title: Plasma ACE2 levels predict outcome of COVID-19 in hospitalized patients

abstract:
BackgroundSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) binds to angiotensin converting enzyme 2 (ACE2) enabling entrance of the virus into cells and causing the infection termed coronavirus disease of 2019 (COVID-19). COVID-19 is a disease with a very broad spectrum of clinical manifestations, ranging from asymptomatic and subclinical infection to severe hyperinflammatory syndrome and death.

MethodsThis study used data from a large longitudinal study of 306 COVID-19 positive patients and 78 COVID-19 negative patients (MGH Emergency Department COVID-19 Cohort with Olink Proteomics). Comprehensive clinical data were collected on this cohort, including 28-day outcomes classified according to the World Health Organization (WHO) COVID-19 outcomes scale. The samples were run on the Olink(R) Explore 1536 platform which includes measurement of the ACE2 protein.

FindingsHigh baseline levels of ACE2 in plasma from COVID-19 patients were associated with worse WHOmax category at 28 days with OR=0.56, 95%-CI: 0.44-0.71 (P < 0.0001). This association was significant in regression models with correction for baseline characteristics, pre-existing medical conditions, and laboratory test results. High levels of ACE2 in plasma from COVID-19 patients were also significantly associated with worse WHO category at the time of blood sampling at both day 0, day 3, and day 7 (P = 0.0004, P < 0.0001, and P < 0.0001, respectively). The levels of ACE2 in plasma from COVID-19 patients with hypertension were significantly higher compared to patients without hypertension (P = 0.0045). The plasma ACE2 levels were also significantly higher in COVID-19 patients with pre-existing heart conditions and kidney disease compared with patients without these pre-existing conditions (P = 0.0363 and P = 0.0303, respectively). There was no difference in plasma ACE2 levels comparing patients with or without pre-existing lung disease, diabetes, or immunosuppressive conditions (P = 0.953, P = 0.291, and P = 0.237, respectively). The associations between high plasma levels of ACE2 and worse WHOmax category during 28 days were more pronounced in COVID-19 positive patients compared with COVID-19 negative patients but the difference was not significant in the two-way ANOVA analysis.

InterpretationThis study suggests that measuring ACE2 is potentially valuable in predicting COVID-19 outcomes. Further, ACE2 levels could be a link between severe COVID-19 disease and its risk factors, namely hypertension, pre-existing heart disease and pre-existing kidney disease. The design of the data analysis using the Olink platform does not allow assessment of quantitative differences. However, previous studies have described a positive correlation between plasma ACE2 and ACE1 activity. This is interesting because ACE1 (serum ACE) analysis is a standardized test in most hospital laboratories. Therefore, our study encourages quantitative investigations of both plasma ACE 1 and 2 in COVID-19.

Key PointsO_ST_ABSQuestionC_ST_ABSCan plasma levels of the receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), angiotensin converting enzyme 2 (ACE2), predict outcome of coronavirus disease of 2019 (COVID-19).

FindingsIn this study of 306 COVID-19 positive patients, high baseline levels of ACE2 in plasma from COVID-19 patients were associated with worse outcome measured by the World Health Organization (WHO) COVID-19 outcomes scale.

MeaningMeasuring ACE2 is potentially valuable in predicting COVID-19 outcomes and link COVID-19 disease and the risk factors hypertension, pre-existing heart disease and pre-existing kidney disease.


title: Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

abstract:
BackgroundTreatment of COVID-19 patients with plasma containing anti-SARS-CoV-2 antibodies may have a beneficial effect on clinical outcomes. We aimed to evaluate the safety and efficacy of convalescent plasma in patients admitted to hospital with COVID-19.

MethodsIn this randomised, controlled, open-label, platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]) several possible treatments are being compared with usual care in patients hospitalised with COVID-19 in the UK. Eligible and consenting patients were randomly allocated to receive either usual care plus high titre convalescent plasma or usual care alone. The primary outcome was 28-day mortality.

FindingsBetween 28 May 2020 and 15 January 2021, 5795 patients were randomly allocated to receive convalescent plasma and 5763 to usual care alone. There was no significant difference in 28-day mortality between the two groups: 1398 (24%) of 5795 patients allocated convalescent plasma and 1408 (24%) of 5763 patients allocated usual care died within 28 days (rate ratio [RR] 1{middle dot}00; 95% confidence interval [CI] 0{middle dot}93 to 1{middle dot}07; p=0{middle dot}93). The 28-day mortality rate ratio was similar in all prespecified subgroups of patients, including in those patients without detectable SARS-CoV-2 antibodies at randomisation. Allocation to convalescent plasma had no significant effect on the proportion of patients discharged from hospital within 28 days (66% vs. 67%; rate ratio 0{middle dot}98; 95% CI 0{middle dot}94-1{middle dot}03, p=0{middle dot}50). Among those not on invasive mechanical ventilation at baseline, there was no significant difference in the proportion meeting the composite endpoint of progression to invasive mechanical ventilation or death (28% vs. 29%; rate ratio 0{middle dot}99; 95% CI 0{middle dot}93-1{middle dot}05, p=0{middle dot}79).

InterpretationAmong patients hospitalised with COVID-19, high-titre convalescent plasma did not improve survival or other prespecified clinical outcomes.

FundingUK Research and Innovation (Medical Research Council) and National Institute of Health Research (Grant refs: MC_PC_19056; COV19-RECPLA).

category: infectious diseases


title: Prevalence of sleep disturbance and associated risk factors in UK Biobank participants with alcohol use disorders and major depression

abstract:
IntroductionCurrent understanding of the differences in sleep disturbance (SD) and associated risk factors in patients with alcohol use disorders (AUD), major depressive disorders (MDD), and comorbid AUD+MDD is limited.

MethodsData from the UK Biobank (UKB) (n=47,825) were utilized to categorize subjects into those with MDD (n=5,991), AUD (n=12,952), both (MDD+AUD)(n=3,219), and controls (n=25,663). We used generalized linear models (GLMs) to test whether rates of SD and sleep duration differed among the groups and determine the clinical predictors of SD. Rates of SD and sleep duration were compared using regression analyses accounting for demographic (age, sex, ethnicity, and Townsend deprivation index) and clinical (body mass index, neuroticism score, and alcohol consumption) factors.

ResultsAfter accounting for diagnostic category, SD was associated with age, female sex, white ethnicity, and higher BMI, neuroticism and alcohol consumption scores (all p<0.0001).

The unadjusted prevalence of SD was 25.6%, 25.9%, 39.2%, and 41.1% in control, AUD, MDD, and MDD+AUD categories respectively. Rates of SD in controls and AUD group as well as MDD alone and MDD+AUD did not differ in unadjusted models (p=0.45 and 0.075, respectively). Prevalence of SD differed in the four groups (p<0.0001 for all pairwise comparisons) after adjusting for demographic confounders. After further adjustment for clinical factors, effect sizes were reduced, but pairwise comparisons remained significant, except in the AUD versus MDD group (all p<0.05). After adjusting for demographic and clinical factors, sleep duration did not differ among the groups.

ConclusionDemographic and clinical characteristics associated with SD were similar in patients with MDD, AUD, and MDD+AUD. The differences in rates of SD between the diagnostic groups were attenuated but persisted after accounting for these confounders. Genetic and other factors capable of influencing SD in patients with MDD, AUD, and comorbid MDD+AUD merit future investigation.

category: addiction medicine


title: Population-based estimates of post-acute sequelae of SARS-CoV-2 infection (PASC) prevalence and characteristics: A cross-sectional study

abstract:
ImportanceEmerging evidence suggests many people have persistent symptoms after acute COVID-19 illness.

ObjectiveTo estimate the prevalence and correlates of persistent COVID-19 symptoms 30 and 60 days post onset using a population-based sample.

Design & SettingThe Michigan COVID-19 Recovery Surveillance Study is a population-based cross-sectional survey of a probability sample of adults with confirmed COVID-19 in the Michigan Disease Surveillance System (MDSS). Respondents completed a survey online or via telephone in English, Spanish, or Arabic between June - December 2020.

ParticipantsLiving non-institutionalized adults (aged 18+) in MDSS with COVID-19 onset through mid-April 2020 were eligible for selection (n=28,000). Among 2,000 adults selected, 629 completed the survey. We excluded 79 cases during data collection due to ineligibility, 6 asymptomatic cases, 7 proxy reports, and 24 cases missing outcome data, resulting in a sample size of 593. The sample was predominantly female (56.1%), aged 45 and older (68.2%), and Non-Hispanic White (46.3%) or Black (34.8%).

ExposuresDemographic (age, sex, race/ethnicity, and annual household income) and clinical factors (smoking status, body mass index, diagnosed comorbidities, and illness severity).

Main outcomes and MeasuresWe defined post-acute sequelae of SARS-CoV-2 infection (PASC) as persistent symptoms 30+ days (30-day COVID-19) or 60+ days (60-day COVID-19) post COVID-19 onset.

Results30- and 60-day COVID-19 were highly prevalent (52.5% and 35.0%), even among respondents reporting mild symptoms (29.2% and 24.5%) and non-hospitalized respondents (43.7% and 26.9%, respectively). Low income was statistically significantly associated with 30-day COVID-19 in adjusted models. Respondents reporting very severe (vs. mild) symptoms had 2.25 times higher prevalence of 30-day COVID-19 (Adjusted Prevalence Ratio [aPR] 2.25, 95% CI 1.46-3.46) and 1.71 times higher prevalence of 60-day COVID-19 (aPR 1.71, 95% 1.02-2.88). Hospitalized (vs. non-hospitalized) respondents had about 40% higher prevalence of both 30-day (aPR 1.37, 95% CI 1.12-1.69) and 60-day COVID-19 (aPR 1.40, 95% CI 1.02-1.93).

Conclusions and RelevancePASC is highly prevalent among cases with severe initial symptoms, and, to a lesser extent, cases with mild and moderate symptoms.

category: epidemiology


title: Increased mortality among individuals hospitalised with COVID-19 during the second wave in South Africa

abstract:
IntroductionSouth Africa experienced its first wave of COVID-19 peaking in mid-July 2020 and a larger second wave peaking in January 2021, in which the SARS-CoV-2 501Y.V2 lineage predominated. We aimed to compare in-hospital mortality and other patient characteristics between the first and second waves of COVID-19.

MethodsWe analysed data from the DATCOV national active surveillance system for COVID-19 hospitalisations. We defined four wave periods using incidence risk for hospitalisation, pre-wave 1, wave 1, pre-wave 2 and wave 2. We compared the characteristics of hospitalised COVID-19 cases in wave 1 and wave 2, and risk factors for in-hospital mortality accounting for wave period using multivariable logistic regression.

