Background
Impulsivity is a multifaceted construct that has recently been recognized as a factor contributing to enhanced vulnerability to drug abuse.
Objectives
In the present review, we focus on ...two facets of impulsivity (and tasks that measure them): (1) impulsive choice (delay discounting task) and (2) inhibitory failure (go/no-go, stop signal reaction time, and five-choice serial reaction time tasks). We also describe how performance on each of these tasks is associated with drug-related behavior during phases of drug abuse that capture the essential features of addiction (acquisition, escalation, and reinstatement of drug-seeking after drug access has terminated). Three hypotheses (H) regarding the relationship between impulsivity and drug abuse are discussed: (1) increased levels of impulsivity lead to drug abuse (H1), (2) drugs of abuse increase impulsivity (H2), and (3) impulsivity and drug abuse are associated through a common third factor (H3).
Conclusion
Impulsivity expressed as impulsive choice or inhibitory failure plays a role in several key transition phases of drug abuse. There is evidence to support all three nonexclusive hypotheses. Increased levels of impulsivity lead to acquisition of drug abuse (H1) and subsequent escalation or dysregulation of drug intake. Drugs of abuse may increase impulsivity (H2), which is an additional contributor to escalation/dysregulation. Abstinence, relapse, and treatment may be influenced by both H1 and H2. In addition, there is a relationship between impulsivity and other drug abuse vulnerability factors, such as sex, hormonal status, reactivity to nondrug rewards, and early environmental experiences that may impact drug intake during all phases of addiction (H3). Relating drug abuse and impulsivity in phases of addiction via these three hypotheses provides a heuristic model from which future experimental questions can be addressed.
The incidence of pediatric-onset inflammatory bowel disease (IBD) is increasing worldwide. We used population-based health administrative data to determine national Canadian IBD incidence, ...prevalence, and trends over time of childhood-onset IBD.
We identified children <16 years (y) diagnosed with IBD 1999-2010 from health administrative data in five provinces (Alberta, Manitoba, Nova Scotia, Ontario, Quebec), comprising 79.2% of the Canadian population. Standardized incidence and prevalence were calculated per 100,000 children. Annual percentage change (APC) in incidence and prevalence were determined using Poisson regression analysis. Provincial estimates were meta-analyzed using random-effects models to produce national estimates.
5,214 incident cases were diagnosed during the study period (3,462 Crohn's disease, 1,382 ulcerative colitis, 279 type unclassifiable). The incidence in Canada was 9.68 (95% CI 9.11 to 10.25) per 100,000 children. Incidence was similar amongst most provinces, but higher in Nova Scotia. APC in incidence did not significantly change over the study period in the overall cohort (+2.06%, 95% CI -0.64% to +4.76%). However, incidence significantly increased in children aged 0-5y (+7.19%, 95% +2.82% to +11.56%). Prevalence at the end of the study period in Canada was 38.25 (95% CI 35.78 to 40.73) per 100,000 children. Prevalence increased significantly over time, APC +4.56% (95% CI +3.71% to +5.42%).
Canada has amongst the highest incidence of childhood-onset IBD in the world. Prevalence significantly increased over time. Incidence was not statistically changed with the exception of a rapid increase in incidence in the youngest group of children.
Inflammatory bowel diseases (IBDs) exist worldwide, with high prevalence in North America. IBD is complex and costly, and its increasing prevalence places a greater stress on health care systems. We ...aimed to determine the past current, and future prevalences of IBD in Canada.
We performed a retrospective cohort study using population-based health administrative data from Alberta (2002–2015), British Columbia (1997–2014), Manitoba (1990–2013), Nova Scotia (1996–2009), Ontario (1999–2014), Quebec (2001–2008), and Saskatchewan (1998–2016). Autoregressive integrated moving average regression was applied, and prevalence, with 95% prediction intervals (PIs), was forecasted to 2030. Average annual percentage change, with 95% confidence intervals, was assessed with log binomial regression.
