bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mechanism of 2′-fucosyllactose degradation by human-associated
Akkermansia
Authors: Padilla Loren , Fricker Ashwana D. , Luna Estefani , Choudhury Biswa , Hughes Elizabeth R. , Panzetta Maria E. , Valdivia Raphael H. , Flores Gilberto E. 
Published: February 2024

ABSTRACT

Among the first microorganisms to colonize the human gut of breastfed infants are bacteria capable of fermenting human milk oligosaccharides (HMOs). One of the most abundant HMOs, 2′-fucosyllactose (2′-FL), may specifically drive bacterial colonization of the intestine. Recently, differential growth has been observed across multiple species of
Akkermansia
on various HMOs including 2′-FL. In culture, we found growth of two species,
A. muciniphila
Muc
T
and
A. biwaensis
CSUN-19,on HMOs corresponded to a decrease in the levels of 2′-FL and an increase in lactose, indicating that the first step in 2′-FL catabolism is the cleavage of fucose. Using phylogenetic analysis and transcriptional profiling, we found that the number and expression of fucosidase genes from two glycoside hydrolase (GH) families, GH29 and GH95, vary between these two species. During the mid-log phase of growth, the expression of several GH29 genes was increased by 2′-FL in both species, whereas the GH95 genes were induced only in
A. muciniphila
. We further show that one putative fucosidase and a β-galactosidase from
A. biwaensis
are involved in the breakdown of 2′-FL. Our findings indicate that the plasticity of GHs of human-associated
Akkermansia
sp. enables access to additional growth substrates present in HMOs, including 2′-FL. Our work highlights the potential for
Akkermansia
to influence the development of the gut microbiota early in life and expands the known metabolic capabilities of this important human symbiont.

IMPORTANCE

Akkermansia
are mucin-degrading specialists widely distributed in the human population.
Akkermansia biwaensis
has recently been observed to have enhanced growth relative to other human-associated
Akkermansia
on multiple human milk oligosaccharides (HMOs). However, the mechanisms for enhanced growth are not understood. Here, we characterized the phylogenetic diversity and function of select genes involved in the growth of
A. biwaensis
on 2′-fucosyllactose (2′-FL), a dominant HMO. Specifically, we demonstrate that two genes in a genomic locus, a putative β-galactosidase and α-fucosidase, are likely responsible for the enhanced growth on 2′-FL. The functional characterization of
A. biwaensis
growth on 2′-FL delineates the significance of a single genomic locus that may facilitate enhanced colonization and functional activity of select
Akkermansia
early in life.
Swine influenza A virus isolates containing the pandemic H1N1 origin matrix gene elicit greater disease in the murine model
Authors: Curran Shelly J. , Griffin Emily F. , Ferreri Lucas M. , Kyriakis Constantinos S. , Howerth Elizabeth W. , Perez Daniel R. , Tompkins S. Mark 
Published: February 2024

ABSTRACT

Since the 1990s, endemic North American swine influenza A viruses (swFLUAVs) contained an internal gene segment constellation, the triple reassortment internal gene (TRIG) cassette. In 2009, the H1N1 pandemic (pdmH1N1) virus spilled back into swine but did not become endemic. However, the pdmH1N1 contributed the matrix gene (pdmM) to the swFLUAVs circulating in the pig population, which replaced the classical swine matrix gene (swM) found in the TRIG cassette, suggesting the pdmM has a fitness benefit. Others have shown that swFLUAVs containing the pdmM have greater transmission efficiency compared to viruses containing the swM gene segment. We hypothesized that the matrix (M) gene could also affect disease and utilized two infection models, resistant BALB/c and susceptible DBA/2 mice, to assess pathogenicity. We infected BALB/c and DBA/2 mice with H1 and H3 swFLUAVs containing the swM or pdmM and measured lung virus titers, morbidity, mortality, and lung histopathology. H1 influenza strains containing the pdmM gene caused greater morbidity and mortality in resistant and susceptible murine strains, while H3 swFLUAVs caused no clinical disease. However, both H1 and H3 swFLUAVs containing the pdmM replicated to higher viral titers in the lungs and pdmM containing H1 viruses induced greater histological changes compared to swM H1 viruses. While the surface glycoproteins and other gene segments may contribute to swFLUAV pathogenicity in mice, these data suggest that the origin of the matrix gene also contributes to pathogenicity of swFLUAV in mice, although we must be cautious in translating these conclusions to their natural host, swine.

