bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cost-effectiveness of implementing HIV and HIV/syphilis dual testing among key populations in Viet Nam: a modeling analysis
Authors: Coomes David , Green Dylan , Barnabas Ruanne , Sharma Monisha , Barr-DiChiara Magdalena , Jamil Muhammad S. , Baggaley Rachel , Owiredu Morkor Newman , Macdonald Virginia , Nguyen Van , Hai Son Vo , Taylor Melanie M. , Wi Teodora E , Johnson Cheryl , Drake Alison L. 
Published: March 2022

ABSTRACTObjectivesKey populations, including sex workers, men who have sex with men, and people who inject drugs, have a high risk of HIV and sexually transmitted infections (STIs). We assessed the health and economic impacts of different HIV and syphilis testing strategies among three key populations in Viet Nam using a dual HIV/syphilis rapid diagnostic test (RDT).SettingWe used the Spectrum AIDS Impact Model to simulate the HIV epidemic in key populations in Viet Nam and evaluated five testing scenarios. We used a 15-year time horizon and all costs are from the provider’s perspective.ParticipantsWe include the entire population of Viet Nam in the model.InterventionsWe model five testing scenarios among key populations: 1) annual testing with an HIV rapid diagnostic test (RDT), 2) annual testing with a dual RDT, 3) biannual testing using dual RDT and HIV RDT, 4) biannual testing using HIV RDT, and 5) biannual testing using dual RDTs.Primary and secondary outcome measuresThe primary outcome is incremental cost-effectiveness ratios (ICERS). Secondary outcomes include HIV and syphilis cases and costs for each proposed intervention.ResultsAnnual testing using a dual HIV/syphilis RDT was cost saving and averted 3,206 HIV cases and treated 7,719 syphilis cases compared to baseline over 15 years. Biannual testing using one dual test and one HIV RDT, or two dual tests both averted an additional 875 HIV cases and were cost-effective ($1,024 and $2,518 per DALY averted, respectively). Annual or biannual HIV testing using HIV RDTs and separate syphilis tests were more costly and less effective than using one or two dual RDTs.ConclusionsAnnual or biannual HIV and syphilis testing using dual RDTs among key populations can be cost-effective and support countries in reaching global reduction goals for HIV and syphilis.STRENGTHS AND LIMITATIONS OF THIS STUDYStrength: Our model presents novel cost-effectiveness estimates for the use of dual HIV/syphilis testing in key populations that can inform health plannersStrength: We include five testing scale up scenarios using both HIV RDT and dual HIV/syphilis RDTStrength: Our model is informed by demographic, behavioral, and biological data from government sources, surveys, surveillance, publicly available reports, databases, and peer-reviewed literatureLimitation: We made some assumptions regarding the timing and uptake of HIV and syphilis testing among key populations that may be inaccurate.Limitation: Our model assumes that increased syphilis testing and treatment will not impact syphilis prevalence, however, it is unknown whether increased testing will reduce or increase syphilis prevalence.
STING activation promotes robust immune response and NK cell-mediated tumor regression in glioblastoma models
Authors: Berger Gilles , Knelson Erik H. , Jimenez-Macias Jorge L. , Nowicki Michal O. , Han Saemi , Panagioti Eleni , Lizotte Patrick H. , Adu-Berchie Kwasi , Stafford Alexander , Dimitrakakis Nikolaos , Zhou Lanlan , Chiocca E. Antonio , Mooney David J. , Barbie David A. , Lawler Sean E. 
Published: March 2022

