title: A multiplexed high-throughput neutralization assay reveals a lack of activity against multiple variants after SARS-CoV-2 infection

abstract:
The detection of SARS-CoV-2-specific antibodies in the serum of an individual indicates prior infection or vaccination. However, it provides limited insight into the protective nature of this immune response. Neutralizing antibodies recognizing the viral Spike are far more revealing, yet their measurement traditionally requires virus- and cell-based systems that are costly, time-consuming, poorly flexible and potentially biohazardous. Here we present a cell-free quantitative neutralization assay based on the competitive inhibition of trimeric SARS-CoV-2 Spike protein binding to the angiotensin converting enzyme 2 (ACE2) viral receptor. This high-throughput method matches the performance of the gold standard live virus infectious assay, as verified with a panel of 206 seropositive donors with varying degrees of infection severity and virus-specific IgG titers, achieving 96.7% sensitivity and 100% specificity. Furthermore, it allows for the parallel assessment of neutralizing activities against multiple SARS-CoV-2 Spike variants of concern (VOC), which is otherwise unpredictable even in individuals displaying robust neutralizing antibody responses. Profiling serum samples from 59 hospitalized COVID-19 patients, we found that although most had high activity against the 2019-nCoV Spike and to a lesser extent the B.1.1.7 variant, only 58% could efficiently neutralize a Spike derivative containing mutations present in the B.1.351 variant. In conclusion, we have developed an assay that has proven its clinical relevance in the large-scale evaluation of effective neutralizing antibody responses to VOC after natural infection and that can be applied to the characterization of vaccine-induced antibody responses and of the potency of human monoclonal antibodies.

Once sentence summaryMultiplexed cell-free neutralization assay for quantitative assessment of serum antibody responses against Spike mutations in SARS-COV-2 variants


title: Impaired HA-specific T follicular helper cell and antibody responses to influenza vaccination are linked to inflammation in humans.

abstract:
Antibody production following vaccination can provide protective immunity to subsequent infection from pathogens such as influenza. However, circumstances where antibody formation is impaired after vaccination, such as in older people, require us to better understand the cellular and molecular mechanisms that underpin successful vaccination in order to improve vaccine design for at risk groups. Here, by studying the breadth of anti-hemagglutinin (HA) IgG, serum cytokines, and B and T cell responses by flow cytometry before and after influenza vaccination, we show that formation of circulating T follicular helper cells (cTfh) cells are the best predictor of high titre antibody responses. Using MHC class II tetramers we demonstrate that HA-specific cTfh cells can derived from pre-existing memory CD4+ T cells and have a diverse TCR repertoire. In older people, the differentiation of HA-specific cells into cTfh cells was impaired. This age-dependent defect in cTfh cell formation was not due to a contraction of the TCR repertoire, but rather was linked with an increased inflammatory gene signature in cTfh cells. Together this suggests that strategies that temporarily dampen inflammation at the time of vaccination may be a viable strategy to boost optimal antibody generation upon immunisation of older people.

One sentence summaryAntibody production upon vaccination requires antigen-specific cTfh cells whose formation is suppressed by pro-inflammatory cytokine signalling.

category: allergy and immunology


title: Detection of SARS-CoV-2 variant 501Y.V2 in Comoros Islands in January 2021

abstract:
Phylogenetic analysis of six SARS-CoV-2 genomes collected from the Comoros islands confirmed local circulation of the 501Y.V2 variant of concern during the countrys first major SARS-CoV-2 wave in January 2021. These findings demonstrate the importance of SARS-CoV-2 genomic surveillance and have implications for ongoing COVID-19 control strategies on the islands.

Article summary lineCirculation of SARS-CoV-2 501Y.V2 variant of concern in the Comoros Islands during a major COVID-19 infection wave in January 2021

category: epidemiology


title: The emergence of SARS-CoV-2 variant(s) and its impact on the prevalence of COVID-19 cases in Nabatieh region, Lebanon

abstract:
BackgroundAn outbreak of an unknown respiratory illness caused by a novel corona-virus, SARS-CoV-2, emerged in the city of Wuhan in Hubei province, China, in December 2019 and was referred to as coronavirus disease-2019 (COVID-19). Soon after, it was declared as a global pandemic by the World Health Organization (WHO) in March 2020. SARS-CoV-2 mainly infects the respiratory tract with different outcomes ranging from asymptomatic infection to severe critical illness leading to death. Different SARS-CoV-2 variants are emerging of which three have raised concerns worldwide due to their high transmissibility among populations.

ObjectiveTo study the prevalence of COVID-19 in the region of Nabatieh - South Lebanon during the past year and assess the presence of SARS-CoV-2 variants and their effect on the spread of infection during times of lock-down. Methods: In our study, 37,474 nasopharyngeal swab samples were collected and analyzed for the detection of SARS-CoV-2 virus in suspected patients attending a tertiary health care center in South Lebanon during the period between March 16, 2020 and February 21, 2021.

ResultsResults demonstrated a variation in the prevalence rates ranging from less than 1% during full lockdown of the country to 8.4% upon easing lockdown restrictions and reaching 27.5% after the holidays and 2021 New Year celebrations. Interestingly, a new variant(s) appeared starting January 2021 with a significant positive association between the prevalence of positive tests and the percentage of the variant(s).

ConclusionOur results indicate that the lockdown implemented by the Lebanese officials presented an effective intervention to contain COVID-19 spread. Our study also showed that lifting lockdown measures during the holidays, which allowed indoor crowded gatherings to occur, caused a surge in COVID-19 cases and rise in the mortality rates nationwide. More importantly, we confirmed the presence of a highly transmissible SARS-CoV-2 variant(s) circulating in the Lebanese community, at least since January 2021 onwards.


title: ddPCR Reveals SARS-CoV-2 Variants in Florida Wastewater

abstract: Wastewater was screened for the presence of functionally significant mutations in SARS-CoV-2 associated with emerging variants of concern (VOC) by ddPCR, and results accorded with sequencing of clinical samples from the same region. We propose that PCR-based screening of wastewater can provide a powerful tool for rapid and inexpensive screening of large population segments for VOC-associated mutations and can hone complementary sampling and sequencing of direct (human) test material to track emerging VOC.


title: The PUPPY Study - Protocol for a Longitudinal Mixed Methods Study Exploring Problems Coordinating and Accessing Primary Care for Attached and Unattached Patients Exacerbated During the COVID-19 Pandemic Year

abstract:
BackgroundThe COVID-19 pandemic significantly disrupted primary care in Canada, with many walk-in clinics and family practices initially closing or being perceived as inaccessible, pharmacies remaining open with restrictions on patient interactions, rapid uptake of virtual care, and reduced referrals for lab tests, diagnostics, and specialist care. The PUPPY Study (Problems Coordinating and Accessing Primary Care for Attached and Unattached Patients Exacerbated During the COVID-19 Pandemic Year) seeks to understand the impact of COVID-19 across the quadruple aim of primary care, with particular focus on the impacts on patients without attachment to a regular provider and those with chronic health conditions.

ObjectiveThe PUPPY Study objective is to understand the impact of COVID-19 across the quadruple aim of primary care.

MethodsThe PUPPY study builds on an existing research program exploring patients access and attachment to primary care, pivoted to adapt to the emerging COVID-19 context. We will undertake a longitudinal mixed methods study to understand critical gaps in primary care access and coordination, comparing data pre- and post-pandemic in three Canadian provinces (Quebec, Ontario, and Nova Scotia). Multiple data sources will be used including: a policy review; qualitative interviews with primary care policymakers, providers (i.e., family physicians, nurse practitioners, and pharmacists), and patients (N=120); and medication prescribing and healthcare billings. The findings will inform the strengthening of primary care during and beyond the COVID-19 pandemic.

ResultsFunding was provided by the Canadian Institutes of Health Research COVID-19 Rapid Funding Opportunity Grant. Ethical approval to conduct this study was granted in Ontario (Queens Health Sciences & Affiliated Teaching Hospitals Research Ethics Board, file number 6028052; Western University Health Sciences Research Ethics Board, project 116591; University of Toronto Health Sciences Research Ethics Board, protocol number 40335), Quebec (Centre integre universitaire de sante et de services sociaux de lEstrie, project number 2020-3446) and Nova Scotia (Nova Scotia Health Research Ethics Board, file number 1024979).

ConclusionsThis is the first study of its kind exploring the impacts of COVID-19 on primary care systems, with particular focus on the issues of patients attachment and access to primary care. Through a multi-stakeholder, cross-jurisdictional approach, the PUPPY Study will generate findings and implications for future policy and practice.

category: primary care research


title: Mental health in the UK Biobank: a roadmap to self-report measures and neuroimaging correlates

abstract: The UK Biobank (UKB) is a highly promising dataset for brain biomarker research into population mental health due to its unprecedented sample size and extensive phenotypic, imaging, and biological measurements. In this study, we aimed to provide a shared foundation for UKB neuroimaging research into mental health with a focus on anxiety and depression. We compared UKB self-report measures and revealed important timing effects between scan acquisition and separate online acquisition of some mental health measures. To overcome these timing effects, we introduced and validated the Recent Depressive Symptoms (RDS-4) score which we recommend for state-dependent and longitudinal research in the UKB. We furthermore tested univariate and multivariate associations between brain imaging derived phenotypes (IDPs) and mental health. Our results showed a significant multivariate relationship between IDPs and mental health, which was replicable. Conversely, effect sizes for individual IDPs were small. Test-retest reliability of IDPs was stronger for measures of brain structure than for measures of brain function. Taken together, these results provide benchmarks and guidelines for future UKB research into brain biomarkers of mental health.

category: psychiatry and clinical psychology


title: COVID-19 and mortality risk in patients with psychiatric disorders

abstract:
COVID-19 has already caused the deaths of over 2.5 million people worldwide. Patients with certain medical conditions and severe psychiatric disorders are at increased risk of dying from it. However, such people have a reduced life expectancy anyway, raising the question whether COVID-19 incurs a specific risk for such patients for dying, over and above the risk of dying from other causes.

