title: Participation after childhood stroke: Is there a relationship with lesion size, motor function and manual ability?

abstract:
BackgroundChildhood arterial ischemic stroke (AIS) is associated with significant morbidity with up to 50% of affected children developing hemiparesis. Hemiparesis is assumed to influence participation within the peer group, but it is unclear to what extent its severity affects participation in different areas of social life.

MethodsThirteen children (mean age 9y6m) with AIS (6 without hemiparesis, 7 with hemiparesis) and 21 controls (mean age 9y8m) participated. We scored hemiparesis severity with hand strength asymmetry (pinch and grip strength), measured with a dynamometer. We assessed manual ability (ABILHAND-Kids), socioeconomic status (Family Affluence Scale) and participation (Participation and Environment Measure - Children and Youth). From structural MRI, we measured lesion size. We investigated differences in participation and its relationship with hemiparesis severity using non-parametric partial correlations (controlling for lesion size, manual ability, and socioeconomic status), interpreted as absent (r<0.25), weak (r=0.25-0.50), moderate (r=0.50-0.75) or strong (r>0.75). Analyses were performed in jamovi 1.6.3.

ResultsChildren with AIS (with or without hemiparesis) showed reduced participation frequency at school (p<0.001), whilst participation at home and in the community resembled that of their peers. Severity of hemiparesis was moderately related to frequency and involvement at home and to involvement and desire for change in the community, although unrelated to school participation.

ConclusionReduced participation in school life requires close attention in the follow-up of children with AIS - regardless of the severity of hemiparesis. Participation at home and in the community is related to hemiparesis severity and may be improved with participation-focused motor intervention strategies.

HighlightsO_LIChildren with stroke participate less frequently at school but are equally involved.
C_LIO_LIDecreased participation at school is not related to hemiparesis severity.
C_LIO_LIParticipation at home and in the community are related to hemiparesis severity.
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title: Acute Brain Ischemia, Infarction and Hemorrhage in Subjects Dying with or Without Autopsy-Proven Acute Pneumonia

abstract: Stroke is one of the most serious complications of Covid-19 disease but it is still unclear whether stroke is more common with Covid-19 pneumonia as compared to non-Covid-19 pneumonia. We investigated the concurrence rate of autopsy-confirmed acute brain ischemia, acute brain infarction and acute brain hemorrhage with autopsy-proven acute non-Covid pneumonia in consecutive autopsies in the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND), a longitudinal clinicopathological study of normal aging and neurodegenerative diseases. Of 691 subjects with a mean age of 83.4 years, acute pneumonia was histopathologically diagnosed in 343 (49.6%); the concurrence rates for histopathologically-confirmed acute ischemia, acute infarction or subacute infarction was 14% and did not differ between pneumonia and non-pneumonia groups while the rates of acute brain hemorrhage were 1.4% and 2.0% of those with or without acute pneumonia, respectively. In comparison, in reviews of Covid-19 publications, reported clinically-determined rates of acute brain infarction range from 0.5% to 20% while rates of acute brain hemorrhage range from 0.13% to 2%. In reviews of Covid-19 autopsy studies, concurrence rates for both acute brain infarction and acute brain hemorrhage average about 10%. Covid-19 pneumonia and non-Covid-19 pneumonia may have similar risks tor concurrent acute brain infarction and acute brain hemorrhage when pneumonia is severe enough to cause death. Additionally, acute brain ischemia, infarction or hemorrhage may not be more common in subjects dying of acute pneumonia than in subjects dying without acute pneumonia.

category: neurology


title: COVID-19 reinfection: A Rapid Systematic Review of Case Reports and Case Series

abstract: The COVID-19 pandemic has infected millions of people worldwide and many countries have been suffering from a large number of deaths. Acknowledging the ability of SARS-CoV-2 to mutate into distinct strains as an RNA virus and investigating its potential to cause reinfection is important for future health policy guidelines. It was thought that individuals who recovered from COVID-19 generate a robust immune response and develop protective immunity, however, since the first case of documented reinfection of COVID-19 in August 2020, there have been a number of cases with reinfection. Many cases are lacking genomic data of the two infections and it remains unclear whether they were caused by different strains. In the present study, we undertook a rapid systematic review to identify cases infected with different genetic strains of SARS-CoV-2 confirmed by polymerase-chain reaction and viral genome sequencing. A total of 17 cases of genetically confirmed COVID-19 reinfection were found. One immunocompromised patient had mild symptoms with the first infection, but developed severe symptoms resulting in death with the second infection. Overall, 68.8% (11/16) had similar severity, 18.8% (3/16) had worse symptoms, and 12.5% (2/16) had milder symptoms with the second episode. Our case series shows that reinfection with different strains is possible and some cases may experience more severe infections with the second episode. The findings also suggest that COVID-19 may continue to circulate even after achieving herd immunity through natural infection or vaccination suggesting the need for longer term transmission mitigation efforts.

category: infectious diseases


title: SARS-CoV-2 N gene dropout and N gene Ct value shift as indicator for the presence of B.1.1.7 lineage in a widely used commercial multiplex PCR assay

abstract:
ObjectivesIncreased importance in detection and surveillance of SARS-CoV-2 has been demonstrated due to the emergence of variants of concern (VOCs). In this study we evaluated if a commercially available real-time SARS-CoV-2 PCR assay can identify B.1.1.7 lineage samples by a specific N gene dropout or Ct value shift compared to the S or RdRP gene.

MethodsPatients samples with confirmed B.1.1.7 variant by whole-genome sequencing and variant-specific PCR (n=48) and non-B.1.1.7 samples (n=53) were tested by the Allplex SARS-CoV-2/FluA/FluB/RSV PCR assay for presence of S, RdRP and N gene of SARS CoV-2. The N gene coding sequence of SARS-CoV-2 with and without D3L mutation (specific for B.1.1.7) were cloned into pCR(R)-TOPO vectors and Allplex SARS-CoV-2/FluA/FluB/RSV PCR assay was performed.

ResultsAll studied B.1.1.7 patient samples showed significantly higher Ct values ({Delta} 6-10, N-gene dropout on Ct values >29) in the N gene compared to the respective values of S and RdRP gene. Receiver operating characteristic (ROC) curve analysis resulted in 100% sensitivity and specificity for {Delta}Ct N/RdRP and {Delta}Ct N/S. As a result of the reversed genetic experiments we found also the shift in Ct values for the 3L variant N-gene.

ConclusionsN gene dropout or Ct value shift is specific for B.1.1.7 positive samples using the Allplex SARS-CoV-2/FluA/FluB/RSV PCR assay. This approach can be used as a rapid tool for B.1.1.7 detection in single assay high throughput diagnostics.


title: Reconstructing the COVID-19 epidemic in Delhi, India: infection attack rate and reporting of deaths

abstract: India reported over 10 million COVID-19 cases and 149,000 deaths in 2020. To estimate exposure and the potential for further spread, we used a SARS-CoV-2 transmission model fit to seroprevalence data from three serosurveys in Delhi and the time-series of reported deaths to reconstruct the epidemic. The cumulative proportion of the population estimated infected was 48.7% (95% CrI 22.1% - 76.8%) by end-September 2020. Using an age-adjusted overall infection fatality ratio (IFR) based on age-specific estimates from mostly high-income countries (HICs), we estimate that 15.0% (95% CrI 9.3% - 34.0%) of COVID-19 deaths were reported. This indicates either under-reporting of COVID-19 deaths and/or a lower age-specific IFR in India compared with HICs. Despite the high attack rate of SARS-CoV-2, a third wave occurred in late 2020, suggesting that herd immunity was not yet reached. Future dynamics will strongly depend on the duration of immunity and protection against new variants.


title: Point-of-care lung ultrasonography for early identification of mild COVID-19: a prospective cohort of outpatients in a Swiss screening center

abstract:
BackgroundEarly identification of SARS-CoV-2 infection is important to guide quarantine and reduce transmission. This study evaluates the diagnostic performance of lung ultrasound (LUS), an affordable, consumable-free point-of-care tool, for COVID-19 screening.

MethodsThis prospective observational cohort included adults presenting with cough and/or dyspnea at a SARS-CoV-2 screening center of Lausanne University Hospital between March 31st and May 8th, 2020. Investigators recorded standardized LUS images and videos in 10 lung zones per subject. Two blinded independent experts reviewed LUS recording and classified abnormal findings according to pre-specified criteria to investigate their predictive value to diagnose SARS-CoV-2 infection according to PCR on nasopharyngeal swabs (COVIDpos vs COVIDneg). We finally combined LUS and clinical findings to derive a multivariate logistic regression diagnostic score.

ResultsOf 134 included patients, 23% (n=30/134) were COVIDpos and 77% (n=103/134) were COVIDneg; 85%, (n=114/134) cases were previously healthy healthcare workers presenting within 2 to 5 days of symptom onset (IQR). Abnormal LUS findings were significantly more frequent in COVIDpos compared to COVIDneg (45% versus 26%, p=0.045) and mostly consisted of focal pathologic B-lines. Combining LUS findings in a multivariate logistic regression score had an area under the receiver-operating curve of 63.9% to detect COVID-19, but improved to 84.5% with the addition of clinical features

ConclusionsCOVIDpos patients are significantly more likely to have lung pathology by LUS. Our findings have potential diagnostic value for COVID-19 at the point of care. Combination of clinical and LUS features showed promising results, which need confirmation in a larger study population.

What is already known on the subjectO_LILung ultrasonography (LUS) is a consumable-free, easy-to-use, portable, non-radiating and non-invasive screening tool that can be performed at the bedside: its diagnostic performance for pneumonia has been established.
C_LIO_LIRecent studies conducted in emergency department showed a correlation between LUS findings and COVID-19 diagnosis.
C_LI

What the study adsO_LIThis is the first study assessing the diagnostic performance of LUS for COVID-19 in outpatients with mild acute respiratory tract infection.
C_LIO_LIMild COVID-19 patients are more likely to have lung pathology by LUS compared with COVID-19 negative.
C_LIO_LICombination of clinical and LUS features showed promising results with a potential diagnostic value for COVID-19 at the point of care.
C_LI


title: Multiplex Antibody Analysis of IgM, IgA and IgG to SARS-CoV-2 in Saliva and Serum from Infected Children and their Close Contacts

abstract:
COVID-19 affects children to a lesser extent than adults but they can still get infected and transmit SARS-CoV-2 to their contacts. Field deployable non-invasive sensitive diagnostic techniques are needed to evaluate the infectivity dynamics of the coronavirus in pediatric populations and guide public health interventions.

