T he pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to >1.5 million infections in the United States (30% of global cases) and >90,000 deaths as of May 20, 2020 (1). Coronavirus disease (COVID-19, the clinical syndrome associated with SARS-Cov-2) is most commonly characterized by respiratory illness and viral pneumonia with fever, cough, and shortness of breath, and progression to acute respiratory distress syndrome in severe cases (2). Although neurologic complications have been noted in previous human coronavirus infections (3-5), there are few in-depth investigations for neurologic syndromes associated with SARS-CoV-2 infection (6). This deficiency can result from the need to reduce unnecessary staff exposure and difficulties in establishing preillness neurologic status without regular family visitors. It is known that neurons and glia express the putative SARS-CoV-2 receptor angiotensin converting enzyme 2 (7), and that the related coronavirus SARS-CoV (responsible for the 2003 SARS outbreak) can inoculate the mouse olfactory bulb (8). If SARS-CoV-2 can enter the central nervous system (CNS) directly or through hematogenous spread, cerebrospinal fluid (CSF) changes, including viral RNA, IgM, or cytokine levels, might support CNS infection as a cause for neurologic symptoms. We report clinical, blood, neuroimaging, and CSF findings for 3 patients with laboratory-confirmed COVID-19 and a range of neurologic outcomes (neuro-COVID). We also show the presence of SARS-CoV-2 antibodies in the blood and CSF of these patients, consistent with CNS penetration of disease. Methods We describe the clinical, laboratory and radiologic findings for 3 patients with respiratory failure and neurologic complications caused by COVID-19. This case series was reviewed and exempted from Emory Institutional Review Board approval. Medical records were reviewed by 4 of the coauthors (K.B., A.A., M.E.M., and W.T.H.). CSF Serologic Analysis, Cytokines, and Molecular Testing We assessed CSF IgM by using an in-house ELISA against SARS-CoV-2 S1 or envelope (E) protein. This ELISA was modified from an in-house blood-based Encephalopathy and Encephalitis Associated with Cerebrospinal Fluid Cytokine Alterations and Coronavirus Disease,

In the Tropics, there is substantial temporal and spatial overlap of diseases propagated by anthropophilic mosquito vectors (such as malaria and dengue) and human helminth diseases (such as onchocerciasis and lymphatic filariasis) that are treated though mass drug administrations (MDA). This overlap will result in mosquito vectors imbibing significant quantities of these drugs when they blood feed on humans. Since many anthelmintic drugs have broad anti-invertebrate effects, the possibility of combined helminth control and mosquito-borne disease control through MDA is apparent. It has been previously shown that ivermectin can reduce mosquito survivorship when administered in a blood meal, but more detailed examinations are needed if MDA is to ever be developed into a tool for malaria or dengue control. We examined concentrations of drugs that follow human pharmacokinetics after MDA and that matched with mosquito feeding times, for effects against the anthropophilic mosquito vectors Anopheles gambiae s.s. and Aedes aegypti. Ivermectin was the only human-approved MDA drug we tested that affected mosquito survivorship, and only An. gambiae s.s. were affected at concentrations respecting human pharmacokinetics at indicated doses. Ivermectin also delayed An. gambiae s.s. re-feeding frequency and defecation rates, and two successive ivermectin-spiked blood meals following human pharmacokinetic concentrations compounded mortality effects compared to controls. These findings suggest that ivermectin MDA in Africa may be used to decrease malaria transmission if MDAs were administered more frequently. Such a strategy would broaden the current scope of polyparasitism control already afforded by MDAs, and which is needed in many African villages simultaneously burdened by many parasitic diseases.

Laboratory and field studies have shown that ivermectin, a drug that targets invertebrate ligand-gated ion channels (LGICs), is potently active against Anopheles spp. mosquitoes at concentrations present in human blood after standard drug administrations; thus ivermectin holds promise as a mass human-administered endectocide that could help suppress malaria parasite transmission. We evaluated other systemic LGIC-targeting drugs for their activities against the African malaria vector Anopheles gambiae using in vitro blood feeding assays. Eprinomectin, selamectin, moxidectin, and N-tert-butyl nodulisporamide were evaluated as potentially systemic drugs having similar modes of action to ivermectin; all primarily are agonists of invertebrate glutamate-gated chloride ion channels. Additionally, nitenpyram and spinosad were evaluated as systemic drugs that primarily work as agonists of nicotinic acetylcholine receptor channels. Only eprinomectin killed Anopheles gambiae at concentrations that were comparable to ivermectin. At sub-lethal doses, nitenpyram and moxidectin marginally affected mosquito re-blood feeding ability. The macrocyclic lactones, particularly eprinomectin, caused significantly increased knockdown and significantly inhibited recovery in blood fed females. These data are a first step in evaluating drugs that might be eventually combined with, or substituted for ivermectin for future malaria parasite transmission control.

Seven different strains of Aedes aegypti (L.), including a genetically diverse laboratory strain, three laboratory-selected permethrin-resistant strains, a standard reference strain, and two recently colonized strains were fed on human blood containing various concentrations of ivermectin. Ivermectin reduced adult survival, fecundity, and hatch rate of eggs laid by ivermectin-treated adults in all seven strains. The LC50 of ivermectin for adults and the concentration that prevented 50% of eggs from hatching was calculated for all strains. Considerable variation in adult survival after an ivermectin-bloodmeal occurred among strains, and all three permethrin-resistant strains were significantly less susceptible to ivermectin than the standard reference strain. The hatch rate after an ivermectin bloodmeal was less variable among strains, and only one of the permethrin-resistant strains differed significantly from the standard reference strain. Our studies suggest that ivermectin induces adult mortality and decreases the hatch rate of eggs through different mechanisms. A correlation analysis of log-transformed LC50 among strains suggests that permethrin and ivermectin cross-resistance may occur.