We analysed the UK Biobank data of half a million middle-aged participants from the UK. From the start of 2020 up to 24th January 2021, 894 participants had died from COVID-19 and another 4,562 had died from other causes. We demonstrate that the risk of dying from COVID-19 among patients with mental health problems, especially those with dementia, schizophrenia, or bipolar disorder, is increased compared to the risk of dying from other causes. This increase among patients with severe psychiatric disorders cannot be explained solely by the higher rate of diabetes or cardiovascular disorders.


title: Participating in vaccine research for COVID-19 in Senegal: trust and information

abstract: This research aims to understand the level and determinants of peoples willingness to participate in a vaccine trial for COVID-19 in Senegal. We conducted a telephone survey among a marginal quota sample of 607 people over 18 years of age. Only 44.3% of the participants wanted to participate in a vaccine trial for COVID-19, with females intending to participate more than males. Participants who intended to be vaccinated against COVID-19 (OR = 6.48, 95% CI [4.12-10.4]) and who thought that being infected with the coronavirus would have a significant impact on their health (OR = 2.34, 95% CI [1.57, 3.51]) were more likely to agree to take part in the COVID-19 vaccine research. Confidence in the vaccine, health personnel, and government in the fight against the pandemic are key factors in intending to participate in vaccine research in Senegal.

category: public and global health


title: Volumetric lung cancer screening reduces unnecessary low-dose computed tomography scans: results from a single-centre prospective trial on 4,119 subjects

abstract:
PurposeTo compare low-dose computed tomography (LDCT) outcome and volume-doubling time (VDT) derived from measured volume (MV) and estimated volume (EV) of pulmonary nodules (PN) detected in a single-centre lung cancer screening trial.

Materials and MethodsMV, EV and VDT were obtained for prevalent pulmonary nodules detected at the baseline round of the bioMILD trial. LDCT outcome (based on bioMILD thresholds) and VDT categories were simulated on a PN- and a screenees-based analysis. Weighted Cohens kappa test was used to assess the agreement between diagnostic categories as per MV and EV.

Results1,583 screenees displayed 2,715 pulmonary nodules. On a PN-based analysis 40.1% PNs would have been included in different LDCT categories if measured by MV or EV. Agreement between MV and EV was moderate ({kappa} = 0.49) and fair ({kappa} = 0.37) for LDCT outcome and VDT categories, respectively.

On a screenees-based analysis, 46% pulmonary nodules would have been included in different LDCT categories if measured by MV or EV. Agreement between MV and EV was moderate ({kappa} = 0.52) and fair ({kappa} = 0.34) for LDCT outcome and VDT categories, respectively.

ConclusionsWithin a simulated lung cancer screening based on recommendation by estimated volumetry, the number of LDCT performed for the evaluation of pulmonary nodules would be higher as compared to the prospective volumetric management.

category: radiology and imaging


title: Immunogenicity of SARS-CoV-2 Vaccine in Dialysis

abstract:
BackgroundPatients receiving maintenance dialysis represent a high risk, immune-compromised population with 15-25% COVID mortality rate who were unrepresented in clinical trials evaluated for mRNA vaccines emergency use authorization.

MethodAll patients receiving maintenance dialysis that received two doses of SARS-CoV-2 mRNA vaccines with antibody test results drawn [≥]14 days after the second dose, as documented in the electronic health record through March 18, 2021 were included. We report seroresponse based on levels of immunoglobulin-G against the receptor binding domain of the S1 subunit of SARS-CoV-2 spike antigen (seropositive [≥]2) using FDA-approved semi-quantitative chemiluminescent assay (ADVIA Centaur(R) XP/XPT COV2G).

ResultsAmong 186 dialysis patients from 32 clinics in 8 states tested 23{+/-}8 days after receiving 2 vaccine doses, mean age was 68{+/-}12 years, with 47% women, 21% Black, 26% residents in long-term care facilities and 97% undergoing in-center hemodialysis. Overall seropositive rate was 165/186 (88.7%) with 70% at maximum titer and with no significant difference in seropositivity between BNT162b2/Pfizer (N=148) and mRNA-1273/Moderna (N=18) vaccines (88.1% vs. 94.4%, p=0.42). Among patients with COVID-19 history, seropositive rate was 38/38 (100%) with 97% at maximum titer.

ConclusionMost patients receiving maintenance dialysis were seropositive after two doses of BNT162b2/Pfizer or mRNA-1273/Moderna vaccine. Early evidence suggests that vaccinated dialysis patients with prior COVID-19 develop robust antibody response. These results support an equitable and aggressive vaccination strategy for eligible dialysis patients, regardless of age, sex, race, ethnicity, or disability, to prevent the extremely high morbidity and mortality associated with COVID-19 in this high risk population.

SignificanceIn this retrospective observational evaluation of SARS-CoV-2 mRNA vaccine response defined by detectable levels of immunoglobulin-G against the receptor binding domain of the S1 subunit of SARS-CoV-2 spike antigen of [≥]2 in serum of patients receiving maintenance dialysis, 165/186 (88.7%) were found to be seropositive (with 70% at maximum titer) at least 14 days after completing the second dose. No significant differences were observed by race or other subgroup or by vaccine manufacturer. Therefore, an equitable and aggressive vaccination strategy for all eligible maintenance dialysis patients, regardless of age, sex, race, ethnicity, or disability, is warranted to prevent the extremely high morbidity and mortality associated with COVID-19 in this high risk population.

category: nephrology


title: Growth charts for individualized evaluation of brain morphometry for preschool children

abstract: Brain development from 1 to 6 years-of-age anchors the rapid development of a wide range of functional capabilities. However, quantitative growth charts of typical development during this age period are lacking, preventing the identification of early brain abnormalities. Here we characterize the time-dependent individual differences of cortical thickness and subcortical volume in 340 typically developing children and construct regional growth curves for these brain morphological measures. The growth curves reflect four types of time-dependence for cortical thickness and subcortical volume metrics. At the individual level, the growth curve model provides percentiles for each brain regions cortical thickness or volume during ages 1 to 6, allowing for individualized inferences of brain developmental status relative to the same-age population. The growth curves further demonstrate clinical utility potentials by identifying children with developmental speech and language disorders, achieving high accuracies on data collected on both 1.5T and 3T scanners. Our results fill the knowledge gap in brain morphometrics in a critical development period and provide an avenue for individualized brain developmental status evaluation, with demonstrated sensitivity and generalizability.

category: neurology


title: Asia Pacific Sepsis Alliance; Critical Care Resources and Disaster Preparedness Survey 2020 Results (March 2021)

abstract:
AimTo investigate critical care resourcing and the clinical management of sepsis in lower-middle income, upper-middle income and high income countries across the Asia Pacific region.

BackgroundSepsis is a time-critical complex condition that requires evidence-based care delivered by appropriate levels of well trained, qualified and experienced staff supported by proactive organisational and quality processes, sophisticated technologies and reliable infrastructure. In 2017, the estimated sepsis incidence in the Asia Pacific region ranged from 120 to 200 per 100,000 population in Australia and New Zealand to 2500 to 3400 per 100,000 population in India. Currently, there is limited information on the organisational structures, human resources, clinical standards, laboratory support and the therapeutic options available in the Asia Pacific region to treat sepsis.

MethodProspective electronic survey.

ResultsRepresentatives of 59 hospitals from 15 countries responded. Provision of critical care and the management of sepsis varied considerably between lower-middle income, upper-middle income and high income countries. Specific differences include nurse to patient ratios and availability of allied health services.

Conventional organ support modalities such as mechanical ventilation and non-invasive ventilation were commonly available. Even advanced life support like extracorporeal membrane oxygenation was available in at least 60% of surveyed ICUs. However, in contrast, essential monitoring devices including EtCO2 were not universally available.

Lower-middle income countries had considerably lower provisions for isolation and surge capacity to support pandemic and disaster management, though basic personal protective equipment was widely available.

A majority of ICUs used the Surviving Sepsis Campaign guidelines or the adapted version for lower-middle income countries, though only 21% of ICUs in lower-middle income countries used the adapted version. While essential antimicrobials were accessible across most ICUs, availability of reserve antibiotics was limited.

ConclusionThe disparities identified in this survey inform healthcare workers and health services, policy makers and governments on the priorities for action to improve the delivery of critical care and sepsis outcomes in this region.

category: health systems and quality improvement


title: High coverage COVID-19 mRNA vaccination rapidly controls SARS-CoV-2 transmission in Long-Term Care Facilities

abstract: Residents of Long-Term Care Facilities (LTCFs) represent a major share of COVID-19 deaths worldwide. Information on vaccine effectiveness in these settings is essential to improve mitigation strategies, but evidence remains limited. To evaluate the early effect of the administration of BNT162b2 mRNA vaccines in LTCFs, we monitored subsequent SARS-CoV-2 documented infections and deaths in Catalonia, a region of Spain, and compared them to counterfactual model predictions from February 6th to March 28th, 2021, the subsequent time period after which 70% of residents were fully vaccinated. We calculated the reduction in SARS-CoV-2 documented infections and deaths as well as the detected county-level transmission. We estimated that once more than 70% of the LTCFs population were fully vaccinated, 74% (58%-81%, 90% CI) of COVID-19 deaths and 75% (36%-86%) of all documented infections were prevented. Further, detectable transmission was reduced up to 90% (76-93%). Our findings provide evidence that high-coverage vaccination is the most effective intervention to prevent SARS-CoV-2 transmission and death. Widespread vaccination could be a feasible avenue to control the COVID-19 pandemic.

category: infectious diseases


title: Detection of SARS-CoV-2 specific IgA in the human milk of COVID-19 vaccinated, lactating health care workers

abstract:
ImportanceIn 2019, a deadly virus known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), responsible for COVID-19, emerged. In December 2020, two mRNA-based COVID-19 vaccines were approved for use in the United States (US) which provide immunity to those receiving the vaccine. Maternally derived antibodies are a key element of infants immunity. Certain vaccines given to pregnant and lactating mothers provide immunity to infants through transmission across the placenta, umbilical cord (IgG) and human milk (IgA). Human milk produced by mothers with a history of COVID-19 infection contains SARS-CoV-2 IgA and IgG.

ObjectiveTo determine whether SARS-CoV-2 specific immunoglobulins are found in human milk after the COVID-19 vaccination, and to characterize the types of immunoglobulins present.

Design, setting, and participantsThis is a prospective observational study conducted at Shands Hospital, University of Florida from December 2020 to March 2021. Twenty-two lactating healthcare workers who received the SARS-CoV-2 mRNA vaccine (Pfizer/BioNtech or Moderna) made up the sample group. Plasma and human milk were collected at three-time points (pre-vaccination, post-first vaccine dose, and post-second vaccine dose). SARS-CoV-2 specific IgA and IgG in human milk and in plasma were measured by ELISA. Maternal demographics was compiled.

ExposuresPfizer/BioNtech or Moderna vaccination.

Main outcome and measureLevels of SARS-CoV-2 IgA and IgG in human milk and plasma.

ResultsWe found significant secretion of SARS-CoV-2 specific IgA and IgG in human milk and plasma after SARS-CoV-2 vaccination.

