Project description:The aim was to determine if opioid neuroimmunopharmacology pathway gene polymorphisms alter serum morphine, morphine-3-glucuronide and morphine-6-glucuronide concentration-response relationships in 506 cancer patients receiving controlled-release oral morphine. Morphine-3-glucuronide concentrations (standardised to 11 h post-dose) were higher in patients without pain control (median (interquartile range) 1.2 (0.7-2.3) versus 1.0 (0.5-1.9) μM, P = 0.006), whereas morphine concentrations were higher in patients with cognitive dysfunction (40 (20-81) versus 29 (14-60) nM, P = 0.02). TLR2 rs3804100 variant carriers had reduced odds (adjusted odds ratio (95% confidence interval) 0.42 (0.22-0.82), P = 0.01) of opioid adverse events. IL2 rs2069762 G/G (0.20 (0.06-0.52)), BDNF rs6265 A/A (0.15 (0.02-0.63)) and IL6R rs8192284 carrier (0.55 (0.34-0.90)) genotypes had decreased, and IL6 rs10499563 C/C increased (3.3 (1.2-9.3)), odds of sickness response (P ≤ 0.02). The study has limitations in heterogeneity in doses, sampling times and diagnoses but still suggests that pharmacokinetics and immune genetics co-contribute to morphine pain control and adverse effects in cancer patients.
Project description:High-throughput biological data analysis commonly involves identifying features such as genes, genomic regions, and proteins, whose values differ between two conditions, from numerous features measured simultaneously. The most widely used criterion to ensure the analysis reliability is the false discovery rate (FDR), which is primarily controlled based on p-values. However, obtaining valid p-values relies on either reasonable assumptions of data distribution or large numbers of replicates under both conditions. Clipper is a general statistical framework for FDR control without relying on p-values or specific data distributions. Clipper outperforms existing methods for a broad range of applications in high-throughput data analysis.
Project description:Police body-worn cameras (BWCs) have been widely promoted as a technological mechanism to improve policing and the perceived legitimacy of police and legal institutions, yet evidence of their effectiveness is limited. To estimate the effects of BWCs, we conducted a randomized controlled trial involving 2,224 Metropolitan Police Department officers in Washington, DC. Here we show that BWCs have very small and statistically insignificant effects on police use of force and civilian complaints, as well as other policing activities and judicial outcomes. These results suggest we should recalibrate our expectations of BWCs' ability to induce large-scale behavioral changes in policing, particularly in contexts similar to Washington, DC.
Project description:Complex landscapes including semi-natural habitats are expected to favour natural enemies thereby enhancing natural pest biocontrol in crops. However, when considering a large number of situations, the response of natural biocontrol to landscape properties is globally inconsistent, a possible explanation being that local agricultural practices counteract landscape effects. In this study, along a crossed gradient of pesticide use intensity and landscape simplification, we analysed the interactive effects of landscape characteristics and local pesticide use intensity on natural biocontrol. During 3 years, using a set of sentinel prey (weed seeds, aphids and Lepidoptera eggs), biocontrol was estimated in 80 commercial fields located in four contrasted regions in France. For all types of prey excepted weed seeds, the predation rate was influenced by interactions between landscape characteristics and local pesticide use intensity. Proportion of meadow and length of interface between woods and crops had a positive effect on biocontrol of aphids where local pesticide use intensity was low but had a negative effect elsewhere. Moreover, the landscape proportion of suitable habitats for crop pests decreased the predation of sentinel prey, irrespectively of the local pesticide use intensity for weed seeds, but only in fields with low pesticide use for Lepidoptera eggs. These results show that high local pesticide use can counteract the positive expected effects of semi-natural habitats, but also that the necessary pesticide use reduction should be associated with semi-natural habitat enhancement to guarantee an effective natural biocontrol.
Project description:Employing 2 different coarse-grained models, we evaluated the effect of intramolecular domain-domain distances and hinge flexibility on the general solution structure of monoclonal antibodies (mAbs), within the context of protein-protein steric repulsion. These models explicitly account for the hinge region, and represent antibodies at either domain or subdomain levels (i.e., 4-bead and 7-bead representations, respectively). Additionally, different levels of mAb flexibility are also considered. When evaluating mAbs as rigid structures, analysis of small-angle scattering profiles showed that changes in the relative internal distances between Fc and Fab domains significantly alter the local arrangement of neighboring molecules, as well as the molecular packing of the concentrated mAb solutions. Likewise, enabling hinge flexibility in either of the mAb models led to qualitatively similar results, where flexibility increases the spatial molecular arrangement at elevated concentrations. This occurs because fluctuations in mAb quaternary structure are modulated by the close proximity between molecules at elevated concentrations (>50 mg mL-1), yielding an increased molecular packing and osmotic compressibility. However, our results also showed that the mechanism behind this synergy between flexibility and packing strongly depends on both the level of structural detail and the number of degrees-of-freedom considered in the coarse-grained model.
