To tackle the COVID-19 outbreak, which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), there is an unmet need for highly accurate diagnostic tests at all stages of infection with rapid results and high specificity. Here, we present a label-free nanoplasmonic biosensor-based, multiplex screening test for COVID-19 that can quantitatively detect 10 different biomarkers (6 viral nucleic acid genes, 2 spike protein subunits, and 2 antibodies) with a limit of detection in the aM range, all within one biosensor platform. Our newly developed nanoplasmonic biosensors demonstrate high specificity, which is of the upmost importance to avoid false responses. As a proof of concept, we show that our detection approach has the potential to quantify both IgG and IgM antibodies directly from COVID-19-positive patient plasma samples in a single instrument run, demonstrating the high-throughput capability of our detection approach. Most importantly, our assay provides receiving operating characteristics, areas under the curve of 0.997 and 0.999 for IgG and IgM, respectively. The calculated p -value determined through the Mann–Whitney nonparametric test is <0.0001 for both antibodies when the test of COVID-19-positive patients ( n = 80) is compared with that of healthy individuals ( n = 72). Additionally, the screening test provides a calculated sensitivity (true positive rate) of 100% (80/80), a specificity (true negative rate) >96% (77/80), a positive predictive value of 98% at 5% prevalence, and a negative predictive value of 100% at 5% prevalence. We believe that our very sensitive, multiplex, high-throughput testing approach has potential applications in COVID-19 diagnostics, particularly in determining virus progression and infection severity for clinicians for an appropriate treatment, and will also prove to be a very effective diagnostic test when applied to diseases beyond the COVID-19 pandemic.
IntroductionCerebral malaria is one of the most severe manifestations of malaria and is a leading cause of acquired neurodisability in African children. Recent studies suggest acute kidney injury (AKI) is a risk factor for brain injury in cerebral malaria. The present study evaluates potential mechanisms of brain injury in cerebral malaria by evaluating changes in cerebrospinal fluid measures of brain injury with respect to severe malaria complications. Specifically, we attempt to delineate mechanisms of injury focusing on blood-brain-barrier integrity and acute metabolic changes that may underlie kidney-brain crosstalk in severe malaria.MethodsWe evaluated 30 cerebrospinal fluid (CSF) markers of inflammation, oxidative stress, and brain injury in 168 Ugandan children aged 18 months to 12 years hospitalized with cerebral malaria. Eligible children were infected with Plasmodium falciparum and had unexplained coma. Acute kidney injury (AKI) on admission was defined using the Kidney Disease: Improving Global Outcomes criteria. We further evaluated blood-brain-barrier integrity and malaria retinopathy, and electrolyte and metabolic complications in serum.ResultsThe mean age of children was 3.8 years (SD, 1.9) and 40.5% were female. The prevalence of AKI was 46.3% and multi-organ dysfunction was common with 76.2% of children having at least one organ system affected in addition to coma. AKI and elevated blood urea nitrogen, but not other measures of disease severity (severe coma, seizures, jaundice, acidosis), were associated with increases in CSF markers of impaired blood-brain-barrier function, neuronal injury (neuron-specific enolase, tau), excitatory neurotransmission (kynurenine), as well as altered nitric oxide bioavailability and oxidative stress (p < 0.05 after adjustment for multiple testing). Further evaluation of potential mechanisms suggested that AKI may mediate or be associated with CSF changes through blood-brain-barrier disruption (p = 0.0014), ischemic injury seen by indirect ophthalmoscopy (p < 0.05), altered osmolality (p = 0.0006) and through alterations in the amino acids transported into the brain.ConclusionIn children with cerebral malaria, there is evidence of kidney-brain injury with multiple potential pathways identified. These changes were specific to the kidney and not observed in the context of other clinical complications.
Background: Severe malaria manifests as various conditions with severe malarial anemia being the most common and cerebral malaria being the most severe and affecting over 200,000 children annually. A 2010 review highlighted blood brain barrier degradation and decreased cerebral perfusion as contributors to the long-term behavioral, cognitive, and neurological sequalae of severe malaria. Since then, new research has identified various surface marker proteins and cytokines/chemokines playing a role in vascular changes and inflammation that progresses to acute kidney injury, retinopathy, and seizures. Our goal is to summarize the updated research and provide further insight into the mechanisms of brain injury and the outcomes that follow cerebral malaria. Project Methods: Hypotheses on future areas of study from the 2010 review were used to generate an outline for the updated review. Search strategies using the PubMed database were developed so that all relevant primary articles pertaining to human (pediatric and adult), murine, and in vitro studies done from 2010-2020 could be identified. The articles were then sorted and inputted into EndNote to generate a library. Review articles, case reports, and articles discussing the treatment of malaria were excluded from this index. Results: 88 articles remarking on vasculopathy, 88 on leukocytes, 114 on cytokines/chemokines, 11 on seizures, 56 on acute kidney injury, and 35 on retinopathy have been identified as promising literature for this review. The results suggest that infected individuals have increased endothelial activation which promotes red blood cell adherence to vasculature and edema. This reduces blood flow to the brain, kidneys, and eyes and causes injury to the organs. Conclusion and Potential Impact: The EndNote library contains current literature on the mechanisms of brain injury secondary to severe malaria, which will be used to write a review article and identify new areas of research to further our understanding of severe malaria pathogenesis and how to target treatments.
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