bluuebunny/crossref_metadata_2025 huggingface dataset:
A Novel Method for Expression and Purification of the C‐Terminal Domain of Apolipoprotein A‐I
Authors: Sallee Daniel , Horn James , Weers Paul
Published: June 2021

Apolipoprotein A‐I (apoA‐I) is the most abundant protein in high‐density lipoprotein, an anti‐antherogenic complex responsible for reverse cholesterol transport. Human apoA‐I is a 243 amino acid protein comprised of two domains, a helix bundle N‐terminal domain, and an unstructured C‐terminal (CT) domain comprising residues 179‐243 which adopts a helical conformation when lipid bound. To better understand the function of the CT apoA‐I, a novel strategy was employed to produce large quantities of this small fragment using a recombinant expression system. The strategy required the introduction of a methionine residue in front of the CT domain to be able to cleave with cyanogen bromide and isolate the desired fragment. However, apoA‐I contains three methionine residues making it difficult to cleave and isolate the correct fragment. Therefore, a new construct was engineered by combining CT apoA‐I with apolipophorin III (apoLp‐III), an insect apolipoprotein that lacks methionine. A unique methionine was then introduced by site‐directed mutagenesis between apoLp‐III and CT apoA‐I. The chimeric protein was expressed in E. coli BL21 cells, purified by nickel affinity chromatography, and cleaved by cyanogen bromide. SDS‐PAGE revealed the presence of three distinct bands at 7 kDa (CT apoA‐I), 18 kDa (apoLp‐III), and a minor band at 26 kDa of uncleaved protein. Then, reversed‐phase HPLC was employed to isolate the 7 kDa fragment. SDS‐PAGE of the first peak eluted from the C8 column confirmed isolation of CT apoA‐I. This novel expression system allows for production of significant quantities of CT apoA‐I needed for the analysis to understand how this important part of apoA‐I functions.

This project was supported by NIH/NIGMS GM089564 and GM008074.
Cervical Cancer Prevention in Low- and Middle-Income Countries
Authors: ALLANSON EMMA R. , SCHMELER KATHLEEN M.
Published: June 2021

Cervical cancer is one of the commonest cancers afflicting women in low and middle income countries, however, both primary prevention with human papillomavirus vaccination, and secondary prevention with screening programs and treatment of preinvasive disease are possible. A coordinated approach to eliminating cervical cancer, as has been called for by the World Health Organization, requires a complex series of steps at all levels of a health system. This article outlines the current state of cervical cancer prevention in low and middle income countries, the innovations being employed to improve outcomes, and consideration of the next steps needed as we move towards global elimination.
Use of an Observer Tool to Enhance Observers' Learning of Anesthesia Residents During High-Fidelity Simulation
Authors: Suet Guillaume , Blanie Antonia , De Montblanc Jacques , Benhamou Dan
Published: June 2021

Introduction

The growing number of learners implies that all of them cannot play an active role during high-fidelity scenarios. Studies suggest a positive educational value when learners are observers only, but it remains uncertain whether learning outcomes might be improved by using an observer tool (OT).

Methods

Eighty-nine anesthesia residents were randomized to use an OT (n = 44, OT+; based on a cognitive aid) or not (n = 45, OT−) when not role-playing. The main outcome parameter was the learning outcomes assessed by comparing the change (before-after) in the response score to a questionnaire dedicated to medical knowledge obtained in the OT+ and OT− groups. The impact of using the OT was also assessed by measuring the perceived stress level and the change of the Anesthetists' Non-Technical Skill items values.

Results

At the end of the session, the mean medical knowledge score (mean ± SD) was higher in the OT+ group than in the OT− group (11.4 ± 2.7 vs. 9.6 ± 2.4, respectively, P = 0.0008). The mean Anesthetists' Non-Technical Skill score and level of stress perceived did not differ between groups. Trainees rated similarly the learning value and satisfaction related to the simulation course.

Conclusions

This study suggests that observing high-fidelity simulation scenarios using an OT based on a cognitive aid increases the medical knowledge gain when compared with that seen in passive observers. This study suggests that the use of an OT improves the educational value of simulation.
Association of Simulation Participation With Diagnostic Reasoning Scores in Preclinical Students
Authors: Hayden Emily M. , Petrusa Emil , Sherman Alexander , Feinstein David M. , Khoury Kimberly , Krupat Edward , Pawlowski John , Oriol Nancy E. , Smithedajkul Patrick Y. , Venkatan Suresh K. , Gordon James A.
Published: June 2021

Purpose

The aim of the study was to evaluate for an association between the number of voluntary mannequin simulation sessions completed during the school year with scores on a year-end diagnostic reasoning assessment among second-year medical students.

Method

This is retrospective analysis of participation in 0 to 8 extracurricular mannequin simulation sessions on diagnostic reasoning assessed among 129 second-year medical students in an end-of-year evaluation. For the final skills assessment, 2 physicians measured students' ability to reason through a standardized case encounter using the Diagnostic Justification (DXJ) instrument (4 categories each scored 0–3 by raters reviewing students' postencounter written summaries). Rater scores were averaged for a total DXJ score (0–12). To provide additional baseline comparison, zero participation students were divided into 2 groups based on intent to participate: those who signed up for extracurricular sessions but never attended versus those who never expressed interest. Scores across the attendance groups were compared with an analysis of variance and trend analysis.

