title: The cellular immune response to COVID-19 deciphered by single cell multi-omics across three UK centres

abstract: The COVID-19 pandemic, caused by SARS coronavirus 2 (SARS-CoV-2), has resulted in excess morbidity and mortality as well as economic decline. To characterise the systemic host immune response to SARS-CoV-2, we performed single-cell RNA-sequencing coupled with analysis of cell surface proteins, providing molecular profiling of over 800,000 peripheral blood mononuclear cells from a cohort of 130 patients with COVID-19. Our cohort, from three UK centres, spans the spectrum of clinical presentations and disease severities ranging from asymptomatic to critical. Three control groups were included: healthy volunteers, patients suffering from a non-COVID-19 severe respiratory illness and healthy individuals administered with intravenous lipopolysaccharide to model an acute inflammatory response. Full single cell transcriptomes coupled with quantification of 188 cell surface proteins, and T and B lymphocyte antigen receptor repertoires have provided several insights into COVID-19: 1. a new non-classical monocyte state that sequesters platelets and replenishes the alveolar macrophage pool; 2. platelet activation accompanied by early priming towards megakaryopoiesis in immature haematopoietic stem/progenitor cells and expansion of megakaryocyte-primed progenitors; 3. increased clonally expanded CD8+ effector:effector memory T cells, and proliferating CD4+ and CD8+ T cells in patients with more severe disease; and 4. relative increase of IgA plasmablasts in asymptomatic stages that switches to expansion of IgG plasmablasts and plasma cells, accompanied with higher incidence of BCR sharing, as disease severity increases. All data and analysis results are available for interrogation and data mining through an intuitive web portal. Together, these data detail the cellular processes present in peripheral blood during an acute immune response to COVID-19, and serve as a template for multi-omic single cell data integration across multiple centers to rapidly build powerful resources to help combat diseases such as COVID-19.


title: Mapping SARS-CoV-2 Antibody Epitopes in COVID-19 Patients with a Multi-Coronavirus Protein Microarray

abstract: The emergence and rapid worldwide spread of SARS-CoV-2 has accelerated research and development for controlling the pandemic. A multi-coronavirus protein microarray was created containing full-length proteins, overlapping protein fragments of varying lengths and peptide libraries from SARS-CoV-2 and four other human coronaviruses. Sera from confirmed COVID-19 patients as well as unexposed individuals were applied to multi-coronavirus arrays to identify specific antibody reactivity. High level IgG, IgM and IgA reactivity to structural proteins S, M and N, as well as accessory proteins, of SARS-CoV-2 were observed that was specific to COVID-19 patients. Overlapping 100, 50 and 30 amino acid fragments of SARS-CoV-2 proteins identified antigenic regions. Numerous proteins of SARS-CoV, MERS-CoV and the endemic human coronaviruses, HCoV-NL63 and HCoV-OC43 were also more reactive with IgG, IgM and IgA in COVID-19 patient sera than in unexposed control sera, providing further evidence of immunologic cross-reactivity between these viruses. The multi-coronavirus protein microarray is a useful tool for mapping antibody reactivity in COVID-19 patients.

category: infectious diseases


title: Real-time optical analysis of a colorimetric LAMP assay for SARS-CoV-2 in saliva with a handheld instrument improves accuracy compared to endpoint assessment

abstract: Controlling the course of the COVID-19 pandemic will require widespread deployment of consistent and accurate diagnostic testing of the novel coronavirus SARS-CoV-2. Ideally, tests should detect a minimum viral load, be minimally invasive, and provide a rapid and simple readout. Current FDA-approved RT-qPCR-based standard diagnostic approaches require invasive nasopharyngeal swabs and involve laboratory-based analyses that can delay results. Recently, a loop mediated isothermal nucleic acid amplification (LAMP) test that utilizes colorimetric readout received FDA approval. This approach utilizes a pH indicator dye to detect drop in pH from nucleotide hydrolysis during nucleic acid amplification. This method has only been approved for use with RNA extracted from clinical specimens collected via nasopharyngeal swabs. In this study, we developed a quantitative LAMP-based strategy to detect SARS-CoV-2 RNA in saliva. Our detection system distinguished positive from negative sample types using a handheld instrument that monitors optical changes throughout the LAMP reaction. We used this system in a streamlined LAMP testing protocol that could be completed in less than two hours to directly detect inactivated SARS-CoV-2 in minimally processed saliva that bypassed RNA extraction, with a limit of detection (LOD) of 50 genomes/reaction. The quantitative method correctly detected virus in 100% of contrived clinical samples spiked with inactivated SARS- CoV-2 at either 1X (50 genomes/reaction) or 2X (100 genomes/reaction) of the LOD. Importantly the quantitative method was based on dynamic optical changes during the reaction so was able to correctly classify samples that were misclassified by endpoint observation of color.


title: A Novel Multiplex PCR Based Detection Assay Using Saliva or Nasopharyngeal Samples for SARS-Cov-2, Influenza A and B: Clinical Validation and Utility for Mass Surveillance.

abstract:
BackgroundThe COVID-19 pandemic has resulted in a significant diversion of human and material resources to COVID-19 diagnostics, to the extent that testing of viral pathogens normally contributing to seasonal respiratory tract infections have been markedly neglected. The global health burden due to influenza viruses and co-infection in COVID-19 patients remains undocumented but clearly pose serious public health consequences. To address these clinical and technical challenges, we have optimized and validated a highly sensitive RT-PCR based multiplex assay for the detection of SARS-CoV-2, Influenza A and B viruses in a single test.

MethodsThis study evaluated clinical specimens (n=1411) that included 1019 saliva and 392 nasopharyngeal swab (NPS) samples collected in either healthcare or community setting. Samples were tested using two assays: FDA-EUA approved SARS-CoV-2 assay that targets N and ORF1ab gene, and the PKamp RT-PCR based assay that targets SARS-CoV-2, Influenza viruses A and B. The limit of detection (LoD) studies was conducted as per the FDA guidelines using SARS-CoV-2 and Influenza A and B reference control materials.

ResultsOf the 1019 saliva samples, 17.0% (174/1019) tested positive for SARS-CoV-2 using either assay. The detection rate for SARS-CoV-2 was higher with our multiplex assay compared to SARS-specific assay [91.9% (160/174) vs. 87.9% (153/174)], respectively. Of the 392 NPS samples, 10.4% (41/392) tested positive for SARS-CoV-2 using either assay. The detection rate for SARS-CoV-2 was higher with our multiplex assay compared to SARS-specific assay [97.5% (40/41) vs. 92.1% (39/41)], respectively. The Ct values for SARS-CoV-2 were comparable between the two assays, whereas the Ct values of the housekeeping gene was significantly lower with multiplex assay compared to SARS-specific assay. The LoD was established as 60 copies/ml for SARS-CoV-2 and 180 copies/ml for Influenza A and B viruses for both saliva and NPS samples.

ConclusionThis study presents clinical validation of a multiplex PCR assay for testing SARS-CoV-2, Influenza A and B viruses, using NPS and saliva samples, and demonstrates the feasibility of implementing the assay without disrupting the existing laboratory workflow. This novel assay uses the same instruments, sample types, supplies, and laboratory personnel as needed for the testing of SARS-CoV-2 virus.


title: Mass Testing with Contact Tracing Compared to Test and Trace for Effective Suppression of COVID-19 in the UK: A rapid review

abstract:
BackgroundMaking testing available to everyone and tracing contacts might be the gold standard towards the control of COVID-19, particularly when significant transmissions are without symptoms. This study evaluated the effectiveness of mass testing and contact tracing in the suppression of COVID-19 compared to conventional Test and Trace in the UK.

DesignA rapid review of available evidence

Primary research questionIs there evidence that mass testing and tracing could suppress community spread of SARS-CoV-2 infections better than Test and Trace?

Secondary research questionWhat is the proportion of asymptomatic cases of SARS-CoV-2 reported during mass testing interventions?

MethodsLiterature was searched in September through December 2020 in Google Scholar, ScienceDirect, Mendeley and PubMed.

ResultsLiterature search yielded 286 articles from Google Scholar, 20 from Science Direct, 14 from Mendeley, 27 from Pubmed and 15 through manual search. Altogether 35 articles were included, making a sample size of close to a million participants.

ConclusionThere was a very low level but promising evidence of 76.9% (95% CI: 46.2 - 95.0, P=0.09) majority vote in favour of the intervention under the primary objective. The overall proportion of asymptomatic cases among those tested positive and tested sample populations under the secondary objective was 40.7% (95% CI: 38.8- 42.5) and 0.01% (95% CI: 0.01 - 0.012) respectively. Conventional test and trace should be superseded by a decentralised and regular mass rapid testing and contact tracing, championed by GP surgeries and low cost community services.


title: Nasopharyngeal and serological anti SARS-CoV-2 IgG/IgA responses in COVID-19 patients.

abstract:
BackgroundThe systemic antibody responses to SARS-CoV-2 in COVID-19 patients has been extensively studied. However, much less is known about the mucosal responses in the upper airways at the site of initial SARS-CoV-2 replication. Local antibody responses in the nasopharyngeal epithelium, that are likely to determine the course of infection, have not been analysed so far nor their correlation with antibody responses in serum.

MethodsThe IgG and IgA antibody responses were analysed in the plasma as well as in nasopharyngeal swabs (NPS) from the first four COVID-19 patients confirmed by RT-qPCR in France. Two were pauci-symptomatic while two developed severe disease. Taking advantage of a comprehensive series of plasma and nasopharyngeal samples, we characterized their antibody profiles from the second week post symptoms onset, by using an in-house ELISA to detect anti-SARS-CoV-2 Nucleoprotein (N) IgG and IgA.

ResultsAnti-N IgG and IgA antibodies were detected in the NPS of severe patients. Overall, the levels of IgA and IgG antibodies in plasma and NPS appeared specific to each patient.

ConclusionsAnti-N IgG and IgA antibodies are detected in NPS, and their levels are related to antibody levels in plasma. The two patients with severe disease exhibited different antibody profiles that may reflect different disease outcome. For the pauci-symptomatic patients, one showed a low anti-N IgG and IgA response in the plasma only, while the other one did not exhibit overt serological response.


title: Understanding non-adherence to tuberculosis medications in India using urine drug metabolite testing: a cohort study

abstract:
BackgroundSuboptimal adherence to tuberculosis (TB) treatment is associated with increased disease recurrence and death. Little research has been conducted in India to understand TB medication non-adherence.

