title: Enhancing Research Data Infrastructure to Address the Opioid Epidemic: The Opioid Overdose Network (02-Net)

abstract:
ObjectiveOpioid Overdose Network is an effort to generalize and adapt an existing research data network, the Accrual to Clinical Trials (ACT) Network, to support design of trials for survivors of opioid overdoses presenting to emergency departments (ED). Four institutions (Medical University of South Carolina (MUSC), Dartmouth Medical School (DMS), University of Kentucky (UK), and University of California San Diego (UCSD)) worked to adapt ACT network. This paper reports their progress.

Materials and MethodsThe approach taken to enhancing ACT network focused on four activities: cloning and extending the ACT infrastructure, developing an e-phenotype and corresponding registry, developing portable natural language processing (NLP) tools to enhance data capture, and developing automated documentation templates to enhance extended data capture.

ResultsAll four institutions were able to replicate their i2b2 and Shared Health Research Information Network (SHRINE) infrastructure. A five category e-phenotype model based on ICD-10 coding was developed from prior published work. Ongoing work is refining this via machine learning and artificial intelligence methods. Portable NLP tools, focused at the sentence level, were also developed to identify uncoded opioid overdose related concepts in provider notes.

Optimal performance was seen in NLP tools that combined rule-based with deep learning methods (F score, 0.94). A template for ED overdose documentation was developed to improve primary data capture. Interactive prompts to physicians inside ED progress notes were effective in promoting use of the template. The template had good system usability and net promoter scores (0.72 and 0.75, respectively, n=13). Work to design ED trials based on the networks data is underway.

Discussion and ConclusionsOverall, initial results suggest that tailoring of existing multipurpose research networks to specific tasks is feasible; however, substantial efforts are required for coordination of the subnetwork and development of new tools for extension of available data.


title: Platelet size as a predictor for severity and mortality in COVID-19 patients: a systematic review and meta-analysis

abstract:
BackgroundParameters reflecting platelet size can be sensitive indicators that circulating platelets are activated and COVID-19 patients are at increased risk of thrombosis. This systematic review aims to assess the association of mean platelet volume (MPV), platelet distribution width (PDW) and platelet-large cell ratio (P-LCR) with disease severity and mortality in COVID-19 patients.

MethodsEnglish and Chinese databases were searched electronically to identify studies reporting data on MPV, PDW or P-LCR in COVID-19 patients. Included articles underwent a quality rating. A meta-analysis was performed using the standard mean difference and interpreted as the common language effect size (CLES).

ResultsTwenty-two studies (11,906 patients) were included in the meta-analysis. Of these, 14 were rated poor and eight were fair. The MPV and P-LCR was significantly higher at hospital admission in severe patients compared to non-severe patients. The MPV, PDW and P-LCR were significantly higher at hospital admission in non-survivors compared to survivors. There was a marked increase in the probability of a severe COVID-19 patient presenting with higher P-LCR at hospital admission than a non-severe patient (CLES: 68.7% [95% CI: 59.8%, 76.5%]), when compared with MPV and PDW ((CLES: 59.2% [95% CI: 53.1%, 65.1%]) and (CLES: 55.9% [95% CI: 50.6%, 62.2%]), respectively).

ConclusionSevere COVID-19 disease is associated with the increased production of larger, younger platelets. When comparing MPV, PDW and P-LCR, P-LCR is the most important biomarker for evaluating platelet activity. P-LCR testing at hospital admission could identify COVID-19 patients with increased risk for thrombotic events, allowing preventative treatment.

Summary TableO_ST_ABSWhat is known on this topicC_ST_ABSO_LIThe incidence of thrombotic complications is high in COVID-19 patients with severe disease.
C_LIO_LIParameters reflecting platelet size can be sensitive indicators that circulating platelets are activated and that COVID-19 patients are at increased risk of thrombosis.
C_LI

What does this paper addO_LIWhen compared to MPV and PDW, P-LCR is the most important biomarker for evaluating platelet activity in COVID-19 patients at hospital admission and could be used to identify patients with increased risk for thrombotic events.
C_LIO_LICurrent evidence is predominantly derived from retrospective design. Prospective studies are warranted to accurately determine cut-off values that may be used in the clinical setting.
C_LI

category: hematology


title: Analysis, quantification, and visualization of RT-LAMP technique for detection of COVID-19

abstract:
BackgroundSARS-Cov-2 is a new virus that caused an epidemic disease, COVID-19. According to the world health organization, detecting the patients/carriers is by the far the most important action to prevent the pandemic. Recently, the loop-mediated isothermal amplification (LAMP) technique has become more popular due to the easy handling of a one-step kit used for the detection of many diseases than RT-PCR-based techniques.

methodsHerein, we used the RT-LAMP technique so as to detect COVID-19. To this end, 40 paired-samples of patients and healthy people had been collected and tested by RT-PCR for N and E genes of SARS-CoV-2. The RT-LAMP test has been performed on samples for the RdRp gene. The sensitivity and specificity of tests have been determined.

ResultsThe testing results are consistent with the conventional RT-qPCR. Additionally, we also showed that a one-step process without RNA extraction is feasible to achieve RNA amplification directly from a sample.

ConclusionWe confirmed that RT-LAMP is a rapid, simple, and sensitive method that can be used as a large-screening method, particularly in regional hospitals with limited access to high-technologies.

category: infectious diseases


title: Serological testing reveals the hidden COVID-19 burden among healthcare workers experiencing a SARS-CoV-2 nosocomial outbreak.

abstract: We describe the results of testing healthcare workers from a tertiary care hospital in Japan, which had experienced a COVID-19 outbreak during the first peak of the pandemic, for SARS-CoV-2 specific antibody seroconversion. Using two chemiluminescent immunoassays and a confirmatory surrogate virus neutralization test, serological testing unveiled that a surprising 42.2% (27/64) of overlooked COVID-19 diagnoses had occurred when case detection had relied solely on SARS-CoV-2 nucleic acid amplification testing. This undetected portion of the COVID-19 iceberg beneath the surface may potentially have led to silent transmissions and triggered the spread. A questionnaire-based risk assessment was further indicative of exposures to specific aerosol-generating procedures, i.e. non-invasive ventilation, having had conveyed the highest transmission risks and served as the origin of outbreak. Our observations are supportive of a multi-tiered testing approach, including the use of serological diagnostics, in order to accomplish exhaustive case detection along the whole COVID-19 spectrum.


title: Scaling SARS-CoV-2 Wastewater Concentrations to Population Estimates of Infection

abstract: Monitoring the progression of SARS-CoV-2 outbreaks requires accurate estimates of infection rates. Estimation methods based on observed cases are biased due to changes in testing over time. Here we report an approach based upon scaling daily concentrations of SARS-CoV-2 RNA in wastewater to infections that produces representative estimates due to the consistent population contribution of fecal material to the sewage collection system.


title: Development and validation of a clinical risk score to predict SARS-CoV-2 infection in emergency department patients: The CCEDRRN COVID-19 Infection Score (CCIS)

abstract:
ObjectivesTo develop and validate a clinical risk score that can accurately quantify an emergency department patients probability of SARS-CoV-2 infection without the need for laboratory testing

DesignCohort study of participants in the Canadian COVID-19 Emergency Department Rapid Response Network (CCEDRRN) registry. Regression models were fitted to predict a positive SARS-CoV-2 test result using clinical and demographic predictors, as well as an indicator of local SARS-CoV-2 incidence.

Setting32 emergency departments in eight Canadian provinces

Participants27,665 consecutively-enrolled patients who were tested for SARS-CoV-2 in participating emergency departments between March 1-October 30,2020

Main outcome measuresPositive SARS-CoV-2 nucleic acid test result within 14 days of an index emergency department encounter for suspected COVID-19 disease

ResultsWe derived a 10-item CCEDRRN COVID-19 Infection Score using data from 21,743 patients. This score included variables from history and physical examination, and an indicator of local disease incidence. The score had a c-statistic of 0.838 with excellent calibration. We externally validated the rule in 5,295 patients. The score maintained excellent discrimination and calibration, and had superior performance compared to another previously published risk score. Score cutoffs were identified that can rule-in or rule-out SARS-CoV-2 infection without the need for nucleic acid testing with 97.4 % sensitivity (95% CI 96.4-98..3) and 95.9% specificity (95% CI 95.5-96.0).

ConclusionsThe CCEDRRN COVID-19 Infection Score uses clinical characteristics and publicly available indicators of disease incidence to quantify a patients probability of SARS-CoV-2 infection. The score can identify patients at sufficiently high risk of SARS-CoV-2 infection to warrant isolation and empiric therapy prior to test confirmation, while also identifying patients at sufficiently low risk of infection that they may not need testing.

Trial registrationCCEDRRN is registered at clinicaltrials.gov (NCT04702945).

FundingThe network is funded by the Canadian Institutes of Health Research (447679), BC Academic Health Science Network Society, BioTalent Canada, Genome BC (COV024; VAC007), Ontario Ministry of Colleges and Universities (C-655-2129), the Saskatchewan Health Research Foundation (5357) and the Fondation CHU de Quebec (Octroi #4007). These organizations are not-for-profit, and had no role in study conduct, analysis, or manuscript preparation.

category: emergency medicine


title: Exploring the relationship between resting state intra-network connectivity and accelerometer-measured physical activity in pediatric concussion: A cohort study.

abstract:
ObjectivesTo explore the association between resting state functional connectivity and accelerometer-measured physical activity in pediatric concussion.

MethodsFourteen children with concussion (aged 14.54 {+/-} 2.39 years, 8 female) were included in this secondary data-analysis. Participants had neuroimaging at 15.3 {+/-} 6.7 days post-injury and subsequently a mean of 11.1 {+/-} 5.0 days of accelerometer data. Intra-network connectivity of the default mode network (DMN), sensorimotor network (SMN), salience network (SN), and fronto-parietal network (FPN) was computed.

ResultsPer general linear models, only intra-network connectivity of the DMN was associated with habitual physical activity levels. More specifically, increased intra-network connectivity of the DMN was significantly associated with higher levels of subsequent accelerometer-measured light physical activity (F(2,11) = 7.053, p = 0.011, Ra 2 = 0.562; {beta} = 0.469), moderate physical activity (F(2,11) = 7.053, p = 0.011, Ra 2 = 0.562; {beta} = 0.725), and vigorous physical activity (F(2,11) = 10.855, p = 0.002, Ra 2 = 0.664; {beta} = 0.79). Intra-network connectivity of the DMN did not significantly predict sedentary time. Likewise, the SMN, SA, and FPN were not significantly associated with either sedentary time or physical activity.

