Performance evaluation of human cough annotators: optimal metrics and sex differences.

INTRODUCTION: Despite its high prevalence and significance, there is still no widely available method to quantify cough. In order to demonstrate agreement with the current gold standard of human annotation, emerging automated techniques require a robust, reproducible approach to annotation. We describe the extent to which a human annotator of cough sounds (a) agrees with herself (intralabeller or intrarater agreement) and (b) agrees with other independent labellers (interlabeller or inter-rater agreement); we go on to describe significant sex differences in cough sound length and epochs size. MATERIALS AND METHODS: 24 participants wore an audiorecording smartwatch to capture 6-24 hours of continuous audio. A randomly selected sample of the whole audio was labelled twice by an expert annotator and a third time by six trained annotators. We collected 400 hours of audio and analysed 40 hours. The cough counts as well as cough seconds (any 1 s of time containing at least one cough) from different annotators were compared and summary statistics from linear and Bland-Altman analyses were used to quantify intraobserver and interobserver agreement. RESULTS: There was excellent intralabeller (less than two disagreements per hour monitored, Pearson's correlation 0.98) and interlabeller agreement (Pearson's correlation 0.96), using cough seconds as the unit of analysis decreased annotator discrepancies by 50% in comparison to coughs. Within this data set, it was observed that the length of cough sounds and epoch size (number of coughs per bout or attach) differed between women and men. CONCLUSION: Given the decreased interobserver variability in annotation when using cough seconds (vs just coughs) we propose their use for manually annotating cough when assessing of the performance of automatic cough monitoring systems. The differences in cough sound length and epochs size may have important implications for equality in the development of cough monitoring tools. TRIAL REGISTRATION NUMBER: NCT05042063.

A field bioassay for assessing ivermectin bio-efficacy in wild malaria vectors.

BACKGROUND: Ivermectin (IVM) mass drug administration is a candidate complementary malaria vector control tool. Ingestion of blood from IVM treated hosts results in reduced survival in mosquitoes. Estimating bio-efficacy of IVM on wild-caught mosquitoes requires they ingest the drug in a blood meal either through a membrane or direct feeding on a treated host. The latter, has ethical implications, and the former results in low feeding rates. Therefore, there is a need to develop a safe and effective method for IVM bio-efficacy monitoring in wild mosquitoes. METHODS: Insectary-reared Anopheles gambiae s.s. were exposed to four IVM doses: 85, 64, 43, 21 ng/ml, and control group (0 ng/ml) in three different solutions: (i) blood, (ii) 10% glucose, (iii) four ratios (1:1, 1:2, 1:4, 1:8) of blood in 10% glucose, and fed through filter paper. Wild-caught An. gambiae s.l. were exposed to 85, 43 and 21 ng/ml IVM in blood and 1:4 ratio of blood-10% glucose mixture. Survival was monitored for 28 days and a pool of mosquitoes from each cohort sacrificed immediately after feeding and weighed to determine mean weight of each meal type. RESULTS: When administered in glucose solution, mosquitocidal effect of IVM was not comparable to the observed effects when similar concentrations were administered in blood. Equal concentrations of IVM administered in blood resulted in pronounced reductions in mosquito survival compared to glucose solution only. However, by adding small amounts of blood to glucose solution, mosquito mortality rates increased resulting in similar effects to what was observed during blood feeding. CONCLUSION: Bio-efficacy of ivermectin is strongly dependent on mode of drug delivery to the mosquito and likely influenced by digestive processes. The assay developed in this study is a good candidate for field-based bio-efficacy monitoring: wild mosquitoes readily feed on the solution, the assay can be standardized using pre-selected concentrations and by not involving treated blood hosts (human or animal) variation in individual pharmacokinetic profiles as well as ethical issues are bypassed. Meal volumes did not explain the difference in the lethality of IVM across the different meal types necessitating further research on the underlying mechanisms.

Effects of larval exposure to sublethal doses of ivermectin on adult fitness and susceptibility to ivermectin in Anopheles gambiae s.s.

