bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pre-pandemic Cognitive Function and COVID-19 Vaccine Hesitancy: Cohort Study
Authors: Batty G. David , Deary Ian J. , Fawns-Ritchie Chloe , Gale Catharine R. , Altschul Drew 
Published: March 2021

AbstractBackgroundWhereas several predictors of COVID-19 vaccine hesitancy have been examined, the role of cognitive function following the widely publicised development of an inoculation is unknown.ObjectiveTo test the association between scores from an array of cognitive function tests and self-reported vaccine hesitancy after the announcement of the successful testing of the Oxford University/AstraZeneca vaccine.Design, Setting, and ParticipantsWe used individual-level data from a pandemic-focused study (COVID Survey), a prospective cohort study nested within Understanding Society (Main Survey). In the week immediately following the announcement of successful testing of the first efficacious inoculation (November/December 2020), data on vaccine intentionality were collected in 11740 individuals (6702 women) aged 16-95. Pre-pandemic scores on general cognitive function, ascertained from a battery of six tests, were captured in 2011/12 wave of the Main Survey.MeasurementsSelf-reported intention to take up a vaccination for COVID-19. To summarise our results, we computed odds ratios with accompanying 95% confidence intervals for general cognitive function adjusted for selected covariates.ResultsOf the study sample, 17.2% (N=1842) indicated they were hesitant about having the vaccine. After adjustment for age, sex, and ethnicity, study members with a lower baseline cognition score were markedly more likely to be vaccine hesitant (odds ratio per standard deviation lower score in cognition; 95% confidence interval: 1.76; 1.62, 1.90). Adjustment for mental and physical health plus household shielding status had no impact on these results, whereas controlling for educational attainment led to partial attenuation but the probability of hesitancy was still elevated (1.52; 1.37, 1.67). There was a linear association for vaccine hesitancy across the full range of cognition scores (p for trend: p<0.0001).LimitationsOur outcome was based on intention rather than behaviour.ConclusionsErroneous social media reports might have complicated personal decision-making, leading to people with lower cognitive ability test scores being vaccine-hesitant. With people with lower cognition also experiencing higher rates of COVID-19 in studies conducted prior to vaccine distribution, these new findings are suggestive of a potential additional disease burden.
The Case for Altruism in Institutional Diagnostic Testing
Authors: Specht Ivan , Sani Kian , Botti-Lodovico Yolanda , Hughes Michael , Heumann Kristin , Bronson Amy , Marshall John , Baron Emily , Parrie Eric , Glennon Olivia , Fry Ben , Colubri Andrés , Sabeti Pardis C. 
Published: March 2021

AbstractAmid COVID-19, many institutions deployed vast resources to test their members regularly for safe reopening. This self-focused approach, however, not only overlooks surrounding communities but also remains blind to community transmission that could breach the institution. To test the relative merits of a more altruistic strategy, we built an epidemiological model that assesses the differential impact on case counts when institutions instead allocate a proportion of their tests to members’ close contacts in the larger community. We found that testing outside the institution benefits the institution in all plausible circumstances, with the optimal proportion of tests to use externally landing at 45% under baseline model parameters. Our results were robust to local prevalence, secondary attack rate, testing capacity, and contact reporting level, yielding a range of optimal community testing proportions from 18% to 58%. The model performed best under the assumption that community contacts are known to the institution; however, it still demonstrated a significant benefit even without complete knowledge of the contact network.
Degradation of lipid based drug delivery formulations during nebulization
Authors: Klein David M. , Poortinga Albert , Verhoeven Frank M. , Bonn Daniel , Bonnet Sylvestre , van Rijn Cees J.M. 
Published: March 2021

AbstractEncapsulating pharmaceuticals in protective lipid based nanoparticles, and nebulizing them towards the target area in the body offers a range of clinical advantages. However, the process of nebulization might possibly damage sensitive nanoparticle structures, such as liposomes, resulting in loss of active pharmaceutical ingredients. We compare this loss for two types of lung inhalation devices: high-frequency piezo-actuated vibrating mesh nebulizers and non-actuated continuous jet nebulizers. We find that vibrating mesh nebulizers cause model liposomes to release more than ten times as much encapsulated material as the continuous jet nebulizers because the energies involved in nebulization are much larger. This result highlights the importance of applying a mild nebulization technology when administering shear-sensitive drug formulations such as lipid nanoparticle based drugs to the lungs.
A simple model for how the risk of pandemics from different virus families depends on viral and human traits
Authors: Doelger Julia , Chakraborty Arup K. , Kardar Mehran 
Published: March 2021

