title: COVID 19 Knowledge, Attitude, and Practice of the Healthcare Providers in United Arab Emirates

abstract:
BackgroundHealth care providers at increased risk of COVID-19 infection, inadequate knowledge and practice about COVID-19, and infection control may lead to increased risk of disease transmission. Early diagnosis and appropriate management of COVID 19 cases is important in preventing transmission and improving patient outcomes. The aim of this study was to assess the knowledge, altitude, and practice of healthcare providers in the United Arab Emirates toward COVID-19 and to examine its determinants.

MethodA cross-sectional study was conducted to assess knowledge, attitudes, and practice (KAP) of Healthcare providers regarding COVID-19. The study was conducted during the COVID-19 pandemic from of April 11 to July 23, using an online anonymous self-administered questionnaire.

ResultsA total of 2371 healthcare providers responded to the survey. A total of 1091 worked in inpatient hospitals, 494 in primary health care, and 388 in emergency and ICU care. The overall performance score for all healthcare providers was as follows: 49.1%, poor score; 41.8 %, intermediate score; and 9.2%, good score with a mean result of 17.14. Factors leading to better overall performance scores were years of experience, pediatricians specialty, and specialists occupation. A total of 55.7% received good direct knowledge from all healthcare providers. In practice, 48% had good practices toward COVID-19. The overall attitude mean was 2.8, from a maximum score of 7, indicating a positive attitude toward COVID-19.

ConclusionsThe study-demonstrated gaps in specific aspects of knowledge and practice that should be focused on in future education and HCP awareness. A structured training program targeting all HCPs is needed to have good clinical knowledge and practice about COVID-19.


title: First dose mRNA vaccination is sufficient to reactivate immunological memory to SARS-CoV-2 in ex COVID-19 subjects

abstract: Characterizing the adaptive immune response to COVID-19 vaccination in individuals who recovered from SARS-CoV-2 infection may define current and future clinical practice. To determine the effect of two doses BNT162b2 mRNA COVID-19 vaccination schedule in individuals who recovered from COVID-19 (ex COVID-19) compared to naive subjects we evaluated SARS-CoV-2 spike-specific T and B cell responses, as well as specific IgG, IgM and neutralizing antibodies titres in 22 individuals who received BNT162b2 mRNA COVID-19 vaccine, 11 of which had a previous history of SARS-CoV-2 infection. Evaluations were performed before vaccination and then weekly until 7 days post second injection. Data obtained clearly showed that one vaccine dose is sufficient to increase both cellular and humoral immune response in ex COVID-19 subjects without any additional improvement after the second dose. On the contrary, the second dose is mandatory in naive ones to further enhance the response. These results question whether a second vaccine jab in ex COVID-19 subjects is required and indicate that millions of vaccine doses may be redirected to naive individuals, thus shortening the time to reach herd immunity.

category: infectious diseases


title: Centenarians and extremely old people living with frailty can elicit durable SARS-CoV-2 spike specific IgG antibodies with virus neutralization functions following virus infection

abstract:
BackgroundThe SARS-CoV-2 (Severe Acute Respiratory Syndrome coronavirus 2) has led to more than 114 million COVID-19 cases and >2.5 million deaths worldwide. Epidemiological analysis has revealed that the risk of developing severe COVID-19 increases with age. Despite a disproportionate number of older individuals and long-term care facilities being affected by SARS-CoV-2 and COVID-19, very little is understood about the immune responses and development of humoral immunity in the extremely old person after SARS-CoV-2 infection. Here we investigated the development of humoral immunity in centenarians following a SARS-CoV-2 outbreak in a long-term care facility.

MethodsExtreme aged individuals and centenarians who were residents in a long-term care facility and infected with or exposed to SARS-CoV-2 were investigated for the development of antibodies to SARS-CoV-2. Blood samples were collected from positive and bystander individuals 30 and 60 days after original diagnosis of SARS-CoV-2 infection. Plasma was used to quantify IgG, IgA, and IgM isotypes and subsequent subclasses of antibodies specific for SARS-CoV-2 spike protein. The function of anti-spike was then assessed by virus neutralization assays against the native SARS-CoV-2 virus.

FindingsFifteen long-term care residents were investigated for SARS-CoV-2 infection. All individuals had a Clinical Frailty scale score [≥]5 and were of extreme older age or were centenarians. Six women with a median age of 98.8 years tested positive for SARS-CoV-2. Anti-spike IgG antibody titers were the highest titers observed in our cohort with all IgG positive individuals having virus neutralization ability. Additionally, 5 out of the 6 positive participants had a robust IgA anti-SARS-CoV-2 response. In all 5, antibodies were detected after 60 days from initial diagnosis.

InterpretationExtreme older frail individuals and centenarians were able to elicit robust IgG and IgA antibodies directed toward SARS-CoV-2 spike protein. The antibodies were able to neutralize the virus. Humoral responses were still detectable after 60 days from initial diagnosis. Together, these data suggest that recovered participants who are of extreme old age would be protected if re-exposed to the same SARS-CoV-2 viral variant. Considering the threat of SARS-CoV-2 and COVID-19 to older age groups and long-term care facilities, the humoral responses to SARS-CoV-2 in older age groups is of public health importance and has implications to vaccine responses.

FundingCanadian Institutes of Health Research (CIHR), NIH/NIAID, Genome Atlantic. VIDO receives operational funding from the Canada Foundation for Innovation through the Major Science Initiatives Fund and by Government of Saskatchewan through Innovation Saskatchewan.


title: Anti-Spike protein assays to determine post-vaccination antibody levels: a head-to-head comparison of five quantitative assays

abstract:
BackgroundReliable quantification of the antibody response to SARS-CoV-2 vaccination is highly relevant for identifying possible vaccine failure and estimating the time of protection. Therefore, we aimed to evaluate the performance of five different Anti-SARS-CoV-2 antibody assays regarding the quantification of anti-spike (S) antibodies induced after a single dose of BNT162b2.

MethodsSera of n=69 SARS-CoV-2 naive individuals 21{+/-}1 days after vaccination with BNT162b2 (Pfizer/BioNTech) were tested using the following quantitative SARS-CoV-2 antibody assays: Roche S total antibody, DiaSorin trimeric spike IgG, DiaSorin S1/S2 IgG, Abbott II IgG, and Serion/Virion IgG. Test agreement was assessed by Passing-Bablok regression. Results were further compared to the percent inhibition calculated from a surrogate virus neutralization test (sVNT) by correlation and ROC (receiver-operating-characteristics) analysis.

ResultsIndividual values were distributed over several orders of magnitude for all assays evaluated. Although the assays were in good overall agreement ({rho}=0.80-0.94), Passing-Bablok regression revealed systematic and proportional differences, which could not be eliminated by converting the results to BAU/mL as suggested by the manufacturers. 7 (10%) individuals had a negative sVNT results (i.e. <30% inhibition). These samples were reliably identified by most assays and yielded low binding antibody levels (ROC-AUCs 0.84-0.93).

ConclusionsAlthough all assays evaluated showed good correlation, readings from different assays were not interchangeable, even when converted to BAU/mL using the WHO international standard for SARS-CoV-2 immunoglobulin. This highlights the need for further standardization of SARS-CoV-2 serology.


title: Investigating the first wave of the COVID-19 pandemic in Ukraine using epidemiological and genomic sequencing data

abstract: The novel coronavirus SARS-CoV-2 was first detected in China in December 2019 and has rapidly spread around the globe. The World Health Organization declared COVID-19 a pandemic in March 2020 just three months after the introduction of the virus. Individual nations have implemented and enforced a variety of social distancing interventions to slow the virus spread, that had different degrees of success. Understanding the role of non-pharmaceutical interventions (NPIs) on COVID-19 transmission in different settings is highly important. While most such studies have focused on China, neighboring Asian counties, Western Europe, and North America, there is a scarcity of studies for Eastern Europe. The aim of this study is to contribute to filling this gap by analyzing the characteristics of the first months of the epidemic in Ukraine using agent-based modelling and phylodynamics. Specifically, first we studied the dynamics of COVID-19 incidence and mortality and explored the impact of epidemic NPIs. Our stochastic model suggests, that even a small delay of weeks could have increased the number of cases by up to 50%, with the potential to overwhelm hospital systems. Second, the genomic data analysis suggests that there have been multiple introductions of SARS-CoV-2 into Ukraine during the early stages of the epidemic. Our findings support the conclusion that the implemented travel restrictions may have had limited impact on the epidemic spread. Third, the basic reproduction number for the epidemic that has been estimated independently from case counts data and from genomic data suggest sustained intra-country transmissions.

category: epidemiology


title: Investigating the first stage of the COVID-19 pandemic in Ukraine using epidemiological and genomic data


title: Long-Term Duration of Antibody Response to SARS CoV-2 in One of the Largest Slums of Buenos Aires

abstract: The durability of the antibody response following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections has not been fully elucidated. We have performed a cross-sectional study in one of the largest slums of Buenos Aires, Barrio Padre Mugica in June 2020, detecting a seroprevalence of 53.4%. To evaluate the persistence of the humoral response against SARS-CoV-2 in this area, we designed a second study assessing only the people that were IgG positive in the first survey. The IgG levels against the full spike (S) protein in 175 individuals that were seropositive, at least 6 months before, were evaluated in a second survey. The positivity rate was 92.0%, 161 from 175 individuals remained IgG positive. We observed a contraction in the overall IgG levels measured by ELISA. The median IgG dropped 62% from June to December 2020. Most of the individuals tested (87%) reported to be asymptomatic or oligo-symptomatic. No difference was found between men and women, but people aged less than 50 showed a lower IgG level in each period compared to older individuals. Our data indicate sustained humoral immunity for at least 6 months in a specific socio-economical setting in a population that was mainly asymptomatic for COVID-19.


title: SARS-CoV2 sero-survey among adults involved in health care and health research in Guinea-Bissau, West Africa

abstract:
BackgroundMany African countries have reported fewer COVID-19 cases than countries elsewhere. By the end of 2020, Guinea-Bissau, West Africa, had <2500 PCR-confirmed cases corresponding to 0.1% of the [~]1.8 million national population. We assessed the prevalence of SARS-CoV2 antibodies in urban Guinea-Bissau.

MethodsWe measured IgG antibody in point-of-care rapid tests among 140 staff and associates at a biometric research field station in Bissau, the capital of Guinea-Bissau, during November 2020.

ResultsOf 140 participants, 25 (18%) were IgG-positive. Among IgG-positives, 12 (48%) reported an episode of illness since the onset of the pandemic. Twenty-five (18%) participants had been PCR-tested between May and September; 7 (28%) were PCR-positive. Four of these 7 tested IgG-negative in the present study. Five participants reported a death in their house, corresponding to a crude annual death rate of 4.5/1000 people; no death was attributed to COVID-19.