BACKGROUND: The effects of ivermectin (endectocide) on mosquito survival make it a potential new malaria vector control tool. The drug can be administered to mosquito disease vectors through blood hosts that include humans and livestock. Its increased use may cause contamination of larval habitats, either directly through livestock excreta or indirectly through leaching or run-off from contaminated soil, albeit in sublethal doses. However, the effects of such exposure on immature stages and the subsequent adults that emerge are poorly understood. This study was undertaken to evaluate the impact of ivermectin exposure on Anopheles gambiae s.s. larvae and its effects on fitness and susceptibility to ivermectin in the emerging adults. METHODS: Laboratory-reared An. gambiae s.s. (Kilifi strain) larvae were exposed to five different ivermectin concentrations; 0, 0.00001, 0.0001, 0.001, and 0.01 ppm, and larval survival was monitored to determine the appropriate sub-lethal dose. Concentrations with survival > 50% (0.00001 and 0.0001 ppm) were selected and used as the sub-lethal doses. The fecundity, fertility, and susceptibility to ivermectin of adults emerging after larval exposure to the sub-lethal doses were examined. RESULTS: Overall, exposure of An. gambiae s.s. aquatic stages to ivermectin caused a dose-dependent reduction in larval survival irrespective of the stage at which the larvae were exposed. Exposure to ivermectin in the larval stage did not have an effect on either the number of eggs laid or the hatch rate. However, exposure of first/second-instar larvae to 0.0001 ppm and third/fourth-instar larvae to 0.001 ppm of ivermectin reduced the time taken to oviposition. Additionally, exposure to ivermectin in the larval stage did not affect susceptibility of the emerging adults to the drug. CONCLUSIONS: This study shows that contamination of larval habitats with ivermectin affects An. gambiae s.s. larval survival and could potentially have an impact on public health. However, there are no carry-over effects on the fecundity, fertility, and susceptibility of the emerging adults to ivermectin. In addition, this study shows that environmental exposure to ivermectin in the larval habitats is unlikely to compromise the efficacy of ivermectin in the emerging adults.

Burden and risk factors of snakebite in Mopeia, Mozambique: Leveraging larger malaria trials to generate data of this neglected tropical disease.

BACKGROUND: Snakebite is a neglected disease that disproportionally affects the rural poor. There is a dearth of evidence regarding incidence and risk factors in snakebite-endemic countries. Without this basic data, it will be impossible to achieve the target of a 50% reduction of snakebite morbidity and mortality by 2030 as set by the World Health Organization. METHODS: This was a descriptive analysis nested in a 2021 community-based demographic survey of over 70,000 individuals conducted in Mopeia, Mozambique, in preparation for a cluster randomized trial to test an intervention for malaria. We describe the incidence rate, demographics, socioeconomic indicators and outcomes of snakebite in this population. FINDINGS: We found the incidence of self-reported snakebite in Mopeia to be 393 bites per 100,000 person-years at risk, with 2% of households affected in the preceding 12 months. Whilst no fatalities were recorded, over 3,000 days of work or school days were lost with an individual household economic impact higher than that of uncomplicated malaria. 1 in 6 of those affected did not fully recover at the time of the study. We found significant relationships between age older than 15, use of firewood for household fuel, and animal possession with snakebite. CONCLUSIONS: This study exposes higher than expected incidence and burden of snakebite in rural Mozambique. Whilst snakebite elimination in Mozambique seems unattainable today, it remains a preventable disease with manageable sequelae. We have shown that snakebite research is particularly easy to nest in larger studies, making this a practical and cost-effective way of estimating its incidence.

Alternative approaches for creating a wealth index: the case of Mozambique.