AbstractDifferent virus families, like influenza or corona viruses, exhibit characteristic traits such as typical modes of transmission and replication as well as specific animal reservoirs in which each family of viruses circulate. These traits of genetically related groups of viruses influence how easily an animal virus can adapt to infect humans, how well novel human variants can spread in the population, and the risk of causing a global pandemic. Relating the traits of virus families to their risk of causing future pandemics, and identification of the key time scales within which public health interventions can control the spread of a new virus that could cause a pandemic, are obviously significant. We address these issues using a minimal model whose parameters are related to characteristic traits of different virus families. A key trait of viruses that “spillover” from animal reservoirs to infect humans is their ability to propagate infection through the human population (fitness). We find that the risk of pandemics emerging from virus families characterized by a wide distribution of the fitness of spillover strains is much higher than if such strains were characterized by narrow fitness distributions around the same mean. The dependences of the risk of a pandemic on various model parameters exhibit inflection points. We find that these inflection points define informative thresholds. For example, the inflection point in variation of pandemic risk with time after the spillover represents a threshold time beyond which global interventions would likely be too late to prevent a pandemic.
SARS-CoV-2 prevalence and transmission in swimming activities: results from a retrospective cohort study
Authors: Termansen Martin Brink , Christiansen Ask Vest , Frische Sebastian 
Published: March 2021

ABSTRACTThere is an urgent need for research on the epidemiology of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing corona virus disease 2019 (COVID-19), as the transmissibility differs between settings and populations. Here we report on a questionnaire-based retrospective cohort study of the prevalence and transmission of SARS-CoV-2 among participants in swimming activities in Denmark in the last five months of 2020 during the COVID-19 pandemic.Eight of 162 swimming activities with a SARS-CoV-2 positive participant led to transmission to 23 other participants. Overall, the percentage of transmission episodes was 4.9% (competitive swimming 8.9%; recreational swimming 1.3%). Overall, the incidence rate of transmission was 19.5 participants per 100.000 pool activity hours (corresponding values: 43.5 and 4.7 for competitive and recreational swimming, respectively).Compliance with precautionary restrictions was highest regarding hand hygiene (98.1%) and lowest in distancing personal sports bags (69.9%). Due to low statistical power, the study showed no significant effect of restrictions.Insight into the risk of transmission of SARS-CoV-2 during indoor swimming is needed to estimate the efficiency of restrictive measures on this and other sports and leisure activities. Only when we know how the virus spreads through various settings, optimal strategies to handle the COVID-19 pandemic can be developed.
Deep clinical phenotyping of Alzheimer’s Disease Patients Leveraging Electronic Medical Records Data Identifies Sex-Specific Clinical Associations
Authors: Tang Alice , Oskotsky Tomiko , Mantyh William , Solsberg Caroline Warly , Zeng Billy , Hu Zicheng , Oskotsky Boris , Dubal Dena , Sirota Marina 
Published: March 2021

AbstractAlzheimer’s Disease (AD) is a devastating disorder that is still not fully understood. Sex modifies AD vulnerability, but the reasons for this are largely unknown. There has been efforts to understand select comorbidities, covariates, and biomarkers of AD, with and without sex stratification - but there has not yet been an integrative, big data approach to identify clinical and sex specific associations with AD in an unbiased manner. Electronic Medical Records (EMR) contain extensive information on patients, including diagnoses, medications, and lab test results, providing a unique opportunity to apply phenotyping approaches to derive insights into AD clinical associations. Here, we utilize EMRs to perform deep clinical phenotyping and network analysis of AD patients to provide insight into its clinical characteristics and sex-specific clinical associations. We performed embeddings and network representation of patient diagnoses to visualize patient heterogeneity and comorbidity interactions and observe greater connectivity of diagnosis among AD patients compared to controls. We performed enrichment analysis between cases and controls and identified multiple known and new diagnostic and medication associations, such as positive associations with AD and hypertension, hyperlipidemia, anemia, and urinary tract infection - and negative associations with neoplasms and opioids. Furthermore, we performed sex-specific enrichment analyses to identify novel sex-specific associations with AD, such as osteoporosis, depression, cardiovascular risk factors, and musculoskeletal disorders diagnosed in female AD patients and neurological, behavioral, and sensory disorders enriched in male AD patients. We also analyzed lab test results, resulting in clusters of patient phenotype groups, and we observed greater calcium and lower alanine aminotransferase (ALT) in AD, as well as abnormal hemostasis labs in female AD. With this method of phenotyping, we can represent AD complexity, and identify clinical factors that can be followed-up for further temporal and predictive analysis or integrate with molecular data to aid in diagnosis and generate hypotheses about disease mechanisms. Furthermore, the negative associations can help identify factors that may decrease likelihood of AD and help motivate future drug repurposing or therapeutic approaches.
Characterizing Post-Acute Sequelae of SARS-CoV-2 Infection across Claims and Electronic Health Record Databases
Authors: Spotnitz Matthew E. , Hripcsak George , Ryan Patrick B. , Natarajan Karthik 
Published: March 2021