We evaluated the utility of high-throughput Luminex-based assays applied to saliva samples to quantify IgM, IgA and IgG antibodies against five SARS-CoV-2 spike (S) and nucleocapsid (N) antigens in the context of a contacts and infectivity longitudinal study. We compared the antibody levels obtained in saliva versus serum/plasma samples from a group of children and adults tested weekly by RT-PCR over 35 days and diagnosed as positive (n=58), and a group of children and adults who consistently tested negative over the follow up period (n=61), in the Summer of 2020 in Barcelona, Spain.

Antibody levels in saliva samples from individuals with confirmed RT-PCR diagnosis of SARS-CoV-2 infection were significantly higher than in negative individuals and correlated with those measured in sera/plasmas. Higher levels of anti-S IgG were found in asymptomatic individuals that could indicate protection against disease in infected individuals. Higher anti-S IgG and IgM levels in serum/plasma and saliva, respectively, in infected children compared to infected adults could also be related to stronger clinical immunity in them. Among infected children, males had higher levels of saliva IgG to N and RBD than females. Despite overall correlation, individual clustering analysis suggested that responses that may not be detected in blood could be patent in saliva, and vice versa, and therefore that both measurements are complementary.

In addition to serum/plasma, measurement of SARS-CoV-2-specific saliva antibodies should be considered as a complementary non-invasive assay to better estimate the percentage of individuals who have experienced coronavirus infection. Saliva antibody detection could allow determining COVID-19 prevalence in pediatric populations, alternative to bleeding or nasal swab, and serological diagnosis following vaccination.


title: Risk of reactivation of hepatitis B virus (HBV) and tuberculosis (TB) and complications of hepatitis C virus (HCV) following Tocilizumab therapy: A systematic review to inform risk assessment in the COVID era

abstract:
Tocilizumab (TCZ), an IL-6 receptor antagonist, is used in the treatment of COVID. However, this agent carries a  black box warning for infection complications, which may include reactivation of tuberculosis (TB) or hepatitis B virus (HBV), or worsening of hepatitis C virus (HCV). Due to the pace of clinical research during the COVID pandemic, prospective evaluation of these risks has not been possible. We undertook a systematic review, generating mean cumulative incidence estimates for reactivation of HBV and TB at 3.3% and 4.3%. We could not generate estimates for HCV. These data derive from heterogeneous studies pre-dating the COVID outbreak, with differing epidemiology and varied approaches to screening and prophylaxis. We underline the need for careful individual risk assessment prior to TCZ prescription, and present an algorithm for clinical stratification. There is an urgent need for ongoing collation of safety data as TCZ therapy is used in COVID.

KEY POINTSUse of tocilizumab treatment in COVID-19 may risk infective complications. We have undertaken a systematic literature review to assess the risks of reactivation of HBV and TB, generating mean estimates of 3.3% and 4.3% incidence, respectively.


title: Chagas disease and SARS-CoV-2 coinfection does not lead to worse in-hospital outcomes: results from the Brazilian COVID-19 Registry

abstract:
ObjectiveChagas disease (CD) continues to be a major public health burden in Latina America, where co-infection with SARS-CoV-2 can occur. However, information on the interplay between COVID-19 and Chagas disease is lacking. Our aim was to assess clinical characteristics and in-hospital outcomes of patients with CD and COVID-19, and to compare it to non-CD patients.

MethodsPatients with COVID-19 diagnosis were selected from the Brazilian COVID-19 Registry, a prospective multicenter cohort, from March to September, 2020. CD diagnosis was based on hospital record at the time of admission. Study data were collected by trained hospital staff using Research Electronic Data Capture (REDCap) tools. Genetic matching for sex, age, hypertension, DM and hospital was performed in a 4:1 ratio.

ResultsOf the 7,018 patients who had confirmed infection with SARS-CoV-2 in the registry, 31 patients with CD and 124 matched controls were included. Overall, the median age was 72 (64.-80) years-old and 44.5% were male. At baseline, heart failure (25.8% vs. 9.7%) and atrial fibrillation (29.0% vs. 5.6%) were more frequent in CD patients than in the controls (p<0.05 for both). C-reactive protein levels were lower in CD patients compared with the controls (55.5 [35.7, 85.0] vs. 94.3 [50.7, 167.5] mg/dL). Seventy-two (46.5%) patients required admission to the intensive care unit. In-hospital management, outcomes and complications were similar between the groups.

ConclusionsIn this large Brazilian COVID-19 Registry, CD patients had a higher prevalence of atrial fibrillation and chronic heart failure compared with non-CD controls, with no differences in-hospital outcomes. The lower C-reactive protein levels in CD patients require further investigation.

Key messagesO_ST_ABSWhat is already known about this subject?C_ST_ABSO_LIPreexisting cardiovascular disease enhances vulnerability to COVID-19.
C_LIO_LICo-infection with SARS-CoV-2 and T.cruzi can occur in patients living in areas in which both infections are epidemic.
C_LI

What does this study add?O_LIDespite a higher frequency of chronic heart failure and atrial fibrillation, our findings do not suggest that co-infection with T.cruzi and SARS-CoV-2 worsens in-hospital outcomes.
C_LIO_LIChagas disease patients were observed to have lower C-reactive protein (CRP) levels.
C_LI

How might this impact on clinical practice?O_LIGiven the current circulation of SARS-CoV-2 at high levels and millions of T cruzi-infected individuals living in Brazil, the risk for co-infections substantially increases.
C_LIO_LIFurther studies are needed to investigate why CRP levels were lower in CD patients. We hypothesized that CD patients might have a lower risk of unregulated inflammatory response to COVID-19, as they already have an active chronic inflammatory and immune response response triggered by T.cruzi infection.
C_LI


title: Characterizing the disproportionate burden of SARS-CoV-2 variants of concern among essential workers in the Greater Toronto Area, Canada

abstract:
STRUCTURED ABSTRACTO_ST_ABSImportanceC_ST_ABSThe emergence of SARS-CoV-2 Variants of Concern (VOC) across North America has been associated with concerns of increased COVID-19 transmission. Characterizing the distribution of VOCs can inform the development and implementation of policies and programs to address the prevention needs of disproportionately affected communities.

ObjectiveWe compared per-capita rates of COVID-19 cases (overall and VOC) from February 3, 2021 to March 10, 2021, across neighborhoods in the health regions of Toronto and Peel, Ontario, by proportion of the population working in essential services and income.

DesignDescriptive epidemiological analysis, integrating COVID-19 surveillance and census data. Per-capita daily epidemic curves were generated using 7-days rolling averages for cases and deaths. Cumulative per-capita rates were determined using census-reported population of each neighbourhood.

SettingThe study setting was the city of Toronto and the region of Peel (the City of Brampton, Mississauga, and Caledon), Canadas largest cities with a combined population of 4.3 million. This area of Canada has had one of the highest incident rates of COVID-19 throughout the pandemic.

ParticipantsWe used person-level data on laboratory-confirmed COVID-19 community cases (N=22,478) and census data for neighborhood-level attributes.

ExposuresWe stratified neighbourhood using dissemination areas which represent geographic areas of approximately 400-700 individuals, into tertiles by ranking the proportion of population in each neighbourhood working in essential services (health, trades, transport, equipment, manufacturing, utilities, sales, services, agriculture); and the per-person equivalent household income.

Main Outcome(s) and Measure(s)The primary outcomes were laboratory-confirmed COVID-19 cases overall and VOC positives by neighbourhood.

ResultsDuring the study period, VOC cases emerged faster in groups with lowest income (growth rate 43.8%, 34.6% and 21.6% by income tertile from lowest to highest), and most essential work (growth rate 18.4%, 30.8% and 50.8% by tertile from lowest tertile of essential workers to highest tertile of essential workers).

Conclusions and RelevanceThe recent introduction of VOC in the large urban area of Toronto has disproportionately affected neighbourhoods with the most essential workers and lowest income levels. Notably, this is consistent with the increased burden of non-VOC COVID-19 cases suggesting shared risk factors. To date, restrictive public health strategies have been of limited impact in these communities suggesting the need for complementary and well-specified supportive strategies including vaccine prioritization to address disparities and overall incidence of both VOC and non-VOC COVID-19.

KEY POINTS

QuestionDoes the emergence of Variants of Concern (VOC) in urban centers in Canada affect groups based on income and essential work status disproportionally?

FindingsWe found a significantly higher cumulative case count and rate of increase of VOC cases amongst those with lowest income and highest essential work status.

MeaningThe distribution of VOC and COVID-19 in general is disproportionately distributed, and mitigation measures, including vaccines should be targeted to the highest risk groups.


title: Human IgG and IgA responses to COVID-19 mRNA vaccines

abstract: SARS-CoV-2 spike antigen-specific IgG and IgA elicited by infection mediate viral neutralization and are likely an important component of natural immunity, however, limited information exists on vaccine induced responses. We measured COVID-19 mRNA vaccine induced IgG and IgA in serum serially, up to 80 days post vaccination in 4 subjects. Spike antigen-specific IgG levels rose exponentially and plateaued 21 days after the initial vaccine dose. After the second vaccine dose IgG levels increased further, reaching a maximum approximately 7-10 days later, and remained elevated (average of 78% peak levels) during the additional 20-50 day follow up period. COVID-19 mRNA vaccination elicited spike antigen-specific IgA with similar kinetics of induction and time to peak levels, but more rapid decline in serum levels following both the 1st and 2nd vaccine doses (<23% peak levels within 80 days of the initial shot). The data demonstrate COVID-19 mRNA vaccines effectively induce spike antigen specific IgG and IgA and highlight marked differences in their persistence in serum.

category: allergy and immunology


title: Evaluation of The Pink Luminous Breast LED-Based Technology Device as a Screening Tool for the Early Detection of Breast Abnormalities

abstract: Breast cancer is the leading cause of sex-specific female cancer death in the United States. Detection at earlier stages contributes to decrease the mortality rate. The mammography is considered the gold standard for breast cancer screening with an estimate sensitivity of 86.9% and a specificity 88.9%. However, these values are negatively affected by the breast, which is consider a risk factor for developing breast cancer. Herein, we validate the novel LED-based FDA Class I medical device Pink Luminous Breast (PLB) by the comparison of two breast screening imaging-based tests using a double blinded approach. The PLB works by emitting a LED red light with a harmless spectrum of 640-800 nanometers, the trans-illuminated breast tissue allows the observation of abnormalities represented by darker or shadowing areas. In this study, we evaluated the sensitivity and specificity of the PLB device as a screening tool for the early detection of breast abnormalities when compared with the mammography as the gold standard. Our results showed that PLB device has a high sensitivity (89.6%) and specificity (96.4%) for detecting breast abnormalities comparable to the adjusted mammography values: 86.3% and 68.9% respectively. Importantly, the percentage of positive dense tissue findings from a total of 340 events was 266 (78.2%) using PLB vs. 248 (72.9%) detected by the mammography. A 100% of the participants responded in a survey that they feel comfortable using the device and visualizing their breast without feeling pain or discomfort during the examination. The PLB positive validation vs the mammography brings the potential to be recommended for routinely breast screening at non-clinical settings. The PLB provides a rapid, non-invasive, portable, and easy-to-use tool for breast screening that can complement the home-based BSE technique or the CBE. In addition, the PLB can be conveniently used for screening breasts with surgical implants. PLB provides an accessible and painless breast cancer screening tool. The use of this device is not intended to replace the mammography as the gold standard for breast screening but rather to use it as an adjunct or complement tool as part of more efficient earlier detection strategies and contribute to decrease this health disparity.

category: epidemiology


title: Covid-19 High Attack Rate Can Lead to High Case Fatality Rate

abstract:
BackgroundDuring the current Covid-19 pandemic case fatality rate (CFR) estimates were subjected to a lot of debates regarding the accuracy of its estimations, predictions, and the reason of across countries variances. In this context, we conduct this study to see the relationship between attack rate (AR) and CFR.