INTRODUCTION: The wealth index is widely used as a proxy for a household's socioeconomic position (SEP) and living standard. This work constructs a wealth index for the Mopeia district in Mozambique using data collected in year 2021 under the BOHEMIA (Broad One Health Endectocide-based Malaria Intervention in Africa) project. METHODS: We evaluate the performance of three alternative approaches against the Demographic and Health Survey (DHS) method based wealth index: feature selection principal components analysis (PCA), sparse PCA and robust PCA. The internal coherence between four wealth indices is investigated through statistical testing. Validation and an evaluation of the stability of the wealth index are performed with additional household income data from the BOHEMIA Health Economics Survey and the 2018 Malaria Indicator Survey data in Mozambique. RESULTS: The Spearman's rank correlation between wealth index ventiles from four methods is over 0.98, indicating a high consistency in results across methods. Wealth rankings and households' income show a strong concordance with the area under the curve value of ~0.7 in the receiver operating characteristic analysis. The agreement between the alternative wealth indices and the DHS wealth index demonstrates the stability in rankings from the alternative methods. CONCLUSIONS: This study creates a wealth index for Mopeia, Mozambique, and shows that DHS method based wealth index is an appropriate proxy for the SEP in low-income regions. However, this research recommends feature selection PCA over the DHS method since it uses fewer asset indicators and constructs a high-quality wealth index.

Burden and risk factors of snakebite in Mopeia, Mozambique: Leveraging larger malaria trials to generate data of this neglected tropical disease

Background: Snakebite is a neglected disease that disproportionally affects the rural poor. There is a dearth of evidence regarding incidence and risk factors in snakebite-endemic countries. Without this basic data, it will be impossible to achieve the target of a 50% reduction of snakebite morbidity and mortality by 2030 as set by the World Health Organization. Methods: This was a descriptive analysis nested in a 2021 community-based demographic survey of over 70,000 individuals conducted in Mopeia, Mozambique, in preparation for a cluster randomized trial to test an intervention for malaria. We describe the incidence rate, demographics, socioeconomic indicators and outcomes of snakebite in this population. Findings: We found the incidence of self-reported snakebite in Mopeia to be 393 bites per 100,000 person-years at risk, with 2% of households affected in the preceding 12 months. Whilst no fatalities were recorded, over 3,000 days of work or school days were lost with an individual household economic impact higher than that of uncomplicated malaria. 1 in 6 of those affected did not fully recover at the time of the study. We found significant relationships between age older than 15, use of firewood for household fuel, and animal possession with snakebite. Conclusions: This study exposes higher than expected incidence and burden of snakebite in rural Mozambique. Whilst snakebite elimination in Mozambique seems unattainable today, it remains a preventable disease with manageable sequelae. We have shown that snakebite research is particularly easy to nest in larger studies, making this a practical and cost-effective way of estimating its incidence.

BOHEMIA a cluster randomized trial to assess the impact of an endectocide-based one health approach to malaria in Mozambique: baseline demographics and key malaria indicators.

BACKGROUND: Many geographical areas of sub-Saharan Africa, especially in rural settings, lack complete and up-to-date demographic data, posing a challenge for implementation and evaluation of public health interventions and carrying out large-scale health research. A demographic survey was completed in Mopeia district, located in the Zambezia province in Mozambique, to inform the Broad One Health Endectocide-based Malaria Intervention in Africa (BOHEMIA) cluster randomized clinical trial, which tested ivermectin mass drug administration to humans and/or livestock as a potential novel strategy to decrease malaria transmission. METHODS: The demographic survey was a prospective descriptive study, which collected data of all the households in the district that accepted to participate. Households were mapped through geolocation and identified with a unique identification number. Basic demographic data of the household members was collected and each person received a permanent identification number for the study. RESULTS: 25,550 households were mapped and underwent the demographic survey, and 131,818 individuals were registered in the district. The average household size was 5 members and 76.9% of households identified a male household head. Housing conditions are often substandard with low access to improved water systems and electricity. The reported coverage of malaria interventions was 71.1% for indoor residual spraying and 54.1% for universal coverage of long-lasting insecticidal nets. The median age of the population was 15 years old. There were 910 deaths in the previous 12 months reported, and 43.9% were of children less than 5 years of age. CONCLUSIONS: The study showed that the district had good coverage of vector control tools against malaria but sub-optimal living conditions and poor access to basic services. The majority of households are led by males and Mopeia Sede/Cuacua is the most populated locality in the district. The population of Mopeia is young (< 15 years) and there is a high childhood mortality. The results of this survey were crucial as they provided the household and population profiles and allowed the design and implementation of the cluster randomized clinical trial. Trial registration NCT04966702.