ConclusionThese findings suggest that there is a positive association between the intra-network connectivity of the DMN and device-measured physical activity in children with concussion. Given that DMN impairment can be commonplace following concussion, this may be associated with lower levels of habitual physical activity, which can preclude children from experiencing the symptom-improving benefits of sub-maximal physical activity.

KEY FINDINGSO_ST_ABSWhat are the new findings?C_ST_ABSO_LIIntra-network connectivity of the default mode network is associated with subsequent accelerometer-measured light, moderate, and vigorous physical activity within the first-month of pediatric concussion
C_LIO_LISimilar associations with physical activity are not observed when examining the intra-network connectivity of the sensorimotor network, salience network, or fronto-parietal network
C_LIO_LIImproved connectivity within the default mode network may lead to increased participation in light to vigorous physical activity in pediatric concussion
C_LI

How might it impact on clinical practice in the future?O_LIDefault mode network impairment is commonplace in concussion, and this may limit children from experiencing the symptom-improving benefits of physical activity
C_LIO_LIAdjunctive interventions (e.g., mindfulness) that improve the health of the default mode network should be further studied in pediatric concussion
C_LI

category: pediatrics


title: Accelerometer-measured habitual physical activity and sedentary time in pediatric concussion: A controlled cohort study.

abstract:
ObjectivesTo characterize and quantify differences in accelerometer-measured physical activity and sedentary time between children with concussion (within the first month of injury) and 1:1 matched healthy controls.

MethodsSecondary analysis of accelerometer data collected on 60 children with concussion and 60 healthy controls matched for age, sex, and season of accelerometer wear. Daily and hourly sedentary time, light physical activity (LPA), moderate physical activity (MPA), and vigorous physical activity (VPA) were compared between groups per independent samples t-tests.

ResultsChildren with concussion (12.74 {+/-} 2.85 years, 31 females) were significantly more sedentary than controls (12.43 {+/-} 2.71 years, 31 females; mean difference [MD], 38.3 minutes/day, p=0.006), and spent less time performing LPA (MD, -19.5 minutes/day, p=0.008), MPA (MD, -9.8 minutes/day, p<0.001), and VPA(MD, -12.0 minutes/day, p<0.001); hour-by-hour analyses showed that these differences were observed from 8:00AM to 9:00PM. Sex-specific analyses identified that girls with concussion were less active and more sedentary than both boys with concussion (MD, 50.8 minutes/day; p=0.010) and healthy girls (MD, 51.1 minutes/day; p<0.010). Days post-injury significantly predicted MPA ({beta}=0.071, p=0.032) and VPA ({beta}=0.095, p=0.004), but not LPA or sedentariness in children with concussion.

ConclusionClinical management should continue to advise against prolonged rest following pediatric concussion, given the activity debt observed within the first-month of injury. Currently, clinical management of concussion is shifting towards prescribing a single bout of daily sub-maximal aerobic exercise. Interventions aimed at reducing overall sedentary time and increasing habitual physical activity in pediatric concussion also warrant study.

KEY FINDINGSO_ST_ABSWhat are the new findings?C_ST_ABSO_LIPer accelerometry, children with concussion are significantly more sedentary than healthy controls within the first-month of injury
C_LIO_LIRelative to healthy controls, in the first-month of injury, children with concussion perform less accelerometer-measured light, moderate, and vigorous physical activity
C_LIO_LIThese patterns of increased sedentary time and reduced physical activity are seen throughout the day, from 8:00 AM to 9:00 PM
C_LIO_LIModerate and vigorous physical activity levels are predicted by days-post injury in children with concussion, and may increase naturally as a consequence of recovery
C_LI

How might it impact on clinical practice in the future?O_LIGiven the accumulating evidence that prolonged rest should be avoided following concussion, primary care clinicians should continue to advocate for light physical activity post-concussion to limit increased sedentary time
C_LI


title: Understanding Adverse Population Sentiment Towards the Spread of COVID-19 in the United States

abstract:
BackgroundDuring the ongoing COVID-19 pandemic, the immediate threat of illness and mortality is not the only concern. In the United States, COVID-19 is not only causing physical suffering to patients, but also great levels of adverse sentiment (e.g., fear, panic, anxiety) among the public. Such secondary threats can be anticipated and explained through sentiment analysis of social media, such as Twitter.

MethodsWe obtained a dataset of geotagged tweets on the topic of COVID-19 in the contiguous United States during the period of 11/1/2019 - 9/15/2020. We classified each tweet into "adverse" and "non-adverse" using the NRC Emotion Lexicon and tallied up the counts for each category per county per day. We utilized the space-time scan statistic to find clusters and a three-stage regression approach to identify socioeconomic and demographic correlates of adverse sentiment.

ResultsWe identified substantial spatiotemporal variation in adverse sentiment in our study area/period. After an initial period of low-level adverse sentiment (11/1/2019 - 1/15/2020), we observed a steep increase and subsequent fluctuation at a higher level (1/16/2020 - 9/15/2020). The number of daily tweets was low initially (11/1/2019 - 1/22/2020), followed by spikes and subsequent decreases until the end of the study period. The space-time scan statistic identified 12 clusters of adverse sentiment of varying size, location, and strength. Clusters were generally active during the time period of late March to May/June 2020. Increased adverse sentiment was associated with decreased racial/ethnic heterogeneity, decreased rurality, higher vulnerability in terms of minority status and language, and housing type and transportation.

ConclusionsWe utilized a dataset of geotagged tweets to identify the spatiotemporal patterns and the spatial correlates of adverse population sentiment during the first two waves of the COVID-19 pandemic in the United States. The characteristics of areas with high adverse sentiment may be relevant for communication of containment measures. The combination of spatial clustering and regression can be beneficial for understanding of the ramifications of COVID-19, as well as disease outbreaks in general.

category: public and global health


title: The impact of a demand-side sanitation and hygiene promotion intervention on sustained behavior change and health in Amhara, Ethiopia: a cluster-randomized trial

abstract:
BackgroundBehaviors related to water, sanitation, and hygiene (WASH) are key drivers of infectious disease transmission, and experiences of WASH are potential influencers of mental well-being. Important knowledge gaps exist related to the content and delivery of effective WASH programs and their associated health impacts, particularly within the contexts of government programs implemented at scale.

MethodsWe developed and tested a demand-side intervention called Andilaye, which aimed to change behaviors related to sanitation, personal hygiene, and household environmental sanitation. This theory-informed intervention was delivered through the existing Ethiopian Health Extension Programme (HEP). It was a multilevel intervention with a catalyzing event at community level and behavior change activities at group and household level. We randomly selected and assigned 50 kebeles (sub-districts) from three woredas (districts), half to receive the Andilaye intervention, and half the standard of care sanitation and hygiene programming (i.e., community-led total sanitation and hygiene [CLTSH]). We collected data on WASH access, behavioral outcomes, and mental well-being.

ResultsA total of 1,589 households were enrolled into the study at baseline; 1,472 households (94%) participated in an endline assessment two years after baseline, and approximately 14 months after the initiation of a multi-level intervention. The intervention did not improve construction of latrines (prevalence ratio [PR] 0.99; 95% CI: 0.82, 1.21) or handwashing stations with water (PR: 0.96; 95% CI: 0.72, 1.26), or the removal of animal feces from the compound (PR=1.10; 95% CI: 0.95, 1.28). Nor did it impact anxiety (PR 0.90; 95% CI: 0.72, 1.11), depression (PR: 0.83; 95% CI: 0.64, 1.07), emotional distress (PR: 0.86; 95% CI: 0.67,1.09) or well-being (PR: 0.90; 95% CI: 0.74, 1.10) scores.

DiscussionWe report limited impact of the intervention, as delivered, on changes inbehavior and mental well-being. The effectiveness of the intervention was limited by poor intervention fidelity. While sanitation and hygiene improvements have been documented in Ethiopia, behavioral slippage, or regression to unimproved practices, in communities previously declared open defecation free is widespread. Evidence from this trial may help address knowledge gaps related to challenges associated with scalable alternatives to CLTSH and inform sanitation and hygiene programming and policy in Ethiopia and beyond.

Trial registrationThis trial was registered with clinicaltrials.gov (NCT03075436) on March 9, 2017.


title: Elderly acceptance of telemedicine use in Hong Kong during and after the COVID-19 pandemic: a cross-sectional cohort survey

abstract:
BackgroundTelemedicine services worldwide have experienced an unprecedented boom since the beginning of the COVID-19 pandemic. Multiple studies have noted telemedicine as an effective alternative to traditional face-to-face management of patients. This study provides insight into public perception and impression of telemedicine in Hong Kong, specifically among the elderly who are the most vulnerable to COVID-19.

MethodsFace-to-face surveys were conducted on elderly relatives of current medical students at the Chinese University of Hong Kong who were aged [≥] 60 years. The survey included socio-demographic details; past medical history; and concerns towards telemedicine use. Univariate and multivariable regression analyses were conducted to examine statistically significant associations. The primary outcomes are consideration of telemedicine use during: (1) a severe outbreak; and (2) after the COVID-19 pandemic.

Results109 surveys were conducted. Multivariable regression analyses revealed that expectation of government subsidies for telemedicine services was the strongest common driver, and also the only positive independent predictors of telemedicine use for both during a severe outbreak, as well as after the COVID-19 pandemic. No negative independent predictors of telemedicine use during severe outbreak were found. Negative independent predictors of telemedicine use after the COVID-19 pandemic included old age, and living in the New Territories.

