustophoresis.ConclusionOur preliminary data indicate that acoustophoresis provides excellent possibilities to detect and characterize CTC-clusters as a putative marker of metastatic disease and outcomes. Moreover, acoustophoresis enables sensitive label-free enrichment of cells with epithelial phenotype in blood and offers opportunities to detect and characterize CTCs undergoing epithelial-to-mesenchymal transitioning and lineage plasticity.
Clinical coding of long COVID in primary care 2020-2023 in a cohort of 19 million adults: an OpenSAFELY analysis
Authors: Henderson Alasdair D , Butler-Cole Ben FC , Tazare John , Tomlinson Laurie A , Marks Michael , Jit Mark , Briggs Andrew , Lin Liang-Yu , Carlile Oliver , Bates Chris , Parry John , Bacon Sebastian CJ , Dillingham Iain , Dennison William A , Costello Ruth E , Wei Yinghui , Walker Alex J , Hulme William , Goldacre Ben , Mehrkar Amir , MacKenna Brian ,   The OpenSAFELY Collaborative, Herrett Emily , Eggo Rosalind M 
Published: December 2023

AbstractBackgroundLong COVID is the patient-coined term for the persistent symptoms of COVID-19 illness for weeks, months or years following the acute infection. There is a large burden of long COVID globally from self-reported data, but the epidemiology, causes and treatments remain poorly understood. Primary care is used to help identify and treat patients with long COVID and therefore Electronic Health Records (EHRs) of past COVID-19 patients could be used to help fill these knowledge gaps. We aimed to describe those with long COVID in primary care records in England.MethodsWith the approval of NHS England we used routine clinical data from over 19 million adults in England linked to SARS-COV-2 test result, hospitalisation and vaccination data to describe trends in the recording of 16 clinical codes related to long COVID between November 2020 and January 2023. We calculated rates per 100,000 person-years and plotted how these changed over time. We compared crude and minimally adjusted rates of recorded long COVID in patient records between different key demographic and vaccination characteristics using negative binomial models.FindingsWe identified a total of 55,465 people recorded to have long COVID over the study period, with incidence of new long COVID records increasing steadily over 2021, and declining over 2022. The overall rate per 100,000 person-years was 177.5 cases in women (95% CI: 175.5-179) and 100.5 men (99.5-102). In terms of vaccination against COVID-19, the lowest rates were observed in those with 3+ vaccine doses (103.5 [95% CI: 101.5-105]). Finally, the majority of those with a long COVID record did not have a recorded positive SARS-COV-2 test 12 weeks before the long COVID record.InterpretationEHR recorded long COVID remains very low compared and incident records of long COVID declined over 2022. We found the lowest rates of recorded long COVID in people with 3 or more vaccine doses. We summarised several sources of possible bias for researchers using EHRs to study long COVID.
Hospital segregation, critical care strain, and inpatient mortality during the COVID-19 pandemic in New York City
Authors: Zhilkova Anna , Alsabahi Laila , Olson Donald , Maru Duncan , Tsao Tsu-Yu , Morse Michelle 
Published: December 2023

