Digital cough monitoring - A potential predictive acoustic biomarker of clinical outcomes in hospitalized COVID-19 patients.

PURPOSE: Recent developments in the field of artificial intelligence and acoustics have made it possible to objectively monitor cough in clinical and ambulatory settings. We hypothesized that time patterns of objectively measured cough in COVID-19 patients could predict clinical prognosis and help rapidly identify patients at high risk of intubation or death. METHODS: One hundred and twenty-three patients hospitalized with COVID-19 were enrolled at University of Florida Health Shands and the Centre Hospitalier de l'Université de Montréal. Patients' cough was continuously monitored digitally along with clinical severity of disease until hospital discharge, intubation, or death. The natural history of cough in hospitalized COVID-19 disease was described and logistic models fitted on cough time patterns were used to predict clinical outcomes. RESULTS: In both cohorts, higher early coughing rates were associated with more favorable clinical outcomes. The transitional cough rate, or maximum cough per hour rate predicting unfavorable outcomes, was 3·40 and the AUC for cough frequency as a predictor of unfavorable outcomes was 0·761. The initial 6 h (0·792) and 24 h (0·719) post-enrolment observation periods confirmed this association and showed similar predictive value. INTERPRETATION: Digital cough monitoring could be used as a prognosis biomarker to predict unfavorable clinical outcomes in COVID-19 disease. With early sampling periods showing good predictive value, this digital biomarker could be combined with clinical and paraclinical evaluation and is well adapted for triaging patients in overwhelmed or resources-limited health programs.

High-throughput digital cough recording on a university campus: A SARS-CoV-2-negative curated open database and operational template for acoustic screening of respiratory diseases.

Objective: Respiratory illnesses have information-rich acoustic biomarkers, such as cough, that can potentially play an important role in screening populations for disease risk. To realize that potential, datasets of paired acoustic-clinical samples are needed for the development and validation of acoustic screening models, and protocols for collecting acoustic samples must be efficient and safe. We collected cough acoustic signatures at a high-throughput SARS-CoV-2 testing site on a college campus. Here, we share logistical details and the dataset of acoustic cough signatures paired with the gold standard in SARS-CoV-2 testing of SARS-CoV-2 genomic sequences using qRT-PCR. Methods: Cough recordings were collected in winter-spring 2021 at a rural residential college (Sewanee, TN, USA), where approximately 2000 students were tested for SARS-CoV-2 on a weekly basis. Cough collection was managed by student volunteers using custom software. Results: 4302 coughs were recorded from 960 participants over 11 weeks. All coughs were COVID-19 negative. Approximately 30 s were required to check-in a participant and collect their cough. Conclusion: The value of acoustic screening tools depends upon our ability to develop and implement them reliably and quickly. For that to happen, high-quality datasets and logistical insights must be collected and shared on an ongoing basis.

The impact of a malaria elimination initiative on school outcomes: Evidence from Southern Mozambique.

Despite the significant improvements achieved over the last ten years, primary education attainment in Mozambique is still low. Potential reasons acting from the demand perspective include ill health, among other factors. In Mozambique, ill health is still largely linked to malaria, which is a leading cause of outpatient contacts, hospital admissions and death, particularly among under-five and school-aged children. Despite this, in Mozambique and more generally, in malaria endemic countries, the identification and measurement of how improved malaria indicators may contribute to better school outcomes remains largely unknown. In particular, there is a low understanding of the extent to which better health translates immediately into school indicators, such as absenteeism and grades. In this study, we exploit the first year of a malaria elimination initiative implemented in Magude district (Southern Mozambique) that started in 2015, as a quasi-experiment to estimate the impact of malaria on selected primary school outcomes. While malaria was not eliminated, its incidence drastically dropped. We use as control a neighbouring district (Manhiça) with similar socio-economic and epidemiological characteristics. By employing a difference-in-differences (DiD) approach, we examine whether the positive health shock translated into improved school outcomes. Using information from school registers, we generated a dataset on school attendance and grades for 9,848 primary-school students from 9 schools (4 in the treated district and 5 in the control district). In our main specification, a repeated cross-section analysis, we find that the elimination initiative led to a 28% decrease in school absenteeism and a 2% increase in students' grades. Our results are robust across different specifications, including a panel DiD individual fixed effects estimate on a sub-sample of students. These findings provide evidence on the negative impact of malaria on primary education attainment and suggest remarkable economic benefits consequent to its elimination.

