Explore the vast range of titles available.

Abstract Background To better understand transmission dynamics, we characterized Plasmodium falciparum genetic diversity in Eswatini, where transmission is low and sustained by importation. Methods Twenty-six P. falciparum microsatellites were genotyped in 66% of confirmed cases (2014–2016; N = 582). Population and within-host diversity were used to characterize differences between imported and locally acquired infections. Logistic regression was used to assess the added value of diversity metrics to classify imported and local infections beyond epidemiology data alone. Results Parasite population in Eswatini was highly diverse (expected heterozygosity [HE] = 0.75) and complex: 67% polyclonal infections, mean multiplicity of infection (MOI) 2.2, and mean within-host infection fixation index (FWS) 0.84. Imported cases had comparable diversity to local cases but exhibited higher MOI (2.4 vs 2.0; P = .004) and lower mean FWS (0.82 vs 0.85; P = .03). Addition of MOI and FWS to multivariate analyses did not increase discrimination between imported and local infections. Conclusions In contrast to the common perception that P. falciparum diversity declines with decreasing transmission intensity, Eswatini isolates exhibited high parasite diversity consistent with high rates of malaria importation and limited local transmission. Estimates of malaria transmission intensity from genetic data need to consider the effect of importation, especially as countries near elimination. In contrast to the commonly held perception that P. falciparum diversity declines with decreasing transmission intensity, infections from Eswatini exhibited high parasite diversity consistent with high rates of malaria importation and limited local transmission.

Accurate estimates of the burden of SARS-CoV-2 infection are critical to informing pandemic response. Confirmed COVID-19 case counts in the U.S. do not capture the total burden of the pandemic because testing has been primarily restricted to individuals with moderate to severe symptoms due to limited test availability. Here, we use a semi-Bayesian probabilistic bias analysis to account for incomplete testing and imperfect diagnostic accuracy. We estimate 6,454,951 cumulative infections compared to 721,245 confirmed cases (1.9% vs. 0.2% of the population) in the United States as of April 18, 2020. Accounting for uncertainty, the number of infections during this period was 3 to 20 times higher than the number of confirmed cases. 86% (simulation interval: 64–99%) of this difference is due to incomplete testing, while 14% (0.3–36%) is due to imperfect test accuracy. The approach can readily be applied in future studies in other locations or at finer spatial scale to correct for biased testing and imperfect diagnostic accuracy to provide a more realistic assessment of COVID-19 burden. Estimating the extent of SARS-CoV-2 infection in a population is challenging due to the limitations of testing. Here, the authors estimate that the true number of infections in the United States in mid-April was up to 20 times higher than the number of confirmed cases.

Malaria-eliminating countries achieved remarkable success in reducing their malaria burdens between 2000 and 2010. As a result, the epidemiology of malaria in these settings has become more complex. Malaria is increasingly imported, caused by Plasmodium vivax in settings outside sub-Saharan Africa, and clustered in small geographical areas or clustered demographically into subpopulations, which are often predominantly adult men, with shared social, behavioural, and geographical risk characteristics. The shift in the populations most at risk of malaria raises important questions for malaria-eliminating countries, since traditional control interventions are likely to be less effective. Approaches to elimination need to be aligned with these changes through the development and adoption of novel strategies and methods. Knowledge of the changing epidemiological trends of malaria in the eliminating countries will ensure improved targeting of interventions to continue to shrink the malaria map.

Hugh Sturrock and colleagues discuss the role of active case detection in low malaria transmission settings. They argue that the evidence for its effectiveness is sparse and that targeted mass drug administration should be evaluated as an alternative or addition to active case detection. Please see later in the article for the Editors' Summary

Background Global interest in malaria elimination has prompted research on active test and treat (TaT) strategies. Methods A systematic review and meta-analysis were conducted to assess the effectiveness of TaT strategies to reduce malaria transmission. Results A total of 72 empirical research and 24 modelling studies were identified, mainly focused on proactive mass TaT (MTaT) and reactive case detection (RACD) in higher and lower transmission settings, respectively. Ten intervention studies compared MTaT to no MTaT and the evidence for impact on malaria incidence was weak. No intervention studies compared RACD to no RACD. Compared to passive case detection (PCD) alone, PCD + RACD using standard diagnostics increased infection detection 52.7% and 11.3% in low and very low transmission settings, respectively. Using molecular methods increased this detection of infections by 1.4- and 1.1-fold, respectively. Conclusion Results suggest MTaT is not effective for reducing transmission. By increasing case detection, surveillance data provided by RACD may indirectly reduce transmission by informing coordinated responses of intervention targeting.

