Thinking clearly about social aspects of infectious disease transmission.

Social and cultural forces shape almost every aspect of infectious disease transmission in human populations, as well as our ability to measure, understand, and respond to epidemics. For directly transmitted infections, pathogen transmission relies on human-to-human contact, with kinship, household, and societal structures shaping contact patterns that in turn determine epidemic dynamics. Social, economic, and cultural forces also shape patterns of exposure, health-seeking behaviour, infection outcomes, the likelihood of diagnosis and reporting of cases, and the uptake of interventions. Although these social aspects of epidemiology are hard to quantify and have limited the generalizability of modelling frameworks in a policy context, new sources of data on relevant aspects of human behaviour are increasingly available. Researchers have begun to embrace data from mobile devices and other technologies as useful proxies for behavioural drivers of disease transmission, but there is much work to be done to measure and validate these approaches, particularly for policy-making. Here we discuss how integrating local knowledge in the design of model frameworks and the interpretation of new data streams offers the possibility of policy-relevant models for public health decision-making as well as the development of robust, generalizable theories about human behaviour in relation to infectious diseases.

Temporal and spatial dynamics of Plasmodium falciparum clonal lineages in Guyana.

Plasmodium parasites, the causal agents of malaria, are eukaryotic organisms that obligately undergo sexual recombination within mosquitoes. In low transmission settings, parasites recombine with themselves, and the clonal lineage is propagated rather than broken up by outcrossing. We investigated whether stochastic/neutral factors drive the persistence and abundance of Plasmodium falciparum clonal lineages in Guyana, a country with relatively low malaria transmission, but the only setting in the Americas in which an important artemisinin resistance mutation (pfk13 C580Y) has been observed. We performed whole genome sequencing on 1,727 Plasmodium falciparum samples collected from infected patients across a five-year period (2016-2021). We characterized the relatedness between each pair of monoclonal infections (n = 1,409) through estimation of identity-by-descent (IBD) and also typed each sample for known or candidate drug resistance mutations. A total of 160 multi-isolate clones (mean IBD ≥ 0.90) were circulating in Guyana during the study period, comprising 13 highly related clusters (mean IBD ≥ 0.40). In the five-year study period, we observed a decrease in frequency of a mutation associated with artemisinin partner drug (piperaquine) resistance (pfcrt C350R) and limited co-occurence of pfcrt C350R with duplications of plasmepsin 2/3, an epistatic interaction associated with piperaquine resistance. We additionally observed 61 nonsynonymous substitutions that increased markedly in frequency over the study period as well as a novel pfk13 mutation (G718S). However, P. falciparum clonal dynamics in Guyana appear to be largely driven by stochastic factors, in contrast to other geographic regions, given that clones carrying drug resistance polymorphisms do not demonstrate enhanced persistence or higher abundance than clones carrying polymorphisms of comparable frequency that are unrelated to resistance. The use of multiple artemisinin combination therapies in Guyana may have contributed to the disappearance of the pfk13 C580Y mutation.

Exposing Anopheles mosquitoes to antimalarials blocks Plasmodium parasite transmission.

Bites of Anopheles mosquitoes transmit Plasmodium falciparum parasites that cause malaria, which kills hundreds of thousands of people every year. Since the turn of this century, efforts to prevent the transmission of these parasites via the mass distribution of insecticide-treated bed nets have been extremely successful, and have led to an unprecedented reduction in deaths from malaria1. However, resistance to insecticides has become widespread in Anopheles populations2-4, which has led to the threat of a global resurgence of malaria and makes the generation of effective tools for controlling this disease an urgent public health priority. Here we show that the development of P. falciparum can be rapidly and completely blocked when female Anopheles gambiae mosquitoes take up low concentrations of specific antimalarials from treated surfaces-conditions that simulate contact with a bed net. Mosquito exposure to atovaquone before, or shortly after, P. falciparum infection causes full parasite arrest in the midgut, and prevents transmission of infection. Similar transmission-blocking effects are achieved using other cytochrome b inhibitors, which demonstrates that parasite mitochondrial function is a suitable target for killing parasites. Incorporating these effects into a model of malaria transmission dynamics predicts that impregnating mosquito nets with Plasmodium inhibitors would substantially mitigate the global health effects of insecticide resistance. This study identifies a powerful strategy for blocking Plasmodium transmission by female Anopheles mosquitoes, which has promising implications for efforts to eradicate malaria.