Results

The class DXJ mean equaled 7.56, with a standard deviation of 2.78 and range of 0 to 12. Post hoc analysis after a significant analysis of variance (F = 4.91, df = 8, 128, P < 0.001) showed those participating in 1 or more extracurricular sessions had significantly higher DXJ scores than those not participating. Students doing 7 extracurricular sessions had significantly higher DXJ scores than those doing 0 and 2 (P < 0.05). Zero attendance groups were not different. A significant linear trend (R = 0.48, F = 38.0, df = 1, 127, P < 0.001) was found with 9 groups. A significant quadratic effect, like a dose-response pattern, was found (F = 18.1, df = 2, 125, P < 0.001) in an analysis including both zero attendance groups, a low (1–4 extracurricular sessions) group and a high (5–8) group.

Conclusions

Higher year-end diagnostic reasoning scores were associated with increased voluntary participation in extracurricular mannequin-based simulation exercises in an approximate dose-response pattern.
Antibody Responses after SARS-CoV-2 Vaccination in Lymphoma
Authors: Lim Sean Hua , Campbell Nicola , Johnson Marina , Joseph-Pietras Debora , Collins Graham P , O’Callaghan Ann , Fox Christopher P , Ahearne Matthew , Johnson Peter WM , Goldblatt David , Davies Andrew J
Published: June 2021

Individuals with lymphoid malignancies have an increased mortality risk from COVID-19. Paradoxically, this population is least likely to be protected by SARS-CoV-2 vaccination as a result of disease- or treatment-related immunosuppression. Current data on vaccine responses in persons with lymphoid malignancies is limited.

PROSECO is a UK multi-centre prospective observational study evaluating COVID-19 vaccine immune responses in individuals with lymphoma. This early interim analysis details the antibody responses to first- and second-SARS-CoV-2 vaccination with either BNT162b2 (Pfizer-BioNTech) and ChAdOx1 (AstraZeneca), in 129 participants. Responses are compared to those obtained in healthy volunteers.

The key findings of this interim analysis are first, 61% of participants who are vaccinated during or within 6 months of receiving systemic anti-lymphoma treatment, do not have detectable antibodies despite two doses of vaccine. Second, individuals with curable disease such has Hodgkin (6/6) and aggressive B-cell non-Hodgkin lymphoma (13/16) develop robust antibody levels to either first or second doses, when vaccinated > 6 months after treatment completion. Third, participants incurable, indolent lymphomas have reduced antibody levels to first and second vaccine doses, irrespective of treatment history. Finally, whilst there was no difference in antibody responses between BNT162b2 and ChAdOx1 in lymphoma participants, BNT162b2 induces 11-fold higher antibody responses than ChAdOx1 after the second dose in healthy donors.

These findings serve to reassure the community that individuals with treated Hodgkin and aggressive B-NHL can develop antibody responses to SARS-CoV-2 vaccine. Simultaneously it also highlights the critical need to identify an alternative strategy against COVID-19 for those undergoing systemic anti-lymphoma treatment, and for individuals with indolent lymphomas.
Data-driven identification of health conditions associated with incident Alzheimer’s disease dementia risk: a 15 years follow-up cohort from electronic health records in France and the United Kingdom
Authors: Nedelec Thomas , Couvy-Duchesne Baptiste , Monnet Fleur , Daly Timothy , Ansart Manon , Gantzer Laurène , Lekens Béranger , Epelbaum Stéphane , Dufouil Carole , Durrleman Stanley
Published: June 2021

Importance

The identification of modifiable risk factors for Alzheimer’s disease (AD) is paramount for early prevention and the targeting of new interventions.

Objective

To assess the associations between health conditions diagnosed in primary care and the risk of incident AD over time.

Design, Setting, and Participants

Data for 20,214 AD patients from the United Kingdom and 19,458 AD patients from France were extracted from The Health Improvement Network (THIN) database. For each AD case, a control was randomly assigned after matching for sex and age at dementia diagnosis. We agnostically tested the associations between 123 different ICD10 diagnoses extracted from health records and AD dementia, by conditional logistic regression. We focused on two time periods: 2 to 10 years vs. 0 to 2 years before the diagnosis of AD, to separate risk factors from early symptoms/comorbidities.

Exposures

We considered all health conditions that had been recorded in more than 0.1% of visits per 1000 person-years in both cohorts, corresponding to 123 potential types of exposure.

Main Outcomes and Measures

Odds ratios (ORs) for the association of AD with the various health conditions were calculated after Bonferroni correction for multiple comparisons.

Results

Ten health conditions were significantly associated with high odds ratios for AD when diagnosed 2 to 10 years before AD, in the British and French samples: major depressive disorder (OR 95% confidence interval (UK):1.23-1.46)), anxiety (1.25-1.47), reaction to severe stress (1.24-1.59), hearing loss (1.11-1.28), constipation (1.22-1.41), spondylosis (1.14-1.39), abnormal weight loss (1.33-1.63), malaise and fatigue (1.14-1.32), memory loss (6.65-8.76) and syncope and collapse (1.1-1.37). Depression was the first comorbid condition associated with AD, appearing at least nine years before the first clinical diagnosis of AD, followed by, anxiety, constipation and abnormal weight loss.

Conclusions and Relevance

These results from two independent primary care databases provide new evidence on the temporality of risk factors and early signs of Alzheimer’s disease. These results could guide new dementia prevention strategies.
Rising Through the Pandemic: A scoping review of quality improvement in public health during the COVID-19 pandemic
Authors: Yin X. Cindy , Pang Michelle , Law Madelyn , Guerra Fiona , O’Sullivan Tracey , Laxer Rachel E. , Schwartz Brian , Khan Yasmin
Published: June 2021

Background

The COVID-19 pandemic generated a growing interest in and need for evidence-based tools to facilitate the implementation of emergency management strategies within public health practice. Quality improvement (QI) has been identified as a key framework and philosophy to guide organizational emergency response efforts; however, the nature and extent to which it has been used in public health settings during the COVID-19 pandemic remains unclear.

