bluuebunny/crossref_metadata_2025_split huggingface dataset:
Emulating a target trial to assess effect modification: an application to obesity in the comparative effectiveness and safety of apixaban versus warfarin in non-valvular atrial fibrillation using electronic health records
Authors: Bin Hammad Turki M , Powell Emma , Baptiste Paris J , Douglas Ian , Wing Kevin 
Published: October 2023

AbstractAnticoagulation therapy is recommended for patients with non-valvular atrial fibrillation (NVAF) and an increased risk of stroke. Although apixaban showed superiority over warfarin in the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) study, little is known about their effects in overweight and obese patients, with concerns that obesity might undermine apixaban’s effects due to the fixed dosing across body mass index (BMI) groups. We emulated a target trial similar to the ARISTOTLE study using Clinical Practice Research Datalink (CPRD) linked data to estimate the 36-month risk ratios (RR) and risk differences of the effects of apixaban compared to warfarin in NVAF patients in a composite of stroke/systemic embolism (SE), major bleeding and all-cause mortality. In 55,826 patients, apixaban did not differ across groups of BMI in stroke/SE with RR (95% CI) of 1.15 (0.81, 1.62) in normal weight, 1.06 (0.70, 1.61) in overweight and 1.23 (0.69, 2.17) in obese patients. In major bleeding, apixaban was not superior to warfarin in the normal weight group (RR (95% CI) 1.10 (0.76, 1.60) but superior in overweight (RR (95% CI) 0.73 (0.57, 0.93) and obese (RR (95 % CI) 0.67 (0.52, 0.87) groups. In NVAF, the effectiveness and safety of apixaban compared to warfarin were consistent across BMI groups.
Virtual Simulated Placements in Healthcare Education: A scoping review
Authors: Samson Juliana , Gilbey Marc , Taylor Natasha , Kneafsey Rosie 
Published: October 2023

AbstractIntroductionA virtual simulated placement (VSP) is a computer-generated version of a practice placement. COVID-19 drove increased adoption of virtual technology in clinical education. Accordingly, the number of VSP publications increased from 2020. This review aims to determine the scope of this literature to inform future research questions.ObjectiveAssess the range and types of evidence related to VSPs across the healthcare professions.Inclusion criteriaStudies that focussed on healthcare students participating in VSPs. Hybrid, augmented reality (AR) and mixed reality (MR) placements were excluded.MethodsFourteen databases were searched, limited to English, and dated from 1stJanuary 2020. Supplementary searches were employed, and an updated search was conducted on 9thJuly 2023. Themes were synthesised using the PAGER framework to highlight patterns, advances, gaps, evidence for practice and research recommendations.ResultsTwenty-eight papers were reviewed. All VSPs were designed in response to pandemic restrictions. Students were primarily from medicine and nursing. Few publications were from developing nations. There was limited stakeholder involvement in the VSP designs and a lack of robust research designs, consistent outcome measures, conceptual underpinnings, and immersive technologies. Despite this, promising trends for student experience, knowledge, communication, and critical thinking skills using VSPs have emerged.ConclusionThis review maps the VSP evidence across medicine, nursing, midwifery and allied health. Before a systematic review is feasible across healthcare, allied health and midwifery research require greater representation. Based on the highlighted gaps, other areas for future research are suggested.WHAT IS ALREADY KNOWN ON THIS TOPICDigital placements in undergraduate nursing and medicine have been studied in one existing systematic review, providing evidence that learning outcomes for knowledge and practice were equivalent to traditional placements.VSPs are a subset of digital placements that are computer-generated. With the increasing trend towards VSPs, an updated scoping review across a wider range of professions was justified.WHAT THIS STUDY ADDSScoping the literature on VSPs across healthcare for undergraduate and postgraduate students, provides a map across professions, specialities, countries, designs, content, and outcomes.HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICYGaps in allied health and midwifery VSP research highlight populations of focus. Future VSPs should consider Interprofessional Education (IPE) and resource sharing with developing countries. The benefits of immersive technologies are yet to be considered, and improvements to VSP design and research methodology are recommended.
Association between Clauss fibrinogen concentration and ROTEM® FIBTEM A5 in women with postpartum haemorrhage: validation of cut-off points
Authors: Gillissen Ada , Golyardi Bahar , van den Akker Thomas , Caram-Deelder Camila , Henriquez Dacia D.C.A. , Bloemenkamp Kitty W.M. , Duvekot Johannes J. , de Maat Moniek P. M. , Eikenboom Jeroen , van der Bom Johanna G. 
Published: October 2023