ResultsPeak rates of COVID-19 cases, admissions and in-hospital deaths in the second wave exceeded the rates in the first wave (138.1 versus 240.1; 16.7 versus 28.9; and 3.3 versus 7.1 respectively per 100,000 persons). The weekly average incidence risk increase in hospitalisation was 22% in wave 1 and 28% in wave 2 [ratio of growth rate in wave two compared to wave one: 1.04, 95% CI 1.04-1.05]. On multivariable analysis, after adjusting for weekly COVID-19 hospital admissions, there was a 20% increased risk of in-hospital mortality in the second wave (adjusted OR 1.2, 95% CI 1.2-1.3). In-hospital case fatality-risk (CFR) increased in weeks of peak hospital occupancy, from 17.9% in weeks of low occupancy (<3,500 admissions) to 29.6% in weeks of very high occupancy (>12,500 admissions) (adjusted OR 1.5, 95% CI 1.4-1.5).

Compared to the first wave, individuals hospitalised in the second wave, were more likely to be older, 40-64 years [OR 1.1, 95% CI 1.0-1.1] and [≥]65 years [OR 1.1, 95% CI 1.1-1.1] compared to <40 years; and admitted in the public sector [OR 2.2, 95% CI 1.7-2.8]; and less likely to have comorbidities [OR 0.5, 95% CI 0.5-0.5].

ConclusionsIn South Africa, the second wave was associated with higher incidence and more rapid increase in hospitalisations, and increased in-hospital mortality. While some of this is explained by increasing pressure on the health system, a residual increase in mortality of hospitalised patients beyond this, could be related to the new lineage 501Y.V2.

RESEARCH IN CONTEXT O_TEXTBOXEvidence before this studyMost countries have reported higher numbers of COVID-19 cases in the second wave but lower case-fatality risk (CFR), in part due to new therapeutic interventions, increased testing and better prepared health systems. South Africa experienced its second wave which peaked in January 2021, in which the variant of concern, SARS-CoV-2 501Y.V2 predominated. New variants have been shown to be more transmissible and in the United Kingdom, to be associated with increased hospitalisation and mortality rates in people infected with variant B.1.1.7 compared to infection with non-B.1.1.7 viruses. There are currently limited data on the severity of lineage 501Y.V2.

Added value of this studyWe analysed data from the DATCOV national active surveillance system for COVID-19 hospitalisations, comparing in-hospital mortality and other patient characteristics between the first and second waves of COVID-19. The study revealed that after adjusting for weekly COVID-19 hospital admissions, there was a 20% increased risk of in-hospital mortality in the second wave. Our study also describes the demographic shift from the first to the second wave of COVID-19 in South Africa, and quantifies the impact of overwhelmed hospital capacity on in-hospital mortality.

Implications of all the available evidenceOur data suggest that the new lineage (501Y.V2) in South Africa may be associated with increased in-hospital mortality during the second wave. Our data should be interpreted with caution however as our analysis is based on a comparison of mortality in the first and second wave as a proxy for dominant lineage and we did not have individual-level data on lineage. Individual level studies comparing outcomes of people with and without the new lineage based on sequencing data are needed. To prevent high mortality in a potential third wave, we require a combination of strategies to slow the transmission of SARS-CoV-2, to spread out the peak of the epidemic, which would prevent hospital capacity from being breached.

C_TEXTBOX

category: public and global health


title: A High Rate of COVID-19 Vaccine Hesitancy Among Arabs: Results of a Large-scale Survey

abstract: In this study, we present the results of the first large-scale multinational study (36,220 participants) that measures vaccine hesitancy among Arab-speaking subjects. Our analysis shows a significant rate of vaccine hesitancy among Arabs in and outside the Arab region (83% and 81%, respectively). The most cited reasons for hesitancy are concerns about side effects and distrust in healthcare policies, vaccine expedited production, published studies and vaccine producing companies. We also found that female participants, participants 30-59 year-old, those with no chronic diseases, those with lower-level of academic education, and those who do not know the type of vaccine authorized in their countries are more hesitant to receive COVID-19 vaccination. On the other hand, participants who regularly receive the influenza vaccine, health care workers, and those from countries with higher rates of COVID-19 infections showed more vaccination willingness. Interactive representation of our results is posted on our project website at https://mainapp.shinyapps.io/CVHAA.


title: Topographical overlapping of the Aβ and Tau pathologies in the Default mode networks predicts Alzheimer's Disease with higher specificity

abstract: While Amyloid-plaques and Tau-tangles are the well-recognized pathologies of Alzheimers disease (AD), they are more often observed in healthy individuals than in AD patients. This discrepancy makes it extremely challenging to utilize these two proteinopathies as reliable biomarkers for the early detection as well as later diagnosis of AD. Using the recent advancements in the imaging technology, our newly developed quantification methods, and publicly available neuroimaging data from 303 individuals, we hypothesize and provide preliminary evidence that topographically overlapping A{beta} and Tau within the DMN play more critical roles in the underlying pathophysiology of AD than the Tau and/or A{beta} pathologies. We first showed that the probability of observing overlapping A{beta} and Tau is significantly higher within the DMN than outside DMN. Then we showed evidence that using A{beta} and Tau overlap can increase the reliability of the prediction of healthy individuals converting to MCI and a lesser degree converting from MCI to AD. These findings shed some light on the complex pathophysiology of AD and suggest that overlapping A{beta} and Tau pathologies within DMN might be a more reliable biomarker of AD for early detection and later diagnosis of the disease.

category: radiology and imaging


title: Efficacy of remdesivir in Japanese patients hospitalised with COVID-19: A large observational study using the COVID-19 Registry Japan

abstract:
ObjectivesAlthough several randomised controlled trials have compared the efficacy of remdesivir with that of placebo, there is limited evidence regarding its effect in the early stage of nonsevere COVID-19 cases.

MethodsWe evaluated the efficacy of remdesivir on the early stage of nonsevere COVID-19 using the COVID-19 Registry Japan, a nationwide registry of hospitalised COVID-19 patients in Japan. Two regimens (start remdesivir therapy within 4 days from admission vs. no remdesivir during hospitalisation) among patients without the need for supplementary oxygen therapy were compared by a three-step processing (cloning, censoring, and weighting) method. The primary outcome was supplementary oxygen requirement during hospitalisation. Secondary outcomes were 30-day fatality risk and risk of invasive mechanical ventilation or extracorporeal membrane oxygenation (IMV/ECMO).

ResultsThe data of 12,657 cases met our inclusion criteria. The  start remdesivir regimen showed a lower risk of supplementary oxygen requirement (hazard ratio: 0.861, p < 0.001). Both 30-day fatality risk and risk of IMV/ECMO introduction were not significantly different between the two regimens (hazard ratios: 1.05 and 0.886, p values: 0.070 and 0.440, respectively).

ConclusionsRemdesivir might reduce the risk of oxygen requirement during hospitalisation in the early stage of COVID-19; however, it had no positive effect on the clinical outcome and reduction of IMV/ECMO requirement.


title: Efficacy of remdesivir in hospitalised COVID-19 patients in Japan: A large observational study using the COVID-19 Registry Japan


title: Anti-SARS-CoV-2 Serology persistence over time in COVID-19 Convalescent Plasma Donors.

abstract:
BackgroundCharacterizing the kinetics of the antibody response to SARS{square}CoV{square}2 is of critical importance to developing strategies that may mitigate the public health burden of COVID-19. We sought to determine how circulating antibody levels change over time following natural infection.

Methods/MaterialsWe conducted a prospective, longitudinal analysis of COVID-19 convalescent plasma (CCP) donors at multiple time points over a 9-month period. At each study visit, subjects either donated plasma or only had study samples drawn. In all cases, anti-SARS-CoV-2 donor testing was performed using semi-quantitative chemiluminescent immunoassays (ChLIA) targeting subunit 1 (S1) of the SARS-CoV-2 spike (S) protein, and an in-house fluorescence reduction neutralization assay (FRNA).

ResultsFrom April to November 2020 we enrolled 202 donors, mean age 47.3 {+/-}14.7 years, 55% female, 75% Caucasian. Most donors reported a mild clinical course (91%, n=171) without hospitalization. One hundred and five (105) (52%) donors presented for repeat visits with a median 42 (12-163) days between visits. The final visit occurred at a median 160 (53-273) days post-symptom resolution. Total anti-SARS-CoV-2 antibodies (Ab), SARS-CoV-2 specific IgG and neutralizing antibodies were detected in 97.5%, 91.1%, and 74% of donors respectively at initial presentation. Neutralizing Ab titers based on FRNA50 were positively associated with mean IgG levels (p = <0.0001). Mean IgG levels and neutralizing titers were positively associated with COVID-19 severity, increased donor age and BMI (p=0.0006 and p=0.0028, p=0.0083 and p=0.0363, (p=0.0008 and p=0.0018, respectively). Over the course of repeat visits, IgG decreased in 74.1% of donors; FRNA50 decreased in 44.4% and remained unchanged in 33.3% of repeat donors. A weak negative correlation was observed between total Ab levels and number of days post-symptom recovery (r = 0.09).

ConclusionAnti-SARS-CoV-2 antibodies were identified in 97% of convalescent donors at initial presentation. In a cohort that largely did not require hospitalization. IgG and neutralizing antibodies were positively correlated with age, BMI and clinical severity, and persisted for up to 9 months post-recovery from natural infection. On repeat presentation, IgG anti-SARS-CoV-2 levels decreased in 56% of repeat donors. Overall, these data suggest that CP donors possess a wide range of IgG and neutralizing antibody levels that are proportionally distributed across demographics, with the exception of age, BMI and clinical severity.


title: Impact of previous COVID-19 on immune response after a single dose of BNT162b2 SARS-CoV-2 vaccine

abstract: Immune response after a single-dose of BNT162b2 vaccine is markedly increased in health care workers with previous SARS-CoV2 exposure, as assessed by positive SARS-CoV2 IgG, particularly after moderate-severe COVID-19. These data may inform the priority of the boosting mRNA second dose in times of vaccine shortage.


title: Association of plasma and CSF cytochrome P450, soluble epoxide hydrolase and ethanolamides metabolism with Alzheimer's disease

abstract: Alzheimers disease shares inflammatory origin with cardiometabolic disorders. Lipid mediators, including oxylipins, endocannabinoids, bile acids and steroids are potent regulators of inflammation, energy metabolism and cell proliferation with well-established involvement in cardiometabolic diseases. However, their role in Alzheimers disease is poorly understood. In the current study we provide comprehensive analysis of plasma and CSF lipid mediators in a case-control comparison of patients with Alzheimers disease, utilizing a targeted quantitative mass spectrometry approach. In both plasma and CSF, we observed Alzheimers disease patients to have elevated components of cytochrome P450/soluble epoxide hydrolase pathway and lower levels of fatty acids ethanolamides, when compared to the healthy controls. Multivariate analysis revealed that circulating metabolites of soluble epoxide hydrolase together with ethanolamides are strong and independent predictors for Alzheimers disease. Both metabolic pathways are potent regulators of inflammation with soluble epoxide hydrolase being reported to be upregulated in the brains of Alzheimers disease patients. This study provides further evidence for the involvement of inflammation in Alzheimers disease and argues for further research into the role of the cytochrome P450/soluble epoxide hydrolase pathway and fatty acid ethanolamides in this disorder. Further, these findings suggest that a combined pharmacological intervention targeting both metabolic pathways may have therapeutic benefits for Alzheimers disease.

category: neurology


title: The Prognostic Value of PD-1/PD-L1 Expression on Tumor Cells and Tumor-Infiltrating Immune Cells in Patients with Colorectal Cancer: a Systematic Review and Meta-Analysis Protocol

abstract:
AimColorectal cancer (CRC) is one of the most common cancers in the world. However, the role of immune checkpoint molecules, especially Programmed cell death protein 1 (PD-1) and Programmed cell death-ligand 1 (PD-L1), in the progression of CRC remains unclear. This systematic review and meta-analysis will investigate the prognostic significance of PD-1/PD-L1 expression on tumor-infiltrating immune cells and tumor cells in patients with colorectal cancer.

