bluuebunny/crossref_metadata_2025_split huggingface dataset:
Empagliflozin in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial
Authors: Horby Peter W , Staplin Natalie , Peto Leon , Emberson Jonathan R , Campbell Mark , Pessoa-Amorim Guilherme , Basnyat Buddha , Thwaites Louise , Van Doorn Rogier , Hamers Raph L , Nel Jeremy , Amuasi John , Rawal Manisha , Ghosh Dipansu , Douse Jonathan , Hamilton Fergus , Kerry Anthony , Thu-Ta Pinky , Widdrington John , Green Chris , Desai Purav , Stewart Richard , Phong Nguyen Thanh , Baillie J Kenneth , Buch Maya H , Faust Saul N , Jaki Thomas , Jeffery Katie , Juszczak Edmund , Knight Marian , Lim Wei Shen , Montgomery Alan , Mukherjee Aparna , Mumford Andrew , Rowan Kathryn , Thwaites Guy , Mafham Marion , Haynes Richard , Landray Martin J ,   RECOVERY Collaborative Group
Published: April 2023

SUMMARYBackgroundEmpagliflozin has been proposed as a treatment for COVID-19 on the basis of its anti-inflammatory, metabolic and haemodynamic effects.MethodsIn this randomised, controlled, open-label trial, several possible treatments are compared with usual care in patients hospitalised with COVID-19. Eligible and consenting adults were randomly allocated in a 1:1 ratio to either usual standard of care alone or usual standard of care plus empagliflozin 10mg once daily for 28 days or until discharge using web-based simple (unstratified) randomisation with allocation concealment. The primary outcome was 28-day mortality. On 3 March the independent data monitoring committee recommended that the investigators review the data and recruitment was consequently stopped on 7 March. The trial is registered with ISRCTN (50189673) andclinicaltrials.gov(NCT04381936).FindingsBetween 8 July 2021 and 6 March 2023, 4271 patients were randomly allocated to receive either empagliflozin (2113 patients) or usual care alone (2158 patients). Overall, 289 (14%) patients allocated to empagliflozin and 307 (14%) patients allocated to usual care died within 28 days (rate ratio 0.96; 95% confidence interval [CI] 0.82-1.13; p=0.64). There was no evidence of significant differences in duration of hospitalisation (median 8 days vs. 8 days) or the proportion of patients discharged from hospital alive within 28 days (79% vs. 78%; rate ratio 1.03; 95% CI 0.96-1.10; p=0.44). Among those not on invasive mechanical ventilation at baseline, there was no evidence of a significant difference in the proportion meeting the composite endpoint of invasive mechanical ventilation or death (16% vs. 17%; risk ratio 0.95; 95% CI 0.84-1.08; p=0.44).InterpretationIn adults hospitalised with COVID-19, empagliflozin was not associated with reductions in 28-day mortality, duration of hospital stay, or risk of progressing to invasive mechanical ventilation or death.FundingUK Research and Innovation (Medical Research Council) and National Institute of Health Research (Grant ref: MC_PC_19056), and Wellcome Trust (Grant Ref: 222406/Z/20/Z).Trial registrationClinicalTrials.govNCT04381936https://clinicaltrials.gov/ct2/show/NCT04381936ISRCTN50189673http://www.isrctn.com/ISRCTN50189673
Genomic Analysis of Human Brain Metastases Treated with Stereotactic Radiosurgery Under the Phase-II Clinical Trial (NCT03398694) Reveals DNA Damage Repair at the Peripheral Tumor Edge
Authors: Shireman Jack M. , White Quinn , Agrawal Namita , Ni Zijian , Chen Grace , Zhao Lei , Gonugunta Nikita , Wang Xiaohu , Mccarthy Liam , Kasulabada Varshitha , Pattnaik Akshita , Ahmed Atique U. , Miller James , Kulwin Charles , Cohen-Gadol Aaron , Payner Troy , Lin Chih-Ta , Savage Jesse J. , Lane Brandon , Shiue Kevin , Kamer Aaron , Shah Mitesh , Iyer Gopal , Watson Gordon , Kendziorski Christina , Dey Mahua 
Published: April 2023