ConclusionsIn spite of low official number of COVID-19 cases, our serosurvey found a high prevalence of IgG-positivity. Most IgG-positives had not been ill. The official number of PCR-confirmed COVID-19 cases grossly underestimates the prevalence during the pandemic. The observed overall mortality rate is not higher than the official Guinean mortality rate of 9.6/1000 people.


title: Elevated mortality among people experiencing homelessness with COVID-19

abstract: We reviewed publicly available data from major U.S. health jurisdictions to compare case fatality rates in people experiencing homelessness (PEH) to the general population. Case fatality among PEH was 1.3 times (95% CI 1.1, 1.5) that of the general population, suggesting that PEH should be prioritized for vaccination.


title: Sensitivity to missing not at random dropout in clinical trials: use and interpretation of the Trimmed Means Estimator

abstract: Outcome values in randomized controlled trials (RCTs) may be missing not at random (MNAR), if patients with extreme outcome values are more likely to drop out (e.g., due to perceived ineffectiveness of treatment, or adverse effects). In such scenarios, estimates from complete case analysis (CCA) and multiple imputation (MI) will be biased. The trimmed means (TM) estimator operates by setting missing values to the most extreme value, and then "trimming" away equal fractions of both treatment groups, estimating the treatment effect using the remaining data. The TM estimator relies on two assumptions, which we term the "strong MNAR" and "location shift" assumptions. In this article, we derive formulae for the bias resulting from the violation of these assumptions for normally distributed outcomes. We propose an adjusted estimator, which relaxes the location shift assumption and detail how our bias formulae can be used to establish the direction of bias of CCA, MI and TM estimates under a range of plausible data scenarios, to inform sensitivity analyses. The TM approach is illustrated with simulations and in a sensitivity analysis of the CoBalT RCT of cognitive behavioural therapy (CBT) in 469 individuals with 46 months follow-up. Results were consistent with a beneficial CBT treatment effect. The MI estimates are closer to the null than the CCA estimate, whereas the TM estimate was further from the null. We propose using the TM estimator as a sensitivity analysis for data where it is suspected that extreme outcome values are missing.


title: A Novel Computer-Assisted Drug-Induced Liver Injury Causality Assessment Tool (DILI-CAT)

abstract:
ObjectiveWe hypothesized that a drug-characteristic DILI-phenotype could be defined and be used to develop a computer-assisted DILI causality assessment-tool (DILI-CAT).

DesignA drug-specific DILI-phenotype was developed for amoxicillin-clavulanate (AMX/CLA), cefazolin, cyproterone, and polygonum multiflorum using data from published case series, and subsequently a DILI-CAT Score (DILI-CAT-S) was created for each drug. The phenotype was made up of the following three parameters: (1) latency, R-value, and (3) AST/ALT ratio (also de Ritis ratio). A point allocation system was developed with points allocated depending on the degree of deviation from the core of published data for the three phenotypic parameters.

ResultsThe four drugs had a significantly different phenotype based on the three parameters utilized. For example, the median cyproterone latency was 150 days versus less than 43 days for the other three drugs (median: 26 for AMX/CLA, 20 for cefazolin, and 20 days for polygonum multiflorum; p<0{middle dot}001). The R-value for the four drugs was also significantly different (median: cyproterone [12.4] and polygonum multiflorum [10.9]) from AMX/CLA (1.44) and cefazolin (1.57; p<0.001). The resulting DILI-CAT-S effectively separated cyproterone and polygonum multiflorum from AMX/CLA and cefazolin, respectively (p<0{middle dot}001). Notably, because of overlap in phenotype AMX/CLA and cefazolin could not be differentiated by DILI-CAT-S.

ConclusionDILI-CAT is a data-driven, diagnostic tool built to define drug-specific phenotypes. Data presented here provide proof of principle that a drug-specific, data-driven causality assessment tool can be developed for different drugs and raise the possibility that such a process could improve and standardize causality assessment methods.

FundingDCR was supported by the NIH, grant P30 DK 123704

category: gastroenterology


title: COVID-19 mRNA vaccine is not detected in human milk

abstract: Several countries have recently approved the use of mRNA vaccines against COVID-19 under an emergency use authorization. However, no pregnant or lactating individuals were included in the Phase 3 clinical trials of these vaccines despite belonging to a group at high risk for severe complications of COVID-19 infection. We show here that the mRNA from anti-COVID BNT162b2 (Pfizer) and mRNA-1273 (Moderna) vaccines is not detected in human breast milk samples collected 4-48 hours post-vaccine. These results strengthen the recommendation of ABM and WHO that lactating individuals who receive the anti-COVID-19 mRNA-based vaccine should continue to breastfeed their infants uninterrupted.

category: pediatrics


title: More than the eye can see; shedding new light on SARS-CoV-2 Lateral Flow Device-based immunoassays

abstract: Containing the global SARS-CoV-2 pandemic has been an unprecedented challenge due to high horizontal transmissivity and asymptomatic carriage rates. Lateral Flow Device (LFD) immunoassays were introduced in late 2020 to detect SARS-CoV-2 infection in asymptomatic or pre-symptomatic individuals rapidly. Whilst LFD technologies have been used for over 60 years, their widespread use as a public health tool during a pandemic is unprecedented. By the end of 2020, data from studies into the efficacy of the LFDs emerged and showed these point-of-care devices to have very high specificity (ability to identify true negatives) but inadequate sensitivity with high false-negative rates. The low sensitivity (<50%) shown in several studies is a critical public health concern, as asymptomatic or pre-symptomatic carriers may wrongly be assumed to be non-infectious, posing a significant risk of further spread in the community. Here we show that the direct visual readout of SARS-CoV-2 LFDs is an inadequate approach to discriminate a potentially infective viral concentration in a bio-sample. We quantified significant immobilized antigen-antibody-label conjugate complexes within the LFDs visually scored as negative using high-sensitivity synchrotron X-ray fluorescence imaging. Correlating quantitative X-ray fluorescence measurements and qRT-PCR determined numbers of viral copies, we identified that negatively scored samples could contain up to 100 PFU (equivalent here to [~]10,000 RNA copies/test). The study demonstrates where the shortcomings arise in many of the current direct-readout SARS-CoV-2 LFDs, namely being a deficiency in the readout as opposed to the potential level of detection of the test, which is orders of magnitude higher. The present findings are of importance, both to public health monitoring during the COVID-19 pandemic and to the rapid refinement of these tools for immediate and future applications.

category: public and global health


title: Public Awareness of Mask Usage in 29 Countries

abstract: This study analyzed the determinants of people wearing masks in 29 countries in 2020 using over 400,000 survey responses. The results showed that there is considerable variance in the awareness of mask usage across countries. People in Asian countries tend to wear masks whereas citizens in Scandinavian countries are less likely to wear them. This study also found that citizens in more democratic and more prosperous countries are less likely to wear masks. Furthermore, females are more likely to wear them. This paper contributes to the literature as it re-examines anecdotes and previous research by using statistical methods to analyze over 400,000 survey responses.


title: A Simple RT-PCR Melting temperature Assay to Rapidly Screen for Widely Circulating SARS-CoV-2 Variants.

abstract:
BackgroundThe increased transmission of SARS-CoV-2 variants of concern (VOC) which originated in the United Kingdom (B.1.1.7), South Africa (B1.351), Brazil (P.1) and in United States (B.1.427/429) requires a vigorous public health response, including real time strain surveillance on a global scale. Although genome sequencing is the gold standard for identifying these VOCs, it is time consuming and expensive. Here, we describe a simple, rapid and high-throughput reverse-transcriptase PCR (RT-PCR) melting temperature (Tm) screening assay that identifies these three major VOCs.

MethodsRT-PCR primers and four sloppy molecular beacon (SMB) probes were designed to amplify and detect the SARS-CoV-2 N501Y (A23063T) and E484K (G23012A) mutations and their corresponding wild type sequences. After RT-PCR, the VOCs were identified by a characteristic Tm of each SMB. Assay optimization and testing was performed with RNA from SARS-CoV-2 USA WA1/2020 (WT), a B.1.17 and a B.1.351 variant strains. The assay was then validated using clinical samples.

ResultsThe limit of detection (LOD) for both the WT and variants was 4 and 10 genomic copies/reaction for the 501 and 484 codon assays, respectively. The assay was 100% sensitive and 100% specific for identifying the N501Y and E484K mutations in cultured virus and in clinical samples as confirmed by Sanger sequencing.

ConclusionWe have developed an RT-PCR melt screening test for the three major VOCs which can be used to rapidly screen large numbers of patient samples providing an early warning for the emergence of these variants and a simple way to track their spread.


title: A STUDY OF ETIOLOGICAL AND CLINICAL PROFILE OF PATIENTS WITH LMN CRANIAL NERVE PALSY IN A TERTIARY CARE CENTER AT THANJAVUR MEDICAL COLLEGE AND HOSPITAL

abstract:
BackgroundNeurological presentation with isolated/multiple cranial nerve palsy is normal and its different causes incorporate infection, autoimmune, neoplastic, and inflammatory pathologies. The etiological range may rely on geological areas. We attempted this study to investigate the clinical range and etiological profile of numerous cranial nerve palsy.

Materials and methodsThis planned observational study was led from January 2020 to January 2021. All the patients with cranial nerve palsy coming to the neurology OPD were taken for examinations. Essential targets were to characterize anatomical disorder/cranial nerve combinations and to set up etiology. The primary goals were to examine related components. Patients with neuromuscular junction disorder, anterior horn cell disease, myopathies, first and second cranial nerve dysfunction were excluded from the study. All patients went through an organized convention of clinical assessment, examinations, and few particular examinations as per clinical protocol for analysis.

ResultsCavernous sinus was the commonest anatomical condition of different cranial nerve paralyses and tuberculous disease was the commonest cause in this investigation.7th cranial nerve was the common isolated nerve involved with idiopathic ethology, diabetes was the most common cause overall found with third nerve involvement.

category: neurology


title: An AI-assisted Online Tool for Cognitive Impairment Detection Using Images from the Clock Drawing Test

abstract:
BackgroundWidespread early dementia detection could drastically increase clinical trial candidates and enable early interventions. Since the Clock Drawing Test (CDT) can be potentially used for diagnosing dementia related diseases, it can be leveraged to devise a computer-aided screening tool.

ObjectiveThis work aims to develop an online screening tool by leveraging Artificial Intelligence and the CDT.

MethodsImages of an analog clock drawn by 3, 263 cognitively intact and 160 impaired subjects were used. First, we processed the images from the CDT by a deep learning algorithm to obtain dementia scores. Then, individuals were classified as belonging to either category by combining CDT image scores with the participants age.

ResultsWe have evaluated the performance of the developed models by applying 5-fold cross validation on 20% of the dataset. The deep learning model generates dementia scores for the CDT images with an Area Under the ROC Curve (AUC) of 81.3% {+/-} 4.3%. A composite logistic regression model using age and the generated dementia scores, yielded an average AUC and average weighted F1 score of 92% {+/-} 0.8% and 94.4% {+/-} 0.7%, respectively.