Conclusions and relevanceOur results show that the mRNA-based COVID-19 vaccines induce SARS-CoV-2 specific IgA and IgG secretion in human milk. Further studies are needed to determine the duration of this immune response, its capacity to neutralize the COVID-19 virus, the transfer of passive immunity to breastfeeding infants, and the potential therapeutic use of human milk IgA to combat SARS-CoV-2 infections and COVID-19.

KEY POINTSO_ST_ABSQuestionC_ST_ABSIs there SARS-CoV-2 specific IgA in the human milk of lactating women after COVID-19 vaccination?

FindingsIn this prospective observational study that included 22 lactating women, we found SARS-CoV-2 specific IgA in the human milk in response to the COVID-19 vaccination series. There is statistically significant secretion of SARS-CoV-2 IgA in human milk after mRNA COVID-19 vaccination series completion (p < 0.0001).

MeaningNewborn immunologic defense is present but immature. SARS-CoV-2 IgA secreted in the human milk could potentially provide COVID-19 protection to nursing infants. These results could guide a strategy for SARS-CoV-2 vaccination among lactating women.


title: Circulating Plasma Biomarkers in Biopsy-Confirmed Kidney Disease: Results from the Boston Kidney Biopsy Cohort

abstract:
BackgroundBiomarkers for non-invasive assessment of histopathology and prognosis are needed in patients with kidney disease.

MethodsUsing a proteomics assay, we measured a multi-marker panel of 225 circulating plasma proteins in a prospective cohort study of 549 individuals with biopsy-confirmed kidney diseases and semi-quantitative assessment of histopathology. We tested the associations of each biomarker with histopathologic lesions and the risks of kidney disease progression (defined as [≥]40% decline in eGFR or ESKD) and death.

ResultsAfter multivariable adjustment and correction for multiple testing, 46 proteins associated with different histopathologic lesions. The top performing markers positively associated with acute tubular injury and interstitial fibrosis and tubular atrophy were kidney injury molecule-1 (KIM-1) and V-set and immunoglobulin domain-containing protein 2 (VSIG2). 30 proteins were significantly associated with kidney disease progression and 35 with death. The top performing markers for kidney disease progression were placental growth factor (PGF; HR 5.4, 95% CI 3.4 to 8.7) and BMP and Activin Membrane Bound Inhibitor (BAMBI; HR 3.0, 95% CI 2.1 to 4.2); the top performing markers for death were TRAIL-receptor-2 (TRAIL-R2; HR 2.9, 95% CI 2.0 to 4.0) and CUB Domain Containing Protein-1 (CDCP1; HR 2.4, 95% CI 1.8, 3.3).

ConclusionWe identified several biomarkers associated with kidney disease histopathology and prognosis - many of which have not been reported previously and may represent important avenues for future research.


title: Trends, wealth inequalities and the role of the private sector in caesarean section in the Middle East and North Africa: a repeat cross-sectional analysis of population-based surveys

abstract:
ObjectiveTo examine trends and variations of caesarean section by economic status and type of healthcare facility in Arab countries in Middle East and North Africa (MENA).

MethodsSecondary data analysis of nationally representative household surveys across nine Arab countries in MENA. The study population was women aged 15-49 years with a live birth in the two years preceding the survey. Temporal changes in the use of caesarean section in each of the nine countries were calculated using generalised linear models and presented as risk differences(RD) with 95% confidence intervals(95%CI). Caesarean section was disaggregated against household wealth index and type of healthcare facility.

ResultsUse of caesarean section ranged from 57.3% (95%CI:55.6-59.1%) in Egypt to 5.7% of births (95%CI:4.9-6.6%) in Yemen. Overall, the use of caesarean section has increased across the MENA region, except in Jordan, where there was no evidence of change (RD -2.3% (95%CI:-6.0-1.4%). Within all MENA countries, caesarean section use was highest in the richest quintile compared poorest quintile, for example, 43.8% (95%CI:38.0-47.6%) vs. 22.6% (95%CI:19.6-25.9%) in Iraq, respectively. Caesarean section was higher in private sector facilities compared to public sector: 21.8% (95%CI:18.2-25.9 %) vs. 15.7% (95%CI:13.3-18.4%) in Yemen, respectively.

ConclusionVariations in caesarean section exist within and between Arab countries, and it was more commonly used amongst the richest quintiles and in private healthcare facilities. The private sector has a prominent role in the trends. Urgent policies and interventions are required to address non-medically indicated intervention.

category: obstetrics and gynecology


title: The Impact of HPV DNA/p16 in Laryngeal/Hypopharyngeal Cancer: a Systematic Review and Meta-analysis.

abstract:
BackgroundThis meta-analysis seeks to investigate the association between HPV and p16 status with overall survival in laryngeal and hypopharyngeal carcinoma.

MethodsMedline, Scopus, EMBASE, and the Cochrane Library were used to identify studies for inclusion. Abstracts that discussed HPV/p16 status and prognosis in laryngeal or hypopharyngeal carcinoma were included. Next, full-text articles were screened and included based upon a checklist established a priori. Pooled hazard ratios for overall survival were generated using a random effects model. RevMan 5.3, Meta Essentials, and OpenMeta[Analyst] were used for statistical analysis.

ResultsThirteen studies published between 2014 and 2019 with sample sizes ranging from 31 to 9,656 were selected for inclusion in this meta-analysis. The pooled data demonstrated that p16 status was not significantly associated with OS in either laryngeal or hypopharyngeal carcinoma with HRs of 1.03 (95% CI: 0.73-1.45; p = 0.88) and 1.02 (95% CI: 0.55-1.86; p = 0.96), respectively. The pooled data showed that HPV status was predictive of OS in laryngeal cancer with 0.63 (95% CI: 0.41-0.97; p = 0.03).

ConclusionsOur results suggest that p16-positivity does not provide a survival benefit in LC and HPC. This is in contrast to studies in the oropharynx, where p16 status is a standard proxy for HPV infection and HPV infection is associated with improved prognosis.

category: otolaryngology


title: The effect of heat events on prehospital and retrieval service utilisation in rural and remote areas: a scoping review

abstract:
IntroductionIt is well established that heatwaves increase demand for emergency transport in metropolitan areas, however little is known about the impact of heat events on demand for prehospital retrieval services in rural and remote areas, or how heatwaves are defined in this context.

Inclusion criteriaPapers were eligible for inclusion if they reported on the impact of a heat event on the activity of a prehospital and retrieval service in a rural or remote area.

MethodsA search of PubMed, Cochrane, Science Direct, CINAHL and Google Scholar databases was undertaken on 18 August 2020, using search terms related to emergency medical transport, extreme heat and rural or remote. Data relevant to the impact of heat on retrieval service activity was extracted, as well as definitions of extreme heat.

ResultsTwo papers were identified, both from Australia. Both found that heat events increased the number of road ambulance call-outs. Both studies used the Excess Heat Factor to define heatwave periods of interest.

ConclusionsThis review found almost no primary literature on demand for prehospital retrieval services in rural and remote areas, and no data specifically related to aeromedical transport. The research did recognise the disproportionate impact of heat-related increase in service demand on rural and regional health services. With the effects of climate change already being felt, there is an urgent need for more research and action in this area.


title: The second wave of COVID-19 incidence and deaths in Germany - driven by values, social status and migration background? A county-scale explainable machine learning approach

abstract:
There is a general consensus that SARS-CoV-2 infections and COVID-19 deaths have hit lower social groups the hardest, however, for Germany individual level information on socioeconomic characteristics of infections and deaths does not exist. The aim of this study was to identify the key features explaining SARS-CoV-2 infections and COVID-19 deaths during the upswing of the second wave in Germany.

We considered information on COVID-19 diagnoses and deaths from 1. October to 15. December 2021 on the county-level, differentiating five two-week time periods. We used 155 indicators to characterize counties in nine geographic, social, demographic, and health domains. For each period, we calculated directly age-standardized COVID-19 incidence and death rates on the county level. We trained gradient boosting models to predict the incidence and death rates with the 155 characteristics of the counties for each period. To explore the importance and the direction of the correlation of the regional indicators we used the SHAP procedure. We categorized the top 20 associations identified by the Shapley values into twelve categories depicting the correlation between the feature and the outcome.

We found that counties with low SES were important drivers in the second wave, as were those with high international migration and a high proportion of foreigners and a large nursing home population. During the period of intense exponential increase in infections, the proportion of the population that voted for the Alternative for Germany (AfD) party in the last federal election was among the top characteristics correlated with high incidence and death rates.

We concluded that risky working conditions with reduced opportunities for social distancing and a high chronic disease burden put populations in low-SES counties at higher risk of SARS-CoV-2 infections and COVID-19 deaths. In addition, noncompliance with Corona measures and spill-over effects from neighbouring counties increased the spread of the virus. To further substantiate this finding, we urgently need more data at the individual level.


title: The second wave of SARS-CoV-2 infections and COVID-19 deaths in Germany - driven by values, social status and migration background? A county-scale explainable machine learning approach


title: Vaccination boosts protective responses and counters SARS-CoV-2-induced pathogenic memory B cells

abstract: Given the rapid spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the recent implementation of SARS-CoV-2 vaccination, we have much to learn about the duration of immune protection and the interface between the immune responses to infection and to vaccination. To address these questions, we monitored immune responses to SARS-CoV-2 infection in convalescent individuals over seven months and following mRNA vaccination. Spike Receptor-Binding-Domain (RBD)-specific circulating antibodies and plasma neutralizing activity generally decreased over time, whereas RBD-specific memory B cells persisted. Additionally, using antibody depletion techniques, we showed that the neutralizing activity of plasma specifically resides in the anti-RBD antibodies. More vigorous antibody and B cell responses to vaccination were observed in previously infected subjects relative to uninfected comparators, presumably due to immune priming by infection. SARS-CoV-2 infection also led to increased numbers of double negative B memory cells, which are described as a dysfunctional B cell subset. This effect was reversed by SARS-CoV-2 vaccination, providing a potential mechanistic explanation for the vaccination-induced reduction in symptoms in patients with "Long-COVID".


title: Using high effective risk of Adult-Senior duo in multigenerational homes to prioritize COVID-19 vaccination

abstract: Universal vaccination on an urgent basis is a way of controlling the COVID-19 infections and deaths. Shortages of vaccine supplies and practical deployment rates on the field necessitate prioritization. The global strategy has been to prioritize those with a high personal risk due to their age or comorbidities and those who constitute the essential workforce of the society. Rather than a systematic age-based roll-down, assigning the next priority requires a local strategy based on the vaccine availability, the effectiveness of these specific vaccines, the population size as well as its age-demographics, the scenario of how the pandemic is likely to develop. The Adult (ages 20-60) - Senior (ages over 60) duo from a multigenerational home presents a high-risk demographic, with an estimated "effective age" of an adult living with a grandparent that is not vaccinated to be 40 years more. Our model suggests that strategically vaccinating the Adults from multigenerational homes in India may be effective in saving the lives of around 70,000 to 200,000 of Seniors, under the different epidemiological scenarios possible with or without strict lockdowns.


title: Measuring the health of people in places: a scoping review of OECD member countries

abstract:
BackgroundDefining and measuring population health in places is fundamental for local and national planning and conducting within-country and cross-national health comparisons. Yet availability and comparability of place-level health data is unknown.