Structured AbstractImportancePost-acute sequelae of SARS-CoV-2 infection (PASC) is emerging as a major public health issue.ObjectiveWe characterized the incidence of PASC, or related symptoms and diagnoses, for COVID-19 and influenza patients.DesignRetrospective cohort study.SettingOur data sources were the IBM MarketScan Commercial Claims and Encounters (CCAE), Optum Electronic Health Record (EHR) and Columbia University Irving Medical Center (CUIMC) databases that were transformed to the Observational Medical Outcome Partnership (OMOP) Common Data Model (CDM) and were part of the Observational Health Sciences and Informatics (OHDSI) network.ParticipantsThe COVID-19 cohort consisted of patients with a diagnosis of COVID-19 or positive lab test of SARS-CoV-2 after January 1st 2020 with a follow up period of at least 30 days. The influenza cohort consisted of patients with a diagnosis of influenza between October 1, 2018 and May 1, 2019 with a follow up period of at least 30 days.InterventionInfection with COVID-19 or influenza.Main Outcomes and MeasuresPost-acute sequelae of SARS-CoV-2 infection (PASC), or related diagnoses, for COVID-19 and influenza patients.ResultsIn aggregate, we characterized the post-acute experience for over 440,000 patients who were diagnosed with COVID-19 or tested positive for SARS-COV-2. The long term sequelae that had a higher incidence in the COVID-19 compared to Influenza cohorts were altered smell or taste, myocarditis, acute kidney injury, dyspnea and alopecia. Additionally, the long term incidences of respiratory illness, musculoskeletal disease, and psychiatric disorders for the COVID-19 population were higher than expected.Conclusions and RelevanceThe long term sequelae of COVID-19 and influenza may be different. Further characterization of PASC on large scale observational healthcare databases is warranted.
Management of COVID-19-related Arterial Thrombosis Leading to Acute Limb-threatening Ischemia
Authors: Ehsan Omer , Khan Mohammad Iqbal , Raza Muhammad Waqas 
Published: March 2021