DiscussionCDT images were subjected to distortion consistent with an image drawn on paper and photographed by a cell phone. The model offers a cost-effective and easily deployable mechanism for detecting cognitive impairment online, without the need to visit a clinic.


title: The UK experience of stereoelectroencephalography in children: An analysis of factors predicting the identification of a seizure onset zone and subsequent seizure freedom

abstract:
ImportanceStereoelectroencephalography (SEEG) is more frequently being used in the pre-surgical evaluation of children with focal epilepsy. Many factors affect the rate of identification of a definable seizure onset zone (SOZ) and subsequent seizure freedom following SEEG-guided epilepsy surgery, which have not been systematically examined in multi-centre studies.

ObjectivesDetermine the rates and factors that predict (a) whether or not a definable putative SOZ was identified on SEEG and (b) subsequent seizure freedom following surgical intervention.

DesignRetrospective cohort study

SettingMulticentre study involving 6 of 7 UK Childrens Epilepsy Surgery Service centres that perform paediatric SEEG in the UK.

ParticipantsAll children undergoing SEEG from 2014 - March 2019 were included. Demographic, non-invasive evaluation, SEEG and operative factors were collected retrospectively from patient records.

Main OutcomesThe two main outcome measures were (a) whether or not a definable putative SOZ was identified on SEEG (binary yes/no outcome) and (b) subsequent seizure freedom following surgical intervention (Engel classification)

FindingsOne hundred and thirty-five patients underwent 139 SEEG explorations using a total of 1767 electrodes. A definable SOZ was identified in 117 patients (85.7%); odds of successfully finding a SOZ were 6.4x greater for non-motor seizures compared to motor seizures (p=0.02) and 3.6x more if [≥] 4 seizures were recorded during SEEG (p=0.03). Of 100 patients undergoing surgical treatment, 47 (47.0%) had an Engel class I outcome at a median follow-up of 1.3 years; the only factor associated with outcome was indication for SEEG (p=0.03). SEEG was safe with one (0.7%) haematoma requiring surgical evacuation and no long-term neurological deficits as a result of the procedure.

Conclusions and RelevanceThis large nationally representative cohort illustrates that, in these patients who may not have otherwise been offered resective surgery, SEEG-guided surgery can still achieve high rates of seizure freedom. Seizure semiology and the number of seizures recorded during SEEG are important factors in the identification of a definable SOZ and the indication for SEEG is an important factor in post-operative outcomes.


title: Habitual Coffee Consumption Increases Risks for Metabolic Diseases: Genome-wide Association Studies and a Phenotype-wide Two Sample Mendelian Randomization Analysis

abstract:
Background and aimsCoffee is one of the most widely consumed beverages in the world and has received considerable concerns regarding its impact on human health. Mendelian randomization (MR) could be valuable to explore the potential health effects of coffee via instrumental variables. In this study, we aim to identify novel genetic loci associated with habitual coffee consumption using genome-wide meta-analysis (GWMA) and to evaluate the broad impact of coffee consumption on human health and disease risk via a large-scale, phenotype-wide, two sample Mendelian randomization (TSMR) analysis.

MethodsWe conducted a genome-wide association study (GWAS) among 283,926 coffee consumers of European ancestry in the UK Biobank (UKBB) to identify single nucleotide polymorphisms (SNPs) associated with the amount of coffee consumption (cups/day, GWAS 1), caffeine intake (GWAS 2) as well as the intake of non-caffeine substance in coffee (GWAS 3). The GWAS 1 results were further combined with the published results from the Coffee and Caffeine Genetics Consortium (CCGC) for a GWMA. TSMR were performed to evaluate the causal-relationship between coffee/caffeine/non-caffeine substance consumption and 1,101 diseases and health traits.

ResultsThe GWMA identified 50 lead SNPs among 19 genomic regions for habitual coffee consumption. Nine out of the 19 loci were novel, including ADAMTSL4-AS1, CACNA2D2, LINC02123-ADCY2, UBD-SNORD32B, SEMA4D-GADD45G, LOC101929457-LINGO1, RAI1, HCN2, and BRWD1. The GWAS 2 and 3 identified 2 (SORCS2 and SLC39A8) and 5 (LINC02060-LINC00461, AGR3-AHR, PRR4-TAS2R14, CYP1A1-CYP1A2, and FTO) genomic regions, respectively. TSMR analysis indicated that coffee consumption increased the risk of high blood lipids, obesity, and diabetes. Meanwhile, intake of caffeine and non-caffeine coffee components decreased and increased some of the blood lipids levels, respectively.

ConclusionsOur study provided evidence that habitual coffee consumption could increase the risk of metabolic perturbations. The bioactive components in coffee, other than caffeine, may be more harmful to human health. Our findings have significant implications for global public health given the increasing burden of metabolic diseases.

category: genetic and genomic medicine


title: Value-based pricing of a COVID-19 vaccine

abstract:
AimThe purpose of this study is to determine the value-based price of a COVID-19 vaccine from a societal perspective in Germany.

MethodsA decision model was constructed using, e.g., information on age-specific fatality rates, intensive care unit (ICU) costs and outcomes, and herd protection threshold. Three strategies were analysed: vaccination (with 95% and 50% efficacy), a mitigation strategy, and no intervention. The base-case time horizon was 5 years. The value of a vaccine included savings from avoiding COVID-19 mitigation measures and health benefits from avoiding COVID-19 related mortality. The value of an additional life year was borrowed from new, innovative oncological drugs, as cancer reflects a condition with a similar morbidity and mortality burden in the general population in the short term as COVID-19.

ResultsA vaccine with a 95% efficacy dominates the mitigation strategy strictly. The value-based price ({euro}1494) is thus determined by the comparison between vaccination and no intervention. This price is particularly sensitive to the probability of ICU admission and the herd protection threshold. In contrast, the value of a vaccine with 50% efficacy is more ambiguous.

ConclusionThis study yields a value-based price for a COVID-19 vaccine with 95% efficacy, which is more than 50 times greater than the purchasing price.

category: health economics


title: Development of an ensemble machine learning prognostic model to predict 60-day risk of major adverse cardiac events in adults with chest pain

abstract:
BackgroundChest pain is the second leading reason for emergency department (ED) visits and is commonly identified as a leading driver of low-value health care. Accurate identification of patients at low risk of major adverse cardiac events (MACE) is important to improve resource allocation and reduce over-treatment.

ObjectivesWe assessed machine learning (ML) methods and electronic health record (EHR) covariate collection for MACE prediction. We aimed to maximize the pool of low-risk patients that were accurately predicted to have less than 0.5% MACE risk and could be eligible for reduced testing ("rule-out" strategy).

Population Studied116,764 adult patients presenting with chest pain in the ED between 2013 and 2015 and evaluated for potential acute coronary syndrome (ACS). 60-day MACE rate was 2%.

Setting21 emergency departments within the Kaiser Permanente Northern California integrated health system. Data analysis was performed May 2018 to August 2021.

MethodsWe evaluated ML algorithms (lasso, splines, random forest, extreme gradient boosting, Bayesian additive regression trees) and SuperLearner stacked ensembling. We tuned ML hyperparameters through nested ensembling, and imputed missing values with generalized low-rank models (GLRM). Performance was benchmarked against individual biomarkers, validated clinical risk scores, decision trees, and logistic regression. We assessed clinical utility through net benefit analysis and explained the models through variable importance ranking and accumulated local effect plots.

ResultsThe SuperLearner ensemble provided the best cross-validated discrimination with areas under the curve of 0.15 for precision-recall (PR-AUC) and 0.87 for receiver operating characteristic (ROC-AUC), and the best accuracy with an index of prediction accuracy of 0.07. The ensembles risk estimates were miscalibrated by 0.2 percentage points on average, and dominated the net benefit analysis at all examined thresholds. At a 0.5% threshold the ensemble model yielded 32 benefit-adjusted workups avoided per 100 patients, compared to 25 for logistic regression and 2-14 for clinical risk scores. The most important predictors were age, troponin, clinical risk scores, and electrocardiogram. GLRM achieved a 90% average reduction in reconstruction error compared to median-mode imputation.

ConclusionCombining ML algorithms with a broad set of EHR covariates improved MACE risk prediction and would reduce over-treatment compared to simpler alternatives, while providing calibrated predictions and interpretability. Patients should receive targeted benefit in their care from thorough detection of nuanced health patterns via ML.

O_QDThe omission of prediction from the major goals of basic medical science has impoverished the intellectual content of clinical work, since a modern clinicians main challenge in the care of patients is to make predictions.

Alvan Feinstein, 1983

C_QD

category: health informatics


title: The relationship between new PCR positive cases and going out in public during the COVID-19 epidemic in Japan

abstract: Suppression of the first wave of COVID-19 in Japan is assumedly attributable to peoples increased risk perception by acquiring information from the government and media reports. In this study, going out in public amidst the spread of COVID-19 infections was investigated by examining new polymerase chain reaction (PCR) positive cases of COVID-19 and its relationship to four indicators of people going out in public (the people flow, the index of web searches for going outside, the number of times people browse restaurants, and the number of hotel guests), from the Regional Economic and Social Analysis System (V-RESAS). Two waves of COVID-19 infections were examined with cross-correlation analysis. In the first wave, all four indicators of going out reacted oppositely with the change in new PCR positive cases, showing a lag period of -1 to +6 weeks. In the second wave, the same relationship was only observed for the index of web searches for going outside. These results suggest that going out in public could not be described by new PCR positive cases alone in the second wave, even though they could explain people going out to some extent in the first wave.

category: health policy


title: Detection of HIV and Mycobacterium tuberculosis among University Students in Port Harcourt, Nigeria

abstract: Assessment of HIV and Mycobacterium tuberculosis infection is crucial to detect HIV and/or Mycobacterium tuberculosis coinfection and the strategy for infection management and treatment. This study assessed the proportion of students with HIV, Mycobacterium tuberculosis, and HIV/Mycobacterium tuberculosis coinfection. Two hundred and thirty-five university students in Port Harcourt, Nigeria were recruited, ages 16 - 39 years. Samples of blood were collected and processed using standard laboratory procedures. All the students were screened for antibodies to HIV using 2 rapid screening strips and a commercially available enzyme-linked immunosorbent assay (ELISA)-based kit for determination of HIV-1/2/P24/O. The presence of Mycobacterium tuberculosis was done using TB rapid kits and a commercially available ELISA-based kit. The results showed that 3.4% of the students were positive for HIV, 2.1% for Mycobacterium tuberculosis and none for HIV/Mycobacterium tuberculosis coinfection. The age-specific infection rate showed a higher HIV infection rate in the age group 16-24 years (4.7%) than [≥]25 years (2.8%). While higher Mycobacterium tuberculosis infection rate occurred in the age group [≥]25 years (2.8%) than in <25 years (2.3%). The gender-specific infection rate showed that females had a higher infection rate (HIV, 4.7% and Mycobacterium tuberculosis, 2.3%) than males (HIV, 2.6% and Mycobacterium tuberculosis, 1.7%). Age and sex were the main correlates (P<0.05) of HIV and Mycobacterium tuberculosis. This study further confirmed the presence of HIV and Mycobacterium tuberculosis infections among University students. These findings suggest the need for regular screening of University students for HIV and Mycobacterium tuberculosis.

category: hiv aids


title: Persistence of symptoms up to 10 months following acute COVID-19 illness

abstract:
ImportanceCOVID-19 symptoms are increasingly recognized to persist among a subset of individual following acute infection, but features associated with this persistence are not well-understood.

