bluuebunny/crossref_metadata_2025 huggingface dataset:
Integrating Operant and Cognitive Behavioral Economics to Inform Infectious Disease Response: Prevention, Testing, and Vaccination in the COVID-19 Pandemic
Authors: Strickland Justin C. , Reed Derek D. , Hursh Steven R. , Schwartz Lindsay P. , Foster Rachel N.S. , Gelino Brett W. , LeComte Robert S. , Oda Fernanda S. , Salzer Allyson R. , Schneider Tadd D. , Dayton Lauren , Latkin Carl , Johnson Matthew W.
Published: January 2021

The role of human behavior to thwart transmission of infectious diseases like COVID-19 is evident. Yet, many areas of psychological and behavioral science are limited in the ability to mobilize to address exponential spread or provide easily translatable findings for policymakers. Here we describe how integrating methods from operant and cognitive approaches to behavioral economics can provide robust policy relevant data. Adapting well validated methods from behavioral economic discounting and demand frameworks, we evaluate in four crowdsourced samples (total N = 1,366) behavioral mechanisms underlying engagement in preventive health behaviors. We find that people are more likely to social distance when specified activities are framed as high risk, that describing delay until testing (rather than delay until results) increases testing likelihood, and that framing vaccine safety in a positive valence improves vaccine acceptance. These findings collectively emphasize the flexibility of methods from diverse areas of behavioral science for informing public health crisis management.
Outcomes and phenotypic expression of rare variants in hypertrophic cardiomyopathy genes amongst UK Biobank participants
Authors: de Marvao Antonio , McGurk Kathryn A , Zheng Sean L , Thanaj Marjola , Bai Wenjia , Duan Jinming , Biffi Carlo , Mazzarotto Francesco , Statton Ben , Dawes Timothy JW , Savioli Nicolò , Halliday Brian P , Xu Xiao , Buchan Rachel J , Baksi A John , Quinlan Marina , Tokarczuk Paweł , Tayal Upasana , Francis Catherine , Whiffin Nicola , Theotokis Pantazis I , Zhang Xiaolei , Jang Mikyung , Berry Alaine , Pantazis Antonis , Barton Paul JR , Rueckert Daniel , Prasad Sanjay K , Walsh Roddy , Ho Carolyn Y , Cook Stuart A , Ware James S , O’Regan Declan P
Published: January 2021

Background

Hypertrophic cardiomyopathy (HCM) is caused by rare variants in sarcomere-encoding genes, but little is known about the clinical significance of these variants in the general population.

Methods

We compared outcomes and cardiovascular phenotypes in UK Biobank participants with whole exome sequencing stratified by sarcomere-encoding variant status.

Results

The prevalence of rare variants (allele frequency <0.00004) in HCM-associated sarcomere-encoding genes in 200,584 participants was 2.9% (n=5,727; 1 in 35), of which 0.24% (n=474, 1 in 423) were pathogenic or likely pathogenic variants (SARC-P/LP). SARC-P/LP variants were associated with increased risk of death or major adverse cardiac events compared to controls (HR 1.68, 95% CI 1.37-2.06, p<0.001), mainly due to heart failure (HR 4.40, 95% CI 3.22-6.02, p<0.001) and arrhythmia (HR 1.55, 95% CI 1.18-2.03, p=0.002). In 21,322 participants with cardiac magnetic resonance imaging, SARC-P/LP were associated with increased left ventricular maximum wall thickness (10.9±2.7 vs 9.4±1.6 mm, p<0.001) and concentric remodelling (mass/volume ratio: 0.63±0.12 vs 0.58±0.09 g/mL, p<0.001), but hypertrophy (≥13mm) was only present in 16% (n=7/43, 95% CI 7-31%). Other rare sarcomere-encoding variants had a weak effect on wall thickness (9.5±1.7 vs 9.4±1.6 mm, p=0.002) with no combined excess cardiovascular risk (HR 1.00 95% CI 0.92-1.08, p=0.9).

Conclusions

In the general population, SARC-P/LP variants have low aggregate penetrance for overt HCM but are associated with an increased risk of adverse cardiovascular outcomes and a sub-clinical cardiomyopathic phenotype. In contrast, rare sarcomeric variants that do not meet criteria to be classified as P/LP appear to have minimal clinical impact.
Counterfactual inference for single-cell gene expression analysis
Authors: Park Yongjin , Kellis Manolis
Published: January 2021

Finding a causal gene is a fundamental problem in genomic medicine. We present a causal inference framework that prioritizes disease genes by adjusting confounders without prior knowledge of control variables. We demonstrate that our method substantially improves statistical power in simulations and real-world data analysis of 70k brain cells collected for dissecting Alzheimer’s disease. We identified that 215 causal genes are differentially regulated by the disease in various cell types, including highly relevant genes with a proper cell type context. Genes found in different types enrich distinctive pathways, implicating the importance of cell types in understanding multifaceted disease mechanisms.
Genomic Epidemiology of SARS-CoV-2 in Esteio, Rio Grande do Sul, Brazil
Authors: Franceschi Vinícius Bonetti , Caldana Gabriel Dickin , de Menezes Mayer Amanda , Cybis Gabriela Bettella , Neves Carla Andretta Moreira , Ferrareze Patrícia Aline Gröhs , Demoliner Meriane , de Almeida Paula Rodrigues , Gularte Juliana Schons , Hansen Alana Witt , Weber Matheus Nunes , Fleck Juliane Deise , Zimerman Ricardo Ariel , Kmetzsch Lívia , Spilki Fernando Rosado , Thompson Claudia Elizabeth
Published: January 2021