IMPORTANCE
The 2009 pandemic H1N1 virus rapidly spilled back into North American swine, reassorting with the already genetically diverse swFLUAVs. Notably, the M gene segment quickly replaced the classical M gene segment, suggesting a fitness benefit. Here, using two murine models of infection, we demonstrate that swFLUAV isolates containing the pandemic H1N1 origin M gene caused increased disease compared to isolates containing the classical swine M gene. These results suggest that, in addition to other influenza virus gene segments, the swFLUAV M gene segment contributes to pathogenesis in mammals.
Random expert sampling for deep learning segmentation of acute ischemic stroke on non-contrast CT
Authors: Ostmeier Sophie , Axelrod Brian , Liu Yongkai , Yu Yannan , Jiang Bin , Yuen Nicole , Pulli Benjamin , Verhaaren Benjamin F J , Kaka Hussam , Wintermark Max , Michel Patrik , Mahammedi Abdelkader , Federau Christian , Lansberg Maarten G , Albers Gregory W , Moseley Michael E , Zaharchuk Gregory , Heit Jeremy J 
Published: February 2024

Background
Outlining acutely infarcted tissue on non-contrast CT is a challenging task for which human inter-reader agreement is limited. We explored two different methods for training a supervised deep learning algorithm: one that used a segmentation defined by majority vote among experts and another that trained randomly on separate individual expert segmentations.

Methods
The data set consisted of 260 non-contrast CT studies in 233 patients with acute ischemic stroke recruited from the multicenter DEFUSE 3 (Endovascular Therapy Following Imaging Evaluation for Ischemic Stroke 3) trial. Additional external validation was performed using 33 patients with matched stroke onset times from the University Hospital Lausanne. A benchmark U-Net was trained on the reference annotations of three experienced neuroradiologists to segment ischemic brain tissue using majority vote and random expert sampling training schemes. The median of volume, overlap, and distance segmentation metrics were determined for agreement in lesion segmentations between (1) three experts, (2) the majority model and each expert, and (3) the random model and each expert. The two sided Wilcoxon signed rank test was used to compare performances (1) to 2) and (1) to (3). We further compared volumes with the 24 hour follow-up diffusion weighted imaging (DWI, final infarct core) and correlations with clinical outcome (modified Rankin Scale (mRS) at 90 days) with the Spearman method.

Results
The random model outperformed the inter-expert agreement ((1) to (2)) and the majority model ((1) to (3)) (dice 0.51±0.04 vs 0.36±0.05 (P<0.0001) vs 0.45±0.05 (P<0.0001)). The random model predicted volume correlated with clinical outcome (0.19, P<0.05), whereas the median expert volume and majority model volume did not. There was no significant difference when comparing the volume correlations between random model, median expert volume, and majority model to 24 hour follow-up DWI volume (P>0.05, n=51).

Conclusion
The random model for ischemic injury delineation on non-contrast CT surpassed the inter-expert agreement ((1) to (2)) and the performance of the majority model ((1) to (3)). We showed that the random model volumetric measures of the model were consistent with 24 hour follow-up DWI.
Patients on vitamin K treatment: is switching to direct-acting oral anticoagulation cost-effective? A target trial on a prospective cohort
Authors: Aebersold Helena , Foster-Witassek Fabienne , Aeschbacher Stefanie , Beer Juerg H , Blozik Eva , Blum Manuel , Bonati Leo , Conte Giulio , Coslovsky Michael , De Perna Maria Luisa , Di Valentino Marcello , Felder Stefan , Huber Carola A , Moschovitis Giorgio , Mueller Andreas , Paladini Rebecca E , Reichlin Tobias , Rodondi Nicolas , Stauber Annina , Sticherling Christian , Szucs Thomas D , Conen David , Kuhne Michael , Osswald Stefan , Schwenkglenks Matthias , Serra-Burriel Miquel 
Published: February 2024

