Advancing the repurposing of ivermectin for malaria

There is ever-increasing anticipation for the potential of mass drug administration of endectocides (also known as systemic insecticides) to reduce malaria transmission, with ivermectin emerging as the most likely first-in-class endectocide.1 More than half of the 46 papers published on this subject in the past decade appeared in the past 2 years. 23 projects are registered in the MESA Track database, of which seven are active today; and, more importantly, trial mapping by the Malaria Ivermectin Roadmap2 shows that abundant new evidence on the topic will be available by 2020

Ivermectin to reduce malaria transmission II. Considerations regarding clinical development pathway

The development of ivermectin as a complementary vector control tool will require good quality evidence. This paper reviews the different eco-epidemiological contexts in which mass drug administration with ivermectin could be useful. Potential scenarios and pharmacological strategies are compared in order to help guide trial design. The rationale for a particular timing of an ivermectin-based tool and some potentially useful outcome measures are suggested

Ivermectin to reduce malaria transmission III. Considerations regarding regulatory and policy pathways

Vector control is a task previously relegated to products that (a) kill the mosquitoes directly at different stages (insecticides, larvicides, baited traps), or (b) avoid/reduce human-mosquito contact (bed nets, repellents, house screening), thereby reducing transmission. The potential community-based administration of the endectocide ivermectin with the intent to kill mosquitoes that bite humans, and thus reduce malaria transmission, offers a novel approach using a well-known drug, but additional steps are required to address technical, regulatory and policy gaps. The proposed community administration of this drug presents dual novel paradigms; first, indirect impact on the community rather than on individuals, and second, the use of a drug for vector control. In this paper, the main questions related to the regulatory and policy pathways for such an application are identified. Succinct answers are proposed for how the efficacy, safety, acceptability, cost-effectiveness and programmatic suitability could result in regulatory approval and ultimately policy recommendations on the use of ivermectin as a complementary vector control tool

Effectiveness of Antiviral Therapy in Highly-Transmissible Variants of SARS-CoV-2: A Modeling and Simulation Study.

As of October 2021, neither established agents (e.g., hydroxychloroquine) nor experimental drugs have lived up to their initial promise as antiviral treatment against SARS-CoV-2 infection. While vaccines are being globally deployed, variants of concern (VOCs) are emerging with the potential for vaccine escape. VOCs are characterized by a higher within-host transmissibility, and this may alter their susceptibility to antiviral treatment. Here we describe a model to understand the effect of changes in within-host reproduction number R0, as proxy for transmissibility, of VOCs on the effectiveness of antiviral therapy with molnupiravir through modeling and simulation. Molnupiravir (EIDD-2801 or MK 4482) is an orally bioavailable antiviral drug inhibiting viral replication through lethal mutagenesis, ultimately leading to viral extinction. We simulated 800 mg molnupiravir treatment every 12 h for 5 days, with treatment initiated at different time points before and after infection. Modeled viral mutations range from 1.25 to 2-fold greater transmissibility than wild type, but also include putative co-adapted variants with lower transmissibility (0.75-fold). Antiviral efficacy was correlated with R0, making highly transmissible VOCs more sensitive to antiviral therapy. Total viral load was reduced by up to 70% in highly transmissible variants compared to 30% in wild type if treatment was started in the first 1-3 days post inoculation. Less transmissible variants appear less susceptible. Our findings suggest there may be a role for pre- or post-exposure prophylactic antiviral treatment in areas with presence of highly transmissible SARS-CoV-2 variants. Furthermore, clinical trials with borderline efficacious results should consider identifying VOCs and examine their impact in post-hoc analysis

Ivermectin to reduce malaria transmission I. Pharmacokinetic and pharmacodynamic considerations regarding efficacy and safety

Ivermectin is an endectocide that has been used broadly in single dose community campaigns for the control of onchocerciasis and lymphatic filariasis for more than 30 years. There is now interest in the potential use of ivermectin regimens to reduce malaria transmission, envisaged as community-wide campaigns tailored to transmission patterns and as complement of the local vector control programme. The development of new ivermectin regimens or other novel endectocides will require integrated development of the drug in the context of traditional entomological tools and endpoints. This document examines the main pharmacokinetic and pharmacodynamic parameters of the medicine and their potential influence on its vector control efficacy and safety at population level. This information could be valuable for trial design and clinical development into regulatory and policy pathways

Advancing the repurposing of ivermectin for malaria

Ivermectin lays the path for a whole new concept: drug-based vector control. Ivermectin, or indeed any effective endectocide, could be administered to eligible members of the at-risk community as a complementary tool for vector control. It could be administered alone or in combination with partner drugs to allow for integrated management of malaria or neglected tropical diseases, directly responding to residual transmission by targeting malaria and some lymphatic filariasis vectors, regardless of their feeding behaviour

Towards a Decentralized Metaverse: Synchronized Orchestration of Digital Twins and Sub-Metaverses

Accommodating digital twins (DTs) in the metaverse is essential to achieving digital reality. This need for integrating DTs into the metaverse while operating them at the network edge has increased the demand for a decentralized edge-enabled metaverse. Hence, to consolidate the fusion between real and digital entities, it is necessary to harmonize the interoperability between DTs and the metaverse at the edge. In this paper, a novel decentralized metaverse framework that incorporates DT operations at the wireless edge is presented. In particular, a system of autonomous physical twins (PTs) operating in a massively-sensed zone is replicated as cyber twins (CTs) at the mobile edge computing (MEC) servers. To render the CTs' digital environment, this zone is partitioned and teleported as distributed sub-metaverses to the MEC servers. To guarantee seamless synchronization of the sub-metaverses and their associated CTs with the dynamics of the real world and PTs, respectively, this joint synchronization problem is posed as an optimization problem whose goal is to minimize the average sub-synchronization time between the real and digital worlds, while meeting the DT synchronization intensity requirements. To solve this problem, a novel iterative algorithm for joint sub-metaverse and DT association at the MEC servers is proposed. This algorithm exploits the rigorous framework of optimal transport theory so as to efficiently distribute the sub-metaverses and DTs, while considering the computing and communication resource allocations. Simulation results show that the proposed solution can orchestrate the interplay between DTs and sub-metaverses to achieve a 25.75 % reduction in the sub-synchronization time in comparison to the signal-to-noise ratio-based association scheme