Declines in prevalence alter the optimal level of sexual investment for the malaria parasite Plasmodium falciparum.

Successful infectious disease interventions can result in large reductions in parasite prevalence. Such demographic change has fitness implications for individual parasites and may shift the parasite's optimal life history strategy. Here, we explore whether declining infection rates can alter Plasmodium falciparum's investment in sexual versus asexual growth. Using a multiscale mathematical model, we demonstrate how the proportion of polyclonal infections, which decreases as parasite prevalence declines, affects the optimal sexual development strategy: Within-host competition in multiclone infections favors a greater investment in asexual growth whereas single-clone infections benefit from higher conversion to sexual forms. At the same time, drug treatment also imposes selection pressure on sexual development by shortening infection length and reducing within-host competition. We assess these models using 148 P. falciparum parasite genomes sampled in French Guiana over an 18-y period of intensive intervention (1998 to 2015). During this time frame, multiple public health measures, including the introduction of new drugs and expanded rapid diagnostic testing, were implemented, reducing P. falciparum malaria cases by an order of magnitude. Consistent with this prevalence decline, we see an increase in the relatedness among parasites, but no single clonal background grew to dominate the population. Analyzing individual allele frequency trajectories, we identify genes that likely experienced selective sweeps. Supporting our model predictions, genes showing the strongest signatures of selection include transcription factors involved in the development of P. falciparum's sexual gametocyte form. These results highlight how public health interventions impose wide-ranging selection pressures that affect basic parasite life history traits.

Resolving drug selection and migration in an inbred South American Plasmodium falciparum population with identity-by-descent analysis.

The human malaria parasite Plasmodium falciparum is globally widespread, but its prevalence varies significantly between and even within countries. Most population genetic studies in P. falciparum focus on regions of high transmission where parasite populations are large and genetically diverse, such as sub-Saharan Africa. Understanding population dynamics in low transmission settings, however, is of particular importance as these are often where drug resistance first evolves. Here, we use the Pacific Coast of Colombia and Ecuador as a model for understanding the population structure and evolution of Plasmodium parasites in small populations harboring less genetic diversity. The combination of low transmission and a high proportion of monoclonal infections means there are few outcrossing events and clonal lineages persist for long periods of time. Yet despite this, the population is evolutionarily labile and has successfully adapted to changes in drug regime. Using newly sequenced whole genomes, we measure relatedness between 166 parasites, calculated as identity by descent (IBD), and find 17 distinct but highly related clonal lineages, six of which have persisted in the region for at least a decade. This inbred population structure is captured in more detail with IBD than with other common population structure analyses like PCA, ADMIXTURE, and distance-based trees. We additionally use patterns of intra-chromosomal IBD and an analysis of haplotypic variation to explore past selection events in the region. Two genes associated with chloroquine resistance, crt and aat1, show evidence of hard selective sweeps, while selection appears soft and/or incomplete at three other key resistance loci (dhps, mdr1, and dhfr). Overall, this work highlights the strength of IBD analyses for studying parasite population structure and resistance evolution in regions of low transmission, and emphasizes that drug resistance can evolve and spread in small populations, as will occur in any region nearing malaria elimination.

COVID-19 vaccination strategies in Africa: A scoping review of the use of mathematical models to inform policy.