ConclusionsGovernment support such as telemedicine-specific subsidies will be crucial in promoting telemedicine use in Hong Kong both during a severe outbreak and after the current COVID-19 pandemic. Robust dissemination of information regarding the pros and cons of telemedicine towards the public, especially towards the elderly population, is warranted.


title: Natural immunity against COVID-19 significantly reduces the risk of reinfection: findings from a cohort of sero-survey participants

abstract: Conflicting reports on the persistence of antibody levels in individuals recovered from COVID-19 infection, suggest that the immunity against COVID-19 may not be lasting for long. In India, by 30th June, 2021, not less than 30 million people were infected with COVID-19 and 0.39 million people were reported to have lost their life to the disease in India. I the current study we followed up with a subsample of our previous sero-survey participants to assess whether natural immunity against SARS-CoV-2 was associated with a reduced risk of re-infection. We conducted telephonic interview of a total of 3038 participants, out of which 2238 participants responded and 5 participants were found to be not alive, as conveyed by their close relatives. There was a non-response rate of 26.1%. Out of the 2238 participants, 1170 were sero-positive and 1068 were sero-negative for antibody against COVID-19. Our survey found that only 3 individuals in the sero-positive group got infected with COVID-19 whereas 127 individuals reported contracting the infection the sero-negative group. Interestingly, from the 127 sero-negative individuals who later contracted COVID-19 infection, 30 needed hospitalization, out of which 12 were on oxygen therapy, four in ICU and one was on ventilator. At the other hand, from the 3 sero-positives re-infected with COVID-19, one had hospitalization, but didnnot require oxygen support or critical care. These findings reinforce the strong plausibility that development of antibody following natural infection not only protects against re-infection by the virus to a great extent, but also safeguards against progression to severe COVID-19 disease.


title: Applying mixture model methods to SARS-CoV-2 serosurvey data from the SEROCoV-POP study

abstract: Serosurveys are an important tool to estimate the true extent of the current SARS-CoV-2 pandemic. So far, most serosurvey data have been analysed with cut-off based methods, which dichotomize individual measurements into sero-positives or negatives based on a predefined cutoff. However, mixture model methods can gain additional information from the same serosurvey data. Such methods refrain from dichotomizing individual values and instead use the full distribution of the serological measurements from pre-pandemic and COVID-19 controls to estimate the cumulative incidence. This study presents an application of mixture model methods to SARS-CoV-2 serosurvey data from the SEROCoV-POP study from April and May 2020 in Geneva (2766 individuals). Besides estimating the total cumulative incidence in these data (8.1% (95% CI: 6.8% - 9.8%)), we applied extended mixture model methods to estimate an indirect indicator of disease severity, which is the fraction of cases with a distribution of antibody levels similar to hospitalised COVID-19 patients. This fraction is 51.2% (95% CI: 15.2% - 79.5%) across the full serosurvey, but differs between three age classes: 21.4% (95% CI: 0% - 59.6%) for individuals between 5 and 40 years old, 60.2% (95% CI: 21.5% - 100%) for individuals between 41 and 65 years old and 100% (95% CI: 20.1% - 100%) for individuals between 66 and 90 years old. Additionally, we find a mismatch between the inferred negative distribution of the serosurvey and the validation data of pre-pandemic controls. Overall, this study illustrates that mixture model methods can provide additional insights from serosurvey data.

category: epidemiology


title: Applying mixture model methods to SARS-CoV-2 serosurvey data from Geneva


title: Identifying and alleviating bias due to differential depletion of susceptible people in post-marketing evaluations of COVID-19 vaccines

abstract: Recent studies have provided key information about SARS-CoV-2 vaccines efficacy and effectiveness (VE). One important question that remains is whether the protection conferred by vaccines wanes over time. However, estimates over time are subject to bias from differential depletion of susceptibles between vaccinated and unvaccinated groups. Here we examine the extent to which biases occur under different scenarios and assess whether serologic testing has the potential to correct this bias. By identifying non-vaccine antibodies, these tests could identify individuals with prior infection. We find in scenarios with high baseline VE, differential depletion of susceptibles creates minimal bias in VE estimates, suggesting that any observed declines are likely not due to spurious waning alone. However, if baseline VE is lower, the bias for leaky vaccines (that reduce individual probability of infection given contact) is larger and should be corrected by excluding individuals with past infection if the mechanism is known to be leaky. Conducting analyses both unadjusted and adjusted for past infection could give lower and upper bounds for the true VE. Studies of VE should therefore enroll individuals regardless of prior infection history but also collect information, ideally through serologic testing, on this critical variable.


title: A database of pediatric drug effects to evaluate ontogenic mechanisms from child growth and development

abstract: Adverse drugs effects (ADEs) in children are common and may result in disability and death. However, current pediatric drug safety methods have not gone beyond event surveillance to identify and evaluate potential biological mechanisms. Children undergo an evolutionarily conserved and physiologically dynamic process of growth and maturation that can alter pharmacokinetics and pharmacodynamics. Our hypothesis is that temporal patterns of drug event reporting are reflective of dynamic mechanisms from child growth and development. We generated a database of 460,837 pediatric ADEs using generalized additive models (GAMs) that we have previously shown identify dynamic risk estimates of adverse drug events1. We identified 19,438 significant drug-event risks where drug risks corresponded with physiological development throughout childhood. Our results identified known pediatric drug effects and risk dynamics across child development that were not known previously. For example, we identified significant risk dynamics of montelukast-induced psychiatric disorders, including enriched risk (Odds Ratio 8.77 [2.51, 46.94]) within the second year of life. We developed a data-driven time- series clustering approach resulting in up to 95.2% precision and 97.8% sensitivity for categorizing risk dynamics across development stages for all ADEs including known but previously development-agnostic pediatric drug effects. We found that our real-world evidence may contain biologically-relevant underpinnings as well, where risk dynamics of CYP enzyme substrates were dependent on the enzymes expression across childhood. We curated this database for the research community to enable, for the first time, evaluation of real-world hypotheses of adverse drug effects across child growth and development.

category: pharmacology and therapeutics


title: Modeling Pulmonary Cystic Fibrosis in a Human Lung Airway-on-a-chip

abstract:
BackgroundCystic fibrosis (CF) is a genetic disease caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR), which results in impaired airway mucociliary clearance, inflammation, infection, and respiratory insufficiency. The development of new therapeutics for CF are limited by the lack of reliable preclinical models that recapitulate the structural, immunological, and bioelectrical features of human CF lungs.

MethodsWe leveraged organ-on-a-chip technology to develop a microfluidic device lined by primary human CF bronchial epithelial cells grown under an air-liquid interface and interfaced with pulmonary microvascular endothelial cells (CF Airway Chip) exposed to fluid flow. The responses of CF and healthy Airway Chips were analyzed in the presence or absence of polymorphonuclear leukocytes (PMNs) and the bacterial pathogen, Pseudomonas aeruginosa.

ResultsThe CF Airway Chip faithfully recapitulated many features of the human CF airways, including enhanced mucus production, increased cilia density and a higher ciliary beating frequency compared to chips lined by healthy bronchial epithelial cells. The CF chips also secreted higher levels of IL-8, which was accompanied by enhanced PMN adhesion to the endothelium and transmigration into the airway compartment. In addition, CF Airway Chips provided a more favorable environment for Pseudomonas aeruginosa growth, which resulted in enhanced secretion of inflammatory cytokines and recruitment of PMNs to the airway.

ConclusionsThe human CF Airway Chip may provide a valuable preclinical tool for pathophysiology studies as well as for drug testing and personalized medicine.

category: respiratory medicine


title: The CT Scan Lung Severity Score and Vaccination Status in COVID-19 patients during the Second Wave in India: Perspective of an Independent Radiology Practice

abstract:
BackgroundThe COVID-19 patients often undergo a high-resolution CT scan to determine extent of their lung involvement. The aim of this study was to determine lung involvement in confirmed/suspected COVID-19 patients (encountered at an independent radiology practice) and its correlation to vaccination status amidst the second COVID-19 wave in India.

MethodsWe retrospectively queried our data since April 2021 to identify adult patients (>17 years) who had confirmed (positive RT-PCR or antigen test) or suspected COVID-19 (classic symptoms but negative RT-PCR) and received a high-resolution CT scan to determine the extent of their lung involvement using the CT severity (CT-SS) score. Patients were classified in 3 groups based on their vaccination status to determine its correlation with the CT-SS score: fully vaccinated, partially vaccinated, and unvaccinated. Basic descriptive statistics, univariate tests and multivariate linear regression analysis were used.

ResultsWe identified 229 patients (median age 45 years, 60% male) of which 205 (89%) had confirmed COVID-19 (positive RT-PCR) and 24 had suspected disease (negative RT-PCT but classic symptoms). Of the 229 patients 29 (13%) had complete vaccination, 38 (17%) had partial vaccination and 162 (70%) had no vaccination. The CT score of the completely vaccinated patients was significantly lower compared to partially or unvaccinated patients (median 0 v. 3.5 v. 10, respectively p<.01). A multivariate linear regression model showed that partial or fully vaccinated patients had lower CT severity score compared to unvaccinated patients (adjusted R squared = 0.47).

ConclusionWe present here the real-world findings from an independent radiology practice (a unique and common practice model), in India amid the second COVID-19 wave showing significantly lower CT severity score in fully or partially vaccinated patients compared to unvaccinated patients. Complete vaccination in patients could be critical in preventing severe lung disease.


title: The CT Scan Lung Severity Score and Vaccination Status in COVID-19 patients in India: Perspective of an Independent Radiology Practice


title: The retrospective observational study of clinical outcomes of single dose infusion of warm blood cardioplegia in patients undergoing cardiac surgery

abstract:
ObjectiveThe aim of the study was to assess the safety and efficacy of a normothermic cardioplegia solution N use and obtain additional information about dosing regimens during normothermic or mild hypothermic cardiac surgery.

MethodsA retrospective observational study included 150 cardio surgery patients. The primary endpoint was the intraoperative acute heart failure development. The secondary endpoints were the postoperative Troponin T concentrations, the need for catecholamine support, and the repeated infusion of a cardioplegia solution.

ResultsThe duration of aortic cross-clamping varied from 17 to 154 minutes, median 59 [interquartile range, 46 - 73] minutes. Spontaneous sinus rhythm recovery was observed in 136 (90.7%) patients. Intraoperative acute heart failure was observed in 1 case. The Troponin T concentrations were 0.331{+/-}0.143 ng/mL after surgery. Mortality was 2% (3 patients). Eight patients received an additional volume of N solution to maintain asystole. Among 16 patients with a cross-clamp duration greater than 90 minutes epinephrine was used in 3 (18.8%) patients in dose of more than 0.05 mcg/kg/min. Among 134 patients cross-clamp duration less than 90 minutes the catecholamine support was used in 4 (3%) patients, p=0.027.

ConclusionsA primary single-dose infusion of cardioplegia solution N provides myocardial protection for 59 [interquartile range, 46 - 73] minutes and up to 154 minutes. The catecholamine support in the group of aortic cross-clamp duration less than 90 minutes was used lesser than in the group of aortic cross-clamp duration greater than 90 minutes (3% and 18.8%, respectively). The cardioprotection during cardiopulmonary bypass surgery especially in elderly patients with concomitant disease needs to be confirmed in a future investigations.

category: surgery


title: HIV Testing Uptake and Late Diagnosis among Urban Population of Ethiopia: A Multilevel Modeling Approach

abstract:
BackgroundExpanding HIV testing and early diagnosis requires a better understanding of determinants to uptake and late diagnosis. We investigated factors contributing to HIV testing uptake and late diagnosis.