The study hypothesis is based on two: 1-evidence suggests that the mortality rate (MR) has a positive influence on case fatality ratio (CFR), 2- and increase number of Covid-19 cases leads to increased mortality rate (MR).

Material and methodsThirty countries and territories were chosen. Inclusion criterion was > 500 Covid-19 reported cases per 10,000 population inhabitants. Data on covid-19 cases and deaths was selected as it was on March 10, 2021. Statistical methods used are descriptive and one-sample Kolmogorov-Smirnov (K-S), the one-way ANOVA, Levene, least significant different (LSD), and matched paired-samples T-tests.

ResultsANOVA test showed a significant difference at P<0.01 among all studied groups concerning AR and CFR mean values. Group of countries with MR [≥] 15 death / 104 inhabitants recorded the highest level of crude mean CFR and AR values, and recorded the highest gap with leftover groups, especially with countries reported MR of <10 death/ 104 inhabitants. There were independence 95% confidence intervals of mean CFR and AR values between countries with [≥] 15 death / 104 MR and countries with MR of <10 death /104. There was a significant difference between countries with MR [≥] 15 death / 104 inhabitants and countries with MR of <10 death / 10 4 inhabitants groups through least significant difference (LSD) test for CFR%(0.042 p-value) and Games Howell (GH) test for AR/104 (p-value 0.000).

ConclusionsTotal and mean AR and CFR are higher in high MR countries compared to low MR countries.


title: Feasibility and effectiveness of daily temperature screening to detect COVID-19 in a large public university setting

abstract:
BackgroundMany persons with active SARS-CoV-2 infection experience mild or no symptoms, presenting barriers to COVID-19 prevention. Regular temperature screening is nonetheless used in some settings, including University campuses, to reduce transmission potential. We evaluated the potential impact of this strategy using a prospective University-affiliated cohort.

MethodsBetween June and August 2020, 2,912 participants were enrolled and tested for SARS-CoV-2 by PCR at least once (median: 3, range: 1-9). Participants reported temperature and symptoms daily via electronic survey using a previously owned or study-provided thermometer. We assessed feasibility and acceptability of daily temperature monitoring, calculated sensitivity and specificity of various fever-based strategies for restricting campus access to reduce transmission, and estimated the association between measured temperature and SARS-CoV-2 test positivity using a longitudinal binomial mixed model.

ResultsMost participants (70.2%) did not initially have a thermometer for taking their temperature daily. Across 5481 total person months, the average daily completion rate of temperature values was 61.6% (IQR: 41.8%-86.2%). Sensitivity for SARS-CoV-2 ranged from 0% (95%CI 0-9.7%) to 40.5% (95%CI 25.6-56.7%) across all strategies for self-report of possible COVID-19 symptoms on day of specimen collection, with corresponding specificity of 99.9% (95%CI 99.8-100%) to 95.3% (95%CI 94.7-95.9%). An increase of 0.1{degrees}F in individual mean body temperature on the same day as specimen collection was associated with 1.11 increased odds of SARS-CoV-2 positivity (95%CI 1.06-1.17).

ConclusionsDaily temperature monitoring was feasible and acceptable; however, the majority of potentially infectious individuals were not detected by temperature monitoring, suggesting that temperature screening is insufficient as a primary means of detection to reduce transmission of SARS-CoV-2.


title: Optimal allocation of PCR tests to minimise disease transmission through contact tracing and quarantine

abstract: PCR testing is a crucial capability for managing disease outbreaks, but it is also a limited resource and must be used carefully to ensure the information gain from testing is valuable. Testing has two broad uses, namely to track epidemic dynamics and to reduce transmission by identifying and managing cases. In this work we develop a modelling framework to examine the effects of test allocation in an epidemic, with a focus on using testing to minimise transmission. Using the COVID-19 pandemic as an example, we examine how the number of tests conducted per day relates to reduction in disease transmission, in the context of logistical constraints on the testing system. We show that if daily testing is above the routine capacity of a testing system, which can cause delays, then those delays can undermine efforts to reduce transmission through contact tracing and quarantine. This work highlights that the two goals of aiming to reduce transmission and aiming to identify all cases are different, and it is possible that focusing on one may undermine achieving the other. To develop an effective strategy, the goals must be clear and performance metrics must match the goals of the testing strategy. If metrics do not match the objectives of the strategy, then those metrics may incentivise actions that undermine achieving the objectives.


title: Disease and Social Media in Post-Natural Disaster Recovery Philippines

abstract:
IntroductionThe Philippines is plagued with natural disasters and resulting precipitating factors for disease outbreaks. The developing country has a strong disease surveillance program during and post-disaster phases; however, latent disease contracted during these emergency situations emerges once the Filipinos return to their homes. Coined the social media capital of the world, the Philippines provides an opportunity to evaluate the potential of social media use in disease surveillance during the post-recovery period. By developing and defining a non-traditional method for enhancing detection of infectious diseases post-natural disaster recovery in the Philippines, this research aims to increase the resilience of affected developing countries through advanced passive disease surveillance with minimal cost and high impact.

MethodsWe collected 50 million geo-tagged tweets, weekly case counts for six diseases, and all natural disasters from the Philippines between 2012 and 2013. We compared the predictive capability of various disease lexicon-based time series models (e.g., Twitters BreakoutDetection, Autoregressive Integrated Moving Average with Explanatory Variable [ARIMAX], Multilinear regression, and Logistic regression) and document embeddings (Gensims Doc2Vec).

ResultsThe analyses show that the use of only tweets to predict disease outbreaks in the Philippines has varying results depending on which technique is applied, the disease type, and location. Overall, the most consistent predictive results were from the ARIMAX model which showed the significance in tweet value for prediction and a role of disaster in specific instances.

DiscussionOverall, the use of disease/sick lexicon-filtered tweets as a predictor of disease in the Philippines appears promising. Due to the consistent and large increase use of Twitter within the country, it would be informative to repeat analysis on more recent years to confirm the top method for prediction. In addition, we suggest that a combination disease-specific model would produce the best results. The model would be one where the case counts of a disease are updated periodically along with the continuous monitoring of lexicon-based tweets plus or minus the time from disaster.


title: Testing and Vaccination to Reduce the Impact of COVID-19 in Nursing Homes: An Agent-Based Approach

abstract:
BackgroundEfforts to protect residents in nursing homes involve non-pharmaceutical interventions, testing, and vaccine. We sought to quantify the effect of testing and vaccine strategies on the attack rate, length of the epidemic, and hospitalization.

MethodsWe developed an agent-based model to simulate the dynamics of SARS-CoV-2 transmission in a nursing home with resident and staff agents. Interactions between 172 residents and 170 staff were assumed based on data from a nursing home in Los Angeles, CA. We simulated scenarios assuming different levels of non-pharmaceutical interventions, testing frequencies, and vaccine efficacy to block transmission.

ResultsUnder the hypothetical scenario of widespread SARS-CoV-2 in the community, 3-day testing frequency minimized the attack rate and the time to eradicate an outbreak. Prioritization of vaccine among staff or staff and residents minimized the cumulative number of infections and hospitalization, particularly in the scenario of high probability of an introduction. Reducing the probability of a virus introduction reduced the demand on testing and vaccine to reduce infections and hospitalizations.

ConclusionsImproving frequency of testing from 7-days to 3-days minimized the number of infections and hospitalizations, despite widespread community transmission. Vaccine prioritization of staff provides the best protection strategy, despite high risk of a virus introduction.


title: Development of a core outcome set for multimorbidity trials in low- and middle-income countries (COSMOS): Study Protocol

abstract:
Introduction Multimorbidity describes the presence of two or more long-term conditions, which can include communicable and non-communicable diseases, and mental disorders. The rising global burden from multimorbidity is well-documented, but trial evidence for effective interventions in low- and middle-income countries (LMICs) is limited. Selection of appropriate outcomes is fundamental to trial design to ensure cross-study comparability, but there is currently no agreement on a core outcome set (COS) to include in trials investigating multimorbidity specifically in LMIC. Our aim is to develop international consensus on two COS for trials of interventions to prevent and treat multimorbidity in LMIC settings.

Methods and AnalysisFollowing methods recommended by the Core Outcome Measures in Effectiveness Trials (COMET initiative), the development of these two COS will occur in three stages: (1) generation of a long list of potential outcomes for inclusion; (2) two-round online Delphi surveys; and (3) consensus meetings. First, to generate an initial list of outcomes, we will conduct a systematic review of multimorbidity intervention and prevention trials and interviews with people living with multimorbidity and their caregivers in LMICs. Outcomes will be classified using an outcome taxonomy. Two-round Delphi surveys will be used to elicit importance scores for these outcomes from people living with multimorbidity, caregivers, healthcare professionals, policy makers, and researchers in LMICs. Finally, consensus meetings will be held to discuss the Delphi survey results and agree outcomes for inclusion in the two COS.

