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

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Comparison of the Protective Effects of Nebivolol and Metoprolol against LPS-Induced Injury in H9c2 Cardiomyoblasts

Here, we, for the first time, compared the cardioprotective effects of third-generation vasodilating beta-blocker nebivolol (Neb) and conventional beta-blocker metoprolol (Met) on LPS-induced injury in H9c2 cardiomyoblasts. Our findings denoted that Neb and Met pretreatment diminish LPS-mediated cytotoxicity and oxidative stress. Concomitantly, LPS-triggered inflammatory cytokines activation was significantly suppressed by Neb but not by Met. Pretreatment with either Neb or Met alleviated LPS-mediated mitochondrial impairment by enhancing the expression of genes related to its biogenesis such as PGC-1α, NRF1, and TFAM. On the contrary, Neb but not Met-upregulated mitochondrial fusion-related genes such as OPA, and MFN2. In summary, our findings suggest that Neb and Met treatment significantly ameliorated the LPS-induced cytotoxicity and oxidative stress. Additionally, these findings suggest that Neb but not Met significantly down-regulates LPS-induced proinflammatory factors, probably by enhancing mitochondrial biogenesis and fusion

Alkaloids and flavone acyl glycosides from Acanthus arboreus

Phytochemical study of Acanthus arboreus resulted in the isolation of three novel alkaloids: 6-hydroxy-benzoxazolinone, 4-hydroxyacanthamine and acanthaminoside. In addition, a new acyl flavonoid apigenin-7-O-beta-D-(6"-trans-p -coumaroyl)-3"-O-acetyl glucopyranoside was also isolated. The known compounds were identified as apigenin, apigenin-7- O-beta-D-(6"-trans-p-coumaroyl) -glucoside, vanillic acid, lupeol, stigmasterol and sitosterol glucoside. The structures were determined by physical, chemical and spectral techniques

Avocado Seeds-Mediated Alleviation of Cyclosporine A-Induced Hepatotoxicity Involves the Inhibition of Oxidative Stress and Proapoptotic Endoplasmic Reticulum Stress

Previous studies reported disrupted hepatic function and structure following the administration of cyclosporine A (CsA) in humans and animals. Recently, we found that avocado seeds (AvS) ameliorated CsA-induced nephrotoxicity in rats. As a continuation, herein we checked whether AvS could also attenuate CsA-induced hepatotoxicity in rats. Subcutaneous injection of CsA (5 mg/kg) for 7 days triggered hepatotoxicity in rats, as indicated by liver dysfunction, redox imbalance, and histopathological changes. Oral administration of 5% AvS powder for 4 weeks ameliorated CsA-induced hepatotoxicity, as evidenced by (1) decreased levels of liver damage parameters (alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and bilirubin), (2) resumed redox balance in the liver (reduced malondialdehyde (MDA) and increased superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx)), (3) downregulated hepatic expression of endoplasmic reticulum (ER) stress-related genes (X-box binding protein 1 (XBP1), binding immunoglobulin protein (BIP), C/EBP homologous protein (CHOP)), and apoptosis-related genes (Bax and Casp3), (4) upregulated expression of the anti-apoptotic gene Bcl2, (5) reduced DNA damage, and (6) improved liver histology. These results highlight the ability of AvS to ameliorate CsA-induced hepatotoxicity via the inhibition of oxidative stress and proapoptotic ER stress

Potential Effect of Biochar on Soil Properties, Microbial Activity and <i>Vicia faba</i> Properties Affected by Microplastics Contamination

Microplastics (MPs) contamination is an emerging issue globally; however, adverse impacts of MPs on soil, plants and microbial activity have not been intensively studied. In this study, the potential effect of different levels of MPs (1.5, 7.5, 15%) has been investigated on soil properties, plant properties (Vicia Faba) and microbial activities through a pot experiment. The effect of biochar (BC: 2%) to mitigate the adverse effects of MP has also been examined. Soil properties (pH, EC, OM, CaCO3 and some elements) have significantly differed due to contamination of soil by MPs as well as by adding BC to the soil. The pH and CaCO3 were significantly increased more than in the control, while EC, TDS, available P, Mn and Fe were significantly decreased lower than the control, which implies adsorption on microplastic. Plant properties, such as enzymes, chlorophyll and fresh and dry weight in roots, were adversely affected by MPs contamination; however, BC mitigated this effect, especially with low contamination levels of MPs. The fresh and dry weight of the shoot was not significantly affected by MPs. The cytogenetic analysis showed that the mitotic index was significantly reduced compared to the control (9.39%), while BC increased the mitotic index at 1.5% MPs (7.11%) although it was less than the control. The percentage of abnormalities of V. faba root tip cells under different levels of MPs was significantly increased more than the control; however, BC mitigated this effect, especially at 7.5% MPs. The total count of bacteria and fungi even in soil or in the rhizosphere area did not follow a clear trend; however, the effect of BC was clear in increasing their activities. Microbial biomass carbon and nitrogen were also significantly affected by MPs and BC. In this study, the BC level was low, however, it mitigated some adverse effects of MPs, especially at 1.5 and 7.5% of MPs. Thus, the BC could be promising in mitigating the negative impacts of MPs when applied with suitable levels that need more future studies

