3-Position Biaryl Endochin-like Quinolones with Enhanced Antimalarial Performance.

ELQ-300 is a potent antimalarial drug with activity against blood, liver, and vector stages of the disease. A prodrug, , exhibits reduced crystallinity and improved in vivo efficacy in preclinical testing, and currently, it is in the developmental pipeline for once-a-week dosing for oral prophylaxis against malaria. Because of the high cost of developing a new drug for human use and the high risk of drug failure, it is prudent to have a back-up plan in place.

Synthesis of Deuterated Endochin-Like Quinolones.

Malaria continues to be a serious and debilitating disease. The emergence and spread of high-level resistance to multiple antimalarial drugs by Plasmodium falciparum has brought about an urgent need for new treatments that will be active against multidrug resistant malaria infections. One such treatment, ELQ-331 (MMV-167), an alkoxy carbonate prodrug of 4(1H)-quinolone ELQ-300, is currently in preclinical development with the Medicines for Malaria Venture.

Effectiveness of Two New Endochin-like Quinolones, ELQ-596 and ELQ-650, in Experimental Mouse Models of Human Babesiosis.

Endochin-like quinolones (ELQs) define a class of small molecule antimicrobials that target the mitochondrial electron transport chain of various human parasites by inhibiting their cytochrome bc complexes. The compounds have shown potent activity against a wide range of protozoan parasites, including the intraerythrocytic parasites and , the agents of human malaria and babesiosis, respectively. First-generation ELQ compounds were previously found to reduce infection by and in animal models of human babesiosis but achieved a radical cure only in combination with atovaquone and required further optimization to address pharmacological limitations.

Stroke thrombolysis given by emergency physicians: The time is here.

Emergency Medicine core clinical privileges include administration of thrombolytic therapy for myocardial infarction and stroke. However, emergency medicine providers have created their own paradigm to rely on neurology specialty consultation to treat acute stroke patients. A 2013 study supported by the American Academy of Neurology showed an 11% shortage of neurologists at that time and projected a 19% shortage by 2025.

The management of trigeminal neuralgia with triptans, a narrative review of the literature.

Objective: The objective of this paper is to present a narrative review of the use of triptans in the treatment of trigeminal neuralgia (TN), as well as to outline possible therapeutic mechanisms of action.

Background: TN is a debilitating neuropathic disorder with a variety of surgical and pharmacological treatments currently available. Despite treatment being heavily individually tailored, some patients remain refractory to management.

Adverse Reactions in a Phase 1 Trial of the Anti-Malarial DM1157: An Example of Pharmacokinetic Modeling and Simulation Guiding Clinical Trial Decisions.

Introduction: There is an urgent need to develop new drugs to treat malaria due to increasing resistance to first-line therapeutics targeting the causative organism, Plasmodium falciparum (P. falciparum). One drug candidate is DM1157, a small molecule that inhibits the formation of hemozoin, which protects P.

A New Scalable Synthesis of ELQ-300, ELQ-316, and other Antiparasitic Quinolones.

The Endochin-Like Quinolone (ELQ) compound class may yield effective, safe treatments for a range of important human and animal afflictions. However, to access the public health potential of this compound series, a synthetic route needed to be devised that lowers costs and is amenable to large scale production. In the new synthetic route described here, a substituted β-keto ester, formed by an Ullmann reaction and subsequent acylation, is reacted with an aniline via a Conrad-Limpach reaction to produce 3-substituted 4(1H)-quinolones such as and .

Carotid Artery Angioplasty and Stenting: 2-Dimensional Operative Video.

Carotid artery angioplasty and stenting (CAS) has been shown to be equally effective as carotid endarterectomy (CEA) for carotid stenosis in both symptomatic and asymptomatic disease.1 In patients who are considered high risk for endarterectomy, CAS is safe and effective.2 While this is a common procedure, proper technique is crucial to ensure that the procedure is safe with minimal risk of stroke.

The Use of Antiplatelet Agents and Heparin in the 24-Hour Postintravenous Alteplase Window for Neurointervention.

Background: Intravenous (IV) alteplase with mechanical thrombectomy has been found to be superior to alteplase alone in select patients with intracranial large vessel occlusion. Current guidelines discourage the use of antiplatelet agents or heparin for 24 h following alteplase. However, their use is often necessary in certain circumstances during thrombectomy procedures.

Unsymmetrical Bisquinolines with High Potency against Malaria.

Quinoline-based scaffolds have been the mainstay of antimalarial drugs, including many artemisinin combination therapies (ACTs), over the history of modern drug development. Although much progress has been made in the search for novel antimalarial scaffolds, it may be that quinolines will remain useful, especially if very potent compounds from this class are discovered. We report here the results of a structure-activity relationship (SAR) study assessing potential unsymmetrical bisquinoline antiplasmodial drug candidates using in vitro activity against intact parasites in cell culture.