Ethics and disseminationThe study has been approved by the Research Governance Committee of the Department of Health Sciences, University of York, UK [HSRGC/2020/409/D:COSMOS]. Each participating country/research group will obtain local ethics board approval. Informed consent will be obtained from all participants. We will disseminate findings through peer-reviewed open access publications, and presentations at global conferences selected to reach a wide range of LMIC stakeholders.

Trial registrationPROSPERO ID CRD42020197293

COMET https://www.comet-initiative.org/Studies/Details/1580

Strengths and limitations of this studyO_LIThe development process follows guidelines and best practice recommendations for developing core outcome sets and integrates four sources of information.
C_LIO_LIInterviews with people living with multimorbidity and caregivers are conducted in several LMICs (in South Asia, Africa and Latin America), by local teams, and in local languages to identify outcomes relevant to them.
C_LIO_LIThe Delphi survey and consensus meetings are conducted in English which limits the breadth of participation in these stages of the process.
C_LIO_LIDespite involvement of a wide range of LMIC stakeholders in the process, there may be some limitations to the generalisability of the final core outcome sets due to the heterogeneity of target conditions and the diversity of countries, cultures and experiences.
C_LI

category: psychiatry and clinical psychology


title: The fMRI signature of acute catatonic state and its response to benzodiazepines

abstract:
We report for the first time, functional MRI markers of the acute retarded catatonic state and its response to benzodiazepines.

In this cross-sectional MRI study, we have compared the resting state whole-brain, within-network and seed (left precentral gyrus)-to-voxel connectivity, as well as cortical complexity between a sample of patients in acute retarded catatonic state (n = 15) and a demographically-matched healthy control sample (n = 15). Additionally, we examined whether the above variables were different between responders (n = 9) and non-responders (n = 6) to lorazepam.

Acute retarded catatonia was characterized by reduced functional connectivity, most robustly within the sensorimotor network, diffuse long-range hyperconnectivity, and seed (left precentral gyrus)-to-voxel hyperconnectivity in the frontoparietal and cerebellar regions. The lorazepam responders showed long-range as well as seed-to-voxel functional hyperconnectivity in comparison to the non-responders. Seed (left precentral gyrus)-to-voxel connectivity was positively correlated to the catatonia motor ratings. The catatonia sample showed a cluster of reduced vertex-wise cortical complexity in the right insular cortex and contiguous areas.

We have identified neuroimaging markers that characterize the acute retarded catatonic state and predict treatment response. We discuss how these novel findings have important translational implications for understanding the pathophysiology of catatonia and for predicting treatment response to benzodiazepines.


title: Computerized Cognitive Training in People with Depression: A Systematic Review and Meta-analysis of Randomized Clinical Trials

abstract:
ImportanceCognitive impairment is a common feature of both symptomatic and remitted states of depression that is associated with poorer psychosocial outcomes and treatment non-response. As such, finding treatments to maintain or enhance cognition in people with depression is imperative.

ObjectiveTo investigate the efficacy of computerized cognitive training (CCT) on cognitive and functional outcomes in people with depression.

Data SourcesMEDLINE, EMBASE and PsycINFO databases were screened through the Ovid interface for eligible studies from inception to 29 June 2020, with no language or publication type restrictions.

Study SelectionTwo independent reviewers conducted duplicate study screening and assessed against the following inclusion criteria: (1) adults with depression, (2) CCT with minimum three hours practice, (3) active or passive control group, (4) cognitive and/or functional outcomes measured at baseline and post-intervention, (5) randomized controlled trials. Of 3666 identified studies, 24 met selection criteria.

Data Extraction and SynthesisThe methods used followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. Data extraction and risk of bias assessment using the revised Cochrane Risk of Bias Tool (RoB2) was conducted independently by two reviewers. Analysis of the pooled results was conducted using robust variance estimation (RVE) based on a correlational dependence model.

Main Outcomes and MeasuresThe primary outcome was change from baseline to post-intervention in overall cognition. Secondary outcomes were depressive symptoms, psychiatric symptoms, psychosocial functioning, daily functioning, subjective cognition, global cognition and domain-specific cognitive function.

ResultsTwenty-four studies encompassing 28 comparisons and 1,141 unique participants met inclusion criteria. The pooled effect size of CCT for overall cognition was small and significant (g=0.26; 95% CI 0.15 to 0.36; P<.001; {tau}2=0.057; I2=37%; prediction interval -0.25 to 0.76) and for depressive symptoms was small and significant (g=0.24; 95% CI 0.04 to 0.45; P=.02; {tau}2=0.075; I2=46%; prediction interval -0.37 to 0.86). Evidence of small-study effect was found for both overall cognition and depressive symptoms, with trim-and-fill analysis imputing two studies for each. Sensitivity analyses of overall cognition and depressive symptoms revealed the main analyses to be robust. Benefits of CCT were also found for psychosocial functioning and domain-specific cognitive function in abstract reasoning, learning/encoding efficiency, retrieval fluency, high working memory, low working memory, inhibition and processing speed. No significant effect was found for psychiatric symptoms, subjective cognition, global cognition or domain-specific cognitive function in short-term memory and shifting. No separate pooled analyses were conducted for daily functioning or verbal reasoning, updating and visual processing domains due to two or less studies reporting outcomes for each. A moderating effect of dose was found for overall cognition, with larger doses of CCT associated with greater effect size estimates.

Conclusions and RelevanceThis systematic review and meta-analysis indicates that CCT is an efficacious intervention for overall cognition, depressive symptoms, psychosocial functioning and domain-specific cognitive function for people with depression.


title: Behavioral and Magnetoencephalographic Correlates of Fear Generalization Are Associated with Responses to Later Virtual Reality Exposure Therapy in Spider Phobia

abstract: As overgeneralization of fear is a pathogenic marker of anxiety disorders, we investigated whether pre-treatment levels of fear generalization in spider-phobic patients are associated with their response to exposure-based treatment, in order to identify pre-treatment correlates of treatment success. Ninety patients with spider phobia completed pre-treatment clinical and magnetoencephalography (MEG) assessments, one session of virtual reality exposure therapy, and a post-treatment clinical assessment. Based on the primary outcome (30% symptom reduction in self-reported symptoms from pre-to post-treatment) they were categorized as responders or non-responders. In a pre-treatment MEG fear generalization paradigm involving fear conditioning with two unconditioned stimuli (UCS), we obtained fear ratings, UCS-expectancy ratings, and event-related fields to conditioned stimuli (CS+, CS-) and 7 different generalization stimuli (GS) on a perceptual continuum from CS+ to CS-. Prior to treatment, non-responders showed behavioral overgeneralization indicated by more linear generalization gradients in fear ratings. Analyses of MEG source estimations revealed that non-responders showed a decline of their (inhibitory) frontal activations to safety-signaling CS- and GS compared to CS+ over time, while responders maintained these activations at early (<300ms) and late processing stages. Results provide initial evidence that pre-treatment differences of behavioral and neural markers of fear generalization are associated with later responses to behavioral exposure. Findings demonstrate the relevance of inhibitory learning functions and their spatio-temporal neural reflections in this interplay. Findings stimulate research on mechanism-based augmentation strategies for behavioral therapies.


title: Epitweetr: Early warning of public health threats using Twitter data

abstract:
BackgroundECDC performs epidemic intelligence activities to systematically collate information from a variety of sources, including Twitter, to rapidly detect public health events. The lack of a freely available, customisable and automated early warning tool using Twitter data, prompted ECDC to develop epitweetr.

The specific objectives are to assess the performance of the geolocation and signal detection algorithms used by epitweetr and to assess the performance of epitweetr in comparison with the manual monitoring of Twitter for early detection of public health threats.

MethodsEpitweetr collects, geolocates and aggregates tweets to generate signals and email alerts. Firstly, we evaluated manually the tweet geolocation characteristics of 1,200 tweets, and assessed its accuracy in extracting the correct location and its performance in detecting tweets with available information on the tweet geolocation. Secondly, we evaluated signals generated by epitweetr between 19 October and 30 November 2020 and we calculated the positive predictive value (PPV). Then, we evaluated the sensitivity, specificity and timeliness of epitweetr in comparison with Twitter manual monitoring.

FindingsThe epitweetr geolocation algorithm had an accuracy of 30.1% and 25.9% at national and subnational levels, respectively. General and specific PPV of the signal detection algorithm was 3.0% and 74.6%, respectively. Epitweetr and/or manual monitoring detected 570 signals and 454 events. Epitweetr had a sensitivity of 78.6% [75.2% - 82.0%] and PPV of 74.6% [70.5% - 78.6%]; and the manual monitoring had a sensitivity of 47.9% [43.8% - 52.0%] and PPV of 97.9% [95.8% - 99.9%]. The median validation time difference between sixteen common events detected by epitweetr and manual monitoring was -48.6 hours [(-102.8) - (-23.7) hours].

InterpretationEpitweetr has shown to have sufficient performance as an early warning tool for public health threats using Twitter data. Having developed epitweetr as a free, open-source tool with several configurable settings and a strong automated component, it is expected to increase its usability and usefulness to public health experts.

FundingNot applicable

Research in contextO_ST_ABSEvidence before this studyC_ST_ABSPrevious reviews have shown how social media, including Twitter, have been used for public health purposes. Most recent studies, in relation to the COVID-19 pandemic, have shown the added value of early warning tools based on Twitter and other social media platforms. They also noted the lack of an open-source tool for real-time monitoring and surveillance.

Added value of this studyEpitweetr is a free, open-source and R-based early warning tool for automatic Twitter data monitoring that will support public health experts in rapidly detecting public health threats. The evaluation of epitweetr presented in this study shows the strengths of the tool which include having good performance, high degree of automation, being a near-real-time tool and being publicly available with various customisable settings. Furthermore, it shows which are the areas of improvement for the next versions of epitweetr.

Implications of all the available evidenceThis tool can be further developed to include more automation and machine learning components to increase usability and information processing time by users.

category: public and global health


title: Development of a Codebook of Online Anti-Vaccination Rhetoric to Manage COVID-19 Vaccine Misinformation

abstract: Vaccine hesitancy (delay in obtaining a vaccine, despite availability) represents a significant hurdle to managing the COVID-19 pandemic. Vaccine hesitancy is in part related to the prevalence of anti-vaccine misinformation and disinformation, which are spread through social media and user-generated content platforms. This study uses qualitative coding methodology to identify salient narratives and rhetorical styles common to anti-vaccine and COVID-denialist media. It organizes these narratives and rhetorics according to theme, imagined antagonist, and frequency. Most frequent were narratives centered on "corrupt elites" and rhetorics appealing to the vulnerability of children. The identification of these narratives and rhetorics may assist in developing effective public health messaging campaigns, since narrative and emotion have demonstrated persuasive effectiveness in other public health communication settings.


title: Continuity of routine immunization programs in Canada during the COVID-19 pandemic

abstract:
IntroductionIn Canada, the COVID-19 pandemic has interrupted many routine health services, placed additional strain on the health care system, and resulted in many Canadians being either unable or unwilling to attend routine immunization appointments. We sought to capture and synthesize information about changes to routine immunization programs in response to the pandemic and plans to catch-up any missed immunizations.