As in other parts of Southeast Asia, efforts to achieve or sustain malaria elimination in Indonesia have been threatened by the emergence of human infection with the primate species P. knowlesi. To understand the transmission dynamics of this species, investigation of P. knowlesi genetic diversity and population structure is needed. A molecular surveillance study was conducted in two phases between June 2014 and September 2018 at five primary health facilities in Aceh Province, Indonesia, an area nearing malaria elimination. Dried blood spot samples were collected from patients presenting with suspected malaria and testing positive for malaria by microscopy. PCR was performed for molecular confirmation and species identification. Forty-six samples were confirmed to be P. knowlesi , of which 41 were amplified with genotyping targeting ten known P. knowlesi microsatellite markers. For samples within a site, nearly all (9 of 10 loci) or all loci were polymorphic. Across sites, multiple identical haplotypes were observed, though linkage distribution in the population was low (index of association (I A S ) = 0.008). The parasite population was indicative of low diversity (expected heterozygosity [HE] =  0.63) and low complexity demonstrated by 92.7% monoclonal infections, a mean multiplicity of infection of 1.06, and a mean within-host infection fixation index (F ST ) of 0.05. Principal coordinate and neighbour-joining tree analyses indicated that P. knowlesi strains from Aceh were distinct from those reported in Malaysia. In a near-elimination setting in Indonesia, we demonstrate the first evidence that P. knowlesi strains were minimally diverse and were genetically distinct from Malaysian strains, suggesting highly localized transmission and limited connectivity to Malaysia. Ongoing genetic surveillance of P. knowlesi in Indonesia can inform tracking and planning of malaria control and elimination efforts.

Measuring neurocognitive functioning in children requires validated, age-appropriate instruments that are adapted to the local cultural and linguistic context. We sought to evaluate the usability and psychometric properties of five tools that assess general intelligence, executive functioning, and sustained attention among Tanzanian children. We adapted five age-appropriate neurocognitive assessment batteries from previously published assessment materials to the Tanzanian context. We enrolled children 6 months to 12 years of age residing in the rural ward of Yombo, Pwani Region. Feasibility and acceptability of all instruments was assessed qualitatively and quantitatively, including measurement of refusal rates, ceiling or floor effects, and time requirements. We assessed internal consistency using Cronbach's alpha and convergent validity using standard correlation analysis. Score gradients across age were explored using polynomial regression analysis. All five instruments required minimal adaptations to the Tanzanian context. Two-hundred sixty one children aged 6 months to 12 years completed the assessment. Refusal rates were consistently low (5.9% at the highest) and no ceiling or floor effects of measurements were observed. Feedback from assessors and caregivers indicated adequate test durations and generally high acceptability of instruments. All instruments showed good internal consistency with Cronbach alphas at least 0.84 for all tests. We found satisfactory convergent validity; all test scores strongly correlated with age. The five instruments identified to assess general intelligence, executive functioning, and sustained attention constructs in Tanzanian children seem to work well in this setting.

Local and cross-border importation remain major challenges to malaria elimination and are difficult to measure using traditional surveillance data. To address this challenge, we systematically collected parasite genetic data and travel history from thousands of malaria cases across northeastern Namibia and estimated human mobility from mobile phone data. We observed strong fine-scale spatial structure in local parasite populations, providing positive evidence that the majority of cases were due to local transmission. This result was largely consistent with estimates from mobile phone and travel history data. However, genetic data identified more detailed and extensive evidence of parasite connectivity over hundreds of kilometers than the other data, within Namibia and across the Angolan and Zambian borders. Our results provide a framework for incorporating genetic data into malaria surveillance and provide evidence that both strengthening of local interventions and regional coordination are likely necessary to eliminate malaria in this region of Southern Africa. The number of malaria cases has dropped in some Southern Africa countries, but others still remain seriously affected. When people travel within and between countries, they can bring the parasites that cause the disease to different areas. This can fuel local transmission or even lead to outbreaks in a malaria-free area. When new malaria patients are diagnosed, they are often asked to report their recent travel history, so that the origin of their infection can be tracked. In theory, this would help to spot regions where the disease is imported from, and design targeted interventions. However, it is difficult to know exactly where the parasites come from based on self-disclosed travel history. At best, this history can provide information about that person's infection but nothing further in the past; at worst this history can be completely incorrect. Parasite DNA, on the other hand, has the potential to bring with it an indelible record of the past. To address the problem of determining where malaria infections came from, Tessema, Wesolowski et al. focused on Northern Namibia, a region where malaria persists despite being practically absent from the rest of the country. Patients movements were assessed using mobile phone call records as well as self-reported travel history In addition, samples from a single drop of blood were taken so that the genetic information of the parasites could be examined. Combining genetic data with travel history and phone records, Tessema, Wesolowski et al. found that, in Northern Namibia, most people had gotten infected by malaria locally. However, the genetic analyses also revealed that certain infections came from places across the Angolan and Zambian borders, information that was much more difficult to obtain using self-report or mobile phone data. A new, separate study by Chang, Wesolowski et al. also supports these results, showing that, in Bangladesh, combining genetic data with travel history and mobile phone records helps to track how malaria spreads. Overall, the work by Tessema, Wesolowski et al. indicate that, in Northern Namibia, it will be necessary to strengthen local interventions to eliminate malaria. However, different countries in the region may also need to coordinate to decrease malaria nearby and reduce the number of cases coming into the country. While genetic data can help to monitor how new malaria cases are imported, this knowledge will be most valuable if it is routinely collected across countries. New tools will also be required to translate genetic data into information that can easily be used for control and elimination programs.