MethodsWe enrolled adult drug-susceptible TB patients, about half of whom were people living with HIV (PLHIV), in Chennai, Vellore, and Mumbai. We conducted a single unannounced home visit to administer a survey assessing reasons for non-adherence and collect a urine sample that was tested for isoniazid content. We described patient-reported reasons for non-adherence and identified factors associated with non-adherence (negative urine test) using multivariable logistic regression. We also assessed the association between non-adherence and unfavorable treatment outcomes.

ResultsOf 650 patients in the cohort, 77 (11.8%) had a negative urine test result. Non-adherence was independently associated with daily wage labor (aOR 3.1, CI: 1.3--7.7), smear-positive pulmonary disease (aOR 2.1, CI: 1.1--4.1), alcohol use (aOR 2.3, CI: 1.1--4.8), and spending 60 minutes or more picking up medication refills (aOR 9.1, CI: 1.8--45.4). PLHIV reported greater barriers to picking up medications than non-PLHIV. Among 167 patients who reported missing doses, common reasons reported included traveling away from home, forgetting, feeling depressed, and running out of pills. The odds of non-adherence was 3.8 (CI: 2.1--6.9) times higher among patients with unfavorable treatment outcomes compared to those with favorable outcomes.

ConclusionAddressing structural and psychosocial barriers will be critical to improve TB treatment adherence in India. Urine isoniazid testing may help identify non-adherent patients to facilitate early intervention during treatment.

Key pointsWe evaluated adherence to tuberculosis medications in 650 Indian patients by conducting urine isoniazid tests collected during unannounced home visits. Structural barriers to collecting medication refills and psychosocial barriers emerged as the most important factors contributing to medication non-adherence.


title: School and community reopening during the COVID-19 pandemic: a mathematical modeling study

abstract:
BackgroundThe closure of communities, including schools, has been adopted to control the coronavirus disease 2019 (COVID-19) epidemic in most countries. Operating schools safely during the pandemic requires a balance between health risks and the need for in-person learning. We use compartmental models to explore school reopening scenarios.

MethodsUsing demographic and epidemiological data between July 31 and November 23, 2020 from the city of Toronto, we developed a Susceptible-Exposed-Asymptomatic-Infectious-Recovered-Hospitalized-Isolated model. Our model with age, household, and community transmission allow us to study the impact of schools open in September 2020. The model mimics the transmission in households, the community, and schools, accounting for differences in infectiousness between adults and children and youth and adults working status. We assessed the extent to which school opening may have contributed to COVID-19 resurgence in the fall and simulated scenarios for the safe reopening of schools up to May 31, 2021. We further considered the impact of the introduction of the new variant of concern.

FindingsThough a slight increase in infections among adults (2.8%) and children (5.4%) is anticipated by the end of the year, safe school opening is possible with stringent nonpharmaceutical interventions (NPIs) decreasing the risk of transmission in the community and the household. We found that while school reopening was not the key driver in virus resurgence, but rather it was community spread that determined the outbreak trajectory, brief school closures did reduce infections when transmission risk within the home was low. When considered possible cross-infection amongst households, communities, and schools, we found that home transmission was crucial for mitigating the epidemic and safely operating schools. Simulating the introduction of a new strain with higher infectiousness, we observed substantial increases in infections, even when both schools and communities are closed.

InterpretationSchools can open safely under strict maintenance of strict public health measures in the community. The gradual opening of schools and communities can only be achieved by maintaining NPIs and mitigating household transmission risk to avoid the broader escape of infections acquired in schools into the community via households. If the new COVID-19 strain is more infectious for children, public spaces, including schools, should be closed, and additional NPIs, including the use of masks, should be extended to toddlers.

FundingThis research was supported by Canadian Institutes of Health Research (CIHR), Natural Sciences and Engineering Research Council of Canada, and York University Research Chair program.

Research in contextO_ST_ABSEvidence before this studyC_ST_ABSThe design of a gradual school reopening strategy remains at the heart of decision-making on reopening after shut-downs to control the epidemic. Although available studies have assessed the risk of school reopening by modelling the transmission across schools and communities, it remains unclear whether the risk is due to increased transmission in adults or children and youth.We used GoogleScholar and PubMed searches to identify previous published works. We used te following terms: "school closure", "covid 19 school closure", "reopening schools", "reopening screening school", "school household second wave model". The search of the studies ended in January 2021. Papers in other languages than English and letters were excluded from the search. Two modelling studies examined the effects of screening and delayed school reopening, two other agent-based modelling studies explored the epidemic spread across different age groups.

Added-value of this studyWe find that the resurgence of COVID-19 in Toronto in fall 2020 mainly resulted from the increase of contact rate among adults in the community, and that the degree of in-person attendance had the most significant impact on transmission in schools. To our knowledge, our work is the first to investigate the resurgence in infections following school reopening and the impact of risk mitigation measures in schools operation during the pandemic. Our novel and comprehensive model considers the age and household structure, but also considers three different settings, school, household and community. We further examined the effects of self-screening procedures, class size, and schooling days on transmission, which enabled us to compare scenarios of school reopening separately for both adults and children and youth, and model the cross-infection between them to avoid potential underestimation. We found that after schools opened, reducing household transmission was crucial for mitigating the epidemic since it can reduce cross-infection amongst households, communities and schools. Lastly, given the recent report of SARS-CoV-2 variant (VOC202012/01), we investigated the impact of the new variant that may be more infectious in children and youth.

Implications of all the available evidenceOur analysis can inform policymakers of planning the safe reopening of schools during COVID-19. We suggest that integrating strict NPIs and school control measures are crucial for safe reopening. When schools are open, reducing transmission risk at home and community is paramount in curbing the spread of COVID-19. Lastly, if children are more susceptible to the new COVID-19 VOC, both schools and community must be closed, the time children spend in essential services locations minimized, and NPIs for those aged less than three years enforced.


title: An optimized stepwise algorithm combining rapid antigen and RT-qPCR for screening of COVID-19 patients

abstract:
BackgroundDiagnosing SARS CoV-2 infection with certainty is essential for appropriate case management. We investigated the combination of rapid antigen detection (RAD) and RT-qPCR assays in a stepwise procedure to optimize the detection of COVID-19.

MethodsFrom August 2020 to November 2020, 43,399 patients were screened in our laboratory for COVID-19 diagnostic by RT-qPCR using nasopharyngeal swab. Overall, 4,691 of the 43,399 were found to be positive, and 200 were retrieved for RAD testing allowing comparison of diagnostic accuracy between RAD and RT-qPCR. Cycle threshold (Ct) and time from symptoms onset (TSO) were included as covariates.

ResultsThe overall sensitivity, specificity, PPV, NPV, LR-, and LR+ of RAD compared with RT- qPCR were 72% (95%CI 62%-81%), 99% (95% CI95%-100%), 99% (95%CI 93%-100%), and 78% (95%CI 70%-85%), 0.28 (95%CI 0.21-0.39), and 72 (95%CI 10-208) respectively. Sensitivity was higher for patients with Ct [≤] 25 regardless of TSO: TSO [≤] 4 days 92% (95%CI 75%-99%), TSO > 4 days 100% (95%CI 54%-100%), and asymptomatic 100% (95%CI 78-100%). Overall, combining RAD and RT-qPCR would allow reducing from only 4% the number of RT-qPCR needed.

ConclusionThis study highlights the risk of misdiagnosing COVID-19 in 28% of patients if RAD is used alone. Thus, negative results from RAD needs to be confirmed by RT-qPCR prior to making treatment decisions. A stepwise analysis that combines RAD and RT-qPCR would be an efficient screening procedure for COVID-19 detection and may facilitate the control of the outbreak.


title: Early Analysis of a potential link between viral load and the N501Y mutation in the SARS-COV-2 spike protein

abstract:
A new variant of SARS-CoV-2 has emerged which is increasing in frequency, primarily in the South East of England (lineage B.1.1.7 (1); VUI-202012/01). One potential hypothesis is that infection with the new variant results in higher viral loads, which in turn may make the virus more transmissible. We found higher (sequence derived) viral loads in samples from individuals infected with the new variant with median inferred viral loads were three-fold higher in individuals with the new variant. Most of the new variants were sampled in Kent and Greater London. We observed higher viral loads in Kent compared to Greater London for both the new variant and other circulating lineages. Outside Greater London, the variant has higher viral loads, whereas within Greater London, the new variant does not have significantly higher viral loads compared to other circulating lineages. Higher variant viral loads outside Greater London could be due to demographic effects, such as a faster variant growth rate compared to other lineages or concentration in particular age-groups. However, our analysis does not exclude a causal link between infection with the new variant and higher viral loads. This is a preliminary analysis and further work is needed to investigate any potential causal link between infection with this new variant and higher viral loads, and whether this results in higher transmissibility, severity of infection, or affects relative rates of symptomatic and asymptomatic infection

Document Description and PurposeThis is an updated report submitted to NERVTAG in December 2020 as part of urgent investigations into the new variant of SARS-COV-2 (VUI-202012/01). It makes full use of (and is restricted to) all sequence data and associated metadata available to us at the time this original report was submitted and remains provisional. Under normal circumstances more genomes and metadata would be obtained and included before making this report public. We will update this preprint when more genomes and metadata are available and before submitting for peer review.


title: Increased peripheral blood neutrophil activation phenotypes and NETosis in critically ill COVID-19 patients

abstract:
BackgroundIncreased inflammation is a hallmark of COVID-19, with pulmonary and systemic inflammation identified in multiple cohorts of patients. Definitive cellular and molecular pathways driving severe forms of this disease remain uncertain. Neutrophils, the most numerous leukocytes in blood circulation, can contribute to immunopathology in infections, inflammatory diseases and acute respiratory distress syndrome (ARDS), a primary cause of morbidity and mortality in COVID-19. Changes in multiple neutrophil functions and circulating cytokine levels over time during COVID-19 may help define disease severity and guide care and decision making.

MethodsBlood was obtained serially from critically ill COVID-19 patients for 11 days. Neutrophil oxidative burst, neutrophil extracellular trap formation (NETosis), phagocytosis and cytokine levels were assessed ex vivo. Lung tissue was obtained immediately post-mortem for immunostaining.

ResultsElevations in neutrophil-associated cytokines IL-8 and IL-6, and general inflammatory cytokines IP-10, GM-CSF, IL-1b, IL-10 and TNF, were identified in COVID-19 plasma both at the first measurement and at multiple timepoints across hospitalization (p < 0.0001). Neutrophils had exaggerated oxidative burst (p < 0.0001), NETosis (p < 0.0001) and phagocytosis (p < 0.0001) relative to controls. Increased NETosis correlated with both leukocytosis and neutrophilia. Neutrophils and NETs were identified within airways and alveoli in the lung parenchyma of 40% of SARS-CoV-2 infected lungs. While elevations in IL-8 and ANC correlated to COVID-19 disease severity, plasma IL-8 levels alone correlated with death.