Methods

We conducted a scoping review of literature published January 2020 – February 2021 and focused on the topic of QI at public health agencies during the COVID-19 pandemic. The search was conducted on four bibliographic databases, in addition to a supplementary grey literature search using custom Google search engines and targeted website search methods. Of the 1,878 peer-reviewed articles assessed, 15 records met the inclusion criteria. An additional 11 relevant records were identified during the grey literature search, for a total of 26 records included in the scoping review.

Results

Records were organized into five topics: 1) collaborative problem solving and analysis with stakeholders; 2) supporting learning and capacity building in QI; 3) learning from past emergencies; 4) implementing QI methods during COVID-19; and 5) evaluating performance using frameworks/indicators.

Conclusions

The literature indicates that QI-oriented activities are occurring at the organizational and program levels to enhance COVID-19 response. To optimize the benefits that QI approaches and methodologies may offer, it is important for public health agencies to focus on both widespread integration of QI as part of an organization’s management philosophy and culture, as well as project level activities at all stages of the emergency management cycle.
COVID 19, Consumption and Inequality: A Systematic Analysis of Rural Population of India
Authors: Kapoor Mudit , Ravi Shamika , Kumar A.K. Shiva
Published: June 2021

Background

COVID19 pandemic has had major impact on consumption levels and inequality within India. Government policy interventions have targeted poor households for cash and food transfers. It is important, however, to study the impact of the pandemic on consumption levels of non-poor in India, and in particular the middle class. In this paper, we aim to quantify the changes in consumption levels and inequality over time, across all groups of rural households in India.

Methods

We analyze three rounds of COVID 19-related shock surveys between May and September 2020. These surveys cover rural households of six large states in India and are representative of more than 442 million (52% of India’s rural population).

Findings

In the early phase of the pandemic, it was the bottom 40% of households that experienced the most severe decline in consumption. But as the pandemic deepened, consumption declined across all classes of households. Besides the poorest, it was particularly severe for the middle class (defined as 40%-80%). We also measure consumption inequality over time and find that the Gini coefficient of consumption distribution increased significantly.

Interpretation

In addition to focusing on poor households, policy responses to alleviate people’s sufferings would have to consider a more comprehensive boost to consumption and compensate for the reduced consumption among middle class families as well.

Funding

None.
The Impact of Face-Masks on Total Mortality Heterogenous Effects by Gender and Age
Authors: De Giorgi Giacomo , Speziali Maria Maddalena , Michalik Felix
Published: June 2021

Governments around the world have been implementing several non-pharmaceutical interventions (NPIs) to fight Covid-19 spread and its associated mortality. We estimate the causal impact of mandatory face-mask wearing policy in public places on (total) mortality in Switzerland. We exploit the staggered introduction of the policy across Swiss cantons using a Difference-in-Difference and an event study approach. We find that the extension of compulsory mask wearing to public places has an heterogeneous impact on mortality, with small positive effects on male mortality entirely driven by older age-cohorts (90+). Finally, we show that adding contact tracing and stricter distancing to compulsory face-mask policy does not lead to better results in terms of mortality.
Inequalities in healthcare disruptions during the Covid-19 pandemic: Evidence from 12 UK population-based longitudinal studies
Authors: Maddock Jane , Parsons Sam , Di Gessa Giorgio , Green Michael J. , Thompson Ellen J. , Stevenson Anna J. , Kwong Alex S.F. , McElroy Eoin , Santorelli Gillian , Silverwood Richard J. , Captur Gabriella , Chaturvedi Nish , Steves Claire J. , Steptoe Andrew , Patalay Praveetha , Ploubidis George B. , Katikireddi Srinivasa Vittal
Published: June 2021

Background

Health systems worldwide have faced major disruptions due to COVID-19 which could exacerbate health inequalities. The UK National Health Service (NHS) provides free healthcare and prioritises equity of delivery, but the pandemic may be hindering the achievement of these goals. We investigated associations between multiple social characteristics (sex, age, occupational social class, education and ethnicity) and self-reported healthcare disruptions in over 65,000 participants across twelve UK longitudinal studies.

Methods

Participants reported disruptions from March 2020 up to late January 2021. Associations between social characteristics and three types of self-reported healthcare disruption (medication access, procedures, appointments) and a composite of any of these were assessed in logistic regression models, adjusting for age, sex and ethnicity where relevant. Random-effects meta-analysis was conducted to obtain pooled estimates.

Results

Prevalence of disruption varied across studies; between 6.4% (TwinsUK) and 31.8 % (Understanding Society) of study participants reported any disruption. Females (Odd Ratio (OR): 1.27 [95%CI: 1.15,1.40]; I2=53%), older persons (e.g. OR: 1.39 [1.13,1.72]; I2=77% for 65-75y vs 45-54y), and Ethnic minorities (excluding White minorities) (OR: 1.19 [1.05,1.35]; I2=0% vs White) were more likely to report healthcare disruptions. Those in a more disadvantaged social class (e.g. OR: 1.17 [1.08, 1.27]; I2=0% for manual/routine vs managerial/professional) were also more likely to report healthcare disruptions, but no clear differences were observed by education levels.

Conclusion

The COVID-19 pandemic has led to unequal healthcare disruptions, which, if unaddressed, could contribute to the maintenance or widening of existing health inequalities.
The impact of Covid-19 vaccination on the Italian healthcare system: a scenario analysis
Authors: Andrea Marcellusi , Gianluca Fabiano , Paolo Sciattella , Massimo Andreoni , Mennini Francesco S
Published: June 2021

Introduction

The objective of this study is to estimate the effects of the national immunisation strategy for Covid-19 in Italy on the national healthcare system.