MethodsA scoping review was performed to identify how Organisation for Economic Co-operation and Development (OECD) countries measure overall health for sub-national geographies within each country. The search was conducted across MEDLINE, Scopus and Google Scholar, supplemented by searching all 38 OECD countries statistical agency and public health institute websites.

ResultsSixty publications were selected, plus extracted information from 37 of 38 OECD countries statistical agency and/or public health institute websites. Data sources varied by categorisation into mortality (n=7) or morbidity (n=5) health indicators: the former mostly from national statistical agencies and the latter from population-level surveys. Region was the most common geographic scale: eight indicators for 26 countries, two indicators for 24 countries and one indicator for 20 countries. Similar but slightly fewer indicators were available for urban areas (max countries per most frequent indicator = 24), followed by municipality (range of 1-14 countries per indicator). Other geographies, particularly those at smaller granularity, were infrequently available across health indicators and countries.

ConclusionHealth indicator data at sub-national geographies are generally only available for a limited number of indicators at large administrative boundaries. Relative uniformity of health indicator question format allows cross-national comparisons. However, wider availability of health indicators at smaller, and non-administrative, geographies is needed to explore the best way to measure population health in local areas.


title: Probability and Estimated Risk of SARS-CoV-2 Transmission in the Air Travel System: A Systemic Review and Meta-Analysis

abstract: As an emerging virus, SARS-CoV-2 and the risk of transmission during air travel is of high interest. This paper estimates the probability of an infectious index passenger in the air travel system transmitting the SARS-CoV-2 virus to a fellow passenger during air travel. Literature was reviewed from May-September 2020 to identify COVID-19 cases related to the air travel system. The studies were limited to publicly available literature for passengers starting in January 2020; studies on other persons such as flight crews were not reviewed. A novel quantitative approach was developed to estimate air travel transmission risk that considers secondary cases, the overall air travel passenger population, and two correction factors for asymptomatic transmission and underreporting. There were at least 2866 index infectious passengers documented to have passed through the air travel system in a 1.4 billion passenger population. With correction factors, the global risk of transmission during air travel is 1:1.7 million. Uncertainty in the correction factors and a 95% credible interval indicate risk ranges from 1 case for every 712,000 travelers to 1 case for every 8 million travelers. The risk of COVID-19 transmission on an aircraft is low, even with infectious persons onboard.


title: A Systematic Review and Meta-Analysis on Mental Illness Symptoms in Spain in the COVID-19 Crisis

abstract:
ObjectiveThis paper systematically reviews and assesses the prevalence of anxiety, depression, and insomnia symptoms in the general population, frontline healthcare workers (HCWs), and adult students in Spain during the COVID-19 crisis.

Data sourcesArticles in PubMed, Embase, Web of Science, PsycINFO, and medRxiv from March 2020 to February 6, 2021.

ResultsThe pooled prevalence of anxiety symptoms in 23 studies comprising a total sample of 85,560 was 20% (95% CI: 15% - 25%, I2 = 99.9%), that of depression symptoms in 23 articles with a total sample comprising of 86,469 individuals was 23% (95% CI: 18% - 28%, I2 = 99.8%), and that of insomnia symptoms in 4 articles with a total sample of 915 were 52% (95% CI: 42-64%, I2 = 88.9%). The overall prevalence of mental illness symptoms in frontline HCWs, general population, and students in Spain are 42%, 19%, and 50%, respectively.

DiscussionThe accumulative evidence from the meta-analysis reveals that adults in Spain suffered higher prevalence rates of mental illness symptoms during the COVID-19 crisis with a significantly higher rate relative to other countries such as China. Our synthesis reveals high heterogeneity, varying prevalence rates and a relative lack of studies in frontline and general HCWs in Spain, calling future research and interventions to pay attention to those gaps to help inform evidence-based mental health policymaking and practice in Spain during the continuing COVID-19 crisis. The high prevalence rates call for preventative and prioritization measures of the mental illness symptoms during the Covid-19 pandemic.


title: Risk factors associated with respiratory infectious disease-related presenteeism: a rapid review

abstract:
BackgroundWorkplace transmission is a significant contributor to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreaks. Previous studies have found that infectious illness presenteeism could contribute to outbreaks in occupational settings and identified multiple occupational and organisational risk factors. Amid the COVID-19 pandemic, it is imperative to investigate presenteeism particularly in relation to respiratory infectious disease (RID). Hence, this rapid review aims to determine the prevalence of RID-related presenteeism, including COVID-19, and examines the reported reasons and associated risk factors.

MethodsThe review followed a Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) search approach and focused on studies published in English and Chinese. Database searches included MEDLINE, EMBASE, Web of Science, China Knowledge Resource Integrated Database (CNKI) and preprint databases MedRxiv and BioRxiv.

ResultsThe search yielded 54 studies, of which four investigated COVID-19-related presenteeism. Prevalence of work presenteeism ranged from 14.1% to 55% for confirmed RID, and 6.6% to 100% for those working with suspected or subclinical RID. The included studies demonstrated that RID-related presenteeism is associated with occupation, sick pay policy, age, gender, health behaviour and perception, vaccination, peer pressure and organisational factors such as presenteeism culture.

ConclusionsThis review demonstrates that presenteeism or non-adherence to isolation guidance is a real concern and can contribute to workplace transmissions and outbreaks. Policies which would support workers financially and improve productivity, should include a range of effective non-pharmaceutical inventions such as workplace testing, promoting occupational health services, reviewing pay and bonus schemes and clear messaging to encourage workers to stay at home when ill. Future research should focus on the more vulnerable and precarious occupational groups, and their inter-relationships, to develop comprehensive intervention programs to reduce RID-related presenteeism.

category: occupational and environmental health


title: Distal mediator-enriched, placental transcriptome-wide analyses illustrate the Developmental Origins of Health and Disease

abstract: As the master regulator in utero, the placenta is core to the Developmental Origins of Health and Disease (DOHaD) hypothesis but is historically understudied. To identify placental gene-trait associations (GTAs) across the life course, we performed distal mediator-enriched transcriptome-wide association studies (TWAS) for 40 traits, integrating placental multi-omics from the Extremely Low Gestational Age Newborn Study. At P < 2.5 x 10-6, we detected 248 GTAs, mostly for neonatal and metabolic traits, across 176 genes, enriched for cell growth and immunological pathways. In aggregate, genetic effects mediated by placental expression significantly explained 4 early-life traits but no later-in-life traits. 89 GTAs showed significant mediation through distal genetic variants, identifying hypotheses for distal regulation of GTAs. Investigation of one hypothesis in human placenta-derived choriocarcinoma cells showed that knockdown of mediator gene EPS15 upregulated predicted targets SPATA13 and FAM214A, both associated with waist-hip ratio in TWAS, and multiple genes involved in metabolic pathways. These results suggest profound health impacts of placental genomic regulation in developmental programming across the life course.

category: genetic and genomic medicine


title: Genetic control of fetal placental genomics contributes to development of health and disease


title: An international, inter-laboratory ring trial confirms the feasibility of an open source, extraction-less "direct" RT-qPCR method for reliable detection of SARS-CoV-2 RNA in clinical samples

abstract: Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) is used worldwide to test and trace the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). "Extraction-less" or "direct" real time-reverse transcription polymerase chain reaction (RT-PCR) is an open-access qualitative method for SARS-CoV-2 detection from nasopharyngeal or oral pharyngeal samples with the potential to generate actionable data more quickly, at a lower cost, and with fewer experimental resources than full RT-qPCR. This study engaged 10 global testing sites, including laboratories currently experiencing testing limitations due to reagent or equipment shortages, in an international interlaboratory ring trial. Participating laboratories were provided a common protocol, common reagents, aliquots of identical pooled clinical samples, and purified nucleic acids and used their existing in-house equipment. We observed 100% concordance across laboratories in the correct identification of all positive and negative samples, with highly similar cycle threshold values. The test also performed well when applied to locally collected patient nasopharyngeal samples, provided the viral transport media did not contain charcoal or guanidine, both of which appeared to potently inhibit the RT-PCR reaction. Our results suggest that open-access, direct RT-PCR assays are a feasible option for more efficient COVID-19 coronavirus disease testing as demanded by the continuing pandemic.


title: You're just there, alone in your room with your thoughts: A qualitative study about the impact of lockdown among young people during the COVID-19 pandemic

abstract:
BackgroundAdolescents and young adults have been greatly affected by quarantine measures during the coronavirus-19 pandemic. Quantitative evidence suggests that many young people have struggled with their mental health throughout "lockdown", but little is understood about the qualitative impact of social distancing restrictions on mental health, wellbeing and social life. We therefore sought to elicit the views and experiences of adolescents and young adults living in the UK during the pandemic.

MethodsSemi-structured qualitative interviews were undertaken with 37 participants aged 13-24.

ResultsWe identified 4 superordinate themes most commonly described by participants about their experiences during the pandemic, including: a) missing social contact during lockdown, b) disruption to education, c) changes to social relationships, and d) improved wellbeing during lockdown. Although we identified some positive experiences during the pandemic, including an increased awareness of mental health and stronger relationship ties, many said they struggled with loneliness, a decline in mental health, and anxiety about socialising after the pandemic.

ConclusionsFindings suggest that some young people may have felt less stigma talking about their mental health now compared to before the COVID-19 pandemic. However, many are worried about how the pandemic has affected their education and social connections and may require additional psychological, practical and social support. Our findings highlight the important role that education providers play in providing a source of information and support to adolescents and young adults during times of uncertainty.


title: Occupational risks of COVID-19 in NHS workers in England

abstract:
ObjectiveTo quantify occupational risks of Covid-19 among healthcare staff during the first wave of the pandemic in England

MethodsUsing pseudonymised data on 902,813 individuals continuously employed by 191 National Health Service trusts during 1.1.19 to 31.7.20, we explored demographic and occupational risk factors for sickness absence ascribed to Covid-19 during 9.3.20 to 31.7.20 (n = 92,880). We estimated odds ratios (ORs) by multivariable logistic regression.