Digital acoustic surveillance for early detection of respiratory disease outbreaks in Spain: a protocol for an observational study.

INTRODUCTION: Cough is a common symptom of COVID-19 and other respiratory illnesses. However, objectively measuring its frequency and evolution is hindered by the lack of reliable and scalable monitoring systems. This can be overcome by newly developed artificial intelligence models that exploit the portability of smartphones. In the context of the ongoing COVID-19 pandemic, cough detection for respiratory disease syndromic surveillance represents a simple means for early outbreak detection and disease surveillance. In this protocol, we evaluate the ability of population-based digital cough surveillance to predict the incidence of respiratory diseases at population level in Navarra, Spain, while assessing individual determinants of uptake of these platforms. METHODS AND ANALYSIS: Participants in the Cendea de Cizur, Zizur Mayor or attending the local University of Navarra (Pamplona) will be invited to monitor their night-time cough using the smartphone app Hyfe Cough Tracker. Detected coughs will be aggregated in time and space. Incidence of COVID-19 and other diagnosed respiratory diseases within the participants cohort, and the study area and population will be collected from local health facilities and used to carry out an autoregressive moving average analysis on those independent time series. In a mixed-methods design, we will explore barriers and facilitators of continuous digital cough monitoring by evaluating participation patterns and sociodemographic characteristics. Participants will fill an acceptability questionnaire and a subgroup will participate in focus group discussions. ETHICS AND DISSEMINATION: Ethics approval was obtained from the ethics committee of the Centre Hospitalier de l'Université de Montréal, Canada and the Medical Research Ethics Committee of Navarre, Spain. Preliminary findings will be shared with civil and health authorities and reported to individual participants. Results will be submitted for publication in peer-reviewed scientific journals and international conferences. TRIAL REGISTRATION NUMBER: NCT04762693.

The short-term impact of a malaria elimination initiative in Southern Mozambique: Application of the synthetic control method to routine surveillance data.

In public health epidemiology, quasi-experimental methods are widely used to estimate the causal impacts of interventions. In this paper, we demonstrate the contribution the synthetic control method (SCM) can make in evaluating public health interventions, when routine surveillance data are available and the validity of other quasi-experimental approaches may be in question. In our application, we evaluate the short-term effects of a large-scale Mass Drug Administration (MDA) based malaria elimination initiative in Southern Mozambique. We apply the SCM to district level weekly malaria incidence data and compare the observed reduction in age group specific malaria incidence. Between August 2015 and April 2017, a total of 13,322 (78%) cases of malaria were averted relative to the synthetic control. During the peak malaria seasons, the elimination initiative resulted in an 87% reduction in Year 1 (December 2015-April 2016), and 79% reduction in Year 2 (December 2016-April 2017). Comparison with an interrupted time series approach shows the SCM accounts for pre-intervention trends in the data and post-intervention weather events influencing malaria cases. We conclude MDA brought about a drastic reduction in malaria burden and can be a useful addition to existing (or new) vector control strategies and tools in accelerating towards elimination.

Modelling distributions of Aedes aegypti and Aedes albopictus using climate, host density and interspecies competition.

Florida faces the challenge of repeated introduction and autochthonous transmission of arboviruses transmitted by Aedes aegypti and Aedes albopictus. Empirically-based predictive models of the spatial distribution of these species would aid surveillance and vector control efforts. To predict the occurrence and abundance of these species, we fit a mixed-effects zero-inflated negative binomial regression to a mosquito surveillance dataset with records from more than 200,000 trap days, representative of 53% of the land area and ranging from 2004 to 2018 in Florida. We found an asymmetrical competitive interaction between adult populations of Aedes aegypti and Aedes albopictus for the sampled sites. Wind speed was negatively associated with the occurrence and abundance of both vectors. Our model predictions show high accuracy (72.9% to 94.5%) in validation tests leaving out a random 10% subset of sites and data since 2017, suggesting a potential for predicting the distribution of the two Aedes vectors.

The effect of early treatment with ivermectin on viral load, symptoms and humoral response in patients with non-severe COVID-19: A pilot, double-blind, placebo-controlled, randomized clinical trial.