Methods

An epidemiological scenario analysis was developed in order to simulate the impact of the Covid-19 pandemic on the Italian national healthcare system in 2021. Hospitalisations, ICU admissions and death rates were modelled based on 2020 data. We forecast the impact of the introduction of a primary prevention strategy on the national healthcare system by considering vaccine efficacy, availability of doses and potential population coverage over time.

Results

In the absence of immunisation, between 57,000 and 63,000 additional deaths are forecast in 2021. Based on the assumptions underlying the two epidemiological scenarios from the 2020 data, our model predicts that cumulative hospital admissions in 2021 will range from 3.4 to 3.9 million. The deployment of vaccine immunisation has the potential to control the evolution of 2021 infections and avoid from 60 to 67 percent of deaths compared to not vaccinating.

Conclusions

In order to inform Italian policymakers on delivering a mass vaccination programme, this study highlights and detects some key factors that must be controlled to ensure that immunisation targets will be met in reasonable time.
Micro RNA-based regulation of genomics and transcriptomics of inflammatory cytokines in COVID-19
Authors: Khokhar Manoj , Tomo Sojit , Purohit Purvi
Published: June 2021

Background

Coronavirus disease 2019 is characterized by the elevation of a wide spectrum of inflammatory mediators, which are associated with poor disease outcomes. We aimed at an in-silico analysis of regulatory microRNA and their transcription factors (TF) for these inflammatory genes that may help to devise potential therapeutic strategies in the future.

Methods

The cytokine regulating immune-expressed genes (CRIEG) was sorted from literature and the GEO microarray dataset. Their co-differentially expressed miRNA and transcription factors were predicted from publicly available databases. Enrichment analysis was done through mienturnet, MiEAA, Gene Ontology, and pathways predicted by KEGG and Reactome pathways. Finally, the functional and regulatory features were analyzed and visualized through Cytoscape.

Results

Sixteen CRIEG were observed to have a significant protein-protein interaction network. The ontological analysis revealed significantly enriched pathways for biological processes, molecular functions, and cellular components. The search performed in the MiRNA database yielded 10 (ten) miRNAs that are significantly involved in regulating these genes and their transcription factors.

Conclusion

An in-silico representation of a network involving miRNAs, CRIEGs, and TF which take part in the inflammatory response in COVID-19 has been elucidated. These regulatory factors may have potentially critical roles in the inflammatory response in COVID-19 and may be explored further to develop targeted therapeutic strategies and mechanistic validation.
Development and usability testing of two arts-based knowledge translation tools for parents about pediatric fever
Authors: Scott Shannon D. , Cunningham Chentel , Le Anne , Hartling Lisa
Published: June 2021

Fever is defined as an elevated body temperature greater or equal to 38 degrees celsius when measured via the ear canal. It is a common bodily response in children and is typically a benign process that is self-limiting. However, fever can be an anxiety provoking event for some parents because their child can look unwell and become irritable as a result. Past attempts at translating medical knowledge about fever and its management strategies into parent-friendly formats exist; however, parent misperceptions about definition and management persist despite these educational tools.

Our research team employs patient engagement techniques to develop resources for parents to enhance the uptake of complex medical knowledge. First, our research group conducts qualitative interviews and knowledge synthesis of the literature. Following analysis, salient themes are used to develop a script and skeleton for our videos and infographics, respectively. Employing this same process, this paper discusses the development and usability testing of two digital tools for fever. Prototypes for the video and infographic were tested by parents in urban and remote emergency department (ED) waiting rooms. A total of 58 surveys were completed by parents. Overall, parents rated both the fever video and infographic favourably, suggesting that patient engaged research methods and digital formats are mediums that can facilitate knowledge transfer.
The effect of obesity-related traits on COVID-19 severe respiratory symptoms is mediated by socioeconomic status: a multivariable Mendelian randomization study
Authors: Cabrera-Mendoza Brenda , Wendt Frank R , Pathak Gita A , De Angelis Flavio , De Lillo Antonella , Koller Dora , Polimanti Renato
Published: June 2021

Background

Obesity has been associated with more severe clinical manifestations of coronavirus disease 2019 (COVID-19). However, this association can be affected by many correlates of these traits. Due to its large impact on human health, socioeconomic status (SES) could at least partially influence the association between obesity and COVID-19 severity. To estimate the independent effect of traits related to body size and SES on the clinical manifestations of COVID-19, we conducted a Mendelian randomization (MR) study analyzing the effect of obesity-related anthropometric traits on COVID-19 outcomes.

Methods

Applying two-sample MR approaches, we evaluated the effects of body mass index (BMI), waist circumference (WC), hip circumference, (HIP) and waist-hip ratio (WHR) studied in up to 234,069 participants from the Genetic Investigation of ANthropometric Traits (GIANT) consortium with respect to three COVID-19 outcomes: severe respiratory COVID-19 (5,101 cases vs. 1,383,241 controls), hospitalized COVID-19 (9,986 cases vs. 1,877,672 controls), and COVID-19 infection (38,984 cases vs. 1,644,784 controls) obtained from the COVID-19 Host Genetics Initiative (HGI). Finally, to test the effect of SES using multivariable MR methods, we analyzed genetic data related to self-reported household income (HI) information from 286,301 UK Biobank (UKB) participants.