MethodsThis protocol has been prospectively registered in the PROSPERO (registration NO. CRD42020156233). A comprehensive electronic search on PubMed/MEDLINE, Scopus, Web of Science (WOS), Embase and ProQuest will be conducted using a combination of MeSH terms of "programmed cell death 1", "programmed cell death ligand 1", "colorectal" and "cancer" between 1 January 1990 and 31 March 2021 with no language limitation. Two independent reviewers will perform study selection, data extraction, and risk of bias assessment. The Newcastle-Ottawa Scale (NOS) for cohort studies will be used to assess the risk of bias. In the case of sufficient data, either random or fixed-effect models, will be used for meta-analysis. Statistical heterogeneity will be evaluated by [X]2 test with the I2 statistic. "Funnel plot", "Beggs statistical test", and "Eggers statistical test and graph" will be used to assess publication bias. Stata V.13 software will be employed for meta-analysis.

Results and conclusionAccording to the meta-analysis of the aggregated data from the relevant primary studies, the relationship between expression of PD-1/PD-L1 and prognostic parameters, including progression-free survival and overall survival, will be reported. The results of the current study will be published in a peer-reviewed journal.

category: oncology


title: Spike vs nucleocapsid SARS-CoV-2 antigen detection: application in nasopharyngeal swab specimens

abstract:
Public health experts emphasize the need for quick, point-of-care SARS-CoV-2 detection as an effective strategy for controlling virus spread. To this end, many "antigen" detection devices were developed and commercialized. These devices are mostly based on detecting SARS-CoV-2s nucleocapsid protein. Recently, alerts issued by both the FDA and the CDC raised concerns regarding the devices tendency to exhibit false positive results. In this work we developed a novel alternative spike-based antigen assay, comprised of four high-affinity, specific monoclonal antibodies, directed against different epitopes on the spikes S1 subunit. The assays performance was evaluated for COVID-19 detection from nasopharyngeal swabs, compared to an in-house nucleocapsid-based assay, composed of antibodies directed against the nucleocapsid. Detection of COVID-19 was carried out in a cohort of 284 qRT-PCR positive and negative nasopharyngeal swab samples. The time resolved fluorescence (TRF) ELISA spike-assay displayed very high specificity (99%) accompanied with a somewhat lower sensitivity (66% for Ct<25), compared to the nucleocapsid ELISA assay which was more sensitive (85% for Ct<25) while less specific (87% specificity). Despite being out-performed by qRT-PCR, we suggest that there is room for such tests in the clinical setting, as cheap and rapid pre-screening tools. Our results further suggest that when applying antigen detection, one must consider its intended application (sensitivity vs specificity), taking into consideration that the nucleocapsid might not be the optimal target. In this regard, we propose that a combination of both antigens might contribute to the validity of the results.

O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=122 SRC="FIGDIR/small/21253148v1_ufig1.gif" ALT="Figure 1">
View larger version (24K):
org.highwire.dtl.DTLVardef@2cdc04org.highwire.dtl.DTLVardef@12090daorg.highwire.dtl.DTLVardef@10603dforg.highwire.dtl.DTLVardef@1e84cfa_HPS_FORMAT_FIGEXP  M_FIG C_FIG Graphic abstractSchematic representation of sample collection and analysis. The figure was created using BioRender.com


title: Determining the risk of developing symptomatic covid-19 infection after attending hospital for radiological examinations: controlled cohort study

abstract:
OBJECTIVETo determine whether brief attendance for outpatient radiological investigations is associated with increased risk of clinically significant coronavirus disease 2019 (covid-19) infection.

DESIGNObservational cohort study with a historical control.

SETTING2 large UK University Hospitals located in Nottingham and Cardiff.

PARTICIPANTSAll 47,340 patients who attended an outpatient radiology appointment at Nottingham University Hospitals and University Hospital of Wales during the first wave of the pandemic in 2020, and 70,655 patients that comprised the control cohort who attended for outpatient radiology the same period in 2019.

MAIN OUTCOME MEASURESThe risk of developing clinically significant covid-19 infection within 28-days of attending a radiological examination. Covid-19 infection rates for the 2020 cohort were compared against a control group who attended in 2019.

RESULTS84 positive SARS-CoV-2 tests were temporally associated with 47,340 radiological examinations across two hospitals in 2020. This low infection rate was higher than the 2019 control cohort; OR 2.507 (1.766 - 3.559) and equates to an approximate 1 positive covid-19 infection per 1000 radiology investigations.

CONCLUSIONSOur data suggests that attending hospitals for outpatient radiological investigations during the pandemic is associated with a very small absolute risk of acquiring clinically significant covid-19 infection. It is unlikely that this risk is directly attributable to radiology attendance, considering the reasons leading individuals to attend hospitals during the pandemic, the true attributable risk will likely be even lower.

TRIAL REGISTRATIONClinicalTrials.gov NCT04544176


title: Comparing Interventions Aimed at Improving Influenza Vaccination Coverage Among Vulnerable Populations: A Systematic Review and Meta-Analysis Protocol

abstract:
BackgroundInfluenza is a major contributor to global disease burden. Vaccination recommendations specifically target populations at increased risk of serious influenza sequelae. The aim of this study is to conduct a systematic review and meta-analysis to evaluate the effectiveness of different quality improvement interventions to increase vaccination rates in high-risk populations.

MethodsRandomized and nonrandomized studies with concurrent control groups will be identified. Interventions to increase vaccination rates will be categorized by strategy type. Overall intervention effects will be calculated using random effects models. Study quality will be assessed using a modified Cochrane Risk of Bias tool.

category: primary care research


title: Polygenic risk scores for psychiatric, inflammatory, and cardio-metabolic traits and diseases highlight possible genetic overlaps with suicide attempt and treatment-emergent suicidal ideation

abstract:
Suicide is the second leading cause of death among young people. Genetics may contribute to suicidal phenotypes and their co-occurrence in other psychiatric and medical conditions. Our study aimed to investigate the association of polygenic risk scores (PRSs) for 22 psychiatric, inflammatory, and cardio-metabolic traits and diseases with suicide attempt (SA) or treatment-worsening/emergent suicidal ideation (TWESI).

PRSs were computed based on summary statistics of genome-wide association studies. Regression analyses were performed between PRSs and SA or TWESI in four clinical cohorts, including up to 3,834 individuals, and results were meta-analyzed across samples. Stratified genetic covariance analyses were performed to investigate the biology underlying cross-phenotype PRS associations. After Bonferroni correction, PRS for major depressive disorder (MDD) was positively associated with SA (p=1.7e-4). Nominal associations were shown between PRSs for coronary artery disease (CAD) (p=4.6e-3) or loneliness (p=0.009) and SA, PRSs for MDD or CAD and TWESI (p=0.033 and p=0.032, respectively). Genetic covariance between MDD and SA was shown in 35 gene sets related to drugs having anti-suicidal effects.

A higher genetic liability for MDD may underlie a higher risk of SA. Further, but milder, possible modulatory factors are genetic risk for loneliness and CAD.

category: psychiatry and clinical psychology


title: Age-related changes in physiology in individuals with bipolar disorder

abstract:
ObjectivesIndividuals with bipolar disorder have reduced life expectancy and may experience accelerated biological ageing. In individuals with bipolar disorder and healthy controls, we examined differences in age-related changes in physiology.

MethodsUK Biobank recruited >500,000 participants, aged 37-73, between 2006-2010. Generalised additive models were used to examine associations between age and grip strength, cardiovascular function, body composition, lung function and bone mineral density. Analyses were conducted separately in males and females with bipolar disorder compared to healthy controls.

ResultsAnalytical samples included up to 272,462 adults (mean age = 56.04 years, SD = 8.15; 49.51% females). We found statistically significant differences between bipolar disorder cases and controls for grip strength, blood pressure, pulse rate and body composition, with standardised mean differences of up to -0.238 (95% CI -0.282 to -0.193). There was limited evidence of differences in lung function, heel bone mineral density or arterial stiffness. Case-control differences were most evident for age-related changes in cardiovascular function (in both sexes) and body composition (in females). These differences did not uniformly narrow or widen with age and differed by sex. For example, the difference in systolic blood pressure between male cases and controls was -1.3 mmHg at age 50 and widened to -4.7 mmHg at age 65. Diastolic blood pressure in female cases was 1.2 mmHg higher at age 40 and -1.2 mmHg lower at age 65.

ConclusionsDifferences in ageing trajectories between bipolar disorder cases and healthy controls were most evident for cardiovascular and body composition measures and differed by sex.


title: Factors influencing COVID rates at local authority level and contribution of variation in vaccine coverage

abstract: We have undertaken a piece of rapid analysis of the most recent COVID-19 weekly rates to examine commonalities across areas with rates exceeding twice the national average. Our preliminary findings point towards an association between higher case rates and deprivation with implications for health inequalities. Furthermore, we also observed an association between higher case rates and lower rates of vaccination. More analysis is needed to further explore these linkages and help fuel what should be an urgent narrative around the need to tackle health inequalities in the COVID era.


title: Chronic cluster headache: a study of the telencephalic and cerebellar cortical thickness

abstract: Previous studies on brain morphological alterations in chronic cluster headache revealed inconsistent findings. The present cross-sectional explorative study determined telencephalic and cerebellar cortex thickness alterations in a relatively wide sample of chronic cluster headache patients (n=28) in relation to matched healthy individuals. The combination of two highly robust state-of-the-art approaches for thickness estimation (Freesurfer and CERES) with an unbiased functional characterization of the abnormal regions, revealed two main results. First, chronic cluster headache patients show cortical thinning in the right middle cingulate cortex and the left posterior insula. This indicates abnormalities in key-regions of pain processing areas, in particular in regions belonging to the spino-thalamic-cortical tract and primarily involved in the sensory-motor aspects of nociception. Second, chronic cluster headache patients present cortical thinning in the left anterior superior temporal sulcus and the left collateral/lingual sulcus, suggesting neuroplastic maladaptations in areas possibly involved in social cognition, which may promote psychiatric comorbidity, frequently observed in these patients.


title: Sleep, pain, and neurodegeneration: A Mendelian randomization study

abstract:
ObjectiveTo examine whether sleep and pain-related traits have a causal effect on the risk of neurodegeneration.

