Similar Prevalence of Plasmodium falciparum and Non-P. falciparum Malaria Infections among Schoolchildren, Tanzania1.

Achieving malaria elimination requires considering both Plasmodium falciparum and non-P. falciparum infections. We determined prevalence and geographic distribution of 4 Plasmodium spp. by performing PCR on dried blood spots collected within 8 regions of Tanzania during 2017. Among 3,456 schoolchildren, 22% had P. falciparum, 24% had P. ovale spp., 4% had P. malariae, and 0.3% had P. vivax infections. Most (91%) schoolchildren with P. ovale infections had low parasite densities; 64% of P. ovale infections were single-species infections, and 35% of those were detected in low malaria endemic regions. P. malariae infections were predominantly (73%) co-infections with P. falciparum. P. vivax was detected mostly in northern and eastern regions. Co-infections with >1 non-P. falciparum species occurred in 43% of P. falciparum infections. A high prevalence of P. ovale infections exists among schoolchildren in Tanzania, underscoring the need for detection and treatment strategies that target non-P. falciparum species.

Core concepts in pharmacoepidemiology: Confounding by indication and the role of active comparators.

Confounding by indication poses a significant threat to the validity of nonexperimental studies assessing effectiveness and safety of medical interventions. While no different from other forms of confounding in theory, confounding by indication often requires specific methods to address the bias it creates in addition to common epidemiological adjustment or restriction methods. Clinical indication influencing treatment prescription is patient-specific and complex, making it challenging to measure within nonexperimental research. Restriction of the study population to patients with the indication for treatment would effectively mitigate confounding by indication and bring about comparability between exposure and comparator populations with respect to probability of the exposure. Active comparators are often an effective practical solution to restrict the study population in this manner when indication cannot be measured accurately. This article discusses various forms of confounding by indication, the utility of active comparators for nonexperimental studies of treatment effects, and the active comparator, new user (ACNU) study design to implicitly condition on indication. Considerations for selecting active comparators and conducting an ACNU study design are discussed to enable increased adoption of these methods, improve quality of nonexperimental studies, and ultimately strengthen our evidence base for intended and unintended treatment effects in relevant target populations.

A novel duplex qualitative real-time PCR assay for the detection and differentiation of Plasmodium ovale curtisi and Plasmodium ovale wallikeri malaria.

Background: P. ovale spp. infections are endemic across multiple African countries and are caused by two distinct non-recombining species, P. ovale curtisi (Poc) and P. ovale wallikeri (Pow). These species are thought to differ in clinical symptomatology and latency, but existing diagnostic assays have limited ability to detect and distinguish them. In this study, we developed a new duplex assay for the detection and differentiation of Poc and Pow that can be used to improve our understanding of these parasites. Methods: Repetitive sequence motifs were identified in available Poc and Pow genomes and used for assay development and validation. We evaluated the analytical sensitivity and specificity of the best-performing assay using a panel of samples from Tanzania and the Democratic Republic of the Congo (DRC), then validated its performance using 55 P. ovale spp. samples and 40 non-ovale Plasmodium samples from the DRC. Poc and Pow prevalence among symptomatic individuals sampled across three provinces of the DRC were estimated. Results: The best-performing Poc and Pow targets had 9 and 8 copies within the reference genomes, respectively. Our duplex assay had 100% specificity and 95% confidence lower limits of detection of 4.2 and 41.2 parasite genome equivalents/µl for Poc and Pow, respectively. Species was determined in 80% of all P. ovale spp.-positive field samples and 100% of those with >10 parasites/µl. Most P. ovale spp. field samples from the DRC were found to be Poc infections. Conclusions: We identified promising multi-copy targets for molecular detection and differentiation of Poc and Pow and used them to develop a new duplex real-time PCR assay that performed well when applied to diverse field samples. Though low-density Pow infections are not reliably detected, the assay is highly specific and can be used for high-throughput studies of P. ovale spp. epidemiology among symptomatic cases in malaria-endemic countries like the DRC.

Epidemiology of Plasmodium malariae and Plasmodium ovale spp. in a highly malaria-endemic country: a longitudinal cohort study in Kinshasa Province, Democratic Republic of Congo.