Results

BMI and WC were associated with severe respiratory COVID-19 (BMI: OR⍰=⍰1.68 p⍰=⍰0.0004; WC: OR⍰=⍰1.72, p⍰=⍰0.007) and COVID-19 hospitalization (BMI: OR=⍰1.62, p⍰=⍰1.35e-06; WC: OR⍰=⍰1.62, p⍰=⍰0.0001). Also, HIP influenced hospitalized COVID-19 (OR⍰=⍰1.31, p⍰=⍰0.012) and COVID-19 infection (OR⍰=⍰1.18, p⍰=⍰0.002). Conversely, HI was associated with lower odds of severe respiratory COVID-19 (OR⍰=⍰0.57, p⍰=⍰0.011) and hospitalized COVID-19 (OR⍰=⍰0.71, p⍰=⍰0.045). Testing these effects in multivariable MR models, we observed that the effect of these obesity-related anthropometric traits on COVID-19 outcomes is not independent of SES effect assessed as HI.

Conclusions

Our findings indicate that low SES is a contributor to the observed association between body size and COVID-19 outcomes.
Spatial Accessibility Modeling of Vaccine Deserts as Barriers to Controlling SARS-CoV-2
Authors: Rader Benjamin , Astley Christina M. , Sewalk Kara , Delamater Paul L. , Cordiano Kathryn , Wronski Laura , Rivera Jessica Malaty , Hallberg Kai , Pera Megan F. , Cantor Jonathan , Whaley Christopher M. , Bravata Dena M. , Brownstein John S.
Published: June 2021

SARS-CoV-2 vaccine distribution is at risk of further propagating the inequities of COVID-19, which in the United States (US) has disproportionately impacted the elderly, people of color, and the medically vulnerable. We identify vaccine deserts - US Census tracts with localized, geographic barriers to vaccine-associated herd immunity - using a comprehensive supply database (VaccineFinder) and an empirically parameterized model of spatial access to essential resources. Incorporating high-resolution COVID-19 burden and time-willing-to-travel for vaccination, we show that early (February – March 2021) vaccine allocation disadvantaged rural and medically vulnerable populations. Data-driven vaccine distribution to vaccine deserts may improve immunization in the hesitant and control SARS-CoV-2.
Vaccination history for diphtheria and tetanus is associated with less severe COVID-19
Authors: Monereo-Sánchez Jennifer , Luykx Jurjen J. , Pinzón-Espinosa Justo , Richard Geneviève , Motazedi Ehsan , Westlye Lars T. , Andreassen Ole A. , van der Meer Dennis
Published: June 2021

Background

COVID-19 is characterized by strikingly large, mostly unexplained, interindividual variation in symptom severity. While some individuals remain nearly asymptomatic, others suffer from severe respiratory failure. It has been hypothesized that previous vaccinations for other pathogens, in particular tetanus, may provide protection against severe COVID-19.

Methods

We made use of data on COVID-19 testing from 103,049 participants of the UK Biobank (mean age 71.5 years, 54.2% female), coupled to immunization records of the last ten years. Using logistic regression, covarying for age, sex, respiratory disease diagnosis, and socioeconomic status, we tested whether individuals vaccinated for tetanus, diphtheria or pertussis, differed from individuals that had only received other vaccinations on 1) undergoing a COVID-19 test, 2) the outcome of this test, and 3) whether they developed severe COVID-19.

Results

We found that individuals with registered diphtheria or tetanus vaccinations were less likely to develop severe COVID-19 than people who had only received other vaccinations (diphtheria OR=0.46, p=3.6×10−4; tetanus OR=0.50, p=5.8×10−4).

Discussion

These results indicate that a history of diphtheria or tetanus vaccinations is associated with less severe manifestations of COVID-19. These vaccinations may protect against severe COVID-19 symptoms by stimulating the immune system. We note the correlational nature of these results, yet the possibility that these vaccinations may influence the severity of COVID-19 warrants follow-up investigations.
REGEN-COV Antibody Combination in Outpatients With COVID-19 – Phase 1/2 Results
Authors: Norton Thomas , Ali Shazia , Sivapalasingam Sumathi , Gao Haitao , Bhore Rafia , Hooper Andrea T. , Hamilton Jennifer D. , Musser Bret J. , Rofail Diana , Im Joseph , Perry Christina , Pan Cynthia , Hosain Romana , Mahmood Adnan , Davis John D. , Turner Kenneth C. , Baum Alina , Kyratsous Christos A. , Kim Yunji , Cook Amanda , Kampman Wendy , Graber Ximena , Acloque Gerard , Sachdeva Yessica , Bocchini Joseph A. , Kohli Anita , Kowal Bari , DiCioccio A. Thomas , Soo Yuhwen , Geba Gregory P. , Stahl Neil , Lipsich Leah , Braunstein Ned , Herman Gary , Yancopoulos George D. , Weinreich David M. ,   the Trial Investigators
Published: June 2021

Background

Continued SARS-CoV-2 infections and COVID-19-related hospitalizations highlight the need for effective anti-viral treatments in the outpatient setting. In a descriptive interim analysis of the phase 1/2 portion of a double-blind phase 1/2/3 trial in COVID-19 outpatients conducted between June 16, 2020 and September 4, 2020, REGEN-COV® (casirivimab plus imdevimab) antibody combination reduced SARS-CoV-2 viral load versus placebo.

Methods

This final phase 1/2 analysis comprises 799 outpatients, including 275 from the previous descriptive analysis (group-1) and 524 from phase 2 (group-2). Patients were randomized (1:1:1) to placebo, REGEN-COV 2400mg, or REGEN-COV 8000mg. Prespecified hierarchical analyses of virologic endpoints were performed in group-2. The proportion of patients with ≥1 COVID-19–related medically attended visit (MAV) through day 29 was assessed in group-1+2. Efficacy was assessed in patients confirmed SARS-CoV-2–positive by baseline nasopharyngeal RT-qPCR. Safety was assessed in all treated patients.