OBJECTIVE: Mathematical models are vital tools to understand transmission dynamics and assess the impact of interventions to mitigate COVID-19. However, historically, their use in Africa has been limited. In this scoping review, we assess how mathematical models were used to study COVID-19 vaccination to potentially inform pandemic planning and response in Africa. METHODS: We searched six electronic databases: MEDLINE, Embase, Web of Science, Global Health, MathSciNet and Africa-Wide NiPAD, using keywords to identify articles focused on the use of mathematical modelling studies of COVID-19 vaccination in Africa that were published as of October 2022. We extracted the details on the country, author affiliation, characteristics of models, policy intent and heterogeneity factors. We assessed quality using 21-point scale criteria on model characteristics and content of the studies. RESULTS: The literature search yielded 462 articles, of which 32 were included based on the eligibility criteria. Nineteen (59%) studies had a first author affiliated with an African country. Of the 32 included studies, 30 (94%) were compartmental models. By country, most studies were about or included South Africa (n = 12, 37%), followed by Morocco (n = 6, 19%) and Ethiopia (n = 5, 16%). Most studies (n = 19, 59%) assessed the impact of increasing vaccination coverage on COVID-19 burden. Half (n = 16, 50%) had policy intent: prioritising or selecting interventions, pandemic planning and response, vaccine distribution and optimisation strategies and understanding transmission dynamics of COVID-19. Fourteen studies (44%) were of medium quality and eight (25%) were of high quality. CONCLUSIONS: While decision-makers could draw vital insights from the evidence generated from mathematical modelling to inform policy, we found that there was limited use of such models exploring vaccination impacts for COVID-19 in Africa. The disparity can be addressed by scaling up mathematical modelling training, increasing collaborative opportunities between modellers and policymakers, and increasing access to funding.

Distinguishing gene flow between malaria parasite populations.

Measuring gene flow between malaria parasite populations in different geographic locations can provide strategic information for malaria control interventions. Multiple important questions pertaining to the design of such studies remain unanswered, limiting efforts to operationalize genomic surveillance tools for routine public health use. This report examines the use of population-level summaries of genetic divergence (FST) and relatedness (identity-by-descent) to distinguish levels of gene flow between malaria populations, focused on field-relevant questions about data size, sampling, and interpretability of observations from genomic surveillance studies. To do this, we use P. falciparum whole genome sequence data and simulated sequence data approximating malaria populations evolving under different current and historical epidemiological conditions. We employ mobile-phone associated mobility data to estimate parasite migration rates over different spatial scales and use this to inform our analysis. This analysis underscores the complementary nature of divergence- and relatedness-based metrics for distinguishing gene flow over different temporal and spatial scales and characterizes the data requirements for using these metrics in different contexts. Our results have implications for the design and implementation of malaria genomic surveillance studies.

Quantifying the dynamics of migration after Hurricane Maria in Puerto Rico.

Population displacement may occur after natural disasters, permanently altering the demographic composition of the affected regions. Measuring this displacement is vital for both optimal postdisaster resource allocation and calculation of measures of public health interest such as mortality estimates. Here, we analyzed data generated by mobile phones and social media to estimate the weekly island-wide population at risk and within-island geographic heterogeneity of migration in Puerto Rico after Hurricane Maria. We compared these two data sources with population estimates derived from air travel records and census data. We observed a loss of population across all data sources throughout the study period; however, the magnitude and dynamics differ by the data source. Census data predict a population loss of just over 129,000 from July 2017 to July 2018, a 4% decrease; air travel data predict a population loss of 168,295 for the same period, a 5% decrease; mobile phone-based estimates predict a loss of 235,375 from July 2017 to May 2018, an 8% decrease; and social media-based estimates predict a loss of 476,779 from August 2017 to August 2018, a 17% decrease. On average, municipalities with a smaller population size lost a bigger proportion of their population. Moreover, we infer that these municipalities experienced greater infrastructure damage as measured by the proportion of unknown locations stemming from these regions. Finally, our analysis measures a general shift of population from rural to urban centers within the island. Passively collected data provide a promising supplement to current at-risk population estimation procedures; however, each data source has its own biases and limitations.

Identity-by-descent with uncertainty characterises connectivity of Plasmodium falciparum populations on the Colombian-Pacific coast.

