bluuebunny/crossref_metadata_2025_split huggingface dataset:
Determinants of anti-PD1 response and resistance in clear cell renal cell carcinoma
Authors: Au Lewis , Hatipoglu Emine , de Massy Marc Robert , Litchfield Kevin , Rowan Andrew , Thompson Rachael , Schnidrig Desiree , Byrne Fiona , Beattie Gordon , Horswell Stuart , Fotiadis Nicos , Hazell Steve , Nicol David , Shepherd Scott Thomas Colville , Fendler Annika , Mason Robert , Attig Jan , Joshi Kroopa , Uddin Imran , Becker Pablo , Sunderland Mariana Werner , Akarca Ayse , Puccio Ignazio , Yang William , Lund Tom , Dhillon Kim , Vasquez Marcos Duran , Ghorani Ehsan , Xu Hang , López José Ignacio , Green Anna , Mahadeva Ula , Borg Elaine , Mitchison Miriam , Moore David , Proctor Ian , Falzon Mary , Furness Andrew , Pickering Lisa , Reading James L. , Salgado Roberto , Marafioti Teresa , Jamal-Hanjani Mariam , Kassiotis George , Chain Benny , Larkin James , Swanton Charles , Quezada Sergio A , Turajlic Samra 
Published: March 2021

SummaryAntigen recognition and T-cell mediated cytotoxicity in clear-cell renal cell carcinoma (ccRCC) remains incompletely understood. To address this knowledge gap, we analysed 115 multiregion tumour samples collected from 15 treatment-naïve patients pre- and post-nivolumab therapy, and at autopsy in three patients. We performed whole-exome sequencing, RNAseq, TCRseq, multiplex immunofluorescence and flow cytometry analyses and correlated with clinical response. We observed pre-treatment intratumoural TCR clonal expansions suggesting pre-existing immunity. Nivolumab maintained pre-treatment expanded, clustered TCR clones in responders, suggesting ongoing antigen-driven stimulation of T-cells. T-cells in responders were enriched for expanded TCF7+CD8+T-cells and upregulated GZMK/B upon nivolumab-binding. By contrast, nivolumab promoted accumulation of new TCR clones in non-responders, replacing pre-treatment expanded clonotypes. In this dataset, mutational features did not correlate with response to nivolumab and human endogenous retrovirus expression correlated indirectly. Our data suggests that nivolumab potentiates clinical responses in ccRCC by binding pre-existing expanded CD8+T-cells to enhance cytotoxicity.
Population homogeneity for the antibody response to COVID-19 BNT162b2 / Comirnaty vaccine is only reached after the second dose, across all adult age ranges
Authors: Viana João F. , Bergman Marie-Louise , Gonçalves Lígia A. , Duarte Nádia , Coutinho Teresa Penha , Borges Patrícia C. , Diwo Christian , Castro Rute , Matoso Paula , Malheiro Vanessa , Brennand Ana , Kosack Lindsay , Akpogheneta Onome , Figueira João M. , Cardoso Conceição , Casaca Ana M. , Alves Paula M. , Nunes Telmo , Penha-Gonçalves Carlos , Demengeot Jocelyne 
Published: March 2021

ABSTRACTBACKGROUNDWhile mRNA vaccines authorized for emergency use are administrated worldwide in an effort to contain the COVID-19 pandemic, little is known about the heterogeneity of the humoral immune response they induce at the population scale.METHODSWe conducted a prospective observational longitudinal study in 1245 hospital care workers and 146 nursing home residents, together covering adult ages from 19 to 99 years. Blood samples were taken before vaccination, 3-5 weeks after the first vaccine dose, and 3 weeks after the second dose of BNT162b2 mRNA COVID-19 (Comirnaty, Pfizer/BioNTech). End points were seroconversion to SARS-CoV-2 spike protein and amount of spike-specific IgG, IgM and IgA following the first dose and the boosting effect of the second vaccination. We also addressed the effect of age, sex and pre-exposure to SARSCov-2 on these parameters.RESULTSAmong 1067 baseline seronegative participants, seroconversion after the first vaccine dose varied from a maximum of 98,6% in the younger age strata [19-29 years] to a minimum of 25.4 % in the older age group [70-100 years], while sex had little effect. Large inter-individual variation in the amplitude of the antibody response were observed in all age strata. The second dose brought seroconversion to high frequency (100% and 94.9% in younger and older age strata, respectively) and homogenised IgG responses to high levels, while IgM and IgA levels remained low and heterogeneous. Previous exposure to SARS-Cov-2 boosted IgG level after a single injection. Seven non-responders were identified after the second dose.CONCLUSIONSIn this large study, covering all adult age ranges, BNT162b2 vaccination resulted in isotypic and heterogeneous antibody responses, advocating for the interval between the two doses not to be extended and for serological monitoring of elderly and immunosuppressed vaccinees.
A Quantitative Framework to Study Potential Benefits and Harms of Multi-cancer Early Detection Testing
Authors: Jiao Boshen , Gulati Roman , Katki Hormuzd A. , Castle Philip E. , Etzioni Ruth 
Published: March 2021

