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The basic reproduction number (R0) is an established concept to describe the potential for an infectious disease to cause an epidemic and to derive estimates of the required effect of interventions for successful control. Calculating R0 from simple deterministic transmission models may result in biased estimates when important sources of heterogeneity related to transmission and control are ignored. Using stochastic simulations with a geographically stratified individual-based SEIR (susceptible, exposed, infectious, recovered) model, we illustrate that if heterogeneity is ignored (i.e. no or too little assumed interindividual variation or assortative mixing) this may substantially overestimate the transmission rate and the potential course of the epidemic. Consequently, predictions for the impact of interventions then become relatively pessimistic. However, should such an intervention be suspended, then the potential for a consecutive epidemic wave will depend strongly on assumptions about heterogeneity, with more heterogeneity resulting in lower remaining epidemic potential, due to selection and depletion of high-risk individuals during the early stages of the epidemic. These phenomena have likely also affected current model predictions regarding COVID-19, as most transmission models assume homogeneous mixing or at most employ a simple age stratification, thereby leading to overcautious predictions of durations of lockdowns and required vaccine coverage levels.

WHO's 2021-30 road map for neglected tropical diseases (NTDs) outlines disease-specific and cross-cutting targets for the control, elimination, and eradication of NTDs in affected countries. For schistosomiasis, the criterion for elimination as a public health problem (EPHP) is defined as less than 1% prevalence of heavy-intensity infections (ie, ≥50 Schistosoma haematobium eggs per 10 mL of urine or ≥400 Schistosoma mansoni eggs per g of stool). However, we believe the evidence supporting this definition of EPHP is inadequate and the shifting distribution of schistosomiasis morbidity towards more subtle, rather than severe, morbidity in the face of large-scale control programmes requires guidelines to be adapted. In this Viewpoint, we outline the need for more accurate measures to develop a robust evidence-based monitoring and evaluation framework for schistosomiasis. Such a framework is crucial for achieving the goal of widespread EPHP of schistosomiasis and to meet the WHO road map targets. We encourage use of overall prevalence of schistosome infection (instead of the prevalence of heavy-intensity infections), development of species-dependent and age-dependent morbidity markers, and construction of a standardised monitoring and evaluation protocol.

BackgroundTo monitor and evaluate soil-transmitted helminth (STH) control programs, the World Health Organization (WHO) recommends screening stools from 250 children across 5 schools, deploying Kato-Katz thick smear (KK). However, it remains unclear whether these recommendations are sufficient to make adequate decisions about stopping preventive chemotherapy (PC) (prevalence of infection MethodologyWe developed a simulation framework to determine the effectiveness and cost of survey designs for decision-making in STH control programs, capturing the operational resources to perform surveys, the variation in egg counts across STH species, across schools, between and within individuals, and between repeated smears. Using this framework and a lot quality assurance sampling approach, we determined the most cost-efficient survey designs (number of schools, subjects, stool samples per subject, and smears per stool sample) for decision-making.Principal findingsFor all species, employing duplicate KK (sampling 4 to 6 schools and 64 to 70 subjects per school) was the most cost-efficient survey design to assess whether prevalence of any infection intensity was above or under 2%. For prevalence of MHI infections, single KK was the most cost-efficient (sampling 11 to 25 schools and 52 to 84 children per school).Conclusions/SignificanceKK is valuable for monitoring and evaluation of STH control programs, though we recommend to deploy a duplicate KK on a single stool sample to stop PC, and a single KK to declare the elimination of STH as a public health problem.Author summaryWorldwide large-scale deworming programs are implemented to reduce the morbidity attributable to intestinal worms in school children. To monitor and evaluate the progress towards the programs goals, Word Health Organization (WHO) has developed both a survey design and a corresponding decision tree based on the prevalence and intensity of infections. However, these programs operate in resource-constrained countries, and hence it is crucial to minimize the operational costs to survey worm infections while ensuring the correctness of the program decision. To further support WHO in more evidence-based recommendations for cost-efficient decision-making, we developed a general framework that captures both the operational resources to perform surveys and the variation in test results when deploying the current diagnostic standard. Subsequently, we determined the most cost-efficient survey design to decide to stop the deworming programs and to verify whether the morbidity attributable to intestinal worms has been eliminated as a public health problem. Generally, we found that the current WHO-recommended survey design may not allow for optimal decision making. Based on our results, we proposed alternative survey designs for each of the worm species and program targets.