As countries move towards malaria elimination, methods to identify infections among populations who do not seek treatment are required. Reactive case detection, whereby individuals living in close proximity to passively detected cases are screened and treated, is one approach being used by a number of countries including Swaziland. An outstanding issue is establishing the epidemiologically and operationally optimal screening radius around each passively detected index case. Using data collected between December 2009 and June 2012 from reactive case detection (RACD) activities in Swaziland, we evaluated the effect of screening radius and other risk factors on the probability of detecting cases by reactive case detection. Using satellite imagery, we also evaluated the household coverage achieved during reactive case detection. Over the study period, 250 cases triggered RACD, which identified a further 74 cases, showing the value of RACD over passive surveillance alone. Results suggest that the odds of detecting a case within the household of the index case were significantly higher than in neighbouring households (odds ratio (OR) 13, 95% CI 3.1-54.4). Furthermore, cases were more likely to be detected when RACD was conducted within a week of the index presenting at a health facility (OR 8.7, 95% CI 1.1-66.4) and if the index household had not been sprayed with insecticide (OR sprayed vs not sprayed 0.11, 95% CI 0.03-0.46). The large number of households missed during RACD indicates that a 1 km screening radius may be impractical in such resource limited settings such as Swaziland. Future RACD in Swaziland could be made more effective by achieving high coverage amongst individuals located near to index cases and in areas where spraying has not been conducted. As well as allowing the programme to implement RACD more rapidly, this would help to more precisely define the optimal screening radius.

Background Rapid diagnostic tests (RDTs) used to diagnose Plasmodium falciparum predominantly target the antigen Histidine Rich Protein 2 (HRP2) exclusively. With the emergence of hrp2/hrp3 gene deletions, RDTs targeting other antigens such as the essential enzyme Lactate Dehydrogenase (LDH) are needed. The dynamics of LDH relative to HRP2 are currently not well described but are needed to inform the use of next-generation (NG-) LDH and HRP2 RDTs that are designed to address hrp2/hrp3 gene deletions. Methods A longitudinal cohort study conducted in a low transmission setting in Namibia was leveraged to compare HRP2 and LDH decay rates. Passive and active case detection were used to recruit individuals with positive HRP2-RDT results. Study participants were treated and subsequently followed weekly until they received two consecutive HRP2-RDT negative results. Blood specimens were characterized for antigen concentration and parasite density. Antigen decay rates were calculated and used to estimate time to negativity (TTN) of NG-RDTs: two HRP2 and LDH-based RDTs (Rapigen Pf and a WHO prequalified Pf/Pv RDT) and an LDH-only RDT (Rapigen Pf/Pv). Results In 135 participants, the starting geometric mean concentrations for HRP2 and LDH were 899 ng/mL and 344 ng/mL respectively. Both antigens followed a biphasic decay rate, with a faster decay rate in the first phase. For current RDTs with an analytical sensitivity of 1 ng/mL for HRP2 and 5 ng/mL for LDH, TTN was 44 and 4 days, respectively. With a NG-RDT with LDH analytical sensitivity of 0.37 ng/mL, average TTN was 9 days. Multiple levels of analytical sensitivity were also modeled. Conclusions In the detection of P. falciparum malaria, LDH versus HRP2-based RDTs had a faster TTN due to a combination of lower accumulated antigen concentrations and faster decay rates, even for more sensitive LDH-based RDTs. Detection of LDH versus HRP2 by RDT is more likely to reflect a new or very recent infection. For NG-RDTs that target both antigens, HRP2 is likely to contribute more to the test signal than LDH in recently treated infections unless the infection has hrp2/hrp3 gene deletions. Antigen decay data combined with analytical sensitivity contributes to understanding RDT performance and interpretation.