AbstractBackgroundMulti-cancer tests permit identification of multiple cancers with one blood draw. The objective of this study was to quantify potential population impact of a multi-cancer test.MethodsWe formulate mathematical expressions for expected numbers of (1) individuals exposed to unnecessary confirmation tests (UCT), (2) cancers detected (CD), and (3) lives saved (LS) given disease prevalence and mortality and the test’s performance and expected mortality reduction. We consider additions of colorectal, liver, lung, ovary, and pancreatic cancer to a test for breast cancer using published performance characteristics of a multi-cancer test and prevalence of each cancer at ages 50, 60, or 70 based on 5-year incidence rates and corresponding 15-year probabilities of cancer death in the Surveillance, Epidemiology, and End Results registry, assuming 20% mortality reduction for each.ResultsUCT depends on screening age but is overwhelmingly determined by overall specificity of the test and is relatively insensitive to the types and number of cancers included. For a given overall specificity, UCT/CD is most favorable for higher-prevalence cancers (e.g., UCT/CD = 5.6 for breast+lung versus 6.5 for breast+liver at age 50). Under a common mortality reduction, UCT/LS is most favorable when the test includes higher-mortality cancers (e.g., UCT/LS = 48.5 for breast+lung versus 74.7 for breast+liver at age 50).ConclusionsThe harm-benefit tradeoffs of multi-cancer testing depend on the number and type of cancers included. Overall specificity is paramount for controlling unnecessary confirmation tests. For a given overall specificity, multi-cancer tests should prioritize prevalent and/or lethal cancers for which curative treatments exist.
Incidence of and factors associated with SARS-CoV-2 infection among people living with HIV in Southern Spain
Authors: Fernandez-Fuertes Marta , Corma-Gomez Anaïs , Torres Eva , Rodriguez-Pineda Elena , Fuentes-Lopez Ana , Rincon Pilar , Fernanddez Nieves , Garcia Federico , Bernal Samuel , Real Luis M , Macias Juan , Pineda Juan A 
Published: March 2021

AbstractBackgroundWhether people living with HIV (PLWH) are at greater risk of acquiring SARS-CoV-2 infection is currently unknown. Prospective serologic studies may allow seroincidence analyses, where all infections are accurately identified. Because of this, we evaluated the incidence of and associated factors with SARS-CoV-2 infection in PLWH in Southern Spain.MethodsThis was a prospective cohort study including PLWH from a University Hospital in Southern Spain. Patients were enrolled if 1) they had attended as outpatients our Unit from August 1st, 2019 to February 8th, 2020; 2) had two subsequent evaluations from February 9th, 2020 to February 15th, 2021. Serum antibodies against SARS-CoV-2 were determined in baseline and intra-pandemic samples.Results710 PLWH were included in the study. Of them, 46 [6.5%, 95% confidence interval (95% CI): 4.8%-8.5%] patients developed SARS-CoV-2 infection. Between May 18th and November 29th, 2020, the rate of seroconversion was 5.3% (95% CI: 3.1%-9%) for the general population in the area of Seville and 2.3% (95% CI: 1.3%-3.6%) for PLWH in this study (p=0.001). After multivariate analysis, adjusted by age and sex, active tobacco smoking was the only factor independently associated with lower risk of SARS-Cov-2 infection (Incidence rate ratio 0.35, 95% CI: 0.18-0.68, p=0.002).ConclusionsThe incidence of SARS-CoV-2 infection among PLWH in Southern Spain during the ongoing pandemic was lower than that reported for the general population in the same area. Tobacco smoking was the only factor independently associated with a lower risk of incident SARS-CoV-2 infection.SummaryThe incidence of SARS-CoV-2 infection among people living with HIV is lower than that of general population in Southern Spain. Active tobacco smoking could be associated with a lower risk of developing COVID-19.
Functional and microstructural brain abnormalities, fatigue, and cognitive dysfunction after mild COVID-19
Authors: Silva Lucas Scardua , Joao Rafael Batista , Nogueira Mateus Henrique , Aventurato Italo Karmann , de Campos Brunno Machado , de Brito Mariana Rabelo , Alvim Marina Koutsodontis Machado , Ludwig Guilherme Vieira Nunes , Rocha Cristiane , Souza Thierry Kaue Alves Silva , da Costa Beatriz Amorim , Mendes Maria Julia , Waku Takeshi , de Oliveira Boldrini Vinicius , Brunetti Natália Silva , Baptista Sophia Nora , Schmitt Gabriel da Silva , de Sousa Jhulia Gabriela Duarte , de Oliveira Cardoso Tânia Aparecida Marchiori , Vieira André Schwambach , Santos Leonilda Maria Barbosa , Farias Alessandro dos Santos , Cendes Fernando , Yasuda Clarissa Lin 
Published: March 2021