Brazil is the third country most affected by Covid-19 pandemic. In spite of this, viral evolution in municipality resolution is poorly understood in Brazil and it is crucial to understand the epidemiology of viral spread. We identified four main circulating lineages in Esteio (Southern Brazil) and their relationship with global, national and regional lineages using phylogenetics and phylodynamics inferences from 21 SARS-CoV-2 genome sequences. We provided a comprehensive view of viral mutations from a time- and age-representative sampling from May to October 2020, in Esteio (RS, Brazil), highlighting two frequent mutations in Spike glycoprotein (D614G and V1176F), an emergent mutation (E484K) in Spike Receptor Binding Domain (RBD) characteristic of the South African lineage B.1.351, and the adjacent replacement of 2 amino acids in Nucleocapsid phosphoprotein (R203K and G204R). A significant viral diversity was evidenced with the identification of 80 different SNPs. The E484K replacement was found in two genomes (9.5%) from samples obtained in mid-October, which is to our best knowledge the earliest description of E484K harboring SARS-CoV-2 in South Brazil. This mutation identified in a small municipality from the RS state demonstrates that it was probably widely distributed in the Brazilian territory, but went unnoticed so far by the lack of genomic surveillance in Brazil. The introduction of E484K mutants shows temporal correlation with later increases in new cases in our state. Importantly, since it has been associated with immune evasion and enhanced interaction with hACE-2, lineages containing this substitution must be the subject of intense surveillance. Our date demonstrates multiple introductions of the most prevalent lineages (B.1.1.33 and B.1.1.248) and the major role of community transmission in viral spreading and the establishment of Brazilian lineages. This represents an important contribution to the epidemiology of SARS-CoV-2.
Cohort Profile: The Birhan Health and Demographic Surveillance System
Authors: Bekele Delayehu , Hunegnaw Bezawit Mesfin , Bekele Chalachew , Van Wickle Kimiko , Tadesse Fisseha , Goddard Frederick G. B. , Mohammed Yahya , Unninayar Sarah , Chan Grace J.
Published: January 2021

The Birhan health and demographic surveillance system (HDSS) was established to determine the magnitude and causes of morbidity and mortality in Ethiopia among pregnant and postpartum women and children. Located in the North Shewa Zone of the Amhara Region, the site includes 16 kebeles (villages) and spans two woredas (districts), Angolela Tera and Kewet/Shewa Robit. The initial census was conducted in May 2018, and core demographic and health events are updated every three months. The site has 18,933 households and a population of 77,766. Over 82.6% of the population is rural.

During the baseline census, all households were geocoded; household members were enumerated; and data were collected on sociodemographic status, housing construction material, economics and asset ownership, care seeking behaviors, and water and sanitation access. During each subsequent round, data on key demographic events such as births, deaths, marital status changes, in-migration, or out-migration were collected for all enumerated household members. Pregnancy surveillance was conducted among married women of reproductive age 15-49 using a pregnancy screening questionnaire and confirmed by urine pregnancy tests. Morbidity and immunization status data for children aged under two years were collected during each round.
Listening to Bluetooth Beacons for Epidemic Risk Mitigation
Authors: Barthe Gilles , Viti Roberta De , Druschel Peter , Garg Deepak , Gomez-Rodriguez Manuel , Ingo Pierfrancesco , Kremer Heiner , Lentz Matthew , Lorch Lars , Mehta Aastha , Schölkopf Bernhard
Published: January 2021

During the ongoing COVID-19 pandemic, there have been burgeoning efforts to develop and deploy digital contact tracing systems to expedite contact tracing and risk notification. Unfortunately, the success of these systems has been limited, partly owing to poor interoperability with manual contact tracing, low adoption rates, and a societally sensitive trade-off between utility and privacy. In this work, we introduce a new privacy-preserving and inclusive system for epidemic risk assessment and notification that aims to address the above limitations. Rather than capturing pairwise encounters between user devices as done by existing systems, our system captures encounters between user devices and beacons placed in strategic locations where infection clusters may originate. Epidemiological simulations using an agent-based model demonstrate several beneficial properties of our system. By achieving bidirectional interoperability with manual contact tracing, our system may help reduce the effective reproduction number already at adoption levels of 10%. The use of location and environmental information provided by beacons allows our system to achieve significantly higher sensitivity and specificity than existing systems and thus may improve the efficacy of contact tracing under limited isolation and testing resources. Moreover, to achieve high utility, it is sufficient to deploy beacons in a small fraction of strategic locations. Finally, our simulations also show that existing systems could inherit these beneficial properties if they integrated the beacons used by our system.
Barriers and facilitators to cross-sector workforce competency assessment in the care of older people residing in care homes
Authors: Tiplady Sue , Thompson Juliana , Cook Glenda , Bainbridge Lesley
Published: January 2021

In recent years, transformation in care delivery towards cross-sector models has occurred with the aim of providing safe, efficient care for older people with complex needs, including those living in care homes. Effective workforce competency development and assessment across sectors is integral to these models. However, there is much evidence to suggest a distinct lack of cross-sector alignment with regard to competency development and assessment, which could lead to variations in practice and affect outcomes for older people. This qualitative study explored the barriers and facilitators to cross-sector workforce competency assessment in the care of older people residing in care homes. Twenty nine staff with responsibility for staff learning and development participated. Data were analysed using Braun and Clarke’s (2006) six phase thematic analysis approach. Findings indicate that a significant challenge to the development of a competent workforce is evidencing competency, due to difficulties in finding appropriate assessors and inconsistencies in the assessment process. Findings also indicate potential solutions including: a system-wide, standardised framework and strategy for assessment of competence; policy for the ‘sign-off’ of competencies that is recognised across organisational boundaries; and adopting practice-based approaches to competence development and assessment.
Data Driven High Resolution Modeling and Spatial Analyses of the COVID-19 Pandemic in Germany
Authors: Schüler Lennart , Calabrese Justin M. , Attinger Sabine
Published: January 2021

