title: Significance testing for small annotations in stratified LD-Score regression

abstract:
S-LDSC is a widely used heritability enrichment method that has helped gain biological insights into numerous complex traits. It has primarily been used to analyze large annotations that contain approximately 0.5% of SNPs or more. Here, we show in simulation that, when applied to small annotations, the block jackknife-based significance testing used in S-LDSC does not always control type 1 error. We show that the inflation of type 1 error for small annotations is due both to the noisiness of the jackknife estimate of the standard error and to the non-normality of the regression coefficient estimates. We use the percent of 0.01 centimorgan blocks in the genome overlapped by the annotation to quantify the size of an annotation and the extent to which the SNPs in the annotation cluster together, and we find thresholds on this value above which type 1 error is controlled. We have implemented a test in the LDSC software that informs users when they compute LD scores for an annotation if the annotation does not pass the threshold for producing controlled type 1 error.

Author SummaryGenetics is a rapidly evolving field that allows us to link our genetic code to the physiological manifestations of disease. A key part of this work is finding regions of the genome that contribute disproportionately to the genetic underpinnings of a disease. A commonly used tool to provide such insight is stratified LD score regression (S-LDSC). S-LDSC allows us to estimate how much a set of genomic regions contributes to the overall heritability of a phenotype, and to test whether this is more than we would expect by chance. Here we show that when we apply S-LDSC to a small set of genomic regions, it does not give an accurate test of whether this set of genomic regions contributes more than we would expect by chance to the phenotype. We characterize what it means to be a "small" set of genomic regions, and we set thresholds to restrict which annotations we test to prevent false positive results.This helps to ensure that as we continue to pursue genetic analyses at scale, we report only truly significant results that will help us further understand the etiology of many of the traits we study.


title: Prediction of COVID-19 Mortality to Support Patient Prognosis and Triage and Limits of Current Open-Source Data

abstract:
This study examines the accuracy and applicability of machine learning methods in early prediction of mortality in COVID-19 patients. Patient symptoms, pre-existing conditions, age and sex were employed as predictive attributes from data spanning 17 countries. Performance on a semi-evenly balanced class sample of 212 patients resulted in high detection accuracy of 92.5%, with strong specificity and sensitivity. Performance on a larger sample of 5,121 patients with only age and mortality information was added as a measure of baseline discriminatory ability. Stratifying - Random Forest - and linear - Logistic Regression - methods were applied, both achieving modestly strong performance, with 77.4%-79.3% sensitivity and 71.4%-72.6% accuracy, highlighting predictive power even on the basis of a single attribute. Mutual information was employed as a dimensionality reduction technique, greatly improving performance and showing how a small number of easily retrievable attributes can provide timely and accurate predictions, with applications for datasets with slowly available variables - such as laboratory results.

Unlike existing studies making use of the same dataset, limitations of the data were extensively explored and detailed, as each results section outlines the main shortcomings of relevant analysis. Future use of this dataset should be cautious and always accompanied by disclaimers on issues of real-life reproducibility. While its open-source nature is a credit to the wider research community and more such datasets should be published, in its current state it can produce valid conclusions only for a limited set of applications, some of which were explored in this study.

category: health informatics


title: Development of a COVID-19 Application Ontology for the ACT Network

abstract: Clinical data networks that leverage large volumes of data in electronic health records (EHRs) are significant resources for research on coronavirus disease 2019 (COVID-19). Data harmonization is a key challenge in seamless use of multisite EHRs for COVID-19 research. We developed a COVID-19 application ontology in the national Accrual to Clinical Trials (ACT) network that enables harmonization of data elements that that are critical to COVID-19 research. The ontology contains over 50,000 concepts in the domains of diagnosis, procedures, medications, and laboratory tests. In particular, it has computational phenotypes to characterize the course of illness and outcomes, derived terms, and harmonized value sets for SARS-CoV-2 laboratory tests. The ontology was deployed and validated on the ACT COVID-19 network that consists of nine academic health centers with data on 14.5M patients. This ontology, which is freely available to the entire research community on GitHub at https://github.com/shyamvis/ACT-COVID-Ontology, will be useful for harmonizing EHRs for COVID-19 research beyond the ACT network.


title: Deep clinical phenotyping of Alzheimer's Disease Patients Leveraging Electronic Medical Records Data Identifies Sex-Specific Clinical Associations

abstract: Alzheimers Disease (AD) is a devastating disorder that is still not fully understood. Sex modifies AD vulnerability, but the reasons for this are largely unknown. There has been efforts to understand select comorbidities, covariates, and biomarkers of AD, with and without sex stratification - but there has not yet been an integrative, big data approach to identify clinical and sex specific associations with AD in an unbiased manner. Electronic Medical Records (EMR) contain extensive information on patients, including diagnoses, medications, and lab test results, providing a unique opportunity to apply phenotyping approaches to derive insights into AD clinical associations. Here, we utilize EMRs to perform deep clinical phenotyping and network analysis of AD patients to provide insight into its clinical characteristics and sex-specific clinical associations. We performed embeddings and network representation of patient diagnoses to visualize patient heterogeneity and comorbidity interactions and observe greater connectivity of diagnosis among AD patients compared to controls. We performed enrichment analysis between cases and controls and identified multiple known and new diagnostic and medication associations, such as positive associations with AD and hypertension, hyperlipidemia, anemia, and urinary tract infection - and negative associations with neoplasms and opioids. Furthermore, we performed sex-specific enrichment analyses to identify novel sex-specific associations with AD, such as osteoporosis, depression, cardiovascular risk factors, and musculoskeletal disorders diagnosed in female AD patients and neurological, behavioral, and sensory disorders enriched in male AD patients. We also analyzed lab test results, resulting in clusters of patient phenotype groups, and we observed greater calcium and lower alanine aminotransferase (ALT) in AD, as well as abnormal hemostasis labs in female AD. With this method of phenotyping, we can represent AD complexity, and identify clinical factors that can be followed-up for further temporal and predictive analysis or integrate with molecular data to aid in diagnosis and generate hypotheses about disease mechanisms. Furthermore, the negative associations can help identify factors that may decrease likelihood of AD and help motivate future drug repurposing or therapeutic approaches.


title: Impact of Clinical and Genomic Factors on SARS-CoV2 Disease Severity

abstract: The SARS-CoV2 virus behind the COVID-19 pandemic is manifesting itself in different ways among infected people. While many are experiencing mild flue-like symptoms or are even remaining asymptomatic after infection, the virus has also led to serious complications, overloading ICUs while claiming more than 2.6 million lives world-wide. In this work, we apply AI methods to better understand factors that drive the severity of the disease. From the UK BioBank dataset we analyzed both clinical and genomic data of patients infected by this virus. Leveraging positive-unlabeled machine learning algorithms coupled with RubricOE, a state-of-the-art genomic analysis framework for genomic feature extraction, we propose severity prediction algorithms with high F1 score. Furthermore, we extracted insights on clinical and genomic factors driving the severity prediction. We also report on how these factors have evolved during the pandemic w.r.t. significant events such as the emergence of the B.1.1.7 SARS-CoV2 virus strain.


title: Axes of Prognosis: Identifying Subtypes of COVID-19 Outcomes

abstract: COVID-19 is a disease with vast impact, yet much remains unclear about patient outcomes. Most approaches to risk prediction of COVID-19 focus on binary or tertiary severity outcomes, despite the heterogeneity of the disease. In this work, we identify heterogeneous subtypes of COVID-19 outcomes by considering  axes of prognosis. We propose two innovative clustering approaches -  Layered Axes and  Prognosis Space - to apply on patients outcome data. We then show how these clusters can help predict a patients deterioration pathway on their hospital admission, using random forest classification. We illustrate this methodology on a cohort from Wuhan in early 2020. We discover interesting subgroups of poor prognosis, particularly within respiratory patients, and predict respiratory subgroup membership with high accuracy. This work could assist clinicians in identifying appropriate treatments at patients hospital admission. Moreover, our method could be used to explore subtypes of  long COVID and other diseases with heterogeneous outcomes.


title: Evaluation of albumin kinetics in mechanically ventilated patients with COVID-19 compared to those with sepsis-induced ARDS

abstract: COVID-19 outcomes like mortality have been associated with albumin alteration. However, it is unclear whether albumin changes in COVID-19 are pathogen specific or not. To this end, we characterized the kinetics of serum albumin in mechanically ventilated patients with COVID-19 compared to mechanically ventilated patients with sepsis-induced Acute Respiratory Distress Syndrome (ARDS). We discovered two phases of alterations in albumin levels during the course of Covid-19 critical illness, but not for the sepsis-induced ARDS. Our findings suggest the metabolic effects of COVID-19 are pathogen-specific and albumin recovery may signal the cessation of a deleterious immune response in this disease.

category: infectious diseases


title: First and second SARS-CoV-2 waves in inner London: A comparison of admission characteristics and the effects of the B.1.1.7 variant

abstract:
IntroductionA second wave of SARS-CoV-2 infection spread across the UK in 2020 linked with emergence of the more transmissible B.1.1.7 variant. The emergence of new variants, particularly during relaxation of social distancing policies and implementation of mass vaccination, highlights the need for real-time integration of detailed patient clinical data alongside pathogen genomic data. We linked clinical data with viral genome sequence data to compare cases admitted during the first and second waves of SARS-CoV-2 infection.

MethodsClinical, laboratory and demographic data from five electronic health record (EHR) systems was collected for all cases with a positive SARS-CoV-2 RNA test between March 13th 2020 and February 17th 2021. SARS-CoV-2 viral sequencing was performed using Oxford Nanopore Technology. Descriptive data are presented comparing cases between waves, and between cases of B.1.1.7 and non-B.1.1.7 variants.