AbstractStereotactic Radiosurgery (SRS) is one of the leading treatment modalities for oligo brain metastasis (BM), however no comprehensive genomic data assessing the effect of radiation on BM in humans exist. Leveraging a unique opportunity, as part of the clinical trial (NCT03398694), we collected post-SRS, delivered via Gamma-knife or LINAC, tumor samples from core and peripheral-edges of the resected tumor to characterize the genomic effects of overall SRS as well as the SRS delivery modality. Using these rare patient samples, we show that SRS results in significant genomic changes at DNA and RNA levels throughout the tumor. Mutations and expression profiles of peripheral tumor samples indicated interaction with surrounding brain tissue as well as elevated DNA damage repair. Central samples show GSEA enrichment for cellular apoptosis while peripheral samples carried an increase in tumor suppressor mutations. There are significant differences in the transcriptomic profile at the periphery between Gamma-knife vs LINAC.
COVID-19 testing avoidance among patients with cardiovascular disease
Authors: Matsumura Koichiro , Tabuchi Takahiro , Yagi Eijiro , Ijichi Takeshi , Hasegawa Misaki , Yamada Nobuhiro , Funauchi Yohei , Kakehi Kazuyoshi , Kawamura Takayuki , Nakazawa Gaku 
Published: April 2023

AbstractBackgroundRapid coronavirus 2019 (COVID-19) testing in symptomatic cases is extremely important for preventing the spread of COVID-19 infection and early therapeutic intervention. In contrast, whether symptomatic patients are tested depends largely on their health literacy, interpretation, and knowledge of COVID-19. We aimed to investigate the rate of COVID-19 testing avoidance despite having common cold symptoms in patients with cardiovascular disease and examine factors related to testing avoidance.MethodsA large-scale epidemiological questionnaire survey, the Japan COVID-19 and Society Internet Survey 2022 (JACSIS), was conducted online from April to May 2022. The rate of COVID-19 testing avoidance was investigated in patients aged 20 to 80 years with cardiovascular risk factors (hypertension, dyslipidemia, or diabetes) or a history of cardiovascular disease (angina, myocardial infarction, or stroke), only those exhibiting common cold symptoms during the 2 months in the survey.ResultsOf the 1,565 eligible patients, 58% (909 patients) did not undergo COVID-19 testing. Multivariate analysis revealed that older age, obesity, non-walking regularly, long sedentary time, eating alone, frequent snacking, and having received 4 COVID-19 vaccinations were independently associated with testing avoidance.ConclusionsIn the chronic phase of the COVID-19 pandemic, prompt COVID-19 testing at the time of symptomatic disease is important, and strategies to reduce testing hesitancy should be considered.
Hemodynamic Response after Intra-Aortic Balloon Counter-Pulsation in Cardiac Amyloidosis and Cardiogenic Shock
Authors: Longinow Joshua , Il’Giovine Zachary J. , Martens Pieter , Higgins Andrew , Ives Lauren , Soltesz Edward G. , Tong Michael Z. , Estep Jerry D. , Starling Randall C. , Tang W.H. Wilson , Hanna Mazen , Lee Ran 
Published: April 2023

ABSTRACTBackgroundIn those with heart failure-related cardiogenic shock, intra-aortic balloon pump may improve hemodynamics and be useful as a bridge to advanced therapies. We explore whether those with cardiac amyloidosis and heart failure-related cardiogenic shock might experience hemodynamic improvement and describe the hemodynamic response after intra-aortic balloon pump.MethodsWe retrospectively identified consecutive patients with a diagnosis of cardiac amyloid, either light-chain or transthyretin, who were admitted to our intensive care unit with heart failure-related cardiogenic shock. Patients were excluded if intra-aortic balloon pump was placed during heart transplant or for shock related to acute myocardial infarction. Invasive hemodynamics before and after intra-aortic balloon pump placement were assessed.ResultsWe identified 23 patients with cardiac amyloid who had an intra-aortic balloon pump placed for heart failure-related cardiogenic shock. One-year survival was 74% and most (65%) were bridged to heart transplant while one was bridged to destination left ventricular assist device. Following intra-aortic balloon pump, mean arterial pressure, cardiac index, and cardiac power index were significantly increased, while mean right atrial pressure, mean pulmonary artery pressure, and pulmonary capillary wedge pressure were all significantly reduced. Smaller left ventricular end diastolic diameter (per cm) was associated with higher likelihood of a cardiac index of < 2.2 L/min/m2following intra-aortic balloon pump (OR 0.16, CI 0.01 – 0.93, P=0.04).ConclusionIntra-aortic balloon pump significantly improved cardiac index while reducing right atrial pressure, mean pulmonary artery pressure, and pulmonary capillary wedge pressure in CA patients with heart failure-related cardiogenic shock.
Conversion of monoclonal IgG to dimeric and secretory IgA restores neutralizing ability and prevents infection of Omicron lineages
Authors: Marcotte Harold , Cao Yunlong , Zuo Fanglei , Simonelli Luca , Sammartino Josè Camilla , Pedotti Mattia , Sun Rui , Cassaniti Irene , Hagbom Marie , Piralla Antonio , Yang Jinxuan , Du Likun , Percivalle Elena , Bertoglio Federico , Schubert Maren , Abolhassani Hassan , Sherina Natalia , Guerra Concetta , Borte Stephan , Razaei Nima , Kumagai-Braesch Makiko , Xue Yintong , Grönwall Caroline , Klareskog Lars , Calzolai Luigi , Cavalli Andrea , Wang Qiao , Robbiani Davide F. , Hust Michael , Shi Zhengli , Feng Liqiang , Svensson Lennart , Chen Ling , Bao Linlin , Baldanti Fausto , Qin Chuan , Xiao Junyu , Hammarström Lennart , Yang Xing Lou , Varani Luca , Xie Xiaoliang Sunney , Pan-Hammarström Qiang 
Published: April 2023

