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This study retrospectively evaluated the safety and efficacy of selective dorsal rhizotomy (SDR) in participants who underwent a rigorous selection process, uniform surgical procedure, and a standardized postoperative rehabilitation process. Outcome measures assessed were the Ashworth scale for spasticity, the Gillette Gait Index (GGI) for overall gait pathology, oxygen cost for gait efficiency, and the Gillette Functional Assessment Questionnaire (functional walking ability scale; [FAQ]) for functional mobility. Outcomes were evaluated for 136 children (81 males, 55 females; mean age 7y 3mo [SD 2y 1mo], range 3y 5moDS18y 9mo) for an average of 18.3 months (SD 4.4mo) postoperatively. All participants had a diagnosis of cerebral palsy (CP): 10 quadriplegia, 19 triplegia, and 107 diplegia. Preoperative Gross Motor Function Classification System levels were: Level I n=6; Level II n=64; Level III n=59, and Level IV n=7. All outcome measures improved for the group as a whole. Spasticity improved with 66 to 92% of possible gain in Ashworth scores; GGI was 7.5 times more likely to have a good as opposed to a poor outcome; energy efficiency improved in over half of the participants, and the FAQ demonstrated a statistically significant improvement of 0.9 levels (p<0.001). The rate of complications was low, with peri- and postoperative complications resolved by time of discharge. [ABSTRACT FROM AUTHOR]

Heart failure is a leading cause of morbidity and mortality 1,2 . Elevated intracardiac pressures and myocyte stretch in heart failure trigger the release of counter-regulatory natriuretic peptides, which act through their receptor (NPR1) to affect vasodilation, diuresis and natriuresis, lowering venous pressures and relieving venous congestion 3-8 . Recombinant natriuretic peptide infusions were developed to treat heart failure but have been limited by a short duration of effect 9,10 . Here we report that in a human genetic analysis of over 700,000 individuals, lifelong exposure to coding variants of the NPR1 gene is associated with changes in blood pressure and risk of heart failure. We describe the development of REGN5381, an investigational monoclonal agonist antibody that targets the membrane-bound guanylate cyclase receptor NPR1. REGN5381, an allosteric agonist of NPR1, induces an active-like receptor conformation that results in haemodynamic effects preferentially on venous vasculature, including reductions in systolic blood pressure and venous pressure in animal models. In healthy human volunteers, REGN5381 produced the expected haemodynamic effects, reflecting reductions in venous pressures, without obvious changes in diuresis and natriuresis. These data support the development of REGN5381 for long-lasting and selective lowering of venous pressures that drive symptomatology in patients with heart failure., (© 2024. The Author(s).)