ResultsThere were 5810 SARS-CoV-2 RNA positive cases comprising inpatients (n=2341), healthcare workers (n=1549), outpatients (n=874), emergency department (ED) attenders not subsequently admitted (n=532), inter-hospital transfers (n=281) and nosocomial cases (n=233). There were two dominant waves of hospital admissions, with wave one starting from March 13th (n=838) and wave two from October 20th (n=1503), both with a temporally aligned rise in nosocomial cases (n=96 in wave one, n=137 in wave two). 1470 SARS-CoV-2 isolates were successfully sequenced, including 216/838 (26%) admitted cases from wave one, 472/1503 (31%) admitted cases in wave two and 121/233 (52%) nosocomial cases. The first B.1.1.7 variant was identified on 15th November 2020 and increased rapidly such that it comprised 400/472 (85%) of sequenced isolates from admitted cases in wave two. Females made up a larger proportion of admitted cases in wave two (47.3% vs 41.8%, p=0.011), and in those infected with the B.1.1.7 variant compared to non-B.1.1.7 variants (48.0% vs 41.8%, p=0.042). A diagnosis of frailty was less common in wave two (11.5% v 22.8%, p<0.001) and in the group infected with B.1.1.7 (14.5% v 22.4%, p=0.001). There was no difference in severity on admission between waves, as measured by hypoxia at admission (wave one: 64.3% vs wave two: 65.5%, p=0.67). However, a higher proportion of cases infected with the B.1.1.7 variant were hypoxic on admission compared to other variants (70.0% vs 62.5%, p=0.029).

ConclusionsAutomated EHR data extraction linked with SARS-CoV-2 genome sequence data provides valuable insight into the evolving characteristics of cases admitted to hospital with COVID-19. The proportion of cases with hypoxia on admission was greater in those infected with the B.1.1.7 variant, which supports evidence the B.1.1.7 variant is associated with more severe disease. The number of nosocomial cases was similar in both waves despite introduction of many infection control interventions before wave two, an observation requiring further investigation.


title: Mortality and Severity in COVID-19 Patients on ACEIs & ARBs - A Meta-Regression Analysis

abstract:
PurposeThe primary objective of this review is to examine studies reporting association of mortality in COVID-19 patients with whether they were on Angiotensin-converting-enzyme inhibitors (ACEIs) and Angiotensin II receptor blockers (ARBs). A secondary objective is to similarly access associations with higher severity of the disease in COVID-19 patients.

Materials and MethodsWe searched multiple COVID-19 databases (WHO, CDC, LIT-COVID) for randomized trials and longitudinal studies from all over the world reporting mortality and severity published before January 18th, 2021. Meta-analyses were performed using 53 studies for mortality outcome and 43 for the severity outcome. Mantel-Haenszel odds ratios were generated to describe overall effect size using random effect models. To account for between study results variations, multivariate meta-Regression was performed with preselected covariates using maximum likelihood method for both the mortality and severity models.

ResultOur findings showed that the use of ACEIs/ARBs did not significantly influence either mortality (OR=1.16 95% CI 0.94 to 1.44, p= 0.15, I2 = 93.2%) or severity (OR=1.18, 95% CI 0.94 to 1.48 p= 0.15, I2 = 91.1%) in comparison to not being on ACEIs/ARBs in COVID-19 positive patients. Multivariate meta-regression for the mortality model demonstrated that 36% of between study variations could be explained by differences in age, gender, and proportion of heart diseases in the study samples. Multivariate meta-regression for the severity model demonstrated that 8% of between study variations could be explained by differences in age, proportion of diabetes, heart disease and study country in the study samples.

ConclusionWe found no association of mortality or severity in COVID-19 patients taking ACEIs/ARBs.


title: Broad decline and subsequent differential re-emergence of respiratory viruses during COVID-19 pandemic response measures, Singapore 2020

abstract:
ImportanceCOVID-19 pandemic control measures affect the prevalence of other respiratory viruses. Effects on some viruses have been described; however, the broader impact and temporal relationship of control measures on virus decline and subsequent re-emergence have not been thoroughly documented. Understanding these phenomena may influence health policies.

ObjectiveTo examine the prevalence of unrelated respiratory viruses in relation to population-wide pandemic response measures and phases in 2020 in Singapore.

Design, Setting, and ParticipantsData from respiratory multiplex PCRs from 3 major hospitals (total 3700 beds) in Singapore were collated. The full dataset consisted of 42,558 test results, 19,898 from 2019 and 22,660 from 2020.

Main Outcomes and MeasuresWeekly virus prevalence data were mapped onto prevailing pandemic response measures, in order to elucidate temporal relationships and differential virus responses. Pre-pandemic data from 2019 were compared with data from 2020.

ResultsEarly response measures, even before national lockdown, were followed by a dramatic reduction of influenza viruses and a more gradual decline of other respiratory viruses, including respiratory syncytial virus, parainfluenza viruses, endemic coronaviruses and metapneumovirus. Marked decline of enterovirus/rhinovirus and adenovirus, however, was only observed during lockdown. About 13 weeks into phased reopening, enterovirus/rhinovirus re-emerged, followed by adenovirus, the latter mainly in the pediatric population. All other viruses remained at low levels until the end of 2020.

Conclusions and RelevanceCOVID-19 control measures in Singapore had a significant impact on a broad range of respiratory viruses. Effects of various control measures varied between phases and different viruses. Influenza viruses declined earliest and most dramatically; relaxation of measures was followed by re-emergence of enterovirus/rhinovirus and adenovirus. These patterns are presumably a result of different propensities for contact versus droplet and overall ease of transmission, and different virus reservoirs. Further studies into these phenomena are a matter of public health importance.

Key PointsO_ST_ABSQuestionC_ST_ABSWhat were the effects of COVID-19 pandemic control measures in Singapore on the prevalence of other respiratory viruses?

FindingsViruses responded differently to control measures. Influenza viruses declined rapidly after early control measures and remained near-absent during reopening after lockdown. Enterovirus/rhinovirus and adenovirus declined later and re-emerged earlier than other viruses during phased reopening.

MeaningPopulation-wide interventions resulted in a broad decline and subsequent differential re-emergence of non-targeted respiratory viruses, corresponding to different patterns of virus response to control measures.


title: Accelerated RNA detection using tandem CRISPR nucleases

abstract: Direct, amplification-free detection of RNA has the potential to transform molecular diagnostics by enabling simple on-site analysis of human or environmental samples. CRISPR-Cas nucleases offer programmable RNA-guided recognition of RNA that triggers cleavage and release of a fluorescent reporter molecule1,2, but long reaction times hamper sensitivity and speed when applied to point-of-care testing. Here we show that unrelated CRISPR nucleases can be deployed in tandem to provide both direct RNA sensing and rapid signal generation, thus enabling robust detection of [~]30 RNA copies/microliter in 20 minutes. Combining RNA-guided Cas13 and Csm6 with a chemically stabilized activator creates a one-step assay that detected SARS-CoV-2 RNA from nasopharyngeal samples with PCR-derived Ct values up to 29 in microfluidic chips, using a compact imaging system. This Fast Integrated Nuclease Detection In Tandem (FIND-IT) approach enables direct RNA detection in a format amenable to point-of-care infection diagnosis, as well as to a wide range of other diagnostic or research applications.


title: Comparison between one and two dose SARS-CoV-2 vaccine prioritisation for a fixed number of vaccine doses

abstract: The swift development of SARS-CoV-2 vaccines has been met with worldwide commendation. How-ever, in the context of an ongoing pandemic there is an interplay between infection and vaccination. Whilst infection can grow exponentially, vaccination rates are generally limited by supply and logistics. With the first SARS-CoV-2 vaccines receiving medical approval requiring two doses, there has been scrutiny on the spacing between doses; an elongated period between doses allows more of the population to receive a first vaccine dose in the short-term generating wide-spread partial immunity. Focusing on data from England, we investigated prioritisation of a one dose or two dose vaccination schedule given a fixed number of vaccine doses and with respect to a measure of maximising averted deaths. We optimised outcomes for two different estimates of population size and relative risk of mortality for at-risk groups within the Phase 1 vaccine priority order. Vaccines offering relatively high protection from the first dose favour strategies that prioritise giving more people one dose, although with increasing vaccine supply eventually those eligible and accepting vaccination will receive two doses. Whilst optimal dose timing can substantially reduce the overall mortality risk, there needs to be careful consideration of the logistics of vaccine delivery.


title: Some Clinical and Immunological Features of Imported COVID-19 Cases in Mongolia

abstract:
SARS-CoV-2 disturbs the normal immune responses causing an uncontrolled inflammatory response in patients with severe COVID-19. The pattern of the immune response to the SARS-CoV-2 in individuals may fluctuate. Some have a virus-dependent protective immune response resulting in asymptomatic or mild disease with elimination of the virus within 7-10 days after onset of infection. Others develop virus non-dependent uncontrolled hyper-inflammation in the later period, leading to severe disease with cytokine storm, acute respiratory distress syndrome, disseminated intravascular coagulation and multi-organ failure.

MethodsThe serum of 72 patients was investigated for titers of 15 cytokines and chemokines using Enzyme-linked immunosorbent assay (ELISA) kits in the serum of peripheral blood samples. The means of groups were compared using ANOVA followed by Tukey multiple post hoc comparisons if the ANOVA p-value was <0.05.

ResultsPatients with pulmonary infiltrates on CT demonstrated a lower percentage of eosinophils (1.38{+/-}1.46%) and elevated level of serum CRP (8.57{+/-}19.10 mg/dL) compared to patients without pulmonary infiltrates (2.52{+/-}1.47% and 1.96{+/-}3.02 mg/dL respectively; p<0.05). ROC analysis for patients aged [≥]35 years showed patients with mild disease (n=3) had a significantly higher titer of IL-1{beta} and MCP-1 (AUC, 0.958 and 0.917 respectively, p<0.05) compared to patients with moderate disease (n=7).


title: Seroprevalence of anti-SARS-CoV-2 IgG antibody among health care workers of anaesthesia departments from various hospital settings in India

abstract:
BackgroundHealth care workers (HCWs) are the most susceptible group to get COVID-19 infection and this group always need special attention as they are the key human resource to contain this pandemic.

ObjectiveTo track down the seroprevalence among a particular group of HCWs working in the anaesthesia department in hospital settings.

Study designTwo rounds of serosurvey were done to track the dynamicity among the 128 and 164 HCWs participants in the first round and second round, respectively. 5 mL of blood was collected and anti-SARS-CoV-2 IgG antibody was tested in Abbott Architect i1000SR.

ResultsThe seroprevalence found in the first and second round was 12.5% and 38.4%, respectively. A significant number (n=61, 77.21%) of seropositivity came from the asymptomatic HCWs group as found in both the survey. There was no significant association among different age, gender and RT-PCR tested groups.