DesignTwo-sample Mendelian randomization using an inverse-variance weighted (IVW) estimate of the summary effect estimates.

SettingGenetic data on sleep and pain-related traits and neurodegenerative disorders (NDD) from various cohorts comprising individuals predominantly of European ancestry.

ParticipantsParticipants from the International Sleep Genetic Epidemiology Consortium (ISGEC), UK Biobank sleep and chronotype research group, International Genomics of Alzheimers patients (IGAP), project MinE, International Age-related Macular Degeneration Consortium (IAMDGC), International Multiple Sclerosis Genetics Consortium (IMSGC), International Parkinsons Disease Genomics Consortium (IPDGC)

ExposuresSelf-reported chronotype (CHR), morning preference (MP), insomnia symptoms (INS), sleep duration (SP), short sleep (SS), long sleep (LS), and multisite chronic pain (MCP)

Main outcome measuresAge-related macular degeneration (AMD), Alzheimers disease (AD), Amyotrophic lateral sclerosis (ALS), Multiple sclerosis (MS), and Parkinsons disease (PD)

ResultsWe considered a threshold of P=0.00142 as significant accounting for multiple testing, and P<0.05 was considered to be suggestive evidence for a potential association. Using direct MR, MP was observed as the strongest risk factor for AMD (ORIVW = 1.19, 95% CI 1.08, 1.32, P = 0.00073). We observed suggestive evidence of influence of different sleep traits on neurodegeneration: CHR on AMD (ORIVW = 1.27, 95% CI 1.08, 1.49, P = 0.0034), SS on AD (ORIVW 1.26, 95% CI 1.08, 1.46, P = 0.0044), and INS on ALS (ORIVW 1.55, 95% CI 1.12, 2.14, P = 0.0123). The association of SS with AD was, however, lost after the exclusion of overlapping UKB samples. Using pain as exposure, our study failed to observe any role of pain in neurodegeneration. Results were largely robust to reverse causal analyses and sensitivity analyses accounting for horizontal pleiotropy.

ConclusionsOur study highlighted the role of morning preference as a risk factor for AMD and provided suggestive evidence of different sleep traits on a wide spectrum of neurodegenerative diseases.


title: Proteome-wide Mendelian randomization identifies causal links between blood proteins and severe COVID-19

abstract: The COVID-19 pandemic death toll now surpasses two million individuals and there is a need for early identification of individuals at increased risk of mortality. Host genetic variation partially drives the immune and biochemical responses to COVID-19 that lead to risk of mortality. We identify and prioritise blood proteins and biomarkers that may indicate increased risk for severe COVID-19, via a proteome Mendelian randomization approach by collecting genome-wide association study (GWAS) summary statistics for >4,000 blood proteins. After multiple testing correction, troponin I3, cardiac type (TNNI3) had the strongest effect (odds ratio (O.R.) of 6.86 per standard deviation increase in protein level), with proteinase 3 (PRTN3) (O.R.=2.48), major histocompatibility complex, class II, DQ alpha 2 (HLA-DQA2) (O.R.=2.29), the C4A-C4B heterodimer (O.R.=1.76) and low-density lipoprotein receptor-related protein associated protein 1 (LRPAP1) (O.R.=1.73) also being associated with higher odds of severe COVID-19. Conversely, major histocompatibility complex class I polypeptide-related sequence A (MHC1A) (O.R.=0.6) and natural cytotoxicity triggering receptor 3 (NCR3) (O.R.=0.46) were associated with lower odds. These proteins are involved in heart muscle contraction, natural killer and antigen presenting cells, and the major histocompatibility complex. Based on these findings, it may be possible to better predict which patients may develop severe COVID-19 and to design better treatments targeting the implicated mechanisms.

category: genetic and genomic medicine


title: Functional Antibodies in COVID-19 Convalescent Plasma

abstract: In the absence of an effective vaccine or monoclonal therapeutic, transfer of convalescent plasma (CCP) was proposed early in the SARS-CoV-2 pandemic as an easily accessible therapy. However, despite the global excitement around this historically valuable therapeutic approach, results from CCP trials have been mixed and highly debated. Unlike other therapeutic interventions, CCP represents a heterogeneous drug. Each CCP unit is unique and collected from an individual recovered COVID-19 patient, making the interpretation of therapeutic benefit more complicated. While the prevailing view in the field would suggest that it is administration of neutralizing antibodies via CCP that centrally provides therapeutic benefit to newly infected COVID-19 patients, many hospitalized COVID-19 patients already possess neutralizing antibodies. Importantly, the therapeutic benefit of antibodies can extend far beyond their simple ability to bind and block infection, especially related to their ability to interact with the innate immune system. In our work we deeply profiled the SARS-CoV-2-specific Fc-response in CCP donors, along with the recipients prior to and after CCP transfer, revealing striking SARS-CoV-2 specific Fc-heterogeneity across CCP units and their recipients. However, CCP units possessed more functional antibodies than acute COVID-19 patients, that shaped the evolution of COVID-19 patient humoral profiles via distinct immunomodulatory effects that varied by pre-existing SARS-CoV-2 Spike (S)-specific IgG titers in the patients. Our analysis identified surprising influence of both S and Nucleocapsid (N) specific antibody functions not only in direct antiviral activity but also in anti-inflammatory effects. These findings offer insights for more comprehensive interpretation of correlates of immunity in ongoing large scale CCP trials and for the design of next generation therapeutic design.


title: Efficacy of high-pressure balloon for the treatment of arteriovenous fistula stenosis: a meta-analysis

abstract:
ObjectiveThe objective of the present study was to compare the effectiveness of high-pressure balloon (HPB) versus conventional balloon angioplasty (BA) in treating arteriovenous fistula (AVF) stenosis.

Materials and MethodsA meta-analysis was conducted using data acquired from PubMed, EMBASE, the Cochrane Library, SinoMed, CNKI, WanFang and VIP databases from the time the databases were established to November 2020. All analyses included in the studies comprised the subgroups of HPB and BA. The patency of AVF was compared between the two groups at 3 months, 6 months and 12 months after operation.

ResultsNine studies comprising 475 patients were included in the meta-analysis. The pooled results revealed that stenosis rate of AVFs treated with HPB was significantly lower than that of AVFs treated with conventional balloon at 3 months (OR= 0.37, 95% CI 0.21 to 0.67, p<0.001) and 6 months after operation (OR= 0.33, 95% CI 0.15 to 0.75, p=0.008). In addition, the technical success rate of HPB groups was high (OR= 0.14, 95% CI 0.05 to 0.35, p<0.001). However, no significant difference was observed between the experimental and control groups at 12 months after operation (OR= 0.61, 95% CI 0.29 to 1.25, p=0.18). No significant publication bias was observed in the analyses.

ConclusionHPB is a potential primary option for the treatment of AVF stenosis, with a lower 3- and 6-month stenosis rate than BA. However, the long-term effect of HPB was not satisfactory; therefore, further research should be conducted to elucidate the relationship between the two groups.

category: cardiovascular medicine


title: Point-of-care ultrasonography for risk stratification of non-critical suspected COVID-19 patients on admission (POCUSCO): a prospective binational study

abstract:
BackgroundLung point-of-care ultrasonography (L-POCUS) is highly effective in detecting pulmonary peripheral patterns and may allow early identification of patients who are likely to develop an acute respiratory distress syndrome (ARDS). We hypothesized that L-POCUS performed during the initial examination would identify non-severe COVID-19 patients with a high risk of getting worse.

MethodsPOCUSCO was a prospective, multicenter study. Non-critical adult patients who were admitted to the emergency department (ED) for suspected or confirmed COVID-19 were included and had L-POCUS performed within 48 hours following admission. The severity of lung damage was assessed using the L-POCUS score based on 36 points for ARDS. The primary outcome was the rate of patients requiring intubation or who died within 14 days following inclusion.

ResultsAmong 296 participating patients, 8 (2.7%) had primary outcome. The area under the curve (AUC) of the receiver operating characteristic of L-POCUS was 0.80 [95%CI:0.60-0.94]. The score values which achieved a sensibility > 95% in defining low-risk patients and a specificity > 95% in defining high-risk patients were <1 and [≥]16, respectively. The rate of patients with an unfavorable outcome was 0/95 (0%[95%CI:0-3.9]) for low-risk patients (score=0) versus 4/184 (2.17%[95%CI:0.8-5.5]) for intermediate-risk patients (score 1-15) and 4/17 (23.5%[95%CI:11.4-42.4]) for high-risk patients (score [≥]16). In patients with confirmed COVID-19 (n=58), the AUC of L-POCUS was 0.97 [95%CI:0.92-1.00].

ConclusionsL-POCUS allows risk-stratification of patients with suspected or confirmed COVID-19. These results should be confirmed in a population with a higher risk of an unfavorable outcome.

Trial registration numberNCT04338100

category: emergency medicine


title: Early-life enteric infection and enteropathy markers are associated with changes in adipokine, apolipoprotein and cytokine profiles later in childhood consistent with those of an adverse cardiometabolic disease risk profile in a Peruvian birth cohort.

abstract:
BackgroundMetabolic syndrome is a cluster of risk factors for cardiovascular disease thought to afflict over a billion people worldwide and is increasingly being identified in younger age groups and socio-economically disadvantaged settings in the global south. Enteropathogen exposure and environmental enteropathy in infancy may lead to metabolic syndrome by disrupting the metabolic profile in a way that is detectable in cardiometabolic markers later in childhood.

Methods217 subjects previously enrolled in a birth cohort in Amazonian Peru were followed up annually from ages 2 to 5 years. Blood samples collected in later childhood were analyzed for a panel of 37 cardiometabolic biomarkers, including adipokines, apolipoproteins, cytokines, and other analytes. These were matched to extant early-life markers of enteropathy ascertained between birth and 2 years of age. Multivariate and multivariable regression models were fitted to test for associations adjusting for confounders.

ResultsFecal and urinary markers of intestinal permeability and inflammation (myeloperoxidase, lactulose and mannitol) measured from birth to 2 years of age were independently associated with later serum concentrations of soluble CD40-ligand, a proinflammatory cytokine correlated with adverse metabolic outcomes. Fecal myeloperoxidase was also strongly, directly associated with later levels of the anti-inflammatory adipocytokine omentin-1. Cumulative enteric protozoa exposure before 2 years of age showed stronger associations with later cardiometabolic markers than enteric viruses and bacteria and overall diarrheal episodes.

