BioRealm (United States)

PurposePremenopausal, estrogen receptor (ER)-positive breast cancer patients should receive tamoxifen for at least 5 years, but many prematurely discontinue. Activation, transport, and deactivation of tamoxifen and its metabolites are controlled by proteins encoded by genes with functional variations. We examined the impact of genetic polymorphisms in the tamoxifen pathway on early treatment discontinuation.MethodsWe included premenopausal women diagnosed with ER-positive breast cancer (2002–2011) in Denmark who initiated tamoxifen. We genotyped 26 genetic variants in 15 enzymes involved in tamoxifen metabolism. Early discontinuation was defined as tamoxifen use for < 5 years. We estimated individual and combined effects of genetic variants using a Bayesian pathway approach. We report Bayes Factors (BF), wherein values > 1 indicate support of an effect of the genetic pathway on discontinuation (compared with no effect).ResultsAmong 3,729 patients, 536 (14%) discontinued tamoxifen within 5 years. Genetic variants involved in tamoxifen activation impacted early discontinuation (BF = 7.5), in a manner driven almost entirely by CYP2D6 activity (BF = 22.6). Several variants in CYP2D6 and transporter genes synergistically increased the hazard of early discontinuation (e.g., CYP2D6*2 and ABCC2; BF = 138).ConclusionsVariants in enzymes responsible for activating tamoxifen metabolites—particularly within CYP2D6—influence early tamoxifen discontinuation. CYP2D6 variants synergistically interact with transporter gene variants, namely ABCC2, to further raise the risk of discontinuation.

ABSTRACT Background: Substance use disorder (SUD) is a heterogeneous disorder. Adapting machine learning algorithms to allow for the parsing of intrapersonal and interpersonal heterogeneity in meaningful ways may accelerate the discovery and implementation of clinically actionable interventions in SUD research. Objectives: Inspired by a study of heavy drinkers that collected daily drinking and substance use (ABQ DrinQ), we develop tools to estimate subject-specific risk trajectories of heavy drinking; estimate and perform inference on patient characteristics and time-varying covariates; and present results in easy-to-use Jupyter notebooks. Methods:We recast support vector machines (SVMs) into a Bayesian model extended to handle mixed effects. We then apply these methods to ABQ DrinQ to model alcohol use patterns. ABQ DrinQ consists of 190 heavy drinkers (44% female) with 109,580 daily observations. Results:We identified male gender (point estimate; 95% credible interval: −0.25;-0.29,-0.21), older age (−0.03;-0.03,-0.03), and time varying usage of nicotine (1.68;1.62,1.73), cannabis (0.05;0.03,0.07), and other drugs (1.16;1.01,1.35) as statistically significant factors of heavy drinking behavior. By adopting random effects to capture the subject-specific longitudinal trajectories, the algorithm outperforms traditional SVM (classifies 84% of heavy drinking days correctly versus 73%). Conclusions: We developed a mixed effects variant of SVM and compare it to the traditional formulation, with an eye toward elucidating the importance of incorporating random effects to account for underlying heterogeneity in SUD data. These tools and examples are packaged into a repository for researchers to explore. Understanding patterns and risk of substance use could be used for developing individualized interventions.

When the Coronavirus (COVID-19) pandemic started to hit in the beginning of 2020, a team led by the IEEE Humanitarian Activities Committee (HAC) and the IEEE Special Interest Group on Humanitarian Technologies (SIGHT) society was formed to brainstorm different ideas which can benefit people from Ottawa and all over the world. One of the discussed ideas was designing a UVC office lamp which can work in presence of humans to eliminate the air germicide. The lamp is designed with materials that can be easily bought on the market and is easy to be manufactured. The lamp has an Ultraviolet C (UVC) output power of 72 W. It also features with over-temperature protection and wireless diagnostic.

