The evolving SARS-CoV-2 epidemic in Africa: Insights from rapidly expanding genomic surveillance

INTRODUCTION Investment in Africa over the past year with regard to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sequencing has led to a massive increase in the number of sequences, which, to date, exceeds 100,000 sequences generated to track the pandemic on the continent. These sequences have profoundly affected how public health officials in Africa have navigated the COVID-19 pandemic. RATIONALE We demonstrate how the first 100,000 SARS-CoV-2 sequences from Africa have helped monitor the epidemic on the continent, how genomic surveillance expanded over the course of the pandemic, and how we adapted our sequencing methods to deal with an evolving virus. Finally, we also examine how viral lineages have spread across the continent in a phylogeographic framework to gain insights into the underlying temporal and spatial transmission dynamics for several variants of concern (VOCs). RESULTS Our results indicate that the number of countries in Africa that can sequence the virus within their own borders is growing and that this is coupled with a shorter turnaround time from the time of sampling to sequence submission. Ongoing evolution necessitated the continual updating of primer sets, and, as a result, eight primer sets were designed in tandem with viral evolution and used to ensure effective sequencing of the virus. The pandemic unfolded through multiple waves of infection that were each driven by distinct genetic lineages, with B.1-like ancestral strains associated with the first pandemic wave of infections in 2020. Successive waves on the continent were fueled by different VOCs, with Alpha and Beta cocirculating in distinct spatial patterns during the second wave and Delta and Omicron affecting the whole continent during the third and fourth waves, respectively. Phylogeographic reconstruction points toward distinct differences in viral importation and exportation patterns associated with the Alpha, Beta, Delta, and Omicron variants and subvariants, when considering both Africa versus the rest of the world and viral dissemination within the continent. Our epidemiological and phylogenetic inferences therefore underscore the heterogeneous nature of the pandemic on the continent and highlight key insights and challenges, for instance, recognizing the limitations of low testing proportions. We also highlight the early warning capacity that genomic surveillance in Africa has had for the rest of the world with the detection of new lineages and variants, the most recent being the characterization of various Omicron subvariants. CONCLUSION Sustained investment for diagnostics and genomic surveillance in Africa is needed as the virus continues to evolve. This is important not only to help combat SARS-CoV-2 on the continent but also because it can be used as a platform to help address the many emerging and reemerging infectious disease threats in Africa. In particular, capacity building for local sequencing within countries or within the continent should be prioritized because this is generally associated with shorter turnaround times, providing the most benefit to local public health authorities tasked with pandemic response and mitigation and allowing for the fastest reaction to localized outbreaks. These investments are crucial for pandemic preparedness and response and will serve the health of the continent well into the 21st century

Biological variation of cardiac markers in patients with aortic valve stenosis

Objective Cardiac biomarkers hold promise for followup and management of aortic valve stenosis (AVS). When interpreting serial biomarker measurements of patients with AVS, it can be challenging to distinguish 'real changes' from 'random fluctuation'. Hence, robust estimation of the biological variation of these biomarkers is essential. In the present study we assessed biological variation of B-type natriuretic peptide (BNP), N-terminus pro-brain natriuretic peptide (NT-proBNP), high-sensitivity troponin-T and high-sensitivity troponin-I (hs-TnT and hsTnI), and ST2 in subjects with stable AVS. Methods Serial blood sampling was performed in 25 subjects with moderate AVS-confirmed by echocardiography-and all free from acute cardiovascular events in the past 6 months. Blood samples were taken on seven standardised occasions during 1 year. Analytical variation (CV A), within-subject biological variation (CV I), between-subject biological variation (CV G), index of individuality (II) and reference change values were calculated for all cardiac biomarkers. Results CV I was highest for BNP (62.0%, 95% CI 52.5 to 75.4) and lowest for hs-TnI (9.2%, 95% CI 2.8 to 13.8). CV G exceeded the CV I for all biomarkers except BNP, and ranged from 19.8% (95% CI 13.8 to 33.4) for ST2 to 57.2% (95% CI 40.4 to 97.3) for hs-TnT. NT-proBNP, hsTnT and ST2 revealed CV A <5%, while BNP and hs-TnI showed a higher CV A (19.7 and 14.9, respectively). All biomarkers except BNP showed marked individuality, with II ranging from 0.21 to 0.67 (BNP 1.34). Conclusion This study provides the first biological variation estimates of cardiac biomarkers in patients with stable AVS. These estimates allow a more evidence-based interpretation of biomarker changes in the follow-up and management of patients with AVS

Sexual function after treatment for sacrococcygeal teratoma during childhood

Background: Children treated for sacrococcygeal teratoma (SCT) may suffer from sexual dysfunction later in life because of the extended pelvic surgery performed, however, structured evaluations have not been performed yet. Methods: The Female Sexual Function Index (FSFI), the International Index of Erectile Function (IIEF) and the Body Image Questionnaire (BIQ) were sent to patients (>= 18 years) treated for SCT in the Dutch pediatric surgical centers after 1970. Results: Forty-five of 76 patients returned the questionnaires; 28 women (median age 27.3 years, range 18.3-41.0) and seven men (median age 22.0 years, range 19.1-36.5) were eligible for analysis. The FSFI and IIEF results were compared to healthy controls. Female patients scored significantly lower on the desire (p=0.014), arousal (p=0.013) and lubrication domain (p=0.019). FSFI total-scores of female patients were significantly lower compared to controls [median 30.5 (IQR 28.6-31.4) vs. median 32.4 (IQR 30.6-33.45) p Conclusion: SCT resection in girls may result in diminished sexual function at adult age with worse self-perceived body image. The possibility of sexual complaints should be integrated in the surveillance strategies for these patients. (C) 2016 Elsevier Inc. All rights reserved

EGFRvIII expression triggers a metabolic dependency and therapeutic vulnerability sensitive to autophagy inhibition

<p>Expression of EGFRvIII is frequently observed in glioblastoma and is associated with increased cellular proliferation, enhanced tolerance to metabolic stresses, accelerated tumor growth, therapy resistance and poor prognosis. We observed that expression of EGFRvIII elevates the activation of macroautophagy/autophagy during starvation and hypoxia and explored the underlying mechanism and consequence. Autophagy was inhibited (genetically or pharmacologically) and its consequence for tolerance to metabolic stress and its therapeutic potential in (EGFRvIII⁺) glioblastoma was assessed in cellular systems, (patient derived) tumor xenopgrafts and glioblastoma patients. Autophagy inhibition abrogated the enhanced proliferation and survival advantage of EGFRvIII⁺ cells during stress conditions, decreased tumor hypoxia and delayed tumor growth in EGFRvIII⁺ tumors. These effects can be attributed to the supporting role of autophagy in meeting the high metabolic demand of EGFRvIII⁺ cells. As hypoxic tumor cells greatly contribute to therapy resistance, autophagy inhibition revokes the radioresistant phenotype of EGFRvIII⁺ tumors in (patient derived) xenograft tumors. In line with these findings, retrospective analysis of glioblastoma patients indicated that chloroquine treatment improves survival of all glioblastoma patients, but patients with EGFRvIII⁺ glioblastoma benefited most. Our findings disclose the unique autophagy dependency of EGFRvIII⁺ glioblastoma as a therapeutic opportunity. Chloroquine treatment may therefore be considered as an additional treatment strategy for glioblastoma patients and can reverse the worse prognosis of patients with EGFRvIII⁺ glioblastoma.</p