Results

Data from 799 outpatients enrolled from June 16, 2020 to September 23, 2020 are reported. Time-weighted average daily reduction in viral load through day 7 was significantly greater in the REGEN-COV combined 2400mg+8000mg group versus placebo in patients with baseline viral load >107 copies/mL (prespecified primary endpoint): -0.68 log10 copies/ml (95% CI, -0.94 to -0.41; P<.0001). This reduction was - 0.73 (P<.0001) and -0.36 (P=.0003) log10 copies/mL in serum antibody–negative patients and in the overall population, respectively. REGEN-COV reduced the proportion of patients with ≥1 COVID-19–related MAV versus placebo (2.8% [12/434] REGEN-COV combined dose group versus 6.5% [15/231] placebo; P=.024; relative risk reduction [RRR]=57%); in patients with ≥1 risk factor for hospitalization, the treatment effect was more pronounced (RRR=71%). Adverse events were similar across groups.

Conclusions

In COVID-19 outpatients enrolled prior to the widespread circulation of delta and omicron variants, treatment with REGEN-COV significantly reduced viral load and COVID-19–related MAVs.
Moving from development to implementation of digital innovations within the NHS: myHealthE, a remote monitoring system for tracking patient outcomes in child and adolescent mental health services
Authors: Morris Anna C , Ibrahim Zina , Moghraby Omer S , Stringaris Argyris , Grant Ian M , Zalewski Lukasz , McClellan Stuart , Moriarty Garry , Simonoff Emily , Dobson Richard JB , Downs Johnny
Published: June 2021

This paper reports our experience of developing, implementing, and evaluating myHealthE (MHE); a digital innovation for Child and Adolescents Mental Health Services (CAMHS) which automates the remote collection and reporting of Patient Reported Outcome Measures (PROMs) into National Health Services (NHS) electronic health care records. We describe the logistical and governance issues encountered in developing the MHE interface with patient identifiable information, and the steps taken to overcome these development barriers. We describe the applications architecture and hosting environment to enable it to be operable within the NHS, as well the as the capabilities needed within the technical team to bridge the gap between academic developers and NHS operational teams. We present evidence on the feasibility and acceptability for this system within clinical services and describe the process of iterative development, highlighting additional functions which were incorporated to increase system utility. This article provides a framework with which to plan, develop and implement automated PROM collection from remote devices back to NHS infrastructure. The challenges and solutions described in this paper will be pertinent to other digital health innovation researchers aspiring to deploy interoperable systems within NHS clinical systems.
From Tabulated Data to Knowledge Graph: A Novel Way of Improving the Performance of the Classification Models in the Healthcare Data
Authors: Zaki Nazar , Mohamed Elfadil A , Habuza Tetiana
Published: June 2021

In sectors like healthcare, having classification models that are both reliable and accurate is vital. Regrettably, contemporary classification techniques employing machine learning disregard the correlations between instances within data. This research, to rectify this, introduces a basic but effective technique for converting tabulated data into data graphs, incorporating structural correlations. Graphs have a unique capacity to capture structural correlations between data, allowing us to gain a deeper insight in comparison to carrying out isolated data analysis. The suggested technique underwent testing once the integration of graph data structure-related elements had been carried out and returned superior results to testing solely employing original features. The suggested technique achieved validity by returning significantly improved levels of accuracy.

Data

The extracted graph topological features datasets are available from:
Evaluation and clinical implications of the time to a positive results of antigen testing for SARS-CoV-2
Authors: Akashi Yusaku , Kiyasu Yoshihiko , Takeuchi Yuto , Kato Daisuke , Kuwahara Miwa , Muramatsu Shino , Ueda Atsuo , Notake Shigeyuki , Nakamura Koji , Ishikawa Hiroichi , Suzuki Hiromichi
Published: June 2021

Antigen tests for severe acute respiratory coronavirus 2 sometimes show positive lines earlier than their specified read time, although the implication of getting the results at earlier time is not well understood. This study aimed to evaluate the clinical utility of an antigen test by evaluating the time period to get positive results and by comparing the test sensitivity with that of a digital immunoassay (DIA) test.

We prospectively collected additional nasopharyngeal samples from patients who had already tested positive for SARS-CoV-2 by reverse transcription PCR. The additional swab was used for an antigen test, QuickNavi™-COVID19 Ag, and the time periods to get positive results were measured. The sensitivity of QuickNavi™-COVID19 Ag was also compared with that of a DIA.

In 84 of 96 (87.5%) analyzed cases, the results of QuickNavi™-COVID19 Ag were positive. The time to obtain positive results was 15.0 seconds in median (inter quartile range: 12.0-33.3, range 11-736), and was extended in samples with higher cycle thresholds (Ct) (p<0.001). Positive lines appeared within a minute in 85.7% of cases and within 5 minutes in 96.4%. The sensitivities of QuickNavi™-COVID19 Ag and the DIA were 87.5% (95% confident interval [CI]: 79.2%-93.4%) and 88.6% (95%CI: 75.4%- 96.2%), respectively. Their results were concordant in 90.9% of cases, with discrepancies present only in cases with Ct values >32.