ObjectiveThe aim of this study was to determine level of HIV Testing Uptake and Late Diagnosis among Urban Population of Ethiopia

DesignWe used data from the Ethiopian Population Based HIV Impact assessment in Ethiopia (EPHIA), conducted in 2017/18. EPHIA was a nationally-representative, cross-sectional and household-based study, conducted in urban Ethiopia which used a two-stage cluster sampling design with stratification into small and large urban areas. The EPHIA data were collected from 19,136 adults aged 15 to 64 years. For current study, we considered self-reports first diagnosis to estimate the testing uptake and also consider HIV LAg avidity Vs Viral Load Vs plasma Antiretroviral drug level algorithm to categorize the late diagnosis. In this analysis, a 2-level multilevel mixed-effect logistic regression model was employed using STATA v16. The effects of individual-level predictors were quantified by the estimates from the fixed-effect part of the model with a p-value less than 0.05 or 95% CI.

ResultBy the year 2017/18, overall 29.4% of people living with HIV (PLHIV) were never tested in urban Ethiopia. Never tested male was significantly higher (32.4%; 95%: 31.0, 33.9) than females (26.4%; 95%: 25.3, 27.5) while it ranged from 28.3% to 47.8% among 45-54 and 15-24 years, respectively. By the same study period, 25.9% (95% CI: 21.7, 30.2) of PLHIV were lately diagnosed and male was significantly higher (36.8%; 95%: 28.0, 46.6) than females (20.8%; 95%: 17.3, 24.9). Late HIV diagnosis was also heterogeneous by various age group categories. Late diagnosis varies by region which ranged from 38.1% in the Gambella to 5.8% in Benishangul Gumuz. HIV testing uptake and late diagnosis was also significantly affected by alcohol use, income and educational status.

ConclusionEthiopia was behind the global target for HIV testing uptake. Late diagnosis of HIV constituted one-quarter of all testing HIV positive, and this was significantly higher among adult males. HIV testing offer and early diagnosis strategy need to focus on addressing geographically highly affected regions, and male and young adolescent age groups. The widowed population group, which is highly affected by HIV, and has low level of testing uptake, may require due attention by the HIV program. It is also suggested that HIV care and treatment programs provide a focus to the disadvantaged populations, especially those with limited education and low income.

category: hiv aids


title: Overall and cause-specific hospitalisation and death after COVID-19 hospitalisation in England: cohort study in OpenSAFELY using linked primary care, secondary care and death registration data

abstract:
BackgroundThere is concern about medium to long-term adverse outcomes following acute COVID-19, but little relevant evidence exists. We aimed to investigate whether risks of hospital admission and death, overall and by specific cause, are raised following discharge from a COVID-19 hospitalisation.

Methods and FindingsWorking on behalf of NHS-England, we used linked primary care and hospital data in OpenSAFELY to compare risks of hospital admission and death, overall and by specific cause, between people discharged from COVID-19 hospitalisation (February-December 2020), and (i) demographically-matched controls from the 2019 general population; (ii) people discharged from influenza hospitalisation in 2017-19. We used Cox regression adjusted for personal and clinical characteristics.

24,673 post-discharge COVID-19 patients, 123,362 general population controls, and 16,058 influenza controls were followed for [≤]315 days. Overall risk of hospitalisation or death (30968 events) was higher in the COVID-19 group than general population controls (adjusted-HR 2.23, 2.14-2.31) but similar to the influenza group (adjusted-HR 0.94, 0.91-0.98). All-cause mortality (7439 events) was highest in the COVID-19 group (adjusted-HR 4.97, 4.58-5.40 vs general population controls and 1.73, 1.60-1.87 vs influenza controls). Risks for cause-specific outcomes were higher in COVID-19 survivors than general population controls, and largely comparable between COVID-19 and influenza patients. However, COVID-19 patients were more likely than influenza patients to be readmitted/die due to their initial infection/other lower respiratory tract infection (adjusted-HR 1.37, 1.22-1.54), and to experience mental health or cognitive-related admission/death (adjusted-HR 1.36, 1.01-2.83); in particular, COVID-19 survivors with pre-existing dementia had higher risk of dementia death. One limitation of our study is that reasons for hospitalisation/death may have been misclassified in some cases due to inconsistent use of codes.

ConclusionsPeople discharged from a COVID-19 hospital admission had markedly higher risks for rehospitalisation and death than the general population, suggesting a substantial extra burden on healthcare. Most risks were similar to those observed after influenza hospitalisations; but COVID-19 patients had higher risks of all-cause mortality, readmissions/death due to the initial infection, and dementia death, highlighting the importance of post-discharge monitoring.


title: Exposition to airborne SARS-CoV-2 in household and hospitals settings as studied by a vacuum cleaner as a high-powered air sampler

abstract:
BackgroundWe aimed to study the presence of SARS-CoV-2 in air surrounding infected healthcare workers (HCW) in their homes versus infected patients who were undergoing potential aerosol-generating medical procedures (AGMP). We also studied the effect of different face masks worn bij infected persons on spread of SARS-CoV-2 into the air.

MethodsWe developed a high-volume air sampler method that uses a household vacuum cleaner with a surgical mask serving as a sample filter. SARS-CoV-2 RNA was harvested from these sample filters and analyzed on the presence of RNA by polymerase chain reaction. We acquired air samples in close aproximity of HCWs wearing different facemasks. Also, we obtained free air samples away from the infected HCWs and samples near intensive care unit (ICU) patients undergoing AGMP. Fog experiments were performed to visualize the airflow around our air sampler.

ResultsAerosols were visibly suctioned into the vacuum cleaner when there was no face mask, whereas wearing a face mask resulted in a delayed and reduced flow of aerosols into the vacuum cleaner. The face masks that were worn by the HCWs were positive in 54-83% of cases. The proportion of positive air samples was higher in household settings of recently infected HCWs (29/41; 70.7%) compared to ICU settings (4/17; 23.5%) (p<0.01).

ConclusionThis high-volume air sampler method was able to detect SARS-CoV-2 RNA in air samples. Air samples in the household environment of recently infected HCWs more frequently contained SARS-CoV-2 in comparison to those obtained in patient rooms during potential AGMP.


title: Upper airway gene expression reveals a more robust innate and adaptive immune response to SARS-CoV-2 in children compared with older adults

abstract: Unlike other respiratory viruses, SARS-CoV-2 disproportionately causes severe disease in older adults and only rarely in children. To investigate whether differences in the upper airway immune response could contribute to this disparity, we compared nasopharyngeal gene expression in 83 children (<19-years-old; 38 with SARS-CoV-2, 11 with other respiratory viruses, 34 with no virus) and 154 adults (>40-years-old; 45 with SARS-CoV-2, 28 with other respiratory viruses, 81 with no virus). Expression of interferon-stimulated genes (ISGs) was robustly activated in both children and adults with SARS-CoV-2 compared to the respective non-viral groups, with only relatively subtle distinctions. Children, however, demonstrated markedly greater upregulation of pathways related to B cell and T cell activation and proinflammatory cytokine signaling, including TNF, IFN{gamma}, IL-2 and IL-4 production. Cell type deconvolution confirmed greater recruitment of B cells, and to a lesser degree macrophages, to the upper airway of children. Only children exhibited a decrease in proportions of ciliated cells, the primary target of SARS-CoV-2, upon infection with the virus. These findings demonstrate that children elicit a more robust innate and adaptive immune response to SARS-CoV-2 infection in the upper airway that likely contributes to their protection from severe disease in the lower airway.


title: Temporal Variations in Seroprevalence of SARS-CoV-2 Infections by Race and Ethnicity in Arkansas.

abstract:
ObjectiveOur objective is to estimate CoV-2 infection rates in a rural state using seroprevalence of antibodies to CoV-2 as an indicator of infection.

Study Design and SettingThis is a single-site study within an academic center and regional programs within the state of Arkansas. We obtained residual serum samples from a convenience sample of adults who were outpatients and came to the hospital or regional clinic for non-COVID-related reasons. We collected remnant in three time periods (August 15 to September 5, September 12 to October 24, and November 7 to December 19).

ResultsIn 2020, the overall age, gender, and race standardized prevalence of CoV-2 antibodies was 2.6% (August to September), 4.1% (September to October), and 7.4% (November to December). There was no difference in seroprevalence between urban compared to rural areas. Positive tests were not uniformly distributed across racial and ethnic minorities. Higher seroprevalence rates were found in Hispanics and Blacks or African Americans compared to whites across all time periods.

ConclusionsIn a state with a large rural population, 2.6-7.4% of people experienced CoV-2 infection by December 2020. Blacks and Hispanics had disproportionately higher rates of CoV-2 infections than whites.

What is new?O_ST_ABSKey findingsC_ST_ABSIn this prospective convenience sampling of remnant sera, we found increasing seroprevalence from 2.6% to 7.4% (August 2020 to December 2020). Higher seroprevalence rates were found in Hispanics and Blacks or African Americans compared to whites across all time periods, and no difference was determined between those individuals from rural or urban areas.

What this adds to what is knownIn a largely rural population, Blacks and Hispanics had disproportionately higher rates of CoV-2 infections than whites, and these populations need to be studied further regarding outcomes.

What is the implication?There are health disparities that exist regarding CoV-2 infections, and we should target vaccination information and education to these groups.

Highlights- SARS-CoV-2 infections increased from 2.6% to 7.4% from August to December 2020.
- Higher seroprevalence was found in Hispanics and Blacks as compared to whites.
- There was no difference in the seroprevalence in rural compared to urban areas.


title: Viral Load of SARS-CoV-2 in Respiratory Aerosols Emitted by COVID-19 Patients while Breathing, Talking, and Singing

abstract:
BackgroundMultiple SARS-CoV-2 superspreading events suggest that aerosols play an important role in driving the COVID-19 pandemic. However, the detailed roles of coarse (>5m) and fine ([≤]5m) respiratory aerosols produced when breathing, talking, and singing are not well-understood.

MethodsUsing a G-II exhaled breath collector, we measured viral RNA in coarse and fine respiratory aerosols emitted by COVID-19 patients during 30 minutes of breathing, 15 minutes of talking, and 15 minutes of singing.

