Neurocognitive predictors of adherence to an online pain self-management program adjunct to long-term opioid therapy.

INTRODUCTION: While pain self-management programs can significantly improve patient outcomes, poor adherence is common and the need for research on predictors of adherence has been noted. A potential, but commonly overlooked, predictor is cognitive function. Our aim, then, was to examine the relative influence of various cognitive functional domains on engagement with an online pain self-management program. METHOD: A secondary analysis of a randomized controlled trial testing the impact of E-health (a 4-month subscription to the online Goalistics Chronic Pain Management Program) plus treatment as usual, relative to treatment as usual alone, on pain and opioid dose outcomes in adults receiving long-term opioid therapy of morphine equivalence dose ≥20 mg; 165 E-health participants who completed an on-line neurocognitive battery were included in this sub-analysis. A variety of demographic, clinical, and symptom rating scales were also examined. We hypothesized that better processing speed and executive functions at baseline would predict engagement with the 4-month E-health subscription. RESULTS: Ten functional cognitive domains were identified using exploratory factor analysis and the resultant factor scores applied for hypothesis testing. The strongest predictors of E-health engagement were selective attention, and response inhibition and speed domains. An explainable machine learning algorithm improved classification accuracy, sensitivity, and specificity. CONCLUSIONS: The results suggest that cognition, especially selective attention, inhibitory control, and processing speed, is predictive of online chronic pain self-management program engagement. Future research to replicate and extend these findings seems warranted. CLINICALTRIALS.GOV REGISTRATION NUMBER: NCT03309188.

Nutrient Limitation Magnifies Fitness Costs of Antimalarial Drug Resistance Mutations.

Drug resistance mutations tend to disrupt key physiological processes and frequently carry fitness costs, which are a central determinant of the rate of spread of these mutations in natural populations. Head-to-head competition assays provide a standard approach to measuring fitness for malaria parasites. These assays typically use a standardized culture medium containing RPMI 1640, which has a 1.4- to 5.5-fold higher concentration of amino acids than human blood. In this rich medium, we predict that fitness costs will be underestimated because resource competition is weak. We tested this prediction using an artemisinin-sensitive parasite edited to contain kelch-C580Y or R561H mutations conferring resistance to artemisinin or synonymous control mutations. We examined the impact of these single amino acid mutations on fitness, using replicated head-to-head competition experiments conducted in media containing (i) normal RPMI, (ii) modified RPMI with reduced amino acid concentration, (iii) RPMI containing only isoleucine, or (iv) 3-fold diluted RPMI. We found a significant 1.3- to 1.4-fold increase in fitness costs measured in modified and isoleucine-only media relative to normal media, while fitness costs were 2.5-fold higher in diluted media. We conclude that fitness costs are strongly affected by media composition and will be significantly underestimated in normal RPMI. Several components differed between media, including pABA and sodium bicarbonate concentrations, so we cannot directly determine which is responsible. Elevated fitness costs in nature will limit spread of artemisinin (ART) resistance but will also promote evolution of compensatory mutations that restore fitness and can be exploited to maximize selection in laboratory experiments.

Genetic architecture of transmission stage production and virulence in schistosome parasites.

Both theory and experimental data from pathogens suggest that the production of transmission stages should be strongly associated with virulence, but the genetic bases of parasite transmission/virulence traits are poorly understood. The blood fluke Schistosoma mansoni shows extensive variation in numbers of cercariae larvae shed and in their virulence to infected snail hosts, consistent with expected trade-offs between parasite transmission and virulence. We crossed schistosomes from two populations that differ 8-fold in cercarial shedding and in their virulence to Biomphalaria glabrata snail hosts, and determined four-week cercarial shedding profiles in F0 parents, F1 parents and 376 F2 progeny from two independent crosses in inbred snails. Sequencing and linkage analysis revealed that cercarial production is polygenic and controlled by five QTLs (i.e. Quantitative Trait Loci). These QTLs act additively, explaining 28.56% of the phenotypic variation. These results demonstrate that the genetic architecture of key traits relevant to schistosome ecology can be dissected using classical linkage mapping approaches.

Fitness Costs and the Rapid Spread of kelch13-C580Y Substitutions Conferring Artemisinin Resistance.

Fitness costs are key determinants of whether drug resistance alleles establish and how fast they spread within populations. More than 125 different kelch13 alleles, each containing a different amino acid substitution, have arisen in Southeast Asian malaria parasite (Plasmodium falciparum) populations under artemisinin selection over the past 15 years in a dramatic example of a soft selective event. However, just one of these alleles (C580Y) is now outcompeting other alleles in multiple different countries and is spreading toward fixation. Here we examine the fitness consequences of C580Y, relative to another less successful kelch13 mutation (R561H), to try to explain the distinctive dynamics of C580Y. We hypothesized that C580Y will show lower fitness costs than other kelch13 substitutions in the absence of artemisinin treatment. We used CRISPR/Cas9 methods to introduce single mutations (C580Y or R561H) or synonymous control edits into a wild-type parasite isolated on the Thailand-Myanmar border, conducted replicated head-to-head competition assays, and determined the outcome of competition using deep sequencing of kelch13 amplicons. Contrary to our predictions, these experiments reveal that C580Y carries higher fitness costs (s [selection coefficient] = 0.15 ± 0.008 [1 standard error {SE}]) than R561H (s = 0.084 ± 0.005). Furthermore, R561H outcompetes C580Y in direct competition (s = 0.065 ± 0.004). We conclude that fitness costs of C580Y in isolation are unlikely to explain the rapid spread of this substitution.