BACKGROUND: Rapid diagnostic tests (RDTs) that rely on the detection of Plasmodium falciparum histidine-rich protein 2 (PfHRP2) have become key tools for diagnosing P. falciparum infection. The utility of RDTs can be limited by PfHRP2 persistence, however it can be a potential benefit in low transmission settings where detection of persistent PfHRP2 using newer ultra-sensitive PfHRP2 based RDTs can serve as a surveillance tool to identify recent exposure. Better understanding of the dynamics of PfHRP2 over the course of a malaria infection can inform optimal use of RDTs. METHODS: A previously published mathematical model was refined to mimic the production and decay of PfHRP2 during a malaria infection. Data from 15 individuals from volunteer infection studies were used to update the original model and estimate key model parameters. The refined model was applied to a cohort of patients from Namibia who received treatment for clinical malaria infection for whom longitudinal PfHRP2 concentrations were measured. RESULTS: The refinement of the PfHRP2 dynamic model indicated that in malaria naïve hosts, P. falciparum parasites of the 3D7 strain produce 33.6 × 10-15 g (95% CI 25.0-42.1 × 10-15 g) of PfHRP2 in vivo per parasite replication cycle, with an elimination half-life of 1.67 days (95% CI 1.11-3.40 days). The refined model included these updated parameters and incorporated individualized body fluid volume calculations, which improved predictive accuracy when compared to the original model. The performance of the model in predicting clearance of PfHRP2 post treatment in clinical samples from six adults with P. falciparum infection in Namibia improved when using a longer elimination half-life of 4.5 days, with 14% to 67% of observations for each individual within the predicted range. CONCLUSIONS: The updated mathematical model can predict the growth and clearance of PfHRP2 during the production and decay of a mono-infection with P. falciparum, increasing the understanding of PfHRP2 antigen dynamics. This model can guide the optimal use of PfHRP2-based RDTs for reliable diagnosis of P. falciparum infection and re-infection in endemic settings, but also for malaria surveillance and elimination programmes in low transmission areas.

The contribution of germline copy number variants (CNVs) to risk of developing cancer in individuals with pathogenic BRCA1 or BRCA2 variants remains relatively unknown. We conducted the largest genome-wide analysis of CNVs in 15,342 BRCA1 and 10,740 BRCA2 pathogenic variant carriers. We used these results to prioritise a candidate breast cancer risk-modifier gene for laboratory analysis and biological validation. Notably, the HR for deletions in BRCA1 suggested an elevated breast cancer risk estimate (hazard ratio (HR) = 1.21), 95% confidence interval (95% CI = 1.09-1.35) compared with non-CNV pathogenic variants. In contrast, deletions overlapping SULT1A1 suggested a decreased breast cancer risk (HR = 0.73, 95% CI 0.59-0.91) in BRCA1 pathogenic variant carriers. Functional analyses of SULT1A1 showed that reduced mRNA expression in pathogenic BRCA1 variant cells was associated with reduced cellular proliferation and reduced DNA damage after treatment with DNA damaging agents. These data provide evidence that deleterious variants in BRCA1 plus SULT1A1 deletions contribute to variable breast cancer risk in BRCA1 carriers.