AbstractImmunotherapy has had a tremendous impact on cancer treatment in the past decade, with hitherto unseen responses at advanced and metastatic stages of the disease. However, the aggressive brain tumor glioblastoma (GBM) is highly immunosuppressive and remains largely refractory to current immunotherapeutic approaches. The cGAS-STING cytoplasmic double stranded DNA (dsDNA) sensing pathway has emerged as a next-generation immunotherapy target with potent local immune stimulatory properties.Here, we investigated the status of the STING pathway in GBM and the modulation of the brain tumor microenvironment (TME) with the STING agonist ADU-S100. Our data reveal the presence of STING in human GBM specimens, where it stains strongly in the tumor vasculature. We show that human GBM explants can respond to STING agonist treatment by secretion of inflammatory cytokines. In murine GBM models, we show a profound shift in the tumor immune landscape after STING agonist treatment, with massive infiltration of the tumor-bearing hemisphere with innate immune cells including inflammatory macrophages, neutrophils and NK populations. Treatment of established murine intracranial GL261 and CT-2A tumors by biodegradable ADU-S100-loaded intracranial implants demonstrated a significant increase in survival in both models and long-term survival with immune memory in GL261. Responses to treatment were abolished by NK cell depletion. This study reveals therapeutic potential and deep remodeling of the TME by STING activation in GBM and warrants the further examination of STING agonists alone or in combination with other immunotherapies such as cancer vaccines, CAR T cells, NK therapies or immune checkpoint blockade.Significance statementModulation of the immune microenvironment is critical for immunosuppressive and therapy refractory tumors like glioblastoma. Activation of the STING pathway deeply remodels the brain tumor environment and attracts innate immune cells and natural killer cell populations, producing a robust antitumor effect with long-term immune memory. We further show that human glioblastoma tissue can respond to the therapy and lay the foundations for combined intracranial immunotherapies by using crosslinked biodegradable brain implants.
Heterogeneity of Inflammation-associated Synovial Fibroblasts in Rheumatoid Arthritis and Its Drivers
Authors: Smith Melanie H , Gao Vianne R , Schizas Michail , Kochen Alejandro , DiCarlo Edward F , Goodman Susan M , Norman Thomas M , Donlin Laura T , Leslie Christina S , Rudensky Alexander Y 
Published: March 2022

AbstractInflammation of non-barrier immunologically quiescent tissues is associated with a massive influx of blood-borne innate and adaptive immune cells. Cues from the latter are likely to alter and expand the spectrum of states observed in cells that are constitutively resident. However, local communications between immigrant and resident cell types in human inflammatory disease remain poorly understood. Here, we explored heterogeneity of synovial fibroblasts (FLS) in inflamed joints of rheumatoid arthritis (RA) patients using paired single cell RNA and ATAC sequencing (scRNA/ATAC-seq), multiplexed imaging, and spatial transcriptomics along within vitromodeling of cell extrinsic factor signaling. These analyses suggest that local exposures to myeloid and T cell derived cytokines, TNFα, IFNγ, IL-1β, or lack thereof, drive six distinct FLS states some of which closely resemble fibroblast states in other disease-affected tissues including skin and colon. Our results highlight a role for concurrent, spatially distributed cytokine signaling within the inflamed synovium.
Tactile Stimulation Improves Cognition, Motor, and Anxiety-Like Behaviours and Attenuates the AD Pathology in Adult APP NL-G-F/NL-G-F mice
Authors: Hossain Shakhawat R. , Karem Hadil , Jafari Zahra , Kolb Bryan E. , Mohajerani Majid H. 
Published: March 2022

AbstractAlzheimer’s Disease (AD) is one of the largest health crises in the world. There are, however, limited but expensive pharmaceutical interventions to treat AD and most of the treatment options are not for cure or prevention, but to slow down the progression of the disease. The aim of this study was to examine the effect of tactile stimulation on AD-like symptoms and pathology in APP NL-G-F/NL-G-F mice, a mouse model of AD. The results show that tactile stimulation improves the AD-like symptoms on tests of cognition, motor, and anxiety-like behaviours and these improvements are associated with reduced AD pathology in APP mice.
Transmembrane protein KIRREL1 regulates Hippo signaling via a feedback loop and represents a potential therapeutic target in YAP/TAZ-active cancers
Authors: Gu Yuan , Wang Yu , Sha Zhao , Li Jian , He Chenxi , Lan Fei , Yu Fa-Xing 
Published: March 2022