BackgroundSoil-transmitted helminth (STH) control programs currently lack evidence-based recommendations for cost-efficient survey designs for monitoring and evaluation. Here, we present a framework to provide evidence-based recommendations, using a case study of therapeutic drug efficacy monitoring based on the examination of helminth eggs in stool.MethodsWe performed an in-depth analysis of the operational costs to process one stool sample for three diagnostic methods (Kato-Katz, Mini-FLOTAC and FECPAKG2). Next, we performed simulations to determine the probability of detecting a truly reduced therapeutic efficacy for different scenarios of STH species (Ascaris lumbricoides, Trichuris trichiuraand hookworms), pre-treatment infection levels, survey design (screen and select (SS); screen, select and retest (SSR) and no selection (NS)) and number of subjects enrolled (10 – 2,000). Finally, we integrated the outcome of the cost assessment into the simulation study to estimate the total survey costs and determined the most cost-efficient survey design.Principal FindingsKato-Katz allowed for both the highest sample throughput and the lowest cost per test, while FECPAKG2required both the most laboratory time and was the most expensive. Counting of eggs accounted for 23% (FECPAKG2) or ≥80% (Kato-Katz and Mini-FLOTAC) of the total time-to-result.NSsurvey designs in combination with Kato-Katz were the most cost-efficient to assess therapeutic drug efficacy in all scenarios of STH species and endemicity.Conclusions/significanceWe confirm that Kato-Katz is the fecal egg counting method of choice for monitoring therapeutic drug efficacy, but that the survey design currently recommended by WHO (SS) should be updated. Our generic framework, which captures laboratory time and material costs, can be used to further support cost-efficient choices for other important surveys informing STH control programs. In addition, it can be used to explore the value of alternative diagnostic techniques, like automated egg counting, which may further reduce operational costs.Author SummaryLarge-scale deworming programs are implemented worldwide to reduce morbidity caused by intestinal worms. As these programs operate in resource-poor-settings, it is important that their operational costs are minimized without jeopardizing the quality of decision-making. We present a framework for evidence-based recommendations for cost-efficient decision-making in deworming programs, using monitoring of therapeutic drug efficacy via stool examination as a case study. To this end, we first assessed the time and the cost of processing stool samples in a laboratory according to different diagnostic methods. Then for each diagnostic method, survey design, and a range of settings (pre-dominant worm species and pre-treatment infection levels), we calculated the probability of correctly detecting a truly reduced therapeutic drug efficacy and the associated operational costs. Generally, the estimated operational costs varied across diagnostic method, survey design, worm species and disease endemicity. Based on our findings, we conclude that the use of the current diagnostic standard, the Kato-Katz method, is justified to assess drug efficacy, but that a change in survey design is warranted. Our methodology, which leverages detailed data on laboratory time and material costs, can also be used to provide evidence-based recommendations for other types of decisions in large-scale deworming programs.

Background Soil-transmitted helminth (STH) control programs currently lack evidence-based recommendations for cost-efficient survey designs for monitoring and evaluation. Here, we present a framework to provide evidence-based recommendations, using a case study of therapeutic drug efficacy monitoring based on the examination of helminth eggs in stool. Methods We performed an in-depth analysis of the operational costs to process one stool sample for three diagnostic methods (Kato-Katz, Mini-FLOTAC and FECPAKG2). Next, we performed simulations to determine the probability of detecting a truly reduced therapeutic efficacy for different scenarios of STH species (Ascaris lumbricoides, Trichuris trichiura and hookworms), pre-treatment infection levels, survey design (screen and select (SS); screen, select and retest (SSR) and no selection (NS)) and number of subjects enrolled (100–5,000). Finally, we integrated the outcome of the cost assessment into the simulation study to estimate the total survey costs and determined the most cost-efficient survey design. Principal findings Kato-Katz allowed for both the highest sample throughput and the lowest cost per test, while FECPAKG2 required both the most laboratory time and was the most expensive. Counting of eggs accounted for 23% (FECPAKG2) or ≥80% (Kato-Katz and Mini-FLOTAC) of the total time-to-result. NS survey designs in combination with Kato-Katz were the most cost-efficient to assess therapeutic drug efficacy in all scenarios of STH species and endemicity. Conclusions/significance We confirm that Kato-Katz is the fecal egg counting method of choice for monitoring therapeutic drug efficacy, but that the survey design currently recommended by WHO (SS) should be updated. Our generic framework, which captures laboratory time and material costs, can be used to further support cost-efficient choices for other important surveys informing STH control programs. In addition, it can be used to explore the value of alternative diagnostic techniques, like automated egg counting, which may further reduce operational costs. Trial Registration ClinicalTrials.gov NCT03465488

