Incomplete Plasmodium falciparum growth inhibition following piperaquine treatment translates into increased parasite viability in the in vitro parasite reduction ratio assay.

Antimalarial resistance to the first-line partner drug piperaquine (PPQ) threatens the effectiveness of artemisinin-based combination therapy. In vitro piperaquine resistance is characterized by incomplete growth inhibition, i.e. increased parasite growth at higher drug concentrations. However, the 50% inhibitory concentrations (IC50) remain relatively stable across parasite lines. Measuring parasite viability of a drug-resistant Cambodian Plasmodium falciparum isolate in a parasite reduction ratio (PRR) assay helped to better understand the resistance phenotype towards PPQ. In this parasite isolate, incomplete growth inhibition translated to only a 2.5-fold increase in IC50 but a dramatic decrease of parasite killing in the PRR assay. Hence, this pilot study reveals the potential of in vitro parasite viability assays as an important, additional tool when it comes to guiding decision-making in preclinical drug development and post approval. To the best of our knowledge, this is the first time that a compound was tested against a drug-resistant parasite in the in vitro PRR assay.

Individual participant data meta-analysis with mixed-effects transformation models.

One-stage meta-analysis of individual participant data (IPD) poses several statistical and computational challenges. For time-to-event outcomes, the approach requires the estimation of complicated nonlinear mixed-effects models that are flexible enough to realistically capture the most important characteristics of the IPD. We present a model class that incorporates general normally distributed random effects into linear transformation models. We discuss extensions to model between-study heterogeneity in baseline risks and covariate effects and also relax the assumption of proportional hazards. Within the proposed framework, data with arbitrary random censoring patterns can be handled. The accompanying $\textsf{R}$ package tramME utilizes the Laplace approximation and automatic differentiation to perform efficient maximum likelihood estimation and inference in mixed-effects transformation models. We compare several variants of our model to predict the survival of patients with chronic obstructive pulmonary disease using a large data set of prognostic studies. Finally, a simulation study is presented that verifies the correctness of the implementation and highlights its efficiency compared to an alternative approach.

Colour vision testing in young children with reduced visual acuity.

PURPOSE: To investigate feasibility, reliability and discriminative validity of pseudoisochromatic (PIC) colour vision tests, the Mollon-Reffin minimalist (MRM) test and the Cambridge Colour Test (CCT) among children (3-10 years) with reduced visual acuity. METHODS: Thirty-three patients with reduced visual acuity and 38 healthy control subjects with age-related normal visual acuity were recruited for this prospective study. Visual acuity in patients was reduced due to amblyopia, binocular maculopathy, or optic neuropathy. Tests were performed in a single 1-hr session. RESULTS: All but two children successfully completed the PIC and MRM tests. Success rate for the CCT was lower, 87%, CI [72%, 96%] for control subjects and 79%, CI [61%, 91%] for patients, with a strong positive effect of age on the odds of successful completion (OR 5.63, p = 0.007). Reliability was high in PIC and MRM tests but comparably lower in CCT. The rate of correct answers in PIC tests was between 88% and 100%. One proband was diagnosed with deuteranomaly with an average Ishihara score of 21%. All children (with the exception of one daltonian) scored at least two points in the MRM test. Sensitivity thresholds in CCT decreased with age with a strong effect size in control subjects and weak to moderate effect size in patients. CONCLUSIONS: Pseudoisochromatic and MRM tests show sufficient feasibility in young children with reduced visual acuity. For CCT feasibility in 3-5-year olds is reduced, most probably due to the longer test duration. Consistent with earlier findings, colour discrimination thresholds decrease with age independent on visual acuity status.