bluuebunny/crossref_metadata_2025_split huggingface dataset:
Virological and serological characterization of critically ill patients with COVID-19 in the UK: a special focus on variant detection
Authors: Ratcliff Jeremy , Nguyen Dung , Fish Matthew , Rhynne Jennifer , Jennings Aislinn , Williams Sarah , Al-Beidh Farah , Bonsall David , Evans Amy , Golubchik Tanya , Gordon Anthony C , Lamikanra Abigail , Tsang Pat , Ciccone Nick , Leuscher Ullrich , Slack Wendy , Laing Emma , Mouncey Paul R , Ziyenge Sheba , Olivera Marta , Ploeg Rutger , Rowan Kathryn M , Shankar-Hari Manu , Roberts David J. , Menon David K , Estcourt Lise , Simmonds Peter , Harvala Heli 
Published: March 2021

ABSTRACTBackgroundTreatment of COVID-19 patients with convalescent plasma containing neutralising antibody to SARS-CoV-2 is under investigation as a means of reducing viral loads, ameliorating disease outcomes, and reducing mortality. However, its efficacy might be reduced in those infected with the emerging B.1.1.7 SARS-CoV-2 variant. Here, we report the diverse virological characteristics of UK patients enrolled in the Immunoglobulin Domain of the REMAP-CAP randomised controlled trial.MethodsSARS-CoV-2 viral RNA was detected and quantified by real-time PCR in nasopharyngeal swabs obtained from study subjects within 48 hours of admission to intensive care unit. Antibody status was determined by spike-protein ELISA. B.1.1.7 strain was differentiated from other SARS-CoV-2 strains by two novel typing methods detecting the B.1.1.7-associated D1118H mutation with allele-specific probes and by restriction site polymorphism (SfcI).FindingsOf 1260 subjects, 90% were PCR-positive with viral loads in nasopharyngeal swabs ranging from 72 international units [IUs]/ml to 1.7×1011IU/ml. Median viral loads were 45-fold higher in those who were seronegative for IgG antibodies (n=314; 28%) compared to seropositives (n=804; 72%), reflecting in part the latter group’s possible later disease stage on enrolment. Frequencies of B.1.1.7 infection increased from early November (<1%) to December 2020 (>60%). Anti-SARS-CoV-2 seronegative individuals infected with wild-type SARS-CoV-2 had significantly higher viral loads than seropositives (medians of 1.2×106and 3.4 ×104IU/ml respectively; p=2×10−9). However, viral load distributions were elevated in both seropositive and seronegative subjects infected with B.1.1.7 (13.4×106and 7.6×106IU/ml; p=0.18).InterpretationHigh viral loads in seropositive B.1.1.7-infected subjects are consistent with increased replication capacity and/or less effective clearance by innate or adaptive immune response of B.1.1.7 strain than wild-type. As viral genotype was associated with diverse virological and immunological phenotypes, metrics of viral load, antibody status and infecting strain should be used to define subgroups for analysis of treatment efficacy.
SWIFT: A Deep Learning Approach to Prediction of Hypoxemic Events in Critically-Ill Patients Using SpO2 Waveform Prediction
Authors: Annapragada Akshaya V. , Greenstein Joseph L. , Bose Sanjukta N. , Winters Bradford D. , Sarma Sridevi V. , Winslow Raimond L. 
Published: March 2021

AbstractHypoxemia is a significant driver of mortality and poor clinical outcomes in conditions such as brain injury and cardiac arrest in critically ill patients, including COVID-19 patients. Given the host of negative clinical outcomes attributed to hypoxemia, identifying patients likely to experience hypoxemia would offer valuable opportunities for early and thus more effective intervention. We present SWIFT (SpO2Waveform ICU Forecasting Technique), a deep learning model that predicts blood oxygen saturation (SpO2) waveforms 5 and 30 minutes in the future using only prior SpO2 values as inputs. When tested on novel data, SWIFT predicts more than 80% and 60% of hypoxemic events in critically ill and COVID-19 patients, respectively. SWIFT also predicts SpO2 waveforms with average MSE below .0007. SWIFT provides information on both occurrence and magnitude of potential hypoxemic events 30 minutes in advance, allowing it to be used to inform clinical interventions, patient triaging, and optimal resource allocation. SWIFT may be used in clinical decision support systems to inform the management of critically ill patients during the COVID-19 pandemic and beyond.
Just 2% of SARS-CoV-2-positive individuals carry 90% of the virus circulating in communities
Authors: Yang Qing , Saldi Tassa K. , Lasda Erika , Decker Carolyn J. , Paige Camille L. , Muhlrad Denise , Gonzales Patrick K. , Fink Morgan R. , Tat Kimngan L. , Hager Cole R. , Davis Jack C. , Ozeroff Christopher D. , Meyerson Nicholas R. , Clark Stephen K. , Fattor Will T. , Gilchrist Alison R. , Barbachano-Guerrero Arturo , Worden-Sapper Emma R. , Wu Sharon S. , Brisson Gloria R. , McQueen Matthew B. , Dowell Robin D. , Leinwand Leslie , Parker Roy , Sawyer Sara L. 
Published: March 2021