In 2018, the prevalence of IBD in Canada was estimated at 725 per 100,000 (95% PI 716–735) and annual average percent change was estimated at 2.86% (95% confidence interval 2.80%–2.92%). The prevalence in 2030 was forecasted to be 981 per 100,000 (95% PI 963–999): 159 per 100,000 (95% PI 133–185) in children, 1118 per 100,000 (95% PI 1069–1168) in adults, and 1370 per 100,000 (95% PI 1312–1429) in the elderly. In 2018, 267,983 Canadians (95% PI 264,579–271,387) were estimated to be living with IBD, which was forecasted to increase to 402,853 (95% PI 395,466–410,240) by 2030.
Forecasting prevalence will allow health policy makers to develop policy that is necessary to address the challenges faced by health systems in providing high-quality and cost-effective care.
BACKGROUND:Ischemia reperfusion injury (I/RI) is a common complication of cardiovascular diseases. Resolution of detrimental I/RI-generated prothrombotic and proinflammatory responses is essential to ...restore homeostasis. Platelets play a crucial part in the integration of thrombosis and inflammation. Their role as participants in the resolution of thromboinflammation is underappreciated; therefore we used pharmacological and genetic approaches, coupled with murine and clinical samples, to uncover key concepts underlying this role.
METHODS:Middle cerebral artery occlusion with reperfusion was performed in wild-type or annexin A1 (AnxA1) knockout (AnxA1) mice. Fluorescence intravital microscopy was used to visualize cellular trafficking and to monitor light/dye–induced thrombosis. The mice were treated with vehicle, AnxA1 (3.3 mg/kg), WRW4 (1.8 mg/kg), or all 3, and the effect of AnxA1 was determined in vivo and in vitro.
RESULTS:Intravital microscopy revealed heightened platelet adherence and aggregate formation post I/RI, which were further exacerbated in AnxA1 mice. AnxA1 administration regulated platelet function directly (eg, via reducing thromboxane B2 and modulating phosphatidylserine expression) to promote cerebral protection post-I/RI and act as an effective preventative strategy for stroke by reducing platelet activation, aggregate formation, and cerebral thrombosis, a prerequisite for ischemic stroke. To translate these findings into a clinical setting, we show that AnxA1 plasma levels are reduced in human and murine stroke and that AnxA1 is able to act on human platelets, suppressing classic thrombin-induced inside-out signaling events (eg, Akt activation, intracellular calcium release, and Ras-associated protein 1 Rap1 expression) to decrease αIIbβ3 activation without altering its surface expression. AnxA1 also selectively modifies cell surface determinants (eg, phosphatidylserine) to promote platelet phagocytosis by neutrophils, thereby driving active resolution. (n=5–13 mice/group or 7–10 humans/group.)
CONCLUSIONS:AnxA1 affords protection by altering the platelet phenotype in cerebral I/RI from propathogenic to regulatory and reducing the propensity for platelets to aggregate and cause thrombosis by affecting integrin (αIIbβ3) activation, a previously unknown phenomenon. Thus, our data reveal a novel multifaceted role for AnxA1 to act both as a therapeutic and a prophylactic drug via its ability to promote endogenous proresolving, antithromboinflammatory circuits in cerebral I/RI. Collectively, these results further advance our knowledge and understanding in the field of platelet and resolution biology.
Activation of the c-Met and epidermal growth factor receptors (EGFR) promotes the growth and survival of non-small cell lung cancer (NSCLC). Specific receptor antagonists have shown efficacy in the ...clinic, but tumors often become resistant to these therapies. We investigated the ability of (-)-epigallocatechin-3-gallate (EGCG) to inhibit cell proliferation, and c-Met receptor and EGFR kinase activation in several NSCLC cell lines.
NSCLC cell lines with variable sensitivity to the EGFR antagonist erlotinib were studied. Cell growth was evaluated using proliferation and colony formation assays. Kinase activation was assessed via Western blot analysis. Experiments were conducted with EGCG, the EGFR antagonist erlotinib, and the c-Met inhibitor SU11274. The antagonists were also tested in a xenograft model using SCID mice.