ConclusionRoutine diagnosis of COVID-19 should be referred among HCWs to identify and act upon unrecognized SARS-CoV-2 infection.


title: Population homogeneity for the antibody response to COVID-19 Comirnaty vaccine is only reached after the second dose

abstract: While mRNA vaccines authorized for emergency use are administrated worldwide in an effort to contain the COVID19 crisis, little is known about the heterogeneity of the immune response they induce. Here, we report the first 6 weeks of a longitudinal study that quantifies the humoral immune response to BNT162b2 mRNA COVID-19 (Pfizer/BioNTech, Comirnaty) in 1245 health care providers, the Lx1000HCW-PZF cohort. We reveal a striking inter-individual variation 3 weeks after the 1st dose administration that only in part related to age and sex. While population homogeneity in robust IgG responses was reached upon 2nd dose administration, IgM and IgA levels remain low and heterogenous. Our findings of isotypic and heterogenous antibody responses to Comirnaty highlight the need for evaluating the efficacy of COVID-19 mRNA vaccine in preventing infection aside disease, and - contrary to what has been proposed - advocate for the interval between the two doses not to be extended.


title: Population homogeneity for the antibody response to COVID-19 BNT162b2/Comirnaty vaccine is only reached after the second dose, across all adult age range.


title: SARS-CoV-2 genome sequencing from COVID-19 in Ecuadorian patients: a whole country analysis.

abstract:
SARS-CoV-2, the etiological agent of COVID-19, was first described in Wuhan, China in December 2019 and has now spread globally. Ecuador was the second country in South America to confirm cases and Guayaquil was one of the first cities in the world to experience high mortality due to COVID-19. The aim of this study was to describe the lineages circulating throughout the country and to compare the mutations in local variants, to the reference strain. In this work we used the MinION platform (Oxford Nanopore Technologies) to sequence the whole SARS-CoV-2 genomes of 119 patients from all provinces of Ecuador, using the ARTIC network protocols. Our data from lineage assignment of the one hundred and nineteen whole genomes revealed twenty different lineages. All genomes presented differences in the S gene compared to the Wuhan reference strain, being the D614G amino acid replacement the most common change. The B.1.1.119 lineage was the most frequent and was found in several locations in the Coast and Andean region. Three sequences were assigned to the new B.1.1.7 lineage. Our work is an important contribution to the understanding of the epidemiology of SARS-CoV-2 in Ecuador and South America.

HighlightsO_LIAll 119 genomes showed mutations compared to the reference strain, which could be important to understand the virulence, severity and transmissibility of the virus.
C_LIO_LIUntil January 17, three sequences were assigned to the new B.1.1.7 lineage.
C_LIO_LIOur findings suggest that there were at least twenty independent introductions of SARS-CoV-2 to Ecuador.
C_LI

Article Summary LineWe report 119 sequences of SARS-CoV-2 across all Ecuadorian provinces, 20 different lineages were found until January 17th, including B.1.1.7.


title: Characterising long COVID more than 6 months after acute infection in adults; prospective longitudinal cohort study, England

abstract:
BackgroundMost individuals with COVID-19 will recover without sequelae, but some will develop long-term multi-system impairments. The definition, duration, prevalence and symptoms associated with long COVID, however, have not been established.

MethodsPublic Health England (PHE) initiated longitudinal surveillance of clinical and non-clinical healthcare workers for monthly assessment and blood sampling for SARS-CoV-2 antibodies in March 2020. Eight months after enrolment, participants completed an online questionnaire including 72 symptoms in the preceding month. Symptomatic mild-to-moderate cases with confirmed COVID-19 were compared with asymptomatic, seronegative controls. Multivariable logistic regression was used to identify independent symptoms associated with long COVID.

FindingsAll 2,147 participants were contacted and 1,671 (77.8%) completed the questionnaire, including 140 (8.4%) cases and 1,160 controls. At a median of 7.5 (IQR 7.1-7.8) months after infection, 20 cases (14.3%) had ongoing (4/140, 2.9%) or episodic (16/140, 11.4%) symptoms. We identified three clusters of symptoms associated with long COVID, those affecting the sensory (ageusia, anosmia, loss of appetite and blurred vision), neurological (forgetfulness, short-term memory loss and confusion/brain fog) and cardiorespiratory (chest tightness/pain, unusual fatigue, breathlessness after minimal exertion/at rest, palpitations) systems. The sensory cluster had the highest association with being a case (aOR 5.25, 95% CI 3.45-8.01). Dermatological, gynaecological, gastrointestinal or mental health symptoms were not significantly different between cases and controls.

InterpretationMost persistent symptoms reported following mild COVID-19 were equally common in cases and controls. While all three clusters identified had a strong association with cases, the sensory cluster had the highest specificity and strength of association, and therefore, most likely to be characteristic of long COVID.

FundingPHE.

Research in contextO_ST_ABSEvidence before this studyC_ST_ABSWe searched PubMed using search terms "long covid*" OR "post COVID*" in adults for studies including cohort, case reports, randomised control trials, cross-sectional and systematic reviews published up to 12 March 2020 without any language restrictions. Most reports included a small number of cases. Larger studies included very specific cohorts, including hospitalised cases and self-selected participants with COVID-19. A systematic review identified 15 studies and, using a broad case definition, concluded that 80% (95% CI 65-92) of patients with SARS-CoV-2 developed one or more long-term symptoms. The five most common symptoms were fatigue (58%), headache (44%), attention disorder (27%), hair loss (25%), and dyspnea (24%), but no assessment was made of these symptoms in uninfected adults.

Added value of this studyIn a prospective, longitudinal cohort of clinical and non-clinical healthcare workers recruited at the start of the pandemic, we found that most self-reported symptoms were as common in 140 adults who developed mild-to-moderate COVID-19 more than 6 months previously compared to 1,160 controls who were asymptomatic and SARS-CoV-2 antibody negative throughout the surveillance period. Compared to controls, we identified three clusters of symptoms affecting the sensory, neurological and cardiorespiratory systems that were more prevalent among cases. Notably, symptoms affecting other organ systems were as prevalent among cases as controls. The high proportion of cases and controls reporting mental health symptoms highlights the toll that the pandemic has had on healthcare workers

Implications of all the available evidenceOur findings highlight the importance of including a representative cohort of cases to assess long-term outcomes of COVID-19 as well as appropriate controls to estimate the relative prevalence of self-reported symptoms to accurately define this new syndrome. Our study adds to the evidence-base for long COVID in adults with mild-to-moderate COVID-19 who contribute to the vast majority of 120+ million infections worldwide. This information is not only important for clinicians, patients and the public, but also for policy makers and healthcare providers who are investing heavily in long-term provisions for COVID-19 survivors.


title: Characterising post-COVID syndrome more than 6 months after acute infection in adults; prospective longitudinal cohort study, England


title: SARS-CoV-2 Seroprevalence in 12 Cities of India from July-December 2020

abstract:
ObjectivesWe sought to understand the spread of SARS-CoV-2 infection in urban India, which has surprisingly low COVID-19 deaths.

DesignCross-sectional and trend analyses of seroprevalence in self-referred test populations, and of reported cases and COVID mortality data.

Participants448,518 self-referred individuals using a nationwide chain of private laboratories with central testing of SARS-CoV-2 antibodies and publicly available case and mortality data.

Setting12 populous cities with nearly 92 million total population.

Main outcome measuresSeropositivity trends and predictors (using a Bayesian geospatial model) and prevalence derived from mortality data and infection fatality rates (IFR).

ResultsFor the whole of India, 31% of the self-referred individuals undergoing antibody testing were seropositive for SARS-CoV-2 antibodies. Seropositivity was higher in females (35%) than in males (30%) overall and in nearly every age group. In these 12 cities, seroprevalence rose from about 18% in July to 41% by December, with steeper increases at ages <20 and 20-44 years than at older ages. The "M-shaped" age pattern is consistent with intergenerational transmission. Areas of higher childhood measles vaccination in earlier years had lower seropositivity. The patterns of increase in seropositivity and in peak cases and deaths varied substantially across cities. In Delhi, death rates and cases first peaked in June and again in November; Chennai had a single peak in July. Based local IFRs and COVID deaths (adjusted for undercounts), we estimate that 43%-65% of adults above age 20 had been infected (range of mid-estimates of 12%-77%) corresponding 26 to 36 million infected adults in these cities, or an average of 9-12 infected adults per confirmed case.

ConclusionEven with relatively low death rates, the large cities of India had remarkably high levels of SARS-CoV-2 infection. Vaccination strategies need to consider widespread intergenerational transmission.


title: Evaluation of pooling of samples for testing SARS-COV- 2 for mass screening of COVID-19

abstract:
BackgroundThe current pandemic of SARS- COV- 2 virus, widely known as COVID-19 has affected millions of people around the world. The World Health Organization (WHO) has recommended vigorous testing to differentiate SARS-CoV-2 from other respiratory infections to aid in guiding appropriate care and management. Situations like this have demanded robust testing strategies and pooled testing of samples for SARS- COV- 2 virus has provided the solution to mass screening of people. The pooled testing strategy can be very effective in testing with limited resources, yet it comes with its own limitations. These limitations need critical consideration when it comes to testing of highly infectious disease like COVID -19.

MethodsThe study evaluated the pooled testing of nasopharyngeal swabs for SARS- COV- 2 by comparing sensitivity of individual sample testing with 4 and 8 pool sample testing. Median cycle threshold (Ct) values were compared. The precision of pooled testing was assessed by doing an inter and intra assay of pooled samples. Coefficient of variance was calculated for inter and intra assay variability.

ResultsThe sensitivity becomes considerably low when the samples are pooled, there is a higher percentage of false negatives with higher pool size and when the patient viral load is low or weak positive samples. High variability was seen in the intra and inter assay, especially in weak positive samples and larger pool size.

ConclusionAs COVID - 19 numbers are still high and testing capacity needs to be high, we have to meticulously evaluate the testing strategy for each country depending on its testing capacity, infrastructure, economic strength, and need to make a serious call on cost effective strategy of resource saving and risk/ cost of missing positive patients.


title: VIRAL AND ANTIBODY TESTING FOR CORONAVIRUS DISEASE 2019 (COVID-19): FACTORS ASSOCIATED WITH POSITIVITY IN ELECTRONIC HEALTH RECORDS FROM THE UNITED STATES

abstract:
AO_SCPLOWBSTRACTC_SCPLOWO_ST_ABSBackgroundC_ST_ABSInsufficient information on SARS-CoV-2 testing results exists in clinical practice from the United States.

MethodsWe conducted an observational retrospective cohort study using Optum(R) de-identified COVID-19 electronic health records from the United States to characterize patients who received a SARS-CoV-2 viral or antibody test between February 20, 2020 and July 10, 2020. We assessed temporal trends in testing and positivity by demographic and clinical characteristics; evaluated concordance between viral and antibody tests; and identified factors associated with positivity via multivariable logistic regression.