AbstractObjectivePoint-of-care tests like FIBTEM A5 have been proposed to guide the treatment of patients who might have low fibrinogen concentrations (≤2 g/L). The aim of this study was to describe fibrinogen concentrations according to previously proposed FIBTEM A5 cut-off points in blood samples collected from women during postpartum haemorrhage.Design and settingProspective multicentre cohort studyPopulation511 women sustaining postpartum haemorrhage. A total of 637 blood samples were drawn during haemorrhage.MethodsClauss fibrinogen concentrations and ROTEM® FIBTEM A5 values were studied to assess the diagnostic properties of previously proposed FIBTEM A5 cut-off points for the detection of low fibrinogen concentrations.Main outcome measuresYouden index, sensitivity and specificityResultsOf 511 women with a median total volume of blood loss of 1500 mL (IQR 1200 to 2000) 31 women (6%) developed Clauss fibrinogen concentrations below 2 g/L. Using FIBTEM A 5 cut-off of ≤ 7 mm: 48% of cases with Clauss fibrinogen ≤2 g/L were missed (FIBTEM A5 > 7mm), and of the 28 samples with FIBTEM A5 ≤ 7mm, 12 (43%) samples had Clauss fibrinogen >2 g/L. Using FIBTEM A5 cut-off of ≤12mm: 13% of cases with Clauss fibrinogen ≤2 g/L were missed and of the 145 samples with a FIBTEM A5 ≤12 mm, 118 had Clauss fibrinogen >2 g/L, resulting in false positive selection of 81% of women. Using FIBTEM A5 ≤ 15 mm: 97% (30/31) of the samples with Clauss fibrinogen ≤2 g/L were accurately selected; yet 89% (248/278) of samples that were selected had a fibrinogen concentration of >2 g/L. Based on the Youden index, the optimal cut-off point in our cohort was a FIBTEM A5 of 12mm with sensitivity 87% and specificity 81%.ConclusionsOur findings suggest that if FIBTEM A5 lower than 12 mm would have been used to detect women with fibrinogen concentrations below 2 g/L in order to treat them with fibrinogen concentrate, 87 % of the women with fibrinogen below 2 g/L would correctly have received fibrinogen. However, most women (81%) receiving fibrinogen concentrate would not have needed it, because they had plasma fibrinogen concentrations above 2 g/L.Fundingno funding was obtained to conduct this research
Associations between life course longitudinal growth and hip shapes at ages 60 to 64 years: evidence from the MRC National Survey of Health and Development
Authors: Staines Katherine A. , Saunders Fiona R. , Ireland Alex , Aspden Richard M. , Gregory Jenny S. , Hardy Rebecca , Cooper Rachel 
Published: October 2023

AbstractWe sought to examine associations between height gain across childhood and adolescence with hip shape in individuals aged 60-64 years from the MRC National Survey of Health and Development, a nationally representative British birth cohort. Height was measured at ages 2, 4, 6, 7, 11 and 15 years, and self-reported at age 20 years. Ten modes of variation in hip shape (HM1-10), described by statistical shape models, were previously ascertained from DXA images taken at ages 60-64 years. Associations between (1) height at each age (2) Super-Imposition by Translation And Rotation (SITAR) growth curve variables of height size, tempo and velocity, and (3) height gain during specific periods of childhood and adolescence, and HM1-10 were tested. Faster growth velocity was associated with a wider, flatter femoral head and neck, as described by positive scores for HM6 (regression coefficient 0.014; 95%CI, 0.08–0.019; P<0.001) and HM7 (regression coefficient 0.07; 95%CI, 0.002-0.013; P=0.009), and negative scores for HM10 (regression coefficient –0.006; 95%CI, – 0.011-0.00, P=0.04) and HM2 (males only, regression coefficient –0.017; 95%CI, –0.026 – – 0.09; P<0.001). Similar associations were observed with greater height size and later height tempo. Examination of height gains during specific periods of childhood and adolescence identified those during the adolescence period as being most consistently associated. Our analyses suggest that individual growth patterns, particularly in the adolescent period, are associated with modest variations in hip shape at 60-64 years, which are consistent with features seen in osteoarthritis.
The Audible Contrast Threshold (ACT™) test: a clinical spectro-temporal modulation detection test
Authors: Zaar Johannes , Simonsen Lisbeth Birkelund , Sanchez-Lopez Raul , Laugesen Søren 
Published: October 2023