EGCG inhibited cell proliferation in erlotinib-sensitive and -resistant cell lines, including those with c-Met overexpression, and acquired resistance to erlotinib. The combination of erlotinib and EGCG resulted in greater inhibition of cell proliferation and colony formation than either agent alone. EGCG also completely inhibited ligand-induced c-Met phosphorylation and partially inhibited EGFR phosphorylation. The triple combination of EGCG/erlotinib/SU11274 resulted in a greater inhibition of proliferation than EGCG with erlotinib. Finally, the combination of EGCG and erlotinib significantly slowed the growth rate of H460 xenografts.
EGCG is a potent inhibitor of cell proliferation, independent of EGFR inhibition, in several NSCLC cell lines, including those resistant to both EGFR kinase inhibitors and those overexpressing c-Met. Therefore, EGCG might be a useful agent to study as an adjunct to other anticancer agents.
Summary Research suggests a potential dysregulation of the stress response in individuals with bulimia nervosa. This study measured both cardiovascular and cortisol reactions to a standardised ...laboratory stress task in individuals identified as showing disordered eating behaviour to determine whether dysregulation of the stress response is characteristic of the two branches of the stress response system. Female students ( N = 455) were screened using two validated eating disorder questionnaires. Twelve women with disordered eating, including self-induced vomiting, and 12 healthy controls were selected for laboratory stress testing. Salivary cortisol and cardiovascular activity, via Doppler imaging and semi-automatic blood pressure monitoring, were measured at resting baseline and during and after exposure to a 10-min mental arithmetic stress task. Compared to controls the disordered eating group showed blunted cortisol, cardiac output, heart rate, and stroke volume reactions to the acute stress, as well as an attenuated vasodilatory reaction. These effects could not be accounted for in terms of group differences in stress task performance, subjective task impact/engagement, age, BMI, neuroticism, cardio-respiratory fitness, or co-morbid exercise dependence. Our findings suggest that disordered eating is characterised by a dysregulation of the autonomic stress-response system. As such, they add further weight to the general contention that blunted stress reactivity is characteristic of a number of maladaptive behaviours and states.
Bacteremia can progress to septic shock and death without appropriate medical intervention. Increasing evidence supports the role of molecular diagnostic panels in reducing the clinical impact of ...these infections through rapid identification of the infecting organism and associated antimicrobial resistance genes. We report the results of a multicenter clinical study assessing the performance of the GenMark Dx ePlex investigational-use-only blood culture identification Gram-negative panel (BCID-GN), a rapid diagnostic assay for detection of bloodstream pathogens in positive blood culture (PBC) bottles. Prospective, retrospective, and contrived samples were tested. Results from the BCID-GN were compared to standard-of-care bacterial identification methods. Antimicrobial resistance genes (ARGs) were identified using PCR and sequence analysis. The final BCID-GN analysis included 2,444 PBC samples, of which 926 were clinical samples with negative Gram stain results. Of these, 109 samples had false-negative and/or -positive results, resulting in an overall sample accuracy of 88.2% (817/926). After discordant resolution, overall sample accuracy increased to 92.9% (860/926). Pre- and postdiscordant resolution sample accuracy excludes 37 Gram-negative organisms representing 20 uncommon genera, 10 Gram-positive organisms, and 1
species present in 5% of samples that are not targeted by the BCID-GN. The overall weighted positive percent agreement (PPA), which averages the individual PPAs from the 27 targets (Gram-negative and ARG), was 94.9%. The limit of detection ranged from 10
to 10
CFU/ml, except for one strain of Fusobacterium necrophorum at 10
CFU/ml.
Children and young adults with hypodiploid B-lymphoblastic leukemia (B-ALL) fare poorly and hematopoietic stem-cell transplantation (HSCT) is often pursued in first complete remission (CR1). We ...retrospectively reviewed the outcomes of children and young adults with hypodiploid B-ALL who were enrolled in recent Children's Oncology Group (COG) trials to evaluate the impact of HSCT on outcome.
Cytogenetic analyses and DNA index were performed at COG-approved laboratories, and hypodiploidy was defined as modal chromosome number less than 44 and/or DNA index less than 0.81. Minimal residual disease (MRD) was determined centrally using flow cytometry at two reference laboratories. Patients with hypodiploid ALL came off protocol therapy postinduction and we retrospectively collected details on their subsequent therapy and outcomes. Event-free survival (EFS) and overall survival (OS) were estimated for the cohort.