Background Due to spatial heterogeneity in onchocerciasis transmission, the duration of ivermectin mass drug administration (MDA) required for eliminating onchocerciasis will vary within endemic areas and the occurrence of transmission “hotspots” is inevitable. The geographical scale at which stop-MDA decisions are made will be a key driver in how rapidly national programs can scale down active intervention upon achieving the epidemiological targets for elimination. Methods We used 2 onchocerciasis models (EPIONCHO-IBM and ONCHOSIM) to predict the likelihood of achieving elimination by 2030 in Africa, accounting for variation in preintervention endemicity levels and histories of ivermectin treatment. We explore how decision making at contrasting geographical scales (community vs larger scale “project”) changes projections on populations still requiring MDA or transitioning to post-treatment surveillance. Results The total population considered grows from 118 million people in 2020 to 136 million in 2030. If stop-MDA decisions are made at project level, the number of people requiring treatment declines from 69–118 million in 2020 to 59–118 million in 2030. If stop-MDA decisions are made at community level, the numbers decline from 23–81 million in 2020 to 15–63 million in 2030. The lower estimates in these prediction intervals are based on ONCHOSIM, the upper limits on EPIONCHO-IBM. Conclusions The geographical scale at which stop-MDA decisions are made strongly determines how rapidly national onchocerciasis programs can scale down MDA programs. Stopping in portions of project areas or transmission zones would free up human and economic resources.

Background Mass drug administration (MDA) with ivermectin is the main strategy for onchocerciasis elimination. Ivermectin is generally safe, but is associated with serious adverse events in individuals with high Loa loa microfilarial densities (MFD). Therefore, ivermectin MDA is not recommended in areas where onchocerciasis is hypo-endemic and L loa is co-endemic. To eliminate onchocerciasis in those areas, a test-and-not-treat (TaNT) strategy has been proposed. We investigated whether onchocerciasis elimination can be achieved using TaNT and the required duration. Methods We used the individual-based model ONCHOSIM to predict the impact of TaNT on onchocerciasis microfilarial (mf) prevalence. We simulated precontrol mf prevalence levels from 2% to 40%. The impact of TaNT was simulated under varying levels of participation, systematic nonparticipation, and exclusion from ivermectin resulting from high L loa MFD. For each scenario, we assessed the time to elimination, defined as bringing onchocerciasis mf prevalence below 1.4%. Results In areas with 30% to 40% precontrol mf prevalence, the model predicted that it would take between 14 and 16 years to bring the mf prevalence below 1.4% using conventional MDA, assuming 65% participation. TaNT would increase the time to elimination by up to 1.5 years, depending on the level of systematic nonparticipation and the exclusion rate. At lower exclusion rates (≤2.5%), the delay would be less than 6 months. Conclusions Our model predicts that onchocerciasis can be eliminated using TaNT in L loa co-endemic areas. The required treatment duration using TaNT would be only slightly longer than in areas with conventional MDA, provided that participation is good., Our model predicts that onchocerciasis can be eliminated using test-and-not-treat (TaNT) in L loa co-endemic areas. The required treatment duration using TaNT would be only slightly longer than in areas with conventional mass drug administration, provided that participation is good.

The design and evaluation of control programs for soil-transmitted helminths (STHs) is based on surveillance data recording measurements of egg counts in the stool of infected individuals, which underpin estimates of the prevalence and average intensity of infection. There is considerable uncertainty around these measurements and their interpretation. The uncertainty is composed of several sources of measurement error and the limit of detection of fecal smear tests on the one hand, and key assumptions on STH biology on the other hand, including assumptions on the aggregation of worms within hosts and on the impact of density-dependent influences on worm reproduction. Using 2 independently developed models of STH transmission we show how different aspects of STH biology and human behavior impact on STH surveillance and control programs and how accounting for uncertainty can help to develop optimal and sustainable control strategies to meet the World Health Organization (WHO) morbidity target for STHs.