Introduction: Older adults are increasingly using medical cannabis (MC). It is unclear if therapeutic effects increase problematic use patterns. The current study addresses this issue by examining symptom trajectories across the day and using trajectories to predict problematic use., Methods: One-hundred six older adults (age range 55-74) who endorsed medical conditions approved for treatment using MC were recruited online. Participants received six text messages/day to assess momentary symptoms for 15 days., Results: Participants provided 5,156 momentary assessments across 1,106 use days. Symptom trajectories were examined across the day. There was a decline in all symptoms following use. Negative affect, pain, and nausea evinced momentary negative reinforcement associations with cannabis intoxication. Momentary negative reinforcement was associated with adverse cannabis outcomes. Declines in post-use trauma symptoms and momentary negative reinforcement effects for negative affect were both associated with cannabis use disorder symptoms., Discussion: These data suggest that MC may be effective in reducing common symptom clusters. However, the negative reinforcing effect (i.e., the link between use and symptom relief at the event level) may complicate the therapeutic nature (i.e., symptom reduction). Identifying interventions to maximize benefits while minimizing costs may increase the efficacy and safety of MC in older adults., Competing Interests: Declaration of competing interest This work was supported by a grant to RDD from the Consortium for Medical Marijuana Clinical Outcomes Research. The Consortium had no influence in the conduct of the study, the analysis, or the interpretation of the results., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objective: The prevalence of smoking combustible cigarettes has decreased, but rates of nicotine vaping among adolescents and young adults have increased dramatically. Vaping is associated with acute health problems and exposes users to toxic metals with unknown long-term consequences. Research on factors influencing vaping is needed to inform the development of effective prevention and intervention methods. Nicotine vaping expectancies, or expected effects related to vaping, may be an important target as they can predict vaping behaviors. The purpose of this study was to examine nicotine expectancy activation patterns with corresponding nicotine vaping behaviors., Method: Using methods from alcohol expectancy research, we applied a memory model approach to identifying nicotine vaping expectancies and modeling organization and activation patterns concerning the frequency of nicotine vaping. We created a memory model-based nicotine expectancy measure based on information from 200 adolescents in 8th and 12th grades, and college students. Our expectancy measure was completed by a second sample of 862 college students., Results: We mapped expectancies into network format using Individual Differences Scaling (INDSCAL) and we modeled likely paths of expectancy activation using Preference Mapping (PREFMAP). Nonusers primarily emphasized a positive-negative expectancy dimension and were more likely to activate expectancies of negative internal experiences about vaping. Students who vaped nicotine daily or almost daily primarily emphasized an external appearance-internal experience expectancy dimension and were more likely to activate expectancies of negative affect reduction and withdrawal relief., Conclusions: Our results identify specific targets for expectancy-based prevention and intervention methods that have the potential to be as effective as similar approaches to preventing and reducing alcohol use.

Two-dimensional (2D) materials with nanometer thickness have the advantage of a large specific surface area and excellent surface accessibility. They have great potential for adsorption, catalysis, and many other applications. 2D zeolitic silicoaluminophosphates (SAPOs) can be synthesized through a dual structure directing agent (SDA) strategy. But the materials have been primarily used in their organic-free form. In this work, we demonstrate that the same synthesis strategy is effective for developing amino-acid-anchored 2D SAPOs through a one-step synthesis. Because of the addition of amino acids, the surficial amino and carboxylic groups serve as active sites for adsorption and catalysis. Congo red adsorption is used to evaluate the potential of using the organic functional groups as active adsorption sites. The 2D SAPO materials have demonstrated excellent Congo red removal efficiency with close to complete removal for certain concentrations. The effects of the amino acid concentration and hydrothermal synthesis time on material morphology development will be discussed. Thorough characterization by SEM, TEM, FTIR, XRD, and nitrogen adsorption has been done to reveal the properties of the amino-acid-anchored 2D SAPOs.

ObjectiveCollege students consume more alcohol and engage in binge drinking more frequently than their non-college attending peers, and prevalence of alcohol-related consequences (e.g., drinking and driving; taking avoidable risks) has not decreased proportionally with decreases in consumption. Social anxiety and alcohol expectancies, or beliefs about the effects of alcohol, have been found to be significantly related to alcohol use and account for significant variance in alcohol use and related consequences. Few studies, however, have examined how other social variables such as need to belong and social connectedness may fit into existing models of increased and risky alcohol use. Methods: Students at a large state university (n = 1,278) completed an online survey measuring alcohol expectancies, need to belong, social anxiety, and social connectedness. Mean age of participants was 19.65 years, and 59.5% self-identified as female, 39.8% male, and 0.7% identified as transgender. Structural equation modeling supported hypothesized relationships between need to belong, social anxiety, social connectedness, alcohol expectancies, and alcohol use, a mean centered variable that included binge drinking, drinking frequency, and amount of consumption. Results: Positive alcohol expectancies related to tension reduction, sociability, and sexuality, were positively related to drinking, such that increased alcohol expectancies were associated with increased drinking. Alcohol expectancies mediated the relationship between need to belong and increased alcohol use, as well as social connectedness and increased alcohol use. Similarly, social anxiety also mediated these relationships. No direct relationships were found between need to belong or social connectedness and alcohol use, suggesting previous research exploring these relationships may have excluded control variables (e.g., biological sex, race/ethnicity) that better explain the impact of need to belong and social connectedness on alcohol use. Conclusion : Prevention and intervention efforts might be more effective in reducing alcohol use if social factors are more broadly targeted.

