Outcomes of the EMDataResource Cryo-EM Ligand Modeling Challenge (preprint)

The EMDataResource Ligand Model Challenge aimed to assess the reliability and reproducibility of modeling ligands bound to protein and protein/nucleic-acid complexes in cryogenic electron microscopy (cryo-EM) maps determined at near-atomic (1.9-2.5 Å) resolution. Three published maps were selected as targets: E. coli beta-galactosidase with inhibitor, SARS-CoV-2 RNA-dependent RNA polymerase with covalently bound nucleotide analog, and SARS-CoV-2 ion channel ORF3a with bound lipid. Sixty-one models were submitted from 17 independent research groups, each with supporting workflow details. We found that (1) the quality of submitted ligand models and surrounding atoms varied, as judged by visual inspection and quantification of local map quality, model-to-map fit, geometry, energetics, and contact scores, and (2) a composite rather than a single score was needed to assess macromolecule+ligand model quality. These observations lead us to recommend best practices for assessing cryo-EM structures of liganded macromolecules reported at near-atomic resolution.

Date of introduction and epidemiologic patterns of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in Mogadishu, Somalia: estimates from transmission modelling of satellite-based excess mortality data in 2020 [version 2;peer review: 2 approved]

Background: In countries with weak surveillance systems, confirmed coronavirus disease 2019 (COVID-19) deaths are likely to underestimate the pandemic’s death toll. Many countries also have incomplete vital registration systems, hampering excess mortality estimation. Here, we fitted a dynamic transmission model to satellite imagery data of cemeteries in Mogadishu, Somalia during 2020 to estimate the date of introduction and other epidemiologic parameters of the early spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in this low-income, crisis-affected setting. Methods: We performed Markov chain Monte Carlo (MCMC) fitting with an age-structured compartmental COVID-19 model to provide median estimates and credible intervals for the date of introduction, the basic reproduction number ( R 0) and the effect of non-pharmaceutical interventions (NPIs) up to August 2020. Results: Under the assumption that excess deaths in Mogadishu March-August 2020 were attributable to SARS-CoV-2 infections, we arrived at median estimates of November-December 2019 for the date of introduction and low R 0 estimates (1.4-1.7) reflecting the slow and early rise and long plateau of excess deaths. The date of introduction, the amount of external seeding, the infection fatality rate (IFR) and the effectiveness of NPIs are correlated parameters and not separately identifiable in a narrow range from deaths data. Nevertheless, to obtain introduction dates no earlier than November 2019 a higher population-wide IFR (≥0.7%) had to be assumed than obtained by applying age-specific IFRs from high-income countries to Somalia’s age structure. Conclusions: Model fitting of excess mortality data across a range of plausible values of the IFR and the amount of external seeding suggests an early SARS-CoV-2 introduction event may have occurred in Somalia in November-December 2019. Transmissibility in the first epidemic wave was estimated to be lower than in European settings. Alternatively, there was another, unidentified source of sustained excess mortality in Mogadishu from March to August 2020.

Date of introduction and epidemiologic patterns of SARS-CoV-2 in Mogadishu, Somalia: estimates from transmission modelling of 2020 excess mortality data (preprint)

IntroductionIn countries with weak surveillance systems confirmed COVID-19 deaths are likely to underestimate the death toll of the pandemic. Many countries also have incomplete vital registration systems, hampering excess mortality estimation. Here, we fitted a dynamic transmission model to satellite imagery data on burial patterns in Mogadishu, Somalia during 2020 to estimate the date of introduction, transmissibility and other epidemiologic characteristics of SARS-CoV-2 in this low-income, crisis-affected setting. MethodsWe performed Markov chain Monte Carlo (MCMC) fitting with an age-structured compartmental COVID-19 model to provide median estimates and credible intervals for the date of introduction, the basic reproduction number (R0) and the effect of non-pharmaceutical interventions in Mogadishu up to September 2020. ResultsUnder the assumption that excess deaths in Mogadishu February-September 2020 were directly attributable to SARS-CoV-2 infection we arrived at median estimates of October-November 2019 for the date of introduction and low R0 estimates (1.3-1.5) stemming from the early and slow rise of excess deaths. The effect of control measures on transmissibility appeared small. ConclusionSubject to study assumptions, a very early SARS-CoV-2 introduction event may have occurred in Somalia. Estimated transmissibility in the first epidemic wave was lower than observed in European settings.

Excess mortality during the COVID-19 pandemic: a geospatial and statistical analysis in Mogadishu, Somalia (preprint)

Background While the impact of the COVID-19 pandemic has been well documented in high-income countries, much less is known about its impact in Somalia where health systems are weak and vital registration is under developed. Methods We used remote sensing and geospatial analysis to quantify the number of burials from January 2017 to September 2020 in Mogadishu. We imputed missing grave counts using surface area data. Simple interpolation and a generalised additive mixed growth model were used to predict both actual and counterfactual burial rates by cemetery and across Mogadishu during the most likely period of COVID-19 excess mortality and to compute excess burials. We also undertook a qualitative survey of key informants to determine the drivers of COVID-19 excess mortality. Results Burial rates increased during the pandemic period with a ratio to pre-pandemic levels averaging 1.5-fold and peaking at 2.2-fold. When scaled to plausible range of baseline Crude Death Rates (CDR), excess death toll between January and September 2020 ranged between 3,200 and 11,800. When compared to burial records of the Barakaat Cemetery Committee our estimates were found to be lower. Conclusions Our study points to considerable under estimation of COVID-19 impact in Banadir and an overburdened public health system struggling to deal with the increasing severity of the epidemic in 2020.