ResultsWith adjustment for employing trust, demographic characteristics, and previous frequency of sickness absence, risk relative to administrative/clerical occupations was highest in additional clinical services (including care assistants) (OR 2.31 [2.25-2.37]), registered nursing and midwifery professionals (OR 2.28 [2.23-2.34]) and allied health professionals (OR 1.94 [1.88-2.01]), and intermediate in doctors and dentists (OR 1.55 [1.50-1.61]). Differences in risk were higher after the employing trust had started to care for documented Covid-19 patients, and were reduced, but not eliminated, following additional adjustment for exposure to infected patients or materials, assessed by a job-exposure matrix. For prolonged Covid-19 sickness absence (episodes lasting >14 days), the variation in risk by staff group was somewhat greater.

ConclusionsAfter allowance for possible bias and confounding by non-occupational exposures, we estimated that relative risks for Covid-19 among most patient-facing occupations were between 1.5 and 2.5. The highest risks were in those working in additional clinical services, nursing and midwifery and in allied health professions. Better protective measures for these staff groups should be a priority. Covid-19 may meet criteria for compensation as an occupational disease in some healthcare occupations.

Key messagesO_LIWhat is already known about this subject?
Healthcare workers and other keyworkers (workers whose job was considered essential to societal functioning) had a higher likelihood of testing positive for COVID-19 than other workers during the first lockdown in England. Amongst healthcare workers, those working in inpatient settings had the highest rate of infection.
C_LIO_LIWhat are the new findings?
Between March and July 2000, the overall risk of COVID-19 sickness absence in National Health Service staff in England was lower at older ages, higher in non-white staff, and (in comparison with administrative and clerical staff) more than doubled in registered nurses and among workers such as healthcare assistants providing support to health professionals. Risk in health care scientists was little different from that in administrative and clerical occupations
C_LIO_LIHow might this impact on policy or clinical practice in the foreseeable future?
Our results suggest that the risk reduction strategies that were in place for healthcare scientists were effective. However, the protection for nursing and supporting health professionals was insufficient. In the event of a further  wave of infections resulting in high hospital admissions, attention should be paid to ensuring that risk reduction strategies for nurses and supporting health professionals are improved.
C_LI


title: GWAS and ExWAS of blood Mitochondrial DNA copy number identifies 73 loci and highlights a potential causal role in dementia

abstract: Mitochondrial DNA copy number (mtDNA-CN) is an accessible blood-based measurement believed to capture underlying mitochondrial function. The specific biological processes underpinning its regulation, and whether those processes are causative for disease, is an area of active investigation. We developed a novel method for array-based mtDNA-CN estimation suitable for biobank-scale studies, called "AutoMitoC". We applied AutoMitoC to 395,781 UKBiobank study participants and performed genome and exome-wide association studies, identifying novel common and rare genetic determinants. Overall, genetic analyses identified 73 loci for mtDNA-CN, which implicated several genes involved in rare mtDNA depletion disorders, dNTP metabolism, and the mitochondrial central dogma. Rare variant analysis identified SAMHD1 mutation carriers as having higher mtDNA-CN (beta=0.23 SDs; 95% CI, 0.18-0.29; P=2.6x10-19), a potential therapeutic target for patients with mtDNA depletion disorders, but at increased risk of breast cancer (OR=1.91; 95% CI, 1.52-2.40; P=2.7x10-8). Finally, Mendelian randomization analyses suggest a causal effect of low mtDNA-CN on dementia risk (OR=1.94 per 1 SD decrease in mtDNA-CN; 95% CI, 1.55-2.32; P=7.5x10-4). Altogether, our genetic findings indicate that mtDNA-CN is a complex biomarker reflecting specific mitochondrial processes related to mtDNA regulation, and that these processes are causally related to human diseases.


title: Germline Mutation Analysis in Sporadic Breast Cancer Cases with Clinical Correlations

abstract: Demographics for breast cancers vary widely among nations. The frequency of germline mutations in breast cancers, which reflects the hereditary cases, has not been investigated adequately in Pakistani population. In the present case series, germ-line mutations in twenty-seven breast cancer candidate genes were investigated in eighty-four sporadic breast cancer patients along with the clinical correlations. The germ-line variants were also assessed in two healthy gender-matched controls. The most frequent parameters associated with hereditary cancer cases are age and ethnicity. Therefore, the clinico-pathological features were evaluated by descriptive analysis and Pearson X2 test (with significant p-value <0.05). The analyses were stratified on the basis of age (<40 years vs >40 years) and ethnicity. The breast cancer gene panel assay was carried out by a genomic capture, massively parallel next generation sequencing assay on Illumina Hiseq2000 assay with 100bp read lengths. Copy number variations were determined by partially-mapped read algorithm. Once the mutation was identified, it was validated by Sanger sequencing. The ethnic analysis stratified on the basis of age showed that the frequency of breast cancer at young age (<40 years) was higher in Sindhis (n=12/19; 64%) in contrast to patients in other ethnic groups. Majority of the patients had stage III (38.1%), grades II and III (46.4%), tumor size 2-5cm (54.8%), and invasive ductal carcinoma (81%). Overall, the analysis revealed germ-line mutations in 11.9% of the patients. The mutational spectrum was restricted to three genes: BRCA1, BRCA2, and TP53. The identified mutations consist of seven novel germ-line mutations, while three mutations have been reported previously. All the mutations are predicted to result in protein truncation. No mutations were identified in the remaining twenty-four candidate breast cancer genes. The present study provides the framework for the development of preventive and treatment strategies against breast cancers in Pakistani population.


title: Behavioral nudges increase COVID-19 vaccinations: Two randomized controlled trials

abstract: Fighting the COVID-19 pandemic requires quick and effective strategies to maximize vaccine uptake. We present two sequential randomized controlled trials (RCTs) that tackle this challenge with behavioral science insights. We deliver text-based nudges to UCLA Health patients one day (first RCT; N=113,229) and eight days (second RCT; N=90,662) after they receive notifications of vaccine eligibility. In the first RCT, text messages designed to make vaccination salient and easy to schedule boost appointment and vaccination rates by 86% and 26%, respectively. Nudges that make patients feel endowed with the vaccine heighten these effects, but addressing vaccine hesitancy via a video-based information intervention does not yield benefits beyond simple text. These results hold across ethnicity and age groups. By contrast, online experiments (N=2,003) soliciting hypothetical responses to the same messages reveal the opposite patterns, underscoring the importance of pilot-testing behavioral nudges in the real world before scaling them up. In the second RCT, we further find that receiving a second reminder boosts appointment and vaccination rates by 52% and 16%, respectively. Our findings suggest that text-based nudges can substantially increase and accelerate COVID-19 vaccinations at almost zero marginal cost, highlighting the promising role of behavioral science in addressing a critical component of the COVID-19 pandemic response.


title: Rapid spread and high impact of the Variant of Concern P.1 in the largest city of Brazil

abstract: First in Manaus in the Brazilian Northern region, the Variant of Concern P.1 traveled 3800 kilometers southeast to endanger Sao Paulo contributing to the collapse of the health system. Here, we show evidence of how fast the VOC P.1 has spread in the most populated city in South America.


title: Effect of COVID-19 on Lipid Profile and its Correlation with Acute Phase Reactants

abstract:
Background and ObjectiveCoronavirus disease 2019 (COVID-19) manifests as multiple clinical and pathological organ dysfunctions. It also disrupts metabolic profile due to the release of pro-inflammatory cytokines causing a systemic inflammation reaction. However, the development and correlation of dyslipidemia with acute phase reactants is unknown. This investigation was performed to assess the pathological alterations of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein (HDL), triglycerides, and total cholesterol levels in COVID-19 patients.

MethodsThis was a prospective study performed on real-world patients to assess serum levels of LDL-C, HDL, TG, TC on COVID-19 patients (mild: 319; moderate: 391; critical: 357) hospitalized at our center between April 2020 through January 2021. Age- and gender-matched controls who had their lipid profiles in the same period were included as the control group.

ResultsLDL-C, HDL, TG, and TC levels were significantly lower in COVID-19 patients when compared with the control group (P < 0.001, 0.047, 0.045, < 0.001, respectively). All parameters decreased gradually with COVID-19 disease severity (LDL-C: median (IQR), mild: 98 (91,134); moderate: 97 (81,113); critical: 68 (68,83); HDL: mild: 45 (37,50); moderate: 46 (41,50); critical: 40 (37,46); TG: mild: 186 (150,245); moderate: 156 (109,198); critical: 111 (98,154); TC: mild: 224 (212,238); moderate: 212 (203,213); critical: 154 (125,187)). LDL-C, TC, and TG were inversely correlated with acute phase reactants (interleukin-6 (IL-6), Procalcitonin, C-reactive protein (CRP), and D-dimers). Logistic regression demonstrated lipid profile, thyroid profile, and acute phase reactants as predictors of severity of COVID-19 disease.