Pharmacokinetics of ivermectin metabolites and their activity against Anopheles stephensi mosquitoes.

BACKGROUND: Ivermectin (22,23-dihydroavermectin B1a: H2B1a) is an endectocide used to treat worm infections and ectoparasites including lice and scabies mites. Furthermore, survival of malaria transmitting Anopheles mosquitoes is strongly decreased after feeding on humans recently treated with ivermectin. Currently, mass drug administration of ivermectin is under investigation as a potential novel malaria vector control tool to reduce Plasmodium transmission by mosquitoes. A "post-ivermectin effect" has also been reported, in which the survival of mosquitoes remains reduced even after ivermectin is no longer detectable in blood meals. In the present study, existing material from human clinical trials was analysed to understand the pharmacokinetics of ivermectin metabolites and feeding experiments were performed in Anopheles stephensi mosquitoes to assess whether ivermectin metabolites contribute to the mosquitocidal action of ivermectin and whether they may be responsible for the post-ivermectin effect. METHODS: Ivermectin was incubated in the presence of recombinant human cytochrome P450 3A4/5 (CYP 3A4/5) to produce ivermectin metabolites. In total, nine metabolites were purified by semi-preparative high-pressure liquid chromatography. The pharmacokinetics of the metabolites were assessed over three days in twelve healthy volunteers who received a single oral dose of 12 mg ivermectin. Blank whole blood was spiked with the isolated metabolites at levels matching the maximal blood concentration (Cmax) observed in pharmacokinetics study samples. These samples were fed to An. stephensi mosquitoes, and their survival and vitality was recorded daily over 3 days. RESULTS: Human CYP3A4 metabolised ivermectin more rapidly than CYP3A5. Ivermectin metabolites M1-M8 were predominantly formed by CYP3A4, whereas metabolite M9 (hydroxy-H2B1a) was mainly produced by CYP3A5. Both desmethyl-H2B1a (M1) and hydroxy-H2B1a (M2) killed all mosquitoes within three days post-feeding, while administration of desmethyl, hydroxy-H2B1a (M4) reduced survival to 35% over an observation period of 3 days. Ivermectin metabolites that underwent deglycosylation or hydroxylation at spiroketal moiety were not active against An. stephensi at Cmax levels. Interestingly, half-lives of M1 (54.2 ± 4.7 h) and M4 (57.5 ± 13.2 h) were considerably longer than that of the parent compound ivermectin (38.9 ± 20.8 h). CONCLUSION: In conclusion, the ivermectin metabolites M1 and M2 contribute to the activity of ivermectin against An. stephensi mosquitoes and could be responsible for the "post-ivermectin effect".

Ivermectin as a novel malaria control tool: Getting ahead of the resistance curse.

Reduction in malaria clinical cases is strongly dependent on the ability to prevent Anopheles infectious bites. Vector control strategies using long-lasting insecticidal nets and indoor residual spraying with insecticides have contributed to significantly reduce the incidence of malaria in many endemic countries, especially in the Sub-Saharan region. However, global progress in reducing malaria cases has plateaued since 2015 mostly due to the increased insecticide resistance and behavioral changes in Anopheles vectors. Additional control strategies are thus required to further reduce the burden of malaria and contain the spread of resistant and invasive Anopheles vectors. The use of endectocides such as ivermectin as an additional malaria control tool is now receiving increased attention, driven by its different mode of action compared to insecticides used so far and its excellent safety record for humans. In this opinion article, we discuss the advantages and disadvantages of using ivermectin for malaria control with a focus on the risk of selecting ivermectin resistance in malaria vectors. We also highlight the importance of understanding how ivermectin resistance could develop in mosquitoes and what its underlying mechanisms and associated molecular markers are, and propose a research agenda to manage this phenomenon.