AbstractOver the last decade, multiple studies have shown that hearing-impaired listeners’ speech-in-noise reception ability, measured with audibility compensation, is closely associated with performance in spectro-temporal modulation (STM) detection tests. STM tests thus have the potential to provide highly relevant beyond-the-audiogram information in the clinic, but the available STM tests have not been optimized for clinical use in terms of test duration, required equipment, and procedural standardization. The present study introduces a quick-and-simple clinically viable STM test, named the Audible Contrast Threshold (ACT) test. First, an experimenter-controlled STM measurement paradigm was developed, in which the patient is presented binaurally with a continuous audibility-corrected noise via headphones and asked to press a pushbutton whenever they hear an STM target sound in the noise. The patient’s threshold is established using a Hughson-Westlake tracking procedure with a three-out-of-five criterion and then refined by post-processing the collected data using a logistic function. Different stimulation paradigms were tested in 28 hearing-impaired participants and compared to data previously measured in the same participants with an established STM test paradigm. The best stimulation paradigm showed excellent test-retest reliability and good agreement with the established laboratory version. Second, the best stimulation paradigm with 1-second noise “waves” (windowed noise) was chosen, further optimized with respect to step size and logistic-function fitting, and tested in a population of 25 young normal-hearing participants using various types of transducers to obtain normative data. Based on these normative data, the “normalized Contrast Level” (in dB nCL) scale was defined, where 0±4 dB nCL corresponds to normal performance and the greater the positive value of dB nCL, the greater the audible contrast loss. Overall, the results of the present study indicate that the ACT test may be considered a reliable, quick-and-simple (and thus clinically viable) test of STM sensitivity. The ACT can be measured directly after the audiogram using the same set up, adding only a few minutes to the process.CITE AS1) In text: Zaar/Simonsen et al. (2023)2) In reference list: Zaar, J./Simonsen L. B., Sanchez-Lopez, R., and Laugesen, S. (2023): “The Audible Contrast Threshold (ACT™) test: a clinical spectro-temporal modulation detection test,” medRxiv.
Partial suppression of BCAA catabolism as a potential therapy for BCKDK deficiency
Authors: Ohl Laura , Kuhs Amanda , Pluck Ryan , Durham Emily , Noji Michael , Philip Nathan D , Arany Zoltan , Ahrens-Nicklas Rebecca C 
Published: October 2023

AbstractBranched chain ketoacid dehydrogenase kinase (BCKDK) deficiency is a recently described inherited neurometabolic disorder of branched chain amino acid (BCAA) metabolism implying increased BCAA catabolism. It has been hypothesized that a severe reduction in systemic BCAA levels underlies the disease pathophysiology, and that BCAA supplementation may ameliorate disease phenotypes. To test this hypothesis, we characterized a recent mouse model of BCKDK deficiency and evaluated the efficacy of enteral BCAA supplementation in this model. Surprisingly, BCAA supplementation exacerbated neurodevelopmental deficits and did not correct biochemical abnormalities despite increasing systemic BCAA levels. These data suggest that aberrant flux through the BCAA catabolic pathway, not just BCAA insufficiency, may contribute to disease pathology. In support of this conclusion, genetic re-regulation of BCAA catabolism, throughDbthaploinsufficiency, partially rescued biochemical and behavioral phenotypes in BCKDK deficient mice. Collectively, these data raise into question assumptions widely made about the pathophysiology of BCKDK insufficiency and suggest a novel approach to develop potential therapies for this disease.
Restriction of Arginine Induces Antibiotic Tolerance inStaphylococcus aureus
Authors: Freiberg Jeffrey A. , Ruiz Valeria M. Reyes , Green Erin R. , Skaar Eric P. 
Published: October 2023