ResultsOur study population included 891,754 patients. Overall positivity rate for SARS-CoV-2 was 9% and 12% for viral and antibody tests, respectively. Positivity rate was inversely associated with the number of individuals tested and decreased over time across regions and race/ethnicities. Among patients who received a viral test followed by an antibody test, concordance ranged from 90%-93% depending on the duration between the two tests which is notable given uncertainties related to specific viral and antibody test characteristics. The following factors increased the odds of viral and antibody positivity in multivariable models: male, Hispanic or non-Hispanic Black and Asian, uninsured or Medicaid insurance, Northeast residence, dementia, diabetes, and obesity. Charlson Comorbidity Index was negatively associated with test positivity. We identified symptoms that were positively associated with test positivity, as well as, commonly co-occurring symptoms / conditions. Pediatric patients had reduced odds of a positive viral test, but conversely had increased odds of a positive antibody test.

ConclusionsThis study identified sociodemographic and clinical factors associated with SARS-CoV-2 testing and positivity within routine clinical practice from the United States.


title: Occupational risk of COVID-19 by country of birth. A register-based study.

abstract:
AimTo assess the role of occupation in the spread of COVID-19 among immigrants in Norway.

MethodsIn 2.729.627 residents in Norway aged 20-70 years and born in Norway, Somalia, Pakistan, Iraq, Afghanistan and Turkey (mean [SD] age 44 (14) years and 51% men), we examined whether persons employed as taxi drivers, bus- and tram drivers, child care workers, nurses, personal care workers in health, food service counter attendants, waiters/bartenders, cleaners and shop sale persons had a higher risk of COVID-19, from April 1st 2020 to December 2nd 2020, compared to 1) Norwegian-born in the same occupational group and 2) all others with the same birth country and aged 20-70 years, using logistic regressions.

ResultsWithin each of the included occupational groups, immigrants had a greatly increased odds of COVID-19 when compared to Norwegian-born (OR [~] 1.66-12.72). However, immigrants working in the selected occupations had the same odds of COVID-19 as person with same birth country not having the same occupation (OR[~]1). Exceptions were Somalian-, Afghani- and Iraqi personal care workers in health services who had an increased odds of COVID-19 (OR 1.61 (95% CI 1.31, 1.98), OR 1.46 (1.06, 2.02) and OR 1.40 (1.03, 1.91), respectively) compared to others from the same country.

ConclusionImmigrants holding various occupations implying close contact with others did not have higher odds of notified infection than others with the same country of birth, except for health care workers. Our study indicates that occupation is not an important driver of the high rates of COVID-19 among immigrants from Somalia, Pakistan, Iraq, Afghanistan and Turkey.


title: Head-to-head performance comparison of self-collected nasal versus professional-collected nasopharyngeal swab for a WHO-listed SARS-CoV-2 antigen-detecting rapid diagnostic test

abstract:
BackgroundIn 2020, the World Health Organization (WHO) recommended two SARS-CoV-2 lateral flow antigen detecting rapid diagnostics tests (Ag-RDTs), both initially with nasopharyngeal (NP) sample collection. Independent head-to-head studies demonstrated for SARS-CoV-2 Ag-RDTs nasal sampling to be a comparable and reliable alternative for nasopharyngeal (NP) sampling.

MethodsWe conducted a head-to-head comparison study of a supervised, self-collected nasal mid-turbinate (NMT) swab and a professional-collected NP swab, using the Panbio Ag-RDT (the second WHO-listed SARS-CoV-2 Ag-RDT, distributed by Abbott). We calculated positive and negative percent agreement and, compared to the reference standard reverse transcription polymerase chain reaction (RT-PCR), sensitivity and specificity for both sampling techniques.

ResultsA SARS-CoV-2 infection could be diagnosed by RT-PCR in 45 of 290 participants (15.5%). Comparing the NMT and NP sampling the positive percent agreement of the Ag-RDT was 88.1% (37/42 PCR positives detected; CI 75.0% - 94.8%). The negative percent agreement was 98.8% (245/248; CI 96.5% - 99.6%). The overall sensitivity of Panbio with NMT sampling was 84.4% (38/45; CI 71.2% - 92.3%) and 88.9% (40/45; CI 76.5% - 95.5%) with NP sampling. Specificity was 99.2% (243/245; CI 97.1% - 99.8%) for both, NP and NMT sampling. The sensitivity of the Panbio test in participants with high viral load (> 7 log10 SARS-CoV-2 RNA copies/mL) was 96.3% (CI 81.7% - 99.8%) for both, NMT and NP sampling.

ConclusionFor the Panbio Ag-RDT supervised NMT self-sampling yields to results comparable to NP sampling. This suggests that nasal self-sampling could be used for scale-up population testing.


title: Increased prevalence of AB group and FY*A red blood cell antigen in Caucasian SARS-CoV-2 convalescent plasma donors

abstract:
IntroductionThe SARS-CoV-2 pandemic has put significant additional pressure on healthcare systems throughout the world. The identification of at-risk population beyond age, pre-existing medical conditions and socioeconomic status has been the subject of only a small part of the global COVID-19 research so far. To this day, more data is required regarding the association between HLA allele and red blood cell (RBC) antigens expression in regard to SARS-CoV-2 infection susceptibility and virus clearance capability, and COVID-19 susceptibility, severity, and duration.

MethodsThe phenotypes for ABO and RhD, and the genotypes for 37 RBC antigens and HLA-A, B, C, DRB1, DQB1 and DPB1 were determined using high throughput platforms (Luminex and Next-generation Sequencing) in 90 Caucasian convalescent plasma donors. The results were compared to expected reference frequencies, local and international databases, and literature.

ResultsThe AB group was significantly increased (1.5x, p=0.018) and a non-significant (2.2x, p=0.030) increase was observed for the FY*A allele frequency in the convalescent cohort (N=90) compared to reference frequencies. Some HLA alleles were found significantly overrepresented (HLA-B*44:02, C*05:01, DPB1*04:01, DRB1*04:01 and DRB1*07:01) or underrepresented (A*01:01, B51:01 and DPB1*04:02) in convalescent individuals compared to the local bone marrow registry population.

ConclusionOur study of infection-susceptible but non-hospitalized Caucasian COVID-19 patients contributes to the global understanding of host genetic factors associated with SARS-CoV-2 infection susceptibility and severity of the associated disease.


title: HLA and red blood cell antigen genotyping in SARS-CoV-2 convalescent plasma donors


title: Longitudinal determination of mRNA-vaccination induced strongly binding SARS-CoV-2 IgG antibodies in a cohort of healthcare workers with and without prior exposure to the novel coronavirus

abstract:
Mass vaccination against the disease caused by the novel coronavirus (COVID-19) was a crucial step in slowing the spread of SARS-CoV-2 in 2021. Even in the face of new variants, it still remains extremely important for reducing hospitalizations and COVID-19 deaths. Only limited data exists about the short- and long-term dynamics of humoral immune response. We present a longitudinal analysis of post-vaccination IgG levels in a cohort of 166 healthcare workers vaccinated with BNT162b2 with weekly follow-up until 35 days past the first dose and monthly follow-up up to 6 months post-vaccination. A subset of the patients continued with follow-up after 6 months and either received a booster dose or got infected during the Delta wave in Romania. Tests were carried out on 1697 samples using a CE-marked IgG ELISA assay developed in-house, containing S1 and N antigens of the wild type virus.

Participants infected with SARS-CoV-2 before vaccination mount a quick immune response, reaching peak IgG levels two weeks after the first dose, while IgG levels of previously uninfected participants mount gradually, increasing abruptly after the second dose. Overall higher IgG levels are maintained for the previously infected group 35-70 days after vaccination. The decrease of IgG levels is gradual, with lower overall values in the infection naive cohort even 7-8 months after vaccination, compared to the previously infected cohort. Administration of a booster dose yielded higher average IgG antibody levels than post second dose in the infection naive group and comparable levels in the previously infected group.

category: allergy and immunology


title: Longitudinal determination of mRNA-vaccination induced strongly binding SARS-CoV-2 IgG antibodies in a cohort of Romanian healthcare workers


title: Comparative assessment of SARS-CoV-2 serology in healthcare workers with Abbott Architect, Roche Elecsys and The Binding site ELISA immunoassays.

abstract:
PurposeSARS-CoV-2 serology testing is key for assessing seroprevalence and antibody response post-vaccination in immunocompromised patients. Evaluation of current SARS-CoV-2 serological assays have been performed on samples from severe COVID-19 hospitalised patients. However, robust assay development requires assessment in asymptomatic and non-hospitalised individuals to determine if serological assays are sensitive to detect waning and mild antibody responses. Our study evaluated the performance characteristics between two high-throughput SARS-CoV-2 IgG nucleocapsid assays (Abbott and Roche) and The binding site (TBS) Anti-Spike IgG/A/M ELISA kit in healthcare workers.

Methods236 samples were collected from Portsmouth Hospital University NHS Trust (PHU) and The Dudley Group NHS Trust and analysed for SARS-CoV-2 serology. We derived concordance, agreement and assay performance as well as using receiver operating characteristic (ROC) curves to redefine the assay threshold of the Abbott assay.

ResultsResult concordance between the Abbott and TBS was 66%. Discrepant samples were analysed using the Roche assay which showed 100% agreement with the TBS assay. In samples analysed >58 days post-PCR, the sensitivity of Abbott and Roche was 100%. In samples analysed >100 days post-PCR the sensitivity of the Abbott assay dropped to 77.2% but remained at 100% for the Roche assay. A redefined Abbott threshold of 0.64 increased the sensitivity to 90% giving results similar to Roche and TBS assays

ConclusionThis study demonstrated Abbott assay had a lower sensitivity in comparison to TBS and Roche. Furthermore, TBS can be implemented as a viable alternative for SARS-CoV-2 serology testing where high-throughput assays are not available on site.

Trial registration number and date of registration

Not applicable.

Trial registration number, date of registration followed by "retrospectively registered"

Not applicable.

AbstractSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) serology testing is key for assessing seroprevalence and antibody response post-vaccination in immunocompromised patients. Here we performed a comparison between two high-throughput nucleocapsid assays (Abbott SARS-CoV-2 IgG and Roche Elecsys Anti-SARS-CoV-2) and The Binding Site (TBS) anti-Spike IgG/A/M-SARS-CoV-2 ELISA kit. 236 samples were collected across 2 sites, Portsmouth Hospital University NHS Trust (PHU) and The Dudley Group NHS Trust. We derived concordance, agreement and assay performance as well as using receiver operating characteristic (ROC) curves to redefine the assay threshold of the Abbott assay. Result concordance between the Abbott and TBS was 66%. Discrepant samples were analysed using the Roche assay which showed 100% agreement with the TBS assay. In samples analysed >58 days post-PCR, the sensitivity of Abbott and Roche was 100%. In samples analysed >100 days post-PCR the sensitivity of the Abbott assay dropped to 77.2% but remained at 100% for the Roche assay. A redefined Abbott threshold of 0.64 increased the sensitivity to 90% giving results similar to the Roche and TBS assays. In conclusion, this study demonstrated Abbott assay had a lower sensitivity in comparison to TBS and Roche. This study established TBS can be implemented as a viable alternative for SARS-CoV-2 serology testing where high-throughput assays are not available on site. Furthermore, anti-spike assays, such as TBS, could be used to monitor vaccination responses to deduce SARS-CoV-2 population-immunity. Further optimisation studies are required to evaluate the performance characteristics of these assays which could facilitate widescale sero-epidemiological surveillance.


title: Emergency medicine patient wait time multivariable prediction models: a multicentre derivation and validation study

abstract:
ObjectivePatients, families and community members would like emergency department wait time visibility. This would improve patient journeys through emergency medicine. The study objective was to derive, internally and externally validate machine learning models to predict emergency patient wait times that are applicable to a wide variety of emergency departments.

MethodsTwelve emergency departments provided three years of retrospective administrative data from Australia (2017-19). Descriptive and exploratory analyses were undertaken on the datasets. Statistical and machine learning models were developed to predict wait times at each site and were internally and externally validated. Model performance was tested on COVID-19 period data (January to June 2020).

ResultsThere were 1,930,609 patient episodes analysed and median site wait times varied from 24 to 54 minutes. Individual site model prediction median absolute errors varied from +/-22.6 minutes (95%CI 22.4,22.9) to +/- 44.0 minutes (95%CI 43.4,44.4). Global model prediction median absolute errors varied from +/-33.9 minutes (95%CI 33.4, 34.0) to +/-43.8 minutes (95%CI 43.7, 43.9). Random forest and linear regression models performed the best, rolling average models under-estimated wait times. Important variables were triage category, last-k patient average wait time, and arrival time. Wait time prediction models are not transferable across hospitals. Models performed well during the COVID-19 lockdown period.

ConclusionsElectronic emergency demographic and flow information can be used to approximate emergency patient wait times. A general model is less accurate if applied without site specific factors.

What is already known on this subject Patients and families want to know approximate emergency wait times, which will improve their ability to manage their logistical, physical and emotional needs whilst waiting
 There are a few small studies from a limited number of jurisdictions, reporting model methods, important predictor variables and accuracy of derived models

What this study adds Our study demonstrates that predicting wait times from simple, readily available data is complex and provides estimates that arent as accurate as patients would like, however rough estimates may still be better than no information
 We present the most influential variables regarding wait times and advise against using rolling average models, preferring random forest or linear regression techniques
 Emergency medicine machine learning models may be less generalisable to other sites than we hope for when we read manuscripts or buy commercial off-the-shelf models or algorithms. Models developed for one site lose accuracy at another site and global models built for whole systems may need customisation to each individual site. This may apply to data science clinical decision instruments as well as operational machine learning models.

category: emergency medicine


title: SARS-CoV-2 prevalence and transmission in swimming activities: results from a retrospective cohort study

abstract:
There is an urgent need for research on the epidemiology of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing corona virus disease 2019 (COVID-19), as the transmissibility differs between settings and populations. Here we report on a questionnaire-based retrospective cohort study of the prevalence and transmission of SARS-CoV-2 among participants in swimming activities in Denmark in the last five months of 2020 during the COVID-19 pandemic.

Eight of 162 swimming activities with a SARS-CoV-2 positive participant led to transmission to 23 other participants. Overall, the percentage of transmission episodes was 4.9% (competitive swimming 8.9%; recreational swimming 1.3%). Overall, the incidence rate of transmission was 19.5 participants per 100.000 pool activity hours (corresponding values: 43.5 and 4.7 for competitive and recreational swimming, respectively).

Compliance with precautionary restrictions was highest regarding hand hygiene (98.1%) and lowest in distancing personal sports bags (69.9%). Due to low statistical power, the study showed no significant effect of restrictions.

Insight into the risk of transmission of SARS-CoV-2 during indoor swimming is needed to estimate the efficiency of restrictive measures on this and other sports and leisure activities. Only when we know how the virus spreads through various settings, optimal strategies to handle the COVID-19 pandemic can be developed.

category: epidemiology


title: A simple model for how the risk of pandemics from different virus families depends on viral and human traits

abstract: Different virus families, like influenza or corona viruses, exhibit characteristic traits such as typical modes of transmission and replication as well as specific animal reservoirs in which each family of viruses circulate. These traits of genetically related groups of viruses influence how easily an animal virus can adapt to infect humans, how well novel human variants can spread in the population, and the risk of causing a global pandemic. Relating the traits of virus families to their risk of causing future pandemics, and identification of the key time scales within which public health interventions can control the spread of a new virus that could cause a pandemic, are obviously significant. We address these issues using a minimal model whose parameters are related to characteristic traits of different virus families. A key trait of viruses that "spillover" from animal reservoirs to infect humans is their ability to propagate infection through the human population (fitness). We find that the risk of pandemics emerging from virus families characterized by a wide distribution of the fitness of spillover strains is much higher than if such strains were characterized by narrow fitness distributions around the same mean. The dependences of the risk of a pandemic on various model parameters exhibit inflection points. We find that these inflection points define informative thresholds. For example, the inflection point in variation of pandemic risk with time after the spillover represents a threshold time beyond which global interventions would likely be too late to prevent a pandemic.


title: Recalibrating SARS-CoV-2 antigen rapid lateral flow test relative sensitivity from validation studies to absolute sensitivity for detecting individuals with live virus

abstract:
Testing for SARS-CoV-2 internationally has focused on COVID-19 diagnosis among symptomatic individuals using reverse transcriptase polymerase chain reaction (PCR) tests. Recently, however, SARS-CoV-2 antigen rapid lateral flow tests (LFT) have been rolled out in several countries for testing asymptomatic individuals in public health programmes. Validation studies for LFT have been largely cross-sectional, reporting sensitivity, specificity and predictive values of LFT relative to PCR. However, because PCR detects genetic material left behind for a long period when the individual is no longer infectious, these statistics can under-represent sensitivity of LFT for detecting infectious individuals, especially when sampling asymptomatic populations. LFTs (intended to detect individuals with live virus) validated against PCR (intended to diagnose infection) are not reporting against a gold standard of equivalent measurements. Instead, these validation studies have reported relative performance statistics that need recalibrating to the purpose for which LFT is being used. We present an approach to this recalibration.

We derive a formula for recalibrating relative performance statistics from LFT vs PCR validation studies to give likely absolute sensitivity of LFT for detecting individuals with live virus. We show the differences between widely reported apparent sensitivities of LFT and its absolute sensitivity as a test of presence of live virus. After accounting for within-individual viral kinetics and epidemic dynamics within asymptomatic populations we show that a highly performant test of live virus should show a LFT-to-PCR relative sensitivity of less than 50% in conventional validation studies, which after re-calibration would be an absolute sensitivity of more than 80%.

Further studies are needed to ascertain the absolute sensitivity of LFT as a test of infectiousness in COVID-19 responses. These studies should include sampling for viral cultures and longitudinal series of LFT and PCR, ideally in cohorts sampled from both contacts of cases and the general population.


title: WiFi mobility models for COVID-19 enable less burdensome and more localized interventions for university campuses

abstract: Infectious diseases, like COVID-19, pose serious challenges to university campuses, which typically adopt closure as a non-pharmaceutical intervention to control spread and ensure a gradual return to normalcy. Intervention policies, such as remote instruction (RI) where large classes are offered online, reduce potential contact but also have broad side-effects on campus by hampering the local economy, students learning outcomes, and community wellbeing. In this paper, we demonstrate that university policymakers can mitigate these tradeoffs by leveraging anonymized data from their WiFi infrastructure to learn community mobility --- a methodology we refer to as WiFi mobility models (WO_SCPLOWIC_SCPLOWMO_SCPLOWOBC_SCPLOW). This approach enables policymakers to explore more granular policies like localized closures (LC). WO_SCPLOWIC_SCPLOWMO_SCPLOWOBC_SCPLOW can construct contact networks that capture behavior in various spaces, highlighting new potential transmission pathways and temporal variation in contact behavior. Additionally, WO_SCPLOWIC_SCPLOWMO_SCPLOWOBC_SCPLOW enables us to design LC policies that close super-spreader locations on campus. By simulating disease spread with contact networks from WO_SCPLOWIC_SCPLOWMO_SCPLOWOBC_SCPLOW, we find that LC maintains the same reduction in cumulative infections as RI while showing greater reduction in peak infections and internal transmission. Moreover, LC reduces campus burden by closing fewer locations, forcing fewer students into completely online schedules, and requiring no additional isolation. WO_SCPLOWIC_SCPLOWMO_SCPLOWOBC_SCPLOW can empower universities to conceive and assess a variety of closure policies to prevent future outbreaks.


title: Empirical networks for localized COVID-19 interventions using WiFi infrastructure at university campuses


title: SARS-CoV-2 spike protein gene variants with N501T and G142D mutation dominated infections in minks in the US

abstract: Large number of minks were infected with SARS-CoV-2 virus containing the spike protein Y453F mutation in Europe, causing zoonosis concerns. To evaluate the genetic characteristics of the US and Canadian mink-derived SARS-CoV-2 sequences, we analyzed all animal-derived (977), all Canadian (19,529) and US (173,277) SARS-CoV-2 sequences deposited in GISAID from December 2019 to March 12, 2021, and identified 2 dominant novel variants, the N501T-G142D variant and N501T-G142D-F486L variant, in the US mink-derived SARS-CoV-2 sequences. These variants were not found in minks from Canada or other countries. The Y453F mutation was not identified in the mink-derive sequences in the US and Canada. The N501T mutation occurred two months earlier in the human than in the minks in the US, and the novel N501T-G142D variant and N501T-G142D-F486L variant were found in human prior to minks. The result of this study indicates that the novel variants may have evolved during human infection and then transmitted to mink populations in the US.