AimsDirect-acting oral anticoagulants (DOACs) have, to a substantial degree, replaced vitamin K antagonists (VKA) as treatments for stroke prevention in atrial fibrillation (AF) patients. However, evidence on the real-world causal effects of switching patients from VKA to DOAC is lacking. We aimed to assess the empirical incremental cost-effectiveness of switching patients to DOAC compared with maintaining VKA treatment.MethodsThe target trial approach was applied to the prospective observational Swiss-AF cohort, which enrolled 2415 AF patients from 2014 to 2017. Clinical data, healthcare resource utilisation and EQ-5D-based utilities representing quality of life were collected in yearly follow-ups. Health insurance claims were available for 1024 patients (42.4%). Overall survival, quality-of-life, costs from the Swiss statutory health insurance perspective and cost-effectiveness were estimated by emulating a target trial in which patients were randomly assigned to switch to DOAC or maintain VKA treatment.Results228 patients switching from VKA to DOAC compared with 563 patients maintaining VKA treatment had no overall survival advantage over a 5-year observation period (HR 0.99, 95% CI 0.45, 1.55). The estimated gain in quality-adjusted life years (QALYs) was 0.003 over the 5-year period at an incremental costs of CHF 23 033 (€ 20 940). The estimated incremental cost-effectiveness ratio was CHF 425 852 (€ 387 138) per QALY gained.ConclusionsApplying a causal inference method to real-world data, we could not demonstrate switching to DOACs to be cost-effective for AF patients with at least 1 year of VKA treatment. Our estimates align with results from a previous randomised trial.
Evaluating the efficacy of biologics with and without methotrexate in the treatment of psoriatic arthritis: a network meta-analysis
Authors: Mease Philip J , Reddy Soumya , Ross Sarah , Lisse Jeffrey R , Reis Paulo , Griffing Kirstin , Sapin Christophe , Vadhariya Aisha , Furst Daniel E 
Published: February 2024

IntroductionAn important consideration in the treatment of patients with psoriatic arthritis (PsA) is whether the addition of methotrexate (MTX) to biologics has greater efficacy than biologic monotherapy with respect to efficacy outcomes in these patients.ObjectivesTo conduct a network meta-analysis (NMA) comparing biologics by treatment class with and without MTX for treatment of adults with active PsA.MethodsA systematic literature review (SLR) identified randomised, double-blinded, controlled trials, and a Bayesian NMA compared biologics with and without MTX by treatment class (tumour necrosis factor inhibitors (TNFi), interleukin-23 inhibitors (IL-23i) and IL-17i). Efficacy outcomes included American College of Rheumatology 20%, 50% and 70% (ACR20, ACR50 and ACR70) improvement response.ResultsThe SLR initially identified 31 studies, of which 17 met feasibility criteria for the NMA by containing the ‘without MTX’ subgroup. For ACR20 efficacy (the most robust assessment examined), all active treatments were significantly better than placebo. No statistically significant differences were demonstrated between biologic monotherapy (for all classes examined) and biologics in combination with MTX for ACR20/50. IL-17i were comparable to IL-23i, and IL-17i were significantly better than TNFi for ACR20. Although limited by fewer trials, TNFi, IL-23i and IL-17i were not statistically different for ACR50/70.ConclusionsConcomitant use of MTX and biologics did not improve ACR efficacy outcomes versus biologic monotherapy. MTX does not appear to be necessary as a background therapy when biologics are used for the achievement of ACR20/50 responses in patients with PsA.
Validity and score interpretation of the 12-item Psoriatic Arthritis Impact of Disease: an analysis of pooled data from two phase 3 trials of bimekizumab in patients with psoriatic arthritis
Authors: Gossec Laure , Orbai Ana-Maria , Coates Laura C , Gladman Dafna D , Ogdie Alexis , Pelligra Christopher G , Ciaravino Valérie , Ink Barbara , Taieb Vanessa , Lambert Jérémy , de Wit Maarten 
Published: February 2024