ConclusionHypolipidemia develops in increasing frequency with severe COVID-19 disease. It inversely correlates with levels of acute-phase reactants, indicating SARS-COV-2 as the causative agent for alteration in lipid and thyroid levels.


title: One-Seq: A Highly Scalable Sequencing-Based Diagnostic for SARS-CoV-2 and Other Single-Stranded Viruses

abstract: The management of pandemics such as COVID-19 requires highly scalable and sensitive viral diagnostics, together with variant identification. Next-generation sequencing (NGS) has many attractive features for highly multiplexed testing, however current sequencing-based methods are limited in throughput by early processing steps on individual samples (e.g. RNA extraction and PCR amplification). Here we report a new method, "One-Seq", that eliminates the current bottlenecks in scalability by enabling early pooling of samples, before any extraction or amplification steps. To enable early pooling, we developed a one-pot reaction for efficient reverse transcription (RT) and upfront barcoding in extraction-free clinical samples, and a "protector" strategy in which carefully designed competing oligonucleotides prevent barcode crosstalk and preserve detection of the high dynamic range of viral load in clinical samples. This method is highly sensitive, achieving a limit of detection (LoD) down to 2.5 genome copy equivalent (gce) in contrived RT samples, 10 gce in multiplexed sequencing, and 2-5 gce with multi-primer detection, suggesting an LoD of 200-500 gce/ml for clinical testing. In clinical specimens, One-Seq showed quantitative viral detection against clinical Ct values with 6 logs of linear dynamic range and detection of SARS-CoV-2 positive samples down to [~]360 gce/ml. In addition, One-Seq reports a number of hotspot viral mutations at equal scalability at no extra cost. Scaling up One-Seq would allow a throughput of 100,000-1,000,000 tests per day per single clinical lab, at an estimated amortized reagent cost of $1.5 per test and turn-around time of 7.5-15 hr.


title: Reliability of Spike Gene Target Failure for ascertaining SARS-CoV-2 lineage B.1.1.7 prevalence in a hospital setting

abstract: The appearance of the SARS-CoV-2 lineage B.1.1.7 in the UK in late 2020, associated with faster transmission, sparked the need to find effective ways to monitor its spread. The set of mutations that characterise this lineage include a deletion in position 69 and 70 of the spike protein, which is known to be associated with Spike Gene Target Failure (SGTF) in a commonly used three gene diagnostic qPCR assay. The lower cost and faster turnaround times compared to whole genome sequencing make the use of qPCR for monitoring of the variant spread an attractive proposition. However, there are several potential issues with this approach. Here we use 826 SARS-CoV-2 samples collected in a hospital setting as part of the Hospital Onset COVID Infection (HOCI) study where qPCR was used for viral detection, followed by whole genome sequencing (WGS), to identify the factors to consider when using SGTF to infer lineage B.1.1.7 prevalence in a hospital setting, with potential implications for locations where this variant has recently been introduced.


title: Trends in National Opioid Prescribing for Dental Procedures among Medicaid Patients

abstract:
BackgroundWe examine trends in opioid prescriptions by dentists for Medicaid-enrolled children and non-senior adults.

MethodsWe utilized the IBM Watson Medicaid claims databases for 2012-2019 and the CDC conversion dataset. Opioid prescriptions were linked to a dental visit when prescribed within three days of the dental visit and if the patient had no medical visit reported during that period. We conducted descriptive analyses for age, procedures performed, treatment history, and prescription strength.

ResultsOur study showed consistent decreases in opioid prescription rates in dentistry during the study period: from 2.7% to 1.6% among children (0-20), and from 28.6% to 12.2% for adults (21-64). The adult opioid prescription rate fell for nonsurgical dental procedures from 9.7% to 2.9%. For surgical procedures, the adult prescription rate fell from 48.0% to 28.7%. Most dental-related opioids were prescribed for oral surgeries (Children: 70.8%, Adults: 58.6%). By 2019, 23% of all opioid prescriptions for children were dental related.

ConclusionWe found that opioid prescription rates in dentistry for Medicaid enrollees declined significantly between 2012 and 2019 for both children and adults. The percent of prescriptions written for nonsurgical visits consistently declined over the observed timeframe. At the same time, opioid prescription rates for both dental surgical procedures and dental nonsurgical procedures decreased as well.

Practical ImplicationsAlthough the trends revealed in our analysis show declining opioid prescription patterns, these results suggest that the overall rate is still too high and prescriptions are being written unnecessarily.

category: dentistry and oral medicine


title: Two Distinct Dynamic Process Models of COVID-19 Spread with Divergent Vaccination Outcomes

abstract:
Kinematic models of contagion-based viral transmission describe patterns of events over time (e.g., new infections), relying typically on systems of differential equations to reproduce those patterns. By contrast, agent-based models of viral transmission seek to relate those events or patterns of events to causes, expressed in terms of factors (parameters) that determine the dynamics that give rise to those events.

This paper is concerned with the dynamics of contagion-based spread of infection. Dynamics that reflect time homogeneous vs inhomogeneous transmission rates are generated via an agent-based infectious disease modeling tool (CovidSIMVL - github.com/ecsendmail/MultiverseContagion). These different dynamics are treated as causal factors and are related to differences in vaccine efficacy in an array of simulated vaccination trials. Visualizations of simulated trials and associated metrics illustrate graphically some cogent reasons for not effectively hard-coding assumptions of dynamic temporal homogeneity, which come  pre-packaged with the mass action incidence assumption that underpins typical equation-based models of infection spread.


title: Analysis on Action Tracking Reports of COVID-19 Informs Control Strategies and Vaccine Delivery in Post-Pandemic Era

abstract: Understanding the spread of SARS-CoV-2 provides important insights for control policies such as social-distancing interventions and vaccine delivery in the post-pandemic era. In this work, we take the advantage of action tracking reports of confirmed COVID-19 patients, which contain the mobility trajectory of patients. We analyzed reports of patients from April 2020 to January 2021 in China, a country where the residents are well-prepared for the "new normal" world following COVID-19 spread. We developed natural language processing (NLP) tools to transform the unstructured text of action-tracking reports to a structured network of social contacts. An epidemiology model was built on top of the network. Our analysis provides important insights for the development of control policies. Under the "new normal" conditions, we find that restaurants, locations less protected by mask-wearing, have a greater risk than any other location categories, including locations where people are present at higher densities (e.g., flight). We find that discouraging railway transports is crucial to avoid another wave of breakout during the Chunyun season (a period of travel in China with extremely high traffic load around the Chinese New Year). By formalizing the challenge of finding the optimal vaccine delivery among various different population groups as an optimization problem, our analysis helps to maximize the efficiency of vaccine delivery under the general situation of vaccine supply shortage. We are able to reduce the numbers of infections and deaths by 7.4% and 10.5% respectively with vaccine supply for only 1% of the population. Furthermore, with 10% vaccination rate, the numbers of infections and deaths further decrease by 52.6% and 78.1% respectively. Our work will be helpful in the design of effective policies regarding interventions, reopening, contact tracing and vaccine delivery in the "new normal" world following COVID-19 spread.


title: An Ecological Study to Investigate Links Between Atmospheric Pollutants From Farming and SARS-CoV-2 Mortality

abstract: Exposure to atmospheric particulate matter and nitrogen dioxide has been linked to SARS-CoV-2 infection and death. We hypothesized that an interaction between SARS-CoV-2 infection and exposure to farming-related atmospheric pollutants worsens the effect of SARS-CoV-2 on mortality. Our objective was investigate this hypothesis by performing an ecological study in five Italian Regions (Piedmont, Lombardy, Veneto, Emilia-Romagna and Sicily) linking all-cause mortality, by province (administrative entities within regions), to atmospheric particulate matter (PM2.5 and PM10) nitrous oxide (N2O), ammonia (NH3) and methane (CH4) mainly produced by agricultural activities. Study outcome was change in all-cause mortality during March-April 2020, compared to March-April 2015-2019 (period) as assessed by mortality rate ratios (MRRs) estimated using multivariate negative binomial regression models that adjusted for air temperature, humidity and population density. The MRR for the interaction of period with NH3 exposure, considering all pollutants together was 1.133, equivalent to a 13.3% increase in mortality over and above that due to period (proxy for COVID-19 mortality) for each ton/km2 increase in NH3 emissions. Although the study was ecological, and did not provide evidence of a causal link between SARS-CoV-2 and farming-related pollutants, in accord with the precautionary principle we recommend application of measures to limit NH3 exposure particularly while the COVID-19 pandemic continues.


title: A comprehensive analysis of outcomes between COVID-19 patients with an elevated serum lipase compared to those with pancreatitis.

abstract:
Background and AimsCOVID-19 patients may have asymptomatic hyperlipasemia without abdominal imaging findings or abdominal pain. In addition, primary and secondary pancreatitis have been described in COVID-19 patients. There is limited information on how the groups compare in outcomes. The aim is to compare outcomes among these groups.

MethodsThis is a retrospective study from 12 hospitals within one healthcare system examining outcomes between hospitalized COVID-19 patients with a lipase <3x upper limit of normal (ULN), asymptomatic hyperlipasemia (>3x ULN), secondary pancreatitis (typical respiratory COVID-19 symptoms and found to have pancreatitis), and primary pancreatitis (presenting with pancreatitis).

ResultsOf 11,883 patients admitted with COVID-19, 1,560 patients were included: 1,155 COVID-19 patients with a normal serum lipase (control group), 270 with an elevated lipase <3x ULN, 46 patients with asymptomatic hyperlipasemia with a lipase 3xULN, 57 patients with secondary pancreatitis, and 32 patients with primary pancreatitis. On adjusted multivariate analysis, the elevated lipase <3x ULN and asymptomatic hyperlipasemia groups had worse outcomes. The mortality was OR1.6 (95% CI 1.2-2.2) and 1.1 (95% CI 0.5-2.3), respectively. The need for mechanical ventilation was OR 2.8 (95% CI 1.2-2.1) and 2.8 (95% CI 1.5-5.2), respectively. Longer length of stay was OR 1.5 (95%CI 1.1-2.0) and 3.16 (95%CI 1.5-6.5), respectively.

ConclusionCOVID-19 patients with an elevated lipase< 3x ULN and asymptomatic hyperlipasemia have generally worse outcomes than those with pancreatitis. This could be attributed to extrapancreatic causes (liver failure, renal failure, enteritis, etc), which may signify a more severe course of clinical disease.

category: gastroenterology


title: Neuroimaging correlates and predictors of response to repeated-dose intravenous ketamine in PTSD

abstract: Promising initial data indicate that the glutamate N-methyl-D-aspartate (NMDA) receptor antagonist ketamine may be beneficial in post-traumatic stress disorder (PTSD). Here, we explore the neural correlates of ketamine-related changes in PTSD symptoms, using a rich battery of functional imaging data (two emotion-processing tasks and one task-free scan), collected from a subset of participants of a randomized clinical trial of repeated-dose intravenous ketamine vs midazolam (total N=21). In a pre-registered analysis, we tested whether changes in an a priori set of imaging measures from a target neural circuit were predictive of improvement in PTSD symptoms, using leave-one-out cross-validated elastic-net regression models (regions of interest in the target circuit consisted of the dorsal and rostral anterior cingulate cortex, ventromedial prefrontal cortex, anterior hippocampus, anterior insula, and amygdala). Improvements in PTSD severity were associated with increased functional connectivity between the ventromedial prefrontal cortex (vmPFC) and amygdala during emotional face-viewing (change score retained in model with minimum predictive error in left-out subjects, standardized regression coefficient [{beta}]=2.90). This effect was stronger in participants who received ketamine compared to midazolam (interaction {beta}=0.86), and persisted following inclusion of concomitant change in depressive symptoms in the analysis model ({beta}=0.69). Improvement following ketamine was also predicted by decreased dorsal anterior cingulate activity during emotional conflict regulation, and increased task-free connectivity between the vmPFC and anterior insula ({beta}s=-2.82, 0.60). Exploratory follow-up analysis via dynamic causal modelling revealed that whilst improvement in PTSD symptoms following either drug was associated with decreased excitatory modulation of amygdala[->]vmPFC connectivity during emotional face-viewing, increased top-down inhibition of the amygdala by the vmPFC was only observed in participants who improved under ketamine. Individuals with low prefrontal inhibition of amygdala responses to faces at baseline also showed greater improvements following ketamine treatment. These preliminary findings suggest that, specifically under ketamine, improvements in PTSD symptoms are accompanied by normalization of hypofrontal control over amygdala responses to social signals of threat.


title: Kidney function and long-term treatment with lithium salts for bipolar disorderDeterminants of mGFR and accuracy of kidney microcysts detection in the diagnosis of CKD

abstract:
Background and objectivesKidney damage during early stages of lithium treatment in bipolar disorder is still hypothetical. We aimed at identifying the determinants of a decreased measured glomerular filtration rate (mGFR) and the accuracy of kidney MRI imaging in its detection.