The SARS-CoV-2 virus has spread around the world with over 90 million infections to date, and currently many countries are fighting the second wave of infections. With neither sufficient vaccination capacity nor effective medication, non-pharmaceutical interventions (NPIs) remain the measure of choice. However, NPIs place a great burden on society, the mental health of individuals, and economics. Therefore the cost/benefit ratio must be carefully balanced and a target-oriented small-scale implementation of these NPIs could help achieve this balance. To this end, we introduce a modified SEIR-class compartment model and parametrize it locally for all 412 districts of Germany. The NPIs are modeled at district level by time varying contact rates. This high spatial resolution makes it possible to apply geostatistical methods to analyse the spatial patterns of the pandemic in Germany and to compare the results of different spatial resolutions. We find that the modified SEIR model can successfully be fitted to the COVID-19 cases in German districts, states, and also nationwide. We propose the correlation length as a further measure, besides the weekly incidence rates, to describe the current situation of the epidemic.
Force of infection: A determinant of vaccine efficacy?
Authors: Kaslow David C.
Published: January 2021

Vaccine efficacy (VE) can vary in different settings. Of the many proposed setting-dependent determinants of VE, force of infection (FoI) stands out as one of the most direct, proximate, and actionable. As highlighted by the COVID-19 pandemic, modifying FoI through non-pharmaceutical interventions (NPIs) use can significantly contribute to controlling transmission and reducing disease incidence and severity absent highly effective pharmaceutical interventions, such as vaccines. Given that NPIs reduce the FoI, the question arises as to if and to what degree FoI, and by extension NPIs, can modify VE, and more practically, as vaccines become available for a pathogen, whether and which NPIs should continue to be used in conjunction with vaccines to optimize controlling transmission and reducing disease incidence and severity.
Evaluation of six commercial SARS-CoV-2 Enzyme-Linked Immunosorbent assays for clinical testing and serosurveillance
Authors: Nicholson Suellen , Karapanagiotidis Theo , Khvorov Arseniy , Douros Celia , Mordant Francesca , Bond Katherine , Druce Julian , Williamson Deborah A , Purcell Damian , Lewin Sharon R , Sullivan Sheena , Subbarao Kanta , Catton Mike
Published: January 2021

Background

Serological testing for SARS-CoV-2 complements nucleic acid tests for patient diagnosis and enables monitoring of population susceptibility to inform the COVID-19 pandemic response. As we move into the era of vaccines, the detection of neutralising antibody will become increasingly important. Many serological tests have been developed under emergency use authorization, but their reliability remains unclear.

Methods

We evaluated the performance of six commercially-available Enzyme-linked Immunosorbent Assays (ELISAs), including a surrogate virus neutralization test, for detection of SARS-CoV-2 immunoglobulins (IgA, IgM, IgG), total or neutralising antibodies and a subset of results were compared to microneutralisation.

Results

For sera collected > 14 days post-symptom onset the Wantai total Ab performed best with highest sensitivity 100% (95% confidence interval: 94.6-100) followed by 93.1% for Euroimmun NCP-IgG,93.1% for GenScript Surrogate Virus Neutralization Test, 90.3% for Euroimmun S1-IgG, 88.9% for Euroimmun S1-IgA and 83.3% for Wantai IgM. Specificity for the best performing assay was 99.5% and for the lowest 97.1%.

Conclusion

Wantai ELISA, detecting total immunoglobulins against SARS-CoV-2 receptor binding domain, had the best performance. Antibody target, timing and longevity of the immune response, and the objectives of testing should be considered in test choice. ELISAs should be used within a confirmatory testing algorithm to ensure reliable results. ELISAs provide high quality results, with flexibility for test numbers without the need for manufacturer specific analyzers.
CovidArray: a microarray-based assay with high sensitivity for the detection of SARS-CoV-2 in nasopharyngeal swabs
Authors: Damin Francesco , Galbiati Silvia , Gagliardi Stella , Cereda Cristina , Dragoni Francesca , Fenizia Claudio , Savasi Valeria , Sola Laura , Chiari Marcella
Published: January 2021

Background

A new coronavirus (SARS-CoV-2) caused the current Covid-19 epidemic. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) is used as the gold standard for clinical detection of SARS-CoV-2. Under ideal conditions RT-qPCR Covid-19 assays have analytical sensitivity and specificity greater than 95%. However, when the sample panel is enlarged including asymptomatic individuals, the sensitivity decreases and false-negative are reported. Moreover, RT-qPCR requires up to 3-6 hours with most of the time involved in RNA extraction from swab samples.

Methods

We introduce CovidArray, a microarray-based assay, to detect SARS-CoV-2 markers N1 and N2 in the nasopharyngeal swabs. The method is based on solid phase hybridization of fluorescently labelled amplicons upon RNA extraction and reverse transcription. This approach combines the physical-optical properties of the silicon substrate with the surface chemistry used to coat the substrate to obtain a diagnostic tool of great sensitivity. Furthermore, we used an innovative approach, RNAGEM, to extract and purify viral RNA in less than 15 minutes. To validate the CovidArray results, we exploited the high sensitivity of the droplet digital PCR (ddPCR) technique.

Result

We correctly assigned 12 nasopharyngeal swabs, previously analyzed by RT-qPCR. Thanks to the CovidArray sensitivity that matches that of the ddPCR, we were able to identify a false-negative sample.