AbstractBackgroundHospital segregation by race, ethnicity, and health insurance coverage is prevalent, with some hospitals providing a disproportionate share of undercompensated care. We assessed whether New York City (NYC) hospitals serving a higher proportion of Medicaid and uninsured patients pre-pandemic experienced greater critical care strain during the first wave of the COVID-19 pandemic, and whether this greater strain was associated with higher rates of in-hospital mortality.MethodsIn a retrospective analysis of all-payer NYC hospital discharge data, we examined changes in admissions, stratified by use of intensive care unit (ICU), from the baseline period in early 2020 to the first COVID-19 wave across hospital quartiles (265,329 admissions), and crude and age-adjusted inpatient mortality rates, also stratified by ICU use, in the first COVID wave across hospital quartiles (23,032 inpatient deaths), based on the proportion of Medicaid or uninsured admissions from 2017-2019 (quartile 1 lowest to 4 highest). Logistic regressions were used to assess the cross-sectional association between ICU strain, defined as ICU volume in excess of the baseline average, and patient-level mortality.ResultsICU admissions in the first COVID-19 wave were 84%, 97%, 108%, and 123% of the baseline levels by hospital quartile 1-4, respectively. The risk-adjusted mortality rates for ICU admissions were36.4 (CI=34.7,38.2), 43.6 (CI=41.5,45.8), 45.9 (CI=43.8,48.1), and 45.7 (CI=43.6,48.0) per 100 admissions, and those for non-ICU admissions were 8.6 (CI=8.3,9.0), 10.9 (CI=10.6,11.3), 12.6 (CI=12.1,13.0), and 12.1 (CI=11.6,12.7) per 100 admissions by hospital quartile 1-4, respectively. Compared with the reference group of 100% or less of the baseline weekly average, ICU admissions on a day for which the ICU volume was 101-150%, 151-200%, and > 200% of the baseline weekly average had odds ratios of 1.17 (95% CI=1.10, 1.26), 2.63 (95% CI=2.31, 3.00), and 3.26 (95% CI=2.82, 3.78) for inpatient mortality, and non-ICU admissions on a day for which the ICU volume was 101-150%, 151-200%, and > 200% of the baseline weekly average had odds ratios of 1.28 (95% CI=1.22, 1.34), 2.60 (95% CI=2.40, 2.82), and 3.44 (95% CI=3.11, 3.63) for inpatient mortality.ConclusionsOur findings are consistent with hospital segregation as a potential driver of COVID-related mortality inequities and highlight the need to desegregate health care to address structural racism, advance health equity, and improve pandemic resiliency.
The potential economic impact of the updated COVID-19 mRNA fall 2023 vaccines in Japan
Authors: Fust K , Joshi K , Beck E , Maschio M , Kohli M , Lee A , Hagiwara Y , van de Velde N , Igarashi A 
Published: December 2023

AbstractThis analysis estimates the economic and clinical impact of a Moderna updated COVID-19 mRNA Fall 2023 vaccine for adults ≥18 years in Japan. A previously developed Susceptible-Exposed-Infected-Recovered (SEIR) model with a 1-year analytic time horizon (September 2023-August 2024) and consequences decision tree were used to estimate symptomatic infections, COVID-19–related hospitalizations, deaths, quality-adjusted life-years (QALYs), costs, and incremental cost-effectiveness ratio (ICER) for a Moderna updated Fall 2023 vaccine versus no additional vaccination, and versus a Pfizer-BioNTech updated mRNA Fall 2023 vaccine. The Moderna vaccine is predicted to prevent 7.2 million symptomatic infections, 272,100 hospitalizations and 25,600 COVID-19 related deaths versus no vaccine. In the base case (healthcare perspective), the ICER was ¥1,300,000/QALY gained ($9,400 USD/QALY gained). Sensitivity analyses suggest results are most affected by COVID-19 incidence, initial vaccine effectiveness (VE), and VE waning against infection. Assuming the relative VE between both bivalent vaccines apply to updated Fall 2023 vaccines, the base case suggests the Moderna version will prevent an additional 1,100,000 symptomatic infections, 27,100 hospitalizations, and 2,600 deaths compared to the Pfizer-BioNTech vaccine. The updated Moderna vaccine is expected to be highly cost-effective at a ¥5 million willingness-to-pay threshold across a wide range of scenarios.
Perioperative Pressure Injury: Bibliometric Analysis
Authors: Handayani Luh Titi , Pandin Moses Glorino Rumambo , Nursalam  
Published: December 2023

BackgroundThe occurrence of pressure injuries in the perioperative period presents a significant clinical hurdle for surgical patients. Surgery is recognized as a risk factor contributing to the onset of pressure injuries, which can manifest shortly after the operation, within a few hours, or up to 72 hours post-surgery. Bibliometric analysis has been carried out to assess publication patterns, rank research studies, and uncover emerging themes in perioperative pressure injury research.MethodData covering the period from 2015 to 2023 were extracted through the indexing metadata of Scopus and CINAHL using the keywords “pressure injury” OR “pressure ulcer” AND “perioperative.” Bibliometric parameters were extracted, and VOSviewer was employed to obtain bibliometric network and overlay visualization results.ResultThe mapping and clustering results from the VOSviewer network and overlay visualization identified various factors, including risk factors, postoperative complications, Electronic Health Record (EHR), prediction models, perioperative leadership, perioperative hypotension, responsibility, skin lesions, positioning, infection, risk assessment, attitude, peripheral nerve injury, and interface injury.ConclusionThe outcomes of mapping, clustering, ranking, and citation analysis of pressure injury in perioperative patients indicate that patient safety is the primary focus. From this main issue, indicators can be developed and transformed into variables that need analysis related to risk assessment, knowledge and attitude, policies, and referrals. The underlying theory in perioperative patient care is the middle-range theory by Myra Estrine Levine, with her esoteric nursing model, Conservation Model of Nursing.
Sexual Dimorphism in Systemic Inflammatory Responses to Femur Fracture in Mice Infected with SARS-CoV-2-Like Virus
Authors: Patrick Matthew , Foster Austin , Aneja Arun , Annamalai Ramkumar T. 
Published: December 2023