ConclusionsCirculating neutrophils in COVID-19 exhibit an activated phenotype with increased oxidative burst, NETosis and phagocytosis. Readily accessible and dynamic, plasma IL-8 and circulating neutrophil function may be potential COVID-19 disease biomarkers.

category: allergy and immunology


title: Elevated Angiopoietin-2 inhibits thrombomodulin-mediated anticoagulation in critically ill COVID-19 patients

abstract: Several studies suggest that hypercoagulation and endothelial dysfunction play central roles in severe forms of COVID-19 infections. We hypothesized that the high levels of the inflammatory cytokine Angiopoietin-2 (ANGPT2) reported in hospitalized COVID-19 patients might promote hypercoagulation through ANGPT2 binding to thrombomodulin with resulting inhibition of thrombin/thrombomodulin-mediated physiological anticoagulation. Plasma was collected from critically ill COVID-19 patients treated in the intensive care unit (ICU) at Uppsala University Hospital and ANGPT2 was measured at admission (61 patients) and after ten days (40 patients). ANGPT2 levels were compared with biochemical parameters, clinical outcome, and survival. We found that ANGPT2 levels were increased in COVID-19 patients in correlation with disease severity, hypercoagulation, and mortality. To test causality, we administered ANGPT2 to wildtype mice and found that it shortened bleeding time in a tail injury model. In further support of a role for ANGPT2 in physiological coagulation, bleeding time was increased in endothelial-specific Angpt2 knockout mice. Using in vitro assays, we found that ANGPT2 inhibited thrombomodulin-mediated anticoagulation and protein C activation in human donor plasma. Our data reveal a novel mechanism for ANGPT2 in hypercoagulation and suggest that Angiopoietin-2 inhibition may be tested in the treatment of hypercoagulation in severe COVID-19 infection.

category: cardiovascular medicine


title: Mortality of Diabetes-related Acute Metabolic Emergencies in COVID-19 patients: a systematic review and meta-analysis

abstract:
PurposeLittle is known on the mortality rate in COVID-19 related acute metabolic emergencies, namely diabetic ketoacidosis (DKA), hyperglycaemic hyperosmolar state (HHS), combined DKA/HHS, and euglycaemic diabetic ketoacidosis (EDKA).

MethodsA systematic literature review was conducted using EMBASE, PubMed/Medline, and Google Scholar from January 1, 2020 to January 9, 2021 to identify all case report series, cross-sectional studies, and meta-analyses of case reports describing mortality rate in DKA, HHS, and EDKA, in COVID-19 patients. The Joanna Briggs Institute critical appraisal checklist for case reports was used for quality assessment.

ResultsFrom 313 identified publications, 4 fulfilled the inclusion criteria and analyzed qualitatively and quantitatively. A systematic review and meta-analysis with subgroup analyses examined mortality rate in a total of 152 COVID-19 patients who had developed DKA, HHS, combined DKA/HHS, or EDKA. Combined mortality rate and confidence intervals (CI) were estimated using random effects model. The study was registered to PROSPERO database (ID: 230737).

ResultsCombined mortality rate was found to be 27.1% [95% CI: 11.2-46.9%]. Heterogeneity was considerable (I2=83%; 95% CI: 56-93%), corrected to 67% according to Von Hippel adjustment for small meta-analyses. Funnel plot presented no apparent asymmetry; Eggers and Beggs test yielded in P=0.44 and P=0.50, respectively. Sensitivity analysis failed to explain heterogeneity.

ConclusionCOVID-19 related acute metabolic emergencies (DKA, HHS, and EDKA) are characterized by considerable mortality; thus, clinicians should be aware of timely detection and immediate treatment commencing.

category: endocrinology


title: Epidemiology of the early COVID-19 epidemic in Orange County, California: comparison of predictors of test positivity, mortality, and seropositivity

abstract: COVID-19 is one of the largest public health emergencies in modern history. Here we present a detailed analysis from a large population center in Southern California (Orange County, population of 3.2 million) to understand heterogeneity in risks of infection, test positivity, and death. We used a combination of datasets, including a population-representative seroprevalence survey, to assess the true burden of disease as well as COVID-19 testing intensity, test positivity, and mortality. In the first month of the local epidemic, case incidence clustered in high income areas. This pattern quickly shifted, with cases next clustering in much higher rates in the north-central area which has a lower socio-economic status. Since April, a concentration of reported cases, test positivity, testing intensity, and seropositivity in a north-central area persisted. At the individual level, several factors (e.g., age, race/ethnicity, zip codes with low educational attainment) strongly affected risk of seropositivity and death.

category: epidemiology


title: Evaluating the effects of re-opening plans on dynamics of COVID-19 in SP

abstract: Coronavirus disease 2019 (COVID-19) was declared a pandemic by the World Health Organization in early March 2020. In Brazil, Sao Paulo is the most affected state, comprising about 20% of the countrys cases. With no vaccine available to date, distancing measures have been taken to reduce virus transmission. To reduce the pandemics effect on the economy, the government of Sao Paulo has proposed a plan consisting of five phases of the gradual re-opening of activities. In this context, we have developed a mathematical model to simulate the gradual re-opening plan on the transmission dynamics of COVID-19, in the city of Sao Paulo. The model shows that a precipitous reopening can cause a higher peak of the disease, which may compromise the local health system. Waiting for the reduction in the incidence of infected individuals for at least 15 days to phase transition is the most efficient strategy compared to the fixed-period scenario at each phase of the re-opening plan.


title: Impact of COVID-19 on Care-Home Mortality and Life Expectancy in Scotland

abstract:
IntroductionCOVID-19 deaths are commoner among care-home residents, but the mortality burden has not been quantified.

MethodsCare-home residency was identified via a national primary care registration database linked to national mortality data. Life expectancy was estimated using Makeham-Gompertz models, to (i) describe yearly life expectancy from Nov 2015 to Oct 2020 (ii) compare life expectancy (during 2016-2018) between care-home residents and the wider Scottish population and (iii) apply care-home life expectancy estimates to COVID-19 death counts to estimate years of life lost (YLL).

ResultsAmong care-home residents, life expectancy in 2015/16 to 2019/20 ranged from 2.7 to 2.3 years for women and 2.3 to 1.8 years for men. Life expectancy was lowest in 2019/20. Age-sex specific life expectancy in 2016-2018 in care-home residents was lower than in the Scottish population (10 and 2.5 years in those aged 70 and 90 respectively). Rather than using national life tables, applying care-home specific life expectancies to COVID-19 deaths yields, mean YLLs for care-home residents were 2.6 and 2.2 for women and men respectively, with total care-home resident YLLs of 3,560 years in women and 2,046 years in men. In people aged over-70, approximately half of deaths and a quarter of YLL attributed to COVID-19 were accounted for by the 5% of over-70s who were care-home residents.

ConclusionPrioritising care-home residents for vaccination is justified not only in terms of total deaths, but also in terms of years of life lost.

Research in contextO_ST_ABSEvidence before this studyC_ST_ABSWe searched PubMed to 1st December 2020, with the terms ("nursing home" OR "care-home" OR "long-term care" OR "residential care") AND ("mortality" OR "life expectancy" OR "length of stay"). We also searched for studies specific to the impact of the COVID-19 pandemic on those living in care-homes. We restricted our search to publications in English. Usual care-home life expectancy, in a UK context, has not previously been defined. One systematic review of length of stay was identified, which found significant heterogeneity in factors and associations. The impact of COVID-19 on excess mortality among care-home residents was noted, but the impact on life expectancy was not reported. Studies evaluating life expectancy among older people in the COVID-19 pandemic have not taken account of residency in their estimates.

Added value of this studyUsing Scottish national representative linked data we describe the usual life expectancy of older adults (aged [≥]70 years) living in care-homes, compared to older people living elsewhere. Deaths among care-home residents account for a considerable proportion of all mortality in older adults, around 19% for men and 30% for women. Life expectancy in care-home residents during the pandemic fell by almost 6 months, from 2.7 to 2.3 years in men and 2.1 to 1.8 years in women. In total, over 5,600 Years of Life were Lost (YLL) by care-home residents in Scotland who died with COVID-19. Around half of COVID-19 deaths and a quarter of YLL in those aged 70 years and over occurred among care-home residents. During the COVID-19 pandemic a smaller proportion of deaths among care-home residents occurred in hospitals.

Implications of all the available evidencePrioritising the 5% of older adults who are care-home residents for vaccination against COVID-19 is justified both in terms of total deaths and total years of life lost. Individual and societal planning for care needs in older age relies on understanding usual care-home life expectancy and patterns of mortality. Understanding life expectancy may help clinicians, residents and their families make decisions about their health care, facilitating more informed discussions around their priorities and wishes. Population-wide estimates of YLL and burden of disease should take account of residency status, given the significant differences between life expectancy of those living in care-homes from their peers in other settings.


title: Variability of Individual Infectiousness Derived from Aggregate Statistics of COVID-19

abstract: The quantification of spreading heterogeneity in the COVID-19 epidemic is crucial as it affects the choice of efficient mitigating strategies irrespective of whether its origin is biological or social. We present a method to deduce temporal and individual variations in the basic reproduction number R directly from epidemic trajectories at a community level. Using epidemic data from the 98 districts in Denmark we estimate an overdispersion factor k for COVID-19 to be about 0.11 (95% confidence interval 0.08 - 0.18), implying that 10 % of the infected cause between 70 % to 87 % of all infections.


title: SARS-CoV-2 reinfection in a cohort of 43,000 antibody-positive individuals followed for up to 35 weeks

abstract:
BackgroundReinfection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been documented, raising public health concerns. Risk and incidence rate of SARS-CoV-2 reinfection were assessed in a large cohort of antibody-positive persons in Qatar.

MethodsAll SARS-CoV-2 antibody-positive persons with a PCR-positive swab [≥]14 days after the first-positive antibody test were individually investigated for evidence of reinfection. Viral genome sequencing was conducted for paired viral specimens to confirm reinfection. Incidence of reinfection was compared to incidence of infection in the complement cohort of those antibody-negative.