Design, setting, participants and measurementsCross sectional cohort study. Systematic evaluation including mGFR of 217 consecutive adult patients treated with lithium carbonate. Kidney MRI imaging in 99 patients with half-Fourier turbo spinecho and Single-shot with long echo time sequences.

ResultsMedian age was 51 [27-62] years, and median lithium treatment duration was 5 [2-14] years. 52% of patients had a stage 2 CKD. In multivariable analysis, the determinants of a lower mGFR were a longer lithium treatment duration ({beta} -0.8 [-1; - 0.6] ml/min/1.73m2 GFR decrease for each year of treatment), a higher age ({beta} -0.4 [-0.6; -0.3] ml/min/1.73m2 for each year of age, p<0.001), albuminuria ({beta} -3.97 [-6.6;-1.3], p=0.003), hypertension ({beta} -6.85 [-12.6;-1.1], p=0.02) and hypothyroidism ({beta} -7.1 [-11.7;-2.5], p=0.003). Serum lithium concentration was not associated with mGFR. Patients with mGFR<60 ml/min/1.73m2 (22%) had a higher prevalence and number of renal microcysts. Renal MRI displayed renal microcyst(s) in 51% of patients, detected as early as one year after lithium treatment initiation. mGFR and lithium treatment duration were strongly correlated in patients with microcyst(s) (r=-0.64, p<0.001), but not in patients with no microcysts (r=-0.24, p=0.09). The presence of microcysts was associated with the detection of an mGFR <45 ml/min/1.73m2 (AUC 0.893, p<0.001, sensitivity 80%, specificity 81% for a cut-off value of 5 microcysts).

ConclusionsBesides usual risk factors of GFR decrease, lithium treatment duration strongly impacted mGFR independently of age, especially in patients with microcysts. Hypothyroidism was also negatively associated with kidney function in these patients. MRI might help detect early lithium-induced kidney damage and inform preventive strategies.


title: Plasma glial fibrillary acidic protein is an early marker of amyloid pathology in Alzheimer's disease

abstract: Although recent clinical trials targeting amyloid-{beta} (A{beta}) in Alzheimers disease (AD) have shown promising results, there is increasing evidence suggesting that understanding alternative disease pathways that interact with A{beta} metabolism and amyloid pathology might be important to halt the clinical deterioration. In particular, there is evidence supporting a critical role of astroglial activation and astrocytosis in AD. However, to this date, no studies have assessed whether astrocytosis is independently related to A{beta} or tau pathology, respectively, in vivo. To address this question, we determined the levels of the astrocytic marker glial fibrillary acidic protein (GFAP) in plasma and cerebrospinal fluid (CSF) of 217 A{beta}-negative cognitively unimpaired individuals, 71 A{beta}-positive cognitively unimpaired individuals, 78 A{beta}-positive cognitively impaired individuals, 63 A{beta}-negative cognitively impaired individuals and 75 patients with a non-AD neurodegenerative disorder from the Swedish BioFINDER-2 study. Subjects underwent longitudinal A{beta} (18F-flutemetamol) and tau (18F-RO948) positron emission tomography (PET) as well as cognitive testing. We found that plasma GFAP concentration was significantly increased in all A{beta}-positive groups compared with subjects without A{beta} pathology (p<0.01). In addition, there were significant associations between plasma GFAP with higher A{beta}-PET signal in all A{beta}-positive groups, but also in cognitively normal individuals with normal A{beta} values (p<0.001), which remained significant after controlling for tau-PET signal. Furthermore, plasma GFAP could predict A{beta}-PET positivity with an area under the curve of 0.76, which was greater than the performance achieved by CSF GFAP (0.69) and other glial markers (CSF YKL-40: 0.64, sTREM2: 0.71). Although correlations were also observed between tau-PET and plasma GFAP, these were no longer significant after controlling for A{beta}-PET. In contrast to plasma GFAP, CSF GFAP concentration was significantly increased in non-AD patients compared to other groups (p<0.05) and correlated with A{beta}-PET only in A{beta}-positive cognitively impaired individuals (p=0.005). Finally, plasma GFAP was associated with both longitudinal A{beta}-PET and cognitive decline, and mediated the effect of A{beta}-PET on tau-PET burden, suggesting that astrocytosis secondary to A{beta} aggregation might promote tau accumulation. Altogether, these findings indicate that plasma GFAP is an early marker associated with brain A{beta} pathology but not tau aggregation, even in cognitively normal individuals with a normal A{beta} status. This suggests that plasma GFAP should be incorporated in current hypothetical models of AD pathogenesis and be used as a non-invasive and accessible tool to detect early astrocytosis secondary to A{beta} pathology.


title: Community level misconception about COVID-19 and its associated factors: Evidence from a cross-sectional study in Bangladesh

abstract:
IntroductionMisconception about COVID-19 has been spread out broadly that the World Health Organization declared it as a major challenge in the fight against the disease. This study aimed to assess common misconceptions about COVID-19 among the rural people of Bangladesh and its associated socio-demographic and media related factors.

MethodsData were collected from 210 respondents selected from three unions of Satkhira District, Bangladesh.The dependent variable was misconception about COVID-19 (Yes, No) which was generated based on the respondents responses to six questions on common misconceptions of COVID-19. Explanatory variables were respondents socio-demographic characteristics, mass media and social media use habits. Descriptive statistics were used to describe the characteristics of the respondents. Univariate and multivariate logistic regression models were used to determine the factors associated with misconception about COVID-19.

ResultsMisconceptions about COVID-19 were found among more than half of the total respondents. More than 50% of the respondents reported they consider COVID-19 as a punishment from God. Besides, most of the respondents reported that they do not think COVID-19 is dangerous (59%), and COVID-19 is a disease (19%). Around 7% of the total respondents reported they consider this virus as a part of a virus war (7.2%). Bivariate analysis found that socio-demographic characteristics of the respondents and factors related to social and mass media were significantly associated with misconception. However, when all the factors included together in the multivariate model, the likelihood of misconception was lower among secondary (AOR, 0.33, 95% CI, 0.13-0.84) and tertiary (AOR, 0.29, 95% CI, 0.09-0.92) educated respondents compared to respondents with primary education.

ConclusionThis study obtained a very higher percentage of the rural people of Bangladesh having one or more misconceptions related to COVID-19. This could be a potential challenge in the fight against the pandemic. Effective use of mass and social media to communicate evidence based information on COVID-19 as well as to educate the public about COVID-19 is important.


title: Predicting severe COVID-19 outcomes for triage and resource allocation

abstract:
BackgroundWhile numerous studies have identified factors associated with severe COVID-19 outcomes, they have yet to quantify these characteristics. Therefore, our studys purpose is to stratify these risk factors and use them to predict outcomes.

Study DesignThis is a retrospective review of the CDC COVID-19 Surveillance Data. Logistic regression models calculated risk estimates for independent variables, and random forest models predicted the chance of severe outcomes.

ResultsOur sample of 3,798,261 patients with COVID-19 consisted mainly of females (51.9%), 10-to 69-year-olds, and White/Non-Hispanics (34.9%). Most were not healthcare workers (90.6%) and did not have preexisting medical conditions (47.1%). Age had an increased risk of severe outcomes that grew every decade of life. White patients had a decreased occurrence of severe outcomes than Non-Whites, except for Pacific Islanders with comparable mortality. The variable selection algorithm detected that three outcomes were more accurate without healthcare worker classification: mechanical ventilation/intubation, pneumonia, and ARDS Acute respiratory distress. However, providers had a decreased risk of severe outcomes overall. Also, patients with preexisting conditions demonstrated an increased risk in all outcomes. Compared to the logistic regressions, the predictive models had a higher performance (AUC>0.8). The death model had the best metrics, followed by hospitalization and ventilation. We amassed these predictive models into the Severe COVID-19 Calculator web application that estimates the probability of severe outcomes.

ConclusionsSeveral patient social and medical demographics recorded by the CDC significantly affect severe COVID-19 outcomes suggesting a multifactorial influence. To account for these variables, a generated Severe Covid-19 Calculator can accurately predict the chance of severe outcomes in citizens that may contract or have COVID-19.

category: health policy


title: Spread of the SARS-CoV-2 UK-variant in the South East of France: impact on COVID-19 patients age, comorbidity profiles and clinical presentation, week 50 2020 to week 8 2021

abstract:
ObjectivesThe variant 20I/501Y.V1, associated to a higher risk of transmissibility, emerged in Nice city (South East of France, French Riviera) during January 2021. The pandemic has resumed late December 2020 in this aera. A high incidence rate together with a fast turn-over of the main circulating variants, provided us the opportunity to analyze modifications in clinical profile and outcome traits.

MethodsObservational study in the University hospital of Nice from December 2020 to February 2021. We analyzed data of sequencing of SARS-CoV-2 from the sewage collector and PCR screening from all positive samples at the hospital. Then, we described the characteristics of all COVID-19 patients admitted in the emergency department (ED) (n=1247) and those hospitalized in the infectious diseases ward or ICU (n=232). Demographic data, clinical signs and severity were recorded by the NEWS-2, SAPS-2 and SOFA scores were recorded and analyzed.

Resultsthe UK-variant was absent in the area in December, then increasingly spread in January representing 59% of the PCR screening performed mid-February. The rate of patients over 65 years admitted to the ED decreased from 63% to 50% (p=0.001). The mean age of hospitalized patients in the infectious diseases ward decreased from 70.7 to 59.2 (p<0.001) while the proportion of patients without comorbidity increased from 16% to 42% (p=0.007). Neither the NEWS-2 score nor the main signs of clinical severity have changed over time.