ConclusionEarly-life markers of enteric infection and enteropathy were associated with numerous changes in adipokine, apolipoprotein and cytokine profiles later in childhood consistent with those of an adverse cardiometabolic disease risk profile in this Peruvian birth cohort. Markers of intestinal permeability and inflammation measured in urine (lactulose, mannitol) and stool (myeloperoxidase, protozoal infections) during infancy, may predict disruptions to cytokine and adipocytokine production in later childhood that are precursors to metabolic syndrome in adulthood. Chronic enteric infections, such as by protozoan pathogens, may be more important drivers of these changes than symptomatic diarrhea or growth faltering.

FundingBill & Melinda Gates Foundation OPP1066146 and OPP1152146.

category: endocrinology


title: Factors associated with maternal tetanus vaccination in Myanmar: An analysis of Demographic and Health Survey data

abstract:
BackgroundTetanus toxoid vaccination is a life-saving maternal and child health intervention. Understanding gaps in maternal vaccination coverage is key to informing progress towards universal health coverage. We assessed maternal tetanus vaccination coverage in Myanmar and investigated factors associated with being unvaccinated.

MethodWe analysed 2015-16 Demographic and Health Survey data including women aged 15-49 years with at least one childbirth in the last five years. The outcome was self-reported receipt of tetanus vaccine at least once during the last pregnancy. We used logistic regression models to assess factors associated with being unvaccinated.

ResultsOverall maternal tetanus vaccination coverage was 85.7%. Sub-national coverage was lowest in the predominantly ethnic minority states of Shan, Kayin, and Chin at 69.6%, 77.4%, and 79.9%, respectively. Factors associated with a lack of vaccination were: not receiving antenatal care (odds ratio (OR): 18.99, 95% confidence interval (CI): 14.21, 25.39); receiving antenatal care at home (OR: 2.05, 95% CI: 1.46, 2.88), private and non-governmental organization clinics (OR: 2.88, 95% CI: 1.81, 4.58, compared to public facilities); and not wanting to go to a health facility alone (OR: 1.53, 95% CI: 1.14, 2.06). Higher educational attainment was associated with lower odds of being unvaccinated (OR: 0.48, 95% CI: 0.32, 0.70 for secondary relative to no education).

InterpretationWe identified regional, structural, and individual differences in maternal tetanus vaccination coverage. Achieving universal coverage of maternal tetanus vaccination will largely depend on the ability to provide accessible antenatal care to most women who do not currently receive it.


title: Sex differences in brain development in fetuses and infants who are at low or high likelihood for autism

abstract:
BackgroundIt is unknown whether the neural underpinnings of autism are present in utero. In addition, it is unclear whether typical neural sexual differentiation, which is associated with the development of autism, is evident in utero. We longitudinally investigated fetal and infant sex differences in brain structure and function, and differences in brain development in those at low and high likelihood for autism. Here, we use the term  typical interchangeably with the term  low-autism likelihood.

MethodsParticipants were longitudinally studied in utero first at 30-33 weeks of gestation, and then as infants 8-12 weeks after birth. We compared total brain volumes and resting-state functional connectivity between 15 female and 15 male low-autism likelihood fetuses (defined as having no first degree autistic relative). We also compared the brain structure and function of these 30 fetuses to a rare group of 11 fetuses (5 females and 6 males) who had an autistic mother or sibling, and therefore a higher likelihood of developing autism. Although a small sample, the high-autism likelihood group are reported as they are challenging to recruit. Additionally, we correlated sex differences in functional connectivity with autism likelihood group differences across the fetal and infant brains.

ResultsThere was a group-by-sex interaction in fetal total brain volume. Typical males, on average, showed faster total brain volume growth in the perinatal period than typical females. The high-autism likelihood group showed lower resting-state functional connectivity at both time-points compared to the typical group, and regions indicating sex differences overlapped with those associated with high-autism likelihood group differences in functional connectivity.

ConclusionsIn utero sexual differentiation of brain structure was more pronounced in fetuses with a high likelihood for autism. Moreover, sexual differentiation of the fetal and infant brain may overlap with the neural development of autism.


title: Exploring the short-term role of particulate matter in the COVID-19 outbreak in USA cities

abstract: The role of particulate matter (PM) in the COVID-19 pandemic is currently being discussed by the scientific community. Long-term (years) exposure to PM is known to affect human health by increasing susceptibility to viral infections as well as to the development of respiratory and cardiovascular symptoms. In the short-term (days to months), PM has been suggested to assist airborne viral transmission. However, confounding factors such as urban mobility prevent causal conclusions. In this study, we explore short-term relationships between PM concentrations and the evolution of COVID-19 cases in a number of cities in the United States of America. We focus on the role of PM in facilitating viral transmission in early stages of the pandemic. We analyzed PM concentrations in two particle size ranges, < 2.5 {micro}m, and between 10 and 2.5 {micro}m (PM2.5 and PM10 respectively) as well as carbon monoxide (CO) and nitrogen dioxide (NO2). Granger causality analysis was employed to identify instantaneous and lagged effects of pollution in peaks of COVID-19 new daily cases in each location. The effect of pollution in shaping the disease spread was evaluated by correlating the logistic growth rate of accumulated cases with pollutants concentrations for a range of time lags and accumulation windows. PM2.5 shows the most significant results in Granger causality tests in comparison with the other pollutants. We found a strong and significant association between PM2.5 concentrations and the growth rate of accumulated cases between the 1st and 18th days after the report of the infection, peaking at the 8th day. By comparing results of PM2.5 with PM10, CO and NO2 we rule out confounding effects associated with mobility. We conclude that PM2.5 is not a first order effect in the cities considered; however, it plays a significant role in facilitating the COVID-19 transmission. We estimate that the growth rate of COVID-19 cases would be risen by 12.5% if PM2.5 is increased from 25 to 35 {micro}g m-3.


title: High-resolution epigenome analysis in nasal samples derived from children with respiratory viral infections reveals striking changes upon SARS-CoV-2 infection

abstract:
BackgroundDNA methylation patterns of the human genome can be modified by environmental stimuli and provide dense information on gene regulatory circuitries. We studied genome-wide DNA methylation in nasal samples from infants (<6 months) applying whole-genome bisulfite sequencing (WGBS) to characterize epigenome response to 10 different respiratory viral infections including SARS-CoV-2.

ResultsWe identified virus-specific differentially methylated regions (vDMR) with human metapneumovirus (hMPV) and SARS-CoV-2 followed by Influenza B (Flu B) causing the weakest vs. strongest epigenome response with 496 vs. 78541 and 14361 vDMR, respectively. We found a strong replication rate of FluB (52%) and SARS-CoV-2 (42%) vDMR in independent samples indicating robust epigenome perturbation upon infection. Among the FluB and SARS-CoV-2 vDMRs, around 70% were hypomethylated and significantly enriched among epithelial cell-specific regulatory elements whereas the hypermethylated vDMRs for these viruses mapped more frequently to immune cell regulatory elements, especially those of the myeloid lineage. The hypermethylated vDMRs were also enriched among genes and genetic loci in monocyte activation pathways and monocyte count. Finally, we perform single-cell RNA-sequencing characterization of nasal mucosa in response to these two viruses to functionally analyze the epigenome perturbations. Which supports the trends we identified in methylation data and highlights and important role for monocytes.

ConclusionsAll together, we find evidence indicating genetic predisposition to innate immune response upon a respiratory viral infection. Our genome-wide monitoring of infant viral response provides first catalogue of associated host regulatory elements. Assessing epigenetic variation in individual patients may reveal evidence for viral triggers of childhood disease.


title: Predicting the Efficacy of COVID-19 Convalescent Plasma Donor Units with the Lumit Dx anti-Receptor Binding Domain Assay.

abstract:
BackgroundThe novel coronavirus SARS-CoV2 that causes COVID-19 has resulted in the death of more than 2.5 million people, but no cure exists. Although passive immunization with COVID-19 convalescent plasma (CCP) provides a safe and viable therapeutic option, the selection of optimal units for therapy in a timely fashion remains a barrier.

Study design and methodsSince virus neutralization is a necessary characteristic of plasma that can benefit recipients, the neutralizing titers of plasma samples were measured using a retroviral-pseudotype assay. Binding antibody titers to the spike (S) protein were also determined by a clinically available serological assay (Ortho-Vitros total IG), and an in-house ELISA. The results of these assays were compared to a measurement of antibodies directed to the receptor binding domain (RBD) of the SARS-CoV2 S protein (Promega Lumit Dx).

ResultsAll measures of antibodies were highly variable, but correlated, to different degrees, with each other. However, the anti-RBD antibodies correlated with viral neutralizing titers to a greater extent than the other antibody assays.

DiscussionOur observations support the use of an anti-RBD assay such as the Lumit Dx assay, as an optimal predictor of the neutralization capability of CCP.


title: What level of neutralising antibody protects from COVID-19? .

abstract: Both previous infection and vaccination have been shown to provide potent protection from COVID-19. However, there are concerns that waning immunity and viral variation may lead to a loss of protection over time. Predictive models of immune protection are urgently needed to identify immune correlates of protection to assist in the future deployment of vaccines. To address this, we modelled the relationship between in vitro neutralisation levels and observed protection from SARS-CoV-2 infection using data from seven current vaccines as well as convalescent cohorts. Here we show that neutralisation level is highly predictive of immune protection. The 50% protective neutralisation level was estimated to be approximately 20% of the average convalescent level (95% CI = 14-28%). The estimated neutralisation level required for 50% protection from severe infection was significantly lower (3% of the mean convalescent level (CI = 0.7-13%, p = 0.0004). Given the relationship between in vitro neutralization titer and protection, we then used this to investigate how waning immunity and antigenic variation might affect vaccine efficacy. We found that the decay of neutralising titre in vaccinated subjects over the first 3-4 months after vaccination was at least as rapid as the decay observed in convalescent subjects. Modelling the decay of neutralisation titre over the first 250 days after immunisation predicts a significant loss in protection from SARS-CoV-2 infection will occur, although protection from severe disease should be largely retained. Neutralisation titres against some SARS-CoV-2 variants of concern are reduced compared to the vaccine strain and our model predicts the relationship between neutralisation and efficacy against viral variants. Our analyses provide an evidence-based prediction of SARS-CoV-2 immune protection that will assist in developing vaccine strategies to control the future trajectory of the pandemic.


title: Antibody response to SARS-CoV-2 vaccination is extremely vivacious in subjects with previous SARS-CoV-2 infection

abstract:
BackgroundThe SARS-CoV-2 pandemic calls for rapid actions, now principally oriented to a world-wide vaccination campaign.