BACKGROUND: Ivermectin inhibits the replication of SARS-CoV-2 in vitro at concentrations not readily achievable with currently approved doses. There is limited evidence to support its clinical use in COVID-19 patients. We conducted a Pilot, randomized, double-blind, placebo-controlled trial to evaluate the efficacy of a single dose of ivermectin reduce the transmission of SARS-CoV-2 when administered early after disease onset. METHODS: Consecutive patients with non-severe COVID-19 and no risk factors for complicated disease attending the emergency room of the Clínica Universidad de Navarra between July 31, 2020 and September 11, 2020 were enrolled. All enrollments occurred within 72 h of onset of fever or cough. Patients were randomized 1:1 to receive ivermectin, 400 mcg/kg, single dose (n = 12) or placebo (n = 12). The primary outcome measure was the proportion of patients with detectable SARS-CoV-2 RNA by PCR from nasopharyngeal swab at day 7 post-treatment. The primary outcome was supported by determination of the viral load and infectivity of each sample. The differences between ivermectin and placebo were calculated using Fisher's exact test and presented as a relative risk ratio. This study is registered at ClinicalTrials.gov: NCT04390022. FINDINGS: All patients recruited completed the trial (median age, 26 [IQR 19-36 in the ivermectin and 21-44 in the controls] years; 12 [50%] women; 100% had symptoms at recruitment, 70% reported headache, 62% reported fever, 50% reported general malaise and 25% reported cough). At day 7, there was no difference in the proportion of PCR positive patients (RR 0·92, 95% CI: 0·77-1·09, p = 1·0). The ivermectin group had non-statistically significant lower viral loads at day 4 (p = 0·24 for gene E; p = 0·18 for gene N) and day 7 (p = 0·16 for gene E; p = 0·18 for gene N) post treatment as well as lower IgG titers at day 21 post treatment (p = 0·24). Patients in the ivermectin group recovered earlier from hyposmia/anosmia (76 vs 158 patient-days; p < 0.001). INTERPRETATION: Among patients with non-severe COVID-19 and no risk factors for severe disease receiving a single 400 mcg/kg dose of ivermectin within 72 h of fever or cough onset there was no difference in the proportion of PCR positives. There was however a marked reduction of self-reported anosmia/hyposmia, a reduction of cough and a tendency to lower viral loads and lower IgG titers which warrants assessment in larger trials. FUNDING: ISGlobal, Barcelona Institute for Global Health and Clínica Universidad de Navarra.

Researchers' perceptions of malaria eradication: findings from a mixed-methods analysis of a large online survey.

BACKGROUND: The value of malaria eradication, the permanent reduction to zero of the worldwide incidence of malaria infection caused by human malaria parasites, would be enormous. However, the expected value of an investment in an intended, but uncertain, outcome hinges on the probability of, and time until, its fulfilment. Though the long-term benefits of global malaria eradication promise to be large, the upfront costs and uncertainty regarding feasibility and timeframe make it difficult for policymakers and researchers to forecast the return on investment. METHODS: A large online survey of 844 peer-reviewed malaria researchers of different scientific backgrounds administered in order to estimate the probability and time frame of eradication. Adjustments were made for potential selection bias, and thematic analysis of free text comments was carried out. RESULTS: The average perceived likelihood of global eradication among malaria researchers approximates the number of years into the future: approximately 10% of researchers believe that eradication will occur in the next 10 years, 30% believe it will occur in the next 30 years, and half believe eradication will require 50 years or more. Researchers who gave free form comments highlighted systemic challenges and the need for innovation as chief among obstacles to achieving global malaria eradication. CONCLUSIONS: The findings highlight the difficulty and complexity of malaria eradication, and can be used in prospective cost-benefit analyses to inform stakeholders regarding the likely return on eradication-specific investments.

Evidence of high bed net usage from a list randomization experiments in rural Gambia.

