Taking the Pulse: perceptions of crime trends and community safety and support for crime control methods in the Canadian Prairies

The present study analyzed crime survey data extracted from the 2012 Saskatchewan Taking the Pulse survey on a sample of 1,700 adult Saskatchewan residents. The focus was on examining perceptions of crime trends, perceived effectiveness of various methods for controlling crime, and their sociodemographic correlates. The majority of survey respondents perceived crime in general to be on the rise (37%) or to have not changed at all (48%) over the last three years. Individuals who perceived crime to have decreased were significantly more likely to support alternatives to punishment as effective methods for reducing crime, while individuals who perceived crime to be on the rise were twice as likely to support the use of punitive methods. Perceptions of community safety were unrelated to preference for one crime reduction method over another. Education level was inversely related to crime trend perceptions (r = -.14) and preference for punitive methods to reduce crime (r = -.20). Finally, the results of logistic regression indicated higher levels of education, higher income, and perceptions of crime decreasing were all uniquely associated with a preference for alternatives to punishment in reducing crime. In these analyses, younger age was predictive of a preference for alternatives in reducing youth crime, while urban residential setting was associated with a preference for alternatives to punishment in reducing crime in general

Modeling Chemical Interaction Profiles: II. Molecular Docking, Spectral Data-Activity Relationship, and Structure-Activity Relationship Models for Potent and Weak Inhibitors of Cytochrome P450 CYP3A4 Isozyme

Polypharmacy increasingly has become a topic of public health concern, particularly as the U.S. population ages. Drug labels often contain insufficient information to enable the clinician to safely use multiple drugs. Because many of the drugs are bio-transformed by cytochrome P450 (CYP) enzymes, inhibition of CYP activity has long been associated with potentially adverse health effects. In an attempt to reduce the uncertainty pertaining to CYP-mediated drug-drug/chemical interactions, an interagency collaborative group developed a consensus approach to prioritizing information concerning CYP inhibition. The consensus involved computational molecular docking, spectral data-activity relationship (SDAR), and structure-activity relationship (SAR) models that addressed the clinical potency of CYP inhibition. The models were built upon chemicals that were categorized as either potent or weak inhibitors of the CYP3A4 isozyme. The categorization was carried out using information from clinical trials because currently available in vitro high-throughput screening data were not fully representative of the in vivo potency of inhibition. During categorization it was found that compounds, which break the Lipinski rule of five by molecular weight, were about twice more likely to be inhibitors of CYP3A4 compared to those, which obey the rule. Similarly, among inhibitors that break the rule, potent inhibitors were 2–3 times more frequent. The molecular docking classification relied on logistic regression, by which the docking scores from different docking algorithms, CYP3A4 three-dimensional structures, and binding sites on them were combined in a unified probabilistic model. The SDAR models employed a multiple linear regression approach applied to binned 1D 13C-NMR and 1D 15N-NMR spectral descriptors. Structure-based and physical-chemical descriptors were used as the basis for developing SAR models by the decision forest method. Thirty-three potent inhibitors and 88 weak inhibitors of CYP3A4 were used to train the models. Using these models, a synthetic majority rules consensus classifier was implemented, while the confidence of estimation was assigned following the percent agreement strategy. The classifier was applied to a testing set of 120 inhibitors not included in the development of the models. Five compounds of the test set, including known strong inhibitors dalfopristin and tioconazole, were classified as probable potent inhibitors of CYP3A4. Other known strong inhibitors, such as lopinavir, oltipraz, quercetin, raloxifene, and troglitazone, were among 18 compounds classified as plausible potent inhibitors of CYP3A4. The consensus estimation of inhibition potency is expected to aid in the nomination of pharmaceuticals, dietary supplements, environmental pollutants, and occupational and other chemicals for in-depth evaluation of the CYP3A4 inhibitory activity. It may serve also as an estimate of chemical interactions via CYP3A4 metabolic pharmacokinetic pathways occurring through polypharmacy and nutritional and environmental exposures to chemical mixtures

