bluuebunny/crossref_metadata_2025_split huggingface dataset:
Development and Evaluation of a new Swiss Made SARS-CoV-2 antigen-detecting rapid test
Authors: P.J. Ducrest 
Published: March 2021

AbstractThere is an urgent need in rapid diagnostic test (RDT) to detect antigen of SARS-CoV-2 to reduce the spread of COVID-19 outbreak. We have developed a rapid and simple point-of-care lateral flow immunoassay (LFIA) detecting nucleocapsid antigen of SARS-CoV-2 in 10 minutes. The aim of this study is to evaluate the diagnostic performance and analytical sensitivity of this RDT. RT-PCR positive nasopharyngeal swab samples (n=20) for SARS-CoV-2 and 40 negative control samples were studied. Analytical sensitivity was assessed using Gamma-irradiated SARS-CoV-2 and the limit of detection (LOD) was determined at 1.4 × 102 TCID50/ml. Overall, RDT diagnostic sensitivity was 90% (95% confidence interval [95%CI]: 67-98%) and specificity 98% (95% CI: 85-100%). The sensitivity was 100% (95% CI: 75-100%) when using only samples with a RT-PCR Cycle threshold lower than 30. This antigen RDT displays a high diagnostic accuracy for SARS-CoV-2 antigen detection in high COVID-19 prevalence settings. Its use could be considered in the absence of routine RT-PCR facilities such in low-income countries.
Early onset leprosy reveals a joint effect of LRRK2 and NOD2 variants
Authors: Dallmann-Sauer Monica , Xu Yong Zhong , da Costa Ana Lúcia França , Tao Shao , Correa-Macedo Wilian , Manry Jérémy , Abel Laurent , Alcaïs Alexandre , Cobat Aurélie , Fava Vinicius M. , Probst Christian M. , Mira Marcelo T. , Schurr Erwin 
Published: March 2021

AbstractLeprosy, caused by Mycobacterium leprae, has a long incubation period and cases with age-of-onset <5 years are rare. Here, we studied a three-generational multiplex leprosy family which included monozygotic twins age <24 months suffering from paucibacillary leprosy. Whole genome sequencing identified a homozygous double mutation in the LRRK2 gene (N551K, R1398H) and a heterozygous mutation in NOD2 (R702W) as candidate variants underlying the early onset phenotype in the twins. The same amino acid substitutions had previously been identified as shared risk-modulating factors for Crohn’s disease and Parkinson’s disease. To evaluate the functional impact of the LRRK2 mutations, we employed genome editing in RAW264.7 cells. Cells expressing the LRRK2 variants displayed reduced respiratory burst and apoptosis following mycobacterial challenge. Moreover, the BCG-induced respiratory burst was significantly lower in LRRK2 wild-type-expressing cells transfected with NOD2 R702W compared with NOD2 wild-type constructs. Employing co-immunoprecipitation, we showed that LRRK2 and NOD2 wild-type proteins interact in RAW cells. This interaction was independent of the LRRK2 variants but strongly reduced for NOD2 R702W. However, N-glycolyl MDP-triggered RIP2 phosphorylation and NF-kB activation were additively reduced by both LRRK2 and NOD2 mutations. Finally, we observed a joint effect of LRRK2 and NOD2 variants on cytokine/chemokine secretion with the most significant reduction of secretion observed for the mutant genotypes carried by the twins. These data demonstrated the pleiotropic effects of LRRK2 and NOD2 in response to mycobacterial infection consistent with a role of the identified mutations in the development of early onset leprosy.One Sentence SummaryVariants of NOD2 and LRRK2 shared between early onset leprosy, Parkinson’s and Crohn’s disease jointly impact the anti-mycobacterial host response.
Non-nucleoside reverse transcriptase inhibitor-based combination antiretroviral therapy is associated with lower cell-associated HIV RNA and DNA levels as compared with therapy based on protease inhibitors
Authors: Pasternak Alexander O. , Vroom Jelmer , Kootstra Neeltje A. , Wit Ferdinand W.N.M. , Bruin Marijn de , Francesco Davide De , Bakker Margreet , Sabin Caroline A , Winston Alan , Prins Jan M. , Reiss Peter , Berkhout Ben 
Published: March 2021