Background: Increasing reports suggest that non-falciparum species are an underappreciated cause of malaria in sub-Saharan Africa, but their epidemiology is not well-defined. This is particularly true in regions of high P. falciparum endemicity such as the Democratic Republic of Congo (DRC), where 12% of the world's malaria cases and 13% of deaths occur. Methods and Findings: The cumulative incidence and prevalence of P. malariae and P. ovale spp. infection detected by real-time PCR were estimated among children and adults within a longitudinal study conducted in seven rural, peri-urban, and urban sites from 2015-2017 in Kinshasa Province, DRC. Participants were sampled at biannual household survey visits (asymptomatic) and during routine health facility visits (symptomatic). Participant-level characteristics associated with non-falciparum infections were estimated for single- and mixed-species infections. Among 9,089 samples collected from 1,565 participants over a 3-year period, the incidence of P. malariae and P. ovale spp. infection was 11% (95% CI: 9%-12%) and 7% (95% CI: 5%-8%) by one year, respectively, compared to a 67% (95% CI: 64%-70%) one-year cumulative incidence of P. falciparum infection. Incidence continued to rise in the second year of follow-up, reaching 26% and 15% in school-age children (5-14yo) for P. malariae and P. ovale spp., respectively. Prevalence of P. malariae, P. ovale spp., and P. falciparum infections during household visits were 3% (95% CI: 3%-4%), 1% (95% CI: 1%-2%), and 35% (95% CI: 33%-36%), respectively. Non-falciparum malaria was more prevalent in rural and peri-urban vs. urban sites, in school-age children, and among those with P. falciparum co-infection. A crude association was detected between P. malariae and any anemia in the symptomatic clinic population, although this association did not hold when stratified by anemia severity. No crude associations were detected between non-falciparum infection and fever prevalence. Conclusions: P. falciparum remains the primary driver of malaria morbidity and mortality in the DRC. However, non-falciparum species also pose an infection risk across sites of varying urbanicity and malaria endemicity within Kinshasa, DRC, particularly among children under 15 years of age. As P. falciparum interventions gain traction in high-burden settings like the DRC, continued surveillance and improved understanding of non-falciparum infections are warranted.

Epidemiology of Plasmodium malariae and Plasmodium ovale spp. in Kinshasa Province, Democratic Republic of Congo.

Reports suggest non-falciparum species are an underappreciated cause of malaria in sub-Saharan Africa but their epidemiology is ill-defined, particularly in highly malaria-endemic regions. We estimated incidence and prevalence of PCR-confirmed non-falciparum and Plasmodium falciparum malaria infections within a longitudinal study conducted in Kinshasa, Democratic Republic of Congo (DRC) between 2015-2017. Children and adults were sampled at biannual household surveys and routine clinic visits. Among 9,089 samples from 1,565 participants, incidences of P. malariae, P. ovale spp., and P. falciparum infections by 1-year were 7.8% (95% CI: 6.4%-9.1%), 4.8% (95% CI: 3.7%-5.9%) and 57.5% (95% CI: 54.4%-60.5%), respectively. Non-falciparum prevalences were higher in school-age children, rural and peri-urban sites, and P. falciparum co-infections. P. falciparum remains the primary driver of malaria in the DRC, though non-falciparum species also pose an infection risk. As P. falciparum interventions gain traction in high-burden settings, continued surveillance and improved understanding of non-falciparum infections are warranted.

Impact of malaria diagnostic choice on monitoring of Plasmodium falciparum prevalence estimates in the Democratic Republic of the Congo and relevance to control programs in high-burden countries.