Conclusions

CovidArray is the first DNA microarray-based assay to detect viral genes in the swabs. Its high sensitivity and the innovative viral RNA extraction by RNAGEM allows to reduce both the amount of false negative results and the total analysis time to about 2 hours.
Extraction of Viral Nucleic Acids with Carbon Nanotubes Increases SARS-CoV-2 RT-qPCR Detection Sensitivity
Authors: Jeong Sanghwa , Grandio Eduardo G. , Navarro Nicole , Pinals Rebecca L. , Ledesma Francis , Yang Darwin , Landry Markita P.
Published: January 2021

The global SARS-CoV-2 coronavirus pandemic has led to a surging demand for rapid and efficient viral infection diagnostic tests, generating a supply shortage in diagnostic test consumables including nucleic acid extraction kits. Here, we develop a modular method for high-yield extraction of viral single-stranded nucleic acids by using ‘capture’ ssDNA sequences attached to carbon nanotubes. Target SARS-CoV-2 viral RNA can be captured by ssDNA-nanotube constructs via hybridization and separated from the liquid phase in a single-tube system with minimal chemical reagents, for downstream quantitative reverse transcription polymerase chain reaction (RT-qPCR) detection. This nanotube-based extraction method enables 100% extraction yield of target SARS-CoV-2 RNA from phosphate buffered saline in comparison to ∼20% extraction yield when instead using a commercial silica-column kit. Notably, carbon nanotubes enable extraction of nucleic acids directly from 50% human saliva, bypassing the need for further biofluid purification and avoiding the use of DNA/RNA extraction kits. Carbon nanotube-based extraction of viral nucleic acids facilitates high-yield and high-sensitivity identification of viral nucleic acids such as the SARS-CoV-2 viral genome with reduced reliance on reagents affected by supply chain obstacles.

Abstract Figure
Identification of novel biomarkers for pyridoxine-dependent epilepsy using untargeted metabolomics and infrared ion spectroscopy - biochemical insights and clinical implications
Authors: Engelke Udo F.H. , van Outersterp Rianne E. , Merx Jona , van Geenen Fred A.M.G. , van Rooij Arno , Berden Giel , Huigen Marleen C.D.G. , Kluijtmans Leo A.J. , Peters Tessa M.A. , Al-Shekaili Hilal H. , Leavitt Blair R. , de Vrieze Erik , Broekman Sanne , van Wijk Erwin , Tseng Laura A. , Kulkarni Purva , Rutjes Floris P.J.T. , Mecinović Jasmin , Struys Eduard A. , Jansen Laura A. , Gospe Sidney M. , Mercimek-Andrews Saadet , Hyland Keith , Willemsen Michèl A.A.P. , Bok Levinus A. , van Karnebeek Clara D.M. , Wevers Ron A. , Boltje Thomas J. , Oomens Jos , Martens Jonathan , Coene Karlien L.M.
Published: January 2021

Pyridoxine-dependent epilepsy (PDE-ALDH7A1), also known as antiquitin deficiency, is an inborn error of lysine metabolism that presents with refractory epilepsy in newborns. Bi-allelic ALDH7A1 variants lead to deficiency of α-aminoadipic semialdehyde dehydrogenase, resulting in accumulation of piperideine-6-carboxylate (P6C), and secondary deficiency of the important co-factor pyridoxal-5’-phosphate (PLP, active vitamin B6) through its complexation with P6C. Vitamin B6 supplementation resolves epilepsy in patients, but despite this treatment, intellectual disability may occur. Early diagnosis and treatment, preferably based on newborn screening, potentially optimize long-term clinical outcome. However, the currently known diagnostic PDE-ALDH7A1 biomarkers are incompatible with newborn screening procedures. Using a combination of the innovative analytical methods untargeted metabolomics and infrared ion spectroscopy, we have been able to discover novel biomarkers for PDE-ALDH7A1: 2S,6S-and 2S,6R-oxopropylpiperidine-2-carboxylic acid (2-OPP) and 6-oxopiperidine-2-carboxylic acid (6-oxoPIP). We demonstrate the applicability of 2-OPP as a PDE-ALDH7A1 biomarker in newborn screening. Additionally, we show that 2-OPP accumulates in brain tissue of patients and Aldh7a1 knock-out mice, and induces epilepsy-like behavior in a zebrafish model system. We speculate that 2-OPP may contribute to ongoing neurotoxicity, also in treated PDE-ALDH7A1 patients. As 2-OPP formation appears to increase upon ketosis, we emphasize the importance of avoiding catabolism in PDE-ALDH7A1 patients.
A High-throughput Microsphere-based Immunoassay of Anti-SARS-CoV-2 IgM Testing for COVID-19 Diagnostics
Authors: Zhang Dayu , Xu Tianyang , Chu Eric , Zhang Aiguo , Du Jinwei , Sha Michael Y.
Published: January 2021