Project description:Implementation of pharmacogenetic testing in clinical care has been slow and with few exceptions is hindered by the lack of real-world evidence on how to best target testing. In this retrospective register-based study, we analyzed a nationwide cohort of 1,425,000 patients discharged from internal medicine or surgical wards and a cohort of 2,178 university hospital patients for purchases and prescriptions of pharmacogenetically actionable drugs. Pharmacogenetic variants were obtained from whole genome genotype data for a subset (n = 930) of the university hospital patients. We investigated factors associated with receiving pharmacogenetically actionable drugs and developed a literature-based cost-benefit model for pre-emptive pharmacogenetic panel testing. In a 2-year follow-up, 60.4% of the patients in the nationwide cohort purchased at least one pharmacogenetically actionable drug, most commonly ibuprofen (25.0%) and codeine (19.4%). Of the genotyped subset, 98.8% carried at least one actionable pharmacogenetic genotype and 23.3% had at least one actionable gene-drug pair. Patients suffering from musculoskeletal or cardiovascular diseases were more prone to receive pharmacogenetically actionable drugs during inpatient episode. The cost-benefit model included frequently dispensed drugs in the university hospital cohort, comprising ondansetron (19.4%), simvastatin (7.4%), clopidogrel (5.0%), warfarin (5.1%), (es)citalopram (5.3%), and azathioprine (0.5%). For untargeted pre-emptive pharmacogenetic testing of all university hospital patients, the model indicated saving €17.49 in direct healthcare system costs per patient in 2 years without accounting for the cost of the test itself. Therefore, it might be reasonable to target pre-emptive pharmacogenetic testing to patient groups most likely to receive pharmacogenetically actionable drugs.
Project description:IntroductionAspirin, clopidogrel, prasugrel and ticagrelor are antiplatelet agents for the prevention of ischemic events in patients with acute coronary syndromes (ACS), percutaneous coronary intervention (PCI) and other indications. Variability in response is observed to different degrees with these agents, which can translate to increased risks for adverse cardiovascular events. As such, potential pharmacogenetic determinants of antiplatelet pharmacokinetics, pharmacodynamics and clinical outcomes have been actively studied.Areas coveredThis article provides an overview of the available antiplatelet pharmacogenetics literature. Evidence supporting the significance of candidate genes and their potential influence on antiplatelet response and clinical outcomes are summarized and evaluated. Additional focus is directed at CYP2C19 and clopidogrel response, including the availability of clinical testing and genotype-directed antiplatelet therapy.Expert opinionThe reported aspirin response candidate genes have not been adequately replicated and few candidate genes have thus far been implicated in prasugrel or ticagrelor response. However, abundant data support the clinical validity of CYP2C19 and clopidogrel response variability among ACS/PCI patients. Although limited prospective trial data are available to support the utility of routine CYP2C19 testing, the increased risks for reduced clopidogrel efficacy among ACS/PCI patients that carry CYP2C19 loss-of-function alleles should be considered when genotype results are available.
Project description:The potential clinical utility of genetic markers associated with response to fluoropyrimidine treatment in colorectal cancer patients remains controversial despite extensive study. Our aim was to test the clinical validity of both novel and previously identified markers of adverse events in a broad clinical setting. We have conducted an observational pharmacogenetic study of early adverse events in a cohort study of 254 colorectal cancer patients treated with 5-fluorouracil or capecitabine. Sixteen variants of nine key folate (pharmacodynamic) and drug metabolising (pharmacokinetic) enzymes have been analysed as individual markers and/or signatures of markers. We found a significant association between TYMP S471L (rs11479) and early dose modifications and/or severe adverse events (adjusted OR = 2.02 [1.03; 4.00], p = 0.042, adjusted OR = 2.70 [1.23; 5.92], p = 0.01 respectively). There was also a significant association between these phenotypes and a signature of DPYD mutations (Adjusted OR = 3.96 [1.17; 13.33], p = 0.03, adjusted OR = 6.76 [1.99; 22.96], p = 0.002 respectively). We did not identify any significant associations between the individual candidate pharmacodynamic markers and toxicity. If a predictive test for early adverse events analysed the TYMP and DPYD variants as a signature, the sensitivity would be 45.5 %, with a positive predictive value of just 33.9 % and thus poor clinical validity. Most studies to date have been under-powered to consider multiple pharmacokinetic and pharmacodynamic variants simultaneously but this and similar individualised data sets could be pooled in meta-analyses to resolve uncertainties about the potential clinical utility of these markers.
Project description:Prior expectations can bias evaluative judgments of sensory information. We show that information about a performer's status can bias the evaluation of musical stimuli, reflected by differential activity of the ventromedial prefrontal cortex (vmPFC). Moreover, we demonstrate that decreased susceptibility to this confirmation bias is (a) accompanied by the recruitment of and (b) correlated with the white-matter structure of the executive control network, particularly related to the dorsolateral prefrontal cortex (dlPFC). By using long-duration musical stimuli, we were able to track the initial biasing, subsequent perception, and ultimate evaluation of the stimuli, examining the full evolution of these biases over time. Our findings confirm the persistence of confirmation bias effects even when ample opportunity exists to gather information about true stimulus quality, and underline the importance of executive control in reducing bias.
Project description:Predicting response to drug or xenobiotic exposure is vital to risk assessment and clinical response rates. Primary human hepatocytes are commonly used to evaluate liver drug metabolism and toxicity. They are the most physiologically relevant in vitro model, retaining expression of most ADME-relevant genes. However, human hepatocytes are source limited, have high donor variability, only survive short term in culture, and lack selection for specific genetic profiles. To overcome the limitations associated with primary hepatocytes we and others are investigating the potential of pluripotent stem cells as an alternative or complementary source for generating hepatocytes. Pluripotent stem cells offer advantages over primary hepatocytes because stem cells have high replicative capacity, potentially providing a limitless source of hepatocytes. Stem cell derived hepatocytes (SCDHs) may also provide an improved in vitro system for evaluating pharmacogenetic relationships, e.g. cytochrome P450 (CYP) enzymes and their impact on drug metabolism and toxicity. To demonstrate the utility of SCDHs in pharmacogenetic screening, we genotyped the five commonly used WiCell® human embryonic stem cell lines (hESC), H1, H7, H9, H13 and H14.