ABSTRACTAlthough post-acute cognitive dysfunction and neuroimaging abnormalities have been reported after hospital discharge in patients recovered from COVID-19, little is known about persistent, long-term alterations in patients who did not require hospitalization. Therefore, we conducted a cross-sectional study of 87 consecutive, non-hospitalized recovered individuals, with a median of 54 days after the laboratory confirmation of COVID-19. We performed structured interviews, neurological examination, and 3T-MRI scans. The MRI study included white matter investigation with diffusion tensor images (DTI) and seed-based resting-state functional MRI (fMRI) connectivity analyses of the default mode network (DMN). In addition, we used validated instruments to examine fatigue, symptoms of anxiety and depression, somnolence, language, memory, and cognitive flexibility.Individuals self-reported a high frequency of headaches (40%) and memory difficulties (33%). The quantitative analyses confirmed symptoms of fatigue (68% of participants), excessive somnolence (35%), symptoms of anxiety (29%), impaired cognitive flexibility (40%) and language dysfunction (33%). In addition, we observed a correlation between DTI fractional anisotropy (FA) and abnormal attention and cognitive flexibility measured by the Trail Making Test part B. The resting-state fMRI study of the DMN showed an association between higher connectivity of the posterior cingulate cortex (PCC) and higher levels of fatigue and somnolence. While greater connectivity of the PCC with bilateral angular gyri was associated with higher fatigue levels, the elevated levels of somnolence correlated with higher connectivity between the PCC and both the left thalamus and putamen.
Willingness to Vaccinate against COVID-19 among Healthcare Workers: An Online Survey in 10 Countries in the Eastern Mediterranean Region
Authors: Elhadi Yasir Ahmed Mohammed , Mehanna Azza , Adebisi Yusuff Adebayo , El Saeh Haider M. , Alnahari Saddam Abdulhakem , Alenezi Omar Hassan , Chbib Diala El , Yahya Zahraa , Ahmed Eiman , Ahmad Shoaib , Uakkas Saad , Sabahelzain Majdi Mohammed , Alyamani Bushra Ahmed , Nemat Arash , Lucero-Prisno Don Eliseo , Zaghloul Ashraf 
Published: March 2021

AbstractBackgroundWillingness of healthcare workers to be vaccinated is an important factor to be consider for successful COVID-19 vaccination programme. Our study aimed to understand the willingness of health workers to receive COVID-19 vaccine and associated concerns across 10 countries in the Eastern Mediterranean Region (EMRO).MethodA cross-sectional study was conducted in January 2021 among healthcare workers using an online survey. A total of 2806 health workers (Physicians, Nurses and Pharmacists) completed and returned the informed consent along with the questionnaire electronically. Data were analyzed using IBM SPSS software package version 20.0. SResultsMore than half of the respondents (58.0%) were willing to receive COVID-19 vaccine, even if the vaccination is not mandatory for them. On the other hand, 25.7% of respondents were not willing to undertake COVID-19 vaccination while 16.3 % answered undecided. The top three reasons for not intending to be vaccinated were unreliability of COVID-19 vaccine clinical trials (62.0%), fear of the side effects of the vaccine (45.3%), and that COVID-19 vaccine will not give immunity for a long period of time (23.1%).ConclusionOverall, our study revealed suboptimal acceptance of COVID-19 vaccine among our respondents in the EMRO region. Significant refusal of COVID-19 vaccine among healthcare professionals can reverse hard-won progress in building public trust in COVID-19 vaccination program. Our findings suggest the need to develop tailored strategies to address concerns identified in the study in order to ensure optimal vaccine acceptance among healthcare workers in the EMRO.
Economic Crisis and Mental Health during the COVID-19 Pandemic in Japan
Authors: Matsubayashi Tetsuya , Ishikawa Yumi , Ueda Michiko 
Published: March 2021