Clinical research professionals (CRPs) are essential contributors to clinical and translational research endeavors, encompassing roles such as research nurses, research coordinators, data managers, and regulatory affairs specialists. This paper reports on the implementation of a novel training program for the CRPs, the Co-mentoring Circles Program, developed by the University of Florida Health Clinical Research Professionals Consortium, and proposes an initial logic model of CRP workforce development informed by the observations, participant feedback, and the established Translational Workforce Logic Model. The co-mentoring program was delivered through an online didactic curriculum and bi-monthly meetings over nine months, from January to September 2022. The formative evaluation identified the factors that support CRP workforce development through knowledge acquisition and professional relationship building. Finally, this paper proposes a logic model of CRP workforce development, including financial and human inputs, didactic and co-mentoring activities, workforce outputs, outputs related to workforce and clinical research study progress, and resulting impacts of increased national capacity for translational research and increased rate of research translation., Competing Interests: Authors have no conflicts of interest to disclose., (© The Author(s) 2024.)

Background : Despite modest reductions in alcohol use among college students, drinking-related harms continue to be prevalent. Group-delivered programs have had little impact on drinking except for experiential expectancy challenge interventions that are impractical because they rely on alcohol administration. Expectancy Challenge Alcohol Literacy Curriculum (ECALC), however, offers a non-experiential alternative suitable for widespread implementation for universal, selective, or indicated prevention. Objectives : ECALC has been effective with mandated students, fraternity members, and small classes of 30 or fewer first-year college students. Larger universities, however, typically have classes with 100 students or more, and ECALC has not yet been tested with groups of this size. To fill this gap, we conducted a group randomized trial in which five class sections with over 100 college students received either ECALC or an attention-matched control presentation and completed follow-up at four weeks. Results : ECALC was associated with significant changes on six subscales of the Comprehensive Effects of Alcohol Scale (CEOA), post-intervention expectancies predicted drinking at four-week follow-up, and there were significant expectancy differences between groups. Compared to the control group, students who received ECALC demonstrated significant expectancy changes and reported less alcohol use at follow-up. Conclusions : Findings suggest ECALC is an effective, single session group-delivered intervention program that can be successfully implemented in large classes.

Activin A has been linked to cardiac dysfunction in aging and disease, with elevated circulating levels found in patients with hypertension, atherosclerosis, and heart failure. Here, we investigated whether Activin A directly impairs cardiomyocyte (CM) contractile function and kinetics utilizing cell, tissue, and animal models. Hydrodynamic gene delivery-mediated overexpression of Activin A in wild-type mice was sufficient to impair cardiac function, and resulted in increased cardiac stress markers (N-terminal pro-atrial natriuretic peptide) and cardiac atrophy. In human-induced pluripotent stem cell-derived (hiPSC) CMs, Activin A caused increased phosphorylation of SMAD2/3 and significantly upregulated SERPINE1 and FSTL3 (markers of SMAD2/3 activation and activin signaling, respectively). Activin A signaling in hiPSC-CMs resulted in impaired contractility, prolonged relaxation kinetics, and spontaneous beating in a dose-dependent manner. To identify the cardiac cellular source of Activin A, inflammatory cytokines were applied to human cardiac fibroblasts. Interleukin -1β induced a strong upregulation of Activin A. Mechanistically, we observed that Activin A-treated hiPSC-CMs exhibited impaired diastolic calcium handling with reduced expression of calcium regulatory genes ( SERCA2 , RYR2 , CACNB2 ). Importantly, when Activin A was inhibited with an anti-Activin A antibody, maladaptive calcium handling and CM contractile dysfunction were abrogated. Therefore, inflammatory cytokines may play a key role by acting on cardiac fibroblasts, causing local upregulation of Activin A that directly acts on CMs to impair contractility. These findings demonstrate that Activin A acts directly on CMs, which may contribute to the cardiac dysfunction seen in aging populations and in patients with heart failure., Competing Interests: SM, JM, QR, YZ, GH, DJ, KP, HE, MPM-P, XJ, DZ, JT, AS, MED, and LM were employees and stockholders of Regeneron Pharmaceuticals, Inc. NTF and MPG were employees and stockholders of TARA Biosystems. SM, JM, and LM had a patent pending (10771US01). The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 MacDonnell, Megna, Ruan, Zhu, Halasz, Jasewicz, Powers, E, del Pilar Molina-Portela, Jin, Zhang, Torello, Feric, Graziano, Shekhar, Dunn, Glass and Morton.)