ObjectiveWe aimed to identify individual features that predicted persistence of symptoms over at least 2 months at the time of survey completion.

Design: Non-probability internet survey. Participants were asked to identify features of acute illness as well as persistence of symptoms at time of study completion. We used logistic regression models to examine association between sociodemographic and clinical features and persistence of symptoms at or beyond 2 months.

SettingTen waves of a fifty-state survey between June 13, 2020 and January 13, 2021.

Participants6,211 individuals who reported symptomatic COVID-19 illness confirmed by positive test or clinician diagnosis.

Exposuresymptomatic COVID-19 illness

ResultsAmong 6,211 survey respondents reporting COVID-19 illness, with a mean age of 37.8 (SD 12.2) years and 45.1% female, 73.9% white, 10.0% Black, 9.9% Hispanic, and 3.1% Asian, a total of 4946 (79.6%) had recovered within less than 2 months, while 491 (7.9%) experienced symptoms for 2 months or more. Of the full cohort, 3.4% were symptomatic for 4 months or more and 2.2% for 6 months or more. In univariate analyses, individuals with persistent symptoms on average reported greater initial severity. In logistic regression models, older age was associated with greater risk of persistence (OR 1.10, 95% CI 1.01-1.19 for each decade beyond 40); otherwise, no significant associations with persistence were identified for gender, race/ethnicity, or income. Presence of headache was significantly associated with greater likelihood of persistence (OR 1.44, 95% CI 1.11-1.86), while fever was associated with diminished likelihood of persistence (OR 0.66, 95% CI 0.53-0.83).

Conclusion and RelevanceA subset of individuals experience persistent symptoms from 2 to more than 10 months after acute COVID-19 illness, particularly those who recall headache and absence of fever. In light of this prevalence, strategies for predicting and managing such sequelae are needed.

Trial RegistrationNA

Key PointsO_ST_ABSQuestionC_ST_ABSWhich individuals are at greatest risk for post-acute sequelae of COVID-19?

FindingsIn this non-probability internet survey, among 6,211 individuals with symptomatic COVID-19 illness, 7.9% experienced persistence of symptoms lasting 2 months or longer. Older age, but not other sociodemographic features, was associated with risk for persistence, as was headache.

MeaningIdentifying individuals at greater risk for symptomatic persistence may facilitate development of targeted interventions.


title: OpenSAFELY: Risks of COVID-19 hospital admission and death for people with learning disabilities - a cohort study.

abstract:
ObjectivesTo assess the association between learning disability and risk of hospitalisation and mortality from COVID-19 in England among adults and children.

DesignWorking on behalf of NHS England, two cohort studies using patient-level data for >17 million people from primary care electronic health records were linked with death data from the Office for National Statistics and hospitalization data from NHS Secondary Uses Service using the OpenSAFELY platform.

SettingGeneral practices in England which use TPP software.

ParticipantsParticipants were males and females, aged up to 105 years, from two cohorts: (1) wave 1, registered with a TPP practice as of 1st March 2020 and followed until 31st August, 2020; (2) wave 2 registered 1st September 2020 and followed until 31st December 2020 (for admissions) or 8th February 2021 (for deaths). The main exposure group was people included on a general practice learning disability register (LDR), with a subgroup of people classified as having profound or severe learning disability. We also identified patients with Down syndrome and cerebral palsy (whether or not on the learning disability register).

Main outcome measures(i) COVID-19 related death, (ii) COVID-19 related hospitalisation. Non-COVID-19 related death was also explored.

ResultsIn wave 1, of 14,301,415 included individuals aged 16 and over, 90,095 (0.63%) were identified as being on the LDR. 30,173 COVID-related hospital admissions, 13,919 COVID-19 related deaths and 69,803 non-COVID deaths occurred; of which 538 (1.8%), 221 (1.6%) and 596 (0.85%) were among individuals on the LDR, respectively. In wave 2, 27,611 COVID-related hospital admissions, 17,933 COVID-19 related deaths and 54,171 non-COVID deaths occurred; of which 383 (1.4%), 260 (1.4%) and 470 (0.87%) were among individuals on the LDR. Wave 1 hazard ratios for individuals on the LDR, adjusted for age, sex, ethnicity and geographical location, were 5.3 (95% confidence interval (CI) 4.9, 5.8) for COVID-19 related hospital admissions and 8.2 (95% CI: 7.1, 9.4) for COVID-19 related death. Wave 2 produced similar estimates. Associations were stronger among those classed as severe-profound and among those in residential care. Down syndrome and cerebral palsy were associated with increased hazard of both events in both waves; Down syndrome to a much greater extent. Hazards of non-COVID-19 related death followed similar patterns with weaker associations.

ConclusionsPeople with learning disabilities have markedly increased risks of hospitalisation and mortality from COVID-19. This raised risk is over and above that seen for non-COVID causes of death. Ensuring prompt access to Covid-19 testing and health care and consideration of prioritisation for COVID-19 vaccination and other targeted preventive measures are warranted.


title: Absent or insufficient anti-SARS-CoV-2 S antibodies at ICU admission are associated to higher viral loads in plasma, antigenemia and mortality in COVID-19 patients

abstract:
Purposeto evaluate the association between anti-SARS-CoV-2 S IgM and IgG antibodies with viral RNA load in plasma, the frequency of antigenemia and with the risk of mortality in critically ill patients with COVID-19.

Methodsanti-SARS-CoV-2 S antibodies levels, viral RNA load and antigenemia were profiled in plasma of 92 adult patients in the first 24 hours following ICU admission. The impact of these variables on 30-day mortality was assessed by using Kaplan-Meier curves and multivariate Cox regression analysis.

Resultsnon survivors showed more frequently absence of anti-SARS-CoV-2 S IgG and IgM antibodies than survivors (26.3% vs 5.6% for IgM and 18.4% vs 5.6% for IgG), and a higher frequency of antigenemia (47.4% vs 22.2%) (p <0.05). Non survivors showed lower concentrations of anti-S IgG and IgM and higher viral RNA loads in plasma, which were associated to increased 30-day mortality and decreased survival mean time. [Adjusted HR (CI95%), p]: [S IgM (AUC [≥]60): 0.48 (0.24; 0.97), 0.040]; [S IgG (AUC [≥]237): 0.47 (0.23; 0.97), 0.042]; [Antigenemia (+): 2.45 (1.27; 4.71), 0.007]; [N1 viral load ([≥] 2.156 copies/mL): 2.21 (1.11; 4.39),0.024]; [N2 viral load ([≥] 3.035 copies/mL): 2.32 (1.16; 4.63), 0.017]. Frequency of antigenemia was >2.5-fold higher in patients with absence of antibodies. Levels of anti-SARS-CoV-2 S antibodies correlated inversely with viral RNA load.

Conclusionabsence / insufficient levels of anti-SARS-CoV-2 S antibodies following ICU admission is associated to poor viral control, evidenced by increased viral RNA loads in plasma, higher frequency of antigenemia, and also to increased 30-day mortality.

Take-home messageabsent or low levels of antibodies against the S protein of SARS-CoV- 2 at ICU admission is associated to an increased risk of mortality, higher frequency of antigenemia and higher viral RNA loads in plasma. Profiling anti-SARS-CoV-2 s antibodies at ICU admission could help to predict outcome and to better identify those patients potentially deserving replacement treatment with monoclonal or polyclonal antibodies.


title: SEROPREVALENCE OF HEPATITIS B VIRUS INFECTION AMONG HIV INFECTED INDIVIDUALS IN UYO, AKWA IBOM STATE, NIGERIA

abstract:
AimHepatitis B and Acquired Immunodeficiency Syndrome (AIDS) are highly endemic in Nigeria and are important causes of death and disability. Co-infection between hepatitis B virus (HBV) and Human Immunodeficiency Virus (HIV) commonly occur as both viruses share a common mode of transmission. This leads to fulminant hepatitis and liver cirrhosis depending on the stages of infection which are acute and chronic stages respectively. This study was carried to determine the prevalence of hepatitis B virus (HBV) among HIV-infected individuals in Uyo, Akwa Ibom State, Nigeria.

MethodsIn this study 176 HIV-infected individuals were recruited comprising 67 males and 109 females. These subjects were screened for the presence of hepatitis B surface antigen (HBsAg) using enzyme linked immunosorbent assay.

ResultsFrom those tested, 11 were positive for HBsAg giving an overall prevalence rate of 6.3%. Co-infection rate of males (8.5%) did not differ significantly (p>0.05) from that of females (6.4%). Co-infection was highest in age group 6-30 years (28.2%). In relation to marital status, singles had the higher co-infection rates (10.5%) than married subjects (4.7%). Among the different occupational groups, students had the highest co-infection rate (22.2%) and was closely followed by business (16.7%). Higher HIV/HBV co-infection was observed among those with CD4 cell count <200 cells/l (15.4%) and those with plasma viral loads (PVL) >5001 copies/mL (13.6%).

ConclusionThis study confirms the high HIV/HBV co-infection rate (6.3%) and thus, there is a need to screen all HIV-positive individuals for HBV infection. A high seroprevalence of HBV among this cohort of HIV-infected individuals contributes to the calls for pre-ART screening for HBV and the necessary paradigm shift in the ART nucleoside backbone to include agent(s) more dually effective against HIV and HBV.


title: Long-term clinical, virological and immunological outcomes in patients hospitalized for COVID-19: antibody response predicts long COVID.

abstract:
ObjectiveLong-term data following SARS-CoV-2 infection are limited. We aimed to characterize the medium and long-term clinical, virological, and immunological outcomes after hospitalization for COVID-19, and to identify predictors of long-COVID.

MethodsProspective, longitudinal study conducted in COVID-19 patients confirmed by RT-PCR. Serial blood and nasopharyngeal samples (NPS) were obtained for measuring SARS-CoV-2 RNA and S-IgG/N-IgG antibodies during hospital stay, and at 1, 2 and 6 months post-discharge. Genome sequencing was performed where appropriate. Patients filled out a COVID19-symptom-questionnaire (CSQ) at 2-month and 6-month visits, and those with highest scores were characterized.