ResultsAmong the 22 study participants, 13 (59%) emitted detectable levels of SARS-CoV-2 RNA in respiratory aerosols, including 3 asymptomatic patients and 1 presymptomatic patient. Viral loads ranged from 63-5,821 N gene copies per expiratory activity per patient. Patients earlier in illness were more likely to emit detectable RNA, and loads differed significantly between breathing, talking, and singing. The largest proportion of SARS-CoV-2 RNA copies was emitted by singing (53%), followed by talking (41%) and breathing (6%). Overall, fine aerosols constituted 85% of the viral load detected in our study. Virus cultures were negative.

ConclusionsFine aerosols produced by talking and singing contain more SARS-CoV-2 copies than coarse aerosols and may play a significant role in the transmission of SARS-CoV-2. Exposure to fine aerosols should be mitigated, especially in indoor environments where airborne transmission of SARS-CoV-2 is likely to occur. Isolating viable SARS-CoV-2 from respiratory aerosol samples remains challenging, and whether this can be more easily accomplished for emerging SARS-CoV-2 variants is an important enquiry for future studies.

Key PointsWe sampled respiratory aerosols emitted by COVID-19 patients and discovered that fine aerosols ([≤]5m) generated during talking and singing contain more SARS-CoV-2 copies than coarse aerosols (>5m) and may play a significant role in the transmission of SARS-CoV-2.


title: Characterising within-hospital SARS-CoV-2 transmission events: a retrospective analysis integrating epidemiological and viral genomic data from a UK tertiary care setting across two pandemic waves

abstract:
Structured abstractO_ST_ABSObjectivesC_ST_ABSTo characterise within-hospital SARS-CoV-2 transmission across two waves of the COVID-19 pandemic.

DesignA retrospective Bayesian modelling study to reconstruct transmission chains amongst 2181 patients and healthcare workers using combined viral genomic and epidemiological data.

SettingA large UK NHS Trust with over 1400 beds and employing approximately 17,000 staff.

Participants780 patients and 522 staff testing SARS-CoV-2 positive between 1st March 2020 and 25th July 2020 (Wave 1); and 580 patients and 299 staff testing SARS-CoV-2 positive between 30th November 2020 and 24th January 2021 (Wave 2).

Main outcome measuresTransmission pairs including who-infected-whom; location of transmission events in hospital; number of secondary cases from each individual, including differences in onward transmission from community and hospital onset patient cases.

ResultsStaff-to-staff transmission was estimated to be the most frequent transmission type during Wave 1 (31.6% of observed hospital-acquired infections; 95% CI 26.9 to 35.8%), decreasing to 12.9% (95% CI 9.5 to 15.9%) in Wave 2. Patient-to-patient transmissions increased from 27.1% in Wave 1 (95% CI 23.3 to 31.4%) to 52.1% (95% CI 48.0 to 57.1%) in Wave 2, to become the predominant transmission type. Over 50% of hospital-acquired infections were concentrated in 8/120 locations in Wave 1 and 10/93 locations in Wave 2. Approximately 40% to 50% of hospital-onset patient cases resulted in onward transmission compared to less than 4% of definite community-acquired cases.

ConclusionsPrevention and control measures that evolved during the COVID-19 pandemic may have had a significant impact on reducing infections between healthcare workers, but were insufficient during the second wave to prevent a high number of patient-to-patient transmissions. As hospital-acquired cases appeared to drive most onward transmissions, more frequent and rapid identification and isolation of these cases will be required to break hospital transmission chains in subsequent pandemic waves.


title: Timeline of SARS-CoV2 spread in Italy: results from an independent serological retesting

abstract:
The massive emergence of COVID19 cases in the first phase of pandemic within an extremely short period of time suggest that an undetected earlier circulation of SARS-CoV-2 might have occurred, as documented by several papers in different countries, including a few that reported positive cases even earlier the first cases identified in Wuhan. Given the importance of this evidence, an independent evaluation was recommended. Here we report the results of SARS-CoV-2 antibodies blind retesting of blood samples collected in the prepandemic period in Italy, and in control samples collected one year before, by two independent centers. Results suggest the presence of SARS-CoV-2 antibodies in some samples collected in the prepandemic period, though the detection of IgM and/or IgG binding and neutralizing antibodies is strongly dependent on the different serological assays and thresholds employed, while being absent in control samples collected one year before. These findings highlight the importance of harmonizing serological assays for testing SARS-CoV-2 virus spreading and may contribute to a better understanding the future virus dynamics.

Article Summary LineWe report the results of an independent retesting of SARS-CoV-2 antibodies in blood samples collected in prepandemic period in Italy and in matched samples collected one year before. The findings indicate the presence of IgM and/or IgG antibodies in selected samples of the prepandemic period only with different performance of serological assays used by the two centers. The results could give highlights on SARS-CoV-2 circulation in the pre-pandemic period and contribute to better predict future virus dynamic.


title: The incidence and in-hospital mortality of COVID-19 patients post-vaccination in eastern India

abstract:
ObjectivesThe comparable effectiveness of Covishield and Covaxin vaccines has not been studied. We compared the effectiveness of Covishield and Covaxin vaccines against moderate to severe COVID-19.

MethodsIn this retrospective observational study, we collected data of patients who were admitted with moderate to severe COVID-19. The vaccination status and comorbidities of the patients were documented. The incidence and in-hospital mortality of COVID-19 patients was assessed. Univariate analysis was performed to determine the risk factors of in-hospital mortality.

ResultsOf 294 patients, 5.1% (n=15) received Covaxin and 26.5% (n=78) received Covishield; 68.4% (n=201) patients were unvaccinated. Of patients who were vaccinated and contracted COVID-19, 24.8% (n=73) had taken the first dose and 6.8% (n=20) had taken the second dose of either vaccine. The in-hospital mortality rate was 13.6% (n=40). 24/40 (60%) people who had hospital mortality were unvaccinated.3/40(7.5%) had succumbed to death after receiving double dose of Covishield, 11/40 (27.5%) had succumbed to death after receiving single dose of Covishield, 2/40(5%) had succumbed to death after receiving single dose of Covaxin, none had reported infection after receiving second dose of Covaxin. No significant association was found with the type of vaccine and the in-hospital mortality (p=0.23). Significant associations with in-hospital mortality were found with the interval before COVID-19 disease and vaccination (OR, 3.02; p=0.01); and the presence of diabetes mellitus (OR, 2.13; p=0.02), cardiovascular diseases (OR, 2.11; p<0.001), and malignancy (OR: 2.33; p=0.0325).

ConclusionThere was no significant difference in the effectiveness of Covaxin and Covishield in terms of the incidence of COVID-19 and in-hospital mortality. Diabetes mellitus, cardiovascular diseases, and malignancies had a significant association with in-hospital mortality in patients with moderate to severe COVID-19.


title: Antibody and T cell responses to Sinopharm/BBIBP-CorV in naive and previously infected individuals in Sri Lanka

abstract:
BackgroundAs there are limited data of the immunogenicity of the Sinopharm/BBIBP-CorV in different populations, antibody responses against different SARS-CoV-2 variants of concern and T cell responses, we investigated the immunogenicity of the vaccine, in individuals in Sri Lanka.

MethodsSARS-CoV-2-specific antibodies were measured in 282 individuals who were seronegative at baseline, and ACE2 receptor blocking antibodies, antibodies to the receptor binding domain (RBD) of the wild type (WT), B.1.1.7, B.1.351 and B.1.617.2, ex vivo and cultured IFN{gamma} ELISpot assays, intracellular cytokine secretion assays and B cell ELISpot assays were carried out in a sub cohort of the vaccinees at 4 weeks and at 6 weeks (2 weeks after the second dose).

Results95% of the vaccinees seroconverted, although the seroconversion rates were significantly lower (p<0.001) in individuals >60 years (93.3%) compared to those who were 20 to 39 years (98.9%). 81.25% had ACE2 receptor blocking antibodies at 6 weeks, and there was no difference in these antibody titres in vaccine sera compared to convalescent sera (p=0.44). Vaccinees had significantly less (p<0.0001) antibodies to the RBD of WT and B.1.1.7, although there was no difference in antibodies to the RBD of B.1.351 and B.1.617.2 compared to convalescent sera. 27.7% of 46.4% of vaccinees had ex vivo IFN{gamma} and cultured ELISpot responses respectively, and IFN{gamma} and CD107a responses were detected by flow cytometry.

ConclusionsSinopharm/BBIBP-CorV appeared to induce high seroconversion rates and induce a similar level of antibody responses against ACE2 receptor, B.1.617.2 and B.1.351 as seen following natural infection.

category: allergy and immunology


title: Glycophorin C in atherosclerotic plaque is associated with major adverse cardiovascular events after carotid endarterectomy.

abstract:
IntroductionHistological assessment studies have identified the presence of intraplaque hemorrhage (IPH) as an indicator of plaque instability and resulting ischemic cerebral sequelae. Although the presence of IPH has been studied extensively in relation to neurological symptoms preceding carotid endarterectomy (CEA) or as a predictor for postoperative risk of major adverse cardiovascular events (MACE), the degree of IPH has not been studied before. Glycophorin, an erythrocyte-specific protein, has been suggested as a marker for the degree of previous hemorrhages in atherosclerotic plaque since erythrocytes are prominently present in IPH. We hypothesized that quantified plaque glycophorin C, as a proxy for the degree of IPH, is associated with destabilizing plaque characteristics, preprocedural symptoms, and increased postoperative risk for MACE.

MethodsWe quantified glycophorin C and six other plaque characteristics with the slideToolkit method. We used human atherosclerotic plaque samples from 1971 consecutive asymptomatic and symptomatic (carotid endarterectomy) patients in the Athero-Express Biobank.

ResultsThe total area of glycophorin C in plaque was larger in individuals with a plaque with IPH compared to individuals with plaque without IPH (p<0.001). Quantified glycophorin C was significantly associated with ipsilateral pre-procedural neurological symptoms (OR:1.27, 95%CI:1.06-1.41, p=0.005). In addition, quantified glycophorin C was independently associated with an increased postoperative risk for MACE (HR:1.31, 95%CI:1.01-1.68, p=0.04). Stratified by sex, quantified glycophorin C was associated with an increased postoperative risk for MACE in male patients (HR:1.50, 95%CI:1.13-1.97, p=0.004), but not in female patients (HR:0.70, 95%CI:0.39-1.27, p=0.23).

ConclusionQuantified glycophorin C, as a proxy for the degree of IPH, was independently associated with the presence of IPH, symptomatic preprocedural symptoms, and with an increased three-year postoperative risk of MACE. These findings indicate that quantified plaque glycophorin C can be considered as a marker for identifying male patients with a high residual risk for secondary MACE after CEA.

category: cardiovascular medicine


title: Exploring relationships between drought and epidemic cholera in Africa using generalised linear models

abstract:
BackgroundTemperature and precipitation are known to affect Vibrio cholerae outbreaks. Despite this, the impact of drought on outbreaks has been largely understudied. Africa is both drought and cholera prone and more research is needed in Africa to understand cholera dynamics in relation to drought.