Insecticide Resistance Status of Aedes aegypti (Diptera: Culicidae) in California by Biochemical Assays.

Insecticide resistance in Aedes aegypti mosquitoes poses a major threat to public health worldwide. There are two primary biological mechanisms that can lead to insecticide resistance, target site and metabolic resistance, both of which confer resistance to specific classes of insecticides. Due to the limited number of chemical compounds available for mosquito control, it is important to determine current enzymatic profiles among mosquito populations.

Plague Epizootic Dynamics in Chipmunk Fleas, Sierra Nevada Mountains, California, USA, 2013-2015.

We describe Yersinia pestis minimum infection prevalence in fleas collected from Tamias spp. chipmunks in the Sierra Nevadas (California, USA) during 2013-2015. Y.

Susceptibility to insecticides and resistance mechanisms in three populations of Aedes aegypti from Peru.

Background: Epidemics of dengue, chikungunya and Zika are a growing threat to areas where Aedes aegypti are present. The efficacy of chemical control of Ae. aegypti is threatened by the increasing frequency of insecticide resistance.

Identification of Molecular Determinants of Resistance to Pyrethroid Insecticides in Aedes aegypti (Diptera: Culicidae) Populations in California, USA.

The first breeding populations of Aedes aegypti (Linnaeus) were identified in California in 2013, and have since been detected in 13 counties. Recent studies suggest two introductions likely occurred, with genetically distinct populations in the central and southern regions of the state. Given the threat of dengue, chikungunya, and Zika virus transmission, it is imperative to understand if these populations harbor genes that could confer resistance to pyrethrin-based insecticides, known as pyrethroids, the most commonly used class of adulticides in the state.

An agent-based model of dengue virus transmission shows how uncertainty about breakthrough infections influences vaccination impact projections.

Prophylactic vaccination is a powerful tool for reducing the burden of infectious diseases, due to a combination of direct protection of vaccinees and indirect protection of others via herd immunity. Computational models play an important role in devising strategies for vaccination by making projections of its impacts on public health. Such projections are subject to uncertainty about numerous factors, however.

First-in-Human Experience With Integration of a Hydrocephalus Shunt Device Within a Customized Cranial Implant.

Background: Implantable shunt devices are critical and life saving for hydrocephalus patients. However, these devices are fraught with high complication rates including scalp dehiscence, exposure, and extrusion. In fact, high shunt valve profiles are correlated with increased complications compared to those with lower profiles.

Carotid Stenosis: Utility of Diagnostic Angiography.

Objective: Carotid artery stenosis is frequently diagnosed through screening tests with noninvasive imaging. Because of differences noted between the various modalities, we sought to investigate our experience comparing noninvasive imaging (ultrasound, computed tomography angiography, magnetic resonance angiography) with invasive imaging (digital subtraction angiography).

Methods: In a multicenter retrospective analysis, 249 carotid vessels were reviewed based on angiography with the associated noninvasive imaging.

Whole metagenome sequencing reveals links between mosquito microbiota and insecticide resistance in malaria vectors.

In light of the declining global malaria burden attained largely due to insecticides, a deeper understanding of the factors driving insecticide resistance is needed to mitigate its growing threat to malaria vector control programs. Following evidence of microbiota-mediated insecticide resistance in agricultural pests, we undertook a comparative study of the microbiota in mosquitoes of differing insecticide resistance status. The microbiota of wild-caught Anopheles albimanus, an important Latin American malaria vector, that were resistant (FEN_Res) or susceptible (FEN_Sus) to the organophosphate (OP) insecticide fenitrothion were characterized and compared using whole metagenome sequencing.

The Impact of the Endovascular Treatment of Cerebral Aneurysms on Headaches.

Objective: The co-occurrence of headaches and cerebral aneurysms is common in clinical practice, although a clear causal relationship has not been ascertained. We aimed to investigate the impact of endovascular obliteration of aneurysms on headaches using a cross-sectional, prospective, open-label protocol. We also sought to characterize the preexisting headaches in patients harboring cerebral aneurysms using the International Classification of Headache Disorders criteria.

Investigation of and Response to 2 Plague Cases, Yosemite National Park, California, USA, 2015.

In August 2015, plague was diagnosed for 2 persons who had visited Yosemite National Park in California, USA. One case was septicemic and the other bubonic. Subsequent environmental investigation identified probable locations of exposure for each patient and evidence of epizootic plague in other areas of the park.

An Analysis of Transient Ischemic Attack Practices: Does Hospital Admission Improve Patient Outcomes?

Introduction: Immediate treatment has been shown to decrease the recurrence of cerebrovascular accidents following transient ischemic attacks (TIA), prompting the use of a specialized neurologic emergency department (Neuro ED) to triage patients. Despite these findings, there is little evidence supporting the notion that hospital admission improves post-TIA outcomes. Through the lens of a Neuro ED, this retrospective chart review of TIA patients examines whether hospital admission improves 90-day outcomes.