ResultsOf 146 patients (60% male, median age 64 years) followed-up, 20.6% required hospital readmission and 5.5% died. At 2-months and 6-months, 9.6% and 7.8% patients, respectively, reported moderate/severe persistent symptoms. SARS-CoV-2 RT-PCR was positive in NPS in 11.8% (median Ct=38) and 3% (median Ct=36) patients at 2-months and 6-months, respectively, but no reinfections were demonstrated.

Antibody titers gradually waned, with seroreversion occurring at 6 months in 27 (27.6%) patients for N-IgG and in 6 (6%) for S-IgG. Adjusted 2-month predictors of the highest CSQ scores (OR [95%CI]) were lower peak S-IgG (0.80 [0.66-0.94]) and higher WHO-severity-score (2.57 [1.20-5.86]); 6-month predictors were lower peak S-IgG (0.89 [0.79-0.99]) and female sex (2.41 [1.20-4.82]); no association was found with prolonged viral shedding.

ConclusionsLate clinical events and persistent symptoms in the medium and long term occurred in a significant proportion of patients hospitalized for COVID-19. Gender, severity of illness and weaker antibody responses, but not viral shedding, were associated with long-COVID.

SummaryThis study characterizes the long-term clinical, virological, and immunological outcomes following COVID-19 hospitalization. We found a significant proportion of late clinical events and persistent symptoms. Gender, severity of illness and weaker antibody responses, but not viral shedding, predicted long-COVID.


title: Risk and mitigation of aerosolisation from lung function testing: results from the AERATOR study.

abstract:
IntroductionLung function tests are fundamental diagnostic and monitoring tools for patients with respiratory symptoms. There is significant uncertainty around whether potentially infectious aerosol is produced during different lung function testing modalities; and limited data on possible mitigation strategies to reduce risk to staff and limit fallow time.

MethodsHealthy volunteers were recruited in an ultraclean, laminar flow theatre and had standardised spirometry as per ERS/ATS guidance, as well as peak flow measurement and FENO assessment of airway inflammation. Aerosol emission was sampled once each second using both Aerodynamic Particle Sizer (APS) and Optical Particle Sizer (OPS), and compared to breathing, speaking and coughing. Mitigation strategies such as a peak flow viral filter and a CPET facemask (to mitigate induced coughing) were tested.

Results33 healthy volunteers were recruited. Aerosol emission was highest in cough (1.61 particles/cm3/sample), followed by unfiltered peak flow (0.76 particles/cm3/sample). Filtered spirometry produced similar peak aerosol emission as talking, and addition of a viral filter to the mouthpiece reduced peak flow aerosol emission to similar levels. The filter made little difference to recorded peak flow values. FENO measurement produced negligible aerosol. Re usable CPET masks with filter reduced aerosol emission when breathing, speaking, and coughing significantly.

ConclusionsCompared to voluntary coughing, all lung function testing produced less aerosol. Filtered spirometry produces similar peak aerosol emission to speaking, and should not be deemed an aerosol generating procedure. The use of viral filters reduces aerosol emission in peak flow by > 10 times, and has little impact on recorded peak flow values. CPET masks are a useful option to reduce aerosol emission from induced coughing while performing spirometry.


title: Inflammatory but not respiratory symptoms associated with ongoing upper airway viral replication in outpatients with uncomplicated COVID-19

abstract:
BackgroundThe vast majority of SARS-CoV-2 infections are uncomplicated and do not require hospitalization, but contribute to ongoing transmission. Our understanding of the clinical course of uncomplicated COVID-19 remains limited.

MethodsWe detailed the natural history of uncomplicated COVID-19 among 120 outpatients enrolled in a randomized clinical trial of Peginterferon Lambda. We characterized symptom trajectory and clusters using exploratory factor analysis, assessed predictors of symptom resolution and cessation of oropharyngeal viral shedding using Cox proportional hazard models, and evaluated associations between symptoms and viral shedding using mixed effects linear models.

ResultsHeadache, myalgias and chills peaked at day 4 after symptom onset; cough peaked on day 9. Two distinct symptom cluster trajectories were identified; one with mild, upper respiratory symptoms, and the other with more severe and prolonged inflammatory symptoms. The median time to symptom resolution from earliest symptom onset was 17 days (95% CI 14-18). Neither enrollment SARS-CoV-2 IgG levels (Hazard ratio [HR] 1.88, 95% CI 0.84-4.20) nor oropharyngeal viral load at enrollment (HR 1.01, 95% CI 0.98-1.05) were significantly associated with the time to symptom resolution. The median time to cessation of viral shedding was 10 days (95% CI 8-12), with higher SARS-CoV-2 IgG levels at enrollment associated with hastened resolution of viral shedding (HR 3.12, 95% CI 1.4-6.9, p=0.005). Myalgia, joint pains, and chills were associated with a significantly greater odds of oropharyngeal SARS-CoV-2 RNA detection.

ConclusionsIn this outpatient cohort, inflammatory symptoms peaked early and were associated with ongoing SARS-CoV-2 replication. SARS-CoV-2 antibody levels were associated with more rapid viral shedding cessation, but not with time to symptom resolution. These findings have important implications for COVID-19 screening approaches and clinical trial design.


title: BNT162b2 COVID-19 mRNA vaccine elicits a rapid and synchronized antibody response in blood and milk of breastfeeding women

abstract: We describe the dynamics of the vaccine-specific antibody response in the breastmilk and serum in a prospective cohort of ten lactating women who received two doses of the Pfizer-BioNTech BNT162b2 COVID-19 mRNA vaccine. The antibody response was rapid and highly synchronized between breastmilk and serum, reaching stabilization 14 days after the second dose. The predominant serum antibody was IgG. The response in the breastmilk included both IgG and IgA with neutralizing capacity.

category: allergy and immunology


title: Low Dose Regimens of BNT162b2 mRNA Vaccine Exceed SARS-Cov-2 Correlate of Protection Estimates for Symptomatic Infection, in those 19-55 Years of Age

abstract:
BackgroundAn exact correlate of protection (CoP) is not yet known for symptomatic COVID-19. However, it is still possible to show a new vaccine regimen exceeds an unknown CoP, provided the regimen shows an equivalent or greater immunological response in all measured indicators relative to the immunological response elicited by a clinically proven vaccine regimen. The principle of comparing immunogenicity between regimens is what the FDA, EMA, and Access Consortium use to authorize modifications to the vaccines for VOC, without requiring clinical efficacy studies before implementation. It is logical to apply the same principle to modifying vaccine doses if the data is available to do so. A two dose 30ug regimen of BNT162b2 has strong clinical evidence of efficacy, as does a single dose 30 ug regimen. The immunological markers for these regimens have been profiled in detail in Phase 1 and 2 trial data.

MethodsThe immunological profile (including binding antibodies, viral neutralization, cytokine profiles, and CD4 and 8 expansion) of the 2 dose 30ug BNT162b2 vaccine is examined, referred to as a highly conservative CoP estimate. The single dose 30 ug BNT162b2 immunological profile is also examined, a tenable CoP estimate. Data from the phase 1 and 2 trials are examined to see if alternate regimens meet or exceed the level of each immune marker measured, relative to the regimens listed above that have proven clinical efficacy.

ResultsFor adults aged 19-55, a 2 dose 10ug BNT162b2 regimen elicits a comparable response to the standard 30 ug dose for each immune indicator, with viral neutralization nearly an order of magnitude greater than the tenable CoP estimate. Similarly, a single dose 10ug BNT 162b2 regimen or a two dose 1ug BNT 162b2 regimen equals or exceeds the immunogenicity of a single 30 ug dose.

ConclusionIf it is reasonable for the FDA, EMA, and Access Consortium to approve vaccine modifications without a clinical trial based on immunogenicity data, three alternate low dose regimens were identified that meet the requirements of having comparable immunogenicity relative to a protocol that has proven clinical efficacy. Immediate implementation of these lower dose regimens should be considered as they have major implications in alleviating vaccine supply, as well as improving vaccine side effect profile, and lowering total cost of vaccination.


title: Estimating the impact of reopening schools on the reproduction number of SARS-CoV-2 in England, using weekly contact survey data

abstract:
BackgroundSchools have been closed in England since the 4th of January 2021 as part of the national restrictions to curb transmission of SARS-CoV-2. The UK Government plans to reopen schools on the 8th of March. Although there is evidence of lower individual-level transmission risk amongst children compared to adults, the combined effects of this with increased contact rates in school settings are not clear.

MethodsWe measured social contacts when schools were both open or closed, amongst other restrictions. We combined these data with estimates of the susceptibility and infectiousness of children compared with adults to estimate the impact of reopening schools on the reproduction number.

ResultsOur results suggest that reopening all schools could increase R from an assumed baseline of 0.8 to between 1.0 and 1.5, or to between 0.9 and 1.2 reopening primary or secondary schools alone.

ConclusionOur results suggest that reopening schools is likely to halt the fall in cases observed in recent months and risks returning to rising infections, but these estimates rely heavily on the current estimates or reproduction number and the current validity of the susceptibility and infectiousness profiles we use.


title: COVID-19 vaccine hesitancy in care home staff: a survey of Liverpool care homes

abstract:
BackgroundCOVID-19 has caused high morbidity and mortality in UK care homes. Vaccinating staff members and residents will protect care homes from severe clinical cases. Uptake of COVID-19 vaccine first doses in care homes has been higher among residents compared to staff members.

MethodsWe aimed to identify causes of lower COVID-19 vaccine uptake amongst care home staff members within the Liverpool City Council region. An anonymised online survey was distributed to all care home managers between the 21st and the 29th of January 2021. Descriptive analysis was performed on responses.

Results46/87 (53%) of Liverpool care homes responded. The mean staff vaccination rate per home was 51.4% (95% CI 43.9-58.8%). The most common reasons for staff not receiving the vaccine were: concerns about lack of vaccine research (37.0%), staff being off-site during vaccination sessions (36.5%), pregnancy and fertility concerns (5.6%), and concerns about allergic reactions (3.2%). Care home managers reported the necessity to combat vaccine hesitancy through meetings and conversations with health professionals, and provision of supporting evidence to dispel vaccine misinformation.

ConclusionsVaccine hesitancy was the main cause for reduced vaccine uptake among care home staff members. These concerns could be addressed by targeted evidence-based training, and a public health communication campaign to build vaccine confidence and increase acceptance of COVID-19 vaccines. The speed of vaccination roll-out has also led to unexpected logistical issues that lowered vaccine uptake rates. Addressing both these challenges could increase uptake by more than 40%.

Key PointsO_LICOVID-19 vaccine uptake rates are lower in staff than residents
C_LIO_LIThree main causes of reduced uptake have been identified: vaccine hesitancy, logistical issues, and medical concerns.
C_LIO_LIThe main reasons for vaccine hesitancy were concerns about limited research into vaccine safety, and concerns about long-term impact on pregnancy and fertility.
C_LIO_LIAddressing care home staff vaccination concerns should be given priority in these settings.
C_LI


title: Post discharge persistent symptoms after COVID-19 in rheumatic and musculoskeletal diseases

abstract:
OBJECTIVESTo describe persistent symptoms and consequences in Rheumatic and Musculoskeletal diseases (RMD) discharged from the hospital after Covid-19; to assess the roll of autoimmune rheumatic diseases (ARD) compared to and non-autoimmune rheumatic and musculoskeletal diseases (NARD) on persistent symptoms and consequences.