The pandemic of novel coronavirus disease COVID-19 is rapidly expanding across the world. A positive result of antibody tests suggests that the individual has potentially been exposed to SARS-CoV-2, thus allowing to identify asymptomatic infections and determine the seroprevalence in a given population. The aim of this study was to evaluate the performances of a newly developed high throughput immunoassay for anti-SARS-CoV-2 IgM antibody detection on the Luminex MAGPIX platform. Clinical agreement studies were performed in 42 COVID-19 patient serum samples and 162 negative donor serum/plasma samples. Positive percent agreement (PPA) was 42.86% (95% CI: 9.90% to 81.59%), 71.43% (95% CI: 29.04% to 96.33%), and 28.57% (95% CI: 13.22% to 48.67%) for samples collected on 0-7 days, 8-14 days, and 2-8 weeks from symptom onset, respectively. Negative Percent Agreement (NPA) was 97.53% (95% CI: 93.80% to 99.32%). There was no cross-reactivity with the SARS-CoV-2 IgG antibody Hemoglobin (200 mg/dL), bilirubin (2 mg/dL), triglyceride (250 mg/dL) and EDTA (10 mM) showed no significant interfering effect on this assay. In conclusion, an anti-SARS-CoV-2 IgM antibody assay with high sensitivity and specificity has been developed. With the high throughput, this assay will speed up the anti-SARS-CoV-2 IgM testing.
Validation of Kiswahili Version of WHOQOLHIVBREF questionnaire among people living with HIV/AIDS in Tanzania: a cross-sectional study
Authors: Kondo Nuru , Mwansisya Tumbwene , Aghan Eric , Ratansi Riaz
Published: January 2021

Background

Quality of life is an important element of surveillance in people living with HIV/AIDS. WHO has developed an HIV specific quality of life tool (WHOQOLHIV-Bref) for assessing Quality of life of HIV individuals. This tool takes into account the different cultural variations that exist worldwide and hence enable assessment of the quality of life across different cultures. Despite its preliminary sound validity and reliability from several studies, the developers recommend it to be validated in different cultures to fully assess its psychometric properties before its adaptation.

Objectives

To evaluate the validity and reliability of WHOQOLHIV-Bref questionnaire in Tanzanian culture among people living with HIV/AIDS.

Methods

This was a cross-sectional study of 103 participants interviewed using a Kiswahili WHOQOLHIV-BREF questionnaire. Of, these participants 47 participants were enrolled to repeat an interview two weeks later. Internal consistency and test-retest reliability were analyzed. Validity was assessed through analysis of translational, concurrent, convergent and discriminant validity while the model performance was assessed by Exploratory and confirmatory factor analysis.

Results

The mean age of the participants was 40.5 ± 9.702 years. Translation validity was assessed through the WHO translational protocol and was found to be good. The internal consistency and test-retest reliability of the Kiswahili version of WHOQOL-HIV BREF were excellent: Cronbach’s alpha values of 0.89-0.90, and ICC of 0.92 p < 0.01 respectively. Concurrent valid was excellent, significant correlations were noted across all domains (correlation coefficient r > 0.3) except for physical and spiritual domains. Confirmatory factor analysis found that the six domain produced an acceptable fit to the data. The convergent and divergent validities were satisfactory.

Conclusion

Kiswahili WHOQOLHIV-Bref was found to be reliable and valid questionnaire among Tanzanian people living with HIV/AIDS. These findings provide support for the use of this tool in assessing the quality of life in Tanzania.
Agreement between state registry, health record, and self-report of influenza vaccination
Authors: Petrie Joshua G. , Fligiel Helene , Lamerato Lois , Martin Emily T. , Monto Arnold S.
Published: January 2021

Background

Documentation of influenza vaccination, including the specific product received, is critical to estimate annual vaccine effectiveness (VE).

Methods

We assessed performance of the Michigan Care Improvement Registry (MCIR) in defining influenza vaccination status relative to documentation by provider records or self-report among subjects enrolled in a study of influenza VE from 2011 through 2019.

Results

The specificity and positive predictive value of MCIR were high; however, >10% of vaccinations were identified only by other sources each season. The proportion of records captured by MCIR increased from a low of 67% in 2013-2014 to a high of 89% in 2018-2019, largely driven by increased capture of vaccination among adults.

Conclusions

State vaccine registries, such as MCIR, are important tools for documenting influenza vaccination, including the specific product received. However, incomplete capture suggests that documentation from other sources and self-report should be used in combination with registries to reduce misclassification.
Lipidomic profiling of human serum enables detection of pancreatic cancer
Authors: Wolrab Denise , Jirásko Robert , Cífková Eva , Höring Marcus , Mei Ding , Chocholoušková Michaela , Peterka Ondřej , Idkowiak Jakub , Hrnčiarová Tereza , Kuchař Ladislav , Ahrends Robert , Brumarová Radana , Friedecký David , Vivo-Truyols Gabriel , Škrha Pavel , Škrha Jan , Kučera Radek , Melichar Bohuslav , Liebisch Gerhard , Burkhardt Ralph , Wenk Markus R. , Cazenave-Gassiot Amaury , Karásek Petr , Novotný Ivo , Hrstka Roman , Holčapek Michal
Published: January 2021

Pancreatic cancer has the worst prognosis among all cancers1. Cancer screening programs based on the analysis of body fluids can improve the survival time of patients, who are often diagnosed too late at an incurable stage2. Several studies have reported the dysregulation of lipid metabolism in tumor cells and tissues3, suggesting that the changes of blood lipidome may accompany tumor growth and progression. Analytical methods based on mass spectrometry (MS) using either direct infusion or chromatographic separation4 are convenient for high-throughput lipidomic profiling. Here we show that the comprehensive quantitation of a wide range of serum lipids reveals statistically significant differences between pancreatic cancer patients and healthy controls visualized by multivariate data analysis. Initial results for 364 human serum samples in the discovery phase were subsequently verified in the qualification phase on 554 samples measured by three independent laboratories, and finally on 830 samples from four blood collection sites in the verification phase. Concentrations suggestive of dysregulation of some very long chain sphingomyelins (SM 42:1, SM 41:1, SM 39:1, and SM 40:1), ceramides (Cer 41:1, and Cer 42:1), and (lyso)phosphatidylcholines (LPC 18:2) were recorded. Some lipid species indicated a potential as biomarkers of survival. The sensitivity and specificity to diagnose pancreatic cancer is over 90%, which outperforms CA 19-9, especially in early stage, and is comparable to established imaging diagnostic methods. The accuracy of lipidomic approach is not influenced by the cancer stage, analytical method, or blood collection site.
Personalized and dynamic antibiograms-an exploration in seven infectious syndromes
Authors: Iandiorio Michelle J. , Fazio Jane C. , Kempaiah Prakasha , Darvasula Ravi , van Regenmortel Marc H. V. , Rivas Ariel L.
Published: January 2021