ABSTRACTObjectiveExamine the occurrence and clinical outcomes of arterial thrombosis leading to limb-threatening ischemia in patients with coronavirus-2019 (COVID-19).Study designProspective, descriptive case series.Patients and MethodsForty-four patients with COVID-19 infection presenting with critical limb ischemia were managed between March 2020 and December 2020. The patients were divided into three groups based on the mode of presentation: 1) those who had been admitted; 2) those presenting in the emergency department; and 3) those presenting to vascular clinics. Clinical evidence suggesting limb ischemia was evaluated with computerized tomographic angiogram. Vascular care was designed according to the need of individual patients, through anticoagulation, revascularization by thrombo-embolectomy, or bypass grafting and amputation.ResultsTen major amputations and 4 deaths (all in patients admitted) occurred among the 44 patients (9.1%). Most patients (32/44) were males, mean age was 55, and limb ischemia occurred among patients as young as 29. The initial period of ischemia was often not appreciated by patients and physicians. Critical limb ischemia was often not correlated with the severity of COVD symptoms: of 17 patients who presented through the emergency room with limb-threatening ischemia, 10 (58.9%) were asymptomatic for respiratory and general symptoms. Comorbidities were common among all 3 patient groups (26/44; 59%). Anticoagulants did not consistently prevent thromboembolic events since all admitted patients were receiving low molecular weight heparin. The rate of revascularization was lower in this population than in the general population with similar limb ischemia.ConclusionAcute limb ischemia in patients with COVID-19 is a vascular emergency that can result in limb loss and even death. The severity of respiratory infection and other symptoms of COVID often are not consistent with the severity and level of vascular involvement. Timely recognition and tailored intervention is needed to save limbs in this population.What this paper adds to existing knowledgeCOVID-19 infection predisposes to arterial and venous thrombosis, but data on arterial thrombosis are sparse. This report describes a series of 44 COVID-19 patients who had arterial thrombosis causing limb-threatening ischemia. Most noteworthy characteristics of the condition are its severity (10 major amputations and 4 deaths); subtle initial expression of the ischemia, which may lead to delayed diagnosis; severity and level of vascular involvement poorly correlated with respiratory symptoms; nearly 60% frequency of comorbidities (diabetes, hypertension, and ischemic heart disease); and low rate of successful revascularization compared with that of usual thromboembolic limb ischemia.
Intra-tumoral epigenetic heterogeneity and aberrant molecular clocks in hepatocellular carcinoma
Authors: Restrepo Paula , Bubie Adrian , Craig Amanda J. , Labgaa Ismail , Schwartz Myron , Thung Swan , Stolovitzky Gustavo , Losic Bojan , Villanueva Augusto 
Published: March 2021

ABSTRACTThere is limited understanding of the epigenetic drivers of tumor evolution in hepatocellular carcinoma (HCC). We quantify epigenetic intra-tumoral heterogeneity (ITH) using regional enhanced reduced-representation bisulfite sequencing (eRRBS) DNA methylation data from 47 early stage, treatment-naive HCC biopsies across 9 patients. Integrating these data with matching RNAseq, targeted DNA sequencing, tumor-infiltrating lymphocyte (TIL) and hepatitis-B viral (HBV) expression, we computed regional differential methylation (DM) ITH signatures across 19,327 promoter regions, and 654,133 CpG islands, while overlapping with known methylation age marker genes (240/354). We found substantial ITH signatures in promoter and enhancer sites across 4/9 patients highlighting novel molecular pathways of tumor progression not otherwise detectable from RNA analysis alone. Additionally, we identify an epigenetic tumoral aging measure that reflects a complex tumor fitness phenotype as a potential proxy for tumor evolution. In order to compute clinical associations with epigenetic tumoral age, we use 450k array data from 377 HCC patients in the TCGA-LIHC single-biopsy cohort to calculate tumoral age and find evidence implying that epigenetically old tumors have lower fitness yet higher TIL burden. Our data reveal a novel, unique epigenetic ITH axis in HCC tumors that furthers our understanding of tumor evolution and may serve as a potential avenue for enhancing patient stratification and treatment.
Neutralization of European, South African, and United States SARS-CoV-2 mutants by a human antibody and antibody domains
Authors: Sun Zehua , Kim Andrew , Sobolewski Michele D , Enick Nathan , Chen Chuan , Adams Cynthia , Jacobs Jana L , McCormick Kevin D , Mellors John W , Dimitrov Dimiter S , Li Wei 
Published: March 2021

AbstractSevere Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) transmission with several emerging variants remain uncontrolled in many countries, indicating the pandemic remains severe. Recent studies showed reduction of neutralization against these emerging SARS-CoV-2 variants by vaccine-elicited antibodies. Among those emerging SARS-CoV-2 variants, a panel of amino acid mutations was characterized including those in the receptor-binding domain (RBD) of the SARS-CoV-2 spike (S) glycoprotein. In the present study, we evaluated our previously identified antibody and antibody domains for binding to these RBD variants with the emerging mutations, and neutralization of pseudo typed viruses carrying spike proteins with such mutations. Our results showed that one previously identified antibody domain, ab6, can bind 32 out of 35 RBD mutants tested in an ELISA assay. All three antibodies and antibody domains can neutralize pseudo typed B.1.1.7 (UK variant), but only the antibody domain ab6 can neutralize the pseudo typed virus with the triple mutation (K417N, E484K, N501Y). This domain and its improvements have potential for therapy of infections caused by SARS-CoV-2 mutants.
Evaluation of the ROX index in SARS-CoV-2 Acute Respiratory failure treated with both High-Flow Nasal Oxygen (HFNO) and Continuous Positive Airway Pressure (CPAP)
Authors: Ghani Hakim , Shaw Michael , Pyae Phyoe , Cama Rigers , Prabhakar Meghna , Navarra Alessio , Mogal Rahul , Barlow Andrew , Nordin Nazril , Vancheeswaran Rama , Lee Janice Yu Ji , Chua Felix 
Published: March 2021