AbstractBACKGROUNDIt remains unclear whether combination antiretroviral therapy (ART) regimens differ in their ability to fully suppress HIV replication. Here, we report the results of two cross-sectional studies that compared levels of cell-associated (CA) HIV markers between individuals receiving suppressive ART containing either a non-nucleoside reverse transcriptase inhibitor (NNRTI) or a protease inhibitor (PI).METHODSCA HIV unspliced RNA and total HIV DNA were quantified in two cohorts (n=100, n=124) of individuals treated with triple ART regimens consisting of two nucleoside reverse transcriptase inhibitors (NRTIs) plus either a NNRTI or a PI. To compare CA HIV RNA and DNA levels between the regimens, we built multivariable models adjusting for age, gender, current and nadir CD4+ count, plasma viral load zenith, duration of virological suppression, NRTI backbone composition, low-level plasma HIV RNA detectability, and electronically-measured adherence to ART.RESULTSIn both cohorts, levels of CA HIV RNA and DNA strongly correlated (rho=0.70 and rho=0.54) and both markers were lower in NNRTI-treated than in PI-treated individuals. In the multivariable analysis, CA RNA in both cohorts remained significantly reduced in NNRTI-treated individuals (padj=0.02 in both cohorts), with a similar but weaker association between the ART regimen and total HIV DNA (padj=0.048 and padj=0.10). No differences in CA HIV RNA or DNA levels were observed between individual NNRTIs or individual PIs, but CA HIV RNA was lower in individuals treated with either nevirapine or efavirenz, compared to PI-treated individuals.CONCLUSIONSAll current classes of antiretroviral drugs only prevent infection of new cells but do not inhibit HIV RNA transcription in long-lived reservoir cells. Therefore, these differences in CA HIV RNA and DNA levels by treatment regimen suggest that NNRTIs are more potent in suppressing HIV residual replication than PIs, which may result in a smaller viral reservoir size.
Virtual peer role-play during COVID-19 pandemic for teaching medical students how to break bad news
Authors: Bouaoud Jebrane , Saintigny Pierre 
Published: March 2021

AbstractIn order to cope with the SARS-CoV-2 pandemic and meet with the educational needs of medical students, we have evaluated the virtual peer role-plays (VPRP), an innovative approach to teach breaking bad news communication skills to medical students. Three scenarios of relational simulation were successively proposed to 237 medical students divided in 10 groups, each supervised by two teachers. Pre- and post-VPRP questionnaires were submitted to evaluate students’ satisfaction. The response rate of the pre- and post-VPRP questionnaires were 89% and 52% respectively. Two-thirds of the students had never participated in a peer role-play session. Most students had low level of confidence in breaking bad news communication and were motivated to participate to the VPRP session. Students’ satisfaction on VPRP session regarding quality (realism, organization), interest, perceived benefits was very positive. In conclusion, VPRP are feasible, of low cost (no material is required), applicable to other healthcare students and is relevant to the growth of teleconsultation.
Is the vitamin D status of patients with COVID-19 associated with reduced mortality?
Authors: Bignardi Paulo R , de Andrade Castello Paula , de Matos Aquino Bruno , Alvares Delfino Vinicius Daher 
Published: March 2021

ABSTRACTObjectiveA systematic review with meta-analysis was performed to assess a possible association between plasma vitamin D levels and mortality in patients with COVID – 19.MethodsPubMed, EMBASE, and Cochrane Library databases were searched. Studies involving COVID-19 patients that reported an association between plasma vitamin D levels and COVID-19 mortality published until February 5, 2021, were included. The risk ratio (RR) and confidence interval (CI) were pooled using a fixed-effects or random-effects model.ResultsA total of 11 studies that measured plasma vitamin D levels at admission were included in the meta-analysis, ten cohorts and one case-controls. Low plasma vitamin D levels (25(OH)D) in patients with COVID-19 were not associated with mortality (RR=1.35, 95%CI 0.84–1.86). Subgroup analysis by vitamin D cut-off (<20 or 25 ng/ml and <10 or 12 ng/ml) showed were not associated with mortality. When the RR in mortality analysis was calculated included four studies that did not perform adjusted analysis for confounding factors, the result was 1.43 (95% CI 1.18-1.69), suggesting that confounders may have led many observational studies to incorrectly estimate the association between vitamin D status and mortality in COVID-19 patients.ConclusionDeficient vitamin D levels were not associated with a higher mortality rate in patients with COVID-19. Randomized clinical trials are needed to assess this association.
Diagnostic accuracy of cerebrospinal fluid and blood biomarkers for the differential diagnosis of sporadic Creutzfeldt-Jakob disease: a (network) meta-analysis
Authors: Rübsamen Nicole , Pape Stephanie , Konigorski Stefan , Zapf Antonia , Rücker Gerta , Karch André 
Published: March 2021