MethodsProvincial/territorial (P/T) public health leaders were interviewed via teleconference between August-October 2020 to collect information on the following topics: how routine immunization delivery was affected during and after initial lockdown periods, plans to catch-up missed doses, and major challenges and achievements in continuing routine immunization programs. Data were coded and categorized according to common responses and descriptive analysis was performed.

ResultsInterviews occurred with participants from 11 of 13 P/Ts. School immunization programs were reported to be most negatively affected by the pandemic (n=9). In the early pandemic period, infant, preschool, and maternal/prenatal programs were prioritized, with most P/Ts continuing these services with adaptations for COVID-19. After the initial lockdown period, all routine programs were continuing with adaptations in most P/Ts. Infant, preschool, and school programs were most often targeted for catch-up through measures such as appointment rebooking and making additional clinics and/or providers available. Major challenges included resource limitations (e.g., staff shortages, PPE shortages, limited infrastructure) (n=11), public health restrictions (n=8), and public hesitancy to attend appointments (n=5).

ConclusionsCanadian routine immunization programs faced some disruptions due to the COVID-19 pandemic, particularly the school, adult, and older adult programs. Further research is needed to determine the measurable impact of the pandemic on routine vaccine coverage levels.


title: Red flags useful to screen for gastrointestinal and hepatic diseases in patients with shoulder pain: a scoping review protocol

abstract:
Shoulder pain (SP) is the third most common musculoskeletal disorder worldwide and its prevalence ranges from 5 to 47%.

However, the clinical presentation of signs and symptoms may hide other serious conditions; the so-called Red Flags (RFs).

For these reasons, clinicians dealing with neuro-musculoskeletal shoulder disorders should pay particular attention during the medical history and clinical examination screening and identifying signs that may cause probable referred symptoms.

Considering the variety of clinical presentations of SP and the importance of the screening for referral, identifying and summarizing the possible gastrointestinal and hepatic diseases among these patients may give a comprehensive overview to the clinicians and consequently may improve the overall management.

To the authors knowledge, there are no published studies on the topic and, in this context, a scoping review is strongly required and corresponded to the objectives of this project.

category: rehabilitation medicine and physical therapy


title: Endogenous interferon-beta but not interferon-alpha or interferon-lambda levels in upper respiratory tract predict clinical outcome in critical COVID-19 patients independent of viral load

abstract: Although the subject of intensive preclinical and clinical research, controversy on the protective vs. deleterious effect of interferon (IFN) in COVID-19 remains. Some apparently conflicting results are likely due to the intricacy of IFN subtypes (type I: IFN-alpha/beta, type III: IFN-lambda), timing and mode of administration (nebulized/subcutaneous) and clinical groups targeted (asymptomatic/mild, moderate, severe/critical COVID-19). Within the COntAGIouS (COvid-19 Advanced Genetic and Immunologic Sampling) clinical trial, we investigated endogenous type I and type III IFNs in nasal mucosa as possible predictors of clinical outcome in critical patients, as well as their correlation to SARS-CoV-2 viral load, using nCounter technology. We found that endogenous IFN-beta expression in the nasal mucosa predicts clinical outcome, independent of viral replication or Apache II score, and should be considered as a prognostic tool in a precision medicine approach of IFN therapy in COVID-19 clinical management.

category: respiratory medicine


title: High-dimensional analysis reveals abnormal B cell subsets associated with specific changes to circulating T and myeloid cell populations in patients with idiopathic inflammatory myopathies

abstract:
ObjectivesThe idiopathic inflammatory myopathies (IIM) are a clinically heterogeneous group of conditions affecting the skin, muscle, joint, and lung in various combinations. This study aims to investigate the immunologic heterogeneity through detailed immunophenotyping of peripheral blood mononuclear cells (PBMCs) in IIM patients and healthy controls.

MethodsWe collected PBMCs from 17 patients with a clinical diagnosis of inflammatory myositis in the inpatient or outpatient setting and performed immunophenotyping using mass cytometry by time of flight (CyTOF) to simultaneously characterize B, T, and myeloid cell subsets. Data were analyzed using a combination of supervised biaxial gating and unsupervised clustering algorithms including t-distributed stochastic neighbor embedding (tSNE), cluster identification, characterization, and regression (CITRUS), and marker enrichment modeling (MEM).

ResultsWe identified two distinct immune signatures amongst IIM patients. In one signature, increased CD19+CXCR4hiCCR7hi cells correlated with increased CD3+CXCR4hiCD38hi (r=0.62, p=0.009) and CD14+CD16-CXCR4+CD38+HLADR-(r=0.61, p=0.01) populations. In the second signature, increased CD19+CD21loCD11c+ cells correlated with an increased CD3+CD4+PD1+ (r=0.60, p=0.01) population. Other shared immunologic features amongst IIM patients compared to healthy controls included decreased surface expression of RP105/CD180 on B cells (median mass intensity 39.9 {+/-} 16.0 v. 60.9 {+/-} 20.1, p=0.002). In the T cell compartment, all circulating CD3+CXCR3+ subsets (2.7 {+/-} 2.4 v. 9.6 {+/-} 8.1% of all PBMCs, p=0.0004) were reduced.

ConclusionBased on circulating B cell phenotype, we identified two distinct immunologic signatures in IIM patients. Future work is needed to determine the significance of these immune signatures for clinical manifestations and treatment responses.

category: rheumatology


title: Tools for measuring sexual and reproductive health and rights (SRHR) indicators in humanitarian settings

abstract:
BackgroundEffective measurement of all health indicators and especially SRHR is difficult in humanitarian settings. Displacement and insecurity due to conflict, natural disasters, and epidemics place women and girls at higher risk of SRHR-related morbidity and mortality and reduce the coverage of essential SRHR services. This scoping review describes the measurement tools, methods, and indicators used to measure SRHR coverage and outcome indicators in humanitarian settings in the past 15 years and presents an accessible dashboard that can be used by governments, researchers and implementing organizations to identify available SRHR measurement tools.

MethodsScientific articles published between January 2004 and May 2019 were identified using Embase, Medline, PsycInfo, CINAHL, Scopus, PAIS index as well as relevant non-peer-reviewed literature available through websites of humanitarian organizations. Publications including data from low- or middle-income countries (LMICs), focused on women and/or girls living in areas impacted by a humanitarian crisis, where data was collected within five years of the crisis were included. Indicators extracted from these publications were categorized according to validated SRHR indicators recommended by the World Health Organization (WHO). Measurement tools, sampling and data collection methods, gap areas (geographical, topical and contextual), and indicators were catalogued for easy access in an interactive Tableau dashboard.

ResultsOur search yielded 42,081 peer-reviewed publications and 2,569 non-peer-reviewed reports. After initial title and abstract screening, 385 publications met the inclusion criteria. SRHR indicators were categorized into nine domains: abortion, antenatal care, family planning, gender-based violence, HIV and sexually transmitted infections, maternal health, maternal mortality, menstrual and gynecological health, and obstetric care (delivery). A total of 65 tools and questionnaires measuring SRHR were identified, of which 25 were designed specifically for humanitarian settings.

DiscussionAlthough SRHR was measured in humanitarian settings, several gaps in measurement were identified. Abortion and gynaecological health were not consistently measured across included studies or validated WHO indicators. Toolkits and indicators identified in this review may be used to inform future SRHR data collection in humanitarian settings. However, identifying and/or developing innovative data collection methodologies should be a research priority, especially in light of the recent COVID-19 pandemic.

category: sexual and reproductive health


title: Predicting disability progression and cognitive worsening in multiple sclerosis using grey matter network measures

abstract:
ObjectiveIn multiple sclerosis (MS), magnetic resonance imaging (MRI) measures at the whole brain or regional level are only modestly associated with disability, while network-based measures are emerging as promising prognostic markers. We sought to demonstrate whether data-driven network-based measures of regional grey matter (GM) volumes predict future disability in secondary progressive MS (SPMS).

Methods

We used cross-sectional structural MRI, and baseline and longitudinal data of Expanded Disability Status Scale [EDSS], 9-Hole Peg Test [9HPT], and Symbol Digit Modalities Test [SDMT], from a clinical trial in 988 people with progressive MS. We processed T1-weighted scans to obtain GM probability maps and applied spatial independent component analysis (ICA) to identify co-varying patterns of GM volume change. We used survival models to determine whether baseline GM network measures predict cognitive and motor worsening.

ResultsWe identified 15 networks of regionally co-varying GM features. Compared with whole brain GM, deep GM, and lesion volumes, ICA-components correlated more closely with clinical outcomes. A mainly basal ganglia component had the highest correlations at baseline with the SDMT and was associated with cognitive worsening (HR= 1.29, 95% CI [1.09-1.52], p< 0.005). Two ICA-components were associated with 9HPT worsening (HR=1.30, 95% CI [1.06:1.60], p<0.01; and HR= 1.21, 95%CI [1.01:1.45], p<0.05). Post-hoc analyses revealed that for 9HPT and SDMT survival models including network-based measures reported a higher discrimination power (respectively, C-index= 0.69, se= 0.03; C-index= 0.71, se= 0.02) compared to models including only whole and regional MRI measures (respectively, C-index= 0.65, se= 0.03; C-index= 0.69, se= 0.02).

ConclusionsThe disability progression was better predicted by networks of covarying GM regions, rather than by single regional or whole-brain measures. Network analysis can be applied in future clinical trials and may play a role in stratifying participants who have the most potential to show a treatment effect.


title: Diagnostic accuracy of cerebrospinal fluid and blood biomarkers for the differential diagnosis of sporadic Creutzfeldt-Jakob disease: a (network) meta-analysis

abstract:
ObjectiveTo conduct a systematic review of cerebrospinal fluid (CSF) and blood biomarkers as diagnostic tests for sporadic Creutzfeldt-Jakob disease (sCJD) in a specialised care setting and to compare diagnostic accuracies in a network meta-analysis (NMA).