Objectives: Sex work sites have been hypothesised to be at the root of the observed heterogeneity in HIV prevalence in sub-Saharan Africa. We determined if proximity to sex work sites is associated with HIV prevalence among the general population in Zimbabwe, a country with one of the highest HIV prevalence in the world. Methods: In this cross-sectional study we use a unique combination of nationally representative geolocated individual-level data from 16,121 adults (age 15–49 years) from 400 sample locations and the locations of 55 sex work sites throughout Zimbabwe; covering an estimated 95% of all female sex workers (FSWs). We calculated the shortest distance by road from each survey sample location to the nearest sex work site, for all sites and by type of sex work site, and conducted univariate and multivariate multilevel logistic regressions to determine the association between distance to sex work sites and HIV seropositivity, controlling for age, sex, male circumcision status, number of lifetime sex partners, being a FSW client or being a stable partner of an FSW client. Results: We found no significant association between HIV seroprevalence and proximity to the nearest sex work site among the general population in Zimbabwe, regardless of which type of site is closest (city site adjusted odds ratio [aOR] 1.010 [95% confidence interval {CI} 0.992–1.028]; economic growth point site aOR 0.982 [95% CI 0.962–1.002]; international site aOR 0.995 [95% CI 0.979–1.012]; seasonal site aOR 0.987 [95% CI 0.968–1.006] and transport site aOR 1.007 [95% CI 0.987–1.028]). Individual-level indicators of sex work were significantly associated with HIV seropositivity: being an FSW client (aOR 1.445 [95% CI 1.188–1.745]); nine or more partners versus having one to three lifetime partners (aOR 2.072 [95% CI 1.654–2.596]). Conclusions: Sex work sites do not seem to directly affect HIV prevalence among the general population in surrounding areas. Prevention and control interventions for HIV at these locations should primarily focus on sex workers and their clients, with special emphasis on including and retaining mobile sex workers and clients into services.

Background Leprosy is known to be unevenly distributed between and within countries. High risk areas or ‘hotspots’ are potential targets for preventive interventions, but the underlying epidemiologic mechanisms that enable hotspots to emerge, are not yet fully understood. In this study, we identified and characterized leprosy hotspots in Bangladesh, a country with one of the highest leprosy endemicity levels globally. Methods We used data from four high-endemic districts in northwest Bangladesh including 20 623 registered cases between January 2000 and April 2019 (among ~ 7 million population). Incidences per union (smallest administrative unit) were calculated using geospatial population density estimates. A geospatial Poisson model was used to detect incidence hotspots over three (overlapping) 10-year timeframes: 2000–2009, 2005–2014 and 2010–2019. Ordinal regression models were used to assess whether patient characteristics were significantly different for cases outside hotspots, as compared to cases within weak (i.e., relative risk (RR) of one to two), medium (i.e., RR of two to three), and strong (i.e., RR higher than three) hotspots. Results New case detection rates dropped from 44/100 000 in 2000 to 10/100 000 in 2019. Statistically significant hotspots were identified during all timeframes and were often located at areas with high population densities. The RR for leprosy was up to 12 times higher for inhabitants of hotspots than for people living outside hotspots. Within strong hotspots (1930 cases among less than 1% of the population), significantly more child cases (i.e., below 15 years of age) were detected, indicating recent transmission. Cases in hotspots were not significantly more likely to be detected actively. Conclusions Leprosy showed a heterogeneous distribution with clear hotspots in northwest Bangladesh throughout a 20-year period of decreasing incidence. Findings confirm that leprosy hotspots represent areas of higher transmission activity and are not solely the result of active case finding strategies.

The COVID-19 pandemic has affected the entire world causing substantial numbers of cases and deaths in most countries. Many have implemented nationwide stringent control to avoid overburdening the health care system. This has paralyzed economic and social activities and may continue to do so until the large-scale availability of a vaccine. We propose an alternative exit strategy to develop herd immunity in a predictable and controllable way: a phased lift of control. This means that successive parts of the country (e.g. provinces) stop stringent control, and COVID-19-related IC admissions are distributed over the country as a whole. Importantly, vulnerable individuals need to be shielded until herd immunity has developed in their area. We explore the characteristics and duration of this strategy using a novel individual-based model for geographically stratified transmission of COVID-19 in a country. The model predicts that individuals will have to experience stringent control for about 14 months on average, but this duration may be almost halved by further developments (more IC beds, better treatments). Clearly, implementation of this strategy would have a profound impact on individuals and society, and should therefore be considered carefully by various other disciplines (e.g. health systems, ethics, economics) before actual implementation.