Characterising connectivity between geographically separated biological populations is a common goal in many fields. Recent approaches to understanding connectivity between malaria parasite populations, with implications for disease control efforts, have used estimates of relatedness based on identity-by-descent (IBD). However, uncertainty around estimated relatedness has not been accounted for. IBD-based relatedness estimates with uncertainty were computed for pairs of monoclonal Plasmodium falciparum samples collected from five cities on the Colombian-Pacific coast where long-term clonal propagation of P. falciparum is frequent. The cities include two official ports, Buenaventura and Tumaco, that are separated geographically but connected by frequent marine traffic. Fractions of highly-related sample pairs (whose classification using a threshold accounts for uncertainty) were greater within cities versus between. However, based on both highly-related fractions and on a threshold-free approach (Wasserstein distances between parasite populations) connectivity between Buenaventura and Tumaco was disproportionally high. Buenaventura-Tumaco connectivity was consistent with transmission events involving parasites from five clonal components (groups of statistically indistinguishable parasites identified under a graph theoretic framework). To conclude, P. falciparum population connectivity on the Colombian-Pacific coast abides by accessibility not isolation-by-distance, potentially implicating marine traffic in malaria transmission with opportunities for targeted intervention. Further investigations are required to test this hypothesis. For the first time in malaria epidemiology (and to our knowledge in ecological and epidemiological studies more generally), we account for uncertainty around estimated relatedness (an important consideration for studies that plan to use genotype versus whole genome sequence data to estimate IBD-based relatedness); we also use threshold-free methods to compare parasite populations and identify clonal components. Threshold-free methods are especially important in analyses of malaria parasites and other recombining organisms with mixed mating systems where thresholds do not have clear interpretation (e.g. due to clonal propagation) and thus undermine the cross-comparison of studies.

A cautionary note on the use of unsupervised machine learning algorithms to characterise malaria parasite population structure from genetic distance matrices.

Genetic surveillance of malaria parasites supports malaria control programmes, treatment guidelines and elimination strategies. Surveillance studies often pose questions about malaria parasite ancestry (e.g. how antimalarial resistance has spread) and employ statistical methods that characterise parasite population structure. Many of the methods used to characterise structure are unsupervised machine learning algorithms which depend on a genetic distance matrix, notably principal coordinates analysis (PCoA) and hierarchical agglomerative clustering (HAC). PCoA and HAC are sensitive to both the definition of genetic distance and algorithmic specification. Importantly, neither algorithm infers malaria parasite ancestry. As such, PCoA and HAC can inform (e.g. via exploratory data visualisation and hypothesis generation), but not answer comprehensively, key questions about malaria parasite ancestry. We illustrate the sensitivity of PCoA and HAC using 393 Plasmodium falciparum whole genome sequences collected from Cambodia and neighbouring regions (where antimalarial resistance has emerged and spread recently) and we provide tentative guidance for the use and interpretation of PCoA and HAC in malaria parasite genetic epidemiology. This guidance includes a call for fully transparent and reproducible analysis pipelines that feature (i) a clearly outlined scientific question; (ii) a clear justification of analytical methods used to answer the scientific question along with discussion of any inferential limitations; (iii) publicly available genetic distance matrices when downstream analyses depend on them; and (iv) sensitivity analyses. To bridge the inferential disconnect between the output of non-inferential unsupervised learning algorithms and the scientific questions of interest, tailor-made statistical models are needed to infer malaria parasite ancestry. In the absence of such models speculative reasoning should feature only as discussion but not as results.

Incubation periods impact the spatial predictability of cholera and Ebola outbreaks in Sierra Leone.