MethodsWe searched Medline, Embase, and the Cochrane Library for diagnostic studies of sCJD biomarkers. Risk of bias was assessed with the QUADAS-2 tool. We used a generalised bivariate model to conduct individual biomarker meta-analyses, and to estimate between-study variability. To investigate sources of heterogeneity, we performed subgroup analyses based on QUADAS-2 quality and clinical criteria. For the NMA, we applied a Bayesian beta-binomial ANOVA model. The study protocol was registered at PROSPERO (CRD42019118830).

ResultsOut of 2,976 publications screened, we included 16 studies, which investigated 14-3-3{beta} Western blot (n=13), 14-3-3{gamma} ELISA (n=3), NfL (n=1), NSE (n=1), p-tau181/t-tau ratio (n=2), RT-QuIC (n=6), S100B (n=3), t-tau (n=12), and t-tau/A{beta}42 ratio (n=1) in CSF. No included study investigated blood biomarkers. Many diagnostic studies excluded had strong limitations in study design. In the NMA, RT-QuIC (0.93; 95% CI [0.87, 0.96]) and NfL (0.94 [0.81, 0.99]) were the most sensitive biomarkers. RT-QuIC was the most specific biomarker (0.96 [0.86, 0.99]), and had the highest balanced accuracy (0.94). Heterogeneity in accuracy estimates was high between studies, especially for specificity.

ConclusionsOur NMA identified RT-QuIC as the overall most accurate biomarker, partially confirming current guidelines. The severe shortcomings identified in many diagnostic studies for sCJD biomarkers need to be addressed in future studies in the field.


title: A realistic way to investigate the design, and mechanical properties of flow diverter stents

abstract:
PurposeBraided flow diverters (FD) are highly sophisticated, delicate, and intricate mechanical devices used to treat intracranial aneurysms and thus saving lives. Testing such devices in vitro, however, remains an unsolved challenge. Here, we evaluate methods that access flow, design, and mechanical properties in vitro.

MethodsFlow properties, cell porosity, and cell area were evaluated by placing FDs in patient-derived, 3D printed models of human vasculature. 4D flow MRI was used to measure fluid dynamics. Laser microscopy was used to measure porosity and cell area with the top of aneurysm sac cut off for the model. New testing methods were developed to investigate the bending, circumferential, and longitudinal radial force continuously over varying diameters.

ResultsThe placement and flow properties of the FD in the vasculature models were successfully measured by MRI, although artifacts occurred. The setup to measure porosity and cell area inside of the model proved successful. The newly discussed methods allowed us to measure the indicated forces, to our knowledge for the first time, continuously.

ConclusionModern and specifically tailored techniques, some of which were presented here for the first time, allow detailed insights into the flow and mechanical properties of braided flow diverter stents.


title: Prediction of Procedural Pain during Endometrial Biopsy

abstract:
Background/ObjectiveEndometrial (EM) biopsy is a commonly-performed gynecological procedure that is associated with side effects such as discomfort and pain. The aim of the current study was to predict procedural pain during EM biopsy.

MethodsWe retrospectively reviewed the medical records of 100 women who underwent EM biopsy between July 2014 and November 2015 in an outpatient clinic of our hospital. Eighty-one patients were included in the final analysis after excluding those who lacked pain data and those who were sedated with midazolam. We examined the association of patient and clinician characteristics with procedural pain, and created a prediction model using characteristics via multiple linear regression analysis.

ResultsEighty-one women underwent EM biopsy (dilatation and curettage, EM sampling). In univariable analysis, history of EM biopsy, endometrial thickness (EMT) and training year of operator (TY) were significantly associated with procedural pain. The initial multivariable model was fitted with significant predictors in a univariable analysis. The p-value of EMT and TY was below the pre-defined threshold (0.2) and the final pain prediction model included EMT and TY. Furthermore, pain during the procedure was calculated by the following equation: pain score (numeric rating scale) = 7.364 + (-0.872) * EM thickness (cm) + (-1.033)*TY.

ConclusionBoth endometrial thickness and training year of operator were useful predictors of the severity of EM biopsy-related pain.

category: obstetrics and gynecology


title: Detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in a fourplex real-time quantitative reverse transcription-PCR assays.

abstract: The early diagnosis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections is required to identify and isolate contagious patients to prevent further transmission of the coronavirus disease 2019 (COVID-19). In this study, we present a multitarget real-time TaqMan reverse transcription PCR (rRT-PCR) assay for the quantitative detection of SARS-CoV-2 and some of its circulating variants harboring mutations that give SARS-CoV-2 a selective advantage. Seven different primer-probe sets that included probes containing locked nucleic acid (LNA) nucleotides were designed to amplify specific wild-type and mutant sequences in Orf1ab, Envelope (E), Spike (S), and Nucleocapsid (N) genes. Furthermore, a newly developed primer-probe set targeted human {beta}2-microglobulin (B2M) as a highly sensitive internal control for RT efficacy. All singleplex and fourplex assays detected [≤] 14 copies/reaction of quantified synthetic RNA transcripts, with a linear amplification range of 9 logarithmic orders. Primer-probe sets for detection of SARS-CoV-2 exhibited no false-positive amplifications with other common respiratory pathogens, including human coronaviruses NL63, 229E, OC43, and HKU-1. Given the emergence of SARS-CoV-2 variants and their rapid spread in some populations, fourplex rRT-PCR assay containing four primer-probe sets represents a reliable approach to detect multiple viral target sequences containing typical mutations of SARS-CoV-2 variants in a single reaction, allowing quicker detection of circulating relevant variants.

category: genetic and genomic medicine


title: A polygenic risk score for coronary heart disease performs well in individuals aged 70 years and older

abstract:
BackgroundThe use of a polygenic risk score (PRS) to predict coronary heart disease (CHD) events has been demonstrated in the general adult population. However, whether predictive performance extends to older individuals is unclear.

AimTo evaluate the predictive value of a PRS for incident CHD events in a prospective cohort of individuals aged 70 years and older.

MethodsWe used data from 12,792 genotyped participants of the ASPREE trial, a randomized placebo-controlled trial investigating the effect of daily 100mg aspirin on disability-free survival in healthy older people. Participants had no previous history of diagnosed atherothrombotic cardiovascular events, dementia, or persistent physical disability at enrolment. We calculated a PRS comprising 1.7 million genetic variants (metaGRS). The primary outcome was a composite of incident myocardial infarction or CHD death over 5 years.

ResultsAt baseline, the median population age was 73.9 years and 54.9% were female. In total, 254 incident CHD events occurred. When the PRS was added to conventional risk factors, it was independently associated with CHD (hazard ratio 1.24 [95% confidence interval [CI] 1.08-1.42], p=0.002). The AUC of the conventional model was 70.53 (95%CI 67.00-74.06), and after inclusion of the PRS increased to 71.78 (95%CI 68.32-75.24, p=0.019), demonstrating improved prediction. Reclassification was also improved, as the continuous net reclassification index after adding PRS to the conventional model was 0.25 (95%CI 0.15-0.28).

ConclusionsA PRS for CHD performs well in older people, suggesting that the clinical utility of genomic risk prediction for CHD extends to this distinct high-risk subgroup.


title: The polymorphism L412F in TLR3 inhibits autophagy and is a marker of severe COVID-19 in males.

abstract: The polymorphism L412F in TLR3 has been associated with several infectious diseases. However, the mechanism underlying this association is still unexplored. Here, we show that the L412F polymorphism in TLR3 is a marker of severity in COVID-19. This association increases in the sub-cohort of males. Impaired autophagy and reduced TNF production was demonstrated in HEK293 cells transfected with TLR3-L412F plasmid and stimulated with specific agonist poly(I:C). A statistically significant reduced survival at 28 days was shown in L412F COVID-19 patients treated with the autophagy-inhibitor hydroxychloroquine (P=0.038). An increased frequency of autoimmune disorders as co-morbidity was found in L412F COVID-19 males with specific class II HLA haplotypes prone to autoantigen presentation. Our analyses indicate that L412F polymorphism makes males at risk of severe COVID-19 and provides a rationale for reinterpreting clinical trials considering autophagy pathways.


title: Increasing Trust in Real-World Evidence Through Evaluation of Observational Data Quality

abstract: Advances in standardization of observational healthcare data have enabled methodological breakthroughs, rapid global collaboration, and generation of real-world evidence to improve patient outcomes. Standardizations in data structure, such as use of Common Data Models (CDM), need to be coupled with standardized approaches for data quality assessment. To ensure confidence in real-world evidence generated from the analysis of real-world data, one must first have confidence in the data itself. The Data Quality Dashboard is an open-source R package that reports potential quality issues in an OMOP CDM instance through the systematic execution and summarization of over 3,300 configurable data quality checks. We describe the implementation of check types across a data quality framework of conformance, completeness, plausibility, with both verification and validation. We illustrate how data quality checks, paired with decision thresholds, can be configured to customize data quality reporting across a range of observational health data sources. We discuss how data quality reporting can become part of the overall real-world evidence generation and dissemination process to promote transparency and build confidence in the resulting output. Transparently communicating how well CDM standardized databases adhere to a set of quality measures adds a crucial piece that is currently missing from observational research. Assessing and improving the quality of our data will inherently improve the quality of the evidence we generate.

category: health informatics


title: Improving COVID-19 vaccination centre operation through computer modelling and simulation

abstract: Mass vaccination is widely considered to offer the only route out of the COVID-19 pandemic in a way that social restrictions can be eased and economic activity can safely resume without compromising healthcare services. For many countries, dedicated vaccination centres are a key part of that effort. However, with no directly comparable historical experience there is little information to guide the operational configuration and management of these sites. In addressing this gap in knowledge, the objective of this study is to demonstrate the value of computer modelling. This is achieved through providing an account of its use in supporting management considerations and decisions at two major vaccination centres, at an early stage of the UKs mass vaccination effort. We report on how modelling insight has influenced the initial setup of one site, including quantification of daily booking numbers. For the same site, we reveal how analysis has informed a significant operational shift in combining two key activities on the vaccination pathway into one. Finally, we describe how, at a second site, modelling has been used to examine pathway stability, in terms of resilience to unforeseen  shocks such as delayed arrivals and staff unavailability. Alongside the open-source simulation software, the modelling insights reported here can support managers to better plan and improve the operation of COVID-19 vaccination centres.

category: health systems and quality improvement


title: Impact of a Population-based Systems Approach on Evidence-based Care for Medicaid-insured Pregnant and Postpartum Women: A Quasi-Experimental Study

abstract:
IntroductionEvidence-based enhanced prenatal/postnatal care (EPC) programs for Medicaid-insured women have significant positive effects on care and health outcomes. However, EPC enrollment rates are typically low, enrolling less than 30% of eligible women. This study investigated the effects of a population-based systems approach on timely EPC participation and other health care utilization.