ConclusionSpread of the UK-variant in the South East of France affects younger and healthier patients.


title: Continuing COVID-19 Vaccination of Front-Line Workers in British Columbia with the AstraZeneca Vaccine: Benefits in the Face of Increased Risk for Prothrombotic Thrombocytopenia

abstract:
BackgroundOn March 29th, 2021, Canadas National Advisory Committee on Immunization (NACI) recommended against using the AstraZeneca COVID-19 vaccine in younger adults pending further review of the risk for Vaccine-Induced Pro-thrombotic Immune Thrombocytopenia (VIPIT). As a result, the province of British Columbia halted its front-line workers vaccination program which used the AstraZeneca vaccine. The province is expected to receive an additional 246,700 doses of AstraZeneca vaccine through US and COVAX until April 11th, enough to provide the first dose of vaccine to all unvaccinated front-line workers. It is unclear whether the alternative, mRNA vaccines can be immediately made available to front-line workers. We evaluated the harms and benefits of delaying vaccination of front-line workers in BC.

MethodsWe reviewed the latest available evidence and used compartmental modelling to 1) compare the expected number of deaths due to COVID-19 and VIPIT under the scenarios of immediately continuing vaccination of front-line workers with the AstraZeneca vaccine or delaying it in favour of mRNA vaccines, and 2) compare the individual mortality risk of immediately receiving the AstraZeneca vaccine with waiting to receive an mRNA vaccine later for different age groups.

ResultsWe estimate that if British Columbia continues the front-line worker vaccination program with the AstraZeneca vaccine, we expect to see approximately 27,000 fewer cases of COVID-19, 500 fewer hospitalizations, 80 fewer COVID-related deaths, and 1,400 fewer cases of Long COVID from April 1st to October 1st, 2021, for an expected number of VIPIT-related deaths of 0.674 [95% CI 0.414-0.997]. In the same period and in areas of high transmission, the projected excess risk of mortality due to COVID-19 and VIPIT was significantly higher in the delayed vaccination with the mRNA vaccine scenario (3.23 to 4.44 times higher risk) than that of immediate vaccination with the AstraZeneca vaccine for those between 30 and 69 years of age. For those under 30, immediate vaccination with the AstraZeneca vaccine posed a higher risk than delayed vaccination with an mRNA vaccine.

ConclusionsThe benefits of immediately continuing immunization of front-line workers with the AstraZeneca vaccine far outweigh the risk both at a societal level and at an individual risk level for those over 40, and those over 30 in high-risk areas.


title: Vaccination of Front-Line Workers with the AstraZeneca COVID-19 Vaccine: Benefits in the Face of Increased Risk for Prothrombotic Thrombocytopenia


title: Clinical malaria incidence following an outbreak in Ecuador was predominantly associated with Plasmodium falciparum with recombinant variant antigen gene repertoires

abstract: To better understand the factors underlying the continued incidence of clinical episodes of falciparum malaria in E-2020 countries targeting elimination, we have characterised Plasmodium falciparum disease transmission dynamics after a clonal outbreak on the northwest coast of Ecuador over a period of two years. We apply a novel, high-resolution genotyping method, the "varcode" based on a single PCR to fingerprint the DBL region of the 40-60 members of the variant surface antigen-encoding var multigene family. Var genes are highly polymorphic within and between genomes, with var repertoires rapidly evolving by outcrossing during the obligatory sexual phase of P. falciparum in the mosquito. The continued incidence of clinical malaria after the outbreak in Ecuador provided a unique opportunity to use varcodes to document parasite microevolution and explore signatures of local disease transmission on the time scale of months to two years post-outbreak. We identified nine genetic varcodes circulating locally with spatiotemporal parasite genetic relatedness networks revealing that diversification of the clonal outbreak parasites by sexual recombination was associated with increased incidence of clinical episodes of malaria. Whether this was due to chance, immune selection or sexual recombination per se is discussed. Comparative analyses to other South American parasite populations where P. falciparum transmission remains endemic elucidated the possible origins of Ecuadorian varcodes. This analysis demonstrated that the majority of clinical cases were due to local transmission and not importation. Nonetheless, some of the varcodes that were unrelated to the outbreak varcode were found to be genetically related to other South American parasites. Our findings demonstrate the utility of the varcode as a high-resolution surveillance tool to spatiotemporally track disease outbreaks using variant surface antigen genes and resolve signatures of recombination in an E-2020 setting nearing elimination.


title: IL-1α Mediates Tissue Specific Inflammation and Severe Respiratory Failure In Covid-19: Clinical And Experimental Evidence

abstract:
BackgroundAcute respiratory distress syndrome (ARDS) in COVID-19 has been associated with dysregulated immune responses leading to catastrophic inflammation. The activation pathways remain to be fully elucidated. We investigated the ability of circulating to induce dysregulated immune responses.

Materials & MethodsCalprotectin and high mobility group box 1 (HMGB1) were associated with ARDS in 60 COVID-19 patients. In a second cohort of 40 COVID-19 patients calprotectin at hospital admission was associated with serum levels of soluble urokinase plasminogen activator receptor (suPAR). A COVID-19 animal model was developed by intravenous injection of plasma from healthy volunteers or patients with COVID-19 ARDS into C57/BL6 mice once daily for 3 consecutive days. In separate experiments, mice were treated with a) the IL-1 receptor antagonist Anakinra or vehicle and b) Flo1-2a anti-murine anti-IL-1 monoclonal antibody or the specific anti-human IL-1 antibody XB2001, or isotype controls. Mice were sacrificed on day 4. Cytokines and myeloperoxidase (MPO) in tissues were measured.

ResultsCalprotectin, but not HMGB1, was elevated ARDS. Higher suPAR readouts indicated higher calprotectin levels. CHallenge of mice with COVID-19 plasma led to inflammatory reactions in murine lung and intestines as evidenced by increased levels of TNF, IL-6, IFN{gamma} and MPO. Anakinra treatment brought these levels down. Similar decrease was found in mice treated with Flo1-2a but not with XB2001.

ConclusionCirculating alarmins, specifically calprotectin, of critically ill COVID-19 patients induces tissue-specific inflammatory responses through an IL-1 mediated mechanism. This could be attenuated through inhibition of IL-1 receptor or specific inhibition of IL-1.


title: IL-1 Mediates Tissue Specific Inflammation and Severe Respiratory Failure In Covid-19: Clinical And Experimental Evidence


title: Sensitivity of rapid antigen testing and RT-PCR performed on nasopharyngeal swabs versus saliva samples in COVID-19 hospitalized patients: results of a prospective comparative trial (RESTART).

abstract:
ObjectivesSaliva sampling could serve as an alternative non-invasive sample for SARS-CoV-2 diagnosis while rapid antigen testing (RAT) might help to mitigate the shortage of reagents sporadically encountered with RT-PCR. Thus, in the RESTART study we compared antigen and RT-PCR testing methods on nasopharyngeal (NP) swabs and salivary samples.

MethodsWe conducted a prospective observational study among COVID-19 hospitalized patients between 10th December 2020 and 1st February 2021. Paired saliva and NP samples were investigated by RT-PCR (Cobas 6800, Roche-Switzerland) and by two rapid antigen tests: One Step Immunoassay Exdia(R) COVID-19 Ag (Precision Biosensor, Korea) and Standard Q(R) COVID-19 Rapid Antigen Test (Roche-Switzerland).

ResultsA total of 58 paired NP-saliva specimens were collected. Thirty-two of 58 (55%) patients were hospitalized in the intensive care unit and the median duration of symptoms was 11 days (IQR 5-19). NP and salivary RT-PCR exhibited sensitivity of 98% and 69% respectively whereas the specificity of these RT-PCRs assays were of 100%. NP RAT exhibited much lower diagnostic performances with sensitivities of 35% and 41% for the Standard Q(R) and Exdia(R) assays respectively, when a wet-swab approach was used (i.e. when the swab was diluted in the viral transport medium (VTM) before testing). The sensitivity of the dry-swab approach was slightly better (47%). These antigen tests exhibited very low sensitivity (4 and 8%) when applied to salivary swabs.

ConclusionsNasopharyngeal RT-PCR is the most accurate test for COVID-19 diagnosis in hospitalized patients. RT-PCR on salivary samples may be used when nasopharyngeal swabs are contraindicated. RAT are not appropriate for hospitalized patients.


title: REACT-1 round 10 report: Level prevalence of SARS-CoV-2 swab-positivity in England during third national lockdown in March 2021

abstract:
BackgroundIn England, hospitalisations and deaths due to SARS-CoV-2 have been falling consistently since January 2021 during the third national lockdown of the COVID-19 pandemic. The first significant relaxation of that lockdown occurred on 8 March when schools reopened.

MethodsThe REal-time Assessment of Community Transmission-1 (REACT-1) study augments routine surveillance data for England by measuring swab-positivity for SARS-CoV-2 in the community. The current round, round 10, collected swabs from 11 to 30 March 2021 and is compared here to round 9, in which swabs were collected from 4 to 23 February 2021.

ResultsDuring round 10, we estimated an R number of 1.00 (95% confidence interval 0.81, 1.21). Between rounds 9 and 10 we estimated national prevalence has dropped by [~]60% from 0.49% (0.44%, 0.55%) in February to 0.20% (0.17%, 0.23%) in March. There were substantial falls in weighted regional prevalence: in South East from 0.36% (0.29%, 0.44%) in round 9 to 0.07% (0.04%, 0.12%) in round 10; London from 0.60% (0.48%, 0.76%) to 0.16% (0.10%, 0.26%); East of England from 0.47% (0.36%, 0.60%) to 0.15% (0.10%, 0.24%); East Midlands from 0.59% (0.45%, 0.77%) to 0.19% (0.13%, 0.28%); and North West from 0.69% (0.54%, 0.88%) to 0.31% (0.21%, 0.45%). Areas of apparent higher prevalence remain in parts of the North West, and Yorkshire and The Humber. The highest prevalence in March was found among school-aged children 5 to 12 years at 0.41% (0.27%, 0.62%), compared with the lowest in those aged 65 to 74 and 75 and over at 0.09% (0.05%, 0.16%). The close approximation between prevalence of infections and deaths (suitably lagged) is diverging, suggesting that infections may have resulted in fewer hospitalisations and deaths since the start of widespread vaccination.

ConclusionWe report a sharp decline in prevalence of infections between February and March 2021. We did not observe an increase in the prevalence of SARS-CoV-2 following the reopening of schools in England, although the decline of prevalence appears to have stopped. Future rounds of REACT-1 will be able to measure the rate of growth or decline from this current plateau and hence help assess the effectiveness of the vaccination roll-out on transmission of the virus as well as the potential size of any third wave during the ensuing months.