BACKGROUND: Recording behaviours that have the potential to impact health can be doubly challenging if the behaviour takes place in private spaces that cannot be observed directly, and where respondents answer what they think the recorder may want to hear. Sleeping under a long-lasting insecticidal net (LLIN) is an important intervention for malaria prevention, yet it is difficult to gauge the extent to which coverage (how many nets are in the community) differs from usage (how many people actually sleep under a net). List randomization, a novel method which partially obscures respondents' answers to sensitive questions, was employed to estimate LLIN usage in The Gambia. METHODS: 802 heads-of-household from 15 villages were recruited into a randomized controlled trial assessing the effect of a housing intervention on malaria. These houses were randomly assigned to a housing intervention versus control, with stratification by village so as to ensure balance between arms. From these, 125 households (63 intervention, 52 control) were randomly selected for participation in the list randomization experiment, along with 68 households from the same villages but which were not part of the housing improvement study, resulting in a total of 196 households for the list randomization experiment. Approximately half (n = 97) of the 196 study participants were randomly assigned to the control group and received a four-question list about non-sensitive behaviours; the intervention group (n = 99) received the same list, with the addition of one question on a sensitive behaviour: whether or not they had used a bed net the previous night. Participants were read the list of questions and then said how many of the statements were true. Bed net usage was estimated by calculating the difference in means between the number of affirmative responses between the two groups. RESULTS: The mean number of affirmative responses in the control group was 2.60 of four statements (95% confidence interval, 95% CI 2.50-2.70), compared with 3.68 (95% CI 3.59-3.78) in the intervention group. Such difference (1.08; 95% CI 94.9-100%) suggests near universal bed net usage. CONCLUSIONS: Bed net usage by household heads in these rural villages was found to be high. Though not entirely unexpected given other studies' estimates of high bed net usage in the area, the list randomization method should be further validated in an area with lower coverage.

The SARS-CoV-2 Ivermectin Navarra-ISGlobal Trial (SAINT) to Evaluate the Potential of Ivermectin to Reduce COVID-19 Transmission in low risk, non-severe COVID-19 patients in the first 48 hours after symptoms onset: A structured summary of a study protocol for a randomized control pilot trial.