AbstractWe analyze data from the Fall 2020 pandemic response efforts at the University of Colorado Boulder (USA), where more than 72,500 saliva samples were tested for SARS-CoV-2 using quantitative RT-PCR. All samples were collected from individuals who reported no symptoms associated with COVID-19 on the day of collection. From these, 1,405 positive cases were identified. The distribution of viral loads within these asymptomatic individuals was indistinguishable from what has been previously reported in symptomatic individuals. Regardless of symptomatic status, approximately 50% of individuals who test positive for SARS-CoV-2 seem to be in non-infectious phases of the disease, based on having low viral loads in a range from which live virus has rarely been isolated. We find that, at any given time, just 2% of individuals carry 90% of the virions circulating within communities, serving as viral “super-carriers” and possibly also super-spreaders.
Evaluation of accuracy, exclusivity, limit-of-detection and ease-of-use of LumiraDx™-Antigen-detecting point-of-care device for SARS-CoV-2
Authors: Krüger Lisa J. , Klein Julian A.F. , Tobian Frank , Gaeddert Mary , Lainati Federica , Klemm Sarah , Schnitzler Paul , Bartenschlager Ralf , Cerikan Berati , Neufeldt Christopher J. , Nikolai Olga , Lindner Andreas K. , Mockenhaupt Frank P. , Seybold Joachim , Jones Terry C. , Corman Victor M. , Pollock Nira R. , Knorr Britta , Welker Andreas , de Vos Margaretha , Sacks Jilian A. , Denkinger Claudia M. ,   for the study team
Published: March 2021

AbstractBackgroundRapid antigen-detecting tests (Ag-RDTs) for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can transform pandemic control. Thus far, sensitivity (≤85%) of lateral-flow assays has limited scale-up. Conceivably, microfluidic immunofluorescence Ag-RDTs could increase sensitivity for SARS-CoV-2 detection.Materials and MethodsThis multi-centre diagnostic accuracy study investigated performance of the microfluidic immunofluorescence LumiraDx™ assay, enrolling symptomatic and asymptomatic participants with suspected SARS-CoV-2 infection. Participants collected a supervised nasal mid-turbinate (NMT) self-swab for Ag-RDT testing, in addition to a professionally-collected nasopharyngeal (NP) swab for routine testing with reverse transcriptase polymerase chain reaction (RT-PCR). Results were compared to calculate sensitivity and specificity. Sub-analyses investigated the results by viral load, symptom presence and duration. An analytical study assessed exclusivity and limit-of-detection (LOD). In addition, we evaluated ease-of-use.ResultsStudy conduct was between November 2nd 2020 and January 21st 2021. 761 participants were enrolled, with 486 participants reporting symptoms on testing day. 120 out of 146 RT-PCR positive cases were detected positive by LumiraDx™, resulting in a sensitivity of 82.2% (95% CI: 75.2%-87.5%). Specificity was 99.3% (CI: 98.3-99.7%). Sensitivity was increased in individuals with viral load ≥ 7 log10 SARS-CoV2 RNA copies/ml (93.8%; CI: 86.2%-97.3%). Testing against common respiratory commensals and pathogens showed no cross-reactivity and LOD was estimated to be 2-56 PFU/mL. The ease-of-use-assessment was favourable for lower throughput settings.ConclusionThe LumiraDx™ assay showed excellent analytical sensitivity, exclusivity and clinical specificity with good clinical sensitivity using supervised NMT self-sampling.
Meta-analytic findings on reading in children with cochlear implants
Authors: Wang Yingying , Sibaii Fatima , Lee Kejin , Gill Makayla J. , Hatch Jonathan L. 
Published: March 2021

