Leveraging Serosurveillance and Postmortem Surveillance to Quantify the Impact of Coronavirus Disease 2019 in Africa.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has had a devastating impact on global health, the magnitude of which appears to differ intercontinentally: For example, reports suggest that 271 900 per million people have been infected in Europe versus 8800 per million people in Africa. While Africa is the second-largest continent by population, its reported COVID-19 cases comprise <3% of global cases. Although social and environmental explanations have been proposed to clarify this discrepancy, systematic underascertainment of infections may be equally responsible. METHODS: We sought to quantify magnitudes of underascertainment in COVID-19's cumulative incidence in Africa. Using serosurveillance and postmortem surveillance, we constructed multiplicative factors estimating ratios of true infections to reported cases in Africa since March 2020. RESULTS: Multiplicative factors derived from serology data (subset of 12 nations) suggested a range of COVID-19 reporting rates, from 1 in 2 infections reported in Cape Verde (July 2020) to 1 in 3795 infections reported in Malawi (June 2020). A similar set of multiplicative factors for all nations derived from postmortem data points toward the same conclusion: Reported COVID-19 cases are unrepresentative of true infections, suggesting that a key reason for low case burden in many African nations is significant underdetection and underreporting. CONCLUSIONS: While estimating the exact burden of COVID-19 is challenging, the multiplicative factors we present furnish incidence estimates reflecting likely-to-worst-case ranges of infection. Our results stress the need for expansive surveillance to allocate resources in areas experiencing discrepancies between reported cases, projected infections, and deaths.

An early warning approach to monitor COVID-19 activity with multiple digital traces in near real time.

Given still-high levels of coronavirus disease 2019 (COVID-19) susceptibility and inconsistent transmission-containing strategies, outbreaks have continued to emerge across the United States. Until effective vaccines are widely deployed, curbing COVID-19 will require carefully timed nonpharmaceutical interventions (NPIs). A COVID-19 early warning system is vital for this. Here, we evaluate digital data streams as early indicators of state-level COVID-19 activity from 1 March to 30 September 2020. We observe that increases in digital data stream activity anticipate increases in confirmed cases and deaths by 2 to 3 weeks. Confirmed cases and deaths also decrease 2 to 4 weeks after NPI implementation, as measured by anonymized, phone-derived human mobility data. We propose a means of harmonizing these data streams to identify future COVID-19 outbreaks. Our results suggest that combining disparate health and behavioral data may help identify disease activity changes weeks before observation using traditional epidemiological monitoring.

An Early Warning Approach to Monitor COVID-19 Activity with Multiple Digital Traces in Near Real-Time.

Non-pharmaceutical interventions (NPIs) have been crucial in curbing COVID-19 in the United States (US). Consequently, relaxing NPIs through a phased re-opening of the US amid still-high levels of COVID-19 susceptibility could lead to new epidemic waves. This calls for a COVID-19 early warning system. Here we evaluate multiple digital data streams as early warning indicators of increasing or decreasing state-level US COVID-19 activity between January and June 2020. We estimate the timing of sharp changes in each data stream using a simple Bayesian model that calculates in near real-time the probability of exponential growth or decay. Analysis of COVID-19-related activity on social network microblogs, Internet searches, point-of-care medical software, and a metapopulation mechanistic model, as well as fever anomalies captured by smart thermometer networks, shows exponential growth roughly 2-3 weeks prior to comparable growth in confirmed COVID-19 cases and 3-4 weeks prior to comparable growth in COVID-19 deaths across the US over the last 6 months. We further observe exponential decay in confirmed cases and deaths 5-6 weeks after implementation of NPIs, as measured by anonymized and aggregated human mobility data from mobile phones. Finally, we propose a combined indicator for exponential growth in multiple data streams that may aid in developing an early warning system for future COVID-19 outbreaks. These efforts represent an initial exploratory framework, and both continued study of the predictive power of digital indicators as well as further development of the statistical approach are needed.

Human Cancers Express TRAILshort, a Dominant Negative TRAIL Splice Variant, Which Impairs Immune Effector Cell Killing of Tumor Cells.

PURPOSE: TNF-related apoptosis inducing ligand (TRAIL) expression by immune cells contributes to antitumor immunity. A naturally occurring splice variant of TRAIL, called TRAILshort, antagonizes TRAIL-dependent cell killing. It is unknown whether tumor cells express TRAILshort and if it impacts antitumor immunity. EXPERIMENTAL DESIGN: We used an unbiased informatics approach to identify TRAILshort expression in primary human cancers, and validated those results with IHC and ISH. TRAILshort-specific mAbs were used to determine the effect of TRAILshort on tumor cell sensitivity to TRAIL, and to immune effector cell dependent killing of autologous primary tumors. RESULTS: As many as 40% of primary human tumors express TRAILshort by both RNA sequencing and IHC analysis. By ISH, TRAILshort expression is present in tumor cells and not bystander cells. TRAILshort inhibition enhances cancer cell lines sensitivity to TRAIL-dependent killing both in vitro and in immunodeficient xenograft mouse models. Immune effector cells isolated from patients with B-cell malignancies killed more autologous tumor cells in the presence compared with the absence of TRAILshort antibody (P < 0.05). CONCLUSIONS: These results identify TRAILshort in primary human malignancies, and suggest that TRAILshort blockade can augment the effector function of autologous immune effector cells.See related commentary by de Miguel and Pardo, p. 5546.