OBJECTIVES: The primary objective is to determine the efficacy of a single dose of ivermectin, administered to low risk, non-severe COVID-19 patients in the first 48 hours after symptom onset to reduce the proportion of patients with detectable SARS-CoV-2 RNA by Polymerase Chain Reaction (PCR) test from nasopharyngeal swab at day 7 post-treatment. The secondary objectives are: 1.To assess the efficacy of ivermectin to reduce the SARS-CoV-2 viral load in the nasopharyngeal swab at day 7 post treatment.2.To assess the efficacy of ivermectin to improve symptom progression in treated patients.3.To assess the proportion of seroconversions in treated patients at day 21.4.To assess the safety of ivermectin at the proposed dose.5.To determine the magnitude of immune response against SARS-CoV-2.6.To assess the early kinetics of immunity against SARS-CoV-2. TRIAL DESIGN: SAINT is a single centre, double-blind, randomized, placebo-controlled, superiority trial with two parallel arms. Participants will be randomized to receive a single dose of 400 µg/kg ivermectin or placebo, and the number of patients in the treatment and placebo groups will be the same (1:1 ratio). PARTICIPANTS: The population for the study will be patients with a positive nasopharyngeal swab PCR test for SARS-CoV-2, with non-severe COVID-19 disease, and no risk factors for progression to severity. Vulnerable populations such as pregnant women, minors (i.e.; under 18 years old), and seniors (i.e.; over 60 years old) will be excluded. Inclusion criteria 1. Patients diagnosed with COVID-19 in the emergency room of the Clínica Universidad de Navarra (CUN) with a positive SARS-CoV-2 PCR. 2. Residents of the Pamplona basin ("Cuenca de Pamplona"). 3. The patient must be between the ages of 18 and 60 years of age. 4. Negative pregnancy test for women of child bearing age*. 5. The patient or his/her representative, has given informed consent to participate in the study. 6. The patient should, in the PI's opinion, be able to comply with all the requirements of the clinical trial (including home follow up during isolation). Exclusion criteria 1. Known history of ivermectin allergy. 2. Hypersensitivity to any component of ivermectin. 3. COVID-19 pneumonia. Diagnosed by the attending physician.Identified in a chest X-ray. 4. Fever or cough present for more than 48 hours. 5. Positive IgG against SARS-CoV-2 by rapid diagnostic test. 6. Age under 18 or over 60 years. 7. The following co-morbidities (or any other disease that might interfere with the study in the eyes of the PI): Immunosuppression.Chronic Obstructive Pulmonary Disease.Diabetes.Hypertension.Obesity.Acute or chronic renal failure.History of coronary disease.History of cerebrovascular disease.Current neoplasm. 8. Recent travel history to countries that are endemic for Loa loa (Angola, Cameroon, Central African Republic, Chad, Democratic Republic of Congo, Ethiopia, Equatorial, Guinea, Gabon, Republic of Congo, Nigeria and Sudan). 9. Current use of CYP 3A4 or P-gp inhibitor drugs such as quinidine, amiodarone, diltiazem, spironolactone, verapamil, clarithromycin, erythromycin, itraconazole, ketoconazole, cyclosporine, tacrolimus, indinavir, ritonavir or cobicistat. Use of critical CYP3A4 substrate drugs such as warfarin. *Women of child bearing age may participate if they use a safe contraceptive method for the entire period of the study and at least one month afterwards. A woman is considered to not have childbearing capacity if she is post-menopausal (minimum of 2 years without menstruation) or has undergone surgical sterilization (at least one month before the study). The trial is currently planned at a single center, Clínica Universidad de Navarra, in Navarra (Spain), and the immunology samples will be analyzed at the Barcelona Institute for Global Health (ISGlobal), in Barcelona (Spain). Participants will be recruited by the investigators at the emergency room and/or COVID-19 area of the CUN. They will remain in the trial for a period of 28 days at their homes since they will be patients with mild disease. In the interest of public health and to contain transmission of infection, follow-up visits will be conducted in the participant's home by a clinical trial team comprising nursing and medical members. Home visits will assess clinical and laboratory parameters of the patients. INTERVENTION AND COMPARATOR: Ivermectin will be administered to the treatment group at a 400µg/Kg dose (included in the EU approved label of Stromectol and Scabioral). The control group will receive placebo. There is no current data on the efficacy of ivermectin against the virus in vivo, therefore the use of placebo in the control group is ethically justified. MAIN OUTCOMES: Primary Proportion of patients with a positive SARS-CoV-2 PCR from a nasopharyngeal swab at day 7 post-treatment. Secondary 1.Mean viral load as determined by PCR cycle threshold (Ct) at baseline and on days 4, 7, 14, and 21.2.Proportion of patients with fever and cough at days 4, 7, 14, and 21 as well as proportion of patients progressing to severe disease or death during the trial.3.Proportion of patients with seroconversion at day 21.4.Proportion of drug-related adverse events during the trial.5.Median levels of IgG, IgM, IgA measured by Luminex, frequencies of innate and SARS-CoV-2-specific T cells assessed by flow cytometry, median levels of inflammatory and activation markers measured by Luminex and transcriptomics.6.Median kinetics of IgG, IgM, IgA levels during the trial, until day 28. RANDOMISATION: Eligible patients will be allocated in a 1:1 ratio using a randomization list generated by the trial statistician using blocks of four to ensure balance between the groups. A study identification code with the format "SAINT-##" (##: from 01 to 24) will be generated using a sequence of random numbers so that the randomization number does not match the subject identifier. The sequence and code used will be kept in an encrypted file accessible only to the trial statistician. A physical copy will be kept in a locked cabinet at the CUN, accessible only to the person administering the drug who will not enrol or attend to patient care. A separate set of 24 envelopes for emergency unblinding will be kept in the study file. BLINDING (MASKING): The clinical trial team and the patients will be blinded. The placebo will not be visibly identical, but it will be administered by staff not involved in the clinical care or participant follow up. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): The sample size is 24 patients: 12 participants will be randomised to the treatment group and 12 participants to the control group. TRIAL STATUS: Current protocol version: 1.0 dated 16 of April 2020. Recruitment is envisioned to begin by May 14th and end by June 14th. TRIAL REGISTRATION: EudraCT number: 2020-001474-29, registered April 1st. Clinicaltrials.gov: submitted, pending number FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

VAR2CSA Serology to Detect Plasmodium falciparum Transmission Patterns in Pregnancy.

Pregnant women constitute a promising sentinel group for continuous monitoring of malaria transmission. To identify antibody signatures of recent Plasmodium falciparum exposure during pregnancy, we dissected IgG responses against VAR2CSA, the parasite antigen that mediates placental sequestration. We used a multiplex peptide-based suspension array in 2,354 samples from pregnant women from Mozambique, Benin, Kenya, Gabon, Tanzania, and Spain. Two VAR2CSA peptides of limited polymorphism were immunogenic and targeted by IgG responses readily boosted during infection and with estimated half-lives of <2 years. Seroprevalence against these peptides reflected declines and rebounds of transmission in southern Mozambique during 2004-2012, reduced exposure associated with use of preventive measures during pregnancy, and local clusters of transmission that were missed by detection of P. falciparum infections. These data suggest that VAR2CSA serology can provide a useful adjunct for the fine-scale estimation of the malaria burden among pregnant women over time and space.