ResultsAmong 43,044 anti-SARS-CoV-2 positive persons who were followed for a median of 16.3 weeks (range: 0-34.6), 314 individuals (0.7%) had at least one PCR positive swab [≥]14 days after the first-positive antibody test. Of these individuals, 129 (41.1%) had supporting epidemiological evidence for reinfection. Reinfection was next investigated using viral genome sequencing. Applying the viral-genome-sequencing confirmation rate, the risk of reinfection was estimated at 0.10% (95% CI: 0.08-0.11%). The incidence rate of reinfection was estimated at 0.66 per 10,000 person-weeks (95% CI: 0.56-0.78). Incidence rate of reinfection versus month of follow-up did not show any evidence of waning of immunity for over seven months of follow-up. Meanwhile, in the complement cohort of 149,923 antibody-negative persons followed for a median of 17.0 weeks (range: 0-45.6), risk of infection was estimated at 2.15% (95% CI: 2.08-2.22%) and incidence rate of infection was estimated at 13.69 per 10,000 person-weeks (95% CI: 13.22-14.14). Efficacy of natural infection against reinfection was estimated at 95.2% (95% CI: 94.1-96.0%). Reinfections were less severe than primary infections. Only one reinfection was severe, two were moderate, and none were critical or fatal. Most reinfections (66.7%) were diagnosed incidentally through random or routine testing, or through contact tracing.

ConclusionsReinfection is rare. Natural infection appears to elicit strong protection against reinfection with an efficacy [~]95% for at least seven months.


title: Ethnic differences in the incidence of clinically diagnosed influenza: an England population-based cohort study 2008-2018

abstract:
We used primary and linked secondary healthcare data to investigate the incidence of clinically diagnosed influenza/influenza-like-illness (ILI) by ethnicity in England from 2008-2018. We identified higher incidence rate ratios for influenza/ILI among South Asian (1.70, 95% CI 1.66-1.75), Black (1.48, 1.44-1.53) and Mixed (1.22, 1.15-1.30) groups compared to White ethnicity.

People from ethnic minority backgrounds are represented disproportionately among patients with severe COVID-19. Recent research has found people of Black and South Asian ethnicity have increased risk of SARS-CoV-2 infection, COVID-19-related hospitalization and death, independent of deprivation, occupation, household size, and underlying health conditions(1,2).

The COVID-19 pandemic has reinforced the importance of seasonal influenza vaccination. By preventing influenza-related hospitalization, vaccination can minimize the risk of hospital-acquired COVID-19 (co-) infection for these individuals and reduce health service pressures, particularly the need for isolation of patients with respiratory symptoms awaiting COVID-19 test results.

In the UK, influenza vaccine is routinely recommended for adults aged [≥]65 years, or people <65 years with underlying health conditions. These recommendations formed the basis of the original guidance to identify patients at moderate- and high-risk of COVID-19. Influenza vaccine recommendations were expanded for the 2020/21 season to include all adults [≥]50 years(3). However, vaccine uptake among clinical risk groups is low, particularly for Black and Mixed Black ethnic groups(4). In addition, people of non-White ethnicity have higher risk of severe outcomes following influenza infection(5,6). It is unclear whether this is driven by the risk of infection or complications, with most research focused on distal outcomes rather than initial infection risk.

Here we investigate the incidence of influenza and influenza-like-illness (ILI) by ethnicity from 2008-2018 among people not eligible for routine influenza vaccination, to consider disparities in infection risk.


title: Modeling the impact of racial and ethnic disparities on COVID-19 epidemic dynamics

abstract: The impact of variable infection risk by race and ethnicity on the dynamics of SARS-CoV-2 spread is largely unknown. Here, we fit structured compartmental models to seroprevalence data from New York State and analyze how herd immunity thresholds (HITs), final sizes, and epidemic risk changes across groups. A simple model where interactions occur proportionally to contact rates reduced the HIT, but more realistic models of preferential mixing within groups increased the threshold toward the value observed in homogeneous populations. Across all models, the burden of infection fell disproportionately on minority populations: in a model fit to Long Island serosurvey and census data, 81% of Hispanics or Latinos were infected when the HIT was reached compared to 34% of non-Hispanic whites. Our findings, which are meant to be illustrative and not best estimates, demonstrate how racial and ethnic disparities can impact epidemic trajectories and result in unequal distributions of SARS-CoV-2 infection.


title: Development of at-home sample collection logistics for large scale SARS-CoV-2 seroprevalence studies

abstract:
In the midst of a pandemic, serologic studies are a valuable tool to understand the course of the outbreak and guide public health and general pandemic management. However, given significant safety constraints including social distancing and stay-at-home orders, sample collection becomes more difficult given traditional phlebotomy protocols. For such studies, a representative sample of the underlying population is paramount to elicit meaningful insights that capture the spread of the infection, particularly when different sub-populations face varying disease burden. We aimed to address these challenges by conducting a fully remote study to investigate the seroprevalence of SARS-CoV-2 in the state of Massachusetts. Leveraging electronic study engagement and at-home self-collection of finger-prick samples, we enrolled 2,066 participants representative of the ethnic and racial composition of Massachusetts. SARS-CoV-2 total IgG seropositivity was 3.15%, and follow-up measurements at days 7, 15, 45, and 90 indicate a generally durable antibody response. A higher risk of infection was observed for healthcare workers and their cohabitants and those with comorbidities, as well as lower-income, less educated, Hispanic, and those in the age groups of 18-29 and 50-59-years-old. High engagement and positive feedback from the participants and quality of self-collected specimens point to the usefulness of this design for future population-level serological studies that more effectively and safely reach a broad representative cohort, thus yielding more comprehensive insights into the burden of infection and disease in populations.

Key pointsO_ST_ABSQuestionC_ST_ABSWe aimed to implement a fully remote seroprevalence study for SARS-CoV-2, leveraging electronic methods and at-home self-collection of specimens to engage a representative study population.

FindingsThe population enrolled reflected the ethnic and racial composition of Massachusetts, revealing a SARS-CoV-2 seroprevalence of 3.15% and higher risk of previous infection associated with healthcare workers/their cohabitants, those with comorbidities, lower-income, less educated, Hispanic, and those in age groups 18-29 and 50-59 years old.

MeaningHigh engagement and positive feedback from participants as well as quality of self-collected specimens point to the usefulness of this design for future population-level serological studies.


title: Importance of patient bed pathways and length of stay differences in predicting COVID-19 bed occupancy in England

abstract:
ObjectivesPredicting bed occupancy for hospitalised patients with COVID-19 requires understanding of length of stay (LoS) in particular bed types. LoS can vary depending on the patients "bed pathway" - the sequence of transfers between bed types during a hospital stay. In this study, we characterise these pathways, and their impact on predicted hospital bed occupancy.

DesignWe obtained data from University College Hospital (UCH) and the ISARIC4C COVID-19 Clinical Information Network (CO-CIN) on hospitalised patients with COVID-19 who required care in general ward or critical care (CC) beds to determine possible bed pathways and LoS. We developed a discrete-time model to examine the implications of using either bed pathways or only average LoS by bed type to forecast bed occupancy. We compared model-predicted bed occupancy to publicly available bed occupancy data on COVID-19 in England between March and August 2020.

ResultsIn both the UCH and CO-CIN datasets, 82% of hospitalised patients with COVID-19 only received care in general ward beds. We identified four other bed pathways, present in both datasets: "Ward, CC, Ward", "Ward, CC", "CC" and "CC, Ward". Mean LoS varied by bed type, pathway, and dataset, between 1.78 and 13.53 days.

For UCH, we found that using bed pathways improved the accuracy of bed occupancy predictions, while only using an average LoS for each bed type underestimated true bed occupancy. However, using the CO-CIN LoS dataset we were not able to replicate past data on bed occupancy in England, suggesting regional LoS heterogeneities.

ConclusionsWe identified five bed pathways, with substantial variation in LoS by bed type, pathway, and geography. This might be caused by local differences in patient characteristics, clinical care strategies, or resource availability, and suggests that national LoS averages may not be appropriate for local forecasts of bed occupancy for COVID-19.


title: Do antibody positive healthcare workers have lower SARS-CoV-2 infection rates than antibody negative healthcare workers? Large multi-centre prospective cohort study (the SIREN study), England: June to November 2020

abstract:
BackgroundThere is an urgent need to better understand whether individuals who have recovered from COVID-19 are protected from future SARS-CoV-2 infection.

MethodsA large multi-centre prospective cohort was recruited from publicly funded hospital staff in the UK. Participants attended regular SARS-CoV-2 PCR and antibody testing (every 2-4 weeks) and completed fortnightly questionnaires on symptoms and exposures. At enrolment, participants were assigned to either the positive cohort (antibody positive or prior PCR/antibody test positive) or negative cohort (antibody negative, not previously known to be PCR/antibody positive). Potential reinfections were clinically reviewed and classified according to case definitions (confirmed, probable, possible (subdivided by symptom-status)) depending on hierarchy of evidence. Individuals in the primary infection were excluded from this analysis if infection was confirmed by antibody only. Reinfection rates in the positive cohort were compared against new PCR positives in the negative cohort using a mixed effective multivariable logistic regression analysis.

FindingsBetween 18 June and 09 November 2020, 44 reinfections (2 probable, 42 possible) were detected in the baseline positive cohort of 6,614 participants, collectively contributing 1,339,078 days of follow-up. This compares with 318 new PCR positive infections and 94 antibody seroconversions in the negative cohort of 14,173 participants, contributing 1,868,646 days of follow-up. The incidence density per 100,000 person days between June and November 2020 was 3.3 reinfections in the positive cohort, compared with 22.4 new PCR confirmed infections in the negative cohort. The adjusted odds ratio was 0.17 for all reinfections (95% CI 0.13-0.24) compared to PCR confirmed primary infections. The median interval between primary infection and reinfection was over 160 days.

InterpretationA prior history of SARS-CoV-2 infection was associated with an 83% lower risk of infection, with median protective effect observed five months following primary infection. This is the minimum likely effect as seroconversions were not included.