To prevent antimicrobial resistance and inform better, antibiograms should distinguish different biomedical situations. It is also desirable that new antibiograms provide in vivo, temporal, and patient-specific immunological information. Here, the informative ability of a pattern recognition-based method was explored with data collected from patients that experienced seven infectious syndromes (pneumonia, endocarditis, tuberculosis, syphilis, as well as skin and soft tissue, intra-abdominal, and/or urinary tract infections associated with meningitis). Interactions among seven dimensions (7D) were investigated: (i) space, (ii) time, (iii) temporal data directionality, (iv) immunological multicellularity, (v) antibiotics, (vi) immunomodulation, and (vii) personalized data. Omissions and ambiguity (confounding different biological situations) occurred when static metrics were used in isolation, such as leukocyte percentages. In contrast, hidden information was uncovered when complexity and dynamics were assessed. The 7D approach grouped together observations that displayed similar immune profiles and identified antibiotics that modulated specific leukocytes. For instance, in tuberculosis, blood monocytes were modulated by isoniazid-related antimicrobials. In spite of the diverse syndromes analyzed, this proof-of-concept discriminated. It is suggested that the simultaneously exploration of numerous dimensions associated with complexity may be biologically interpretable, prevent ambiguity, promote research, expand machine learning-oriented methods, and support personalized medicine.
Model-driven mitigation measures for reopening schools during the COVID-19 pandemic
Authors: McGee Ryan S. , Homburger Julian R. , Williams Hannah E. , Bergstrom Carl T. , Zhou Alicia Y.
Published: January 2021

Reopening schools is an urgent priority as the COVID-19 pandemic drags on. To explore the risks associated with returning to in-person learning and the value of mitigation measures, we developed stochastic, network-based models of SARS-CoV-2 transmission in primary and secondary schools. We find that a number of mitigation measures, alone or in concert, may reduce risk to acceptable levels. Student cohorting, in which students are divided into two separate populations that attend in-person classes on alternating schedules, can reduce both the likelihood and the size of outbreaks. Proactive testing of teachers and staff can help catch introductions early, before they spread widely through the school. In secondary schools, where the students are more susceptible to infection and have different patterns of social interaction, control is more difficult. Especially in these settings, planners should also consider testing students once or twice weekly. Vaccinating teachers and staff protects these individuals and may have a protective effect on students as well. Other mitigations, including mask-wearing, social distancing, and increased ventilation, remain a crucial component of any reopening plan.
Willingness to volunteer of medical students during the COVID-19 pandemic: Assessment at a tertiary care hospital in India
Authors: Sra Manraj , Gupta Amulya , Jaiswal Abhishek , Yadav Kapil , Goswami Anil , Goswami Kiran
Published: January 2021

Background and Objectives

The involvement of medical students in strategies to control COVID-19 might be considered to cope with the shortage of healthcare workers. This study aims at assessing the level of knowledge about COVID-19, willingness to volunteer, potential areas of involvement and reasons for deterrence towards volunteering among medical students.

Methods

A cross-sectional study was conducted among undergraduate medical students of a tertiary care teaching hospital in New Delhi. A web-based questionnaire was used to elicit demographic information, knowledge of COVID-19, willingness to volunteer and reasons for deterrence for working during COVID-19 pandemic and self-declared knowledge in six domains.

Results

A total of 292 students participated in the study with a mean age of 19.9±3.1 years. The mean (S.D.) knowledge score of COVID-19 was 6.9 (1.1) (maximum score 10). Knowledge score was significantly different among preclinical (6.5), paraclinical (7.18), and clinical groups (7.03). Almost three fourth (75.3%) participants were willing to volunteer in COVID-19 pandemic, though 67.8% had not received any training in emergency medicine or public health crisis management. Willingness to work was maximum in areas of social work and indirect patient care (62.3% each). Lack of personal protective equipment was cited as a highly deterrent factor for volunteering (62.7%) followed by fear of transmitting the infection to family (45.9%), fear of causing harm to the patient (34.2%), and absence of treatment (22.2%).

Interpretation & conclusions

Majority of the students were willing to volunteer even though they had not received adequate training. Students may serve as an auxiliary force during the pandemic, especially in the non-clinical setting.
Projected spread of COVID-19’s second wave in South Africa under different levels of lockdown
Authors: Are Elisha B. , Colijn Caroline
Published: January 2021

South Africa is currently experiencing a second wave of resurgence in COVID-19 infection. In this modelling study, we use a Bayesian compartmental model to project possible spread of the second wave of COVID-19 in South Africa under various levels of lockdown restrictions. Our model suggests that strict lockdown restrictions will have to be in place up to the end of March 2021 before cases can drop to levels observed, in September to early November 2020, after the first wave. On the one hand, extended lockdown restrictions have negative consequences – albeit effective, they are not sustainable over extended periods. On the other hand, short lockdown restrictions over a few weeks will not have a lasting effect on the spread of the disease. Lockdown restrictions need to be supplemented with increased rapid testing, palliative support for the vulnerable, and implementations of other non-pharmaceutical interventions (NPIs) such as mask mandate. These multifaceted approaches could help keep cases under control until vaccines are widely available.
Oral ulcers of COVID-19 patients: a scoping review protocol
Authors: Riad Abanoub , Issa Julien , Chuchmova Veronika , Slezakova Simona , Gomaa Esraa , Pokorna Andrea , Klugarova Jitka , Klugar Miloslav
Published: January 2021

Objective

This scoping review aims to systematically identify the types, characteristics, and possible pathophysiologic etiologies of the oral ulcers that emerge in COVID-19 patients.