Risk Factors for Outbreaks of COVID-19 in Care Homes Following Hospital Discharge: A National Cohort Analysis (preprint)

Background: Adult residential and nursing care homes are settings in which older and often vulnerable people live in close proximity. This population experiences a higher proportion of respiratory and gastrointestinal illnesses than the general population and has been shown to have a high morbidity and mortality in relation to COVID-19.Methods: We examined 3,115 hospital discharges to 1,068 Welsh adult care homes and the subsequent outbreaks of COVID-19 occurring over an 18 week period between 22 February and 27 June 2020. A Cox proportional hazards regression model was used to assess the impact of time-dependent exposure to hospital discharge on the incidence of the first known outbreak, over a window of 7-21 days after discharge, and adjusted for care home characteristics, including size, type of provision and health board.Results: A total of 330 homes experienced an outbreak of COVID-19, and 544 homes received a discharge from hospital over the study period. The exposure to discharge from hospital was not associated with a significant increase in the risk of a new outbreak (hazard ratio 1·15, 95% CI 0·89, 1·47, p = 0.29) after adjusting for care home characteristics. Care home size was by far the most significant predictor. Hazard ratios (95% CI) in comparison to homes of <10 residents were: 3·40 (1·99, 5·80) for 10-24 residents; 8·25 (4·93, 13·81) for 25-49 residents; and 17·35 (9·65, 31·19) for homes of 50+ residents. When stratified for care home size, the outbreak rates were similar for periods when homes were exposed to a hospital discharge, in comparison to periods when homes were unexposed.Conclusion: Our analyses showed that large homes were at considerably greater risk of outbreaks throughout the epidemic, and after adjusting for care home size, a discharge from hospital was not associated with a significant increase in risk.Funding Statement: No specific funding was sought or provided for this work.Declaration of Interests: None declared.Ethics Approval Statement: This analysis was carried out as part of the ongoing response to the Covid-19 epidemic in Wales, under the governance of the Public Health Wales Incident Management Team, so ethical approval was not required.

Self-sampling of capillary blood for serological testing of SARS-CoV-2 by COVID-19 IgG ELISA (preprint)

Serological testing is emerging as a powerful tool to progress our understanding of COVID-19 exposure, transmission and immune response. Large-scale testing is limited by the need for in-person blood collection by staff trained in venepuncture. Capillary blood self-sampling and postage to laboratories for analysis could provide a reliable alternative. Two-hundred and nine matched venous and capillary blood samples were obtained from thirty nine participants and analysed using a COVID-19 IgG ELISA to detect antibodies against SARS-CoV-2. Thirty seven out of thirty eight participants were able to self-collect an adequate sample of capillary blood ([≥]50 l). Using plasma from venous blood collected in lithium heparin as the reference standard, matched capillary blood samples, collected in lithium heparin-treated tubes and on filter paper as dried blood spots, achieved a Cohen's kappa coefficient of >0.88 (near-perfect agreement). Storage of capillary blood at room temperature for up to 7 days post sampling did not affect concordance. Our results indicate that capillary blood self-sampling is a reliable and feasible alternative to venepuncture for serological assessment in COVID-19.

Dynamics of IgG seroconversion and pathophysiology of COVID-19 infections (preprint)

We report dynamics of seroconversion to SARS-CoV-2 infections detected by IgG ELISA in 177 individuals diagnosed by RT-PCR. Longitudinal analysis identifies 2-8.5% of individuals who do not seroconvert even weeks after infection. They are younger than seroconverters who have increased co-morbidity and higher inflammatory markers such as C-Reactive Protein. Higher antibody responses are associated with non-white ethnicity. Antibody responses do not decline during follow up almost to 2 months. Serological assays increase understanding of disease severity. Their application in regular surveillance will clarify the duration and protective nature of humoral responses to SARS-CoV-2.

Rapid development of COVID-19 rapid diagnostics for low resource settings: accelerating delivery through transparency, responsiveness, and open collaboration (preprint)

In January, Mologic, embarked on a product development pathway for COVID-19 diagnostics focusing on ELISA and rapid diagnostic tests (RDTs), with anticipated funding from Wellcome Trust and DFID. 755 clinical samples from known COVID-19 patients and hospital negative controls were tested on Mologics IgG ELISA. The reported sensitivity on 191 SGUL prospectively enrolled patients was 95% on day 7 or more post diagnosis, and 97% 10 days or more post-diagnosis. A specificity panel comprising 564 samples pre-December 2019 were tested to include most common respiratory pathogens, other types of coronavirus, and flaviviruses. Specificity in this panel was 97%. This is the first in a series of Mologic products for COVID-19, which will be deployed for COVID-19 diagnosis, contact tracing and sero-epidemiological studies to estimate disease burden and transmission with a focus on ensuring access, affordability, and availability to lowest resource settings.