Bi-directional drones to strengthen healthcare provision: experiences and lessons from Madagascar, Malawi and Senegal.

Drones are increasingly being used globally for the support of healthcare programmes. Madagascar, Malawi and Senegal are among a group of early adopters piloting the use of bi-directional transport drones for health systems in sub-Saharan Africa. This article presents the experiences as well as the strengths, weaknesses, opportunities and threats (SWOT analysis) of these country projects. Methods for addressing regulatory, feasibility, acceptability, and monitoring and evaluation issues are presented to guide future implementations. Main recommendations for governments, implementers, drone providers and funders include (1) developing more reliable technologies, (2) thorough vetting of drone providers' capabilities during the selection process, (3) using and strengthening local capacity, (4) building in-country markets and businesses to maintain drone operations locally, (5) coordinating efforts among all stakeholders under government leadership, (6) implementing and identifying funding for long-term projects beyond pilots, and (7) evaluating impacts via standardised indicators. Sharing experiences and evidence from ongoing projects is needed to advance the use of drones for healthcare.

Mapping the potential use of endectocide-treated cattle to reduce malaria transmission.

Treating cattle with endectocide is a longstanding veterinary practice to reduce the load of endo and ectoparasites, but has the potential to be added to the malaria control and elimination toolbox, as it also kills malaria mosquitoes feeding on the animals. Here we used openly available data to map the areas of the African continent where high malaria prevalence in 2-10 year old children coincides with a high density of cattle and high density of the partly zoophilic malaria vector Anopheles arabiensis. That is, mapping the areas where treating cattle with endectocide would potentially have the greatest impact on reducing malaria transmission. In regions of Africa that are not dominated by rainforest nor desert, the map shows a scatter of areas in several countries where this intervention shows potential, including central and eastern sub-Saharan Africa. The savanna region underneath the Sahel in West Africa appears as the climatic block that would benefit to the largest extent from this intervention, encompassing several countries. West Africa currently presents the highest under-10 malaria prevalence and elimination within the next twenty years cannot be contemplated there with currently available interventions alone, making the use of endectocide treated cattle as a complementary intervention highly appealing.

A Systematic Review of the Incremental Costs of Implementing a New Vaccine in the Expanded Program of Immunization in Sub-Saharan Africa.

Background. The World Health Organization is planning a pilot introduction of a new malaria vaccine in three sub-Saharan African countries. To inform considerations about including a new vaccine in the vaccination program of those and other countries, estimates from the scientific literature of the incremental costs of doing so are important. Methods. A systematic review of scientific studies reporting the costs of recent vaccine programs in sub-Saharan countries was performed. The focus was to obtain from each study an estimate of the cost per dose of vaccine administered excluding the acquisition cost of the vaccine and wastage. Studies published between 2000 and 2018 and indexed on PubMed could be included and results were standardized to 2015 US dollars (US$). Results. After successive screening of 2119 titles, and 941 abstracts, 58 studies with 80 data points (combinations of country, vaccine type, and vaccination approach-routine v. campaign) were retained. Most studies used the so-called ingredients approach as costing method combining field data collection with documented unit prices per cost item. The categorization of cost items and the extent of detailed reporting varied widely. Across the studies, the mean and median cost per dose administered was US$1.68 and US$0.88 with an interquartile range of US$0.54 to US$2.31. Routine vaccination was more costly than campaigns, with mean cost per dose of US$1.99 and US$0.88, respectively. Conclusion. Across the studies, there was huge variation in the cost per dose delivered, between and within countries, even in studies using consistent data collection tools and analysis methods, and including many health facilities. For planning purposes, the interquartile range of US$0.54 to US$2.31 may be a sufficiently precise estimate.

What is the true tuberculosis mortality burden? Differences in estimates by the World Health Organization and the Global Burden of Disease study.