HIV elite control is associated with reduced TRAILshort expression.

OBJECTIVE: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) dependent apoptosis has been implicated in CD4 T-cell death and immunologic control of HIV-1 infection. We have described a splice variant called TRAILshort, which is a dominant negative ligand that antagonizes TRAIL-induced cell death in the context of HIV-1 infection. HIV-1 elite controllers naturally control viral replication for largely unknown reasons. Since enhanced death of infected cells might be responsible, as might occur in situations of low (or inhibited) TRAILshort, we tested whether there was an association between elite controller status and reduced levels of TRAILshort expression. DESIGN: Cohort study comparing TRAILshort and full length TRAIL expression between HIV-1 elite controllers and viremic progressors from two independent populations. METHODS: TRAILshort and TRAIL gene expression in peripheral blood mononuclear cells (PBMCs) was determined by RNA-seq. TRAILshort and TRAIL protein expression in plasma was determined by antibody bead array and proximity extension assay respectively. RESULTS: HIV-1 elite controllers expressed less TRAILshort transcripts in PBMCs (P = 0.002) and less TRAILshort protein in plasma (P < 0.001) than viremic progressors. CONCLUSION: Reduced TRAILshort expression in PBMCs and plasma is associated with HIV-1 elite controller status.

Wet Markets and Food Safety: TripAdvisor for Improved Global Digital Surveillance.

BACKGROUND: Wet markets are markets selling fresh meat and produce. Wet markets are critical for food security and sustainable development in their respective regions. Due to their cultural significance, they attract numerous visitors and consequently generate tourist-geared information on the Web (ie, on social networks such as TripAdvisor). These data can be used to create a novel, international wet market inventory to support epidemiological surveillance and control in such settings, which are often associated with negative health outcomes. OBJECTIVE: Using social network data, we aimed to assess the level of wet markets' touristic importance on the Web, produce the first distribution map of wet markets of touristic interest, and identify common diseases facing visitors in these settings. METHODS: A Google search was performed on 31 food market-related keywords, with the first 150 results for each keyword evaluated based on their relevance to tourism. Of all these queries, wet market had the highest number of tourism-related Google Search results; among these, TripAdvisor was the most frequently-occurring travel information aggregator, prompting its selection as the data source for this study. A Web scraping tool (ParseHub) was used to extract wet market names, locations, and reviews from TripAdvisor. The latter were searched for disease-related content, which enabled assignment of GeoSentinel diagnosis codes to each. This syndromic categorization was overlaid onto a mapping of wet market locations. Regional prevalence of the most commonly occurring symptom group - food poisoning - was then determined (ie, by dividing the number of wet markets per continent with more than or equal to 1 review containing this syndrome by the total number of wet markets on that continent with syndromic information). RESULTS: Of the 1090 hits on TripAdvisor for wet market, 36.06% (393/1090) conformed to the query's definition; wet markets were heterogeneously distributed: Asia concentrated 62.6% (246/393) of them, Europe 19.3% (76/393), North America 7.9% (31/393), Oceania 5.1% (20/393), Africa 3.1% (12/393), and South America 2.0% (8/393). Syndromic information was available for 14.5% (57/393) of wet markets. The most frequently occurring syndrome among visitors to these wet markets was food poisoning, accounting for 54% (51/95) of diagnoses. Cases of this syndrome were identified in 56% (22/39) of wet markets with syndromic information in Asia, 71% (5/7) in Europe, and 71% (5/7) in North America. All wet markets in South America and Oceania reported food poisoning cases, but the number of reviews with syndromic information was very limited in these regions (n=2). CONCLUSIONS: The map produced illustrates the potential role of touristically relevant social network data to support global epidemiological surveillance. This includes the possibility to approximate the global distribution of wet markets and to identify diseases (ie, food poisoning) that are most prevalent in such settings.

Cis-acting elements in its 3' UTR mediate post-transcriptional regulation of KRAS.

Multiple RNA-binding proteins and non-coding RNAs, such as microRNAs (miRNAs), are involved in post-transcriptional gene regulation through recognition motifs in the 3' untranslated region (UTR) of their target genes. The KRAS gene encodes a key signaling protein, and its messenger RNA (mRNA) contains an exceptionally long 3' UTR; this suggests that it may be subject to a highly complex set of regulatory processes. However, 3' UTR-dependent regulation of KRAS expression has not been explored in detail. Using extensive deletion and mutational analyses combined with luciferase reporter assays, we have identified inhibitory and stabilizing cis-acting regions within the KRAS 3' UTR that may interact with miRNAs and RNA-binding proteins, such as HuR. Particularly, we have identified an AU-rich 49-nt fragment in the KRAS 3' UTR that is required for KRAS 3' UTR reporter repression. This element contains a miR-185 complementary element, and we show that overexpression of miR-185 represses endogenous KRAS mRNA and protein in vitro. In addition, we have identified another 49-nt fragment that is required to promote KRAS 3' UTR reporter expression. These findings indicate that multiple cis-regulatory motifs in the 3' UTR of KRAS finely modulate its expression, and sequence alterations within a binding motif may disrupt the precise functions of trans-regulatory factors, potentially leading to aberrant KRAS expression.