Real-World Outcomes of Brexucabtagene Autoleucel (Brexu-cel) for Relapsed or Refractory (R/R) Mantle Cell Lymphoma (MCL): A CIBMTR Subgroup Analysis of High-Risk Characteristics

Background: Patients (pts) with R/R MCL and TP53 mutation/deletion, or high Ki-67 proliferation index (PI), have historically had limited treatment options with dismal outcomes. Brexu-cel is a CAR T-cell therapy approved in the US for adults with R/R MCL. Real-world data has been consistent with that of clinical trials (Kambhampati et al. 2023). In a 3-year follow-up of ZUMA-2 (Wang et al. 2022), outcomes were comparable across various high-risk subgroups (TP53 mutation, Ki-67 PI ≥ 30% or ≥ 50%). Here, we describe real-world outcomes of brexu-cel in R/R MCL by high-risk features, including deletion of TP53 or 17p, Ki-67 PI, and by ZUMA-2 eligibility. Methods : A total of 500 pts receiving brexu-cel for R/R MCL from 84 US centers between 07/2020−12/2022 were prospectively enrolled in the CIBMTR observational database for a post-authorization safety study. In this analysis, 446 pts were included, excluding pts with prior non-transplant cellular therapy, missing data for analysis, or no follow-up. Effectiveness outcomes were overall response rate (ORR), complete response (CR) rate, duration of response (DOR), progression-free survival (PFS), overall survival (OS) and relapse/progressive disease (REL/PD). Safety outcomes included cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), prolonged cytopenias, infections requiring treatment, subsequent neoplasms, and non-relapse mortality (NRM). Analyses conducted included univariate as well as multivariate logistic regression and Cox proportional hazard models fit to identify covariates with an impact on outcomes. Results : Of the 446 pts included and who had available data, 20% (44/220) had deletion of TP53/17p at diagnosis; Ki-67 PI ≥ 50% at diagnosis was seen in 42% (107/252). Pts with deletion of TP53/17p were less likely to undergo prior autologous hematopoietic cell transplant (11% vs 30%). Pts with Ki-67 PI ≥ 50% were more likely to receive Bruton's tyrosine kinase inhibitor (BTKi) (92% vs 81%) and bridging therapy (52% vs 37%), but less likely to receive bendamustine (47% vs 62%). Pts with either high-risk feature tended to have a shorter time from diagnosis to brexu-cel infusion. Overall, 67% (297/446) of pts would not have met ZUMA-2 eligibility criteria, mainly due to pulmonary impairment (33%), cardiac impairment (21%), prior malignancy (21%), low platelet count (20%), and no prior BTKi (18%). With a median follow-up of 12.2 mo, DOR, PFS and OS were evaluated at 12 mo. CR was 84% (ORR, 95%; DOR, 46%; PFS, 54%; OS, 55%) for pts with deletion of TP53/17p vs 80% (ORR, 90%; DOR, 65%; PFS, 61%; OS, 77%) in those without. CR for pts with Ki-67 PI ≥ 50% vs < 50% was 84% (ORR, 93%; DOR, 60%; PFS, 58%; OS, 77%) vs 83% (ORR, 92%; DOR, 69%; PFS, 63%; OS, 73%); for pts eligible vs ineligible to ZUMA-2, CR was 84% (ORR, 92%; DOR, 73%; PFS, 70%; OS, 82%) vs 79% (ORR, 90%; DOR, 60%; PFS, 57%; OS, 71%). Safety endpoints were largely consistent among all subgroups. Prolonged neutropenia and thrombocytopenia occurred more frequently in pts with vs without deletion of TP53/17p (25% vs 12% and 28% vs 17%, respectively). Grade ≥ 3 CRS occurred more frequently in ZUMA-2-ineligible vs eligible pts (13% vs 7%). After multivariable adjustment, all effectiveness and most safety outcomes were consistent regardless of deletion of TP53/17p. Deletion of TP53/17p approached an association with decreased OS (HR 1.79 [95% CI 0.99−3.25]), and was associated with more frequent prolonged neutropenia (OR 2.85 [1.30−6.27]) and prolonged thrombocytopenia (OR 2.18 [1.04−4.57]) although these did not result in significant difference in infections requiring treatment (HR 1.22 [0.79−1.90]) nor NRM (HR 2.00 [0.77−5.21]). The remaining outcomes were consistent regardless of deletion of TP53/17p. Comparable outcomes were observed between pts with Ki-67 PI ≥ 50% and < 50%. Conclusions: These real-world findings with 12 mo of follow-up suggest that outcomes of brexu-cel treatment are largely consistent, including a high CR rate, regardless of ZUMA-2 eligibility or the high-risk feature subgroups analyzed. Although pts without deletion of TP53/17p appeared to have longer OS than pts with deletion of TP53/17p, the data further support brexu-cel as the standard of care across pts with R/R MCL, including those with high-risk features. An updated dataset is planned to be analyzed and results can be presented at the conference. *SK and NA are equal contributors