METHODSWe performed a cross-sectional observational study. RMD attended at a rheumatology outpatient clinic in Madrid with Covid-19 that required hospital admission were included. The main outcomes were persistence of symptoms and health consequences related to Covid19 after discharge. Independent variable was RMD group (ARD and NARD) and covariates were sociodemographic, clinical, and treatments. We ran a multivariable logistic regression model to assess the risk by RMD group on main outcomes.

RESULTSWe included 105 patients and 51.5% had ARD. 68.57% reported at least one persistent symptom. The most frequent were dyspnea, fatigue, and chest pain. 31 patients had consequences. Lung damage was found in 11.4% of the patients, 18% had blood test abnormalities (10% lymphopenia), two died, one developed central retinal vein occlusion and one patient developed optic neuritis. 11 patients required readmission due to Covid-19 problems (16.7% ARD vs 3.9% NARD; p=0.053). No statistically significant differences by RMD groups were found in the final models.

CONCLUSIONMany RMD patients have persistent symptoms, similar to other populations. This study also highlights that lung damage is the most frequent consequence. ARD compared to NARD does not seem to differ in terms of persistent symptoms or consequences, although ARD might have a greater number of readmissions due to Covid-19.

category: rheumatology


title: Innovating Pathology Learning via Kahoot! Game-based Tool: A Quantitative Study of Students` Perceptions and Academic Performance

abstract:
IntroductionPathology teaching for medical undergraduate students linking basic and clinical sciences together is a challenging task. Kahoot! is a game-based online digital formative assessment tool that can engage students in its learning. This study analyzed the effect of Kahoot! use on student[s] learning of Pathology.

MethodsThe study was carried out on the first-year Pathology students at Helwan University, Faculty of Medicine, after ending a basic Pathology course. The study is a retrospective quasi-experimental quantitative study. Academic performance of students in Pathology was compared between Kahoot! and non-Kahoot! users (55 students each). In addition, an online survey was introduced to the 55 Kahoot! user students to investigate their perceptions on Kahoot!. Survey and test score data were analyzed by appropriate tests using IBM-SPSS (Statistical Package for Social Sciences) Version 21.0. The level of significance was P <0.05.

ResultsKahoot! enhanced Pathology understanding (83.6%), retaining knowledge (87.3%), made learning fun and motivating (89.1%). Other mentioned advantages of Kahoot! were practicing for the exam (40%), simple and easy to use (36.4%), competitive (18.2%), self-confidence booster (10.9%), forming a comprehensive image of the lecture (9%), quick (9%), and imagining skills booster (5.5%). Mentioned disadvantages included no explanation for the answers to the questions (20%). A quarter of the students stated that the time limit for the questions was short (27.3%). Kahoot! use was significantly associated with better Pathology academic performance (P=0.001), and it was not related to the general academic performance of the students (P=0.06). The majority of users (85.4%) recommended its continuous future use.

ConclusionsThe study offers an endorsement to the use of Kahoot! for gamifying formative assessment of Pathology and can provide a basis for the design of an online Kahoot!-based continuous formative assessment plans implemented outside-classroom in the Pathology curricula.

category: medical education


title: COVID-19 vaccine response in pregnant and lactating women: a cohort study

abstract:
BackgroundPregnant and lactating women were excluded from initial COVID-19 vaccine trials; thus, data to guide vaccine decision-making are lacking. We sought to evaluate the immunogenicity and reactogenicity of COVID-19 mRNA vaccination in pregnant and lactating women.

Methods131 reproductive-age vaccine recipients (84 pregnant, 31 lactating, and 16 non-pregnant) were enrolled in a prospective cohort study at two academic medical centers. Titers of SARS-CoV-2 Spike and RBD IgG, IgA and IgM were quantified in participant sera (N=131), umbilical cord sera (N=10), and breastmilk (N=31) at baseline, 2nd vaccine dose, 2-6 weeks post 2nd vaccine, and delivery by Luminex, and confirmed by ELISA. Titers were compared to pregnant women 4-12 weeks from native infection (N=37). Post-vaccination symptoms were assessed. Kruskal-Wallis tests and a mixed effects model, with correction for multiple comparisons, were used to assess differences between groups.

ResultsVaccine-induced immune responses were equivalent in pregnant and lactating vs non-pregnant women. All titers were higher than those induced by SARS-CoV-2 infection during pregnancy. Vaccine-generated antibodies were present in all umbilical cord blood and breastmilk samples. SARS-CoV-2 specific IgG, but not IgA, increased in maternal blood and breastmilk with vaccine boost. No differences were noted in reactogenicity across the groups.

ConclusionsCOVID-19 mRNA vaccines generated robust humoral immunity in pregnant and lactating women, with immunogenicity and reactogenicity similar to that observed in non-pregnant women. Vaccine-induced immune responses were significantly greater than the response to natural infection. Immune transfer to neonates occurred via placental and breastmilk.

category: obstetrics and gynecology


title: Exploration of interethnic variation and repurposed drug efficacy in the treatment of SARS-CoV-2 Infection (COVID-19)

abstract: The COVID-19 global pandemic has led to repurposing of drugs, with little underlying evidence for treatment safety and efficacy. This may increase complications for patients with acute viral respiratory infections. UGT1A1 and CYP2D6 enzymes are involved in the metabolism of atazanavir and fluvoxamine repurposed for COVID-19. This study aimed to elucidate the role of interethnic variation in these enzymes in the efficacy of repurposed drug therapies. A retrospective cohort of 101 Jordanian Arab samples were genotyped using Affymetrix DMET Plus Premier Package. Comprehensive global population genetic structure analyses were performed for CYP2D6 and UGT1A1 allele frequencies across multi-ethnic populations of over 131,000 global subjects from 417 published reports, revealing that Jordanian Arabs share the closest sequence homology to European and Near East populations. The East Asian populations have significantly over-representaiton of individuals with diplotype pairs for reduced atazanavir metabolism compared to the African populations and are more likely to show impaired UGT1A1 metabolism. East Asian populations are also 4.4x more likely to show impaired fluvoxamine metabolism than South Central Asian and Oceanian populations, and 8x more likely than other ancestry populations. The results here support previous findings that interethnic variation should be used for developing proper population-specific dosage guidelines.


title: SARS-CoV-2 infects blood monocytes to activate NLRP3 and AIM2 inflammasomes, pyroptosis and cytokine release

abstract:
SARS-CoV-2 causes acute respiratory distress that can progress to multiorgan failure and death in some patients. Although severe COVID-19 disease is linked to exuberant inflammation, how SARS-CoV-2 triggers inflammation is not understood. Monocytes are sentinel blood cells that sense invasive infection to form inflammasomes that activate caspase-1 and gasdermin D (GSDMD) pores, leading to inflammatory death (pyroptosis) and processing and release of IL-1 family cytokines, potent inflammatory mediators. Here we show that ~10% of blood monocytes in COVID-19 patients are dying and infected with SARS-CoV-2. Monocyte infection, which depends on antiviral antibodies, activates NLRP3 and AIM2 inflammasomes, caspase-1 and GSDMD cleavage and relocalization. Signs of pyroptosis (IL-1 family cytokines, LDH) in the plasma correlate with development of severe disease. Moreover, expression quantitative trait loci (eQTLs) linked to higher GSDMD expression increase the risk of severe COVID-19 disease (odds ratio, 1.3, p<0.005). These findings taken together suggest that antibody-mediated SARS-CoV-2 infection of monocytes triggers inflammation that contributes to severe COVID-19 disease pathogenesis.

One sentence summaryAntibody-mediated SARS-CoV-2 infection of monocytes activates inflammation and cytokine release.


title: A 1 to 1000 SARS-CoV-2 reinfection proportion in members of a large healthcare provider in Israel: a preliminary report

abstract: With more than 100 million confirmed COVID-19 cases as of March 2021, reinfection is still considered to be rare. In light of increasing reports of reinfected COVID-19 patients, the need to better understand the real risk for reinfection is critical, with potential effects on public health policies aimed at containing the spread of SARS-CoV-2. In this descriptive preliminary report, we conducted a large-scale assessment on the country level of the possible occurrence of COVID-19 reinfection within the members of a large healthcare provider in Israel. Out of 149,735 individuals with a documented positive PCR test between March 2020 and January 2021, 154 had two positive PCR tests at least 100 days apart, reflecting a reinfection proportion of 1 per 1000. Given our strict inclusion criteria, we believe these numbers represent true reinfection incidence in MHS and should be clinically regarded as such.


title: Apt interpretation of comprehensive lipoprotein data in large-scale epidemiology - disclosure of fundamental structural and metabolic relationships

abstract:
AimsQuantitative lipoprotein analytics by NMR spectroscopy is currently commonplace in large-scale studies. One methodology has become widespread and is currently being utilised also in large biobanks. It allows comprehensive characterisation of 14 lipoprotein subclasses, clinical lipids, apolipoprotein A-I and B. The details of these data are conceptualised here in relation to lipoprotein metabolism with particular attention to the fundamental characteristics of subclass particle numbers, lipid concentrations and compositional measures.

Methods and ResultsThe NMR methodology was applied to fasting serum samples from Northern Finland Birth Cohort 1966 and 1986 with 5,651 and 5,605 participants, respectively. All results were highly coherent between the cohorts. Circulating lipid concentrations in a particular lipoprotein subclass arise predominantly as the result of the circulating number of those subclass particles. The spherical lipoprotein particle shape, with a radially oriented surface monolayer, imposes size-dependent biophysical constraints for the lipid composition of individual subclass particles and inherently restricts the accommodation of metabolic changes via compositional modifications. The new finding that the relationship between lipoprotein subclass particle concentrations and the particle size is log-linear reveal that circulating lipoprotein particles are also under rather strict metabolic constraints for both their absolute and relative concentrations.

ConclusionThe fundamental structural and metabolic relationships between lipoprotein subclasses elucidated in this study empower detailed interpretation of lipoprotein metabolism. Understanding the intricate details of these extensive data is consequential for the precise interpretation of novel therapeutic opportunities and for fully utilising the potential of forthcoming analyses of genetic and metabolic data in extensive biobanks.

One-sentence SummaryNMR spectroscopy facilitates comprehensive characterisation of lipoprotein subclass metabolism and offers additional value to epidemiology, genetics and pharmacology in large-scale studies and biobanks.