BOHEMIA a cluster randomized trial to assess the impact of an endectocide-based one health approach to malaria in Mozambique: baseline demographics and key malaria indicators

Many geographical areas of sub-Saharan Africa, especially in rural settings, lack complete and up-to-date demographic data, posing a challenge for implementation and evaluation of public health interventions and carrying out large-scale health research. A demographic survey was completed in Mopeia district, located in the Zambezia province in Mozambique, to inform the Broad One Health Endectocide-based Malaria Intervention in Africa (BOHEMIA) cluster randomized clinical trial, which tested ivermectin mass drug administration to humans and/or livestock as a potential novel strategy to decrease malaria transmission. Methods: The demographic survey was a prospective descriptive study, which collected data of all the households in the district that accepted to participate. Households were mapped through geolocation and identified with a unique identification number. Basic demographic data of the household members was collected and each person received a permanent identification number for the study. Results: 25,550 households were mapped and underwent the demographic survey, and 131,818 individuals were registered in the district. The average household size was 5 members and 76.9% of households identified a male household head. Housing conditions are often substandard with low access to improved water systems and electricity. The reported coverage of malaria interventions was 71.1% for indoor residual spraying and 54.1% for universal coverage of long-lasting insecticidal nets. The median age of the population was 15 years old. There were 910 deaths in the previous 12 months reported, and 43.9% were of children less than 5 years of age. Conclusions: The study showed that the district had good coverage of vector control tools against malaria but sub-optimal living conditions and poor access to basic services. The majority of households are led by males and Mopeia Sede/Cuacua is the most populated locality in the district. The population of Mopeia is young (< 15 years) and there is a high childhood mortality. The results of this survey were crucial as they provided the household and population profiles and allowed the design and implementation of the cluster randomized clinical trial. Trial registration NCT04966702.

Long-term exposure to air pollution and severe COVID-19 in Catalonia: a population-based cohort study.

The association between long-term exposure to ambient air pollutants and severe COVID-19 is uncertain. We followed 4,660,502 adults from the general population in 2020 in Catalonia, Spain. Cox proportional models were fit to evaluate the association between annual averages of PM2.5, NO2, BC, and O3 at each participant's residential address and severe COVID-19. Higher exposure to PM2.5, NO2, and BC was associated with an increased risk of COVID-19 hospitalization, ICU admission, death, and hospital length of stay. An increase of 3.2 µg/m3 of PM2.5 was associated with a 19% (95% CI, 16-21) increase in hospitalizations. An increase of 16.1 µg/m3 of NO2 was associated with a 42% (95% CI, 30-55) increase in ICU admissions. An increase of 0.7 µg/m3 of BC was associated with a 6% (95% CI, 0-13) increase in deaths. O3 was positively associated with severe outcomes when adjusted by NO2. Our study contributes robust evidence that long-term exposure to air pollutants is associated with severe COVID-19.

Seroprevalence and socioeconomic impact of the first SARS-CoV-2 infection wave in a small town in Navarre, Spain.

The characterization of the antibody response to SARS-CoV-2 and its determinants are key for the understanding of COVID-19. The identification of vulnerable populations to the infection and to its socioeconomic impact is indispensable for inclusive policies. We conducted an age-stratified cross-sectional community-based seroprevalence survey between June 12th and 19th 2020-during the easing of lockdown-in Cizur, Spain. We quantified IgG, IgM and IgA levels against SARS-CoV-2 spike and its receptor-binding domain in a sample of 728 randomly selected, voluntarily registered inhabitants. We estimated a 7.9% seroprevalence in the general population, with the lowest seroprevalence among children under ten (n = 3/142, 2.1%) and the highest among adolescents (11-20 years old, n = 18/159, 11.3%). We found a heterogeneous immune-response profile across participants regarding isotype/antigen-specific seropositivity, although levels generally correlated. Those with technical education level were the most financially affected. Fifty-five percent had visited a supermarket and 43% a sanitary centre since mid-February 2020. When comparing by gender, men had left the household more frequently. In conclusion, few days after strict lockdown, the burden of SARS-CoV-2 infection was the lowest in children under 10. The findings also suggest that a wider isotype-antigen panel confers higher sensitivity. Finally, the economic impact biases should be considered when designing public health measures.