QuickNavi™-COVID19 Ag immediately showed positive results in most cases, and the time to a positive reaction may have indicated the viral load. In addition, the sensitivity of the test was comparable to the DIA.
Plasma zinc status and hyperinflammatory syndrome in hospitalized COVID-19 patients: an observational study
Authors: Verschelden Gil , Noeparast Maxim , Noparast Maryam , Lauwers Maïlis , Michel Charlotte , Cotton Frédéric , Goyvaerts Cleo , Hites Maya
Published: June 2021

Deficiency of the element zinc is associated with cytokine releasing syndrome (CRS) and the related acute respiratory distress syndrome as well as impaired antiviral response. Similar complications associate with severe SARS-CoV-2.

We conducted a prospective, single-center, observational study in a tertiary university hospital (CUB-Hopital Erasme, Brussels) to address the zinc status, the association between the plasma zinc concentration, development of CRS, and the clinical outcomes in PCR-confirmed and hospitalized COVID-19 patients. One hundred and thirty-nine eligible patients were included between May 2020 and November 2020 (median age of 65 years [IQR, 54 to 77]).

Our cohort’s mean plasma zinc concentration was 56.2 µg/dL (standard deviation [SD], 14.8) compared to 75.7 µg/dL (SD = 18.9 µg/dL) in the retrospective non-COVID-19 control group (N = 1513;P<.001). Markedly, the absolute majority of patients (96%) were zinc deficient (<80 µg/dL).

The mean zinc concentration was lower in patients with CRS compared to those without CRS (−5 µg/dL; 95% CI, -10.5 to 0.051;P= 0.048).

Among the tested outcomes, zinc concentration is significantly correlated with only the length of hospital stay (rho = -0.19;P= 0.022), but not with mortality or morbidity. As such, our findings do not support the role of zinc as a robust prognostic marker among hospitalized COVID-19 patients who in our cohort presented high prevalence of zinc deficiency. It might be more beneficial to explore the role of zinc as a biomarker for assessing the risk of developing a tissue-damaging CRS and predicting outcomes in patients diagnosed with COVID-19 at the early stage of the disease.
Parental inflammatory bowel disease and autism in the offspring: Triangulating the evidence using four complementary study designs
Authors: Sadik Aws , Dardani Christina , Pagoni Panagiota , Havdahl Alexandra , Stergiakouli Evie , Grove Jakob , Khandaker Golam M. , Sullivan Sarah A. , Zammit Stan , Jones Hannah J. , Smith George Davey , Dalman Christina , Karlsson Håkan , Gardner Renee M. , Rai Dheeraj
Published: June 2021

Importance

Evidence linking parental diagnoses of inflammatory bowel disease (IBD) with offspring autism is inconclusive.

Objective

To investigate associations between parental diagnoses of IBD and offspring autism and elucidate their underlying aetiology by conducting four complementary studies.

Design, Setting and Participants

(1) Nationwide population-based cohort study using Swedish registers to examine associations between parental IBD diagnoses and autism diagnoses in offspring, (2) Linkage disequilibrium (LD)-score regression to estimate the genetic correlation between the phenotypes. (3) Polygenic risk score (PRS) analyses in the Avon Longitudinal Study of Parents and Children (ALSPAC) to investigate associations between maternal genetic liability to IBD and autism factor mean score in offspring. (4) Two-sample Mendelian randomization (MR) to assess bidirectional causal links between genetic liability to IBD and autism.

Results

Observational analyses provided evidence of an association between parental IBD diagnoses and offspring autism diagnosis in mutually adjusted models (maternal: OR= 1.32; 95% CI: 1.25 to 1.40; p<0.001; paternal: OR= 1.09; 95% CI: 1.02 to 1.17; p=0.012; n=2 324 227, 52.3% male). PRS analyses in ALSPAC indicated associations between maternal PRS for IBD subtypes and a measure of broad autism phenotype, autism factor mean score, in the offspring (UC: βPRS= 0.02; 95%CI: 0.003 to 0.05; p= 0.02; R2=0.06; Crohn’s: βPRS= 0.03; 95%CI: 0.01 to 0.05; p= 0.004; R2= 0.06; n= 7357, 50.3% male). MR analyses provided evidence of a potential causal effect of genetic liability for IBD, especially ulcerative colitis, on autism (ORMR= 1.03; 95%CI: 1.01 to 1.06). There was little evidence to suggest a causal effect of genetic liability to autism on risk of IBD, or a genetic correlation between the two conditions.

Conclusions and relevance

Triangulating evidence from a nationwide register-based cohort study, genetic correlation, polygenic risk score analyses and MR, we found evidence of a potentially causal link between parental, particularly maternal, diagnoses and genetic liability to IBD and offspring autism. Perinatal immune system dysregulation, micronutrient malabsorption and anaemia may be implicated.
Increased risk of death in covid-19 hospital admissions during the second wave as compared to the first epidemic wave. A prospective dynamic cohort study in South London, UK
Authors: Cusinato Martina , Gates Jessica , Jajbhay Danyal , Planche Tim , Ong Yee-Ean
Published: June 2021

Objective

To assess whether mortality of patients admitted for covid-19 treatment was different in the second UK epidemic wave of covid-19 compared to the first wave accounting for improvements in the standard of care available and differences in the distribution of risk factors between the two waves.

Design

Single-centre, analytical, dynamic cohort study.

Participants

2,701 adults (≥18 years) with SARS-CoV-2 infection confirmed by polymerase chain reaction (PCR) and/or clinico-radiological diagnosis of covid-19, who required hospital admission to covid-19 specific wards, between January 2020 and March 2021. There were 884 covid-19 admissions during the first wave (before 30 Jun 2020) and 1,817 during the second wave.

Outcome measures

in-hospital covid-19 associated mortality, ascertained from clinical records and Medical Certificate Cause of Death.