AbstractThe emergence of Omicron lineages and descendent subvariants continues to present a severe threat to the effectiveness of vaccines and therapeutic antibodies. We have previously suggested that an insufficient mucosal IgA response induced by the mRNA vaccines is associated with a surge in breakthrough infections. Here, we further show that the intramuscular mRNA and/or inactivated vaccines cannot sufficiently boost the mucosal sIgA response in uninfected individuals, particularly against the Omicron variant. We thus engineered and characterized recombinant monomeric, dimeric and secretory IgA1 antibodies derived from four neutralizing IgG monoclonal antibodies targeting the receptor-binding domain of the spike protein (01A05, rmAb23, DXP-604 and XG014). Compared to their parental IgG antibodies, dimeric and secretory IgA1 antibodies showed a higher neutralizing activity against different variants of concern (VOCs), in part due to an increased avidity. Importantly, the dimeric or secretory IgA1 form of the DXP-604 antibody significantly outperformed its parental IgG antibody, and neutralized the Omicron lineages BA.1, BA.2 and BA.4/5 with a 50-150-fold increase in potency, reaching the level of the most potent monoclonal antibodies described till date. In hACE2 transgenic mice, a single intranasal dose of the dimeric IgA DXP-604 conferred prophylactic and therapeutic protection against Omicron BA.5. Conversion of IgA and dimerization further enhanced or restored the neutralizing ability against the emerging Omicron sub-variants (DXP-604 for BQ.1, BQ.1.1 and BA2.75; 01A05 for BA2.75, BA.2.75.2 and XBB.1). Thus, dimeric or secretory IgA delivered by nasal administration may potentially be exploited for the treatment and prevention of Omicron infection, thereby providing an alternative tool for combating immune evasion by subvariants and, potentially, future VOCs.One Sentence SummaryEngineered dimeric and secretory IgA1 neutralized Omicron variant with higher potency than parental IgG.
Gut community structure as a risk factor for infection inKlebsiella-colonized patients
Authors: Vornhagen Jay , Rao Krishna , Bachman Michael A. 
Published: April 2023