AbstractThis meta-analysis study aims to quantify the group differences in reading skills between children with cochlear implants and their hearing peers and between children with cochlear implants and children with hearing aids (aged between 3 to 18 years old). Of the 5,642 articles screened, 47 articles met predetermined inclusion criteria (published between 2002 and 2019). The robust variance estimation based meta-analysis models were used to synthesize all the effect sizes. Children with cochlear implants scored significantly lower than their hearing peers in phonological awareness (g = - 1.62, p < .001), vocabulary (g = -1.50, p < .001), decoding (g = -1.24, p < .001), and reading comprehension (g = -1.39, p < .001), but not for fluency (g = -.67, p = .054). Compared to children with hearing aids, children with cochlear implants scored significantly lower in phonological awareness (g = -.30, p = .028). The percentage of unilateral cochlear implant negatively impacts the group difference between children with cochlear implants and their hearing peers. Findings from this study confirm a positive shift in reading outcomes for profoundly deaf children due to cochlear implantation. Some children with cochlear implants may need additional supports in educational settings.
COVID-19 test positivity: predictive value of various symptoms in a large community-based testing program in California
Authors: Miller Dave P. , Morrow Scott , Califf Robert M. , Kaiser Cameron , Kapur Ritu , Starsiak Casimir , Mega Jessica , Marks William J. 
Published: March 2021

AbstractBackgroundMuch of the early data on COVID-19 symptomatology was captured in the hospital setting. In a community setting the symptoms most predictive of SARS-CoV-2 positivity may be different. Data from the California sites of a COVID-19 community testing program are presented here.MethodsPrior to being tested, participants in the Baseline COVID-19 Testing Program completed an online screener, in which they self-reported basic demographics and the presence or absence of 10 symptoms. Both positive and negative COVID-19 RT-PCR tests were linked back to the screener data. A multivariable model of positivity was fit using generalized estimating equations, adjusting for month of testing as a fixed effect and accounting for clustering of data within each test site.ResultsAmong 547,018 first-time tests in California in 2020, positivity rates were 3.4%, 9.9%, and 19.8% for participants with no symptoms, 1 symptom, or 2 or more symptoms at the time of screening, respectively. All ten symptoms were individually associated with higher positivity rates, but only six of ten symptoms were associated with higher positivity when adjusting for other symptoms. Major symptoms with highest predictive value were recent loss of taste or smell, fever, and coughing with ORs of 3.27, 1.97, and 1.95, respectively. Shortness of breath and vomiting or diarrhea were negatively associated with positivity adjusting for other symptoms and, absent other symptoms, participants with these symptoms did not have significantly higher positivity rates than asymptomatic participants.ConclusionsRecent loss of taste and smell should be elevated to a major symptom along with fever and coughing in public health messaging and in our community approach to testing and surveillance, while mild to moderate shortness of breath should be de-emphasized as a sensitive early predictor of COVID-19 positivity.
Combining explainable machine learning, demographic and multi-omic data to identify precision medicine strategies for inflammatory bowel disease
Authors: Gardiner Laura-Jayne , Carrieri Anna Paola , Bingham Karen , Macluskie Graeme , Bunton David , McNeil Marian , Pyzer-Knapp Edward O. 
Published: March 2021