Our institution developed a 1-hour mandatory narcotics-prescribing education program as well as postoperative opioid-prescribing guidelines in response to the opioid epidemic. The purpose of this study was to evaluate the effect of this hospital-wide opioid education and subsequent institution of postoperative opioid guidelines on opioid-prescribing practices after ambulatory surgery. This retrospective study was performed at 1 academic orthopaedic hospital. In November 2016, a 1-hour mandatory opioid education program was completed by all hospital prescribers. Postoperative opioid guidelines were then developed and were disseminated in February 2017. All postoperative narcotic prescriptions after ambulatory procedures performed by 3 separate services (hand, sports, and foot and ankle services) were evaluated over 4 months prior to and after the mandatory opioid education and subsequent release of service-specific guidelines. Overall, there was a significant decrease in pills and total oral morphine equivalents prescribed after dissemination of guidelines compared with the pre-intervention cohort procedures (p < 0.001) performed by the sports and hand services. With regard to the sports medicine service, the mean difference in pills prescribed was 6.47 pills (95% confidence interval [CI], 5.4 to 7.5 pills) for knee arthroscopy, 5.6 pills (95% CI, 2.5 to 8.7 pills) for shoulder arthroscopy, and 16.3 pills (95% CI, 13.6 to 19.1 pills) for hip arthroscopy. With regard to the hand service, the mean difference in pills prescribed was 13.0 pills (95% CI, 10.2 to 15.8 pills) for level-1 procedures, 12.4 pills (95% CI, 9.9 to 15.0 pills) for carpal tunnel release, and 21.7 pills (95% CI, 18.0 to 25.3 pills) for distal radial fractures. The decrease in pills prescribed in the post-intervention cohort amounts to almost 30,000 fewer opioid pills prescribed per year after these 6 procedures alone. There was no significant change (p > 0.05) in either the number of pills or the oral morphine equivalents prescribed after any of the 3 procedures performed by the foot and ankle service (ankle arthroscopy, bunion surgery, and Achilles tendon repair). We developed a prescriber education program and followed up with consensus-based guidelines for postoperative opioid prescriptions. These interventions caused a significant decrease in excessive opioid-prescribing practices after ambulatory orthopaedic surgery at our hospital. We urge initiatives by national orthopaedic organizations to develop and promote education programs and procedure and disease-specific opioid-prescribing guidelines.

Toxicity of Toxaphene in the Rat and Beagle Dog. CHU, I., VILLENEUVE, D.C, SUN, C., SECOURS, V., PROCTER, B., ARNOLD, E., CLEGG, D., REYNOLDS, L., AND VALLI, V.E. (1986). Fundam Appl. Toxicol. 7, 406-418. Residues of the insecticidal mixture, toxaphene, have been found in Great Lakes fish. The purpose of the present study was to assess the subchronic toxicity of toxaphene in the rat and beagle dog. In the rat study, groups of 10 male and 10 female animals were fed diets containing 0, 4, 20, 100, or 500 ppm of the test compound for 13 weeks. No clinical signs of toxicity or spontaneous deaths were observed. Toxaphene treatment up to 500 ppm had no effects on weight gain or food consumption. The liver/body weight ratio and hepatic microsomal enzyme activities (phenobarbital type) were increased in both sexes fed 500 ppm of the test compound. Toxaphene at the highest dose also caused kidney enlargement in male but not in female rats. Dose-dependent histological changes were seen in the kidney, thyroid, and liver. Changes in the liver and thyroid were considered to be adaptative but the injury in the proximal tubules of the kidney was focally severe. Groups of six male and six female beagle dogs were fed toxaphene in gelatin capsules at 0, 0.2, 2.0, and 5.0 mg/kg body wt/day for 13 weeks. Food consumption and growth rate were not affected. All animals survived the entire treatment period. No clinical signs of toxicity were observed. The liver/body weight ratio and serum alkaline phosphatase were increased in dogs of both sexes fed 5.0 mg/kg. Mild to moderate dose-dependent histological changes were observed in the liver and thyroid. Toxaphene was accumulated in a dose-dependent manner in the fat and liver of dogs and rats. Based on the biochemical, histological, and residue data, it was concluded that the no-adverse-effect levels of the pesticide were 4.0 ppm (0.35 mg/kg) for the rat and 0.2 mg/kg for the dog.