AbstractDysregulation of the Hippo tumor suppressor pathway and hyperactivation of YAP/TAZ are frequently observed in human cancers and represent promising therapeutic targets. However, strategies targeting the mammalian Hippo pathway are limited due to the lack of a well-established cell surface regulator. By combining protein interactome data and clinical data, we have identified transmembrane protein KIRREL1 as an upstream regulator of the Hippo pathway. KIRREL1 interacts with Hippo pathway components SAV1 and LATS1/2 via its intracellular C-terminal domain and promotes LATS1/2 activation by MST1/2 (Hippo kinases), in turn inhibiting YAP/TAZ activity and target gene expression. Conversely, YAP/TAZ directly induce the expression of KIRREL1 in a TEAD1-4–dependent manner. In mouse liver tumors driven by YAP activation, KIRREL1 protein is robustly induced. Moreover, KIRREL1 expression positively correlates with canonical YAP/TAZ target gene expression in clinical tumor specimens and predicts poor prognosis. Finally, transgenic expression of KIRREL1 effectively blocked tumorigenesis in a mouse intrahepatic cholangiocarcinoma model, suggesting an important role of KIRREL1 in inhibiting cancer development. Together, these findings indicate that KIRREL1 constitutes a negative feedback mechanism regulating the Hippo pathway, and serves as a cell surface marker and potential drug target in cancers with YAP/TAZ dependency.
Reduced gene templates for supervised analysis of scale-limited CRISPR-Cas9 fitness screens
Authors: Vinceti Alessandro , Perron Umberto , Trastulla Lucia , Iorio Francesco 
Published: March 2022

SummaryPooled genome-wide CRISPR-Cas9 screens are furthering our mechanistic understanding of human biology and have allowed us to identify new oncology therapeutic targets. Scale-limited CRISPR-Cas9 screens – typically employing guide RNA libraries targeting subsets of functionally related genes, individual biological pathways, or portions of the druggable genome – constitute an optimal setting for investigating narrow hypotheses and they are easier to execute on complex models, such as organoids and in vivo models. Different supervised methods are used for the computational analysis of genome-wide CRISPR-Cas9 screens; most are not well suited for scale-limited screens as they require large sets of positive/negative control genes (gene templates) to be included among the screened ones. We have developed a computational framework identifying optimal subsets of known essential and nonessential genes (at different subsampling percentages) that can be used as templates for supervised analyses of scale-limited CRISPR-Cas9 screens, while having a reduced impact on the size of the employed library.HighlightsScale-limited CRISPR-Cas9 screens are experimentally easier than genome-wide screensReference gene templates are used for supervised analyses of genome-wide screensReduced templates allow supervised analyses of scale-limited CRISPR-Cas9 screensWe present optimal reduced templates and a computational method to assemble themGraphical abstract
Mutation patterns in SARS-COV-2 Alpha and Beta variants indicate non-neutral evolution
Authors: Kurpas Monika , Kimmel Marek 
Published: March 2022

AbstractDue to the emergence of new variants of the SARS-CoV-2 coronavirus, the question of how the viral genomes evolved, leading to the formation of highly infectious strains, becomes particularly important. Two early emergent strains, Alpha and Beta, characterized by a significant number of missense mutations, provide natural testing samples.In this study we are exploring the history of each of the segregating sites present in Alpha and Beta variants of concern, to address the question whether defining mutations were accumulating gradually leading to the formation of sequence characteristic of these variants.Our analysis exposes data features that suggest other than neutral evolution of SARS-CoV-2 genomes, leading to emergence of variants of concern. We observe only small number of possible combinations of mutations indicating rapid evolution of genomes. In addtion, mutation patterns observed in whole genome samples of Alpha and Beta variants also indicate presence of stronger selection than in remaining genome samples.
Evolutionary analysis of genomes of SARS-CoV-2-related bat viruses suggests old roots, constant effective population size, and possible increase of fitness
Authors: Kurpas Monika , Jaksik Roman , Kimmel Marek 
Published: March 2022