ObjectivesTo investigate psychometric performance of the 12-item Psoriatic Arthritis Impact of Disease (PsAID-12) total and individual item scores in patients with psoriatic arthritis (PsA) and to estimate score change thresholds and scores corresponding to different levels of symptom/impact severity.MethodsData up to week 16 from 1252 patients with active PsA enrolled in two randomised controlled trials of bimekizumab (BE OPTIMAL (NCT03895203) and BE COMPLETE (NCT03896581)) were used to assess construct validity (correlations with other patient-reported outcomes), known-groups validity (based on Minimal Disease Activity index, Disease Activity Index for Psoriatic Arthritis and Psoriatic Arthritis Disease Activity Score), reliability (Cronbach’s alpha and intraclass correlation coefficients (ICCs)) and responsiveness (sensitivity to change). Clinically meaningful within-patient improvement thresholds were estimated by anchor-based and distribution-based analyses, and symptom/impact severity thresholds were estimated by receiver operating characteristic curve analyses.ResultsThe mean (SD) PsAID-12 total score at baseline was 4.19 (1.94). PsAID-12 scores demonstrated good convergent validity and good known-groups validity. Internal consistency reliability (Cronbach’s alpha 0.95) and test–retest reliability (ICC ≥ 0.70) were also good. Responsiveness was acceptable (correlations ≥0.30 for most scores). Improvement thresholds were estimated at 1.5–2 points for the PsAID-12 total score and 2 or 3 points for item scores. Thresholds for different levels of symptom/impact severity could be derived for most PsAID-12 items.ConclusionsThe PsAID-12 demonstrated robust psychometric properties in a large sample of patients with active PsA, supporting its use as a fit-for-purpose patient-reported outcome in this population. Furthermore, thresholds for score interpretation were derived.
Comparison of the ASAS Health Index in patients classified as radiographic axial spondyloarthritis (axSpA) or non-radiographic axSpA in the ASAS Health Index international validation study
Authors: Fong Warren , Woon Ting Hui , Kwan Yu Heng , Braun Jürgen , van der Heijde Désirée , Boonen Annelies , Kiltz Uta 
Published: February 2024

ObjectivesTo determine if there were differences in the Assessment of SpondyloArthritis international Society Health Index (ASAS HI) scores between patients classified as radiographic axial spondyloarthritis (r-axSpA) and non-radiographic axSpA (nr-axSpA), and to identify factors associated with higher ASAS HI scores in both disease phenotypes.MethodsThis study was an ancillary analysis of the ASAS HI international validation project performed in 23 countries. Patients were included if they were ≥18 years of age and diagnosed with axSpA. Univariable and multivariable analysis were performed to determine if ASAS HI scores differed between the axSpA phenotypes, and to identify other variables associated with ASAS HI scores. We also tested for potential interactions between the axSpA phenotype and significant variables identified through the multivariable regression.ResultsA total of 976 patients were included, with 703 having r-axSpA and 273 nr-axSpA. Patients with r-axSpA reported higher (worse) ASAS HI scores compared with those with nr-axSpA (6.8 (4.4) vs 6.0 (4.0), p=0.02), but the axSpA phenotype was not associated with ASAS HI scores in the multivariable regression (β: −0.19, 95% CI: −0.56 to 0.19). Female gender, having worse physical function (Bath Ankylosing Spondylitis Functional Index), disease activity (Ankylosing Spondylitis Disease Activity Score) and anxiety and depressive symptoms (Hospital Anxiety and Depression Scale) were associated with higher ASAS HI scores. No interactions were found to be significant.ConclusionOverall health and functioning are similarly affected in patients with r-axSpA and nr-axSpA. Female patients, having worse physical function, disease activity, anxiety and depressive symptoms were independently associated with higher ASAS HI scores.
Understanding pediatric surgical needs in North Korea: a modeling analysis
Authors: Hsu Phillip J , Yoon Sangchul , Park Kee B 
Published: February 2024