AbstractStaphylococcus aureusis responsible for a substantial number of invasive infections globally each year. These infections are problematic because they are frequently recalcitrant to antibiotic treatment, particularly when they are caused by Methicillin-ResistantStaphylococcus aureus(MRSA). Antibiotic tolerance, the ability for bacteria to persist despite normally lethal doses of antibiotics, is responsible for most antibiotic treatment failure in MRSA infections. To understand how antibiotic tolerance is induced,S. aureusbiofilms exposed to multiple anti-MRSA antibiotics (vancomycin, ceftaroline, delafloxacin, and linezolid) were examined using both quantitative proteomics and transposon sequencing. These screens indicated that arginine metabolism is involved in antibiotic tolerance within a biofilm and led to the hypothesis that depletion of arginine withinS. aureuscommunities can induce antibiotic tolerance. Consistent with this hypothesis, inactivation ofargH,the final gene in the arginine synthesis pathway, induces antibiotic tolerance under conditions in which the parental strain is susceptible to antibiotics. Arginine restriction was found to induce antibiotic tolerance via inhibition of protein synthesis. Finally, althoughS. aureusfitness in a mouse skin infection model is decreased in anargHmutant, its ability to survivein vivoduring antibiotic treatment with vancomycin is enhanced, highlighting the relationship between arginine metabolism and antibiotic tolerance duringS. aureusinfection. Uncovering this link between arginine metabolism and antibiotic tolerance has the potential to open new therapeutic avenues targeting previously recalcitrantS. aureusinfections.Significance StatementMethicillin-ResistantStaphylococcus aureus(MRSA) is a leading bacterial cause of morbidity and mortality worldwide. Despite the availability of numerous antibiotics within vitroefficacy against MRSA, there are still high rates of antibiotic treatment failure inS. aureusinfections, suggesting antibiotic tolerance is common during human infections. Here, we report a direct connection between the metabolism of arginine, an essential amino acid inS. aureus, and tolerance to multiple classes of antibiotics. This represents a key pathway towards broad antibiotic tolerance inS. aureusand therefore an attractive target to help repotentiate current antibiotics and potentially reduce treatment failure.
Bacterial pore-forming toxin pneumolysin drives pathogenicity through shed toxin-loaded host extracellular vesicles
Authors: Parveen Saba , Bhat Chinmayi V , Aziz Shaheena , Arya J , Dutta Asmita , Dutta Somit , Show Sautan , Sharma Kuldeep , Johnson John Bernet , Nongthomba Upendra , Banerjee Anirban , Subramanian Karthik 
Published: October 2023

AbstractStreptococcus pneumoniaeis a global priority respiratory pathogen that kills over a million people annually and produces the pore-forming cytotoxin, pneumolysin (PLY). Host cells expel membrane assembled toxin by shedding microvesicles, but the composition and pathophysiological sequelae of the toxin-induced host extracellular vesicles (EVs) are unknown. Here, we found that EVs shed from PLY-challenged monocytes (PLY-EVs) harbor membrane-bound toxin that induced cytotoxicity upon fusion with recipient cells. EVs from human monocytes challenged with recombinant PLY as well as PLY-expressing pneumococcal strains, but not the isogenic PLY mutant, primed dendritic cells and evoked higher pro-inflammatory cytokines upon infection. Proteomic analysis revealed that PLY-EVs are enriched for key antimicrobial and inflammatory host proteins such as IFI16, NLRC4, PTX3 and MMP9.In vivo, zebrafish and mice administered with PLY-EVs showed mortality, pericardial edema, tissue damage and inflammation. Our findings show that host EVs bearing the cytotoxin PLY constitute a previously unexplored mechanism of pneumococcal pathogenesis.
Receptor cavity-based screening reveals potential allosteric modulators of gonadotropin receptors in carp (Cyprinus carpio)
Authors: Atre Ishwar , Hollander-Cohen Lian , Lankry Hodaya , Levavi-Sivan Berta 
Published: October 2023