AbstractIt is of vital practical interest to understand the co-evolution of bat β-coronaviruses with their hosts, since a number of these most likely crossed the species boundaries and infected humans. Complete sequences of 47 consensus genomes are available for bat β-coronaviruses related to the SARS-CoV-2 human virus. We carried out several types of evolutionary analyses using these data. First, using the publicly available BEAST 2 software, we generated phylogenetic trees and skyline plots. The roots of the trees, both for the entire sequences and subsequences coding for the E and S proteins as well as the 5’ and 3’ UTR regions, are estimated to be located from several decades to more than a thousand years ago, while the effective population sizes remained largely constant. Motivated by this, we developed a simple estimator of the effective population size in a Moran model with constant population, which, under the model is equal to the expected age of the MRCA measured in generations. Comparisons of these estimates to those produced by BEAST 2 shows qualitative agreement. We also compared the site frequency spectra (SFS) of the bat genomes to those provided by the Moran Tug-of-War model. Comparison does not exclude the possibility that overall fitness of the bat β-coronaviruses was increasing over time as a result of directional selection. Stability of interactions of bats and their viruses was considered likely on the basis of specific manner in which bat immunity is tuned, and it seems consistent with our analysis.
Anatomical structures, cell types, and biomarkers of the healthy human blood vasculature
Authors: Boppana Avinash , Lee Sujin , Malhotra Rajeev , Halushka Marc , Quardokus Ellen M , Herr Bruce W. , Börner Katy , Weber Griffin M 
Published: March 2022

AbstractMore than 150 scientists from 17 consortia are collaborating on an international project to build a Human Reference Atlas, which maps all 37 trillion cells in the healthy adult human body. The initial release of this atlas provided hierarchical lists of the anatomical structures, cell types, and biomarkers in 11 organs. Here, we describe the methods we used as part of this initiative to build the first open, computer-readable, and comprehensive database of the adult human blood vasculature, called the Human Reference Atlas-Vasculature Common Coordinate Framework (HRA-VCCF). It includes 961 vessels and their branching connections, 10 cell types, and 10 biomarkers. With this paper we are releasing additional details on vessel types and subtypes, branching sequence, anastomoses, portal systems, microvasculature, functional tissue units, mappings to regions vessels supply or drain, and links to 3D reference objects. Future versions will add variants, geometric properties of vessels, and connections to the lymph vasculature; and, it will iteratively expand and improve the database as additional experimental data become available through the participating consortia.
High Viral Specific Antibody Convalescent Plasma Effectively Neutralizes SARS-CoV-2 Variants of Concern
Authors: Li Maggie , Beck Evan J. , Laeyendecker Oliver , Eby Yolanda , Tobian Aaron AR , Caturegli Patrizio , Wouters Camille , Chiklis Gregory R. , Block William , McKie Robert , Joyner Michael , Wiltshire Timothy D. , Dietz Allan B. , Gniadek Thomas J. , Shapiro Arell , Yarava Anusha , Lane Karen , Hanley Daniel , Bloch Evan M. , Shoham Shmuel , Cachay Edward R. , Meisenberg Barry R. , Huaman Moises A. , Fukuta Yuriko , Patel Bela , Heath Sonya L. , Levine Adam C. , Paxton James H. , Anjan Shweta , Gerber Jonathan M. , Gebo Kelly A. , Casadevall Arturo , Pekosz Andrew , Sullivan David J. ,   the CSSC group
Published: March 2022

AbstractThe ongoing evolution of SARS-Co-V2 variants to omicron severely limits available effective monoclonal antibody therapies. Effective drugs are also supply limited. Covid-19 convalescent plasma (CCP) qualified for high antibody levels effectively reduces immunocompetent outpatient hospitalization. The FDA currently allows outpatient CCP for the immunosuppressed. Viral specific antibody levels in CCP can range ten-to hundred-fold between donors unlike the uniform viral specific monoclonal antibody dosing. Limited data are available on the efficacy of polyclonal CCP to neutralize variants. We examined 108 pre-delta/pre-omicron donor units obtained before March 2021, 20 post-delta COVID-19/post-vaccination units and one pre-delta/pre-omicron hyperimmunoglobulin preparation for variant specific virus (vaccine-related isolate (WA-1), delta and omicron) neutralization correlated to Euroimmun S1 IgG antibody levels. We observed a 2-to 4-fold and 20-to 40-fold drop in virus neutralization from SARS-CoV-2 WA-1 to delta or omicron, respectively. CCP antibody levels in the upper 10% of the 108 donations as well as 100% of the post-delta COVID-19/post-vaccination units and the hyperimmunoglobulin effectively neutralized all three variants. High-titer CCP neutralizes SARS-CoV-2 variants despite no previous donor exposure to the variants.Key pointsAll of the post-delta COVID-19/post vaccination convalescent plasma effectively neutralizes the omicron and delta variants.High-titer CCP and hyperimmunoglobulin neutralizes SARS-CoV-2 variants despite no previous donor exposure to the variants.
Descriptive epidemiology of cardiorespiratory fitness in UK adults: The Fenland Study
Authors: Gonzales Tomas I. , Westgate Kate , Hollidge Stefanie , Lindsay Tim , Wijndaele Katrien , Forouhi Nita G. , Griffin Simon , Wareham Nick , Brage Soren 
Published: March 2022