Between 2003 and 2011, 8,522 patients with National Cancer Institute standard-risk and high-risk B-ALL were enrolled in COG AALL03B1 ( ClinicalTrials.gov identifier: NCT00482352). Hypodiploidy occurred in 1.5% of patients (n = 131), 98.3% of whom achieved CR after induction therapy. Five-year EFS and OS were 52.2% ± 4.9% and 58.9% ± 4.8%, respectively. Outcomes for patients undergoing CR1 HSCT were not significantly improved: 5-year EFS and OS were 57.4% ± 7.0% and 66.2% ± 6.6% compared with 47.8% ± 7.5% and 53.8% ± 7.6%, respectively ( P = .49 and .34, respectively) for those who did not undergo transplantation. Patients with MRD of 0.01% or greater at the end of induction had 5-year EFS and OS of 26.7% ± 9.3% and 29.3% ± 10.1%, respectively, and HSCT had no significant impact on outcomes.
Children and young adults with hypodiploid B-ALL continue to fare poorly and do not seem to benefit from CR1 HSCT. This is especially true for patients with MRD of 0.01% or greater at the end of induction. New treatment strategies are urgently needed for these patients.
With the approach of respiratory virus season in the Northern Hemisphere, clinical microbiology and public health laboratories will need rapid diagnostic assays to distinguish severe acute ...respiratory syndrome coronavirus 2 (SARS-CoV-2) from influenza virus and respiratory syncytial virus (RSV) infections for diagnosis and surveillance. In this study, the clinical performance of the Xpert Xpress SARS-CoV-2/Flu/RSV test (Cepheid, Sunnyvale, CA, USA) for nasopharyngeal swab specimens was evaluated in four centers: Johns Hopkins Medical Microbiology Laboratory, Northwell Health Laboratories, NYC Public Health Laboratory, and Los Angeles County/University of Southern California (LAC+USC) Medical Center. A total of 319 nasopharyngeal swab specimens, positive for SARS-CoV-2 (
= 75), influenza A virus (
= 65), influenza B virus (
= 50), or RSV (
= 38) or negative (
= 91) by the standard-of-care nucleic acid amplification tests at each site, were tested using the Cepheid panel test. The overall positive percent agreement for the SARS-CoV-2 target was 98.7% (
= 74/75), and the negative agreement was 100% (
= 91), with all other analytes showing 100% total agreement (
= 153). Standard-of-care tests to which the Cepheid panel was compared included the Cepheid Xpert Xpress SARS-CoV-2, Cepheid Xpert Xpress Flu/RSV, GenMark ePlex respiratory panel, BioFire respiratory panel 2.1 and v1.7, DiaSorin Simplexa COVID-19 Direct, and Hologic Panther Fusion SARS-CoV-2 assays. The Xpert Xpress SARS-CoV-2/Flu/RSV test showed high sensitivity and accuracy for all analytes included in the test. This test will provide a valuable clinical diagnostic and public health solution for detecting and differentiating SARS-CoV-2, influenza A and B virus, and RSV infections during the current respiratory virus season.
The rod photoreceptors are implicated in a number of devastating retinal diseases. However, routine imaging of these cells has remained elusive, even with the advent of adaptive optics imaging. Here, ...we present the first in vivo images of the contiguous rod photoreceptor mosaic in nine healthy human subjects. The images were collected with three different confocal adaptive optics scanning ophthalmoscopes at two different institutions, using 680 and 775 nm superluminescent diodes for illumination. Estimates of photoreceptor density and rod:cone ratios in the 5°-15° retinal eccentricity range are consistent with histological findings, confirming our ability to resolve the rod mosaic by averaging multiple registered images, without the need for additional image processing. In one subject, we were able to identify the emergence of the first rods at approximately 190 μm from the foveal center, in agreement with previous histological studies. The rod and cone photoreceptor mosaics appear in focus at different retinal depths, with the rod mosaic best focus (i.e., brightest and sharpest) being at least 10 μm shallower than the cones at retinal eccentricities larger than 8°. This study represents an important step in bringing high-resolution imaging to bear on the study of rod disorders.
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