In this study we verified if, in individuals with a previous SARS-CoV-2 infection, a single dose of mRNA vaccine would be immunologically equivalent to a full vaccine schedule in naive individuals.

MethodsHealth care workers (184) with a previous SARS-CoV-2 infection were sampled soon before the second dose of vaccine and between 7 and 10 days after the second dose, the last sampling time was applied to SARS-CoV-2 naive individuals, too.

Antibodies against SARS-CoV-2 were measured using Elecsys(R) Anti-SARS-CoV-2 S immunoassay.

The study was powered for non-inferiority. We used non parametric tests and Pearson correlation test to perform inferential analysis.

ResultsAfter a single vaccine injection, the median titer of specific antibodies in individuals with previous COVID-19 was 30,527 U/ml (IQR 19,992-39,288) and in subjects with previous SARS-CoV-2 asymptomatic infection was 19,367.5 U/ml (IQR 14,688-31,353) (P=0.032). Both results were far above the median titer in naive individuals after a full vaccination schedule: 1,974.5 U/ml (IQR 895-3,455) (P<0.0001). Adverse events after vaccine injection were more frequent after the second dose of vaccine (mean 0.95, 95%CI from 0.75 to 1.14 versus mean 1.91, 95%CI from 1.63 to 2.19)(P<0.0001) and in exposed compared to naive (mean 1.63; 95%CI from 1.28 to 1.98 versus mean 2.35; 95%CI from 1.87 to 2.82)(P=0.015).

ConclusionIn SARS-CoV-2 naturally infected individuals a single mRNA vaccine dose seems sufficient to reach immunity. Modifying current dosing schedules would speed-up vaccination campaigns.


title: Prognosis of Acute Ischaemic Stroke in Cancer Patients: A National Inpatient Sample Study

abstract:
Background and PurposeWhilst cancer is a risk factor for acute ischaemic stroke (AIS), its impact on AIS prognosis between metastatic and non-metastatic (MC and NMC) disease is poorly understood. Furthermore, the receipt of intravenous thrombolysis (IVT) and endovascular thrombectomy (ET) and their outcomes is poorly researched.

MethodsAIS admissions from the National Inpatient Sample (NIS) were included (October 2015-December 2017). Multivariable logistic regressions adjusting for a wide range of confounders analysed the relationship between NMC and MC and AIS in-hospital outcomes (mortality, prolonged hospitalisation >4 days and routine home discharge). Interaction terms with IVT and ET were also computed to explore their impact amongst cancer patients.

Results221,249 records representative of 1,106,045 admissions were included. There were 38,855 (3.51%) patients with co-morbid cancers: NMC=53.78% and MC=46.22%. NMC was associated with 23% increased odds of in-hospital mortality (odds ratio (95% confidence interval) = 1.23 (1.07-1.42)), which was mainly driven by pancreatic and respiratory cancers. This association was entirely offset by both IVT and ET. MC was associated with 2-fold increased odds of in-hospital mortality (2.16 (1.90-2.45)), which was mainly driven by respiratory, pancreatic and colorectal cancers. This association was only offset by ET. Both NMC and MC were significantly associated with prolonged hospitalisation and decreased odds of routine discharge.

ConclusionsCancer patients are at higher odds of acute adverse outcomes after AIS and warrant robust primary prevention. IVT and ET improve these outcomes and should thus be offered routinely unless otherwise contraindicated in this group of stroke patients.


title: Prediction of COVID-19 mortality among hospitalized patients in Sudan

abstract:
BackgroundCOVID-19 was primarily reported in China. The mortality rate across countries had ranged from 1% up to more than 10% and it is underestimated in some countries. Advanced age is the most frequently reported factor associated to mortality. Other factors were the presence of comorbidities such as diabetes mellitus, hypertension and obesity. Several models for mortality prediction had been developed to assist in improving the prognosis. The aim of our study was to assess the factors related to mortality among COVID-19 patients and develop a prediction model based on these factors.

MethodsA retrospective cohort study assessed the factors related to the mortality among COVID-19 patients who attended Imperial Hospital isolation centre on November-December, 2020, Khartoum, Sudan. Statistical tests performed were chi-square test, odds ratio and regression to develop the prediction model. Tests were considered statistically significant when p < 0.05.

Results105 patients were studied. 29% of the patients were deceased, while, 71% were discharged alive. A statistically significant association was found between the age and severity with regards to mortality rate (p=0.034, 0.018 respectively). The model equation for mortality prediction: Mortality = -14.724+ (1.387* Age) + (-0.323* Gender) + (1.814* Admission) + (0.193* Ischemic Heart Disease) + (-0.369* Fever) + (1.595* Cough) + (1.953* Complications) + (0.149* Duration of hospitalization) + (0.999* Enoxaparin dose).

ConclusionsAge, admission ward, cough and enoxaparin dose were statistically significant predictors for COVID-19 mortality (p= 0.014, 0.011, 0.015, 0.006 respectively).


title: Autologous cardiac micrografts as support therapy to coronary artery bypass surgery

abstract:
ObjectivesCardio-regenerative cell therapies offer additional biologic support to coronary artery bypass surgery (CABG) for treating the myocardium suffering from or damaged by ischemia. This phase 1, open-label study assessed the safety and feasibility of epicardial transplantation of atrial appendage micrografts (AAMs) in patients undergoing CABG surgery.

MethodsTwelve consecutive patients destined for CABG surgery were included in the study. Six patients received AAMs during their operation and six patients were CABG-operated without AAMs treatment. Data from 30 elective CABG patients was collected for a conjunctive control group. The AAMs were processed during the operation from a biopsy collected from the right atrial appendage. They were delivered epicardially on the infarct scar site identified in preoperative CMR. The primary outcome measures at six-months follow-up were i) patient safety in terms of hemodynamic and cardiac function over time and ii) feasibility of therapy administration in a clinical setting. Secondary outcome measures were left ventricular wall thickness, change in myocardial scar tissue volume, changes in left ventricular ejection fraction, plasma concentrations of N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels, NYHA class, number of days in hospital and changes in the quality of life.

ResultsEpicardial transplantation of AAMs was safe and feasible to be performed in conjunction with CABG surgery. CMR demonstrated an increase in viable cardiac tissue at the infarct site in patients receiving AAMs treatment.

ConclusionTransplantation of AAMs shows good clinical applicability as adjuvant therapy to cardiac surgery and can additionally serve as a delivery platform for cardiac gene therapies.

Trial RegistrationClinicalTrials.gov identifier NCT02672163


title: Interventions to control nosocomial transmission of SARS-CoV-2: a modelling study

abstract:
BackgroundEmergence of more transmissible SARS-CoV-2 variants requires more efficient control measures to limit nosocomial transmission and maintain healthcare capacities during pandemic waves. Yet, the relative importance of different strategies is unknown.

MethodsWe developed an agent-based model and compared the impact of personal protective equipment (PPE), screening of healthcare workers (HCWs), contact tracing of symptomatic HCWs, and restricting HCWs from working in multiple units (HCW cohorting) on nosocomial SARS-CoV-2 transmission. The model was fit on hospital data from the first wave in the Netherlands (February until August 2020) and assumed that HCWs used 90% effective PPE in COVID-19 wards and self-isolated at home for seven days immediately upon symptom onset. Intervention effects on the effective reproduction number (RE), HCW absenteeism and the proportion of infected individuals among tested individuals (positivity rate) were estimated for a more transmissible variant.

ResultsIntroduction of a variant with 56% higher transmissibility increased - all other variables kept constant - RE from 0.4 to 0.65 (+63%) and nosocomial transmissions by 303%, mainly because of more transmissions caused by pre-symptomatic patients and HCWs. Compared to baseline, PPE use in all hospital wards (assuming 90% effectiveness) reduced RE by 85% and absenteeism by 57%. Screening HCWs every three days with perfect test sensitivity reduced RE by 67%, yielding a maximum test positivity rate of 5%. Screening HCWs every three or seven days assuming time-varying test sensitivities reduced RE by 9% and 3%, respectively. Contact tracing reduced RE by at least 32% and achieved higher test positivity rates than screening interventions. HCW cohorting reduced RE by 5%. Sensitivity analyses for 50% and 70% effectiveness of PPE use did not change interpretation.

ConclusionsIn response to the emergence of more transmissible SARS-CoV-2 variants, PPE use in all hospital wards might still be most effective in preventing nosocomial transmission. Regular screening and contact tracing of HCWs are also effective interventions, but critically depend on the sensitivity of the diagnostic test used.


title: A human multisystem disorder with autoinflammation, leukoencephalopathy and hepatopathy is caused by mutations in C2orf69

abstract:
BackgroundDeciphering the function of the many genes previously classified as uncharacterized "open reading frame" (orf) completes our understanding of cell function and its pathophysiology.

MethodsWhole-exome sequencing, yeast 2-hybrid and transcriptome analyses together with molecular characterization are used here to uncover the function of the C2orf69 gene.

ResultsWe identify loss-of-function mutations in the uncharacterized C2orf69 gene in eight individuals with brain abnormalities involving hypomyelination and microcephaly, liver dysfunction and recurrent autoinflammation. C2orf69 contains an N-terminal signal peptide that is required and sufficient for mitochondrial localization. Consistent with mitochondrial dysfunction, patients show signs of respiratory chain defect and a CRISPR-Cas9 knockout cell model of C2orf69 shows comparable respiratory chain defects. Patient-derived cells reveal alterations in immunological signaling pathways. Deposits of PAS-positive material in tissues from affected individuals together with decreased glycogen branching enzyme 1 (GBE1) activity indicate an additional impact of C2orf69 on glycogen metabolism.

ConclusionOur study identifies C2orf69 as an important regulator of human mitochondrial function and suggests an additional influence on other metabolic pathways.

Graphical Abstract

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title: Age-dependent impact of the major common genetic risk factor for COVID-19 on severity and mortality

abstract:
BackgroundThere is considerable variability in COVID-19 outcomes amongst younger adults--and some of this variation may be due to genetic predisposition. We characterized the clinical implications of the major genetic risk factor for COVID-19 severity, and its age-dependent effect, using individual-level data in a large international multi-centre consortium.

MethodThe major common COVID-19 genetic risk factor is a chromosome 3 locus, tagged by the marker rs10490770. We combined individual level data for 13,424 COVID-19 positive patients (N=6,689 hospitalized) from 17 cohorts in nine countries to assess the association of this genetic marker with mortality, COVID-19-related complications and laboratory values. We next examined if the magnitude of these associations varied by age and were independent from known clinical COVID-19 risk factors.

