Cross-validated stepwise regression for identification of novel non-nucleoside reverse transcriptase inhibitor resistance associated mutations

<p>Abstract</p> <p>Background</p> <p>Linear regression models are used to quantitatively predict drug resistance, the phenotype, from the HIV-1 viral genotype. As new antiretroviral drugs become available, new resistance pathways emerge and the number of resistance associated mutations continues to increase. To accurately identify which drug options are left, the main goal of the modeling has been to maximize predictivity and not interpretability. However, we originally selected linear regression as the preferred method for its transparency as opposed to other techniques such as neural networks. Here, we apply a method to lower the complexity of these phenotype prediction models using a 3-fold cross-validated selection of mutations.</p> <p>Results</p> <p>Compared to standard stepwise regression we were able to reduce the number of mutations in the reverse transcriptase (RT) inhibitor models as well as the number of interaction terms accounting for synergistic and antagonistic effects. This reduction in complexity was most significant for the non-nucleoside reverse transcriptase inhibitor (NNRTI) models, while maintaining prediction accuracy and retaining virtually all known resistance associated mutations as first order terms in the models. Furthermore, for etravirine (ETR) a better performance was seen on two years of unseen data. By analyzing the phenotype prediction models we identified a list of forty novel NNRTI mutations, putatively associated with resistance. The resistance association of novel variants at known NNRTI resistance positions: 100, 101, 181, 190, 221 and of mutations at positions not previously linked with NNRTI resistance: 102, 139, 219, 241, 376 and 382 was confirmed by phenotyping site-directed mutants.</p> <p>Conclusions</p> <p>We successfully identified and validated novel NNRTI resistance associated mutations by developing parsimonious resistance prediction models in which repeated cross-validation within the stepwise regression was applied. Our model selection technique is computationally feasible for large data sets and provides an approach to the continued identification of resistance-causing mutations.</p

Socio-demographic factors associated with pet ownership amongst adolescents from a UK birth cohort

Background: In developed nations, pet ownership is common within families. Both physical and psychological health benefits may result from owning a pet during childhood and adolescence. However, it is difficult to determine whether these benefits are due to pet ownership directly or to factors linked to both pet ownership and health. Previous research found associations between a range of socio-demographic factors and pet ownership in seven-year-old children from a UK cohort. The current study extends this research to adolescence, considering that these factors may be important to consider in future Human-Animal Interaction (HAI) research across childhood.Results:The Avon Longitudinal Study of Parents and Children (ALSPAC) collected pet ownership data prospectively via maternal reports from gestation up to age 10 years old and via self-report retrospectively at age 18 for ages 11(n= 3063) to 18 years old (n= 3098) on cats, dogs, rabbits, rodents, birds, fish, tortoise/turtles and horses. The dataset also contains a wide range of potential confounders, including demographic and socio-economic variables.The ownership of all pet types peaked at age 11 (80%) and then decreased during adolescence, with the exclusion of cats which remained constant (around 30%), and dogs which increased through 11–18 years (26–37%). Logistic regression was used to build multivariable models for ownership of each pet type at age 13 years, and the factors identified in these models were compared to previously published data for 7 year-olds in the same cohort. There was some consistency with predictors reported at age 7. Generally sex, birth order, maternal age, maternal education, number of people in the household, house type, and concurrent ownership of other pets were associated with pet ownership at both 7 and 13 years (the direction of association varied according to pet type).Factors that were no longer associated with adolescent pet ownership included child ethnicity, paternal education,and parental social class.Conclusions:A number of socio-demographic factors are associated with pet ownership in childhood and adolescence and they differ according to the type of pet, and age of child. These factors are potential confounders that must be considered in future HAI studies

K70Q Adds High-Level Tenofovir Resistance to “Q151M Complex” HIV Reverse Transcriptase through the Enhanced Discrimination Mechanism