Where the Lake Meets the Sea: Strong Reproductive Isolation Is Associated with Adaptive Divergence between Lake Resident and Anadromous Three-Spined Sticklebacks

Contact zones between divergent forms of the same species are often characterised by high levels of phenotypic diversity over small geographic distances. What processes are involved in generating such high phenotypic diversity? One possibility is that introgression and recombination between divergent forms in contact zones results in greater phenotypic and genetic polymorphism. Alternatively, strong reproductive isolation between forms may maintain distinct phenotypes, preventing homogenisation by gene flow. Contact zones between divergent freshwater-resident and anadromous stickleback (Gasterosteus aculeatus L.) forms are numerous and common throughout the species distribution, offering an opportunity to examine these contrasting hypotheses in greater detail. This study reports on an interesting new contact zone located in a tidally influenced lake catchment in western Ireland, characterised by high polymorphism for lateral plate phenotypes. Using neutral and QTL-linked microsatellite markers, we tested whether the high diversity observed in this contact zone arose as a result of introgression or reproductive isolation between divergent forms: we found strong support for the latter hypothesis. Three phenotypic and genetic clusters were identified, consistent with two divergent resident forms and a distinct anadromous completely plated population that migrates in and out of the system. Given the strong neutral differentiation detected between all three morphotypes (mean F-ST = 0.12), we hypothesised that divergent selection between forms maintains reproductive isolation. We found a correlation between neutral genetic and adaptive genetic differentiation that support this. While strong associations between QTL linked markers and phenotypes were also observed in this wild population, our results support the suggestion that such associations may be more complex in some Atlantic populations compared to those in the Pacific. These findings provide an important foundation for future work investigating the dynamics of gene flow and adaptive divergence in this newly discovered stickleback contact zone

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2–4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Gender Differences in Demographic and Pharmacological Factors in Patients Diagnosed with Late-Onset of Alzheimer’s Disease

Background: Whether gender differences exist in late-onset of Alzheimer’s disease (LOAD) treated with cholinesterase inhibitors (ChEIs) is not fully understood. This study investigated demographic and pharmacological characteristics in LOAD patients to determine gender differences in LOAD patients treated with ChEIs alone and ChEIs with other medications. Methods: This 5-year retrospective data analysis included 9290 LOAD AD patients with 2949 men patients and 6341 women. Potential predictors of demographic and pharmacological characteristics associated gender differences in patients treated with and without ChEIs therapy were determined using univariate analysis, while multivariable models adjusted for demographic and pharmacological variables. Results: In the adjusted analysis, men patients with LOAD that presented with a history of alcohol use (ETOH) (OR = 1.339, 95% CI, 1.072–1.672, p = 0.010), treated with second generation antipsychotics (SGAs) (OR = 1.271, 95% CI, 1.003–1.610, p = 0.047), citalopram (OR = 5.103, 95% CI, 3.423–7.607, p < 0.001), memantine (OR = 4.409, 95% CI, 3.704–5.249, p < 0.001), and buspirone (OR = 2.166, 95% CI, 1.437–3.264, p < 0.001) were more likely to receive ChEIs therapy, whereas older men were less likely to be treated with ChEIs therapy. Women who were African Americans (OR = 1.387, 95% CI, 1.168–1.647, p < 0.001), that received memantine (OR = 3.412, 95% CI, 3.034–3.837, p < 0.001), selective serotonin reuptake inhibitor (SSRIs) (OR = 1.143, 95% CI, 1.016–1.287, p = 0.026), and a history of ETOH (OR = 2.109, 95% CI, 1.724–2.580, p < 0.001) were more likely to receive ChEIs therapy, whereas older women were less likely to receive ChEIs therapy. Conclusion: In both men and women patients, those with increasing age were less likely to be treated with ChEI therapy, while patients treated with memantine were also likely to receive ChEI therapy. Our findings highlight the importance for clinicians to optimize ChEI in LOAD to improve treatment effectiveness and eliminate gender differences in ChEI therapy