AbstractThe primary risk factor for infection with members ofthe Klebsiella pneumoniaespecies complex is prior gut colonization, and infection is often caused by the colonizing strain. Despite the importance of the gut as a reservoir for infectiousKlebsiella, little is known about the association between the gut microbiome and infection. To explore this relationship, we undertook a case-control study comparing the gut community structure ofKlebsiella-colonized intensive care and hematology/oncology patients. Cases wereKlebsiella-colonized patients infected by their colonizing strain (N = 83). Controls wereKlebsiella-colonized patients that remained asymptomatic (N = 149). First, we characterized the gut community structure ofKlebsiella-colonized patients agnostic to case status. Next, we determined that gut community data is useful for classifying cases and controls using machine learning models and that the gut community structure differed between cases and controls.Klebsiellarelative abundance, a known risk factor for infection, had the greatest feature importance but other gut microbes were also informative. Finally, we show that integration of gut community structure with bacterial genotype or clinical variable data enhanced the ability of machine learning models to discriminate cases and controls. This study demonstrates that including gut community data with patient- andKlebsiella-derived biomarkers improves our ability to predict infection inKlebsiella-colonized patients.ImportanceColonization is generally the first step in pathogenesis for bacteria with pathogenic potential. This step provides a unique window for intervention since a given potential pathogen has yet to cause damage to its host. Moreover, intervention during the colonization stage may help alleviate the burden of therapy failure as antimicrobial resistance rises. Yet, to understand the therapeutic potential of interventions that target colonization, we must first understand the biology of colonization and if biomarkers at the colonization stage can be used to stratify infection risk. The bacterial genusKlebsiellaincludes many species with varying degrees of pathogenic potential. Members of theK. pneumoniaespecies complex have the highest pathogenic potential. Patients colonized in their gut by these bacteria are at higher risk of subsequent infection with their colonizing strain. However, we do not understand if other members of the gut microbiota can be used as a biomarker to predict infection risk. In this study, we show that the gut microbiota differs between colonized patients that develop an infection versus those that do not. Additionally, we show that integrating gut microbiota data with patient and bacterial factors improves the ability to predict infections. As we continue to explore colonization as an intervention point to prevent infections in individuals colonized by potential pathogens, we must develop effective means for predicting and stratifying infection risk.
Widespread alterations of diffusion tensor imaging metrics in patients with schizophrenia without current auditory hallucinations
Authors: Nerland Stener , Slapø Nora Berz , Barth Claudia , Mørch-Johnsen Lynn , Jørgensen Kjetil Nordbø , Beck Dani , Wortinger Laura A. , Westlye Lars T. , Jönsson Erik G. , Andreassen Ole A. , Maximov Ivan I. , Geier Oliver M. , Agartz Ingrid 
Published: April 2023

AbstractBackgroundStudies have linked auditory hallucinations (AH) in schizophrenia-spectrum disorders (SCZ) to altered cerebral white matter microstructure within the language and auditory processing circuitry (LAPC). However, the neuroanatomical distribution and specificity to the LAPC remains unclear. Here, we investigated the relationship between AH and DTI among patients with SCZ using diffusion tensor imaging (DTI).MethodsWe included patients with SCZ with (AH+; n=59) and without (AH-; n=81) current AH, and 140 age-and-sex-matched controls. Fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), and axial diffusivity (AD) were extracted from 39 fibre tracts. We used principal component analysis (PCA) to identify general factors of variation across fibre tracts and DTI metrics. Regression models adjusted for sex, age, and age2were used to compare tract-wise DTI metrics and PCA factors between AH+, AH-, and healthy controls and to assess associations with clinical characteristics.ResultsWidespread differences relative to controls were observed for MD and RD in patients without current AH. Only limited differences in two fibre tracts were observed between AH+ and controls. Unimodal PCA factors based on MD, RD, and AD, as well as multimodal PCA factors, differed significantly relative to controls for AH-, but not AH+. We did not find any significant associations between PCA factors and clinical characteristics.ConclusionsContrary to previous studies, DTI metrics differed mainly in patientswithoutcurrent AH compared to controls, indicating a widespread neuroanatomical distribution. Our results challenge the notion that altered DTI metrics in the LAPC is a specific feature underlying AH.
CRISPR-Cas9 mediated endogenous utrophin upregulation improves Duchenne Muscular Dystrophy
Authors: Guiraud Simon , Dastidar Sumitava , Mazed Fetta , Amor Fatima , Ralu Maelle , de Cian Anne , Richard Isabelle , Ronzitti Giuseppe , Tedesco Francesco Saverio , Amendola Mario 
Published: April 2023

AbstractDuchenne muscular dystrophy (DMD) is a lethal neuromuscular disorder caused by loss of dystrophin. Upregulation of utrophin (UTRN), a dystrophin paralogue, is a promising therapeutic avenue. Here, we present a CRISPR-Cas9-mediated strategy to increase utrophin expression by disrupting microRNA (miR) binding sites (BS). Using a Cas9/gRNA ribonucleoprotein (RNP) complex we disrupted several miR BS in DMD myoblasts and selected the Let-7c BS has crucial for UTRN repression. Interestingly, Cas9/gRNA indels were as efficient as the complete removal of Let-7c BS in upregulating UTRN expression, without any major off-targets. In three-dimensional human DMD cultures, Cas9/gRNA-mediated editing resulted in significant utrophin upregulation and functional improvements of calcium dysregulation and muscle contraction. Finally, Let-7c BS disruption in mdx animals by systemic rAAVs mediated delivery of Cas9 and gRNA resulted in utrophin upregulation and amelioration of the muscle histopathological phenotype. These findings provide the foundations for a universal (mutation-independent) gene editing therapeutic strategy for DMD.One Sentence SummaryCRISPR-Cas9 has the potential to upregulate utrophin to treat all DMD patients.
Allosteric coupling asymmetry mediates paradoxical activation of BRAF by type II inhibitors
Authors: Rasmussen Damien M. , Semonis Manny M. , Greene Joseph T. , Muretta Joseph M. , Thompson Andrew R. , Ramos Silvia Toledo , Thomas David D. , Pomerantz William C.K. , Freedman Tanya S. , Levinson Nicholas M. 
Published: April 2023