FundingDepartment of Health and Social Care and Public Health England, with contributions from the Scottish, Welsh and Northern Irish governments.


title: Direct Simulation of the CoVid-19 epidemic

abstract: AO_SCPLOWBSTRACTC_SCPLOWWe introduce an agent-based model to simulate the epidemiological dynamics of COVID-19. Most computational models proposed to study this epidemic do no take into account human mobility. We present a direct simulation model where mobility plays a key role and propose as well four quarantine strategies. The results show that the no-quarantine strategy does lead to a high peak of contagions with no rebound. Quarantined strategies, for their part, show a re-emergence of the epidemic with smaller and softer peaks.


title: Epidemiological Investigation of New SARS-CoV-2 Variant of Concern 202012/01 in England

abstract: Lighthouse Labs network tests for the presence of RNA of SARS-CoV-2, the causative agent of COVID-19. The Thermofisher TaqPath assay targets three regions of SARS-CoV-2; ORF1ab, N and S-genes. The assay identified a drop in S-gene target detection among positive samples due to the circulation of a new SARS-CoV-2 Variant of Concern (VOC) designated as 202012/01. By end of December 2020, 60% of daily positive test results at Alderley Park Lighthouse Labs, were linked to the new Variant of Concern. This timeline view identifies the rapid spread of the variant across the country.


title: Modelling the Spreading of the SARS-CoV-2 in Presence of the Lockdown and Quarantine Measures by a "Kinetic-Type Reactions" Approach

abstract: We propose a realistic model for the evolution of the COVID-19 pandemic subject to the lockdown and quarantine measures, which takes into account the time-delay for recovery or death processes. The dynamic equations for the entire process are derived by adopting a kinetic-type reactions approach. More specifically, the lockdown and the quarantine measures are modelled by some kind of inhibitor reactions where susceptible and infected individuals can be trapped into inactive states. The dynamics for the recovered people is obtained by accounting people who are only traced back to hospitalised infected people. To get the evolution equation we take inspiration from the Michaelis-Mentens enzyme-substrate reaction model (the so-called MM reaction) where the enzyme is associated to the available hospital beds, the substrate to the infected people, and the product to the recovered people, respectively. In other words, everything happens as if the hospitals beds act as a catalyzer in the hospital recovery process. Of course, in our case the reverse MM reactions has no sense in our case and, consequently, the kinetic constant is equal to zero. Finally, the O.D.E.s for people tested positive to COVID-19 is simply modelled by the following kinetic scheme S + I {Rightarrow} 2I with I {Rightarrow} R or I {Rightarrow} D, with S, I, R, and D denoting the compartments Susceptible, Infected, Recovered, and Deceased people, respectively. The resulting kinetic-type equations provide the O.D.E.s, for elementary reaction steps, describing the number of the infected people, the total number of the recovered people previously hospitalised, subject to the lockdown and the quarantine measure, and the total number of deaths. The model foresees also the second wave of Infection by Coronavirus. The tests carried out on real data for Belgium, France and Germany confirmed the correctness of our model.


title: Optimal piecewise constant vaccination and lockdown policies for COVID-19

abstract: We formulate a controlled system of ordinary differential equations, with vaccination and lockdown interventions as controls, to simulate the mitigation of COVID-19. The performance of the controls is measured through a cost functional involving vaccination and lockdown costs as well as the burden of COVID19 quantified in DALYs. We calibrate parameters with data from Mexico City and Valle de Mexico. By using differential evolution, we minimize the cost functional subject to the controlled system and find optimal policies that are constant in time intervals of a given size. The main advantage of these policies relies on its practical implementation since the health authority has to make only a finite number of different decisions. Our methodology to find optimal policies is relatively general, allowing changes in the dynamics, the cost functional, or the frequency the policymaker changes actions.


title: Bayesian Variable Selection Utilizing Posterior Probability Credible Intervals

abstract: In recent years, there has been growing interest in the problem of model selection in the Bayesian framework. Current approaches include methods based on computing model probabilities such as Stochastic Search Variable Selection (SSVS) and Bayesian LASSO and methods based on model choice criteria, such as the Deviance Information Criterion (DIC). Methods in the first group compute the posterior probabilities of models or model parameters often using a Markov Chain Monte Carlo (MCMC) technique, and select a subset of the variables based on a prespecified threshold on the posterior probability. However, these methods rely heavily on the prior choices of parameters and the results can be highly sensitive when priors are changed. DIC is a Bayesian generalization of the Akaikes Information Criterion (AIC) that penalizes for large number of parameters, it has the advantage that can be used for selection of mixed effect models but tends to prefer overparameterized models. We propose a novel variable selection algorithm that utilizes the parameters credible intervals to select the variables to be kept in the model. We show in a simulation study and a real-world example that this algorithm on average performs better than DIC and produces more parsimonious models.


title: Optimal SARS-CoV-2 vaccine allocation using real-time seroprevalence estimates in Rhode Island and Massachusetts

abstract: As three SARS-CoV-2 vaccines come to market in Europe and North America in the winter of 2020-2021, distribution networks will be in a race against a major epidemiological wave of SARS-CoV-2 that began in autumn 2020. Rapid and optimized vaccine allocation is critical during this time. With 95% efficacy reported for two of the vaccines, near-term public health needs require that distribution is prioritized to the elderly, health-care workers, teachers, essential workers, and individuals with co-morbidities putting them at risk of severe clinical progression. Here, we evaluate various age-based vaccine distributions using a validated mathematical model based on current epidemic trends in Rhode Island and Massachusetts. We allow for varying waning efficacy of vaccine-induced immunity, as this has not yet been measured. We account for the fact that known COVID-positive cases may not be included in the first round of vaccination. And, we account for current age-specific immune patterns in both states. We find that allocating a substantial proportion (> 75%) of vaccine supply to individuals over the age of 70 is optimal in terms of reducing total cumulative deaths through mid-2021. As we do not explicitly model other high mortality groups, this result on vaccine allocation applies to all groups at high risk of mortality if infected. Our analysis confirms that for an easily transmissible respiratory virus, allocating a large majority of vaccinations to groups with the highest mortality risk is optimal. Our analysis assumes that health systems during winter 2020-2021 have equal staffing and capacity to previous phases of the SARS-CoV-2 epidemic; we do not consider the effects of understaffed hospitals or unvaccinated medical staff. Vaccinating only seronegative individuals avoids redundancy in vaccine use on individuals that may already be immune, and will result in 1% to 2% reductions in cumulative hospitalizations and deaths by mid-2021. Assuming high vaccination coverage (> 28%) and no major relaxations in distancing, masking, gathering size, or hygiene guidelines between now and spring 2021, our model predicts that a combination of vaccination and population immunity will lead to low or near-zero transmission levels by the second quarter of 2021.


title: The Relationship between Chronological Age, Dental Age, and Salivary Alkaline Phosphatase in Indonesian Children Aged 8-14 Years: A Cross-Sectional Study

abstract:
BackgroundInability to predict dental age accurately has long been the Achilles heel of pediatric dentistry. Whilst dental age has an important aspect in clinical practice, saliva can be one of the most practically important diagnostic tools to estimate biological age.

AimsThis study was aimed to analyze a correlation between chronological age, dental age, and salivary alkaline phosphatase in Indonesian children aged 8-14 years.

MethodsThis study was an observational study with cross-sectional design. Twenty healthy children (10 boys; age 10.504 {+/-} 1.895 years) were selected by a consecutive sampling. Chronological age was assessed by recording date of birth. Dental age was assessed by orthopantamogram following Demirjians method. Salivary samples were collected by passive drool method and estimation of alkaline phosphatase was done by autoanalyzer.

ResultsNormality test was assessed using Kolmogorov-Smirnov and Shapiro-Wilk test. Statistical analyses were assessed using Spearmans rank-order correlation coefficients. Results are presented as mean {+/-} standard deviation (SD). Mean chronological age was10.504 {+/-} 1.895 years, mean Demirjians score was 91.74 {+/-} 5.972, and mean salivary alkaline phosphatase was 291.563 {+/-} 115.135 pg/ml. There is a very strong positive correlation between chronological age and dental age (r=+0.804; p<0.001). On the contrary, levels of salivary alkaline phosphatase was negatively correlated to dental age (r=-0.780; p<0.001) and chronological age (r=-0.508; p=0.022).

ConclusionsThis study showed a strong correlation between dental age, chronological age, and salivary alkaline phosphatase; hence, estimation of dental age and salivary alkaline phosphatase in Indonesian children during early and late childhood has significant meaning to chronological age.

category: forensic medicine


title: Machine learning approach for biopsy-based identification of eosinophilic esophagitis reveals importance of global features

abstract:
GoalEosinophilic esophagitis (EoE) is an allergic inflammatory condition characterized by eosinophil accumulation in the esophageal mucosa. EoE diagnosis includes a manual assessment of eosinophil levels in mucosal biopsies--a time-consuming, laborious task that is difficult to standardize. One of the main challenges in automating this process, like many other biopsy-based diagnostics, is detecting features that are small relative to the size of the biopsy.

ResultsIn this work, we utilized hematoxylin- and eosin-stained slides from esophageal biopsies from patients with active EoE and control subjects to develop a platform based on a deep convolutional neural network (DCNN) that can classify esophageal biopsies with an accuracy of 85%, sensitivity of 82.5%, and specificity of 87%. Moreover, by combining several downscaling and cropping strategies, we show that some of the features contributing to the correct classification are global rather than specific, local features.

ConclusionsWe report the ability of artificial intelligence to identify EoE using computer vision analysis of esophageal biopsy slides. Further, the DCNN features associated with EoE are based on not only local eosinophils but also global histologic changes. Our approach can be used for other conditions that rely on biopsy-based histologic diagnostics.

Impact StatementDeep convolutional neural network (DCNN), together with a systematic downscaling approach, can classify esophageal biopsies with high accuracy and reveals a global nature of the histologic features of eosinophilic esophagitis. Our approach of systematic analysis of the image size versus downscaling tradeoff can be used to improve disease classification performance and insight gathering in digital pathology.

category: gastroenterology


title: Multi-strain fermented milk promotes gut microbiota recovery after Helicobacter pylori therapy: a randomised, controlled trial

abstract:
BACKGROUNDHelicobacter pylori (Hp) eradication therapy can alter gut microbiota, provoking gastro-intestinal (GI) symptoms that can be improved by probiotics. The effect on Hp patients of a Test fermented milk containing yogurt and three Lacticaseibacillus (L. paracasei CNCM I-1518, CNCM I-3689, L. rhamnosus CNCM I-3690) strains was assessed on antibiotic associated diarrhea (AAD) (primary aim), GI-symptoms, gut microbiota composition and metabolites. In this aim, a randomized, double-blind, controlled trial was performed in 136 adults under Hp-treatment (14-day amoxicillin, clarithromycin, pantoprazole), who consumed the Test or a Control product for 28 days. Feces were analysed for gut microbiota composition, short chain fatty acids (SCFA), calprotectin, and viability of ingested strains.

RESULTSNo effect of Test product was observed on AAD occurrence or duration, rating scores or number of days of GI symptoms. Hp-treatment induced a significant alteration in bacterial and fungal composition, a decrease of bacterial count and alpha-diversity, an increase of Candida and of calprotectin, and a decrease of SCFA concentration. Following Hp treatment, in the Test as compared to Control group, intra-subject beta-diversity distance from baseline was lower (padj=0.02), Escherichia-Shigella (padj=0.0082) and Klebsiella (padj= 0.013) were significantly less abundant, and concentrations of major SCFA (p=0.035) and valerate (p = 0.045) were higher. Viable Lp and Lr strains from the Test product were mainly detected during product consumption in feces.