Background: The World Health Organization (WHO) and the Global Burden of Disease (GBD) study at the Institute for Health Metrics and Evaluation (IHME) periodically provide global estimates of tuberculosis (TB) mortality. We compared the 2015 WHO and GBD TB mortality estimates and explored which factors might drive the differences. Methods: We extracted the number of estimated TB-attributable deaths, disaggregated by age, HIV status, sex and country from publicly available WHO and GBD datasets for the year 2015. We 'standardized' differences between sources by adjusting each country's difference in absolute number of deaths by the average number of deaths estimated by both sources. Results: For 195 countries with estimates from both institutions, WHO estimated 1 768 482 deaths attributable to TB, whereas GBD estimated 1 322 916 deaths, a difference of 445 566 deaths or 29% of the average of the two estimates. The countries with the largest absolute differences in deaths were Nigeria (216 621), Bangladesh (49 863) and Tanzania (38 272). The standardized difference was not associated with HIV prevalence, prevalence of multidrug resistance or global region, but did show correlation with the case detection rate as estimated by WHO [r = -0.37, 95% confidence interval (CI): -049; -0.24] or, inversely, with case detection rate based on GBD data (r = 0.44, 95% CI: 0.31; 0.54). Countries with a recent national prevalence survey had higher standardized differences (higher estimates by WHO) than those without (P = 0.006). After exclusion of countries with recent prevalence surveys, the overall correlation between both estimates was r = 0.991. Conclusions: A few countries account for the large global discrepancy in TB mortality estimates. The differences are due to the methodological approaches used by WHO and GBD. The use and interpretation of prevalence survey data and case detection rates seem to play a role in the observed differences.

Combination of indoor residual spraying with long-lasting insecticide-treated nets for malaria control in Zambezia, Mozambique: a cluster randomised trial and cost-effectiveness study protocol.

BACKGROUND: Most of the reduction in malaria prevalence seen in Africa since 2000 has been attributed to vector control interventions. Yet increases in the distribution and intensity of insecticide resistance and higher costs of newer insecticides pose a challenge to sustaining these gains. Thus, endemic countries face challenging decisions regarding the choice of vector control interventions. METHODS: A cluster randomised trial is being carried out in Mopeia District in the Zambezia Province of Mozambique, where malaria prevalence in children under 5 is high (68% in 2015), despite continuous and campaign distribution of long-lasting insecticide-treated nets (LLINs). Study arm 1 will continue to use the standard, LLIN-based National Malaria Control Programme vector control strategy (LLINs only), while study arm 2 will receive indoor residual spraying (IRS) once a year for 2 years with a microencapsulated formulation of pirimiphos-methyl (Actellic 300 CS), in addition to the standard LLIN strategy (LLINs+IRS). Prior to the 2016 IRS implementation (the first of two IRS campaigns in this study), 146 clusters were defined and stratified per number of households. Clusters were then randomised 1:1 into the two study arms. The public health impact and cost-effectiveness of IRS intervention will be evaluated over 2 years using multiple methods: (1) monthly active malaria case detection in a cohort of 1548 total children aged 6-59 months; (2) enhanced passive surveillance at health facilities and with community health workers; (3) annual cross-sectional surveys; and (4) entomological surveillance. Prospective microcosting of the intervention and provider and societal costs will be conducted. Insecticide resistance status pattern and changes in local Anopheline populations will be included as important supportive outcomes. DISCUSSION: By evaluating the public health impact and cost-effectiveness of IRS with a non-pyrethroid insecticide in a high-transmission setting with high LLIN ownership, it is expected that this study will provide programmatic and policy-relevant data to guide national and global vector control strategies. TRIAL REGISTRATION NUMBER: NCT02910934.

IP-10 Kinetics in the First Week of Therapy are Strongly Associated with Bacteriological Confirmation of Tuberculosis Diagnosis in HIV-Infected Patients.

Simple effective tools to monitor the long treatment of tuberculosis (TB) are lacking. Easily measured host derived biomarkers have been identified but need to be validated in larger studies and different population groups. Here we investigate the early response in IP-10 levels (between day 0 and day 7 of TB therapy) to identify bacteriological status at diagnosis among 127 HIV-infected patients starting TB treatment. All participants were then classified as responding or not responding to treatment blindly using a previously described IP-10 kinetic algorithm. There were 77 bacteriologically confirmed cases and 41 Xpert MTB/RIF® and culture negative cases. Most participants had a measurable decline in IP-10 during the first 7 days of therapy. Bacteriologically confirmed cases were more likely to have high IP-10 levels at D0 and had a steeper decline than clinically diagnosed cases (mean decline difference 2231 pg/dl, 95% CI: 897-3566, p = 0.0013). Bacteriologically confirmed cases were more likely to have a measurable decline in IP-10 at day 7 than clinically diagnosed cases (48/77 (62.3%) vs 13/41 (31.7%), p < 0.001). This study confirms the association between a decrease in IP-10 levels during the first week of treatment and a bacteriological confirmation at diagnosis in a large cohort of HIV positive patients.