ABSTRACTObjectiveTo conduct a systematic review of cerebrospinal fluid (CSF) and blood biomarkers as diagnostic tests for sporadic Creutzfeldt-Jakob disease (sCJD) in a specialised care setting and to compare diagnostic accuracies in a network meta-analysis (NMA).MethodsWe searched Medline, Embase, and the Cochrane Library for diagnostic studies of sCJD biomarkers. Risk of bias was assessed with the QUADAS-2 tool. We used a generalised bivariate model to conduct individual biomarker meta-analyses, and to estimate between-study variability. To investigate sources of heterogeneity, we performed subgroup analyses based on QUADAS-2 quality and clinical criteria. For the NMA, we applied a Bayesian beta-binomial ANOVA model. The study protocol was registered at PROSPERO (CRD42019118830).ResultsOut of 2,976 publications screened, we included 16 studies, which investigated 14-3-3β Western blot (n=13), 14-3-3γ ELISA (n=3), NfL (n=1), NSE (n=1), p-tau181/t-tau ratio (n=2), RT-QuIC (n=6), S100B (n=3), t-tau (n=12), and t-tau/Aβ42 ratio (n=1) in CSF. No included study investigated blood biomarkers. Many diagnostic studies excluded had strong limitations in study design. In the NMA, RT-QuIC (0.93; 95% CI [0.87, 0.96]) and NfL (0.94 [0.81, 0.99]) were the most sensitive biomarkers. RT-QuIC was the most specific biomarker (0.96 [0.86, 0.99]), and had the highest balanced accuracy (0.94). Heterogeneity in accuracy estimates was high between studies, especially for specificity.ConclusionsOur NMA identified RT-QuIC as the overall most accurate biomarker, partially confirming current guidelines. The severe shortcomings identified in many diagnostic studies for sCJD biomarkers need to be addressed in future studies in the field.
Automatic identification of risk factors for SARS-CoV-2 positivity and severe clinical outcomes of COVID-19 using Data Mining and Natural Language Processing
Authors: Schöning Verena , Liakoni Evangelia , Drewe Jürgen , Hammann Felix 
Published: March 2021

ABSTRACTObjectivesSeveral risk factors have been identified for severe clinical outcomes of COVID-19 caused by SARS-CoV-2. Some can be found in structured data of patients’ Electronic Health Records. Others are included as unstructured free-text, and thus cannot be easily detected automatically. We propose an automated real-time detection of risk factors using a combination of data mining and Natural Language Processing (NLP).Material and methodsPatients were categorized as negative or positive for SARS-CoV-2, and according to disease severity (severe or non-severe COVID-19). Comorbidities were identified in the unstructured free-text using NLP. Further risk factors were taken from the structured data.Results6250 patients were analysed (5664 negative and 586 positive; 461 non-severe and 125 severe). Using NLP, comorbidities, i.e. cardiovascular and pulmonary conditions, diabetes, dementia and cancer, were automatically detected (error rate ≤2%). Old age, male sex, higher BMI, arterial hypertension, chronic heart failure, coronary heart disease, COPD, diabetes, insulin only treatment of diabetic patients, reduced kidney and liver function were risk factors for severe COVID-19. Interestingly, the proportion of diabetic patients using metformin but not insulin was significantly higher in the non-severe COVID-19 cohort (p<0.05).Discussion and conclusionOur findings were in line with previously reported risk factors for severe COVID-19. NLP in combination with other data mining approaches appears to be a suitable tool for the automated real-time detection of risk factors, which can be a time saving support for risk assessment and triage, especially in patients with long medical histories and multiple comorbidities.
Increasing Trust in Real-World Evidence Through Evaluation of Observational Data Quality
Authors: Blacketer Clair , Defalco Frank J , Ryan Patrick B , Rijnbeek Peter R 
Published: March 2021