title: The Case for Altruism in Institutional Diagnostic Testing

abstract: Amid COVID-19, many institutions deployed vast resources to test their members regularly for safe reopening. This self-focused approach, however, not only overlooks surrounding communities but also remains blind to community transmission that could breach the institution. To test the relative merits of a more altruistic strategy, we built an epidemiological model that assesses the differential impact on case counts when institutions instead allocate a proportion of their tests to members close contacts in the larger community. We found that testing outside the institution benefits the institution in all plausible circumstances, with the optimal proportion of tests to use externally landing at 45% under baseline model parameters. Our results were robust to local prevalence, secondary attack rate, testing capacity, and contact reporting level, yielding a range of optimal community testing proportions from 18% to 58%. The model performed best under the assumption that community contacts are known to the institution; however, it still demonstrated a significant benefit even without complete knowledge of the contact network.


title: Improved Prediction of COVID-19 Transmission and Mortality Using Google Search Trends for Symptoms in the United States

abstract: Accurate forecasting of emerging infectious diseases can guide public health officials in making appropriate decisions related to the allocation of public health resources. Due to the exponential spread of the COVID-19 infection worldwide, several computational models for forecasting the transmission and mortality rates of COVID-19 have been proposed in the literature. To accelerate scientific and public health insights into the spread and impact of COVID-19, Google released the Google COVID-19 search trends symptoms open-access dataset. Our objective is to develop 7 and 14 -day-ahead forecasting models of COVID-19 transmission and mortality in the US using the Google search trends for COVID-19 related symptoms. Specifically, we propose a stacked long short-term memory (SLSTM) architecture for predicting COVID-19 confirmed and death cases using historical time series data combined with auxiliary time series data from the Google COVID-19 search trends symptoms dataset. Considering the SLSTM networks trained using historical data only as the base models, our base models for 7 and 14 -day-ahead forecasting of COVID cases had the mean absolute percentage error (MAPE) values of 6.6% and 8.8%, respectively. On the other side, our proposed models had improved MAPE values of 3.2% and 5.6%, respectively. For 7 and 14 -day-ahead forecasting of COVID-19 deaths, the MAPE values of the base models were 4.8% and 11.4%, while the improved MAPE values of our proposed models were 4.7% and 7.8%, respectively. We found that the Google search trends for "pneumonia," "shortness of breath," and "fever" are the most informative search trends for predicting COVID-19 transmission. We also found that the search trends for "hypoxia" and "fever" were the most informative trends for forecasting COVID-19 mortality.


title: Smoking methylation marks for prediction of urothelial cancer risk

abstract:
BackgroundSelf-reported information may not accurately capture smoking exposure. We aimed to evaluate whether smoking-associated DNA methylation markers improve urothelial cell carcinoma (UCC) risk prediction.

MethodsConditional logistic regression was used to assess associations between blood-based methylation and UCC risk using two matched case-control samples, N=404 pairs from the Melbourne Collaborative Cohort Study (MCCS) and N=440 pairs from the Womens Health Initiative (WHI) cohort, respectively. Results were pooled using fixed-effects meta-analysis. We developed methylation-based predictors of UCC and evaluated their prediction accuracy on two replication datasets using the area under the curve (AUC).

ResultsThe meta-analysis identified associations (P<4.7x10-5) for 29 of 1,061 smoking-associated methylation sites, but these were substantially attenuated after adjustment for self-reported smoking. Nominally significant associations (P<0.05) were found for 387 (36%) and 86 (8%) of smoking-associated markers without/with adjustment for self-reported smoking, respectively, with same direction of association as with smoking for 387 (100%) and 79 (92%) markers. A Lasso-based predictor was associated with UCC risk in one replication dataset in MCCS (N=134, odds ratio per SD [OR]=1.37, 95%CI=1.00-1.90) after confounder adjustment; AUC=0.66, compared with AUC=0.64 without methylation information. Limited evidence of replication was found in the second testing dataset in WHI (N=440, OR=1.09, 95%CI=0.91-1.30).

ConclusionsCombination of smoking-associated methylation marks may provide some improvement to UCC risk prediction. Our findings need further evaluation using larger datasets.

ImpactDNA methylation may be associated with UCC risk beyond traditional smoking assessment and could contribute to some improvements in stratification of UCC risk in the general population.


title: Is attachment style in early childhood associated with mental health difficulties in late adolescence?

abstract:
BackgroundAlthough existing research has suggested an association between insecure attachment styles and mental health difficulties, these studies often have small sample sizes, use cross-sectional designs, and measure attachment as a discrete variable at a single point. It is also unclear whether these associations persist into late adolescence. In this prospective study we aimed to determine whether insecure attachment style in early childhood is associated with depression and self-harm at 18 years.

MethodsWe used data from the Avon Longitudinal Study of Parents and Children cohort. Mothers completed attachment related questionnaires when their child was 18, 30, and 42 months old. Offspring depression and lifetime self-harm was assessed at 18 years using the Clinical Interview Schedule-Revised. Attachment was derived as a latent variable in a structural equation modelling framework. Logistic regression was performed on participants with complete attachment data (n=7032) to examine the association between attachment style and depression and self-harm, with adjustment for potential confounders. Differential dropout was accounted for using multiple imputation.

ResultsWe found some evidence for an association between attachment quality and depression and self-harm. In the fully adjusted imputed model, a one standard deviation increase in insecure attachment was associated with a 13% increase in the odds of depression at age 18 (OR=1.13; 95%CI=1.00 to 1.27) and a 14% increase in the odds of self-harm at age 18 (OR=1.14; 95%CI=1.02 to 1.25).

ConclusionsOur findings strengthen the evidence suggesting that an insecure attachment style assessed in early childhood is associated with mental health difficulties in late adolescence. If this association is causal, policies to support parenting or attachment-based interventions to improve attachment quality could help reduce mental health difficulties in adolescence/young adulthood.

category: psychiatry and clinical psychology


title: How safe is Covishield (ChAdOx1nCoV-19) vaccine? Experience from a tertiary care hospital in South India

abstract:
BackgroundCOVID vaccine has been recently rolled out for Health care workers in India. Though vaccine trials and data are available, people, including HCWs, need more real-life data from their contexts to get over the vaccine hesitancy. We aimed to determine the incidence of Adverse Event Following Immunisation (AEFI) among HCWs after their first dose of ChAdOx1nCoV-19 vaccine

MethodsWe conducted a cross-sectional study among 218 staff of a tertiary care hospital. We circulated a google form with informed consent on the hospital WhatsApp platform and asked them to self-report their vaccination experience.

ResultsTwo thirds (69.7% (152/218), 95% CI: 63.1-75.7) had minor AEFI, and none had severe AEFI. Body ache (46.8% (102/218), 95% CI :40 - 53.6) was the most common symptom followed by headache (30.3% (66/218), 95% CI :24.2 - 36.8) and fever (22% 948/218), 95% CI :16.7 - 28.1). Most of them (39.4% (87/218) 95% CI:32.9 - 46.2) experienced symptoms within 4-24 hours after taking the vaccine while 22.3% (49/218) (95% CI: 17.1 - 28.6) experienced it after a day. Majority of the HCWs (78.9% (172/218), 95% CI: 72.8 - 84.1) were anxious before the vaccination. Younger age group and female gender were significantly associated with AEFI compared to their counterparts.

ConclusionHCWs experienced minor, self-limiting AEFI with the first dose of ChAdOx1nCoV-19. The hospital reported no serious AEFI following the vaccination

category: public and global health


title: Transcriptome analysis of PBMCs reveals distinct immune response in the asymptomatic and re-detectable positive COVID-19 patients

abstract: The existence of asymptomatic and re-detectable positive COVID-19 patients presents the disease control challenges of COVID-19. Most studies on immune response of COVID-19 have focused on the moderately or severely symptomatic patients, however little is known about the immune response in asymptomatic and re-detectable positive patients. Here we performed a comprehensive analysis of the transcriptomic profiles of PBMCs from 48 COVID-19 patients which include 8 asymptomatic, 13 symptomatic, 15 recovering and 12 RP patients. Our analysis revealed a down-regulation of IFN response and complement activation in the asymptomatic patients compared with the symptomatic, indicating a weaker immune response of the PBMCs in the asymptomatic patients. In addition, we observed a lower expression of the cytokines and chemokines in the PBMC of asymptomatic and symptomatic patients. In contrast, the cytokines and chemokines level in the RP patients are higher than the recovering. GSEA analysis showed the enrichment of TNFa/NF-{kappa}B and influenza infection in the RP patients compared with the recovering patients, indicating a flu-like, hyper-inflammatory immune response in the PBMC of RP patients. Thus our findings could extend our understanding of host immune response during the progression COVID-19 disease and help the clinical management and the immunotherapy development for COVID-19.

category: respiratory medicine


title: Exploring the laminar connectome

abstract: The human connectome is the complete structural description of the network of connections and elements that form the  wiring diagram of the brain. Due to the current scarcity of information regarding laminar end points of white matter tracts inside cortical grey matter, tractography remains focused on cortical partitioning into regions, while ignoring radial partitioning into laminar components. To overcome this biased representation of the cortex as a single homogenous unit, we use a recent data-derived model of cortical laminar connectivity, which has been further explored and corroborated in the macaque brain by comparison to published studies. The model integrates multimodal MRI imaging datasets of both white matter connectivity and grey matter laminar composition into a laminar-level connectome. In this study we model the laminar connectome of healthy human brains (N=30) and explore them via a set of neurobiologically meaningful complex network measures. Our analysis demonstrates a subdivision of network hubs that appear in the standard connectome into each individual component of the laminar connectome, giving a fresh look into the role of laminar components in cortical connectivity and offering new prospects in the fields of both structural and functional connectivity.

category: neurology


title: Modelling the laminar connectome of the human brain


title: Pregnancy loss and postpartum mortality in a sub-Saharan African setting

abstract:
ObjectiveStudies from industrialized countries report a harmful association between pregnancy loss and postpartum mortality. However, the nature of this relationship has not been established in resource limited sub-Saharan Africa. Given the potential implications of this knowledge for risk stratification and subsequent maternal health in sub-Saharan Africa, our study sought to use data from one of the continents largest and longest running population-based cohorts to investigate the relationship between pregnancy loss and postpartum mortality.