CONCLUSIONSThe study showed that 14-day Hp triple therapy alters gut bacterial and fungal community, their metabolites and gut inflammatory markers. Consumption of a multi-strain fermented milk can induce faster recovery of the microbiota composition and SCFA production and limit the bloom of pathobionts. (ClinicalTrials.gov, NCT02900196; First Posted : September 14, 2016; https://www.clinicaltrials.gov/ct2/show/NCT02900196).


title: Epidemiology and antibiotic resistance profile of Helicobacter pylori infection in Cameroon: a systematic review with meta-analysis

abstract:
ObjectivesAlthough global epidemiology of Helicobacter pylori (HP) infection is well characterized, country-specific figure is more accurate for context-specific tailored interventions. The aim was to determine the prevalence, factors associated with infection, antibiotic resistance profile, and genotypes of HP in Cameroon.

DesignA systematic review with meta-analysis.

ParticipantsPeople living in Cameroon regardless of their clinical profile.

Data sources and synthesisObservational studies published in PubMed, EMBASE, African Index Medicus, African Journals Online, and Health Sciences and Diseases up to October 12th, 2020. Study selection, data extraction, and methodological quality assessment were done by two independent authors. Random-effect meta-analysis served to pool prevalence data.

ResultsFifteen studies were included. None investigated the genotypes of HP. Among symptomatic patients, the most common used test, urea breath test on gastric biopsy, yielded a prevalence 57.8% (95% confidence interval (CI): 34.3-79.5) of HP infection. This prevalence significantly varied between 47.0% (95%CI: 43.0-51.0) for antigen test in stool samples and 71.2% (95%CI: 59.1-81.9) for Giemsa on gastric biopsy; p = 0.0006. One study in asymptomatic children reported the prevalence of 52.3% (95%CI: 44.9-59.6) using antigen test for stool samples. Among the six studies investigating factors associated with HP infection, one performed a multivariable model and identified being student as protective factor compared to being employed (Odds ratio: 0.09; 95%CI: 0.02-0.49). For antibiotics used for first line treatment, HP was resistant to amoxicillin (85.6-97.1%), metronidazole (93.2-97.9%), and clarithromycin (13.6-44.7%) as reported in two studies.

LimitationData were from six of the ten regions of Cameroon, hindering the generalizability of the findings to the country.

ConclusionThis study depicted a high prevalence of HP infection and a worrying resistance profile to first-line antibiotics. When waiting for well-conducted studies, updated guidelines are needed for clinical practice for first-line antibiotic treatment.

RegistrationPROSPERO, CRD42020220084.

Strengths and limitations of this studyO_LINot all the 10 regions of the country were represented in this study, hindering the generalizability of the findings.
C_LIO_LIWe were not able to substantially investigate sources of heterogeneity in the prevalence of Helicobacter pylori infection due to scarcity of data.
C_LIO_LIEvidence investigating factors associated with Helicobacter pylori infection are weak and there was scarcity on data exploring antibiotic resistance profile of Helicobacter pylori.
C_LIO_LIThis study is the first to provide an estimate of the epidemiology and resistance profile of Helicobacter pylori in Cameroon.
C_LI


title: Development and evaluation of rapid data-enabled access to routine clinical information to enhance early recruitment to the national clinical platform trial of COVID-19 community treatments

abstract:
BackgroundThe COVID-19 pandemic has presented unique challenges for rapidly designing, initiating, and delivering therapeutic clinical trials. PRINCIPLE is the UK national platform investigating repurposed therapies for COVID-19 treatment of older people in the community at high risk of complications. Standard methods of patient recruitment were failing to meet the required pace and scale of enrolment.

This paper describes the development and appraisal of a near real-time, data-driven, ethical approach for enhancing recruitment in community care by contacting people with a recent COVID-19 positive test result from the central NHS Test and Trace service within 24-48 hours of their test result.

MethodsA multi-disciplinary team was formed to solve the technical, ethical, public perception, logistical and information governance issues required to provide a near-real time (within 24-48 hours of receiving a positive test) feed of potential trial participants from test result data to the research team. PRINCIPLE was also given unique access to the Summary Care Record (SCR) to ensure safe prescribing, and to enable the trial team to quickly and safely bring consented patients into the trial. A survey of the public was used to understand public perceptions of the use of test data for this proposed methodology.

ResultsPrior to establishing the data service, PRINCIPLE registered on average 87 participants per week. This increased by up to 87 additional people registered per week from the test data, contributing to an increase from 1,013 recruits to PRINCIPLE at the start of October 2020 to 2,802 recruits by 20th December 2020.

While procedural caveats were identified by the public consultation, out of 2,639 people contacted by PRINCIPLE following a positive test result, no one raised a concern about being approached.

ConclusionsThis paper describes a novel approach to using near-real time NHS operational data to recruit community-based patients within a few days of presentation with acute illness.

This approach increased recruitment, and reduced time between positive test and randomisation, allowing more rapid evaluation of treatments and increased safety for participants. End-to-end public and patient involvement in the design of the approach provided evidence to inform information governance decisions.

Trial registrationPRINCIPLE is funded by UK Research and Innovation and the Department of Health and Social Care through the National Institute for Health Research.

EudraCT number: 2020-001209-22

ISRCTN registry: ISRCTN86534580

REC number: 20/SC/058

IRAS number: 281958

category: primary care research


title: Sleep disorders predict the one-year onset, persistence, but not remission of psychotic experiences in 10-11 year old children: a longitudinal analysis of the ABCD cohort data

abstract: The relationship between sleep disorder and psychotic experiences in preadolescence has not been extensively studied despite the potential for intervention. The current study addresses this relationship using the Adolescent Brain Cognitive Development (ABCD) cohort, which provides baseline data from 11,830 10 to 11-year-olds; for 4910 of these 1-year follow-up data is also available. A set of pre-registered multi-level regression models were applied to test whether a) sleep disorder is associated with psychotic experiences at baseline; b) baseline sleep disorder predicts psychotic experiences at follow-up; c) the persistence of sleep disorder predicts persistence of psychotic experiences at follow-up; d) the remission of sleep disorder predicts the remission of psychotic experiences at follow-up. After controlling for potential confounders, sleep disorder was associated with psychotic experiences cross-sectionally (OR=1.40, 95% CI 1.20-1.63), at one-year follow-up (OR=1.32, 95% CI 1.11-1.57), and the persistence of sleep disorder predicted the persistence of psychotic experiences (OR=1.72, 95% CI 1.44-2.04). However, remission of sleep problems did not predict remission of psychotic experiences (OR=1.041, 95% CI 0.80-1.35). The results indicate that sleep disorders in preadolescence are common and associated with psychotic experiences, although the lack of co-remission raises questions about the mechanism of association. However, given these findings, and existing evidence in later adolescence and adults, further investigation of sleep as a preventative mental health intervention in this age group is warranted.

category: psychiatry and clinical psychology


title: Individual level prediction of emerging suicide events in the pharmacologic treatment of bipolar disorder

abstract:
BackgroundPatients with bipolar disorder have a high lifetime risk of suicide. Predicting, preventing and managing suicidal behavior are major goals in clinical practice. Changes in suicidal thoughts and behavior are common in the course of treatment of bipolar disorder.

MethodsUsing a dataset from a randomized clinical trial of bipolar disorder treatment (N=98), we tested predictors of future suicidal behavior identified through a review of literature and applied marginal variable selection and machine learning methods. The performance of the models was assessed using the optimism-adjusted C statistic.

ResultsNumber of prior hospitalizations, number of prior suicide attempts, current employment status and Hamilton Depression Scale were identified as predictors and a simple logistic regression model was constructed. This model was compared with a model incorporating interactions with treatment group assignment, and more complex variable selection methods (LASSO and Survival Trees). The best performing models had average optimism-adjusted C-statistics of 0.67 (main effects only) and 0.69 (Survival Trees). Incorporating medication group did not improve prediction performance of the models.

ConclusionsThese results suggest that models with a few predictors may yield a clinically meaningful way to stratify risk of emerging suicide events in patients who are undergoing pharmacologic treatment for bipolar disorder.

Significance StatementThis study aims to find out whether suicide events that occur during the pharmacological treatment of bipolar disorder, a severe psychiatric disorder that is highly associated with suicide behavior, can be predicted. Using existing methods, we developed and compared several predictive models. We showed that these models performed similarly to predictive models of other outcomes, such as treatment efficacy, in unipolar and bipolar depression. This suggests that suicide events during bipolar disorder may be a feasible target for individualized interventions in the future.


title: Predicting Emerging Themes in Rapidly Expanding COVID-19 Literature with Dynamic Word Embedding Networks and Machine Learning

abstract: Evidence from peer-reviewed literature is the cornerstone for designing responses to global threats such as COVID-19. The collection of knowledge and interpretation in publications needs to be distilled into evidence by leveraging natural language in ways beyond standard meta-analysis. Several studies have focused on mining evidence from text using natural language processing, and have focused on a handful of diseases. Here we show that new knowledge can be captured, tracked and predicted using the evolution of unsupervised word embeddings and machine learning. Our approach to decipher the flow of latent knowledge in time-varying networks of word-vectors captured thromboembolic complications as an emerging theme in more than 77,000 peer-reviewed publications and more than 11,000 WHO vetted preprints on COVID-19. Furthermore, machine learning based prediction of emerging links in the networks reveals autoimmune diseases, multisystem inflammatory syndrome and neurological complications as a dominant research theme in COVID-19 publications starting March 2021.

category: public and global health


title: Impact of training modules on physicians perspective of COVID-19: An online survey

abstract:
BackgroundThe outbreak of COVID-19 has remained a massive challenge for healthcare workers specially physicians. Effective professional training has a crucial role in preparing doctors for responding to pandemics.

ObjectiveTo assess the effectiveness of existing training modules on enhancing knowledge, ensuring safe practice, and improving behavior on COVID-19 among physicians.

MethodsThis is a descriptive, cross-sectional, online survey; where a virtual questionnaire was used to collect data through online professional platforms. A pre-tested survey tool was employed to assess the impact of professional training on infection prevention and control.

ResultsTotal 161 physicians participated in this survey from 15 different countries. Most of the respondents (72%) received training from various sources like the workplace (60%) and international agencies (21%), through the in-person or online format. Knowledge assessment revealed advanced (43%) and competent (40%) understanding by the participants. Improving knowledge progression was displayed by the cohort who received professional training (p<0.00). Physicians positive behavior and good practices were observed with the training modules.