ABSTRACTPatients with femur fractures who are concurrently infected with COVID-19 face a threefold increase in mortality, likely due to a compounded inflammatory response. Furthermore, sex-specific differences in immune responses to COVID-19 have been documented, implicating gender as a potential modulator of disease severity in these comorbid conditions. Understanding the inflammatory interplay underlying this association is critical for the development of effective, targeted therapies to mitigate mortality.In this study, we investigated the systemic, sex-specific inflammatory response in mice that sustain a fracture while infected with a murine coronavirus (MHV), which belongs to the same genus as SARS-CoV-2. Our findings reveal that the combined inflammatory incidents of MHV infection and fracture disrupt the systemic immune response in both female and male mice, leading to immune dysregulation characterized by altered cell recruitment and disruption of the normal inflammatory cascade. Notably, the study identifies sex-specific differences in immune response, with female subjects exhibiting significantly elevated levels of inflammatory cytokines, including IL-18 and TNFα, while males exhibit a diminished response. These sexually dimorphic differences are also reflected in the systemic immune cell populations, suggesting that the quantity of immune factors released may contribute to the observed discrepancies. Notably, these differences were minimal or moderate in animals that either got an MHV infection or fracture alone.Our findings indicate that the overproduction of proinflammatory cytokines, such as IFNγ, IL-18, and TNFα—reminiscent of cytokine storm syndrome—drives immune dysregulation, exacerbating outcomes in patients with these comorbidities. The observed sex-specific responses may be influenced by factors such as sex hormones, including estrogen, highlighting the importance of considering gender in therapeutic approaches. These insights provide a foundation for the development of tailored interventions to improve outcomes for COVID-19 patients with musculoskeletal trauma, including fractures.
Membrane specificity of the human cholesterol transfer protein STARD4
Authors: Talandashti Reza , Ek Larissa van , Gehin Charlotte , Xue Dandan , Moqadam Mahmoud , Gavin Anne-Claude , Reuter Nathalie 
Published: December 2023

AbstractSTARD4 regulates cholesterol homeostasis by transferring cholesterol between plasma membrane and endoplasmic reticulum. The STARD4 structure features a helix-grip fold surrounding a large hydrophobic cavity holding the sterol. Its access is controlled by a gate formed by two flexible loops - Ω1 and Ω4- and the C-terminal α-helix. Besides this, little is known about the mechanisms by which STARD4 binds to membranes and extract/releases cholesterol. All available structures of STARD4 are without a bound sterol and display the same closed conformation of the gate. The cholesterol transfer activity of the mouse STARD4 is enhanced in the presence of anionic lipids, and in particular of phosphatidylinositol biphosphates (PIP2) for which two binding sites were proposed on the mouse STARD4 surface. Yet only one of these sites is conserved in human STARD4. We here report the results of a liposome microarray-based assay and microseconds-long molecular dynamics simulations of apo-and holo forms of human STARD4 with complex lipid bilayers mimicking the composition of the donor and acceptor membranes. We show that the binding of apo form of human STARD4 is sensitive to the presence of PIP2 through two specific binding sites, one of which was not identified on mouse STARD4. We report two novel conformations of the gate in holo-STARD4: a yet-unobserved close conformation and an open conformation of Ω4 shedding light on the opening/closure mechanism needed for cholesterol uptake/release. Overall, the modulation of human STARD4 membrane-binding by lipid composition, and by the presence of the cargo supports the capacity of human STARD4 to achieve directed transfer between specific organelle membranes.
Comparison of the mechanism of antimicrobial action of the gold(I) compound auranofin in Gram-positive and Gram-negative bacteria
Authors: Quadros Barsé Laísa , Ulfig Agnes , Varatnitskaya Marharyta , Vázquez-Hernández Melissa , Yoo Jihyun , Imann Astrid M. , Lupilov Natalie , Fischer Marina , Becker Katja , Bandow Julia E. , Leichert Lars I. 
Published: December 2023