MethodsThis quasi-experimental, population-based, difference-in-difference study used linked birth certificates, Medicaid claims, and EPC data from complete statewide Medicaid birth cohorts retrieved from 2009-2017 and analyzed in 2019-20. System strategies included cross-agency leadership, clinical-community linked practices, Community Health Worker care, mental health coordination, and patient empowerment. Outcomes included EPC participation and early enrollment, prenatal care adequacy, emergency department contact, and postpartum care.

ResultsPrenatal EPC (7.4 absolute percentage points; 95% CI: 6.3--8.5) and first trimester EPC, (12.4; 95% CI: 10.2--14.5) increased among women served by practices that co-located EPC resources, relative to the comparator group. First trimester EPC improved in the county (17.9; 95% CI: 15.7--20.0); ED decreased in the practices (-11.1; 95% CI: -12.3-- -9.9) and postpartum care improved (7.1; 95% CI: 6-- 8.2) in the county. EPC participation for Black women served by the practices improved (4.4; 95% CI: 2.2--6.6), as well as early EPC (12.3; 95% CI: 9.0--15.6) and postpartum visits (10.4; 95% CI: 8.3--12.4).

ConclusionsA population systems approach improved EPC participation and service utilization for Medicaid-insured women in a county population, for those in practices that co-located EPC resources, and for Black women.


title: Pooling-in-a-pod: A Strategy for COVID-19 Testing to Facilitate Safe Return to School

abstract:
The COVID-19 pandemic has prompted widespread primary and secondary school closures. Routine testing of asymptomatic students and staff, as part of a comprehensive program, can help schools open safely. "Pooling-in-a-pod" is a public health surveillance strategy whereby testing cohorts are composed based on social relationships and physical proximity. Pooling-in-a-pod allowed for weekly on-site point-of-care testing of all staff and students at an independent preschool to grade 12 school in Washington, D.C. Staff and older students self-collected anterior nares samples, and trained staff collected samples from younger students. Overall, 6,746 samples were tested for 815 students and 276 staff between November 30, 2020, and March 3, 2021. The average pool size was 7.3 people. Sample collection to pool result time averaged 40 minutes. The direct testing cost per person per week was $24.77, including swabs. One surveillance test pool was positive. During the study period, daily new cases in Washington, D.C., ranged from 24 - 46 per 100,000 population. A post-launch survey found most parents (90.3%), students (93.4%), and staff (98.8%) were willing to participate in pooled testing with confirmatory tests for positive pool members. The school reported a 32.6% decrease in virtual learning after initiation of the program. Pooling-in-a-pod is feasible, cost-effective, and an acceptable COVID-19 surveillance strategy for schools. School officials and policymakers can leverage this strategy to facilitate safe, sustainable, in-person schooling.

SUMMARY

1) What is the current understanding of this subject?Routine COVID-19 testing as part of a comprehensive strategy to operate schools safely is currently not widely implemented.

2) What does this report add to the literature?"Pooling-in-a-pod," is a public health surveillance strategy whereby cohorts are composed based on social relationships and physical proximity. 6,746 samples were tested in 969 pools (average pool size 7.3 people) in a Washington, D.C. school, thereby requiring fewer test kits and less expense. The program was widely acceptable.

3) What are the implications for public health practice?Pooling-in-a-pod allows for more accessible testing to facilitate safe in-person schooling and minimize the negative effects of distance learning.


title: A SIMPLE, HOME-THERAPY ALGORYTHM TO PREVENT HOSPITALIZATION OF COVID-19 PATIENTS: A RETROSPECTIVE OBSERVATIONAL MATCHED-COHORT STUDY

abstract:
BackgroundEffective simple, home-treatment algorithms implemented on the basis of a pathophysiologic and pharmacologic rationale to accelerate recovery and prevent hospitalization of patients with early coronavirus disease 2019 (COVID-19) would have major implications for patients and health care providers.

MethodsThis academic, matched-cohort study compared outcomes of 90 consecutive consenting patients with mild COVID-19 treated at home by their family physicians from October 2020 to January 2021 according to the proposed recommendation algorithm with those of 90 age-, sex-, and comorbidities-matched patients who received other therapeutic regimens. Primary outcome was time to resolution of major symptoms. Secondary outcomes included prevention of hospitalization. Analyses were by intention-to-treat.

FindingsAll patients achieved complete remission. The median [IQR] time to resolution of major symptoms was 18 [14-23] days in the  recommended schedule cohort and 14 [7-30] days in the matched  control cohort (p=0{middle dot}033). Minor symptoms persisted in a lower percentage of patients in the  recommended than in the  control cohort (23{middle dot}3% versus 73{middle dot}3%, respectively, p<0{middle dot}0001) and for a shorter period (p=0{middle dot}0107). Two patients in the  recommended cohort were hospitalized compared to 13 (14{middle dot}4%) controls (Log-rank test, p=0{middle dot}0038). Prevention algorithm abated the days and cumulative costs of hospitalization by >90% (from 481 to 44 days and from 296 to 28 thousand Euros, respectively. 1{middle dot}2 patients had to be treated to save one hospitalization event.

InterpretationImplementation of an early, home-treatment algorithm failed to accelerate recovery from major symptoms of COVID-19, but almost blunted the risk of hospitalization and related treatment costs.

RO_SCPLOWESEARCHC_SCPLOWO_SCPCAP C_SCPCAPO_SCPLOWINC_SCPLOW CO_SCPLOWONTEXTC_SCPLOWO_ST_ABSEvidence before this studyC_ST_ABSWe searched PubMed and the Cochrane Library for peer-reviewed articles published in any language up to March 19, 2021, using the search terms ("2019-nCoV" or "SARS-CoV-2" or "COVID-19") and ("early" or "outpatient" or "treatment" or "home"). Our search did not identify any randomised clinical trials or observational studies that assessed the effectiveness of treatment regimens targeting early mild symptoms of COVID-19 in the outpatient setting.

Added value of this studyIn this fully academic, observational matched-cohort study, we found that early home-treatment of 90 consecutive patients with mild COVID-19 by their family physicians according to the proposed recommendation algorithm, designed on the basis of a pathophysiologic and pharmacologic rationale, significantly reduced the risk of hospitalisation compared to 90 age-, sex-, and comorbidities-matched patients who received other therapeutic regimens. Days of hospitalization and related treatment costs were reduced by more than 90%. Just 1.2 patients needed to be treated to save one hospitalization event. The  recommended schedule cohort required a few more days to achieve resolution of major symptoms, including fever, dyspnea, musculoskeletal pain, headache and cough compared to the  control cohort. Symptoms, such as anosmia and ageusia/dysgeusia, persisted less commonly and for a shorter period in the  recommendation than in the  control cohort.

Implications of the available evidenceThe finding that the implementation of the proposed simple treatment algorithm during the initial, mild phase of COVID-19 has the potential to prevent disease progression, eventually limiting the need of hospital admission may have major implications for patients and health care providers. Indeed, preventing hospitalisations due to worsening of COVID-19 will not only save lives, but will also contribute to remarkably reduce treatment costs and to reshape health care systems that are overburdened because of the pandemic effects.


title: A SIMPLE, HOME-THERAPY ALGORITHM TO PREVENT HOSPITALIZATION FOR COVID-19 PATIENTS: A RETROSPECTIVE OBSERVATIONAL MATCHED-COHORT STUDY


title: Impact of the COVID-19 Pandemic on Antimicrobial Resistance (AMR) Surveillance, Prevention and Control: A Global Survey

abstract:
SynopsisO_ST_ABSObjectivesC_ST_ABSThe COVID-19 pandemic has had a substantial impact on health systems. The WHO Antimicrobial Resistance (AMR) Collaborating Centres Network conducted a survey to assess the effects of COVID-19 on AMR surveillance, prevention and control.

MethodsFrom October-December 2020, WHO Global Antimicrobial Resistance and Use Surveillance System (GLASS) national focal points completed a questionnaire including Likert-scales and open-ended questions. Data were descriptively analysed, income/regional differences were assessed, and free-text questions were thematically analysed.

ResultsSeventy-three countries across income levels participated. During the COVID-19 pandemic, 67% reported limited ability to work with AMR partnerships; decreases in funding were frequently reported by low- and middle-income countries (LMICs; p<0.01). Reduced availability of nursing, medical and public health staff for AMR was reported by 71%, 69% and 64%, respectively, whereas 67% reported stable cleaning staff availability. The majority (58%) reported reduced reagents/consumables, particularly LMICs (p<0.01). Decreased numbers of cultures, elective procedures, chronically ill admissions and outpatients and increased intensive care unit admissions reported could bias AMR data. Reported overall infection prevention and control (IPC) improvement could decrease AMR rates, whereas increases in selected inappropriate IPC practices and antibiotic prescribing could increase rates. Most did not yet have complete data on changing AMR rates due to COVID-19.

ConclusionsThis was the first survey to explore the global impact of COVID-19 on AMR among GLASS countries. Responses revealed universal patterns but also captured country variability. Although focus is understandably on COVID-19, gains in detecting and controlling AMR, a global health priority, cannot afford to be lost.


title: COVID-19 antibody seroprevalence in Duhok, Kurdistan Region, Iraq: A population-based study

abstract:
ObjectiveThis population-based study aimed to evaluate the seroprevalence of antibodies to SARS-CoV-2 in Duhok City, Kurdistan Region of Iraq.

MethodsWe analyzed the national COVID-19 database that contains data regarding COVID-19 testing, management, and clinical outcomes in Duhok. For this study, different subdistricts within each district of Duhok were considered distinct clusters. Blood samples were collected from and questionnaires were administered to eligible and consenting participants who were members of different families from the subdistricts. Immunoassays were conducted to detect antibodies against SARS-CoV-2, and the associations between certain variables were investigated.

ResultsThe average number cases of COVID-19 before November 2020 was 23141 {+/-} 4364, which was significantly higher than the average number of cases between November 2020 and February 2021 (3737 {+/-} 2634; P = 0.001). A total of 743 individuals agreed to participate and were enrolled in the study. Among the participants, 465/743 (62.58%) were found to have antibodies against severe acute respiratory syndrome coronavirus 2. Among the participants with antibodies, 262/465 (56.34%) denied having any history of COVID-19-related symptoms. The most common symptom was fever (81.77%), followed by myalgia (81.28%). We found that antibody levels increased steadily with age (Pearson correlation coefficient = 0.117; P = 0.012). A significant association was found between antibody levels and the presence of symptoms (P = 0.023; odds ratio = 1.0023; 95% confidence interval = 1.0002-1.0061).