BackgroundSixty-five percent of children worldwide lack access to surgical care, the majority of whom live in low-income and middle-income countries (LMICs). Developing surgical infrastructure requires information on surgical need; however, this information is often limited in LMICs. North Korea (Democratic People’s Republic of Korea, DPRK) has a low amount of publicly available data. Here, we analyzed available modeled data to understand the causes of pediatric deaths due to conditions treatable with surgery in DPRK.MethodsWe used World Bank data and models from the Institute for Health Metrics and Evaluation to identify causes of pediatric deaths affecting pediatric patients (age <20 years). We compared mortality of disease between DPRK and countries with similar economic status.ResultsBetween 1990 and 2019, the number of overall pediatric deaths has decreased. In 2019, 32.2% of all pediatric deaths in DPRK were caused by surgical conditions. The leading categories of surgical conditions were injuries (53.9%), congenital conditions (34.2%), tumors (8.8%), and abdominal conditions (3.2%). DPRK has a lower relative rate of pediatric deaths compared with other LMICs with similar gross domestic product per capita. However, it has a higher relative rate of pediatric deaths due to conditions requiring treatment with surgery. Transport injuries contribute significantly to the high rate of pediatric deaths in DPRK.ConclusionsAlthough DPRK may be allocating overall resources toward pediatric healthcare more efficiently than economic peers, DPRK may benefit from improvement in pediatric surgical capacity. Improved availability of data and close international collaboration could be potential solutions to bridge this gap.
The 50th anniversary of the coupled channels Born approximation (CCBA) and the coupled reaction channels (CRC) theories of nucleon transfer reactions (a unique interplay between theory, experiment and computer technology, conducted during the most tumultuous period in modern American society)
Authors: Ascuitto Robert J. , Vaagen Jan S. 
Published: February 2024

AbstractNucleon transfer reactions have played a fundamental role in understanding the single-particle components, shell structure and collective properties of atomic nuclei. The conventional distorted wave Born approximation (DWBA) envisioned the nucleon transfer reaction as a one-step process, which proceeds directly from the ground state of the target nucleus to a state of the residual nucleus. The coupled channels Born approximation (CCBA) and coupled reaction channels (CRC) theories evolved because a number of nucleon transfer reaction cross sections could not be reconciled within the DWBA. These coupled channels models revealed that, in addition to the “one-step” process of the DWBA, “multi-step” nucleon transfer processes involving accessary pathways can participate in populating the final nuclear state. In the CCBA, the auxiliary pathways involved inelastic excitations of the target and/or residual nucleus, whereas, in the CRC, the pathways included sequential nucleon transfer passing through nuclear states of an intermediate partition. Coherent addition of contributions from one-step and multi-step nucleon transfer processes resulted in dramatic alterations in reaction cross sections, which were experimentally confirmed. The CCBA and CRC linked the structure of the nuclei participating in a reaction to modalities of nucleon transfer arising during the relative motion between the interacting ions. These complementary theories inexorably changed physicists’ interpretations of nucleon transfer reactions and, in doing so, heralded in the new field of direct heavy-ion reactions.
Abstract A015: Mutations in mismatch repair genes that alter subcellular localization of the protein predict resistance to standard therapy but response to cell cycle inhibitors
Authors: Mazumder Aloran , Haricharan Svasti 
Published: February 2024

Abstract
Hormone positive breast cancer is one of the most common cancer types in U.S. Every year, over 150,000 patients are detected with this cancer type of which, &gt;40,000 patients will go on to die of their disease. We recently identified defects in a principal mismatch repair (MMR) gene, MLH1, as a driver of resistance to standard-care treatment and poor patient outcomes. Moreover, we demonstrated increased sensitivity to palbociclib, a CDK4/6 inhibitor, in experimental model systems in vitro and in vivo and in clinical trial data. MLH1 is mutated in 5-10% of treatment-resistant tumors, i.e., 4,000 patient tumors every year. However, most of these mutations are missense and variants of unknown significance (VUS). The impact of these mutations on mismatch repair capability and on treatment resistance remains uncertain. Here, we use experimental model systems (ER+/HER2- breast cancer cells, organoid models, and patient tumors) to study how variants of MLH1 and its subcellular localization predicts resistance to standard endocrine therapy but sensitivity to cell cycle inhibitors. We also assessed the ability of nuclear MLH1 to induce activation of G1/S cell cycle checkpoints by activating Chk2. Currently, there are few tests available in the clinic to predict response to therapies early in the timeline of hormone positive breast cancer patients. Due to the nature of the disease, this can result in years of overtreatment. Overtreatment comes at great financial, physical, and emotional cost to patients and their families. We for the first time show that stalling nuclear translocation of MLH1 inhibits Chk2 activation which counterbalances CDK4/6 activity. Therefore, cytoplasmic Mlh1 may be first in-class biomarker for CDK4/6 response in cancer types.
Citation Format: Aloran Mazumder, Svasti Haricharan. Mutations in mismatch repair genes that alter subcellular localization of the protein predict resistance to standard therapy but response to cell cycle inhibitors [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr A015.