Background Monitoring and evaluation (M&E) is a key component of large-scale neglected tropical diseases (NTD) control programs. Diagnostic tests deployed in these M&E surveys are often imperfect, and it remains unclear how this affects the population-based program decision-making. Methodology We developed a 2-stage lot quality assurance sampling (LQAS) framework for decision-making that allows for both imperfect diagnostics and spatial heterogeneity of infections. We applied the framework to M&E of soil-transmitted helminth control programs as a case study. For this, we explored the impact of the diagnostic performance (sensitivity and specificity), spatial heterogeneity (intra-cluster correlation), and survey design on program decision-making around the prevalence decisions thresholds recommended by WHO (2%, 10%, 20% and 50%) and the associated total survey costs. Principal findings The survey design currently recommended by WHO (5 clusters and 50 subjects per cluster) may lead to incorrect program decisions around the 2% and 10% prevalence thresholds, even when perfect diagnostic tests are deployed. To reduce the risk of incorrect decisions around the 2% prevalence threshold, including more clusters (≥10) and deploying highly specific diagnostic methods (≥98%) are the most-cost saving strategies when spatial heterogeneity is moderate-to-high (intra-cluster correlation >0.017). The higher cost and lower throughput of improved diagnostic tests are compensated by lower required sample sizes, though only when the cost per test is US$ and sample throughput is ≥3 per hour. Conclusion/Significance Our framework provides a means to assess and update M&E guidelines and guide product development choices for NTD. Using soil-transmitted helminths as a case study, we show that current M&E guidelines may severely fall short, particularly in low-endemic and post-control settings. Furthermore, specificity rather than sensitivity is a critical parameter to consider. When the geographical distribution of an NTD within a district is highly heterogeneous, sampling more clusters (≥10) may be required.

Background The World Health Organization recommends monitoring Onchocerca volvulus Ov16 serology in children aged Methods The individual-based transmission model, EPIONCHO-IBM, was used to assess (1) the most informative age groups for serological monitoring using receiver operating characteristic curves for different elimination thresholds under various age-dependent exposure assumptions, including those of ONCHOSIM (another widely used model), and (2) the influence of within-human density-dependent parasite establishment (included in EPIONCHO-IBM but not ONCHOSIM) on positive predictive values for different serological thresholds. Results When assuming EPIONCHO-IBM exposure patterns, children aged Conclusions Selecting appropriate seromonitoring age groups depends critically on age-dependent exposure patterns. The role of density dependence on elimination thresholds largely explains differing EPIONCHO-IBM and ONCHOSIM elimination predictions.

The low prevalence levels associated with lymphatic filariasis elimination pose a challenge for effective disease surveillance. As more countries achieve the World Health Organization criteria for halting mass treatment and move on to surveillance, there is increasing reliance on the utility of transmission assessment surveys (TAS) to measure success. However, the long-term disease outcomes after passing TAS are largely untested. Using 3 well-established mathematical models, we show that low-level prevalence can be maintained for a long period after halting mass treatment and that true elimination (0% prevalence) is usually slow to achieve. The risk of resurgence after achieving current targets is low and is hard to predict using just current prevalence. Although resurgence is often quick (