Forecasting the spatiotemporal spread of infectious diseases during an outbreak is an important component of epidemic response. However, it remains challenging both methodologically and with respect to data requirements, as disease spread is influenced by numerous factors, including the pathogen's underlying transmission parameters and epidemiological dynamics, social networks and population connectivity, and environmental conditions. Here, using data from Sierra Leone, we analyze the spatiotemporal dynamics of recent cholera and Ebola outbreaks and compare and contrast the spread of these two pathogens in the same population. We develop a simulation model of the spatial spread of an epidemic in order to examine the impact of a pathogen's incubation period on the dynamics of spread and the predictability of outbreaks. We find that differences in the incubation period alone can determine the limits of predictability for diseases with different natural history, both empirically and in our simulations. Our results show that diseases with longer incubation periods, such as Ebola, where infected individuals can travel farther before becoming infectious, result in more long-distance sparking events and less predictable disease trajectories, as compared to the more predictable wave-like spread of diseases with shorter incubation periods, such as cholera.

Multiple blood feeding in mosquitoes shortens the Plasmodium falciparum incubation period and increases malaria transmission potential.

Many mosquito species, including the major malaria vector Anopheles gambiae, naturally undergo multiple reproductive cycles of blood feeding, egg development and egg laying in their lifespan. Such complex mosquito behavior is regularly overlooked when mosquitoes are experimentally infected with malaria parasites, limiting our ability to accurately describe potential effects on transmission. Here, we examine how Plasmodium falciparum development and transmission potential is impacted when infected mosquitoes feed an additional time. We measured P. falciparum oocyst size and performed sporozoite time course analyses to determine the parasite's extrinsic incubation period (EIP), i.e. the time required by parasites to reach infectious sporozoite stages, in An. gambiae females blood fed either once or twice. An additional blood feed at 3 days post infection drastically accelerates oocyst growth rates, causing earlier sporozoite accumulation in the salivary glands, thereby shortening the EIP (reduction of 2.3 ± 0.4 days). Moreover, parasite growth is further accelerated in transgenic mosquitoes with reduced reproductive capacity, which mimic genetic modifications currently proposed in population suppression gene drives. We incorporate our shortened EIP values into a measure of transmission potential, the basic reproduction number R0, and find the average R0 is higher (range: 10.1%-12.1% increase) across sub-Saharan Africa than when using traditional EIP measurements. These data suggest that malaria elimination may be substantially more challenging and that younger mosquitoes or those with reduced reproductive ability may provide a larger contribution to infection than currently believed. Our findings have profound implications for current and future mosquito control interventions.

A nowcasting framework for correcting for reporting delays in malaria surveillance.

Time lags in reporting to national surveillance systems represent a major barrier for the control of infectious diseases, preventing timely decision making and resource allocation. This issue is particularly acute for infectious diseases like malaria, which often impact rural and remote communities the hardest. In Guyana, a country located in South America, poor connectivity among remote malaria-endemic regions hampers surveillance efforts, making reporting delays a key challenge for elimination. Here, we analyze 13 years of malaria surveillance data, identifying key correlates of time lags between clinical cases occurring and being added to the central data system. We develop nowcasting methods that use historical patterns of reporting delays to estimate occurred-but-not-reported monthly malaria cases. To assess their performance, we implemented them retrospectively, using only information that would have been available at the time of estimation, and found that they substantially enhanced the estimates of malaria cases. Specifically, we found that the best performing models achieved up to two-fold improvements in accuracy (or error reduction) over known cases in selected regions. Our approach provides a simple, generalizable tool to improve malaria surveillance in endemic countries and is currently being implemented to help guide existing resource allocation and elimination efforts.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Transmission Dynamics Should Inform Policy.

It is generally agreed that striking a balance between resuming economic and social activities and keeping the effective reproductive number (R0) below 1 using nonpharmaceutical interventions is an important goal until and even after effective vaccines become available. Therefore, the need remains to understand how the virus is transmitted in order to identify high-risk environments and activities that disproportionately contribute to its spread so that effective preventative measures could be put in place. Contact tracing and household studies, in particular, provide robust evidence about the parameters of transmission. In this Viewpoint, we discuss the available evidence from large-scale, well-conducted contact-tracing studies from across the world and argue that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission dynamics should inform policy decisions about mitigation strategies for targeted interventions according to the needs of the society by directing attention to the settings, activities, and socioeconomic factors associated with the highest risks of transmission.