ABSTRACTBackgroundNon-invasive respiratory support including high-flow nasal oxygen (HFNO), and continuous positive airway pressure (CPAP) have been used to provide therapy in selected SARS-CoV-2 patients with acute respiratory failure (ARF). The value of the ROX index, a validated benchmark for outcomes in HFNO is unknown in CPAP.ObjectiveCan the ROX, a validated benchmark in HFNO be used for measuring treatment outcomes of CPAP in SARS-COV-2 ARF?Study Design and MethodsA non-randomised prospective protocol driven observational non-intensive care unit study in 130 SARS-COV-2 patients with ARF treated with non-invasive therapy from March 2020 to January 2021. The primary end point was failure of therapy (death or escalation). Secondary outcomes included time to failure including invasive mechanical ventilation (IMV) or death, the effect of escalation to CPAP from HFNO and the utility of ROX in ARF.ResultsHFNO was better than CPAP in treating SARS-COV-2 ARF: 17/35 (48.5%) with successful HFNO therapy versus 24/95 (25.2%) with CPAP. The ROX index was more sensitive to outcomes with CPAP compared to HFNO and distinguished treatment failure early at 1, 4, 6, 12, and 24 hours with the highest sensitivity at 24 hours (ROX-24h). The AUC for the ROX-24h was 0.77 for HFNO (P<0.0001), and 0.84 for CPAP (P<0.0001). The ROX-24h cut-points predicted failure with HFNO when < 3.9 (PPV 71%, NPV 75%) and CPAP < 4.3 (PPV 75%, NPV 91%). For success, ROX-24h cut-points of 7.6 for HFNO (PPV 85%, NPV 48%) and 6.1 for CPAP (PPV 88%, NPV 62%) were observed. Escalation from HFNO to CPAP was mostly not successful.ConclusionARF in SARS-COV-2 can be successfully managed by non-invasive support. The ROX index, validated for HFNO, provides a timely, low resource measure for both HFNO and CPAP avoiding delayed intubation.Trial registrationStudy approved by NHS HRAREC (20/HRA/2344;ethics 283888)KEY MESSAGEWhat is the key question?Can the ROX, a validated benchmark in high-flow nasal oxygen (HFNO) be used for measuring treatment outcomes of continuous positive airway pressure (CPAP) in SARS-COV-2 ARF?What is the bottom line?The ROX index, validated for HFNO, provides a timely, low resource measure for both HFNO and CPAP support avoiding delayed intubation.Why read on?The present study compares the efficacy of HFNO and CPAP, two common globally used modalities of treatment for SARS-CoV-2 and notes the superior utility of the ROX-24h in CPAP to predict outcome, enabling timely escalation decisions.
Quantitative single cell 5hmC sequencing reveals non-canonical gene regulation by non-CG hydroxymethylation
Authors: Fabyanic Emily B. , Hu Peng , Qiu Qi , Wang Tong , Berríos Kiara N. , Flournoy Jennifer , Connolly Daniel R. , Zhou Zhaolan , Kohil Rahul M. , Wu Hao 
Published: March 2021

ABSTRACTOxidative modification of 5-methylcytosine (5mC) generates 5-hydroxymethylcytosine (5hmC), a DNA modification that exhibits unique epigenetic regulatory functions and impacts diverse biological processes. However, standard single-nucleus/cell bisulfite sequencing methods cannot resolve the base ambiguity between 5mC and 5hmC to accurately measure cell-type specific epigenomic patterns and gene regulatory functions of 5hmC or true 5mC. Here, we develop single-nucleus 5hmC sequencing (snhmC-seq) for quantitative and unbiased 5hmC profiling in single cells by harnessing differential deaminase activity of APOBEC3A towards 5mC and chemically protected 5hmC. We used snhmC-seq to profile single nuclei from cryopreserved mouse brain samples to reveal epigenetic heterogeneity of 5hmC at single-cell resolution and uncovered a non-canonical gene regulatory role of genic 5hmC in non-CG context.