Results

The crude mortality rate was 25% lower during the second wave (2.23 and 1.66 deaths per 100 person-days in first and second wave respectively). However, after accounting for age, sex, dexamethasone, oxygen requirements, symptoms at admission and Charlson Comorbidity Index, mortality hazard ratio associated with covid-19 hospital admissions was 1.62 (95% confidence interval 1.26, 2.08) times higher in the second wave compared to the first.

Conclusions

Analysis of covid-19 admissions recorded in St. Georges Hospital, shows a larger second epidemic wave, with a lower crude mortality in hospital admissions. Nevertheless, after accounting for other factors underlying risk of death for covid-19 admissions was higher in the second wave. These findings are temporally and ecologically correlated with an increased circulation of SARS-CoV-2 variant of concern 202012/1 (alpha).
A Survey of Copy Number Variants Associated with Neurodevelopmental Disorders in a Large-Scale, Multi-Ancestry Biobank
Authors: Birnbaum Rebecca , Mahjani Behrang , Loos Ruth J.F. , Sharp Andrew J.
Published: June 2021

BACKGROUND

Past clinical genetic studies have identified rare, copy number variants (CNVs) as risk factors for multiple neurodevelopmental disorders (NDD), including autism spectrum disorder and schizophrenia. However, the broad, clinical characterization of these NDD-CNVs in large population cohorts, especially of diverse ancestry, is relatively understudied. We characterized the clinical presentation of NDD-CNVs in the BioMe biobank, comprising ∼25,000 individuals across diverse ancestry, medical and neuropsychiatric clinical presentation, with a mean age of 50.3 years.

METHODS

Individuals within the BioMe biobank harboring NDD-CNVs were identified using a consensus of two CNV calling algorithms, based on whole-exome sequencing and genotype array data, followed by a series of novel, in-silico clinical assessments.

RESULTS

The overall prevalence of a set of 64 NDD-CNVs was calculated at ∼2.5%, with prevalence varying by locus, corroborating the presence of some relatively, highly-prevalent NDD-CNVs (i.e., 15q11.2 deletion/duplication, 2q13(NPHP1) deletion/duplication). An aggregate set of rare, NDD-CNVs were enriched for congenital disorders (OR=1.8, p-value=0.02) and major depressive disorders (OR=1.3, p-value=0.04) in multi-ancestry analyses, and major depressive-disorder in an African ancestry-stratified group (OR=1.8, p-value=0.01). In a meta-analysis of medical diagnoses (n=195 hierarchically-clustered diagnostic codes), an aggregated set of rare, NDD-CNVs was significantly associated with obstructive sleep apnea (Z-score=3.6 p=3.2×10−4). Further, an aggregated set of rare, NDD-CNVs was associated with increased body mass index (BMI) in a multi-ancestry analysis (Beta=0.14, p-value=0,04), and in Hispanic-stratified analyses (Beta=0.30, p-value=4.2×10−3). For 38 common serum laboratory tests, there was no identified association with an aggregate set of NDD-CNVs.

CONCLUSION

The current analyses elucidated clinical features of individuals harboring NDD-CNVs, in a large-scale, multi-ancestry biobank, identifying enrichments for congenital disorders and major depressive disorder, as well as identifying associations with obesity-related phenotypes, obstructive sleep apnea and increased BMI. Future recall of individuals harboring NDD-CNVs will allow for further clinical assessments beyond the electronic health records (EHR) presently analyzed, including neurocognitive and neuroimaging outcomes.
Pretransplant BK virus-specific T-cell-mediated immunity and serotype specific antibodies may have utility in identifying patients at risk for BK virus associated haemorrhagic cystitis after allogeneic HSCT
Authors: Šťastná-Marková Markéta , Hamšíková Eva , Hainz Petr , Hubáček Petr , Kroutilová Marie , Kryštofová Jitka , Ludvíková Viera , Musil Jan , Pecherková Pavla , Saláková Martina , Šroller Vojtěch , Vydra Jan , Němečková Šárka
Published: June 2021

BK polyomavirus (BKV) persists lifelong in the urinary tract with asymptomatic urinary shedding in healthy individuals. In immunocompromised persons after transplantation of hematopoietic stem cells (HSCT) the BKV high-rate replication is associated with haemorrhagic cystitis (HC) with a reported incidence of 17 %. Numerous studies of reconstitution of the immune system after HSCT have established the principal role of T cell effectors in the control of viral replication and reactivation. The value of pretransplant BKV-specific antibodies in transplanted patients for the protection from viral disease was long considered insignificant. We hypothesized that the status of BKV immunity prior to HSCT could provide evidence for the BKV tendency to reactivate and that examining the level of subtype-specific antibodies and T-cell response in individual patients could help to predict the risk of BKV reactivation and HC. Evaluation of the risk of HC in relation to pretransplant anti-BKV1,2,4 IgG levels together with clinical factors known before transplantation revealed that patients with „medium” anti-BKV IgG and significant clinical risk (SR) have a very significantly increased HC risk in comparison with the reference group of “low” anti-BKV IgG level and low clinical risk (LR) (P=0.0009). Predictive value of pretransplant BKV specific IgG was confirmed on the level of virus genotypes. Analysis of pretransplant T cell immunity to BKV antigens VP1 and LTag has shown that magnitude of IFN-gamma T cell response inversely corelated with posttransplant DNAuria. We hypothesize that the control of BKV latency by BKV specific T cells before HSCT would be one of the factors that influence BKV reactivation after HSCT. Our study has shown that prediction using a combination of clinical and immunological pretransplant risk factors can help early identification of patients who are at risk of developing BKV disease after HSCT.