BackgroundThe economic crisis induced by the COVID-19 pandemic can have a serious impact on population mental health. This study seeks to understand whether the economic shocks associated with the pandemic have a differential impact by sex because the current pandemic may have disproportionally affected women compared to men.MethodsWe analyzed data from original online monthly surveys of the general population in Japan conducted between April 2020 and February 2021 (N=9000). We investigate whether individuals who had experienced a major job-related were more likely to have experienced depressive symptoms (PHQ-9) and anxiety disorders (GAD-7) during the pandemic and also if its effect varied by sex.ResultsThe results of logistic regression suggest that depressive and anxiety symptoms were more prevalent among those who had recently experienced drastic changes in employment and working conditions, as well as among individuals with low income and those without college education. We also found that female respondents who had experienced a major employment-related change were more likely to have experienced both depression and anxiety disorders, but its effect on male workers was limited to depressive symptoms.LimitationsWe do not have data on the pre-COVID mental health conditions of our respondents, and our findings are descriptive. Some segments of the population may not be represented in our sample because our surveys were conducted online.ConclusionsCOVID-induced economic shocks can have a differential detrimental effect on mental health depending on the sex of workers. The mental health of female workers can be particularly vulnerable.
P1 variants and key amino acid mutations at the Spike gene identified using Sanger protocols
Authors: Cabral Gabriela Bastos , Ahagon Cintia Mayumi , Lopez-Lopes Giselle Ibette Silva , Hussein Igor Mohamed , Guimaraes Paula Morena , Cilli Audrey , Silva Valeria Oliveira , Timenetsky Maria do Carmo CT , de Jesus Alves Ivy , Bombonatte Andrea GC , dos Santos Fabiana C Pereira , Brígido Luís Fernando de Macedo 
Published: March 2021

ABSTRACTSARS-CoV-2 variants, along with vaccination, mark the second year of the pandemic. The spike region is a focal point in COVID-19 pathogenesis, with different amino acid changes potentially modulating vaccine response and some being part of variant signatures. NGS is the standard tool to sequence the virus but limitations of different sources hinders expansion of genomic surveillance in many places. To improve surveillance capability we developed a Sanger based sequencing protocol to obtain coverage of most (>95%) spike gene. Eleven nasopharyngeal swabs collections had RNA extracted for real time PCR diagnosis and leftover RNA had up to 3785 bp sequenced at an ABI3500 using dye termination chemistry of nested PCR products of two reactions of one-step RT-PCR. P1 amino acid mutations signatures were present in 18% (2/11), with 82% (9/11) with three or more additional amino acid changes (GISAID CoVsurver list). Most sequences (86%, 6/7) from 2021 have the E484K, whereas the mutation was not present in samples collected in 2020 (0/4, p=0.015).The swiftness that favorable mutations to the virus may prevail and their potential impact in vaccines and other current interventions need broader surveillance and more public health attention.
Prediction of COVID-19 Mortality to Support Patient Prognosis and Triage and Limits of Current Open-Source Data
Authors: Doyle Riccardo 
Published: March 2021

AbstractThis study examines the accuracy and applicability of machine learning methods in early prediction of mortality in COVID-19 patients. Patient symptoms, pre-existing conditions, age and sex were employed as predictive attributes from data spanning 17 countries. Performance on a semi-evenly balanced class sample of 212 patients resulted in high detection accuracy of 92.5%, with strong specificity and sensitivity. Performance on a larger sample of 5,121 patients with only age and mortality information was added as a measure of baseline discriminatory ability. Stratifying - Random Forest - and linear - Logistic Regression - methods were applied, both achieving modestly strong performance, with 77.4%-79.3% sensitivity and 71.4%-72.6% accuracy, highlighting predictive power even on the basis of a single attribute. Mutual information was employed as a dimensionality reduction technique, greatly improving performance and showing how a small number of easily retrievable attributes can provide timely and accurate predictions, with applications for datasets with slowly available variables - such as laboratory results.Unlike existing studies making use of the same dataset, limitations of the data were extensively explored and detailed, as each results section outlines the main shortcomings of relevant analysis. Future use of this dataset should be cautious and always accompanied by disclaimers on issues of real-life reproducibility. While its open-source nature is a credit to the wider research community and more such datasets should be published, in its current state it can produce valid conclusions only for a limited set of applications, some of which were explored in this study.
The PKN1- TRAF1 signaling axis as a potential new target for chronic lymphocytic leukemia
Authors: Edilova Maria I. , Law Jaclyn C. , Zangiabadi Safoura , Ting Kenneth , Mbanwi Achire N. , Arruda Andrea , Uehling David , Isaac Methvin , Prakesch Michael , Al-awar Rima , Minden Mark D. , Abdul-Sater Ali A. , Watts Tania H. 
Published: March 2021