ABSTRACTBackgroundCardiorespiratory fitness is rarely measured in population studies. Most studies of fitness do not examine differences by population subgroups or seasonal trends.MethodsWe used a validated submaximal exercise test to measure fitness in 5976 women and 5316 men, residing in England. We expressed fitness as maximal oxygen consumption per kilogram total body mass (VO2maxtbm) and fat free mass (VO2maxffm). Descriptive statistics were computed across anthropometric and sociodemographic characteristics, as well as across the year. Progressive multivariable analyses were performed to examine mediation by physical activity energy expenditure (PAEE) and BMI.ResultsMean±SD VO2maxtbm was lower in women (35.4±7.6 ml·min-1·kg-1) than men (42.1±7.4 ml·min-1·kg-1) but VO2maxffm was similar (women: 59.7±11.8 ml·min-1·kg-1; men: 62.5±10.4 ml·min-1·kg-1). Fitness was inversely associated with age but not after adjustment for PAEE. People in more physically demanding jobs were fitter compared to those in sedentary jobs but this association was attenuated in women and reversed in men following adjustment for total PAEE. PAEE and BMI and were positively associated with fitness at all levels of adjustment when fitness was expressed relative to fat-free mass. Fitness during summer was 4% higher than the winter among women, but did not differ by season among men.ConclusionsFitness was inversely associated with age but less steeply than anticipated, suggesting older generations are comparatively fitter than younger generations. PAEE and BMI were stronger determinants of the variance in fitness than any other characteristic including age. This emphasizes the importance of modifiable physical activity behaviours in public health interventions.KEY MESSAGESFitness was inversely associated with age but less steeply than anticipated, suggesting older generations are comparatively fitter than younger generationsRelationships between cardiorespiratory fitness and sociodemographic characteristics were primarily mediated by physical activity.A one standard deviation difference in physical activity had the same impact on cardiorespiratory fitness as being 25 years younger
Patients with CLL have similar high risk of death upon the omicron variant of COVID-19 as previously during the pandemic
Authors: Niemann Carsten U , Cunha-Bang Caspar da , Helleberg Marie , Ostrowski Sisse Rye , Brieghel Christian 
Published: March 2022

AbstractPrevious studies have shown that patients with chronic lymphocytic leukemia (CLL) and coronavirus disease 2019 (COVID-19) have high mortality rates. The omicron variant has been reported to give milder disease in the general population, but outcomes of infections with the omicron variant among immunocompromised patients have not previously been reported. In a population-based cohort we assessed rates of hospitalizations, ICU-admissions, and 30-day all-cause mortality among all patients with CLL from Eastern Denmark testing positive for severe adult respiratory syndrome coronavirus 2 (SARS-CoV-2) in time periods before and after dominance of the omicron variant. Rates of hospitalizations and ICU-admissions declined significantly, whereas 30-day mortality remained as high as 23% in the period with dominance of the omicron sublineage BA.2 variant. Thus, patients with CLL in general and in particular those above 70 years of age with one or more comorbidities should be considered for closer monitoring and pre-emptive antiviral therapy upon a positive SARS-CoV-2 test.Key pointsThe omicron variant of COVID-19 leads to high fatality rates in CLL, despite milder disease in the background populationPatients with CLL who test positive for SARS-CoV-2 in the era of the omicron variant should be considered for pre-emptive antiviral therapyExplanation of noveltyThe omicron variant has been reported to give milder disease in the general population, but outcomes of infections with the omicron variant among immunocompromised patients have not previously been reported. These population-based data on outcome for patients with CLL upon infection with the omicron variant of SARS-CoV-2 warrants closer monitoring and pre-emptive antiviral therapy upon a positive SARS-CoV-2 test for patients with CLL.