ABSTRACTThe antirheumatic gold(I) compound auranofin has been suggested to exhibit bactericidal activity by disrupting the thiol homeostasis through direct inhibition of bacterial thioredoxin reductase (TrxB). While highly effective at killing Gram-positive bacteria, it lacks significant activity against Gram-negative species for reasons that largely remain unclear. Here, we aimed to elucidate the molecular mechanisms underlying the low susceptibility of the Gram-negative model organismEscherichia colito auranofin when compared to the Gram-positive model organismBacillus subtilis. A change in the proteome ofE. coliexposed to auranofin suggested that the effect of this gold compound is a combination of inactivation of thiol-containing enzymes, upregulation of proteins involved in basal metabolism, and the consequent induction of systemic oxidative stress. Susceptibility tests inE. colimutants lacking the proteins upregulated upon auranofin treatment suggested that none of them are directly involved inE. coli’s high tolerance to auranofin. To elucidate factors that could make Gram-negative bacteria less susceptible to auranofin, we testedE. colicells lacking the efflux pump component TolC. These cells were more sensitive to auranofin treatment than the wild type, but not to an extent that would fully explain the observed difference in susceptibility of Gram-positive and Gram-negative organisms. We thus tested ifE. coli’s thioredoxin reductase (TrxB) is inherently less sensitive to auranofin than TrxB fromB. subtilis, which was not the case.E. colicells lacking components of the thioredoxin-system were also only marginally more susceptible to auranofin. However,E. colistrains lacking the low molecular weight thiol glutathione, but not glutathione reductase, showed a high susceptibility to auranofin. Bacterial cells expressing the genetically encoded redox probe roGFP2 allowed us to observe the oxidation of cellular protein thiolsin situ. In line with their susceptibility, the kinetics of probe oxidation and the degree of oxidation promoted by auranofin is significantly higher in Gram-positive bacteria when compared to Gram-negative bacteria. Based on our findings, we hypothesize that auranofin leads to a global disturbance in the cellular thiol redox homeostasis in bacteria, but Gram-negative bacteria are inherently more resistant due to the presence of drug export systems and high cellular concentrations of glutathione.
Editing of highly homologous gamma-globin genes by nickase deficient Base Editor mitigates large intergenic deletions
Authors: George Anila , Ravi Nithin Sam , Vaishnavi B , Marepally Srujan , Thangavel Saravanbhavan , Velayudhan Shaji R , Srivastava Alok , Mohankumar Kumarasamypet Murugesan 
Published: December 2023

AbstractBase editing in gamma-globin promoter is a promising approach for reactivation of fetal-hemoglobin. Recent studies have shown that base editing could result in genotoxic events at the gamma globin locus including 4.9 kb large deletion of intervening region due to nicking in the paralogousHBG1 andHBG2 genes. Although the deletion frequency is less than what is observed with Cas9, it could diminish the therapeutic potential. We sought to evaluate if large deletion could be overcome while maintaining the editing efficiency by replacing the nCas9 of ABE8e with a catalytically inactive deadCas9 (dCas9). Using 3 therapeutically relevant gRNAs targeting the gamma globin promoter, we performed a comprehensive evaluation of the editing outcome and frequency of large deletion using dCas9, nCas9, dCas9-ABE8e and nCas9-ABE8e. Our findings indicate that while nicking in itself induced large deletions, the frequency reduced upon efficient base editing. Notably, there was no appreciable deletion with the use of dCas9-ABE8e making it a safer approach, in terms of genome integrity, for therapeutic genome editing in the gamma-globin locus. Further, we also demonstrate that dCas9 ABE8e can edit efficiently in primary human CD34+ hematopoietic stem and progenitor cells (HSPCs) to achieve therapeutic benefits.