AbstractTRAF1 is a pro-survival adaptor molecule in TNFR superfamily (TNFRSF) signaling. TRAF1 is overexpressed in many B cell cancers including refractory chronic lymphocytic leukemia (CLL). Little has been done to assess the role of TRAF1 in human cancer. Here we show that the protein kinase C related kinase Protein Kinase N1 (PKN1) is required to protect TRAF1 from cIAP-mediated degradation during constitutive CD40 signaling in lymphoma. We show that the active phospho-Thr774 form of PKN1 is constitutively expressed in CLL but minimally detected in unstimulated healthy donor B cells. Through a screen of 700 kinase inhibitors, we identified two inhibitors, OTSSP167 and XL-228, that inhibited PKN1 in the nanomolar range and induced dose-dependent loss of TRAF1 in RAJI cells. OTSSP167 and XL-228 treatment of primary patient CLL samples led to a reduction in TRAF1, pNF-κB p65, pS6, pERK, Mcl-1 and Bcl-2 proteins, and induction of activated caspase-3. OTSSP167 synergized with venetoclax in inducing CLL death, correlating with loss of TRAF1, Mcl-1 and Bcl-2. Although correlative, these findings suggest the PKN1-TRAF1 signaling axis as a potential new target for CLL. These findings also suggest OTSSP167 and venetoclax as a combination treatment for TRAF1 high CLL.
Physical, cognitive and mental health impacts of COVID-19 following hospitalisation – a multi-centre prospective cohort study
Authors:   PHOSP-COVID Collaborative Group, Evans Rachael Andrea , McAuley Hamish , Harrison Ewen M , Shikotra Aarti , Singapuri Amisha , Sereno Marco , Elneima Omer , Docherty Annemarie B , Lone Nazir I , Leavy Olivia C , Daines Luke , Baillie J Kenneth , Brown Jeremy S , Chalder Trudie , De Soyza Anthony , Diar Bakerly Nawar , Easom Nicholas , Geddes John R , Greening Neil J , Hart Nick , Heaney Liam G , Heller Simon , Howard Luke , Jacob Joseph , Jenkins R Gisli , Jolley Caroline , Kerr Steven , Kon Onn M , Lewis Keir , Lord Janet M , McCann Gerry P , Neubauer Stefan , Openshaw Peter JM , Pfeffer Paul , Rowland Matthew , Semple Malcolm G , Singh Sally J , Sheikh Aziz , Thomas David , Toshner Mark , Chalmers James D , Ho Ling-Pei , Horsley Alex , Marks Michael , Poinasamy Krisnah , Wain Louise V , Brightling Christopher E 
Published: March 2021

BackgroundThe impact of COVID-19 on physical and mental health, and employment following hospitalisation is poorly understood.MethodsPHOSP-COVID is a multi-centre, UK, observational study of adults discharged from hospital with a clinical diagnosis of COVID-19 involving an assessment between two- and seven-months later including detailed symptom, physiological and biochemical testing. Multivariable logistic regression was performed for patient-perceived recovery with age, sex, ethnicity, body mass index (BMI), co-morbidities, and severity of acute illness as co-variates. Cluster analysis was performed using outcomes for breathlessness, fatigue, mental health, cognition and physical function.FindingsWe report findings of 1077 patients discharged in 2020, from the assessment undertaken a median 5 [IQR4 to 6] months later: 36% female, mean age 58 [SD 13] years, 69% white ethnicity, 27% mechanical ventilation, and 50% had at least two co-morbidities. At follow-up only 29% felt fully recovered, 20% had a new disability, and 19% experienced a health-related change in occupation. Factors associated with failure to recover were female, middle-age, white ethnicity, two or more co-morbidities, and more severe acute illness. The magnitude of the persistent health burden was substantial and weakly related to acute severity. Four clusters were identified with different severities of mental and physical health impairment: 1) Very severe (17%), 2) Severe (21%), 3) Moderate with cognitive impairment (17%), 4) Mild (46%), with 3%, 7%, 36% and 43% feeling fully recovered, respectively. Persistent systemic inflammation determined by C-reactive protein was related to cluster severity, but not acute illness severity.InterpretationWe identified factors related to recovery from a hospital admission with COVID-19 and four different phenotypes relating to the severity of physical, mental, and cognitive health five months later. The implications for clinical care include the potential to stratify care and the need for a pro-active approach with wide-access to COVID-19 holistic clinical services.Funding: UKRI and NIHR