ABSTRACTAdvances in standardization of observational healthcare data have enabled methodological breakthroughs, rapid global collaboration, and generation of real-world evidence to improve patient outcomes. Standardizations in data structure, such as use of Common Data Models (CDM), need to be coupled with standardized approaches for data quality assessment. To ensure confidence in real-world evidence generated from the analysis of real-world data, one must first have confidence in the data itself. The Data Quality Dashboard is an open-source R package that reports potential quality issues in an OMOP CDM instance through the systematic execution and summarization of over 3,300 configurable data quality checks. We describe the implementation of check types across a data quality framework of conformance, completeness, plausibility, with both verification and validation. We illustrate how data quality checks, paired with decision thresholds, can be configured to customize data quality reporting across a range of observational health data sources. We discuss how data quality reporting can become part of the overall real-world evidence generation and dissemination process to promote transparency and build confidence in the resulting output. Transparently communicating how well CDM standardized databases adhere to a set of quality measures adds a crucial piece that is currently missing from observational research. Assessing and improving the quality of our data will inherently improve the quality of the evidence we generate.
Task-related excitatory/inhibitory ratios in the fronto-striatal circuitry predict attention control deficits in attention-deficit/hyperactivity disorder
Authors: Mamiya Ping C. , Richards Todd L. , Edden Richard A.E. , Lee Adrian K.C. , Stein Mark A. , Kuhl Patricia K. 
Published: March 2021

AbstractReduced GABA concentrations at rest in the fronto-striatal circuitry are repeatedly implicated in cognitive symptoms of ADHD. However, recent evidence has suggested that GABA and its precursor, glutamate, are capable of undergoing dynamic modifications in response to environments. Yet, it remains unclear how the dynamics between glutamate and GABA may change when people are exerting their control of attention, and whether they would predict attention control deficits in ADHD. To study this question, we used MR spectroscopy to quantify GABA and glutamate+glutamine (Glx) concentrations in the anterior cingulate cortex (ACC) and the caudate nucleus in the fronto-striatal circuitry while subjects were performing attention control tasks. We studied 19 adults with ADHD (31-51 years) and 16 adults without ADHD (28-54). We found GABA and Glx concentrations during the tasks increased in both subjects with or without ADHD, but the extent of increases was significantly reduced in subjects with ADHD. Notably, E/I ratios (Glx/GABA) also increased and significantly predicted error rates while subjects with or without ADHD performed the Stroop and Flanker tasks. Critically, regression models including E/I ratios, GABA concentrations, and the ADHD diagnosis significantly predicted task performance in these tasks. Furthermore, clear interactions among these factors predicted the impaired attention control in the Flanker task in subjects with ADHD. These findings demonstrate for the first time that E/I ratios in the ACC and the caudate nucleus increased when people exerted their control of attention, and suggest that reduced GABA contribution to E/I ratio in these two brain regions may account for cognitive deficits in ADHD.
A differential regulatory T cell signature distinguishes the immune landscape of COVID-19 hospitalized patients from those hospitalized with other respiratory viral infections
Authors: Vick Sarah C. , Frutoso Marie , Mair Florian , Konecny Andrew J. , Greene Evan , Wolf Caitlin R. , Logue Jennifer K. , Boonyaratanakornkit Jim , Gottardo Raphael , Schiffer Joshua T. , Chu Helen Y. , Prlic Martin , Lund Jennifer M. 
Published: March 2021

AbstractSARS-CoV-2 infection has caused a lasting global pandemic costing millions of lives and untold additional costs. Understanding the immune response to SARS-CoV-2 has been one of the main challenges in the past year in order to decipher mechanisms of host responses and interpret disease pathogenesis. Comparatively little is known in regard to how the immune response against SARS-CoV-2 differs from other respiratory infections. In our study, we compare the peripheral blood immune signature from SARS-CoV-2 infected patients to patients hospitalized pre-pandemic with Influenza Virus or Respiratory Syncytial Virus (RSV). Our in-depth profiling indicates that the immune landscape in patients infected by SARS-CoV-2 is largely similar to patients hospitalized with Flu or RSV. Similarly, serum cytokine and chemokine expression patterns were largely overlapping. Unique to patients infected with SARS-CoV-2 who had the most critical clinical disease state were changes in the regulatory T cell (Treg) compartment. A Treg signature including increased frequency, activation status, and migration markers was correlated with the severity of COVID-19 disease. These findings are particularly relevant as Tregs are being discussed as a therapy to combat the severe inflammation seen in COVID-19 patients. Likewise, having defined the overlapping immune landscapes in SARS-CoV-2, existing knowledge of Flu and RSV infections could be leveraged to identify common treatment strategies.HighlightsThe immune landscapes of hospitalized pre-pandemic RSV and influenza patients are similar to SARS-CoV-2 patientsSerum cytokine and chemokine expression patterns are largely similar between patients hospitalized with respiratory virus infections, including SARS-CoV-2, versus healthy donorsSARS-CoV-2 patients with the most critical disease displayed unique changes in the Treg compartmentadvances in understanding and treating SARS-CoV-2 could be leveraged for other common respiratory infectionsGraphical Abstract
Acoustic Remote Control of Bacterial Immunotherapy
Authors: Abedi Mohamad H. , Yao Michael S. , Mittelstein David R. , Bar-Zion Avinoam , Swift Margaret , Lee-Gosselin Audrey , Shapiro Mikhail G. 
Published: March 2021