Key MessagesO_LIThe circulating particle number of a lipoprotein subclass is the defining measure for its lipid concentrations; the particle lipid composition is only in a minor role. The relationship between circulating lipoprotein subclass particle concentrations and the particle size is log-linear.
C_LIO_LIThe overall structure of lipoprotein subclass particles with a spherical shape and an oriented surface monolayer poses strong size-dependent biomolecular constraints for their lipid composition.
C_LIO_LIThe circulating lipoprotein subclass particle concentrations in humans are metabolically constraint for both elemental absolute and relative concentration ranges.
C_LIO_LIThe smallest HDL particle concentrations are negatively associated with those of large HDL and generally the associations of the smallest HDL particles are similar to those of apolipoprotein B-containing particles.
C_LIO_LIThe apolipoprotein B-containing particles constitute less than 10% of all lipoprotein particles but carry around two thirds of circulating lipoprotein lipids. LDL and IDL particles amount to almost 90% of all apolipoprotein B-containing particles.
C_LIO_LIThe supplemental role of lipoprotein subclass data in cardiometabolic risk assessment is slight.
C_LIO_LIIn the current era of biobanks and big data, the combination of lipoprotein subclass data with drug-target Mendelian randomization analyses provides great scientific synergy, intricate details and potential cost savings in drug development.
C_LI

Graphical abstract / key messages

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title: Tocilizumab efficacy in COVID-19 patients is associated with respiratory severity-based stages

abstract:
BackgroundTocilizumab treatment is investigated, and effectiveness in ICU-admitted COVID-19 patients has been reported. Although controversy exists regarding the efficacy of tocilizumab treatment, it has been suggested that tocilizumab might show positive results depending on patient severity status. We examined an association between tocilizumab and distinct disease severity stages.

Methods and FindingsFrom March 3 to March 23 2020, 494 consecutively admitted COVID-19 patients received tocilizumab or standard treatment alone. Data were obtained retrospectively. Clinical respiratory severity (CRS) stages were defined by patient oxygenation status and were also associated to scores of WHO clinical progression scale. We categorized patients in three stages, mild/moderate CRS1 (FiSpO2<0.35; WHO score 5), moderate/severe CRS2 (FiO2=0.5/high flow mask; WHO score 6) and severe/critical CRS3 (FiO2<80%/high flow/prone position or mechanical ventilation; score>6). The primary outcome was the composite of death or ICU admission in patients of stages CRS1, CRS2, and CRS3, as well as in total patients. We also addressed mortality alone in total patients. Kaplan-Maier curves, Cox proportional regression and inverse probability weighting marginal structural models were used. We conducted the study from March 3 to April 7 2020 with broad-ranged severity patients; 167 tocilizumab-treated and 327 untreated. CRS1 patients showed no apparent benefit after treatment, while the risk of the primary outcome was greatly reduced in CRS2 treated participants ((HR=0.22; 95% CI (0.16-0.44)). Moreover, tocilizumab treatment was associated with significantly decreased CRS2 patient proportion that reached the outcome compared to non-treated controls (27.8.0% vs. 65.4%; p<0.001). Severe/critical CRS3 patients, also showed benefit after treatment (HR=0.38; 95% CI (0.16-90)), although not as robust as was that of CRS2 treated individuals. Tocilizumab was associated with reduced outcome risk in total patients (HR=0.42; 95% CI (0.26-0.66)) after CRS adjustment, but not if CRS classification was not accounted as confounding factor (HR=1.19; 95% CI (0.84-1.69)). The outcome of mortality alone upon tocilizumab treatment was significant (HR=0.58; 95% CI (0.35-0.96)) after accounting for CRS classification.

ConclusionsTocilizumab treatment is associated with reduced COVID-19 escalation in CRS2 patients, suggesting efficacy in moderate/severe non-ICU-admitted patients. CRS classification could represent an essential confounding factor in evaluating tocilizumab in studies of broad-ranged severity patients.


title: Quantification of the spread of SARS-CoV-2 variant B.1.1.7 in Switzerland

abstract:
BackgroundIn December 2020, the United Kingdom (UK) reported a SARS-CoV-2 Variant of Concern (VoC) which is now named B.1.1.7. Based on initial data from the UK and later data from other countries, this variant was estimated to have a transmission fitness advantage of around 40-80% [1, 2, 3].

AimThis study aims to estimate the transmission fitness advantage and the effective reproductive number of B.1.1.7 through time based on data from Switzerland.

MethodsWe generated whole genome sequences from 11.8% of all confirmed SARS-CoV-2 cases in Switzerland between 14 December 2020 and 11 March 2021. Based on these data, we determine the daily frequency of the B.1.1.7 variant and quantify the variants transmission fitness advantage on a national and a regional scale.

ResultsWe estimate B.1.1.7 had a transmission fitness advantage of 43-52% compared to the other variants circulating in Switzerland during the study period. Further, we estimate B.1.1.7 had a reproductive number above 1 from 01 January 2021 until the end of the study period, compared to below 1 for the other variants. Specifically, we estimate the reproductive number for B.1.1.7 was 1.24 [1.07-1.41] from 01 January until 17 January 2021 and 1.18 [1.06-1.30] from 18 January until 01 March 2021 based on the whole genome sequencing data. From 10 March to 16 March 2021, once B.1.1.7 was dominant, we estimate the reproductive number was 1.14 [1.00-1.26] based on all confirmed cases. For reference, Switzerland applied more non-pharmaceutical interventions to combat SARS-CoV-2 on 18 January 2021 and lifted some measures again on 01 March 2021.

ConclusionThe observed increase in B.1.1.7 frequency in Switzerland during the study period is as expected based on observations in the UK. In absolute numbers, B.1.1.7 increased exponentially with an estimated doubling time of around 2-3.5 weeks. To monitor the ongoing spread of B.1.1.7, our plots are available online.


title: A Comparative Analysis of Clinical Stage 3 COVID-19 Vaccines using Knowledge Representation

abstract: The emergence of a novel SARS-CoV-2 coronavirus at the end of 2019 and its accelerated spread worldwide to become a pandemic has had, from the medical biotechnology point of view, an unprecedented global response, to the point that there are currently 176 vaccine candidates in preclinical stage, 66 in clinical stage, of which 19 are in phase 3, and 5 of these are massively applied worldwide. The purpose of the present work is to elaborate a hierarchical landscape of the current status of phase 3 vaccines, taking into account their attributes of technological platform, safety and efficacy. The methodology used was that of conceptual knowledge representation, resulting in, firstly, an appropriate classification of stage 3 vaccines, The Conceptual Lattice for COVID-19 vaccines, constructed according to how they relate to each other with respect to the set of their attributes. Secondly, the approach used allows proposing rational strategies for the design of heterologous vaccination schemes, which are urgently needed to control the pandemic.


title: COVID-19-associated school closures and related efforts to sustain education and subsidized meal programs, United States, February 18-June 30, 2020

abstract: Pre-emptive school closures are frontline community mitigation measures recommended by CDC for implementation during severe pandemics. This study describes the spatiotemporal patterns of publicly announced school closures implemented in response to the coronavirus disease 2019 (COVID-19) pandemic and assesses how public K-12 districts adjusted their methods of education delivery and provision of subsidized meals. During February 18-June 30, 2020, we used daily systematic media searches to identify publicly announced coronavirus disease 2019 (COVID-19)-related school closures lasting [≥]1 day in the United States (US). We also collected statewide school closure policies from state government websites. Data on distance learning and subsidized meal programs were collected from a stratified sample of 600 school districts. The first COVID-19-associated school closure occurred on February 27, 2020 in Washington state. By March 30, 2020, all but one US public school districts were closed, representing the first-ever nearly synchronous nationwide closure of public K-12 schools in the US. Approximately 100,000 public schools were closed for [≥]8 weeks because of COVID-19, affecting >50 million K-12 students. Of 600 districts sampled, the vast majority offered distance learning (91.0%) and continued provision of subsidized meal programs (78.8%) during the closures. Despite the sudden and prolonged nature of COVID-19-associated school closures, schools demonstrated flexibility by implementing distance learning and alternate methods to continue subsidized meal programs.


title: Dynamic Training of a Novelty Classifier Algorithm for Real-Time Early Seizure Onset Detection

abstract:
The objective of this study was to develop an adaptive framework for seizure detection in real-time that is practical to use in the Epilepsy Monitoring Unit (EMU) as a warning signal, and whose output helps characterize epileptiform activity. Our framework uses a one-class Support Vector Machine (SVM) that is being trained dynamically according to past activity in all available channels. This is done to evaluate the novelty of the current instance according to previous activity. Our algorithm was tested on intracranial EEG from human epilepsy patients that are admitted to the EMU for presurgical evaluation. In this study, we compared multiple configurations for using a one-class SVM to assess if there is significance over specific neural features or electrode locations. Our results show our algorithm is capable of running in real-time and achieving a high performance for early seizure-onset detection with a low false-positive rate and robustness to different types of seizure-onset patterns as well as to the number of channels used. This algorithm offers a solution to warning systems in the EMU as well as a tool for seizure characterization during post-hoc analysis of intracranial EEG data for surgical resection of the epileptogenic network.

HighlightsO_LIThis study proposes a dynamic training algorithm that efficiently detects sudden novel changes in intracranial electroencephalographic activity, creating a reliable seizure onset detection algorithm that does not need prior training.
C_LIO_LIThe algorithm described has the capability to be implemented in real-time, independently of the number of channels that are being analyzed.
C_LIO_LIThe presented detector shows high performance and reliability to be easily implemented in the Epilepsy Monitoring Unit to quickly alert clinical staff of seizure events.
C_LI


title: Explainable AI for Retinal Prostheses: Predicting Electrode Deactivation from Routine Clinical Measures

abstract: To provide appropriate levels of stimulation, retinal prostheses must be calibrated to an individuals perceptual thresholds ( system fitting). Nonfunctional electrodes may then be deactivated to reduce power consumption and improve visual outcomes. However, thresholds vary drastically not just across electrodes but also over time, thus calling for a more flexible electrode deactivation strategy. Here we present an explainable artificial intelligence (XAI) model fit on a large longitudinal dataset that can 1) predict at which point in time the manufacturer chose to deactivate an electrode as a function of routine clinical measures ( predictors) and 2) reveal which of these predictors were most important. The model predicted electrode deactivation from clinical data with 60.8% accuracy. Performance increased to 75.3% with system fitting data, and to 84% when thresholds from follow-up examinations were available. The model further identified subject age and time since blindness onset as important predictors of electrode deactivation. An accurate XAI model of electrode deactivation that relies on routine clinical measures may benefit both the retinal implant and wider neuroprosthetics communities.


title: SAMGEP: A Novel Method for Prediction of Phenotype Event Times Using the Electronic Health Record

abstract:
ObjectiveWhile there exist numerous methods to predict binary phenotypes using electronic health record (EHR) data, few exist for prediction of phenotype event times, or equivalently phenotype state progression. Estimating such quantities could enable more powerful use of EHR data for temporal analyses such as survival and disease progression. We propose Semi-supervised Adaptive Markov Gaussian Embedding Process (SAMGEP), a semi-supervised machine learning algorithm to predict phenotype event times using EHR data.