AbstractInflammatory bowel diseases (IBDs), including ulcerative colitis and Crohn’s disease, affect several million individuals worldwide. These diseases are heterogeneous at the clinical, immunological and genetic levels and result from a complex interaction between the host and environmental factors. Investigating drug efficacy in cultured human fresh IBD tissues can improve our understanding of the reasons why certain medications are more or less effective for different patients.We propose an explainable machine learning (ML) approach that combines bioinformatics and domain insight, to informatively integrate multi-modal data to predict inter-patient specific variation in drug response. Using explanation of our models, we interpret the models’ predictions inferring unique combinations of important features associated with human tissue pharmacological responses. The inferred multi-modal features originate from multi-omic data (genomic and transcriptomic), demographic, medicinal and pharmacological data and all are associated with drug efficacy generated by a preclinical human fresh IBD tissue assay.To pharmacologically assess patient variation in response to IBD treatment, we used the reduction in the release of the inflammatory cytokine TNFα from the fresh IBD tissues in the presence or absence of test drugs, as a measure of drug efficacy. The TNF pathway is a common target in current therapies for IBD; we initially explored the effects of a mitogen-activated protein kinase (MAPK) inhibitor on the production of TNFα; however, we later show the approach can be applied to other targets, test drugs or mechanisms of interest. Our best model was able to predict TNFα levels from a combination of integrated demographic, medicinal and genomic features with an error as low as 4.98% on unseen patients. We incorporated transcriptomic data to validate and expand insights from genomic features. Our results showed variations in drug effectiveness between patients that differed in gender, age or condition and linked new genetic polymorphisms in our cohort of IBD patients to variation in response to the anti-inflammatory treatment BIRB796 (Doramapimod).Our approach models drug response in a relevant human tissue model of IBD while also identifying its most predictive features as part of a transparent ML-based precision medicine strategy.
Effect of Pre-harvest Calcium Chloride and Salicylic Acid Spray on Morphological and Biochemical Traits of Guava (Psidium guajava)
Authors: Kaushik Lochan , Kumar Rahul , Reddy Dilip Kumar , Kaushik Prashant 
Published: March 2021

AbstractGuava is a small, tropical fruit tree grown in various tropical and subtropical regions. Salicylic acid (SA) is a phenolic compound that enhances disease resistance and delays the fruit ripening process. Calcium is an essential cell component that delays ripening, particularly softening of the fruit. The effect of foliar spray of CaCl2, and SA, on the physical and biochemical traits of guava was investigated in the present investigation. The application of CaCl22% + SA 2mM was more effective as compared with both when applied alone. The data were recorded on fruit set (%), fruit weight (g), fruit length (cm), fruit diameter (cm), fruit yield (kg), ripening period (days), TSS, acidity, total sugar, ascorbic acid, nitrogen, phosphorus, potassium. CaCl22% + SA 2mM was showed better performance in all cases, followed by SA 2mM and CaCl22%. Overall, this work determines the influence on guava's essential traits by pre-harvest calcium chloride and salicylic acid.
Conserved structures of neural activity in sensorimotor cortex of freely moving rats allow cross-subject decoding
Authors: Melbaum Svenja , Russo Eleonora , Eriksson David , Schneider Artur , Durstewitz Daniel , Brox Thomas , Diester Ilka 
Published: March 2021

Our knowledge about neuronal activity in the sensorimotor cortex relies primarily on stereotyped movements that are strictly controlled in experimental settings. It remains unclear how results can be carried over to less constrained behavior like that of freely moving subjects. Toward this goal, we developed a self-paced behavioral paradigm that encouraged rats to engage in different movement types. We employed bilateral electrophysiological recordings across the entire sensorimotor cortex and simultaneous paw tracking. These techniques revealed behavioral coupling of neurons with lateralization and an anterior–posterior gradient from the premotor to the primary sensory cortex. The structure of population activity patterns was conserved across animals despite the severe under-sampling of the total number of neurons and variations in electrode positions across individuals. We demonstrated cross-subject and cross-session generalization in a decoding task through alignments of low-dimensional neural manifolds, providing evidence of a conserved neuronal codeOne-sentence summarySimilarities in neural population structures across the sensorimotor cortex enable generalization across animals in the decoding of unconstrained behavior.Graphical abstractConserved structures of neural activity in freely moving rats allow for cross-subject decoding.(a) We conducted electrophysiological recordings across the bilateral sensorimotor cortex of six freely moving rats. Neural activities were projected into a low-dimensional space with LEMs (22). (b) In a decoding task, points in the aligned low-dimensional neural state space were used as input for a classifier that predicted behavioral labels. Importantly, training and testing data originated from different rats. (c) Our procedure led to successful cross-subject generalization for sessions with sufficient numbers of recorded units. The rat and brain drawings are adapted fromscalablebrainatlas.incf.organd SciDraw.
Generation and mutational analysis of a transgenic mouse model of human SRY
Authors: Thomson Ella , Zhao Liang , Chen Yen-Shan , Longmuss Enya , Ng Ee Ting , Sreenivasan Rajini , Croft Brittany , Song Xin , Sinclair Andrew , Weiss Michael , Pelosi Emanuele , Koopman Peter 
Published: March 2021