ConclusionIt became evident from this study, that professional training is effective in enhancing knowledge, improving behavior, and ensuring safe practices. Hence, designing such training modules for the physicians is warranted to tackle ongoing and future pandemics.


title: Implementing Essential Coaching for Every Mother during COVID-19: A Pilot Pre-Post Intervention Study

abstract:
ObjectivesThe primary objective was to evaluate the preliminary impact of Essential Coaching for Every Mother on self-efficacy, social support, postpartum anxiety and postpartum depression. The second objective was to explore the acceptability of the Essential Coaching for Every Mother program provided during the COVID-19 pandemic.

MethodsA prospective pre-post study was conducted with first time mothers in Nova Scotia, Canada between July 15th and September 19th, 2020. Participants completed a self-report survey at enrolment (after birth) and six-weeks postpartum. Various standardized measures were used and qualitative feedback on the program was also collected. Paired t-tests were carried out to determine changes from baseline to follow-up on psychosocial outcomes and qualitative feedback was analysed through thematic analysis.

ResultsA total of 88 women enrolled. Self-efficacy increased between baseline (B) and follow-up (F) (B:33.33; F:37.11, p=0.000) while anxiety (STAI) declined (B:38.49; F:34.79; p=0.004). In terms of acceptability, 89% of participants felt that the number of messages were just right, 84.5% felt the messages contained all the information they needed relative to caring for a newborn and 98.8% indicated they would recommend this program to other new mothers.

ConclusionEssential Coaching for Every Mother may play a role in increasing maternal self-efficacy and decreasing anxiety, although future work with a control group is needed to delineate the true effects of the program. Overall, mothers were satisfied with the Essential Coaching for Every Mother program and would recommend it for other mothers, during COVID-19 and beyond.


title: Sterilization of disposable face masks with respect to COVID-19 shortages; a nationwide field study including 19 sterilisation departments

abstract:
ObjectiveFace masks also referred to as half masks are essential to protect healthcare professionals, working in close contact with patients having Covid-19 related symptoms. During the threating deficit, healthcare institutions sought an approach to re-use face masks or to acquire imported masks. The objective of this study is to assess the quality of sterilised and imported FFP2/KN95 face mask materials.

Designprospective, bench-to-bedside

SettingGeneral healthcare including 19 hospitals in the Netherlands

InterventionsFace masks were reprocessed using a medical autoclave at 121{degrees}C.

MethodsA 48 minutes steam sterilization process of single-use face masks with 15 min holding time at a 121 {degrees}C was developed, validated and implemented in 19 different hospitals. Steam and H2O2 plasma sterilized as well as new, imported masks are tested in a custom-made, non-standard EN-149, test set-up that measures Particle Filtration Efficiency (PFE) and pressure drops.

ResultsPFE validation data of 84 masks indicated differences of 2.3{+/-}2 % (mean{+/-}SD) between the custom build test set-up and a continues flow according to the EN-149. Test data showed the mean PFE values of 444 sterilised FFP2 face masks from 19 CSSD were 90{+/-}11% (mean{+/-}SD) and of 474 imported KN95/FFP2 face masks 83{+/-}16% (mean{+/-}SD). Differences in PFE between sterilisation departments were found.

ConclusionFace masks can be reprocessed with 121 0 C steam or H2O2 plasma sterilization with minimum reduction of PFE. PFE comparison between sterilised mask and new, imported mask filter material indicates that most reprocessed masks of high quality brands outperform new imported face masks of unknown brands. Although the PFE of tested face mask material from different sterilisation departments remained efficient, different types of sterilisation equipment can result in different PFE outcomes.

Strengths and limitations of this study- Reprocessing face masks at 121 {degrees}C steam Sterilization, a simple method to be used by hospitals in times of shortages
- Laboratory findings to evaluate the safety and quality of face mask material
- The study is limited and restricted to selected FFP-2 face masks
- This study is a first of its kind in quality and safety check of the vast growing face masks, entering our markets
- The study focusses on testing environmental dry particles in a rapid test setup


title: SARS-CoV-2 infection control implementation based on sources of infection showing directions for three age groups in Japan

abstract:
BackgroundSome aspects of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission in children and adults remain unclear. This report describes different SARS-CoV-2 transmission patterns by age group in Japan.

Methods and findingsThis retrospective observational case series study analyzed transmission patterns of real-time polymerase chain reaction (RT-PCR)-confirmed SARS-CoV-2 infections found by local health authorities and commercial laboratories during January 14 through July 31, 2020 in Japan. After ascertaining the infection source for every symptomatic case as clusters at households, daycare facilities, schools, hospitals and workplaces etc., their associated transmission patterns were analyzed. Identified cases were divided into three groups: underage, < 20; adults, 20-59; and elderly people 60 years old and older. The reproductive number (R)s of respective transmission directions found for the respective age groups were compared.

Of 26,986 total cases, 23,746 unknown cases were found, leaving 3,240 ascertained sources of infection (12.0%) comprising 125 (3.9%) underage, 2350 (72.5%) adult, and 765 (23.6%) elderly people. The respective Rs of underage infection sources directed to underage, adult, and elderly people were estimated respectively as 0.0415 (95% CI, 0.0138-0.0691), 1.11 (95% CI, 0.9171-1.3226), and 0.2811 (95% CI, 0.2074-0.3687). The respective Rs of adult infection source directed to underage, adult, and elderly people were estimated respectively as 0.0140 (95% CI, 0.0120-0.0162), 0.5392 (95% CI, 0.5236-0.5550), and 0.1135 (95% CI, 0.1074-0.1197). The respective Rs of elderly infection source directed to underage, adult, and elderly people were estimated as 0.065 (95% CI, 0.0039-0.0091), 0.3264 (95% CI, 0.3059-0.3474), and 0.3991 (95% CI, 0.3757-0.4229).

ConclusionsThe main sources of SARS-CoV-2 infection were adults and elderly people. The R of underage people directed to adults was greater than 1 because of close familial contact but they were unlikely to become carriers transmitting SARS-CoV-2 because they accounted for a minority for transmissions. Apparently, SARS-CoV-2 was transmitted among adults and elderly people, suggesting that infection control of SARS-CoV-2 should be managed specifically by generation.


title: Early Stopping in Experimentation with Real-time Functional Magnetic Resonance Imaging Using the Sequential Probability Ratio

abstract:
IntroductionFunctional magnetic resonance imaging (fMRI) often involves long scanning durations to ensure the associated brain activity can be detected. However, excessive experimentation can lead to many undesirable effects, such as from learning and/or fatigue effects, discomfort for the subject, excessive motion artifacts and loss of sustained attention on task. Overly long experimentation can thus have a detrimental effect on signal quality and accurate voxel activation detection. Here, we propose dynamic experimentation with real-time fMRI using a novel statistically-driven approach that invokes early stopping when sufficient statistical evidence for assessing the task-related activation is observed.

MethodsVoxel-level sequential probability ratio test (SPRT) statistics based on general linear models (GLMs) were implemented on fMRI scans of a mathematical 1-back task from 12 healthy teenage subjects and 11 teenage subjects born extremely preterm (EPT). This approach is based on likelihood ratios and allows for systematic early stopping based on statistical error thresholds. We adopt a two-stage estimation approach that allows for accurate estimates of GLM parameters before stopping is considered. Early stopping performance is reported for different first stage lengths, and activation results are compared with full durations. Finally, group comparisons are conducted with both early stopped and full duration scan data. Numerical parallelization was employed to facilitate completion of computations involving a new scan within every repetition time (TR).

ResultsUse of SPRT demonstrates the feasibility and efficiency gains of automated early stopping, with comparable activation detection as with full protocols. Dynamic stopping of stimulus administration was achieved in around half of subjects, with typical time savings of up to 33% (4 minutes on a 12 minute scan). A group analysis produced similar patterns of activity for control subjects between early stopping and full duration scans. The EPT group, individually, demonstrated more variability in location and extent of the activations compared to the normal term control group. This was apparent in the EPT group results, reflected by fewer and smaller clusters.

ConclusionA systematic statistical approach for early stopping with real-time fMRI experimentation has been implemented. This dynamic approach has promise for reducing subject burden and fatigue effects.

category: radiology and imaging


title: Early Stopping in Experimentation with Real-time Functional Magnetic Resonance Imaging Using a Modified Sequential Probability Ratio Test


title: Susceptibility vessel sign as a predictor for recanalization and clinical outcome in acute ischaemic stroke: A Systematic Review and Meta-analysis

abstract:
T2*-weighted MRI using GRE and SWI sequences can potentially prognosticate the recanalization rate and clinical outcomes in patients with acute ischaemic stroke, using susceptibility vessel sign (SVS) and prominent hypointense vessel sign (PHVS).

A literature search on PubMed, EMBASE databases and other sources from inception up to 01 February 2020 was conducted. 15 studies which reported SVS and PHVS were included in qualitative synthesis. 9 studies on SVS were included in quantitative synthesis i.e. meta-analysis.

Meta-analysis did not show any significant difference in the recanalization rate between SVS (+) group and SVS (-) group (RR = 0.95, 95% CI = 0.87-1.05, p = 0.33). Treatment subgroup analysis (intravenous thrombolysis, IVT- or mechanical thrombectomy, MT-only) does not show significant association between the SVS and IVT-only (RR = 0.73, 95% CI = 0.51-1.05, P=0.09); or MT-only groups (RR = 0.99, 95% CI = 0.90-1.09, P=0.90). No significant association between poor clinical outcome at 3 months and presence of SVS (RR = 1.42, 95% CI = 0.79-2.57, p = 0.24). Treatment subgroup analysis revealed significant association of the SVS and poor clinical outcome at 3 months in the MT-only (RR = 0.67, 95% CI = 0.55-0.82, p = 0.0001) or no thrombolytic treatment (RR = 2.83, 95% CI = 1.69-4.75, p < 0.0001).