FindingsWe found that rs10490770 risk allele carriers experienced an increased risk of all-cause mortality (hazard ratio [HR] 1{middle dot}4, 95% confidence interval [CI] 1{middle dot}2-1{middle dot}6) and COVID-19 related mortality (HR 1{middle dot}5, 95%CI 1{middle dot}3-1{middle dot}8). Risk allele carriers had increased odds of several COVID-19 complications: severe respiratory failure (odds ratio [OR] 2{middle dot}0, 95%CI 1{middle dot}6-2{middle dot}6), venous thromboembolism (OR 1{middle dot}7, 95%CI 1{middle dot}2-2{middle dot}4), and hepatic injury (OR 1{middle dot}6, 95%CI 1{middle dot}2-2{middle dot}0). Risk allele carriers [≤] 60 years had higher odds of death or severe respiratory failure (OR 2{middle dot}6, 95%CI 1{middle dot}8-3{middle dot}9) compared to those > 60 years OR 1{middle dot}5 (95%CI 1{middle dot}3-1{middle dot}9, interaction p-value=0{middle dot}04). Amongst individuals [≤] 60 years who died or experienced severe respiratory COVID-19 outcome, we found that 31{middle dot}8% (95%CI 27{middle dot}6-36{middle dot}2) were risk variant carriers, compared to 13{middle dot}9% (95%CI 12{middle dot}6-15{middle dot}2%) of those not experiencing these outcomes. Prediction of death or severe respiratory failure among those [≤] 60 years improved when including the risk allele (AUC 0{middle dot}82 vs 0{middle dot}84, p=0{middle dot}016) and the prediction ability of rs10490770 risk allele was similar to, or better than, most established clinical risk factors.

InterpretationThe major common COVID-19 risk locus on chromosome 3 is associated with increased risks of morbidity and mortality--and these are more pronounced amongst individuals [≤] 60 years. The effect on COVID-19 severity was similar to, or larger than most established risk factors, suggesting potential implications for clinical risk management.

FundingFunding was obtained by each of the participating cohorts individually.


title: Mutation hotspots, geographical and temporal distribution of SARS-CoV-2 lineages in Brazil, February 2020 to February 2021: insights and limitations from uneven sequencing efforts

abstract: The COVID-19 pandemic has already reached approximately 110 million people and it is associated with 2.5 million deaths worldwide. Brazil is the third worst-hit country, with approximately 10.2 million cases and 250 thousand deaths. International efforts have been established to share information about SARS-CoV-2 epidemiology and evolution. However, sequencing facilities and research investments are very heterogeneous across different regions and countries. The understanding of the SARS-CoV-2 evolution plays a significant role in the development of effective strategies for public health and disease management. We aimed to analyze the available and high-quality genome sequences from Brazil between February 2020 and February 2021 to identify mutation hotspots, geographical and temporal distribution of SARS-CoV-2 lineages by using phylogenetics and phylodynamics analyses. We describe heterogeneous and episodic sequencing efforts, the progression of the different lineages along time, evaluating mutational spectra and frequency oscillations derived from the prevalence of novel and specific lineages across different Brazilian regions. We found at least seven major (1-7) and two minor clades (4.2 and 5.3) related to the six most prevalent lineages in the country and described its spatial distribution and dynamics. The emergence and recent frequency shift of lineages (P.1 and P.2) containing mutations of concern in the spike protein (e. g., E484K, N501Y) draws attention due to their association with immune evasion and enhanced receptor binding affinity. Improvements in genomic surveillance are of paramount importance and should be extended in Brazil to better inform policy makers and enable evidence-based decisions to fight the COVID-19 pandemic.


title: Forecasting the COVID-19 epidemic integrating symptom search behavior: an infodemiology study

abstract:
BackgroundPrevious studies have suggested associations between trends of web searches and COVID-19 traditional metrics. It remains unclear whether models incorporating trends of digital searches lead to better predictions.

MethodsAn open-access web application was developed to evaluate Google Trends and traditional COVID-19 metrics via an interactive framework based on principal components analysis (PCA) and time series modelling. The app facilitates the analysis of symptom search behavior associated with COVID-19 disease in 188 countries. In this study, we selected data of eight countries as case studies to represent all continents. PCA was used to perform data dimensionality reduction, and three different time series models (Error Trend Seasonality, Autoregressive integrated moving average, and feed-forward neural network autoregression) were used to predict COVID-19 metrics in the upcoming 14 days. The models were compared in terms of prediction ability using the root-mean-square error (RMSE) of the first principal component (PC1). Predictive ability of models generated with both Google Trends data and conventional COVID-19 metrics were compared with those fitted with conventional COVID-19 metrics only.

FindingsThe degree of correlation and the best time-lag varied as a function of the selected country and topic searched; in general, the optimal time-lag was within 15 days. Overall, predictions of PC1 based on both searched termed and COVID-19 traditional metrics performed better than those not including Google searches (median [IQR]: 1.43 [0.74-2.36] vs. 1.78 [0.95-2.88], respectively), but the improvement in prediction varied as a function of the selected country and timeframe. The best model varied as a function of country, time range, and period of time selected. Models based on a 7-day moving average led to considerably smaller RMSE values as opposed to those calculated with raw data (median [IQR]: 0.74 [0.47-1.22] vs. 2.15 [1.55-3.89], respectively).

InterpretationThe inclusion of digital online searches in statistical models may improve the prediction of the COVID-19 epidemic.

FundingEOSCsecretariat.eu has received funding from the European Unions Horizon Programme call H2020-INFRAEOSC-05-2018-2019, grant Agreement number 831644.

category: health informatics


title: Ensemble Forecasts of Seasonal Dengue Epidemics

abstract: As a common vector-borne disease, dengue fever still remains a lot of challenges to forecast for which the significant distinction of epidemic scale is affected by multiple factors, such as mosquito density, meteorological conditions, geographical environment, travel and so on. To track down the epidemic scale and forecast the remaining time of epidemic season, the population size affected by the epidemic is evaluated before the compartmental model is optimized by assimilation observation with filtering method. In retrospective forecast of dengue pandemic for Guangzhou from 2014-2015 seasons, accurate forecast of dengue cases is generated with an accurate prediction of peak time in all time periods. The real-time forecast system shows a good performance on capturing the trajectory of dengue transmission and scale of epidemic.


title: Outcome of Different Therapeutic Interventions in Mild COVID-19 Patients in a Single OPD Clinic of West Bengal: A Retrospective study

abstract:
IntroductionWith over 87,273,380 cases being reported and 1,899,440 deaths worldwide as of 9th January 2021, Coronavirus disease 2019 (COVID-19) has become the worst-hit pandemic till date. Every day clinicians are bombarded with many new treatment options that claim to be better than the others.

Materials and methodsAfter screening the electronic database of COVID-19 patients retrospectively, 56 patients with mild COVID-19 infection matched the inclusion criteria and were divided into the four following groups - group having used Hydroxychloroquine (HCQ), group using doxycycline (DOX) + Ivermectin (IVR) combination, group receiving only azithromycin (AZ) and, group receiving only symptomatic treatment. The studys primary objective was to see Clinical response of well-being (CRWB) reporting time after initiating treatment onset between the four different treatment arms.

ResultsCRWB did not differ between the four groups receiving four different managements (p-value 0.846). There was significant correlation between blood levels of LDH (p-value 0.001), CRP (p-value 0.03) and D-dimer (p-value 0.04) with CRWB in IVR+DOX group and, between LDH (p-value 0.001), CRP (p-value 0.01) and age (p-value 0.035) with CRWB in the symptomatic management group.

ConclusionMild COVID-19 infection in patients having low-risk to progress can be managed symptomatically without any specific drug intervention.


title: SARS-CoV-2 seroassay optimization and performance in a population with high background reactivity in Mali

abstract: Serological tests are an indispensable tool to understand the epidemiology of the SARS-CoV-2 pandemic, particularly in areas where molecular diagnostics are limited. Poor assay performance may hinder the utility of these tests, including high rates of false-positivity previously reported in sub-Saharan Africa. From 312 Malian samples collected prior to 2020, we measured antibodies to the commonly tested SARS-CoV-2 antigens and four other betacoronaviruses by ELISA, and assessed functional cross-reactivity in a subset by SARS-CoV-2 pseudovirus neutralization assay. We then evaluated the performance of an ELISA developed in the US, using two-antigen SARS-CoV-2 spike protein and receptor-binding domain. To optimize test performance, we compared single and two-antigen approaches using existing assay cutoffs and population-specific cutoffs for Malian control samples (positive and negative). Background reactivity to SARS-CoV-2 antigens was common in pre-pandemic samples compared to US controls (43.4% (135/311) for spike protein, 22.8% (71/312) for RBD, and 33.9% (79/233) for nucleocapsid protein). SARS-CoV-2 reactivity correlated weakly with other betacoronavirus reactivity, varied between Malian communities, and increased with age. No pre-pandemic samples demonstrated functional activity. Regardless of the cutoffs applied, specificity improved using a two-antigen approach. Test performance was optimal using a two-antigen assay with population-specific cutoffs derived from ROC curve analysis [Sensitivity: 73.9% (51.6-89.8), Specificity: 99.4% (97.7-99.9)]. In the setting of high background reactivity, such as sub-Saharan Africa, SARS-CoV-2 serological assays need careful qualification is to characterize the epidemiology of disease, prevent unnecessary harm, and allocate resources for targeted control measures.


title: Rapid detection of SARS-CoV-2 variants of concern identifying a cluster of B.1.1.28/P.1 variant in British Columbia, Canada

abstract: Using a real-time RT-PCR-based algorithm to detect SARS-CoV-2 variants of concern, we rapidly identified 77 variants (57-B.1.1.7, 7-B.1.351, and 13-B.1.1.28/P.1). This protocol enabled our laboratory to screen all SARS-CoV-2 positive samples for variants, and identified a cluster of B.1.1.28/P.1 cases, a variant not previously known to circulate in British Columbia.


title: Prospective validation of smartphone-based heart rate and respiratory rate measurement algorithms

abstract: Measuring vital signs plays a key role in both patient care and wellness, but can be challenging outside of medical settings due to the lack of specialized equipment. In this study, we prospectively evaluated smartphone camera-based techniques for measuring heart rate (HR) and respiratory rate (RR) for consumer wellness use. HR was measured by placing the finger over the rear-facing camera, while RR was measured via a video of the participants sitting still in front of the front-facing camera. In the HR study of 95 participants (with a protocol that included both measurements at rest and post exercise), the mean absolute percent error (MAPE) {+/-} standard deviation of the measurement was 1.6% {+/-} 4.3%, which was significantly lower than the pre-specified goal of 5%. No significant differences in the MAPE were present across colorimeter-measured skin-tone subgroups: 1.8% {+/-} 4.5% for very light to intermediate, 1.3% {+/-} 3.3% for tan and brown, and 1.8% {+/-} 4.9% for dark. In the RR study of 50 participants, the mean absolute error (MAE) was 0.78 {+/-} 0.61 breaths/min, which was significantly lower than the pre-specified goal of 3 breath/min. The MAE was low in both healthy participants (0.70 {+/-} 0.67 breaths/min), and participants with chronic respiratory conditions (0.80 {+/-} 0.60 breaths/min). Our results validate that smartphone camera-based techniques can accurately measure HR and RR across a range of pre-defined subgroups.


title: Performance of popular pulse oximeters compared with simultaneous arterial oxygen saturation or clinical-grade pulse oximetry: a cross-sectional validation study in intensive care patients

abstract:
BackgroundThe demand for pulse oximeters is high in the current COVID-19 pandemic. Despite their popularity, clinical studies to evaluate the reliability in obtaining information on a patients oxygenation status, are lacking.