MethodsWe conducted a population-based cohort study involving 25048 postpartum women from KwaZulu-Natal, South Africa. The study data was collected during biannual/triannual general household surveys, which also incorporated a pregnancy questionnaire for women who reported a pregnancy between survey waves. Pregnancy loss was defined as a pregnancy which ended in abortion, miscarriage, or stillbirth. Postpartum mortality was defined as the death of a woman, from any cause, within one year after the date that her pregnancy ended. We used a quasi-poisson regression model, adjusted for maternal age and other setting-specific predictors of postpartum mortality, to investigate the relationship between pregnancy loss and postpartum mortality.

ResultsThe incidence of postpartum mortality was three times higher in women who experienced pregnancy loss (Adjusted Incidence Rate Ratio: 3.23, 95% Confidence Interval: 2.13-4.71), when compared with women who had live births.

ConclusionOur results reveal a clear association between pregnancy loss and increased postpartum mortality in a typical rural sub-Saharan African setting. Women who have recently experienced pregnancy loss should be targeted with a package of risk reduction interventions, including additional opportunities for medical care or psychosocial support.

category: obstetrics and gynecology


title: Calculating variant penetrance using family history of disease and population data

abstract:
PurposeGenetic penetrance is the probability of a phenotype manifesting if one harbours a specific pathogenic variant. For most Mendelian genes, penetrance is incomplete and may be age-dependent. Accurate penetrance estimates are important in many biomedical fields including genetic counselling, disease research, and for gene therapy. The main methods for its estimation are limited in situations where large family pedigrees are not available, the disease is rare, late onset, or complex.

MethodsHere we present a novel method for penetrance estimation in autosomal dominant phenotypes. It uses population-scale data regarding the distribution of a variant among unrelated people affected (cases) and unaffected (controls) by an associated phenotype and can be operated using samples of affected people only by considering family disease history.

ResultsThe method is validated within simulation studies. Candidate variant-disease case studies yield estimates which align with existing disease knowledge and estimates derived using established methods.

ConclusionWe have presented a valid method for penetrance estimation in autosomal dominant traits which avoids kinship-specific penetrance estimates and the ascertainment biases that can arise when sampling rare variants among control populations. It can be accessed from our public web server (https://adpenetrance.rosalind.kcl.ac.uk) and is available as an open-source R library (https://github.com/ThomasPSpargo/adpenetrance).

category: genetic and genomic medicine


title: Weak humoral immune reactivity among residents of long-term care facilities following one dose of the BNT162b2 mRNA COVID-19 vaccine

abstract:
BackgroundSeveral Canadian provinces are extending the interval between COVID-19 vaccine doses to increase population vaccine coverage more rapidly. However, immunogenicity of these vaccines after one dose is incompletely characterized, particularly among the elderly, who are at greatest risk of severe COVID-19.

MethodsWe assessed SARS-CoV-2 humoral responses pre-vaccine and one month following the first dose of BNT162b2 mRNA vaccine, in 12 COVID-19 seronegative residents of long-term care facilities (median age, 82 years), 18 seronegative healthcare workers (HCW; median age, 36 years) and 4 convalescent HCW. Total antibody responses to SARS-CoV-2 nucleocapsid (N) and spike protein receptor binding domain (S/RBD) were assessed using commercial immunoassays. We quantified IgG and IgM responses to S/RBD and determined the ability of antibodies to block S/RBD binding to ACE2 receptor using ELISA. Neutralizing antibody activity was also assessed using pseudovirus and live SARS-CoV-2.

ResultsAfter one vaccine dose, binding antibodies against S/RBD were [~]4-fold lower in residents compared to HCW (p<0.001). Inhibition of ACE2 binding was 3-fold lower in residents compared to HCW (p=0.01) and pseudovirus neutralizing activity was 2-fold lower (p=0.003).While six (33%) seronegative HCW neutralized live SARS-CoV-2, only one (8%) resident did (p=0.19). In contrast, convalescent HCW displayed 7- to 20-fold higher levels of binding antibodies and substantial ability to neutralize live virus after one dose.

InterpretationExtending the interval between COVID-19 vaccine doses may pose a risk to the elderly due to lower vaccine immunogenicity in this group. We recommend that second doses not be delayed in elderly individuals.


title: Early super-spreader events are a likely determinant of novel SARS-CoV-2 variant predominance

abstract: The emergence of multiple new SARS-CoV-2 variants, characterized to varying degrees by increased infectivity, higher virulence and evasion of vaccine and infection-induced immunologic memory, has hampered international efforts to contain the virus. While it is generally believed that these variants first develop in single individuals with poor immunologic control of the virus, the factors governing variant predominance in the population remain poorly characterized. Here we present a mathematical framework for variant emergence accounting for the highly variable number of people secondarily infected by individuals with SARS-CoV-2 infection. Our simulations suggest that threatening new variants probably develop within infected people fairly commonly, but that most die out and do not achieve permanence in the population. Variants that predominate are more likely to be associated with higher infectiousness, but also the occurrence of a super-spreader event soon after introduction into the population.


title: P1 variant and amino acid mutations at Spike gene identified using Sanger protocol

abstract: SARS-CoV-2 variants, along with vaccination, mark the second year of the pandemic. The spike region is a focal point in COVID-19 pathogenesis, with different amino acid changes potentially modulating vaccine response and some being part of variant signatures. NGS is the standard tool to sequence the virus but limitations of different sources hinders expansion of genomic surveillance in many places. To improve surveillance capability we developed a Sanger based sequencing protocol to obtain coverage of most (>95%) spike gene. Eleven nasopharyngeal swabs collections had RNA extracted for real time PCR diagnosis and leftover RNA had up to 3785 bp sequenced at an ABI3500 using dye termination chemistry of nested PCR products of two reactions of one-step RT-PCR. P1 amino acid mutations signatures were present in 18% (2/11), with 82% (9/11) with three or more additional amino acid changes (GISAID CoVsurver list). Most sequences (86%, 6/7) from 2021 have the E484K, whereas the mutation was not present in samples collected in 2020 (0/4, p=0.015).The swiftness that favorable mutations to the virus may prevail and their potential impact in vaccines and other current interventions need broader surveillance and more public health attention.


title: Ventilation procedures to minimize the airborne transmission of viruses at schools

abstract: Reducing the transmission of SARS-CoV-2 through indoor air is the key challenge of the COVID-19 pandemic. Crowded indoor environments, such as schools, represent possible hotspots for virus transmission since the basic non-pharmaceutical mitigation measures applied so far (e.g. social distancing) do not eliminate the airborne transmission mode. There is widespread consensus that improved ventilation is needed to minimize the transmission potential of airborne viruses in schools, whether through mechanical systems or ad-hoc manual airing procedures in naturally ventilated buildings. However, there remains significant uncertainty surrounding exactly what ventilation rates are required, and how to best achieve these targets with limited time and resources. This paper uses a mass balance approach to quantify the ability of both mechanical ventilation and ad-hoc airing procedures to mitigate airborne transmission risk in the classroom environment. For naturally-ventilated classrooms, we propose a novel feedback control strategy using CO2 concentrations to continuously monitor and adjust the airing procedure. Our case studies show how such procedures can be applied in the real world to support the reopening of schools during the pandemic. Our results also show the inadequacy of relying on absolute CO2 concentration thresholds as the sole indicator of airborne transmission risk.


title: Self-reported smell and taste recovery in COVID-19 patients: a one-year prospective study

abstract:
PurposeThe aim of the present study was to estimate the one-year prevalence and recovery rate of self-reported chemosensory dysfunction in a series of subjects with previous mild-to-moderate symptomatic COVID-19.

MethodsProspective study based on the SNOT-22 (item sense of smell or taste) and additional outcomes.

Results268/315 patients (85.1%) completing the survey at baseline also completed the follow-up interview. The 12-months prevalence of self-reported COVID-19 associated chemosensory dysfunction was 21.3% (95% CI: 16.5-26.7%). Of the 187 patients who complained of COVID-19 associated chemosensory dysfunction at baseline, 130 (69.5%; 95% CI 62.4-76.0%) reported complete resolution of smell or taste impairment, 41 (21.9%) reported a decrease in the severity, and 16 (8.6%) reported the symptom was unchanged or worse one year after onset. The risk of persistence was higher for patients reporting a baseline SNOT-22 score > o = 4 (OR=3.32; 95% CI: 1.32-8.36) as well as for those requiring > o = 22 days for a negative swab (OR=2.18; 95% CI: 1.12-4.27).

ConclusionA substantial proportion of patients with previous mild-to-moderate symptomatic COVID-19 characterized by new onset of chemosensory dysfunction still complained on altered sense of smell or taste one-year after the onset.


title: Relationship between COVID-19 pandemic and ecological, economic, and social characteristics

abstract:
COVID-19 pandemic had huge impacts on the global world, with both a negative impact on society and economy, but a positive one on nature. But this universal effect resulted in different infection rates from country to country. We analyzed the relationship between the pandemic and ecological, economic, and social characteristics. All of these data were collected in 140 countries at 6 time points. Correlations were studied using univariate and multivariate regression models.

The world was interpreted as a single global ecosystem consisting of ecosystem units representing countries. We first studied 140 countries around the world together, and infection rates were related to per capita GDP, Ecological Footprint, median age, urban population, and Biological Capacity, globally. We then ranked 140 countries by infection rate and created 4 equal groups, each with 35 countries. In the first group, the infection rate was very high and was related to the Ecological Footprint (consumption) and GDP per capita (production). This group is dominated by developed countries and their ecological characteristics have proven to be particularly significant. In groups 2, 3, and 4, infection rates were high, moderate, and low, and were primarily associated with median age and urban population.

In the scientific discussion, we have interpreted why infection is high in developed countries. Sustainable ecosystems are balanced, unlike the ecosystems of developed countries. According to science, the resilience and health of both natural ecosystems and humans are closely linked to the world of microbial communities. Our results suggest that both the economy and society need to be in harmony with nature, creating sustainable ecosystems in developed countries as well.


title: Intention of Healthcare Workers to Receive COVID-19 Vaccine: A Cross-Sectional Survey in 10 Countries in Eastern Mediterranean Region

abstract:
BackgroundWillingness of healthcare workers to be vaccinated is an important factor to be consider for successful COVID-19 vaccination programme. Our study aimed to understand the willingness of health workers to receive COVID-19 vaccine and associated concerns across 10 countries in the Eastern Mediterranean Region (EMRO).