In conclusion, there is a significant association between the presence of SVS and poor clinical outcome in patients who underwent MT or without treatment, and no definitive association between the presence of SVS and recanalization rate for acute ischemic stroke.


title: Can prognostic factors for indirect muscle injuries in elite football (soccer) players be identified using data from preseason screening? An exploratory analysis using routinely-collected periodic health examination records.

abstract: This study used periodic health examination (PHE) data from 134 outfield elite male football players, over 5 seasons (1st July 2013 to 19th May 2018). Univariable and multivariable logistic regression models were used to determine prognostic associations between 36 variables and time-loss, lower extremity index indirect muscle injuries (I-IMIs). Non-linear associations were explored using fractional polynomials. During 317 participant-seasons, 138 I-IMIs were recorded. Univariable associations were determined for previous calf indirect muscle injury (IMI) frequency (OR=1.80, 95% confidence interval (CI) = 1.09 to 2.97), hamstring IMI frequency (OR=1.56, 95% CI=1.17 to 2.09), if the most recent hamstring IMI occurred > 12 months but < 3 years prior to PHE (OR= 2.95, 95% CI = 1.51 to 5.73) and age (OR =1.12 per 1-year increase, 95% CI = 1.06 to 1.18). Multivariable analyses demonstrated that if a players most recent previous hamstring IMI was >12 months but <3 years prior to PHE (OR= 2.24, 95% CI = 1.11 to 4.53), then this was the only variable with added prognostic value over and above age (OR=1.12 per 1-year increase, 95%CI = 1.05 to 1.18). Allowing non-linear associations conferred no advantage over linear ones. Therefore, PHE has limited use for injury risk prediction.

category: sports medicine


title: Developing research knowledge through special study module: Notes from year 2 medical students

abstract:
IntroductionSpecial Study Module is a mandatory research project implemented in some medical curriculum. For the successful application of evidence-based practice, physicians must understand research methodology before the appraisal of relevant evidence. The objective of this paper is to provide a brief overview of the effectiveness of student research modules in enhancing research understanding.

MethodsSecond-year students of undergraduate medical programs were included in this study. At the beginning and after completion of literature review type research projects, the same student cohort completed a questionnaire comprising sections on perceived competency, attitude, and knowledge on research skills. Data from 163 participants who completed both pre and post-survey were analyzed.

ResultsPaired t-test revealed significant differences in self-perceived knowledge, attitude, and assessed knowledge of the subjects before and after completing the research modules. Multivariate analysis also displayed a significant increase in self-perceived and assessed knowledge by carrying out the project. No significant association was exhibited by gender and ethnicity.

ConclusionsIn summary, the research module improved students understanding of research methodology as well as the structure of scientific communication. Further studies to assess the effect of various types of research modules in different study populations are warranted.

category: medical education


title: Knowledge of and Attitudes on Artificial Intelligence in Healthcare: A Provincial Survey Study of Medical Students

abstract:
BackgroundThere has been growing acknowledgement that undergraduate medical education (UME) must play a formal role in instructing future physicians on the promises and limitations of artificial intelligence (AI), as these tools are integrated into medical practice.

MethodsWe conducted an exploratory survey of medical students knowledge of AI, perceptions on the role of AI in medicine, and preferences surrounding the integration of AI competencies into medical education. The survey was completed by 321 medical students (13.4% response rate) at four medical schools in Ontario.

ResultsMedical students are generally optimistic regarding AIs capabilities to carry out a variety of healthcare functions, from clinical to administrative, with reservations about specific task types such as personal counselling and empathetic care. They believe AI will raise novel ethical and social challenges. Students are concerned about how AI will affect the medical job market, with 25% responding that it was actively impacting their choice of specialty. Students agree that medical education must do more to prepare them for the impact of AI in medicine (79%), and the majority (68%) believe that this training should begin at the UME level.

ConclusionsMedical students expect AI will be widely integrated into healthcare and are enthusiastic to obtain AI competencies in undergraduate medical education.


title: Medical students' perception of live lectures compared to video lectures in basic sciences medical education: a cross-sectional survey of medical colleges in Pakistan

abstract:
BackgroundLive lectures are commonly used in medical education, yet many students prefer video lectures instead. As different learning modalities may affect knowledge, it was necessary to explore medical students perspectives about the two learning modalities in Pakistan.

ObjectivesThis study aimed to explore and compare the medical students perspectives regarding live lectures and video lectures.

MethodsThis cross-sectional study used an online questionnaire. This was distributed to medical students via internet platforms after institutional approval. Data were analyzed with SPSS version 23 using descriptive statistics.

Results585 students, from 11 medical colleges across six cities of Pakistan, were enrolled. 64.4% (n=377) of the students were females, while 34.0% (n=199) were males. The first years comprised 32.7% (n=191), second years, 29.2% (n=171), and third years, 38.1% (n=223) of the total. The commonest reason for attending live lectures was  they are compulsory. The commonest reason for not attending was  poor teaching quality. 5.0% (n=29) of 585 students reported live lectures and 51.8% (n=290 of 560) found video lectures to be  very helpful in concept clarification. 85.1% (n=258) of 303 students found video lectures more effective for learning. For 45.4% (n=254) of students, video lectures improved their grades a lot; more students used video lectures for exam preparation over the years. 50.6% (n=296) of students wanted video lectures to be compulsory, compared with 28.5% (n=167) for live lectures. The main improvement in live lectures was not using slides.

ConclusionMedical students in Pakistan prefer video lectures over live lectures for learning and exam preparation. More students wanted video lectures to be compulsory in medical education. Several improvements have been suggested for live lectures.

O_TEXTBOXSummary box

Section 1: What is already known on this topic?

O_LIMedical students prefer video-based learning over attending live lectures.
C_LIO_LIThe choice of learning modality (video lectures versus live lectures) may affect knowledge and examination scores.
C_LIO_LIStudies have not compared the effectiveness of commercial video lectures (created by any individual, not necessarily affiliated with a medical college, board examination preparation company, or independent person) to live lectures.
C_LI

Section 2: What this study adds?

O_LIMedical students prefer video lectures to live lectures in basic sciences medical education and most want video lectures to be compulsory in medical education.
C_LIO_LIMedical students find video lectures more effective in concept clarification and use them more often in exam preparation and believe video lectures improve their grades.
C_LIO_LIMedical students do not want (PowerPoint) slides to be used in live lectures.
C_LI

C_TEXTBOX


title: Combinatorial clinically driven blood biomarker functional genomics significantly enhances genotype-phenotype resolution and diagnostics in neuromuscular disease

abstract:
Purpose50-60% of neuromuscular-disease patients remain undiagnosed even after extensive genetic testing that hinders precision-medicine/clinical-trial-enrollment. Importantly, those with DNA-based molecular diagnosis often remain without known molecular mechanism driving different degrees of disease severity that hinders patient stratification and trial-readiness. These are due to: a) clinical-genetic-heterogeneity (eg: limb-girdle-muscular-dystrophies(LGMDs)>30-subtypes); b) high-prevalence of variants-of-uncertain-significance (VUSs); (c) unresolved genotype-phenotype-correlations for patient stratification, and (d) lack of minimally-invasive biomarker-driven-assays. We therefore implemented a combinatorial phenotype-driven blood-biomarker functional-genomics approach to enhance diagnostics and trial-readiness by elucidating disease mechanisms of a neuromuscular-disease patient-cohort clinically-suspected of Dysferlinopathy/related-LGMD, the second-most-prevalent LGMD in the US.

MethodsWe used CD14+monocyte protein-expression-assay on 364 Dysferlinopathy/related-LGMD-suspected patient-cohort without complete molecular-diagnosis or genotype-phenotype correlation; and then combined with blood-based targeted-transcriptome-sequencing (RNA-Seq) with tiered-analytical-algorithm correlating with clinical-measurements for a subset of patients.

ResultsOur combinatorial-approach significantly increased the diagnostic-yield from 25% (N=326; 18%-27%; 95%CI) to 82% (N=38; 69.08% to 84.92%; 95% CI) by combining monocyte-assay with enhanced-RNA-Seq-analysis and clinical-correlation, following ACMG-AMP-guidelines. The tiered-analytical-approach detected aberrant-splicing, allele-expression-imbalance, nonsense-mediated-decay, and compound-heterozygosity without parental/offspring-DNA-testing, leading to VUS-reclassifications, identification of variant-pathomechanisms, and enhanced genotype-phenotype resolution including those with carrier-range Dysferlin-protein-expression and milder-symptoms, allowing patient-stratification for better trial-readiness. We identified uniform-distribution of pathogenic-variants across DYSF-gene-domains without any hotspot suggesting the relevance of upcoming gene-(full-DYSF-cDNA)-therapy trials.

ConclusionOur results show the relevance of using a clinically-driven multi-tiered-approach utilizing a minimally-invasive biomarker-functional-genomic platform for precision-medicine-diagnostics, trial-recruitment/monitoring, elucidating pathogenic-mechanisms for patient stratification to enhance better trial outcomes, which in turn, will guide more rational use of current-therapeutics and development of novel-interventions for neuromuscular-disorders, and applicable to other genetic-disorders.

category: neurology


title: Vaginal bacterial load in the second trimester is associated with early preterm birth recurrence: a nested case-control study

abstract:
ObjectiveTo assess the association between vaginal microbiome (VMB) composition and recurrent early spontaneous preterm birth (sPTB)/preterm prelabour rupture of membranes (PPROM).

DesignNested case-control study.

SettingUK tertiary referral hospital.

SampleHigh-risk women with previous sPTB/PPROM <34+0 weeks gestation who had a recurrence (n=22) or delivered at [≥]37+0 weeks without PPROM (n=87).

MethodsVaginal swabs collected between 15-22 weeks gestation were analysed by 16S rRNA gene sequencing and 16S quantitative PCR.

Main outcome measureRecurrent early sPTB/PPROM.

Results28/109 high-risk women had anaerobic vaginal dysbiosis, with the remainder dominated by lactobacilli (L. iners 36/109, L. crispatus 23/109, or other 22/109). VMB type, diversity, and stability were not associated with recurrence. Women with a recurrence, compared to those without, had a higher median vaginal bacterial load (8.64 vs. 7.89 log10 cells/l, adjusted odds ratio (aOR)=1.90, 95% confidence interval (CI)=1.01-3.56, p=0.047) and estimated Lactobacillus concentration (8.59 vs. 7.48 log10 cells/l, aOR=2.35, CI=1.20-4.61, p=0.013). A higher recurrence risk was associated with higher median bacterial loads for each VMB type after stratification, although statistical significance was reached only for L. iners-domination (aOR=3.44, CI=1.06-11.15, p=0.040). Women with anaerobic dysbiosis or L. iners-domination had a higher median vaginal bacterial load than women with a VMB dominated by L. crispatus or other lactobacilli (8.54, 7.96, 7.63, and 7.53 log10 cells/l, respectively).

ConclusionsVaginal bacterial load is associated with early sPTB/PPROM recurrence. Domination by lactobacilli other than L. iners may protect women from developing high bacterial loads. Future PTB studies should quantify vaginal bacteria and yeasts.

FundingWellbeing of Women, London, UK

Tweetable abstractIncreased vaginal bacterial load in the second trimester may be associated with recurrent early spontaneous preterm birth.

category: obstetrics and gynecology