Malaria programs rely upon a variety of diagnostic assays, including rapid diagnostic tests (RDTs), microscopy, polymerase chain reaction (PCR), and bead-based immunoassays (BBA), to monitor malaria prevalence and support control and elimination efforts. Data comparing these assays are limited, especially from high-burden countries like the Democratic Republic of the Congo (DRC). Using cross-sectional and routine data, we compared diagnostic performance and Plasmodium falciparum prevalence estimates across health areas of varying transmission intensity to illustrate the relevance of assay performance to malaria control programs. Data and samples were collected between March-June 2018 during a cross-sectional household survey across three health areas with low, moderate, and high transmission intensities within Kinshasa Province, DRC. Samples from 1,431 participants were evaluated using RDT, microscopy, PCR, and BBA. P. falciparum parasite prevalence varied between diagnostic methods across all health areas, with the highest prevalence estimates observed in Bu (57.4-72.4% across assays), followed by Kimpoko (32.6-53.2%), and Voix du Peuple (3.1-8.4%). Using latent class analysis to compare these diagnostic methods against an "alloyed gold standard," the most sensitive diagnostic method was BBA in Bu (high prevalence) and Voix du Peuple (low prevalence), while PCR diagnosis was most sensitive in Kimpoko (moderate prevalence). RDTs were consistently the most specific diagnostic method in all health areas. Among 9.0 million people residing in Kinshasa Province in 2018, the estimated P. falciparum prevalence by microscopy, PCR, and BBA were nearly double that of RDT. Comparison of malaria RDT, microscopy, PCR, and BBA results confirmed differences in sensitivity and specificity that varied by endemicity, with PCR and BBA performing best for detecting any P. falciparum infection. Prevalence estimates varied widely depending on assay type for parasite detection. Inherent differences in assay performance should be carefully considered when using community survey and surveillance data to guide policy decisions.

Enhancing Concussion Management in the National Football League: Evolution and Initial Results of the Unaffiliated Neurotrauma Consultants Program, 2012-2017.

BACKGROUND: The real-time detection of concussive injury in professional sports can be challenging for the healthcare provider on the sideline. It can be difficult to monitor all on-field players during active game play and diagnose complex injuries such as concussion during a fast-paced athletic event. OBJECTIVE: To enhance the in-game identification of potentially concussed professional athletes, the National Football League (NFL) initiated an Unaffiliated Neurotrauma Consultants (UNC) program in 2013, which, in tandem with other in-arena spotters and live video review systems, is designed to improve the safety of the players through enhanced concussion detection efforts. METHODS: This paper reports on the evolution of the UNC program, describes its participants and training requirements, details the role of UNC involvement, and delineates the systematic revisions and enhancements completed each year in the program. RESULTS: UNC reporting compliance has increased from 56% in 2014 to 100% in 2017. During the 2016 and 2017 seasons, (1) UNCs submitted an average of 1.9 evaluations per game, and (2) the UNC concussion assessments yielded sensitivity (93.4%-97.4%) and specificity (81.0%-88.3%) values. CONCLUSION: The UNC program has enhanced the detection of concussion in NFL players. Directions for research and future program improvements are addressed.

Higher Rates of Lower Extremity Injury on Synthetic Turf Compared With Natural Turf Among National Football League Athletes: Epidemiologic Confirmation of a Biomechanical Hypothesis.

BACKGROUND: Biomechanical studies have shown that synthetic turf surfaces do not release cleats as readily as natural turf, and it has been hypothesized that concomitant increased loading on the foot contributes to the incidence of lower body injuries. This study evaluates this hypothesis from an epidemiologic perspective, examining whether the lower extremity injury rate in National Football League (NFL) games is greater on contemporary synthetic turfs as compared with natural surfaces. HYPOTHESIS: Incidence of lower body injury is higher on synthetic turf than on natural turf among elite NFL athletes playing on modern-generation surfaces. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: Lower extremity injuries reported during 2012-2016 regular season games were included, with all 32 NFL teams reporting injuries under mandated, consistent data collection guidelines. Poisson models were used to construct crude and adjusted incidence rate ratios (IRRs) to estimate the influence of surface type on lower body injury groupings (all lower extremity, knee, ankle/foot) for any injury reported as causing a player to miss football participation as well as injuries resulting in ≥8 days missed. A secondary analysis was performed on noncontact/surface contact injuries. RESULTS: Play on synthetic turf resulted in a 16% increase in lower extremity injuries per play than that on natural turf (IRR, 1.16; 95% CI, 1.10-1.23). This association between synthetic turf and injury remained when injuries were restricted to those that resulted in ≥8 days missed, as well as when categorizations were narrowed to focus on distal injuries anatomically closer to the playing surface (knee, ankle/foot). The higher rate of injury on synthetic turf was notably stronger when injuries were restricted to noncontact/surface contact injuries (IRRs, 1.20-2.03; all statistically significant). CONCLUSION: These results support the biomechanical mechanism hypothesized and add confidence to the conclusion that synthetic turf surfaces have a causal impact on lower extremity injury.