AimTo evaluate the performance of pulse oximeters under clinical conditions, with arterial blood gas measurement (SaO2) as reference standard.

MethodsWe studied the accuracy of ten top-selling pulse oximeters in Europe and the USA in an intensive care population at the Flevoziekenhuis in Almere, the Netherlands. The studied pulse oximeters were: AFAC FS10D, AGPTEK FS10C, ANAPULSE ANP 100, Cocobear, Contec CMS50D1, HYLOGY MD-H37, Mommed YM101, PRCMISEMED F4PRO, PULOX PO-200, and Zacurate Pro Series 500DL. Adult patients in whom an SaO2 measurement was obtained as part of routine care were asked for inclusion. Directly after obtaining the SaO2 blood sample we obtained the pulse oximeter readings (SpO2) of the investigational devices, in random order. Outcomes were bias (SpO2 - SaO2) mean, root mean square difference (ARMS), mean absolute error (MAE), and accuracy in identifying hypoxemia (SaO2[≤]90%). As a clinical index test, we included a hospital-grade SpO2-monitor.

ResultsIn 35 consecutive patients we obtained 2,258 SpO2-readings and 234 SaO2-samples. Mean bias ranged from -0.6 to -4.8. None of the pulse oximeters had an ARMS[≤]3%, the requirement set by ISO-standards and required for FDA 501(k) clearance. The MAE ranged from 2.3 to 5.1, and 5 out of 10 pulse oximeters met the requirements of [≤]3%. For hypoxemia, negative predictive values were 98-99%. Positive predictive values ranged from 11-30%. Highest accuracy (95%CI) were found for Contec CMS50D1; 91% (86-94) and Zacurate Pro Series 500DL; 90% (85-94). The hospital-grade SpO2-monitor had an ARMS of 3.0 and MAE of 1.9, and an accuracy of 95% (91-97%).

ConclusionDirect-to-consumer pulse oximeters do not meet ISO-standards required for FDA-clearance, but can accurately rule out hypoxemia.


title: Disparities in the pace of biological aging among midlife adults of the same chronological age have implications for future frailty risk and policy

abstract: All humans age, but some age faster than others. Variation in biological aging can be measured in midlife, but the implications of this variation are poorly understood. We tested associations between biological aging and indicators of future frailty risk in the Dunedin cohort of 1037 infants born the same year and followed to age 45. Participants Pace of Aging was quantified by tracking declining function in 19 biomarkers indexing the cardiovascular, metabolic, renal, hepatic, immune, dental, and pulmonary systems across ages 26, 32, 38, and 45 years, in 2019. Participants with faster Pace of Aging had more cognitive difficulties, signs of advanced brain aging, diminished sensory-motor functions, older appearance, and more pessimistic perceptions of aging. People who are aging more rapidly than same-age peers in midlife may prematurely need supports to sustain independence that are usually reserved for older adults. Chronological age does not adequately identify need for such supports.


title: COVID-19 lockdowns may reduce resistance genes diversity in the human microbiome and the need for antibiotics

abstract: 2.Recently, much attention has been paid to the COVID-19 pandemic, yet bacterial resistance to antibiotics remains a serious and unsolved public health problem, which kills thousands of people annually, being an insidious and silent pandemic. In this study, we explored the idea of confinement and the tightening of the hygiene measures to contain the spreading of coronavirus, to simulate the effect that it has on lowering the spreading of pathogenic bacteria in a human network, and on the need to use antibiotics. For that, we used computational biology to generate simulations.


title: Evolutionary and phenotypic characterization of spike mutations in a new SARS-CoV-2 Lineage reveals two Variants of Interest

abstract: Molecular epidemiology of SARS-CoV-2 aims to monitor the appearance of new variants with the potential to change the virulence or transmissibility of the virus. During the first year of SARS-CoV-2 evolution, numerous variants with possible public health impact have emerged. We have detected two mutations in the Spike protein at amino acid positions 1163 and 1167 that have appeared independently multiple times in different genetic backgrounds, indicating they may increase viral fitness. Interestingly, the majority of these sequences appear in transmission clusters, with the genotype encoding mutations at both positions increasing in frequency more than single-site mutants. This genetic outcome that we denote as Lineage B.1.177.637, belongs to clade 20E and includes 12 additional single nucleotide polymorphisms but no deletions with respect to the reference genome (first sequence in Wuhan). B.1.177.637 appeared after the first wave of the epidemic in Spain, and subsequently spread to eight additional countries, increasing in frequency among sequences in public databases. Positions 1163 and 1167 of the Spike protein are situated in the HR2 domain, which is implicated in the fusion of the host and viral membranes. To better understand the effect of these mutations on the virus, we examined whether B.1.177.637 altered infectivity, thermal stability, or antibody sensitivity. Unexpectedly, we observed reduced infectivity of this variant relative to the ancestral 20E variant in vitro while the levels of viral RNA in nasopharyngeal swabs did not vary significantly. In addition, we found the mutations do not impact thermal stability or antibody susceptibility in vaccinated individuals but display a moderate reduction in sensitivity to neutralization by convalescent sera from early stages of the pandemic. Altogether, this lineage could be considered a Variant of Interest (VOI), we denote VOI1163.7. Finally, we detected a sub-cluster of sequences within VOI1163.7 that have acquired two additional changes previously associated with antibody escape and it could be identified as VOI1163.7.V2. Overall, we have detected the spread of a new Spike variant that may be advantageous to the virus and whose continuous transmission poses risks by the acquisition of additional mutations that could affect pre-existing immunity.


title: SARS-CoV-2 antibody prevalence and determinants of six ethnic groups living in Amsterdam, the Netherlands: a population-based cross-sectional study, June-October 2020

abstract:
BackgroundEthnic minorities have higher rates of SARS-CoV-2 diagnoses, but little is known about ethnic differences in past exposure. We aimed to determine whether prevalence and determinants of SARS-CoV-2 exposure varied between six ethnic groups in Amsterdam, the Netherlands.

MethodsParticipants aged 25-79 years enrolled in a population-based prospective cohort were randomly selected within ethnic groups and invited to test for SARS-CoV-2-specific antibodies and answer COVID-19 related questions. We estimated prevalence and determinants of SARS-CoV-2 exposure within ethnic groups using survey-weighted logistic regression adjusting for age, sex and calendar time.

ResultsBetween June 24-October 9, 2020, we included 2497 participants. Adjusted SARS-CoV-2 seroprevalence was comparable between ethnic-Dutch (25/498; 5.5%, 95%CI=3.2-7.9), South-Asian Surinamese (22/451; 4.8%, 95%CI=2.1-7.5), African Surinamese (22/400; 8.2%, 95%CI=3.0-13.4), Turkish (30/408; 7.8%, 95%CI=4.3-11.2) and Moroccan (32/391; 7.0%, 95%CI=4.0-9.9) participants, but higher among Ghanaians (95/327; 26.5%, 95%CI=18.7-34.4). 57.1% of SARS-CoV-2-positive participants did not suspect or were unsure of being infected, which was lowest in African Surinamese (18.2%) and highest in Ghanaians (90.5%). Determinants of SARS-CoV-2 exposure varied across ethnic groups, while the most common determinant was having a household member suspected of infection. In Ghanaians, seropositivity was associated with older age, larger household sizes, living with small children, leaving home to work and attending religious services.

ConclusionsNo remarkable differences in SARS-CoV-2 seroprevalence were observed between the largest ethnic groups in Amsterdam after the first wave of infections. The higher infection seroprevalence observed among Ghanaians, which passed mostly unnoticed, warrants wider prevention efforts and opportunities for non-symptom-based testing.


title: Universal Rule for Covid 19 and Herd Immunity in the US

abstract:
A new Universal rule for Covid 19 data is derived in this paper using the SIR model.

It relates infection and removal rates and is validated by the global Covid 19 data. Over 186,000 data points, from 190 countries and the states of the US, for the period April 1 to December 12, 2020 - fall on a single line, as the Universal rule predicts, transcending geography, ethnicity and race.

The Universal rule requires that Herd immunity begin when just 25% of the population is vaccinated. With the anticipated 100 million vaccinations in the first 100 days of the Biden administration, Herd immunity may be imminent in the US.

The Universal rule promotes a temporary stasis with continuing infections and hospitalizations and becomes a barrier to runaway infections, making it practically impossible to reach Herd immunity, as Sweden discovered. Reduced infected population seems to be a third option to stifle the epidemic - a little known accomplishment, first by North Dakota and subsequently by twelve other U.S. states, including South Dakota.


title: May we overcome the current serious limitations for distributing reconstituted mRNA vaccines?

abstract: There is an urgent need to ameliorate the transport of the reconstituted vaccines to the vaccination sites to improve the COVID-19 vaccination campaigns. The maintenance of the integrity of the mRNA of the different COVID-19 reconstituted vaccines after continuous movement at room temperature during at least three hours ensures the safety of a ground transportation.

category: pharmacology and therapeutics


title: A Longitudinal Resource for Studying Connectome Development and its Psychiatric Associations During Childhood

abstract: Most psychiatric disorders are chronic, associated with high levels of disability and distress, and present during pediatric development. Scientific innovation increasingly allows researchers to probe brain-behavior relationships in the developing human. As a result, ambitions to (1) establish normative pediatric brain development trajectories akin to growth curves, (2) characterize reliable metrics for distinguishing illness, and (3) develop clinically useful tools to assist in the diagnosis and management of mental health and learning disorders have gained significant momentum. To this end, the NKI-Rockland Sample initiative was created to probe lifespan development as a large-scale multimodal dataset. The NKI-Rockland Sample Longitudinal Discovery of Brain Development Trajectories substudy (N=369) is a 24- to 30-month multi-cohort longitudinal pediatric investigation (ages 6.0-17.0 at enrollment) carried out in a community-ascertained sample. Data include psychiatric diagnostic, medical, behavioral, and cognitive phenotyping, as well as multimodal brain imaging (resting fMRI, diffusion MRI, morphometric MRI, arterial spin labeling), genetics, and actigraphy. Herein, we present the rationale, design, and implementation of the Longitudinal Discovery of Brain Development Trajectories protocol.


title: A longitudinal resource for studying connectome development and its psychiatric associations during childhood