BackgroundSoil-transmitted helminths affect almost 2 billion people globally. Hookworm species contribute to most of the related morbidity. Hookworms mainly cause anaemia, due to blood loss at the site of the attachment of the adult worms to the human intestinal mucosa. The World Health Organization (WHO) aims to eliminate hookworm morbidity by 2030 through achieving a prevalence of moderate and heavy intensity (M&HI) infections below 2%. In this paper, we aim to assess the suitability of this threshold to reflect hookworm-attributable morbidity.Methodology/Principal FindingsWe developed a hierarchical statistical model to simulate individual haemoglobin concentrations in association with hookworm burdens, accounting for low haemoglobin values attributable to other causes. The model was fitted to individual-level data within a Bayesian framework. Then, we generated different endemicity settings corresponding to infection prevalence ranging from 10% to 90% (0% to 55% M&HI prevalence), using 1, 2 or 4 Kato-Katz slides. For each scenario, we estimated the prevalence of anaemia due to hookworm. Our results showed that on average, haemoglobin falls below the WHO threshold for anaemia when intensities are above 2000 eggs per gram of faeces. For the different simulated scenarios, the estimated prevalence of anaemia attributable to hookworm ranges from 0% to 30% (95%-PI: 24% - 36%) being mainly associated to the prevalence of M&HI infections. Simulations show that a 2% prevalence of M&HI infections in adults corresponds to a prevalence of hookworm-attributable anaemia lower than 1%.Conclusions/SignificanceOur results support the use of the current WHO thresholds of 2% prevalence of M&HI as a proxy for hookworm morbidity. A single Kato-Katz slide may be sufficient to assess the achievement of the morbidity target. Further studies are needed to elucidate haemoglobin dynamics pre- and post-control, ideally using longitudinal data in adults and children.Author summarySoil-transmitted helminths affect almost 2 billion people globally. About 65% of the related morbidity is attributable to hookworm infection, especially anaemia, which is caused by adult worms attaching to the intestinal mucosa of the human host to feed on blood. The World Health Organization (WHO) defines the target for the elimination of morbidity as reaching moderate-to-heavy intensity infections prevalence < 2%. In this paper, we aim to assess the suitability of the current WHO threshold to reflect hookworm-attributable anaemia. To this end, we developed a statistical model to simulate individual haemoglobin concentrations in association with hookworm burdens in adults, accounting for low haemoglobin values attributable to other causes, such as malnutrition and malaria. We used model outcomes to estimate the prevalence of hookworm-attributable anaemia in different endemicity scenarios. Our predictions suggested that anaemia is mainly associated to moderate-to-heavy intensity infection and that the 2% threshold corresponds to a prevalence of hookworm-attributable anaemia

Background In line with movement restrictions and physical distancing essential for the control of the COVID-19 pandemic, WHO recommended postponement of all neglected tropical disease (NTD) control activities that involve community-based surveys, active case finding, and mass drug administration in April, 2020. Following revised guidance later in 2020, and after interruptions to NTD programmes of varying lengths, NTD programmes gradually restarted in the context of an ongoing pandemic. However, ongoing challenges and service gaps have been reported. This study aimed to evaluate the potential effect of the programmatic interruptions and strategies to mitigate this effect. Methods For seven NTDs, namely soil-transmitted helminths, schistosomiasis, lymphatic filariasis, onchocerciasis, trachoma, visceral leishmaniasis, and human African trypanosomiasis, we used mathematical transmission models to simulate the effect of programme interruptions on the dynamics of each of these diseases in different endemic settings. We also explored the potential benefit of implementing mitigation strategies, primarily in terms of minimising the delays to control targets. Findings We show that the effect of the COVID-19-induced interruption in terms of delay to achieving elimination goals might in some cases be much longer than the duration of the interruption. For schistosomiasis, onchocerciasis, trachoma, and visceral leishmaniasis, a mean delay of 2–3 years for a 1-year interruption is predicted in areas of highest prevalence. We also show that these delays can largely be mitigated by measures such as additional mass drug administration or enhanced case-finding. Interpretation The COVID-19 pandemic has brought infectious disease control to the forefront of global consciousness. It is essential that the NTDs, so long neglected in terms of research and financial support, are not overlooked, and remain a priority in health service planning and funding. Funding Bill & Melinda Gates Foundation, Medical Research Council, and the UK Foreign, Commonwealth & Development Office.

Starting and stopping preventive chemotherapy (PC) for soil-transmitted helminthiasis is typically based on the prevalence of infection as measured by Kato-Katz (KK) fecal smears. Kato-Katz-based egg counts can vary highly over repeated stool samples and smears. Consequentially, the sensitivity of KK-based surveys depends on the number of stool samples per person and the number of smears per sample. Given finite resources, collecting multiple samples and/or smears means screening fewer individuals, thereby lowering the statistical precision of prevalence estimates. Using population-level data from various epidemiological settings, we assessed the performance of different sampling schemes executed within the confines of the same budget. We recommend the use of single-slide KK for determining prevalence of moderate-to-heavy intensity infection and policy decisions for starting and continuing PC; more sensitive sampling schemes may be required for policy decisions involving stopping PC. Our findings highlight that guidelines should include specific guidance on sampling schemes.