AbstractThe gonadotropins follicle stimulating hormone (FSH) and luteinizing hormone (LH) are key regulators of sexual development and the reproductive cycle in vertebrates. Unlike most G protein-coupled receptors (GPCR), the FSHR and LHR have large extracellular domains containing multiple leucine-rich repeats, which leads to an elaborate mechanism of receptor activation via orthosteric sites that is difficult to manipulate synthetically. To bypass the orthosteric mechanism, in this study using carp as a model organism we identified allosteric sites capable of receptor activation on the transmembrane domain, which are spatially separated from the orthosteric sites. We have further generated pharmacophore hypothesis based on the structural motifs and exposed residues of these cavities. Using available online small compound libraries consisting of >70000 small molecules, we have thereon used receptor cavity-based hypothesis and other screening stages to identify potential modulators of the allosteric binding site on the carp FSHR and LHRin-silico. We then examined byin vitrotransactivation assay the effect of four candidate compounds on FSHR and LHR, as compared to the activity of native ligands. Our results reveal both specific and dual effective allosteric modulators for FSHR and LHR, demonstrating the potential of our approach for efficient pharmacophore-based screening.
Evaluation of purine-nucleoside degrading ability andin vivouric acid lowering ofStreptococcus thermophilus(ID-PDP3), a novel antiuricemia strain
Authors: Kim Dayoung , Moon Jin Seok , Kim Ji Eun , Jang Ye-Ji , Choi Han Sol , Oh Ikhoon 
Published: October 2023

AbstractThis study evaluated 15 lactic acid bacteria in terms of their ability to degrade inosine and hypoxanthine—which are the intermediates in purine metabolism—for the management of hyperuricemia and gout. After a preliminary screening based on HPLC, CR1 (Lactiplantibacillus plantarum) and GZ1 (Lactiplantibacillus pentosus) showed the highest nucleoside degrading rates and were therefore selected for further characterization. IDCC 2201 (S. thermophilus), which possessed thehptgene encoding hypoxanthine-guanine phosphoribosyltransferase (HGPRT) and exhibited purine degradation, was also selected. These three selected strains were examined in terms of the effect of probiotics on lowering serum uric acid in a rat model of potassium oxonate (PO)-induced hyperuricemia. Among them, the level of serum uric acid was most reduced by IDCC 2201 (p < 0.05). Further, analysis of the microbiome showed that administration of IDCC 2201 recovered the ratio of Bacteroidetes/Firmicutes in the intestinal microbial composition unbalanced by hyperuricemia and showed a difference in the intestinal microbial composition compared to the group administered with allopurinol. Moreover, intestinal short-chain fatty acids (SCFAs) were significantly increased. Ultimately, the findings show that IDCC 2201 lowers uric acid levels by degrading purine-nucleosides and restores intestinal flora and SCFAs, ultimately suggesting that IDCC 2201 is a promising candidate for use as an adjuvant treatment in patients with hyperuricemia.
Serum-deprivation response of ARPE-19 cells; expression patterns relevant to age-related macular degeneration
Authors: Peterson Katherine M. , Mishra Sanghamitra , Asaki Esther , Powell John I. , He Yiwen , Berger Alan E. , Rajapakse Dinusha , Wistow Graeme 
Published: October 2023

AbstractARPE-19 cells are derived from adult human retinal pigment epithelium (RPE). The response of these cells to the stress of serum deprivation mimics some important processes relevant to age-related macular degeneration (AMD). Here we extend the characterization of this response using RNASeq and EGSEA gene set analysis of ARPE-19 cells over nine days of serum deprivation. This experiment confirmed the up-regulation of cholesterol and lipid-associated pathways that increase cholesterol levels in these cells. The gene expression analysis also identified other pathways relevant to AMD progression. There were significant changes in extracellular matrix gene expression, notably a switch from expression of collagen IV, a key component of Bruch’s membrane (part of the blood-retina barrier), to expression of a fibrosis-like collagen type I matrix. Changes in the expression profile of the extracellular matrix led to the discovery that amelotin is induced in AMD and is associated with the development of the calcium deposits seen in late-stage geographic atrophy. The transcriptional profiles of other pathways, including inflammation, complement, and coagulation, were also modified, consistent with immune response patterns seen in AMD. As previously noted, the cells resist apoptosis and autophagy but instead initiate a gene expression pattern characteristic of senescence, consistent with the maintenance of barrier function even as other aspects of RPE function are compromised. Other differentially regulated genes were identified that open new avenues for investigation. Our results suggest that ARPE-19 cells maintain significant stress responses characteristic of native RPE that are informative for AMD. As such, they provide a convenient system for discovery and for testing potential therapeutic interventions.