BOHEMIA: Broad One Health Endectocide-based Malaria Intervention in Africa-a phase III cluster-randomized, open-label, clinical trial to study the safety and efficacy of ivermectin mass drug administration to reduce malaria transmission in two African settings.

BACKGROUND: Residual malaria transmission is the result of adaptive mosquito behavior that allows malaria vectors to thrive and sustain transmission in the presence of good access to bed nets or insecticide residual spraying. These behaviors include crepuscular and outdoor feeding as well as intermittent feeding upon livestock. Ivermectin is a broadly used antiparasitic drug that kills mosquitoes feeding on a treated subject for a dose-dependent period. Mass drug administration with ivermectin has been proposed as a complementary strategy to reduce malaria transmission. METHODS: A cluster randomized, parallel arm, superiority trial conducted in two settings with distinct eco-epidemiological conditions in East and Southern Africa. There will be three groups: human intervention, consisting of a dose of ivermectin (400 mcg/kg) administered monthly for 3 months to all the eligible population in the cluster (>15 kg, non-pregnant and no medical contraindication); human and livestock intervention, consisting human treatment as above plus treatment of livestock in the area with a single dose of injectable ivermectin (200 mcg/kg) monthly for 3 months; and controls, consisting of a dose of albendazole (400 mg) monthly for 3 months. The main outcome measure will be malaria incidence in a cohort of children under five living in the core of each cluster followed prospectively with monthly RDTs DISCUSSION: The second site for the implementation of this protocol has changed from Tanzania to Kenya. This summary presents the Mozambique-specific protocol while the updated master protocol and the adapted Kenya-specific protocol undergo national approval in Kenya. BOHEMIA will be the first large-scale trial evaluating the impact of ivermectin-only mass drug administration to humans or humans and cattle on local malaria transmission TRIAL REGISTRATION: ClinicalTrials.gov NCT04966702 . Registered on July 19, 2021. Pan African Clinical Trials Registry PACTR202106695877303.

Correction: A systematic review and an individual patient data meta-analysis of ivermectin use in children weighing less than fifteen kilograms: Is it time to reconsider the current contraindication?

[This corrects the article DOI: 10.1371/journal.pntd.0009144.].

Inferring the epidemiological benefit of indoor vector control interventions against malaria from mosquito data.

The cause of malaria transmission has been known for over a century but it is still unclear whether entomological measures are sufficiently reliable to inform policy decisions in human health. Decision-making on the effectiveness of new insecticide-treated nets (ITNs) and the indoor residual spraying of insecticide (IRS) have been based on epidemiological data, typically collected in cluster-randomised control trials. The number of these trials that can be conducted is limited. Here we use a systematic review to highlight that efficacy estimates of the same intervention may vary substantially between trials. Analyses indicate that mosquito data collected in experimental hut trials can be used to parameterize mechanistic models for Plasmodium falciparum malaria and reliably predict the epidemiological efficacy of quick-acting, neuro-acting ITNs and IRS. Results suggest that for certain types of ITNs and IRS using this framework instead of clinical endpoints could support policy and expedite the widespread use of novel technologies.

Acoustic surveillance of cough for detecting respiratory disease using artificial intelligence.

Research question: Can smartphones be used to detect individual and population-level changes in cough frequency that correlate with the incidence of coronavirus disease 2019 (COVID-19) and other respiratory infections? Methods: This was a prospective cohort study carried out in Pamplona (Spain) between 2020 and 2021 using artificial intelligence cough detection software. Changes in cough frequency around the time of medical consultation were evaluated using a randomisation routine; significance was tested by comparing the distribution of cough frequencies to that obtained from a model of no difference. The correlation between changes of cough frequency and COVID-19 incidence was studied using an autoregressive moving average analysis, and its strength determined by calculating its autocorrelation function (ACF). Predictors for the regular use of the system were studied using a linear regression. Overall user experience was evaluated using a satisfaction questionnaire and through focused group discussions. Results: We followed-up 616 participants and collected >62 000 coughs. Coughs per hour surged around the time cohort subjects sought medical care (difference +0.77 coughs·h-1; p=0.00001). There was a weak temporal correlation between aggregated coughs and the incidence of COVID-19 in the local population (ACF 0.43). Technical issues affected uptake and regular use of the system. Interpretation: Artificial intelligence systems can detect changes in cough frequency that temporarily correlate with the onset of clinical disease at the individual level. A clearer correlation with population-level COVID-19 incidence, or other respiratory conditions, could be achieved with better penetration and compliance with cough monitoring.