MethodsSAMGEP broadly consists of four steps: (i) assemble time-evolving EHR features predictive of the target phenotype event, (ii) optimize weights for combining raw features and feature embeddings into dense patient-timepoint embeddings, (iii) fit supervised and semi-supervised Markov Gaussian Process models to this embedding progression to predict marginal phenotype probabilities at each timepoint, and (iv) take a weighted average of these supervised and semi-supervised predictions. SAMGEP models latent phenotype states as a binary Markov process, conditional on which patient-timepoint embeddings are assumed to follow a Gaussian Process.

ResultsSAMGEP achieves significantly improved AUCs and F1 scores relative to common machine learning approaches in both simulations and a real-world task using EHR data to predict multiple sclerosis relapse. It is particularly adept at predicting a patients longitudinal phenotype course, which can be used to estimate population-level cumulative probability and count process estimators. Reassuringly, it is robust to a variety of generative model parameters.

DiscussionSAMGEPs event time predictions can be used to estimate accurate phenotype progression curves for use in downstream temporal analyses, such as a survival study for comparative effectiveness research.


title: Performance and Operational Evaluation of the Access Bio CareStart Rapid Antigen Test in a High-throughput Drive-through Community Testing Site in Massachusetts

abstract:
BackgroundTo facilitate deployment of point-of-care testing for SARS-CoV-2, we evaluated the Access Bio CareStart COVID-19 Antigen test in a high-throughput, drive-through, free community testing site using anterior nasal (AN) swab RT-PCR for clinical testing.

MethodsConsenting symptomatic and asymptomatic children ([≤]18 years) and adults received dual AN swabs. CareStart testing was performed with temperature/humidity monitoring. All tests had two independent reads to assess inter-operator agreement. Patients with positive CareStart results were called and instructed to isolate pending RT-PCR results. The paired RT-PCR result was the reference for sensitivity and specificity calculations.

ResultsOf 1603 participants, 1245 adults and 253 children had paired RT-PCR/CareStart results and complete symptom data. 83% of adults and 87% of children were asymptomatic. CareStart sensitivity/specificity were 84.8% (95% confidence interval [CI] 71.1-93.7)/97.2% (92.0-99.4) and 85.7% (42.1-99.6)/89.5% (66.9-98.7) in adults and children, respectively, within 5 days of symptoms. Sensitivity/specificity were 50.0% (41.0-59.0)/99.1% (98.3-99.6) in asymptomatic adults and 51.4% (34.4-68.1)/97.8% (94.5-99.4) in asymptomatic children. Sensitivity in all 234 RT-PCR-positive people was 96.3% with cycle threshold (Ct) [≤]25, 79.6% with Ct [≤]30, and 61.4% with Ct [≤]35. All 21 false positive CareStart tests had faint but normal bands. Inter-operator agreement was 99.5%. Operational challenges included identification of faint test bands and inconsistent swab elution volumes.

ConclusionsCareStart had high sensitivity in people with Ct [≤]25 and moderate sensitivity in symptomatic people overall. Specificity was unexpectedly lower in symptomatic versus asymptomatic people. Excellent inter-operator agreement was observed, but operational challenges indicate that operator training is warranted.


title: Transmission, infectivity, and antibody neutralization of an emerging SARS-CoV-2 variant in California carrying a L452R spike protein mutation

abstract: We identified a novel SARS-CoV-2 variant by viral whole-genome sequencing of 2,172 nasal/nasopharyngeal swab samples from 44 counties in California. Named B.1.427/B.1.429 to denote its 2 lineages, the variant emerged around May 2020 and increased from 0% to >50% of sequenced cases from September 1, 2020 to January 29, 2021, exhibiting an 18.6-24% increase in transmissibility relative to wild-type circulating strains. The variant carries 3 mutations in the spike protein, including an L452R substitution. Our analyses revealed 2-fold increased B.1.427/B.1.429 viral shedding in vivo and increased L452R pseudovirus infection of cell cultures and lung organoids, albeit decreased relative to pseudoviruses carrying the N501Y mutation found in the B.1.1.7, B.1.351, and P.1 variants. Antibody neutralization assays showed 4.0 to 6.7-fold and 2.0-fold decreases in neutralizing titers from convalescent patients and vaccine recipients, respectively. The increased prevalence of a more transmissible variant in California associated with decreased antibody neutralization warrants further investigation.


title: Modified Oxacillin Resistant Staphylococcus aureus detected in neonatal intensive care patients

abstract: Active surveillance in our neonatal intensive care unit identified Staphylococcus aureus cultures from two infants with heterogeneity in methicillin resistance between isolated subclones lacking mecA and mecC. Whole-genome analysis of 4 modified (MODSA) and 4 methicillin-susceptible (MSSA) subclones for each culture identified either truncating mutations in the cyclic diadenosine monophosphate phosphodiesterase enzyme (GdpP), or a nonsynonymous substitution in penicillin binding protein 2 (PBP2). These cases highlight the difficulty in identifying non-mecA/non-mecC-mediated methicillin-resistance in clinical laboratories.


title: Early estimates of SARS-CoV-2 B.1.1.7 variant emergence in a university setting

abstract: Recent identification of the highly transmissible novel SARS-CoV-2 variant in the United Kingdom (B.1.1.7) has raised concerns for renewed pandemic surges worldwide 1,2. B.1.1.7 was first identified in the US on December 29, 2020 and may become dominant by March 2021 3. However, the regional prevalence of B.1.1.7 is largely unknown because of limited molecular surveillance for SARS-CoV-2 4. Quantitative PCR data from a surveillance testing program on a large university campus with roughly 30,000 students provides local situational awareness at a pivotal moment in the COVID-19 pandemic.


title: Shotgun mass spectrometry-based lipid profiling identifies and distinguishes between chronic inflammatory diseases

abstract:
BackgroundInflammation impacts several acute and chronic diseases causing localized stress and cell death, releasing tissue-specific lipids into the circulation from inflamed cells and tissues. The plasma lipidome may be expected to reflect the type of inflammation and the specific cells and tissues involved. However, deep lipid profiles of major chronic inflammatory diseases have not been compared.

MethodsWe compare the plasma lipidomes of patients suffering from two etiologically distinct chronic inflammatory diseases, atherosclerosis-related cardiovascular disease (CVD) including ischemic stroke (IS), and systemic lupus erythematosus (SLE), to each other and to age-matched controls. The controls had never suffered from any of these diseases. Blood plasma lipidomes were screened by a top-down shotgun MS-based analysis without liquid chromatographic separation. Lipid profiling based on MS was performed on a cohort of 427 individuals. The cohort constitutes 85 controls (control), 217 with cardiovascular disease (further classified into CVD 1-5), 21 ischemic stroke patients (IS), and 104 patients suffering from systemic lupus erythematosis (SLE). 596 lipids were profiled which were quality filtered for further evaluation and determination of potential biomarkers. Lipidomes were compared by linear regression and evaluated by machine learning classifiers.

ResultsMachine learning classifiers based on the plasma lipidomes of patients suffering from CVD and SLE allowed clear distinction of these two chronic inflammatory diseases from each other and from healthy age-matched controls and body mass index (BMI). We demonstrate convincing evidence for the capability of lipidomics to separate the studied chronic and inflammatory diseases from controls based on independent validation test set classification performance (CVD vs control - Sensitivity: 0.90, Specificity: 0.98; IS vs control - Sensitivity: 1.0, Specificity: 1.0; SLE vs control - Sensitivity: 1, Specificity: 0.88) and from each other (SLE vs CVD {square} Sensitivity: 0.91, Specificity: 1). Preliminary linear discriminant analysis plots using all data clearly separated the clinical groups from each other and from the controls. In addition, CVD severities, as classified into five clinical groups, were partially separable by linear discriminant analysis. Notably, significantly dysregulated lipids between pathological groups versus control displayed a reverse lipid regulation pattern compared to statin treated controls versus non treated controls.

ConclusionDysregulation of the plasma lipidome is characteristic of chronic inflammatory diseases. Lipid profiling accurately identifies the diseases and in the case of CVD also identifies sub-classes. Dysregulated lipids are partially but not fully counterbalanced by statin treatment.

category: cardiovascular medicine


title: Rationale, protocol and baseline characteristics of the metabolome, microbiome, and dietary salt intervention study (MetaSalt)

abstract: High sodium intake has been recognized as an important risk factor for hypertension, but the role of gut microbiota composition and metabolomic profiles in the association between dietary sodium intake and blood pressure (BP) is uncertain. The metabolome, microbiome, and dietary salt intervention study (MetaSalt) study was conducted to investigate whether low- and high-dietary sodium intake influences BP by changing the microbial and metabolomic profiles. This is a family-based, multicentre intervention study conducted in four rural field-centres across three provinces in rural Northern China. Probands with untreated prehypertension or stage-1 hypertension were identified through a community-based BP screening, and their family members included siblings, offspring, spouses and parents were subsequently included. During the dietary intervention, low-salt and high-salt diets were provided free of charge to all participants. A total of 529 participants in four field centres were included in our study, with a mean age of 48.1 years old, and about 36.7% of them were male, 76.5% had a middle school (69.5%) or higher (7.0%) diploma, 23.4% had a history of smoke, 24.4% were current drinkers. The mean systolic and diastolic BP levels in the baseline were 129.54 mm Hg and 81.02 mm Hg for all participants, and significantly decreased during the low-salt intervention and increased during the high-salt intervention. Our study is well placed to check the impacts of dietary sodium intake on microbial and metabolomic profiles, which will have important implications for discovering the mechanisms in the development of hypertension and subsequent cardiovascular disease.


title: COVID-19 vaccine distrust in Colombian university students: Frequency and associated variables

abstract: The study aimed to know the frequency and variables associated with COVID-19 vaccine distrust in students of a Colombian university. A cross-sectional study was carried out which participated emerging adult students of a Colombian university. A total of 1,136 students between 18 and 29 years (M= 22.0, SD = 3.0); most of them were female (66.0%), non-health students (82.8%), low-income (79.0%), and residents of urban areas (84.9%). It was frequent low institutional trust (74.8%), low cognitive, social capital (27.9%), low fear of COVID-19 (49.5%), low perceived stress related to COVID-19 (83.5%), and high COVID-19 vaccine distrust (78.9%). Non-health carrier (Adjusted OR = 3.63, 95%CI 2.58-5.10), rural residence (AOR = 1.85, 95%CI 1.13-3.04), low income (AOR = 1.84, 95%CI 1.31-2.57), and perceived stress related to COVID-19 (AOR = 1.74, 95%CI 1.20-2.54) were related to high COVID-19 vaccine distrust. In conclusion, COVID-19 vaccine distrust is high among emerging adult Colombian university students. The COVID-19 vaccine distrust is related to non-health science carriers, rural residents, low-income, and low-perceived stress related to COVID-19. The COVID-19 related health literacy should be improved in students of this university considering socio-cultural background.