Background\ud Methicillin resistant Staphylococcus aureus (MRSA) bacteria cause serious, often healthcare-associated infections and are frequently highly resistant to diverse antibiotics. Multiple MRSA clonal complexes (CCs) have evolved independently and countries have different prevalent CCs. It is unclear when and why the dominant CC in a region may switch.\ud \ud Methods\ud We developed a mathematical deterministic model of MRSA CC competing for limited resource. The model distinguishes ‘standard MRSA’ and multidrug resistant sub-populations within each CC, allowing for resistance loss and transfer between same CC bacteria. We first analysed how dynamics of this system depend on growth-rate and resistance-potential differences between CCs, and on their resistance gene accumulation. We then fit the model to capture the longitudinal CC dynamics observed at a single UK hospital, which exemplified the UK-wide switch from mainly CC30 to mainly CC22.\ud \ud Results\ud We find that within a CC, gain and loss of resistance can allow for co-existence of sensitive and resistant sub-populations. Due to more efficient transfer of resistance at higher CC density, more drug resistance can accumulate in the population of a more prevalent CC. We show how this process of density dependent competition, together with prevalence disruption, could explain the relatively sudden switch from mainly CC30 to mainly CC22 in the UK hospital setting. Alternatively, the observed hospital dynamics could be reproduced by assuming that multidrug resistant CC22 evolved only around 2004.\ud \ud Conclusions\ud We showed how higher prevalence may advantage a CC by allowing it to acquire antimicrobial resistances more easily. Due to this density dependence in competition, dominance in an area can depend on historic contingencies; the MRSA CC that happened to be first could stay dominant because of its high prevalence advantage. This then could help explain the stability, despite frequent stochastic introductions across borders, of geographic differences in MRSA CC.

Background Mass drug administration (MDA) is the main strategy towards lymphatic filariasis (LF) elimination. Progress is monitored by assessing microfilaraemia (Mf) or circulating filarial antigenaemia (CFA) prevalence, the latter being more practical for field surveys. The current criterion for stopping MDA requires Methodolgy/Principal findings We verified that our model captures observed patterns in Mf and CFA prevalence during annual MDA, assuming that CFA tests are positive if at least one adult worm is present. We then assessed how well elimination can be predicted from CFA prevalence in 6-7-year-old children or from Mf or CFA prevalence in the 5+ or 15+ population, and determined safe (>95% positive predictive value) thresholds for stopping MDA. The model captured trends in Mf and CFA prevalences reasonably well. Elimination cannot be predicted with sufficient certainty from CFA prevalence in 6-7-year olds. Resurgence may still occur if all children are antigen-negative, irrespective of the number tested. Mf-based criteria also show unfavourable results (PPV Conclusions/Significance For African areas with moderate to high pre-treatment Mf prevalence that have had 6 or more rounds of annual ivermectin/albendazole MDA with adequate coverage, we recommend to adopt a CFA threshold prevalence of 10% in adults (15+) for stopping MDA. This could be combined with Mf testing of CFA positives to ensure absence of a significant Mf reservoir for transmission.

At the time of writing (February 2021), it is 1 y since the coronavirus disease 2019 (COVID-19) pandemic began to become a pandemic. To date, there have been >100 million cases of COVID-19 diagnosed globally, leading to at least 2.2 million deaths. The indirect effects of the pandemic on other health conditions, as well as economic and societal well-being, are accruing at an alarming rate. Probably due to its young population, perhaps combined with recent experience of combating large-scale epidemics, such as Ebola in 2014 and 2016, sub-Saharan Africa has been affected relatively modestly by COVID-19, with a death toll of about 60 000 cases so far, mainly in South Africa. However, these reported numbers may be underestimates, given the limitations of the local health systems. Also, the future course of the pandemic is highly uncertain, especially where large-scale vaccination campaigns may be more challenging than in high-income countries. Model predictions suggest that suspension of control efforts for malaria, TB and HIV in low- and middle-income countries could lead to deaths on a similar scale to those from COVID-19 itself. Similar effects were seen during the Ebola outbreak in West Africa, where the number of excess deaths due to other factors (including maternal mortality and particularly malaria) was estimated to be of the same order of magnitude as the number of deaths directly due to Ebola.