MethodsHere, we analyse a range of environmental and socioeconomic covariates and fit generalised linear models to publicly available national data, to test for associations with several indices of drought and make cholera outbreak projections to 2070 under three scenarios of global change, reflecting varying trajectories of CO2 emissions, socio-economic development, and population growth.

ResultsThe best-fit model implies that drought is a significant risk factor for African cholera outbreaks, alongside positive effects of population, temperature and poverty and a negative effect of freshwater withdrawal. The projections show that following stringent emissions pathways and expanding sustainable development may reduce cholera outbreak occurrence in Africa, although these changes were spatially heterogeneous.

ConclusionsDespite an effect of drought in explaining recent cholera outbreaks, future projections highlighted the potential for sustainable development gains to offset drought-related impacts on cholera risk. Future work should build on this research investigating the impacts of drought on cholera on a finer spatial scale and potential non-linear relationships, especially in high-burden countries which saw little cholera change in the scenario analysis.


title: Post-COVID-19 symptoms are not uncommon among recovered patients-A cross-sectional online survey among the Indian population.

abstract:
BackgroundCoronavirus disease-2019 (COVID-19) can have a myriad of symptoms. However, it is now known that most patients recovered from COVID-19 have symptoms related to COVID-19. There is a paucity of literature on post-COVID-19 symptoms from India. Hence we aimed to assess the incidence of post-COVID-19 symptoms in patients recovered from COVID-19. Methods: An online Microsoft forms survey was conducted through multiple social media platforms.

ResultsOf the 5,347 individuals who received and clicked the link, a total of 2038 infected patients responded (Supplementary figure). Approximately 48% (967/2038) had recovered from COVID-19 within 1-3 months (short-term recovered), 34.2% (375/2038) had recovered from COVID-19 >3 months ago (long recovered), and 18.4% (375) were recovered within the last one month (recently recovered). Nearly 38% (770/2038) had a history of hospitalization for COVID-19. Of them, 34.28% (264/770) required oxygen therapy during the hospital stay. Most patients were discharged within 5-10 days of hospital stay (54%, 415/770). Only 5.58% (43/770) required a stay of more than 20 days. Seventy-five percent (575/770) of the hospitalized patients received steroid therapy. Of those who received steroid therapy, 56.5% (325/575) had not required oxygen therapy. Forty percent (233/575) of patients received steroid therapy for two weeks, 24% (138/575) for one week, 33.73% received steroids only during the hospital stay, and 1.73% were still on steroid therapy during the survey.

Most importantly, of the 2038 respondents, 41.8% (851/2038) still had persistent symptoms related to COVID-Most common symptom was fatigue (64.15%), followed by body pain (31%) and gastrointestinal symptoms (25%) (Figure). Six percent (49/851) of them required hospitalization for post-COVID-19 symptoms. Forty-six percent (449/967) in the short term recovered group (1-3 months), 40.1% (279/696) in the long-recovered group, and 32.8% (123/375) in the recently recovered group had persistent symptoms related to COVID-19 (P=0.001). Forty-eight percent (374/770) of the hospitalized patients developed post-COVID-19 symptoms, while only 37.6% (477/1268) developed post-COVID-19 symptoms among the non-hospitalized patients (P<0.001). Fifty-three percent (303/575) of those who received steroids developed post-COVID-19 symptoms, while only 36.41% (71/195) of those who did not receive steroids developed post-COVID-19 symptoms (P<0.001). 49% (159/325) of patients who received steroids despite being not requiring oxygen developed post-COVID-19 symptoms compared to only 37.5% (543/1449) who did not receive steroids and were not on oxygen therapy (P<0.001). Nearly 40% (336/851) of respondents felt that post-COVID-19 symptoms are not being appropriately treated or taken care of seriously.

ConclusionsPost-COVID-19 symptoms are common in patients who recovered from COVID-19. These symptoms are more often noted in patients who received steroid therapy. Post-COVID-19 symptomatology is present in a significant number of patients and requires to be addressed seriously.


title: Genome-wide association analysis reveals extensive genetic overlap between mood instability and psychiatric disorders but divergent patterns of genetic effects

abstract: Mood instability (MOOD) is a transdiagnostic phenomenon with a prominent neurobiological basis. Recent genome-wide association studies found significant positive genetic correlation between MOOD and major depression (DEP) and weak correlations with other psychiatric disorders. We investigated the polygenic overlap between MOOD and psychiatric disorders beyond genetic correlation to better characterize putative shared genetic determinants. Summary statistics for schizophrenia (SCZ, n=105,318), bipolar disorder (BIP, n=413,466), DEP (n=450,619), attention-deficit hyperactivity disorder (ADHD, n=53,293) and MOOD (n=363,705), were analysed using the bivariate causal mixture model and conjunctional false discovery rate methods to estimate the proportion of shared variants influencing MOOD and each disorder, and identify jointly associated genomic loci. MOOD correlated positively with all psychiatric disorders, but with wide variation in strength (rg=0.10-0.62). Of 10.4K genomic variants influencing MOOD, 4K-9.4K were estimated to influence psychiatric disorders. MOOD was jointly associated with DEP at 163 loci, SCZ at 110, BIP at 60 and ADHD at 25, with consistent genetic effects in independent samples. Fifty-three jointly associated loci were overlapping across two or more disorders (transdiagnostic), seven of which had discordant effect directions on psychiatric disorders. Genes mapped to loci associated with MOOD and all four disorders were enriched in a single gene-set, "synapse organization". The extensive polygenic overlap indicates shared molecular underpinnings across MOOD and psychiatric disorders. However, distinct patterns of genetic correlation and effect directions of shared loci suggest divergent effects on corresponding neurobiological mechanisms which may relate to differences in the core clinical features of each disorder.

category: psychiatry and clinical psychology


title: COVID-19 Chest X-Ray Image Classification Using Deep Learning

abstract: The rise of the coronavirus disease 2019 (COVID-19) pandemic has made it necessary to improve existing medical screening and clinical management of this disease. While COVID-19 patients are known to exhibit a variety of symptoms, the major symptoms include fever, cough, and fatigue. Since these symptoms also appear in pneumonia patients, this creates complications in COVID-19 detection especially during the flu season. Early studies identified abnormalities in chest X-ray images of COVID-19 infected patients that could be beneficial for disease diagnosis. Therefore, chest X-ray image-based disease classification has emerged as an alternative to aid medical diagnosis. However, manual detection of COVID-19 from a set of chest X-ray images comprising both COVID-19 and pneumonia cases is cumbersome and prone to human error. Thus, artificial intelligence techniques powered by deep learning algorithms, which learn from radiography images and predict presence of COVID-19 have potential to enhance current diagnosis process. Towards this purpose, here we implemented a set of deep learning pre-trained models such as ResNet, VGG, Inception and EfficientNet in conjunction with developing a computer vision AI system based on our own convolutional neural network (CNN) model: Deep Learning in Healthcare (DLH)-COVID. All these CNN models cater to image classification exercise. We used publicly available resources of 6,432 images and further strengthened our model by tuning hyperparameters to provide better generalization during the model validation phase. Our final DLH-COVID model yielded the highest accuracy of 96% in detection of COVID-19 from chest X-ray images when compared to images of both pneumonia-affected and healthy individuals. Given the practicality of acquiring chest X-ray images by patients, we also developed a web application (link: https://toad.li/xray) based on our model to directly enable users to upload chest X-ray images and detect the presence of COVID-19 within a few seconds. Taken together, here we introduce a state-of-the-art artificial intelligence-based system for efficient COVID-19 detection and a user-friendly application that has the capacity to become a rapid COVID-19 diagnosis method in the near future.

category: radiology and imaging


title: Cluster analysis of transcriptomic datasets to identify endotypes of Idiopathic Pulmonary Fibrosis

abstract:
BackgroundConsiderable clinical heterogeneity in Idiopathic Pulmonary Fibrosis (IPF) suggests the existence of multiple disease endotypes. Identifying these endotypes could allow for a biomarker-driven personalised medicine approach in IPF. To improve our understanding of the pathogenesis of IPF by identifying clinically distinct groups of patients with IPF that could represent distinct disease endotypes.

MethodsWe co-normalised, pooled and clustered three publicly available blood transcriptomic datasets (total 220 IPF cases). We compared clinical traits across clusters and used gene enrichment analysis to identify biological pathways and processes that were over-represented among the genes that were differentially expressed across clusters. A gene-based classifier was developed and validated using three additional independent datasets (total 194 IPF cases).

FindingsWe identified three clusters of IPF patients with statistically significant differences in lung function (P=0{middle dot}009) and mortality (P=0{middle dot}009) between groups. Gene enrichment analysis implicated dysregulation of mitochondrial homeostasis, apoptosis, cell cycle and innate and adaptive immunity in the pathogenesis underlying these groups. We developed and validated a 13-gene cluster classifier that predicted mortality in IPF (high-risk clusters vs low-risk cluster: hazard ratio= 4{middle dot}25, 95% confidence interval= [2{middle dot}14, 8{middle dot}46], P=3{middle dot}7x10-5).

InterpretationWe have identified blood gene expression signatures capable of discerning groups of IPF patients with significant differences in survival. These clusters could be representative of distinct pathophysiological states, which would support the theory of multiple endotypes of IPF. Although more work must be done to confirm the existence of these endotypes, our classifier could be a useful tool in patient stratification and outcome prediction in IPF.

FundingL.V.W. holds a GSK/British Lung Foundation Chair in Respiratory Research (C17-1). R.G.J. is supported by a National Institute for Health Research (NIHR) Research Professorship (NIHR reference RP-2017-08-ST2-014). P.L.M. is supported by an Action for Pulmonary Fibrosis Mike Bray fellowship. T.M. Maher is supported by a National Institute for Health Research Clinician Scientist Fellowship (CS-2013-13-017) and a British Lung Foundation Chair in Respiratory Research (C17-3). I.N. is supported by a National Heart, Lung, and Blood Institute (NHLBI) grant (R01HL145266). D.A.S. is supported by NHLBI grants (UG3HL151865, R01HL097163, P01HL092870, X01HL134585 and UH3HL123442) and a United States Department of Defense grant (W81XWH-17-1-0597). The GSE110147 study was supported by the Roche Multi Organ Transplant Academic Enrichment Fund, Lawson Research Institute Internal Research Fund and Western Strategic Support for CIHR Success, Seed Grant. The research was partially supported by the NIHR Leicester Biomedical Research Centre; the views expressed are those of the author(s) and not necessarily those of the National Health Service (NHS), the NIHR, or the Department of Health.