Introduction

The oral cavity is a vulnerable niche for the most diverse microbial ecosystem in the human body; therefore, it presents a wide array of mucocutaneous complications that could indicate various acute and chronic conditions. The COVID-19-related oral conditions, including oral ulcers, had been widely debated as direct manifestations or indirect complications of the SARS-CoV-2 infection. According to a preliminary search of PROSPERO, MEDLINE, the Cochrane Database of Systematic Reviews and theJBI Evidence Synthesis, there is no published nor registered scoping review concerned with the oral ulcers of COVID-19 patients.

Inclusion criteria

The review will include studies included COVID-19 patients whose infection had been confirmed by RT-PCR testing regardless of infection severity and clinical course. Only the studies that reported COVID-19 patients with oral ulcers.

Methods

A three-phase search strategy will be carried out: an initial limited search, a full electronic search, and hand search using the reference lists of all included records. The main bibliographic databases of published literature will include MEDLINE® (Ovid), EMBASE (Elsevier), and Cochrane COVID-19 Study Register. All identified records will be managed using EndNote 9.2, and the titles and abstracts will be screened against the inclusion criteria before the full text of all potentially relevant studies will be examined. The data will be presented in tabular form, rating maps, and narrative summary.

Registration

This protocol had been pre-registered in Open Science Framework (OSF) Registries.[1]
Adaptive design methods in dialysis clinical trials – a systematic review
Authors: Judge Conor , Murphy Robert , Reddin Catriona , Cormican Sarah , Smyth Andrew , O’Halloran Martin , O’Donnell Martin J
Published: January 2021

Background

Adaptive design methods are intended to improve efficiency of clinical trials and are relevant to evaluating interventions in dialysis populations. We sought to quantify the use of adaptive designs in dialysis clinical trials.

Methods

We completed a full text systematic review and adhered to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines. Our review utilised a machine learning classifier and a novel full text systematic review method. We searched MEDLINE (Pubmed) and performed a detailed data extraction of trial characteristics and a completed a narrative synthesis of the data.

Results

50 studies, available as 66 articles, were included after full text review. 31 studies were conducted in a dialysis population and 19 studies had renal replacement therapy as a primary or secondary outcome. While the absolute number of adaptive design methods is increasing over time, the relative use of adaptive design methods in dialysis trials is decreasing over time (6.1% in 2009 to 0.3% in 2019). Adaptive design methods impacted 52% of dialysis trials they were used in. Group sequential designs were the most common type of adaptive design method used. Acute Kidney Injury (AKI) was studied in 27 trails (54%), End Stage Kidney Disease (ESKD) was studied in 22 trials (44%) and Chronic Kidney Disease (CKD) was studied in 1 trial (2%). 26 studies (52%) were supported by public funding. 41 studies (82%) did not report their adaptive design method in the title or abstract and would not be detected by a standard systematic.

Conclusions

Adaptive design methods are employed in dialysis trials, but there has been a decline in their relative use over time.

Registration Number

PROSPERO: CRD42020163946

Significance statement

What was previously known about the specific topic of the manuscript?

The use of adaptive designs methods in dialysis trials is unquantified.

What were the most important findings? If studies are animals, this should be specified

Although absolute numbers of adaptive design trials have increased over time, the proportion of dialysis trials using an adaptive design has reduced. Among trials that employed an adaptive design, 52% of dialysis trials were revised due to the adaptive criteria. Group sequential designs were the most common type of adaptive design method used in dialysis randomized clinical trials. Acute Kidney Injury (AKI) was studied in 54% of trials and End Stage Kidney Disease (ESKD) was studied in 44% of trials, which used an adaptive design.

How does the new information advance a new understanding of the kidney and its diseases?

Adaptive design methods are effective in dialysis trials, but their relative use has declined over time.
S-ketamine in patient-controlled analgesia reduces opioid consumption in a dose-dependent manner after major lumbar fusion surgery: a randomized, double-blind, placebo-controlled clinical trial
Authors: Brinck Elina C.V. , Virtanen Taru , Mäkelä Sanna , Soini Venla , Hynninen Ville-Veikko , Mulo Jukka , Savolainen Urmas , Rantakokko Juho , Maisniemi Kreu , Liukas Antti , Olkkola Klaus T. , Kontinen Vesa , Tarkkila Pekka , Peltoniemi Marko , Saari Teijo I.
Published: January 2021

BACKGROUND

Spinal fusion surgery causes severe pain. Strong opioids, commonly used as postoperative analgesics, may have unwanted side effects. S-ketamine may be an effective analgesic adjuvant in opioid patient-controlled analgesia (PCA). However, the optimal adjunct S-ketamine dose to reduce postoperative opioid consumption is still unknown.

METHODS

We randomized 107 patients at two tertiary hospitals in a double-blinded, placebo-controlled clinical trial of adults undergoing major lumbar spinal fusion surgery. Patients were randomly allocated to four groups in order to compare the effects of three different doses of adjunct S-ketamine (0.25, 0.5, and 0.75 mg ml−1) or placebo on postoperative analgesia in oxycodone PCA. Study drugs were administered for 24 hours postoperative after which oxycodone-PCA was continued for further 48 hours. Our primary outcome was cumulative oxycodone consumption at 24 hours after surgery.