ABSTRACTThe type II class of RAF inhibitors currently in clinical trials paradoxically activate BRAF at subsaturating concentrations. Activation is mediated by induction of BRAF dimers, but why activation rather than inhibition occurs remains unclear. Using biophysical methods tracking BRAF dimerization and conformation we built an allosteric model of inhibitor-induced dimerization that resolves the allosteric contributions of inhibitor binding to the two active sites of the dimer, revealing key differences between type I and type II RAF inhibitors. For type II inhibitors the allosteric coupling between inhibitor binding and BRAF dimerization is distributed asymmetrically across the two dimer binding sites, with binding to the first site dominating the allostery. This asymmetry results in efficient and selective induction of dimers with one inhibited and one catalytically active subunit. Our allosteric models quantitatively account for paradoxical activation data measured for 11 RAF inhibitors. Unlike type II inhibitors, type I inhibitors lack allosteric asymmetry and do not activate BRAF homodimers. Finally, NMR data reveal that BRAF homodimers are dynamically asymmetric with only one of the subunits locked in the active αC-in state. This provides a structural mechanism for how binding of only a single αC-in inhibitor molecule can induce potent BRAF dimerization and activation.
Latent inter-organ mechanism of idiopathic pulmonary fibrosis unveiled by a generative computational approach
Authors: Kozawa Satoshi , Tejima Kengo , Takagi Shunki , Kuroda Masataka , Nogami-Itoh Mari , Kitamura Hideya , Niwa Takashi , Ogura Takashi , Natsume-Kitatani Yayoi , Sato Thomas N. 
Published: April 2023

AbstractIdiopathic pulmonary fibrosis (IPF) is a chronic and progressive disease characterized by complex lung pathogenesis affecting approximately three million people worldwide. While the molecular and cellular details of the IPF mechanism is emerging, our current understanding is centered around the lung itself. On the other hand, many human diseases are the products of complex multi-organ interactions. Hence, we postulate that a dysfunctional crosstalk of the lung with other organs plays a causative role in the onset, progression and/or complications of IPF. In this study, we employed a generative computational approach to identify such inter-organ mechanism of IPF. The approach works as follows: 1) To find unexpected relatedness of IPF to other diseases of non-lung organs and to identify molecular features that define such relatedness, 2) To identify differentially expressed genes between the lung tissues of IPF vs. those of non-IPF pulmonary disease patients, 3) To detect ligand-receptor relationships across multiple organs and their upstream and downstream signaling pathways in 1) and 2), 4) To generate a map of the inter-organ IPF mechanism with the molecular and cellular resolution. This approach found unexpected molecular relatedness of IPF to neoplasm, diabetes, Alzheimer’s disease, obesity, atherosclerosis, and arteriosclerosis. Furthermore, as a potential mechanism underlying this relatedness, we uncovered a putative molecular crosstalk system across the lung and the liver. In this inter-organ system, a secreted protein, kininogen 1, from hepatocytes in the liver interacts with its receptor, bradykinin receptor B1 in the lung. This ligand-receptor interaction across the liver and the lung leads to the activation of calmodulin pathways in the lung, leading to the activation of interleukin 6 and phosphoenolpyruvate carboxykinase 1 pathway across these organs. Furthermore, we retrospectively identified several pre-clinical and clinical evidence supporting this inter-organ mechanism of IPF. In conclusion, such feedforward and feedback system across the lung and the liver provides a unique opportunity for the development of the treatment and/or diagnosis of IPF. Furthermore, the result illustrates a generative computational framework for machine-mediated synthesis of mechanisms that facilitates and complements the traditional experimental approaches in biomedical sciences.