Longitudinal passive cough monitoring and its implications for detecting changes in clinical status.

Research question: What is the impact of the duration of cough monitoring on its accuracy in detecting changes in the cough frequency? Materials and methods: This is a statistical analysis of a prospective cohort study. Participants were recruited in the city of Pamplona (Northern Spain), and their cough frequency was passively monitored using smartphone-based acoustic artificial intelligence software. Differences in cough frequency were compared using a one-tailed Mann-Whitney U test and a randomisation routine to simulate 24-h monitoring. Results: 616 participants were monitored for an aggregated duration of over 9 person-years and registered 62 325 coughs. This empiric analysis found that an individual's cough patterns are stochastic, following a binomial distribution. When compared to continuous monitoring, limiting observation to 24 h can lead to inaccurate estimates of change in cough frequency, particularly in persons with low or small changes in rate. Interpretation: Detecting changes in an individual's rate of coughing is complicated by significant stochastic variability within and between days. Assessing change based solely on intermittent sampling, including 24-h, can be misleading. This is particularly problematic in detecting small changes in individuals who have a low rate and/or high variance in cough pattern.

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.

Insecticide-treated livestock: a potential One Health approach to malaria control in Africa.

New vector-control tools are urgently needed to reduce malaria in areas where there is significant transmission after deployment of indoor residual spraying (IRS) and insecticide treated nets. Insecticide-treated livestock (ITL) is a potential novel strategy by which zoophagic mosquitos are killed after feeding upon animals treated with an insecticide. Although there are several insecticide candidates in the pipeline with a wide efficacy range against mosquitos, additional field studies with epidemiological outcomes are required to test the impact of this intervention on malaria transmission. Insecticides under consideration have long been used in livestock to improve animal health and productivity, but each has food and environmental safety considerations. Therefore, moving ITL from a concept to implementation will require a One Health framework.

Treatment of Pregnant Women with Ivermectin during Mass Drug Distribution: Time to Investigate Its Safety and Potential Benefits.

To date, pregnant women are excluded from programmes delivering community-directed treatment of ivermectin (CDTI) for onchocerciasis and preventive chemotherapy of other helminthiases because of concerns over ivermectin safety during pregnancy. This systematic exclusion sustains an infection reservoir at the community level and deprives a vulnerable population from known benefits-there are indications that treating O. volvulus infected women may improve pregnancy outcomes and reduce the risk that their children develop onchocerciasis-associated morbidities. Furthermore, teratogenic effects are seen in non-clinical experiments at doses that far exceed those used in CDTI. Lastly, early, undetected and undeclared pregnancies are being systematically exposed to ivermectin in practice. Treatment of this population requires appropriate supporting evidence, for which we propose a three-pronged approach. First, to develop a roadmap defining the key steps needed to obtain regulatory clearance for the safe and effective use of ivermectin in all pregnant women who need it. Second, to conduct a randomised placebo-controlled double-blind clinical trial to evaluate the safety and benefits of ivermectin treatment in O. volvulus infected pregnant women. Such a trial should evaluate the possible effects of ivermectin in reducing adverse pregnancy outcomes and neonatal mortality, as well as in reducing the incidence of onchocerciasis-associated epilepsy. Third, to establish a pregnancy registry for women who inadvertently received ivermectin during pregnancy. This situation is not unique to ivermectin. Access to valuable therapies is often limited, delayed, or denied to pregnant women due to a lack of evidence. Concerns over protecting vulnerable people may result in harming them. We need to find acceptable ways to build robust evidence towards providing essential interventions during pregnancy.