HIV-1 carrying the “Q151M complex” reverse transcriptase (RT) mutations (A62V/V75I/F77L/F116Y/Q151M, or Q151Mc) is resistant to many FDA-approved nucleoside RT inhibitors (NRTIs), but has been considered susceptible to tenofovir disoproxil fumarate (TFV-DF or TDF). We have isolated from a TFV-DF-treated HIV patient a Q151Mc-containing clinical isolate with high phenotypic resistance to TFV-DF. Analysis of the genotypic and phenotypic testing over the course of this patient's therapy lead us to hypothesize that TFV-DF resistance emerged upon appearance of the previously unreported K70Q mutation in the Q151Mc background. Virological analysis showed that HIV with only K70Q was not significantly resistant to TFV-DF. However, addition of K70Q to the Q151Mc background significantly enhanced resistance to several approved NRTIs, and also resulted in high-level (10-fold) resistance to TFV-DF. Biochemical experiments established that the increased resistance to tenofovir is not the result of enhanced excision, as K70Q/Q151Mc RT exhibited diminished, rather than enhanced ATP-based primer unblocking activity. Pre-steady state kinetic analysis of the recombinant enzymes demonstrated that addition of the K70Q mutation selectively decreases the binding of tenofovir-diphosphate (TFV-DP), resulting in reduced incorporation of TFV into the nascent DNA chain. Molecular dynamics simulations suggest that changes in the hydrogen bonding pattern in the polymerase active site of K70Q/Q151Mc RT may contribute to the observed changes in binding and incorporation of TFV-DP. The novel pattern of TFV-resistance may help adjust therapeutic strategies for NRTI-experienced patients with multi-drug resistant (MDR) mutations

Dog bite prevention:Effect of a short educational intervention for preschool children

This study aimed to investigate whether preschool children can learn how to interpret dogs' behaviours, with the purpose of helping avoid dog bites. Three- to five-year-old children (N = 70) were tested on their ability to answer questions about dogs' emotional states before and after participating in either an educational intervention about dog behaviour (intervention group) or an activity about wild animals (control group). Children who had received training about dog behaviour (intervention group) were significantly better at judging the dogs' emotional states after the intervention compared to before. The frequency with which they referred to relevant behaviours in justifying their judgements also increased significantly. In contrast, the control group's performance did not differ significantly between the two testing times. These results indicate that preschool children can be taught how to correctly interpret dogs' behaviours. This implies that incorporating such training into prevention programmes may contribute to reducing dog bite incidents

Children reading to dogs: a systematic review of the literature

Background Despite growing interest in the value of human-animal interactions (HAI) to human mental and physical health the quality of the evidence on which postulated benefits from animals to human psychological health are based is often unclear. To date there exist no systematic reviews on the effects of HAI in educational settings specifically focussing on the perceived benefits to children of reading to dogs. With rising popularity and implementation of these programmes in schools, it is essential that the evidence base exploring the pedagogic value of these initiatives is well documented. Methods Using PRISMA guidelines we systematically investigated the literature reporting the pedagogic effects of reading to dogs. Because research in this area is in the early stages of scientific enquiry we adopted broad inclusion criteria, accepting all reports which discussed measurable effects related to the topic that were written in English. Multiple online databases were searched during January-March 2015; grey literature searches were also conducted. The search results which met the inclusion criteria were evaluated, and discussed, in relation to the Oxford Centre for Evidence Based Medicine levels of evidence; 27 papers were classified as Level 5, 13 as Level 4, 7 as Level 2c and 1 as Level 2b. Conclusion The evidence suggests that reading to a dog may have a beneficial effect on a number of behavioural processes which contribute to a positive effect on the environment in which reading is practiced, leading to improved reading performance. However, the evidence base on which these inferences are made is of low quality. There is a clear need for the use of higher quality research methodologies and the inclusion of appropriate controls in order to draw causal inferences on whether or how reading to dogs may benefit children’s reading practices. The mechanisms for any effect remain a matter of conjectur