RESULTS

Of the 100 patients analyzed, patients receiving 0.75 mg ml−1 S-ketamine in oxycodone PCA needed 25% less oxycodone at 24 h postoperatively (61.2 mg) compared with patients receiving 0.5 mg ml−1 (74.7 mg) or 0.25 mg ml−1 (74.1 mg) S-ketamine in oxycodone or oxycodone alone (81.9 mg) (mean difference: −20.6 mg; 95% confidence interval [CI]: −41 to −0.20; P = 0.048). A beneficial effect in mean change of pain intensity at rest was seen in the group receiving 0.75 mg ml−1 S-ketamine in oxycodone PCA compared with patients receiving lower ketamine doses or oxycodone alone (standardized effect size: 0.17, 95% CI: 0.013–0.32, P = 0.033). The occurrence of adverse events was similar among the groups.

CONCLUSIONS

Oxycodone PCA containing S-ketamine as an adjunct at a ratio of 1: 0.75 decreased cumulative oxycodone consumption at 24 h after major lumbar spinal fusion surgery without additional adverse effects.
Implant- and anesthesia-related factors affecting threshold intensities for vagus nerve stimulation
Authors: Ahmed Umair , Chang Yao-Chuan , Lopez Maria F. , Wong Jason , Datta-Chaudhuri Timir , Rieth Loren , Al-Abed Yousef , Zanos Stavros
Published: January 2021

Vagus nerve stimulation (VNS) is used as therapy in epilepsy and depression and is tested as a potential treatment for several chronic disorders. Typically, VNS is delivered at increasing stimulus intensity until a response is observed (threshold intensity). Factors that affect threshold intensities for engagement of different fiber types and concomitant physiological responses have not been studied. We determined neural and physiological responses to increasing stimulus intensities of VNS in anesthetized and awake animals, and examined the effect of implant- and anesthesia-related factors on threshold intensities in a rodent model of VNS. In acute and long-term cervical vagus nerve implants (53 and 14 rats, respectively) VNS was delivered under isoflurane, ketamine-xylazine, or awake at different intensities. Stimulus-evoked compound action potentials (eCAPs) were recorded, elicited physiological responses were registered, including changes heart rate (HR), breathing, and blood pressure (BP), and threshold intensities were determined. The intensity that elicits eCAPs (“neural threshold”) is significantly lower than what elicits a physiological response (“physiological threshold”, PT) (25 μA ±1.8 vs. 70 μA ±5.2, respectively; Mean ±SEM). Changes in BP occur at the lowest stimulus intensities (80 μA ±7), followed by changes in HR (105 μA ±8.4) and finally in breathing (310 μA ±32.5). PT is lower with than without electrode insulation (60 μA ±12, vs. 700 μA ±123). PT and electrode impedance are correlated in long-term (r=0.47;p<0.001) but not in acute implants (r=-0.34;pNS); both PT and impedance increase with implant age (Pearson correlationr=0.44;p<0.001 and r=0.64; p<0.001, respectively). PT is lowest when animals are awake (210 μA ±33; Mean ±SEM), followed by ketamine-xylazine (630 μA ±154), and isoflurane (1075 μA ±131). The sequence of physiological responses with increasing VNS intensity is similar in both anesthetized and awake states. Implant age, electrical impedance and the type of anesthesia affect VNS threshold and should be accounted for when determining stimulation dose.
Identifying the Link Between Chemical Exposures and Breast Cancer in African American Women via ToxCast High Throughput Screening Data
Authors: Polemi Katelyn , Nguyen Vy , Heidt Julien , Kahana Adam , Jolliet Olivier , Colacino Justin A.
Published: January 2021

Among women, breast cancer is the most prevalent form of cancer worldwide and has the second highest mortality rate of any cancer in the United States. The breast cancer related death rate is 40% higher in African American women compared to European American women. The incidence of triple negative breast cancer (TNBC), an aggressive subtype of breast cancer for which there is no targeted therapy, is approximately three times higher in non-Hispanic Black women (NHBW) compared to non-Hispanic White women (NHWW). The drivers of these differences in breast cancer incidence and mortality are still poorly understood, and likely lie in an interaction between genetic and environmental factors. Here, we aimed to identify chemical exposures which may play a role in breast cancer disparities. Using chemical biomonitoring data from the National Health and Nutrition Examination Survey (NHANES) and biological activity data from the EPA’s ToxCast program, we assessed the toxicological profiles of chemicals with higher biomarker concentrations in US NHBW. We conducted a literature search to identify a gene set of breast cancer targets included in ToxCast to analyze the response of prioritized chemicals in these assays. Forty-three chemical biomarkers are significantly higher in NHBW. Investigation of these chemicals in ToxCast resulted in a total of 32,683 assays for analysis, 5,172 of which contained nonzero values for the concentration at which the dose-response fitted model reaches the cutoff considered “active” and the scaled top value of dose response curve. Of these chemicals BPA, PFOS, and thiram are most comprehensively assayed. 2,5-dichlorophenol, 1,4-dichlorobenzene, and methyl and propyl parabens had higher biomarker concentrations in NHBW and moderate testing and activity in ToxCast. The distribution of active concentrations for these chemicals in ToxCast assays are comparable to biomarker concentrations in NHBW. Through this integrated analysis, we have identified that multiple chemicals, including thiram, propylparaben, and p,p’ DDE, with disproportionate exposures in NHBW, have breast cancer associated biological activity at human exposure relevant doses.