Putting research into contextO_ST_ABSEvidence before this studyC_ST_ABSWe searched PubMed Central in February 2020 with the search terms "idiopathic pulmonary fibrosis", "gene expression" and "cluster analysis" with no restrictions on publication date or language. Previous transcriptomic cluster analyses have found that differences in gene expression can be used to predict disease status, severity and outcome in IPF. A previous transcriptomic prognostic biomarker has been developed that can predict outcome in IPF using blood expression data from 52 genes.

Added value of this studyBy utilising new methods of data co-normalisation and machine learning, we were able to combine multiple publicly available datasets and perform one of the largest transcriptomic studies in IPF to-date with a total of 416 IPF cases across the discovery and validation stages. We identified three clusters of patients, one of which appeared to contain, on average, the healthiest subjects with favourable lung function and survival over time. These clusters were defined using expression from groups of genes that were significantly enriched for many different biological pathways and processes, including metabolic changes, apoptosis, cell cycle and immune response, and so could be representative of distinct pathophysiological states. Additionally, we developed a 13-gene expression-based classifier to assign individuals with IPF to one of the clusters and validated this classifier using three additional independent cohort of IPF patients (totalling 194 IPF cases). As the clusters were associated with survival, our classifier could potentially be used to predict outcome in IPF.

Implications of all the available evidenceOur findings support the hypothesis that the disease consists of multiple endotypes. The clusters identified in this study could provide some valuable insight into the underlying biological processes that may be driving the considerable clinical heterogeneity in IPF. With further development, our gene expression-based classifier could be a useful tool for patient stratification and outcome prediction in IPF.


title: Positive Mental Training in patients with Multiple Sclerosis experiencing psychological distress: A Preliminary Randomised Controlled Trial

abstract:
IntroductionPsychological distress is a major issue in multiple sclerosis (MS), having a significant impact on quality of life. Antidepressants are generally unhelpful for subsyndromal symptomatology, and psychological treatment approaches often not accessible or too cognitively demanding for some patients. There is an urgent need for low-cost interventions to improve wellbeing in MS.

MethodsThis was a pilot randomised controlled trial (RCT) of Positive Mental Training (PosMT), a low intensity intervention providing training in positivity, optimism and resilience previously shown to improve anxious and depressive symptomotology. 28 patients with MS were randomised to the intervention and 30 to the control group.

ResultsFollow-up data was obtained from 39 patents. The majority of participants receiving PosMT reported that they had used the intervention, with few reporting side effects. The intervention group reported a significant improvement in self-rated health as measured by the EuroQual visual analogue scale, F(4,34) = 3.204, p = 0.025, R2 = 0.274.

DiscussionThis preliminary RCT found that PosMT in its current form could be used by patients with MS with little difficulty. Despite the small size of the study, allocation to the intervention was found to be associated with a significant improvement in self-rated health. Given the low cost of PosMT and its easy availability (it can simply be downloaded from a website), this pilot RCT suggests it could be a useful tool for MS patients. We believe this intervention warrants further study, ideally in a large multi-centre RCT.

category: neurology


title: Association between willingness to receive the COVID-19 vaccine and sources of health information among Japanese workers: a cohort study

abstract:
BackgroundIt is important to achieve herd immunity by vaccinating as many people as possible to end the COVID-19 pandemic. We investigated the relationship between willingness to receive vaccination and sources of health information among those who did not want to be vaccinated against COVID-19.

MethodsThis prospective cohort study collected data using a self-administered questionnaire survey. The baseline survey was conducted during December 22-25, 2020, and the follow-up survey during February 18-19, 2021. Participants were aged 20-65 years and worked at the time of the baseline survey (N = 33,087). After excluding 6,051 invalid responses, we included responses from 27,036 participants at baseline. In total, 19,941 people responded to the follow-up survey (74% follow-up rate). We excluded 7,415 participants who answered "yes" to the question "If a COVID-19 vaccine becomes available, would you like to get it?" in the baseline survey. We finally analyzed 12,526 participants.

ResultsThe odds ratio for change in willingness to be vaccinated from "no" to "yes" differed by source of health information. Compared with workers that used TV as a source of information, significantly fewer people who reported getting information from the Internet and friends/colleagues were willing to get the vaccine.

ConclusionsIt is important to approach workers who do not watch TV when implementing workplace vaccination programs. It is likely that willingness to be vaccinated can be increased through an active company policy whereby the top management recommend vaccination, coupled with an individual approach by occupational health professionals.

Trial registrationNot applicable.

category: occupational and environmental health


title: Identifying Louisiana Communities at the Crossroads of Environmental and Social Vulnerability, COVID-19, and Asthma

abstract: The COVID-19 pandemic has disproportionately affected the socially and environmentally vulnerable, including through indirect effects on other health conditions. Asthma is one such condition, which may be exacerbated by both prolonged adverse in-home exposures if quarantining in unhealthy homes and prolonged outdoor exposures if the ambient air quality is unhealthy or hazardous. As both are often the case in Environmental Justice (EJ) communities, here we have analyzed data at the census tract (CT) level for Louisiana to assess any correlation between social and environmental vulnerability, and health issues like COVID-19 and asthma. Higher Social Vulnerability Index (SVI), Particulate Matter less than 2.5 {micro}m in diameter (PM2.5) and Ozone levels were associated with higher rates of cumulative COVID-19 incidence at various time points during the pandemic, as well as higher average annual asthma hospitalization rates and estimated asthma prevalence. Further, cumulative COVID-19 incidence during the first three months of the pandemic was moderately correlated with both asthma hospitalizations and estimated prevalence, suggesting similar underlying factors may be affecting both conditions. Additionally, 137 CTs were identified where social and environmental vulnerabilities co-existed, of which 75 (55%) had high estimated prevalence of asthma. These areas are likely to benefit from asthma outreach that considers both social and environmental risk factors. Fifteen out of the 137 CTs (11%) not only had higher estimated prevalence of asthma but also a high burden of COVID-19. Further research in these areas may help to elucidate any common social determinants of health that underlie both asthma and COVID-19 burdens, as well as better clarify the possible role of the environment as related to the COVID-19 burden in Louisiana.


title: Taller height and risk of coronary heart disease and cancer: a within-sibship Mendelian randomization study

abstract:
Taller people have lower risk of coronary heart disease but higher risk of many cancers. Mendelian randomization studies in unrelated individuals have suggested that these relationships are potentially causal. However, Mendelian randomization estimates from samples of unrelated individuals are sensitive to demography (population stratification, assortative mating) and familial (indirect genetic) effects. Height could influence disease risk via anatomic and physiological effects of height (e.g., number of cells or the bore of arteries) or previous results may have been confounded by early-life environmental factors (e.g., parental socioeconomic position and nutrition).

In this study, we performed within-sibship Mendelian randomization analyses using 77,757 siblings, a design robust against demography and indirect genetic effects of parents. Within-sibship Mendelian randomization estimated that one SD taller height lowers odds of coronary heart disease by 14% (95% CI: 3% to 23%) but increases odds of cancer by 18% (95% CI: 3% to 34%). There was some evidence that taller height reduces systolic blood pressure and LDL cholesterol, which may mediate some of the protective effect of taller height on coronary heart disease risk.

For the first time, we have demonstrated that purported effects of height on adulthood disease risk are unlikely to be explained by demographic or familial factors, and so likely reflect an individual-level causal effect. Disentangling the mechanisms via which height affects disease risk may improve understanding of the aetiologies of atherosclerosis and carcinogenesis.

category: genetic and genomic medicine


title: Public opinion on sharing data from UK health services for clinical and research purposes without explicit consent

abstract:
1.BACKGROUNDIn the UK, National Health Service (NHS/HSC) data is variably shared between healthcare organizations for direct care, and increasingly used in de-identified forms for research. Few large-scale studies have examined public opinion on sharing, including the treatment of mental health (MH) versus physical health (PH) data.

METHODSPre-registered anonymous online survey open to all UK residents, recruiting Feb-Sep 2020. Participants were randomized to one of three framing statements regarding MH versus PH data.

FINDINGSParticipants numbered 29275; 40% had experienced a MH condition. A majority supported identifiable data sharing for direct clinical care without explicit consent, but 20% opposed this. Preference for clinical/identifiable sharing decreased with distance and was slightly less for MH than PH data, with a small framing effect. Preference for research/de-identified data sharing without explicit consent showed the same small PH/MH and framing effects, plus greater preference for sharing structured data than de-identified free text. There was net support for research sharing to the NHS, academic institutions, and national research charities, net ambivalence about sharing to profit-making companies researching treatments, and net opposition to sharing to other companies (similar to sharing publicly). De-identified linkage to non-health data was generally supported, except to data held by private companies. We report demographic influences on preference. A clear majority supported a single NHS mechanism to choose uses of their data. Support for data sharing increased during the pandemic.

INTERPRETATIONSupport for healthcare data sharing for direct care without explicit consent is broad but not universal. There is net support for the sharing of de-identified data for research to the NHS, academia, and the charitable sector, but not the commercial sector. A single national NHS-hosted system for patients to control the use of their NHS data for clinical purposes and for research would have broad public support.

FUNDINGMRC.

category: health informatics


title: Prevalence of anti-platelet factor4/polyanionic antibodies after COVID-19 vaccination with ChAdOx1 nCoV-19 and CoronaVac in Thais

abstract:
IntroductionVaccine-induced thrombotic thrombocytopenia (VITT) has been reported after vaccination with the adenoviral vector COVID-19 vaccine ChAdOx1 nCoV-19 in European countries. To date, no case of VITT has been reported in Thais after COVID-19 vaccination. We determined the frequency of anti-PF4/polyanionic antibodies in the Thai population receiving the COVID-19 vaccines.

MethodsWe conducted a cross-sectional study to evaluate the prevalence of anti-PF4/polyanionic antibodies in health care workers who received COVID-19 vaccination with ChAdOx1 nCoV-19 or CoronaVac within 7-35 days. A control population who had not been vaccinated was also included. Anti-PF4/polyanionic antibodies were detected using enzyme-link immunosorbent assay (ELISA). Functional assay with platelet aggregation was performed for all positive anti-PF4/polyanionic antibody ELISA tests.