ABSTRACTRapid advances in synthetic biology are driving the development of genetically engineered microbes as therapeutic agents for a multitude of human diseases, including cancer. In particular, the immunosuppressive microenvironment of solid tumors creates a favorable niche for systemically administered bacteria to engraft in the tumor and release therapeutic payloads. However, such payloads can be harmful if released in healthy tissues where the bacteria also engraft in smaller numbers. To address this limitation, we engineer therapeutic bacteria to be controlled by focused ultrasound, a form of energy that can be applied noninvasively to specific anatomical sites such as solid tumors. This control is provided by a temperature-actuated genetic state switch that produces lasting therapeutic output in response to briefly applied focused ultrasound hyperthermia. Using a combination of rational design and high-throughput screening we optimized the switching circuits of engineered cells and connected their activity to the release of immune checkpoint inhibitors. In a clinically relevant cancer model, ultrasound-activated therapeutic microbes successfully turned onin situand induced a marked suppression of tumor growth. This technology provides a critical tool for the spatiotemporal targeting of potent bacterial therapeutics in a variety of biological and clinical scenarios.
A UVB-responsive common variant at chr7p21.1 confers tanning response and melanoma risk via regulation of the aryl hydrocarbon receptor gene (AHR)
Authors: Xu Mai , Mehl Lindsey , Zhang Tongwu , Thakur Rohit , Sowards Hayley , Myers Timothy , Jessop Lea , Chesi Alessandra , Johnson Matthew E , Wells Andrew D , Michael Helen T , Bunda Patricia , Jones Kristine , Higson Herbert , Hennessey Rebecca C , Jermusyk Ashley , Kovacs Michael A , Landi Maria Teresa , Iles Mark M , Goldstein Alisa M ,   Melanoma Meta-Analysis Consortium, Choi Jiyeon , Chanock Stephen J , Grant Struan F A , Chari Raj , Merlino Glenn , Law Matthew H , Brown Kevin M 
Published: March 2021

AbstractGenome-wide association studies have identified a melanoma-associated locus on chromosome band 7p21.1 with rs117132860 as the lead SNP, and a secondary independent signal marked by rs73069846. rs117132860 is also associated with tanning ability and cutaneous squamous cell carcinoma (cSCC). As ultraviolet radiation (UVR) is a key environmental exposure for all three traits, we investigated the mechanisms by which this locus contributes to melanoma risk, focusing on cellular response to UVR. Fine-mapping of melanoma GWAS identified four independent sets of candidate causal variants. A GWAS region-focused Capture-C study of primary melanocytes identified physical interactions between two causal sets and the promoter of the aryl hydrocarbon receptor gene (AHR). Subsequent chromatin state annotation, eQTL, and luciferase assays identified rs117132860 as a functional variant and reinforcedAHRas a likely causal gene. As AHR plays critical roles in cellular response to dioxin and UVR, we explored links between this SNP andAHRexpression after both 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and ultraviolet B (UVB) exposure. Allele-specific AHR binding to rs117132860-G was enhanced following both, consistent with predicted weakened AHR binding to the risk/poor-tanning rs117132860-A allele, and allele-preferentialAHRexpression driven from the protective rs117132860-G allele was observed following UVB exposure. Small deletions surrounding rs117132860 via CRISPR abrogates AHR binding, reduces melanocyte cell growth, and prolongs growth arrest following UVB exposure. These data suggestAHRis a melanoma susceptibility gene at the 7p21.1 risk locus, and rs117132860 is a functional variant within a UVB-responsive element, leading to allelicAHRexpression, and altering melanocyte growth phenotypes upon exposure.