ConclusionsA significant reduction in the number of COVID-19 cases was observed. This might be due to the high prevalence of SARS-CoV-2 antibodies in Duhok. However, infection-prevention measures should be followed as it remains unclear whether acquired immunity is protective against reinfection. It expected that the infection rates during the next wave will not be as high as the first wave due to the high infection rate in the society.


title: Serological profiles of pan-coronavirus-specific responses in COVID-19 patients using a multiplexed electro-chemiluminescence-based testing platform

abstract: Serological assessment of SARS-CoV-2 specific responses are an essential tool for determining the prevalence of past SARS-CoV-2 infections in the population especially when testing occurs after symptoms have developed and limited contact tracing is in place. The goal of our study was to test a new 10-plex electro-chemiluminescence-based assay to measure IgM and IgG responses to the spike proteins from multiple human coronaviruses including SARS-CoV-2, assess the epitope specificity of the SARS-CoV-2 antibody response against full-length spike protein, receptor-binding domain and N-terminal domain of the spike protein, and the nucleocapsid protein. We carried out the assay on samples collected from three sample groups: subjects diagnosed with COVID-19 from the U.S. Army hospital at Camp Humphreys in Pyeongtaek, South Korea; healthcare administrators from the same hospital but with no reported diagnosis of COVID-19; and pre-pandemic samples. We found that the new CoV-specific multiplex assay was highly sensitive allowing plasma samples to be diluted 1:30,000 with a robust signal. The reactivity of IgG responses to SARS-CoV-2 nucleocapsid protein and IgM responses to SARS-CoV-2 spike protein could distinguish COVID-19 samples from non-COVID-19 and pre-pandemic samples. The data from the three sample groups also revealed a unique pattern of cross-reactivity between SARS-CoV-2 and SARS-CoV-1, MERS-CoV, and seasonal coronaviruses HKU1 and OC43. Our findings show that the CoV-2 IgM response is highly specific while the CoV-2 IgG response is more cross-reactive across a range of human CoVs and also showed that IgM and IgG responses show distinct patterns of epitope specificity. In summary, this multiplex assay was able to distinguish samples by COVID-19 status and characterize distinct trends in terms of cross-reactivity and fine-specificity in antibody responses, underscoring its potential value in diagnostic or serosurveillance efforts.


title: Toward Community Surveillance: Detecting Intact SARS-CoV-2 Using Exogeneous Oligonucleotide Labels

abstract: The persistence of the COVID-19 pandemic demands a dramatic increase in testing efficiency. Testing pooled samples for SARS-CoV-2 could meet this need; however, the sensitivity of RT-qPCR, the gold standard, significantly decreases with an increasing number of samples pooled. Here, we introduce DIVER, a method that quantifies intact virus and is robust to sample dilution. DIVER first tags viral particles with exogeneous oligonucleotides, then captures the tagged particles on ACE2-functionalized beads, and finally quantifies the oligonucleotide tags using qPCR. Using spike-presenting liposomes and Spike-pseudotyped lentivirus as SARS-CoV-2 models, we show that DIVER can detect 1x105 liposomes and 100 pfu lentivirus and can successfully identify positive samples in pooling experiments. Overall, DIVER is well-positioned for efficient sample pooling and expanded community surveillance.


title: Droplet Digital RT-PCR to detect SARS-CoV-2 variants of concern in wastewater.

abstract: Wastewater surveillance has shown to be a valuable and efficient tool to obtain information about the trends of COVID-19 in the community. Since the recent emergence of new variants, associated with increased transmissibility and/or antibody escape (variants of concern), there is an urgent need for methods that enable specific and timely detection and quantification of the occurrence of these variants in the community. In this study we demonstrate the use of RT-ddPCR on wastewater samples for specific detection of mutation N501Y. This assay enabled simultaneous enumeration of the concentration of variants with the 501Y mutation and Wild Type (WT, containing 501N) SARS-CoV-2 RNA. Detection of N501Y was possible in samples with mixtures of WT with low proportions of lineage B.1.351 (0.5%). The method could accurately determine the proportion of N501Y and WT in mixtures of SARS-CoV-2 RNA. The application to raw sewage samples from the cities of Amsterdam and Utrecht demonstrated that this method can be applied to determine the concentrations and the proportions of WT and N501Y containing SARS-CoV-2 RNA in wastewater samples. The emergence of N501Y in Amsterdam and Utrecht wastewater aligned with the emergence of B.1.1.7 as causative agent of COVID-19 in the Netherlands, indicating that RT-ddPCR of wastewater samples can be used to monitor the emergence of the N501Y mutation in the community. It also indicates that RT-ddPCR could be used for sensitive and accurate monitoring of current (like K417N, E484K) or future mutations present in SARS-CoV-2 variants of concern. Monitoring emergence of these mutations in the community via wastewater is rapid, efficient and valuable in supporting public health decision-making.


title: Tocilizumab in hospitalized COVID-19 patients: A meta-analysis of randomized controlled trials

abstract:
BackgroundTo date, only dexamethasone has been shown to reduce mortality in COVID-19 patients. Tocilizumab has been recently added to the treatment guidelines for hospitalized COVID-19 patients, but data remains conflicting.

MethodsElectronic databases such as MEDLINE, EMBASE and Cochrane central were searched from March 1, 2020, until February 28th, 2021, for randomized controlled trials evaluating the efficacy of tocilizumab in hospitalized COVID-19 patients. The outcomes assessed were all-cause mortality at 28 days, mechanical ventilation, and time to discharge.

ResultsEight studies (with 6,311 patients) were included in the analysis. In total, 3,267 patients received tocilizumab, and 3,044 received standard care/placebo. Pooled analysis showed a significantly decreased risk of all-cause mortality at 28 days (RR 0.90, 95% CI 0.83-0.97, p=0.009) and progression to mechanical ventilation (RR 0.79, 95% CI 0.70-0.90, p=0.0002) in the tocilizumab arm compared to standard therapy or placebo. In addition, there was a trend towards improved median time to hospital discharge (RR 1.18, 95% CI 1.05-1.34, p=0.007).

ConclusionsTocilizumab therapy improves outcomes of mortality and need for mechanical ventilation, in hospitalized patients with COVID-19 infection compared with standard therapy or placebo. Our findings suggest the efficacy of tocilizumab therapy in hospitalized COVID-19 patients and strengthen the concept that tocilizumab is a promising therapeutic intervention to improve mortality and morbidity in COVID-19 patients.


title: Expansion of Cytotoxic CD4+ T cells in the lungs in severe COVID-19

abstract:
The contributions of T cells infiltrating the lungs to SARS-CoV-2 clearance and disease progression are poorly understood. Although studies of CD8+ T cells in bronchoalveolar lavage and blood have suggested that these cells are exhausted in severe COVID-19, CD4+ T cells have not been systematically interrogated within the lung parenchyma. We establish here that cytotoxic CD4+ T cells (CD4+CTLs) are prominently expanded in the COVID-19 lung infiltrate. CD4+CTL numbers in the lung increase with disease severity and progression is accompanied by widespread HLA-DR expression on lung epithelial and endothelial cells, increased apoptosis of epithelial cells and tissue remodeling. Based on quantitative evidence for re-activation in the lung milieu, CD4+ CTLs are as likely to drive viral clearance as CD8+ T cells and may also be contributors to lung inflammation and eventually to fibrosis in severe COVID-19.

Graphical Abstract

O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=138 SRC="FIGDIR/small/21253885v1_ufig1.gif" ALT="Figure 1">
View larger version (42K):
org.highwire.dtl.DTLVardef@198a382org.highwire.dtl.DTLVardef@16b3cdorg.highwire.dtl.DTLVardef@769032org.highwire.dtl.DTLVardef@1f4cd1c_HPS_FORMAT_FIGEXP  M_FIG C_FIG In BriefIn severe COVID-19 cytotoxic CD4+ T cells accumulate in draining lymph nodes and in the lungs during the resolving phase of the disease. Re-activated cytotoxic CD4+ T cells and cytotoxic CD8+ T cells are present in roughly equivalent numbers in the lungs at this stage and these cells likely collaborate to eliminate virally infected cells and potentially induce fibrosis. A large fraction of epithelial and endothelial cells in the lung express HLA class II in COVID-19 and there is temporal convergence between CD4+CTL accumulation and apoptosis in the lung.

HighlightsO_LIIn severe COVID-19, activated CD4+ CTLs accumulate in the lungs late in disease
C_LIO_LIThese cells likely participate in SARS-CoV-2 clearance, collaborating with CD8+ T cells many of which exhibit an exhausted phenotype
C_LIO_LIT cells likely contribute to the late exacerbation of inflammation
C_LIO_LICD4+CTLs have been linked to fibrosis in many disorders and could also be responsible for the eventual induction of fibrosis in a subset of COVID-19 patients
C_LI

SummaryThe contributions of T cells infiltrating the lungs to SARS-CoV-2 clearance and disease progression are poorly understood. Although studies of CD8+ T cells in bronchoalveolar lavage and blood have suggested that these cells are exhausted in severe COVID-19, CD4+ T cells have not been systematically interrogated within the lung parenchyma. We establish here that cytotoxic CD4+ T cells (CD4+CTLs) are prominently expanded in the COVID-19 lung infiltrate. CD4+CTL numbers in the lung increase with disease severity and progression is accompanied by widespread HLA-DR expression on lung epithelial and endothelial cells, increased apoptosis of epithelial cells and tissue remodeling. Based on quantitative evidence for re-activation in the lung milieu, CD4+ CTLs are as likely to drive viral clearance as CD8+ T cells and may also be contributors to lung inflammation and eventually to fibrosis in severe COVID-19.


title: Optimizing SARS-CoV-2 Variant of Concern Screening: Experience from British Columbia, Canada, Early 2021

abstract: Comprehensive and timely testing is required for SARS-CoV-2 variant of concern (VoC) screening. Whole genome sequencing (WGS) provides the broadest means to detect circulating VoCs, but requires longer turnaround time than targeted molecular testing by quantitative polymerase chain reaction (qPCR). We demonstrated the feasibility of a combined testing approach for VoC prevalence assessment in British Columbia, and showed high concordance between qPCR testing and WGS. This directly informed wider VoC screening strategy implementation, and public health efforts.