Mortality in Puerto Rico after Hurricane Maria.

BACKGROUND: Quantifying the effect of natural disasters on society is critical for recovery of public health services and infrastructure. The death toll can be difficult to assess in the aftermath of a major disaster. In September 2017, Hurricane Maria caused massive infrastructural damage to Puerto Rico, but its effect on mortality remains contentious. The official death count is 64. METHODS: Using a representative, stratified sample, we surveyed 3299 randomly chosen households across Puerto Rico to produce an independent estimate of all-cause mortality after the hurricane. Respondents were asked about displacement, infrastructure loss, and causes of death. We calculated excess deaths by comparing our estimated post-hurricane mortality rate with official rates for the same period in 2016. RESULTS: From the survey data, we estimated a mortality rate of 14.3 deaths (95% confidence interval [CI], 9.8 to 18.9) per 1000 persons from September 20 through December 31, 2017. This rate yielded a total of 4645 excess deaths during this period (95% CI, 793 to 8498), equivalent to a 62% increase in the mortality rate as compared with the same period in 2016. However, this number is likely to be an underestimate because of survivor bias. The mortality rate remained high through the end of December 2017, and one third of the deaths were attributed to delayed or interrupted health care. Hurricane-related migration was substantial. CONCLUSIONS: This household-based survey suggests that the number of excess deaths related to Hurricane Maria in Puerto Rico is more than 70 times the official estimate. (Funded by the Harvard T.H. Chan School of Public Health and others.).

Accounting for red blood cell accessibility reveals distinct invasion strategies in Plasmodium falciparum strains.

The growth of the malaria parasite Plasmodium falciparum in human blood causes all the symptoms of malaria. To proliferate, non-motile parasites must have access to susceptible red blood cells, which they invade using pairs of parasite ligands and host receptors that define invasion pathways. Parasites can switch invasion pathways, and while this flexibility is thought to facilitate immune evasion, it may also reflect the heterogeneity of red blood cell surfaces within and between hosts. Host genetic background affects red blood cell structure, for example, and red blood cells also undergo dramatic changes in morphology and receptor density as they age. The in vivo consequences of both the accessibility of susceptible cells, and their heterogeneous susceptibility, remain unclear. Here, we measured invasion of laboratory strains of P. falciparum relying on distinct invasion pathways into red blood cells of different ages. We estimated invasion efficiency while accounting for red blood cell accessibility to parasites. This approach revealed different tradeoffs made by parasite strains between the fraction of cells they can invade and their invasion rate into them, and we distinguish "specialist" strains from "generalist" strains in this context. We developed a mathematical model to show that generalist strains would lead to higher peak parasitemias in vivo compared to specialist strains with similar overall proliferation rates. Thus, the ecology of red blood cells may play a key role in determining the rate of P. falciparum parasite proliferation and malaria virulence.

The Microbiome of Size-Fractionated Airborne Particles from the Sahara Region.

Diverse airborne microbes affect human health and biodiversity, and the Sahara region of West Africa is a globally important source region for atmospheric dust. We collected size-fractionated (>10, 10-2.5, 2.5-1.0, 1.0-0.5, and <0.5 µm) atmospheric particles in Mali, West Africa and conducted the first cultivation-independent study of airborne microbes in this region using 16S rRNA gene sequencing. Abundant and diverse microbes were detected in all particle size fractions at levels higher than those previously hypothesized for desert regions. Average daily abundance was 1.94 × 105 16S rRNA copies/m3. Daily patterns in abundance for particles <0.5 µm differed significantly from other size fractions likely because they form mainly in the atmosphere and have limited surface resuspension. Particles >10 µm contained the greatest fraction of daily abundance (51-62%) and had significantly greater diversity than smaller particles. Greater bacterial abundance of particles >2.5 µm that are bigger than the average bacterium suggests that most airborne bacteria are present as aggregates or attached to particles rather than as free-floating cells. Particles >10 µm have very short atmospheric lifetimes and thus tend to have more localized origins. We confirmed the presence of several potential pathogens using polymerase chain reaction that are candidates for viability and strain testing in future studies. These species were detected on all particle sizes tested, including particles <2.5 µm that are expected to undergo long-range transport. Overall, our results suggest that the composition and sources of airborne microbes can be better discriminated by collecting size-fractionated samples.