MethodA cross-sectional study was conducted in January 2021 among healthcare workers using an online survey. A total of 2806 health workers (Physicians, Nurses and Pharmacists) completed and returned the informed consent along with the questionnaire electronically. Data were analyzed using IBM SPSS software package version 20.0. S

ResultsMore than half of the respondents (58.0%) were willing to receive COVID-19 vaccine, even if the vaccination is not mandatory for them. On the other hand, 25.7% of respondents were not willing to undertake COVID-19 vaccination while 16.3 % answered undecided. The top three reasons for not intending to be vaccinated were unreliability of COVID-19 vaccine clinical trials (62.0%), fear of the side effects of the vaccine (45.3%), and that COVID-19 vaccine will not give immunity for a long period of time (23.1%).

ConclusionOverall, our study revealed suboptimal acceptance of COVID-19 vaccine among our respondents in the EMRO region. Significant refusal of COVID-19 vaccine among healthcare professionals can reverse hard-won progress in building public trust in COVID-19 vaccination program. Our findings suggest the need to develop tailored strategies to address concerns identified in the study in order to ensure optimal vaccine acceptance among healthcare workers in the EMRO.


title: Willingness to Vaccinate against COVID-19 among Healthcare Workers: An Online Survey in 10 Countries in the Eastern Mediterranean Region


title: Evaluation of the Panbio™ COVID-19 Ag Rapid Test at an Emergency Room in a Hospital in Sao Paulo, Brazil

abstract:
IntroductionThe performance characteristics of the Panbio COVID-19 Ag test were evaluated against RT-PCR - considered the gold-standard for the detection of SARS-CoV-2 - at an emergency room in Sao Paulo, Brazil. The study aimed to determine the sensitivity, specificity, positive percent agreement (PPA), and negative percent agreement (NPA) as compared to RT-PCR.

MethodsSpecimens from 127 suspected patients were tested by both the Panbio COVID-19 Ag test and by RT-PCR.

ResultsEvaluation of the agreement between the Panbio COVID-19 Ag test and RT-PCR indicated an overall sensitivity of 84% (95%CI, 75-93.8%) and an overall specificity of 98% (95%CI, 96-98.8%). The Panbio COVID-19 Ag test showed 97% sensitivity and 99% NPA for subjects with Ct values [≤] 25 (N=37).

ConclusionThe Panbio COVID-19 Ag test is suitable for use as a diagnostic test for the rapid screening of patients presenting COVID-19 symptoms, or those suspected with being infected, prior to being admitted to hospital.


title: Rapid, widespread, and preferential increase of SARS-CoV-2 B.1.1.7 variant in Houston, TX, revealed by 8,857 genome sequences

abstract: Genetic variants of the SARS-CoV-2 virus have become of great interest worldwide because they have the potential to detrimentally alter the course of the SARS-CoV-2 pandemic, and disease in individual patients. We recently sequenced 20,453 SARS- CoV-2 genomes from patients with COVID-19 disease in metropolitan Houston (population 7 million), dating from March 2020 to early February 2021. We discovered that all major variants of concern or interest are circulating in the region. To follow up on this discovery, we analyzed 8,857 genome sequences from patients in eight Houston Methodist hospitals dispersed throughout the metroplex diagnosed from January 1, 2021 to March 7, 2021. This sample represents 94% of Houston Methodist cases and 4.8% of all reported cases in metropolitan Houston during this period. We discovered rapid, widespread, and preferential increase of the SARS-CoV-2 UK B.1.1.7 throughout the region. The estimated case doubling time in the Houston area is 6.9 days. None of the 648 UK B.1.1.7 samples identified had the E484K change in spike protein that can cause decreased recognition by antibodies.

category: pathology


title: An automated Dashboard to improve laboratory COVID-19 diagnostics management

abstract:
BackgroundIn response to the CoVID-19 pandemic, our microbial diagnostic laboratory located in a university hospital has implemented several distinct SARS-CoV-2 RT-PCR systems in a very short time. Thanks to our automated molecular diagnostic platform, more than 140000 SARS-CoV-2 RT-PCR tests were achieved over 12 months, with peaks higher than 1500 daily tests. A dashboard was developed to give access to Key Performance Indicators (KPIs) to improve laboratory operational management.

MethodsRT-PCR data extraction of four respiratory viruses - SARS-CoV-2, influenza A and B and RSV - from our laboratory information system (LIS), was automated. Important KPIs were identified and the visualization was achieved using an in-house dashboard based on the open-source language R (Shiny). Information is updated every 4 hours.

ResultsThe dashboard is organized into three main parts. The "Filter" page presents all the KPIs, divided into five sections: i) general and gender-related indicators, ii) number of tests and positivity rate, iii) cycle threshold and viral load, iv) test durations, and v) not valid results. Filtering allows to select a given period, a dedicated instrument, a given specimen, or a requester for instance. The "Comparison" page allows a custom charting of all the available variables, which represents more than 182 combinations. The "Data" page gives the user access to the raw data in table format, with the possibility of filtering, allowing for a deeper analysis and data download in Excel format.

ConclusionsThe dashboard, that gives a rapid access to a huge number of up-to-date information, represents a reliable and user-friendly tool improving the decision-making process, resource planning and quality management. The dashboard represent an added value for diagnosric laboratories during a pandemic, where rapid and efficient adaptation is mandatory.

category: health systems and quality improvement


title: The absence of islet autoantibodies in clinically diagnosed older-adult onset type 1 diabetes suggests an alternative pathology, advocating for routine testing in this age group.

abstract:
ObjectiveIslet autoantibodies at diagnosis are not well studied in older-adult onset (>30years) type 1 diabetes due to difficulties of accurate diagnosis. We used a type 1 diabetes genetic risk score (T1DGRS) to identify type 1 diabetes aiming to evaluate the prevalence and pattern of autoantibodies in older-adult onset type 1 diabetes.

MethodsWe used a 30 variant T1DGRS in 1866 white-European individuals to genetically confirm a clinical diagnosis of new onset type 1 diabetes. We then assessed the prevalence and pattern of GADA, IA2A and ZnT8A within genetically consistent type 1 diabetes across three age groups (<18years (n=702), 18-30years (n=524) and >30years (n=588)).

FindingsIn autoantibody positive cases T1DGRS was consistent with 100% type 1 diabetes in each age group. Conversely in autoantibody negative cases, T1DGRS was consistent with 93%(56/60) of <18years, 55%(37/67) of 18-30years and just 23%(34/151) of >30years having type 1 diabetes. Restricting analysis to genetically consistent type 1 diabetes showed similar proportions of positive autoantibodies across age groups (92% <18years, 92% 18-30years, 93% >30years)[p=0.87]. GADA was the most common autoantibody in older-adult onset type 1 diabetes, identifying 95% of autoantibody positive cases versus 72% in those <18years.

InterpretationOlder adult-onset type 1 diabetes has identical rates but different patterns of positive autoantibodies to childhood onset. In clinically suspected type 1 diabetes in older-adults, absence of autoantibodies strongly suggests non-autoimmune diabetes. Our findings suggest the need to change guidelines from measuring islet autoantibodies where there is diagnostic uncertainty to measuring at least GADA in all suspected adult type 1 diabetes cases.

category: endocrinology


title: Polygenic basis and biomedical consequences of telomere length variation

abstract: Telomeres, the end fragments of chromosomes, play key roles in cellular proliferation and senescence1. Here we characterize the genetic architecture of naturally-occurring variation in leucocyte telomere length (LTL) and identify causal links between LTL and biomedical phenotypes in 472,174 well-characterized participants in UK Biobank2. We identified 197 independent sentinel variants associated with LTL at 138 genomic loci (108 novel). Genetically-determined differences in LTL were associated with multiple biological traits, ranging from height to bone marrow function, as well as several diseases spanning neoplastic, vascular, and inflammatory pathologies. Finally, we estimated that at age 40 years, people with >1-SD shorter compared to [≥]1-SD longer LTL than the population mean had 2.5 years lower life expectancy. Overall, we furnish novel insights into the genetic regulation of LTL, reveal LTLs wide-ranging influences on physiological traits, diseases, and longevity, and provide a powerful resource available to the global research community.


title: Low prevalence of COVID-19 Exposure is Coincident with Self-reported Compliance with Public Health Guidelines among Essential Employees at an Institute of Higher Education

abstract:
ImportanceDetailed analysis of infection rates paired with behavioral and employee reported risk factors are vital to understanding how COVID-19 transmission may be inflamed or mitigated in the workplace. Institutes of Higher Education are heterogeneous work units that supported continued in person employment during COVID-19, providing an excellent test site for occupational health evaluation.

ObjectiveTo evaluate self-reported behaviors and SARS-CoV-2 among essential in-person employees during the first six months of the COVID-19 pandemic.

DesignCross-sectional, conducted from July 13-September 2, 2020.

SettingInstitute of Higher Education in Fort Collins, Colorado.

ParticipantsEmployees identified to be an essential in-person employee during the first six months of the pandemic (1,522 invited, 1,507 qualified, 603 (40%) completed the survey). Of those completing the survey, 84.2% (508) elected to participate in blood and nasal swab sample collection to assess active SARS-CoV-2 infection via qRT-PCR, and past infection by serology (overall completion rate of 33.7%). Eligibility included > 18 years old, able to read and understand English, not currently experiencing cough, shortness of breath or difficulty breathing, fever >100.4F (38C), chills/shaking with chills, muscle pain, new or worsening headaches, sore throat or new loss of sense of taste/smell.

ExposureSelf-reported COVID-19 protective behaviors

Main Outcome(s) and Measure(s)Current SARS-CoV-2 infection detected by qRT-PCR or previous SARS-CoV-2 infection detected by IgG SARS-CoV-2 testing platform.

ResultsThere were no qRT-PCR positive tests, and only 2 (0.39%) contained seroreactive IgG antibodies. Participants were 60% female, 90% non-Hispanic white, mean age 41 years (18-70 years). Handwashing and mask wearing were reported frequently both at work (98% and 94% respectively) and outside work (91% and 95% respectively) while social distancing was reported less frequently at work (79%) then outside of work (92%) [p < .001]. Participants were more highly motivated to avoid exposures out of concern for spreading to others (83%) than for personal implications (63%) [p < .001].

Conclusions and RelevanceThis is one of the first reports to document that complex work environments can be operated safely during the COVID-19 pandemic when employees report compliance with public health practices both at and outside work.