ResultsA total of 646 participants were included in the study. 221 received ChAdOx1 nCoV-19, 232 received CoronaVac, and 193 participants were in the control group. The prevalence of anti-PF4 antibodies was 2.3% (95% confidence interval [CI] 0.7 to 5.2), 1.7% (95% CI, 0.5 to 4.4) in the ChAdOx1 nCoV-19 and CoronaVac groups, respectively. There was no positive test in the control group. None of the PF4/polyanionic positive sera induced platelet aggregation.

ConclusionWe found a low prevalence of anti-PF4 antibodies in Thais after vaccination with ChAdOx1 nCoV-19 and CoronaVac. Low titer positive PF4/polyanionic ELISA results should be interpreted with caution when screening asymptomatic individuals after vaccination against COVID-19.

HighlightsO_LIHigh titer PF4/polyanion antibodies are associated with vaccine-induced immune thrombotic thrombocytopenia (VITT).
C_LIO_LILow titer PF4/polyanion antibodies occur after vaccination with ChAdOx1 nCoV-19 and CoronaVac in some vaccinees.
C_LIO_LIThese PF4/polyanion antibodies do not activate platelets and lack of association with VITT.
C_LIO_LILow-titer positive PF4/polyanionic ELISA results should be interpreted with caution when screening asymptomatic individuals after vaccination against COVID-19.
C_LI

category: hematology


title: Low seropositivity and sub-optimal neutralisation rates in patients fully vaccinated against COVID-19 with B cell malignancies.

abstract:
Patients with haematological malignancies are at increased risk of severe disease and death from COVID-19 and are less likely to mount humoral immune responses to COVID-19 vaccination, with the B cell malignancies a particularly high-risk group.

Our COV-VACC study is evaluating the immune response to COVID-19 vaccination in patients with B cell malignancies. Eligible patients were either receiving active treatment or had received treatment within the last 24 months. Patients were vaccinated with either the BNT162b2 (Pfizer-BioNTech) (n=41) or ChAdOx1 nCoV-19 (Oxford-AstraZeneca) (n=14) vaccines. The median age of participants was 60 years (range: 27-82) and 50% were receiving systemic anti-cancer therapy (SACT) at the time of vaccination. This interim analysis from the first 55 participants describes anti-S seropositivity rates, neutralising antibody activity and association with peripheral lymphocyte subsets.

After the first vaccine dose, 36% overall had detectable anti-S antibodies rising to 42% after the second dose. Sera from seropositive patients was assessed for neutralisation activity in vitro. Of the seropositive patients after first dose (n=17), only 41% were able to neutralise SARS-CoV-2 pseudotyped virus with a 50% inhibitory dilution factor (ID50) of >1:50. After two doses (n=21) 57% of the seropositive patients had detectable neutralisation activity (median ID50 of 1:469, range 1:70 - 1:3056). Total blood lymphocyte, CD19, CD4 and CD56 counts were significantly associated with seropositivity. Patients vaccinated more than 6 months after completing therapy were significantly more likely to develop antibodies than those within 6 months of treatment or on active treatment; OR: 5.93 (1.29 - 27.28).

Our data has important implications for patients with B cell malignancies as we demonstrate a disconnect between anti-S seropositivity and virus neutralisation in vitro following vaccination against COVID-19.

Urgent consideration should be given to revaccinating patients with B-cell malignancies after completion of anti-cancer treatment as large numbers currently remain at high risk of infection with the increasing transmission of SARS-CoV-2 in many countries.

category: infectious diseases


title: Social determinants of health exacerbate disparities in COVID-19 illness severity and lasting symptom complaints

abstract:
BACKGROUNDIncreasing reports of long-term symptoms following COVID-19 infection, even among mild cases, necessitates systematic investigation into the prevalence and type of lasting illness. Notably, there is limited data regarding the influence of social determinants of health, like perceived discrimination and economic stress, which may exacerbate COVID-19 health risks. The primary goals of this study are to test the bearing of subjective experiences of discrimination, financial security, and quality of care on illness severity and lasting symptom complaints.

METHODS1,584 recovered COVID-19 patients that experienced mild to severe forms of the disease provided information about their illness, medical history, lasting symptoms, and psychosocial information. Prevalence data isolated differences in patients infected early versus late in the pandemic. Path analyses examined hypothesized associations between discrimination, illness severity, and lasting symptoms. Post hoc logistic regressions tested social determinants hypothesized to predict neurological, cognitive, or mood symptoms.

RESULTS70.6% of patients reported presence of one or more lasting symptoms after recovery. Neural systems were especially impacted, and 19.4% and 25.1% of patients reported mood or cognitive/memory complaints, respectively. Path models demonstrated that frequency and stress about experiences of discrimination predicted increased illness severity and increased lasting symptom count, even when adjusting for sociodemographic factors and mental/physical health comorbidities. Notably, this effect was specific to stress related to discrimination, and did not extend to general stress levels. Further, perceived but not objective socioeconomic status (SES) was associated with increased lasting symptom complaints after recovery. Finally, associations between discrimination and illness differed with individual perceptions about quality of medical care.

CONCLUSIONSLasting symptoms after recovery from COVID-19 are highly prevalent and neural systems are significantly impacted. Importantly, psychosocial factors (perceived discrimination and perceived SES) can exacerbate individual health risk. This study provides actionable directions for improved health outcomes by establishing that sociodemographic risk and medical care influence near and long-ranging health outcomes.


title: SARS-CoV-2 infection in fully vaccinated individuals of old age strongly boosters the humoral immune response

abstract:
IntroductionProphylactic vaccination against SARS-CoV-2 is one of the most important measures to contain the COVID-19 pandemic. Recently, break-through infections following vaccination against this virus have been reported. Here, we describe the humoral immune response of break-through infections in fully vaccinated individuals of old age from an outbreak in a nursery home.

MethodsIn cooperation with the local health authority, blood samples from fully vaccinated and infected as well as fully vaccinated and uninfected residents of the nursery home were collected four weeks after the onset of the outbreak. The humoral immune response was determined in a neutralisation assay with replication-competent virus isolates and by a quantitative ELISA.

ResultsIn this outbreak a total of 23 residents and four health care workers were tested positive for SARS-CoV-2. Four residents were unvaccinated, including one with a severe course of disease who later deceased. Despite their old age, all vaccinated residents showed no or only mild disease. Comparison of the humoral immune response revealed significantly higher antibody levels in fully vaccinated infected individuals compared to fully vaccinated uninfected individuals (p<0.001). Notably, although only a minority of the vaccinated uninfected group showed neutralisation capacity against SARS-CoV-2, all vaccinated and infected individuals showed high-titer neutralisation of SARS-CoV-2 including the alpha and beta variant.

DiscussionLarge SARS-CoV-2 outbreaks can occur in fully vaccinated populations, but seem to associate with mild disease. SARS-CoV-2 infection in fully vaccinated individuals is a strong booster of the humoral immune response providing enhanced neutralisation capacity against immune evasion variants.


title: ABO and Rh blood groups, demographics, and comorbidities in COVID-19 related deaths: a retrospective study in Split-Dalmatia County, Croatia

abstract:
AimTo examine ABO and Rh blood group distribution in COVID-19 related deaths considering demographics and pathological conditions.

Materials and MethodsWe conducted a retrospective study at the University Hospital Centre Split, Croatia, that included 245 COVID-positive individuals that died from April 8, 2020, to January 25, 2021. From the hospital database, we extracted data on their blood groups, demographics, and pre-existing comorbidities. To compare findings with the general population, we used information from collected blood group donations (n = 101357) and statistical reports of non-COVID deaths from 2019 (n = 4968).

ResultsThe proportion of males was significantly higher in analyzed subjects than in non- COVID deaths from 2019 (63.7% vs. 48.9%, P < 0.001), while the proportion of older individuals did not differ (P = 0.8). The most common pre-existing diseases were hypertension (59.6%), diabetes (37.1%), heart failure (28.8%), digestive disorder (26.5%), and solid tumor (21.6%). The ABO distribution in the deceased and donors group showed statistically significant differences, with the higher prevalence of A/AB group and lower prevalence of 0, but with individual differences significant only for AB and non-AB groups. There was a significantly reduced proportion of females within the deceased with group 0 (P = 0.014) and a higher proportion of AB individuals with coronary heart disease (P = 0.024), while other differences were not significant.

ConclusionThe study confirmed a higher risk of death in male individuals. The lower proportion of type 0 in deceased individuals was more pronounced in females, implying that group 0 is not necessarily an independent protective factor. Among analyzed comorbidities, coronary heart disease was identified as a potential risk factor for AB individuals.


title: Vaccination is Australia's most important COVID-19 public health action, even though herd immunity is unlikely

abstract:
The Australian National Cabinet four-step plan to transition to post-pandemic re-opening begins with vaccination to achieve herd protection and protection of the health system against a surge in COVID-19 cases. Assuming a pre-vaccination reproduction number for the Delta variant of 5, we show that for the current Mixed program of vaccinating over 60s with AstraZeneca and 16-60s with Pfizer we would not achieve herd immunity. We would need to cover 85% of the population (including many 5-16 year-olds to achieve herd immunity).

At lower reproduction number of 3 and our current Mixed strategy, we can achieve herd immunity without vaccinating 5-15 year olds. This will be achieved at a 60% coverage pursuing a strategy targetting high transmitters or 70% coverage using a strategy targetting the vulnerable first. A reproduction number of 7 precludes achieving herd immunity, however vaccination is able to prevent 75% of deaths compared with no vaccination.

We also examine the impact of vaccination on death in the event that herd immunity is not achieved. Direct effects of vaccination on reducing death are very good for both Pfizer and AstraZeneca vaccines. However we estimate that the Mixed or Pfizer program performs better than the AstraZeneca program.

Furthermore, vaccination levels below the herd immunity threshold can lead to substantial (albeit incomplete) indirect protection for both vaccinated and unvaccinated populations. Given the potential for not reaching herd immunity, we need to consider what level of severe disease and death is acceptable, balanced against the consequences of ongoing aggressive control strategies.

O_TEXTBOXThe known: SARS CoV-2 variants are known to be more transmissible than the original Wuhan strain, making herd immunity challenging.

The new: We find that vaccinating the older-vulnerable age groups first leads to fewer deaths and is the optimal strategy vaccine coverage is under 70%. Herd immunity achieved solely through vaccinating adults is unlikely, but can still be expected to prevent substantial numbers of deaths.

The implications: Australia is unlikely to achieve herd immunity unless vaccination is combined with substantial public health measures. Even without herd immunity, vaccination remains a highly effective means to mitigate the impact of COVID-19.

C_TEXTBOX