Variation in human mobility and its impact on the risk of future COVID-19 outbreaks in Taiwan.

BACKGROUND: As COVID-19 continues to spread around the world, understanding how patterns of human mobility and connectivity affect outbreak dynamics, especially before outbreaks establish locally, is critical for informing response efforts. In Taiwan, most cases to date were imported or linked to imported cases. METHODS: In collaboration with Facebook Data for Good, we characterized changes in movement patterns in Taiwan since February 2020, and built metapopulation models that incorporate human movement data to identify the high risk areas of disease spread and assess the potential effects of local travel restrictions in Taiwan. RESULTS: We found that mobility changed with the number of local cases in Taiwan in the past few months. For each city, we identified the most highly connected areas that may serve as sources of importation during an outbreak. We showed that the risk of an outbreak in Taiwan is enhanced if initial infections occur around holidays. Intracity travel reductions have a higher impact on the risk of an outbreak than intercity travel reductions, while intercity travel reductions can narrow the scope of the outbreak and help target resources. The timing, duration, and level of travel reduction together determine the impact of travel reductions on the number of infections, and multiple combinations of these can result in similar impact. CONCLUSIONS: To prepare for the potential spread within Taiwan, we utilized Facebook's aggregated and anonymized movement and colocation data to identify cities with higher risk of infection and regional importation. We developed an interactive application that allows users to vary inputs and assumptions and shows the spatial spread of the disease and the impact of intercity and intracity travel reduction under different initial conditions. Our results can be used readily if local transmission occurs in Taiwan after relaxation of border control, providing important insights into future disease surveillance and policies for travel restrictions.

Every Body Counts: Measuring Mortality From the COVID-19 Pandemic.

As of mid-August 2020, more than 170 000 U.S. residents have died of coronavirus disease 2019 (COVID-19); however, the true number of deaths resulting from COVID-19, both directly and indirectly, is likely to be much higher. The proper attribution of deaths to this pandemic has a range of societal, legal, mortuary, and public health consequences. This article discusses the current difficulties of disaster death attribution and describes the strengths and limitations of relying on death counts from death certificates, estimations of indirect deaths, and estimations of excess mortality. Improving the tabulation of direct and indirect deaths on death certificates will require concerted efforts and consensus across medical institutions and public health agencies. In addition, actionable estimates of excess mortality will require timely access to standardized and structured vital registry data, which should be shared directly at the state level to ensure rapid response for local governments. Correct attribution of direct and indirect deaths and estimation of excess mortality are complementary goals that are critical to our understanding of the pandemic and its effect on human life.

Resistance to Plasmodium falciparum in sickle cell trait erythrocytes is driven by oxygen-dependent growth inhibition.

Sickle cell trait (AS) confers partial protection against lethal Plasmodium falciparum malaria. Multiple mechanisms for this have been proposed, with a recent focus on aberrant cytoadherence of parasite-infected red blood cells (RBCs). Here we investigate the mechanistic basis of AS protection through detailed temporal mapping. We find that parasites in AS RBCs maintained at low oxygen concentrations stall at a specific stage in the middle of intracellular growth before DNA replication. We demonstrate that polymerization of sickle hemoglobin (HbS) is responsible for this growth arrest of intraerythrocytic P. falciparum parasites, with normal hemoglobin digestion and growth restored in the presence of carbon monoxide, a gaseous antisickling agent. Modeling of growth inhibition and sequestration revealed that HbS polymerization-induced growth inhibition following cytoadherence is the critical driver of the reduced parasite densities observed in malaria infections of individuals with AS. We conclude that the protective effect of AS derives largely from effective sequestration of infected RBCs into the hypoxic microcirculation.