AbstractSRY is the Y-chromosomal gene that determines male sex development in humans and most other mammals. After three decades of study, we still lack a detailed understanding of which domains of the SRY protein are required to engage pathway of gene activity leading to testis development. Some insight has been gained from the study of genetic variations underlying differences/disorders of sex determination (DSD), but the lack of a system of experimentally generating SRY mutations and studying their consequences in vivo has limited progress in the field. To address this issue, we generated a mouse model carrying a humanSRYtransgene able to drive male sex determination in XX mice. Using CRISPR-Cas9 gene editing, we generated novel genetic modifications in each ofSRY’s three domains (N-terminal, HMG box, and C-terminal) and performed detailed analysis of their molecular and cellular effects on embryonic testis development. Our results provide new functional insights unique to humanSRYand the causes of DSD, and present a versatile and powerful system in which to demonstrate causality ofSRYvariations in DSD, to functionally study theSRYvariation database, and to characterize new pathogenicSRYvariations found in DSD.
Identifying Dihydropyrimidine Dehydrogenase as a Novel Regulator of Hepatic Steatosis
Authors: Sullivan Kelly E. , Kumar Sheetal , Zhang Ye , de Koning Emily , Yuan Jing , Fan Fan 
Published: March 2021

AbstractPyrimidine catabolism is implicated in hepatic steatosis. Dihydropyrimidine Dehydrogenase (DPYD) is an enzyme responsible for uracil and thymine catabolism, and DPYD human genetic variability affects clinically observed toxicity following 5-Fluorouracil (5-FU) administration. In anin vitromodel of diet-induced steatosis, the pharmacologic inhibition of DPYD resulted in protection from lipid accumulation. Additionally, a gain-of-function mutation of DPYD, created through clustered regularly interspaced short palindromic repeats associated protein 9 (CRISPR-Cas9) engineering, led to an increased lipid burden, which was associated with altered mitochondrial functionality in a hepatocarcionma cell line. The studies presented herein describe a novel role for DPYD in hepatocyte metabolic regulation as a modulator of hepatic steatosis.
Modulation of fatty acid elongation sustains sexually dimorphic hydrocarbons and female attractiveness inBlattella germanica(L.)
Authors: Pei Xiao-Jin , Fan Yong-Liang , Bai Yu , Bai Tian-Tian , Schal Coby , Zhang Zhan-Feng , Chen Nan , Li Sheng , Liu Tong-Xian 
Published: March 2021

AbstractInsect cuticular hydrocarbons (CHCs) serve as important intersexual signaling chemicals and generally show variation between the sexes, but little is known about the generation of sexually dimorphic hydrocarbons (SDHCs) in insects. Here, we report the molecular mechanism and biological significance that underling the generation of SDHC in the German cockroach,Blattella germanica. Sexually mature females possess more C29 cuticular hydrocarbons (CHCs), especially the contact sex pheromone precursor 3,11-DimeC29. RNAi screen against fatty acid elongase gene family members and combined with heterologous expression revealed that bothBgElo12andBgElo24were involved in HC production, butBgElo24is of wide catalytic activities and is able to provides substrates forBgElo12, and only the female-enrichedBgElo12was responsible for sustaining female-specific HC profile. RepressingBgElo12masculinized the female CHC profile, decreased contact sex pheromone level and consequently reduced the sexual attractiveness of female cockroaches. Moreover, the asymmetric expression ofBgElo12between the sexes is modulated by sex differentiation cascade. Specifically, male-specificBgDsxrepresses the transcription ofBgElo12in males, whileBgTrais able to remove this effect in females. Our study reveals a novel molecular mechanism responsible for the formation of SDHCs, and also provide evidences on shaping of the SDHCs by sexual selection, as females use them to generate high levels of contact sex pheromone.
Orexigen: Valuing Contrave
Authors: Calkins Tim 
Published: March 2021

In January 2013, small biotechnology firm Orexigen was in the final stages of testing Contrave, a promising new pharmaceutical product for the treatment of obesity. At the time, Orexigen had no products in the market, so all its hopes of financial success rested on this new treatment. Contrave had proven to be highly effective in clinical trials, and Orexigen executives were confident it would receive FDA approval.
At the same time, a much larger pharmaceutical company was considering acquiring Orexigen. Because the decision to acquire would ultimately be a financial one, the project team from the large company had to complete a valuation for Orexigen's only significant product in its pipeline, Contrave. What was the new product actually worth?