Prevention programs may have contributed to modest declines in alcohol use among college students in recent years, but negative consequences continue to be pervasive. First year college students (FYCS) are particularly vulnerable, and there is clearly a need for more effective methods to reduce risk. Meta-analyses focused on expectancy challenge (EC) have found this approach to be effective, but "experiential" EC that includes a drinking exercise is not suitable for most FYCS, many of whom are underage. A non-experiential alternative, the Expectancy Challenge Alcohol Literacy Curriculum (ECALC), is practical for widespread implementation. ECALC has been effective with mandated students and members of fraternities, and in the present study, we focused on evaluating effects with FYCS. In a group randomized trial, 48 class sections of a course designed for FYCS received either ECALC or an attention-matched control presentation. ECALC was associated with significant changes on six expectancy subscales of the Comprehensive Effects of Alcohol Scale (CEOA). Structural equation modeling was used to examine the mediated effects of the intervention on alcohol-related harms via alcohol expectancies. There were significant indirect effects from condition to alcohol use (IND = -0.04, p <.001) and alcohol harms (IND = -0.07, p <.001). This model accounted for 54% of the variance in alcohol use and 46% of the variance in alcohol-related harms. These findings suggest ECALC is an effective, single session group-delivered program that can be incorporated into classroom curricula., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

The gut-brain connection refers to communication between the brain and gastrointestinal (GI) system. Disorders of gut-brain interaction (DGBI) are characterized by GI symptoms that accompany distress and disability. Epidemiological research has suggested DGBI rates in emerging adults are increasing. This study investigated the relationship between GI health, distress, and disability in emerging adults across time. Emerging adults were recruited. A repeated-measure design with a 1-month time lag was used to collect data via an online survey (N = 861) across five academic semesters (Spring 2019 to Summer 2020). Measurement equivalence across time was established and a cross-lagged panel model (CLPM) was specified. Distress at Time 1 predicted GI symptoms at Time 2 (β = .206, SE = .084, p < .05). GI symptoms at Time 1 predicted disability at Time 2 (β = .117, SE = .039, p < .01). Higher disability at Time 1 predicted distress at Time 2 (β = .092, SE = .027, p < .01). The cross-lagged design offers stronger causal inferences than cross-sectional studies used to study the effects of GI symptoms. Findings provide initial evidence of a directional pathway between brain and gut rather than a bidirectional network. Findings highlight the importance of psychogastroenterology., (© 2022 The International Association of Applied Psychology.)

Aims: The HERMES (HEart failure Molecular Epidemiology for Therapeutic targetS) consortium aims to identify the genomic and molecular basis of heart failure., Methods and Results: The consortium currently includes 51 studies from 11 countries, including 68 157 heart failure cases and 949 888 controls, with data on heart failure events and prognosis. All studies collected biological samples and performed genome-wide genotyping of common genetic variants. The enrolment of subjects into participating studies ranged from 1948 to the present day, and the median follow-up following heart failure diagnosis ranged from 2 to 116 months. Forty-nine of 51 individual studies enrolled participants of both sexes; in these studies, participants with heart failure were predominantly male (34-90%). The mean age at diagnosis or ascertainment across all studies ranged from 54 to 84 years. Based on the aggregate sample, we estimated 80% power to genetic variant associations with risk of heart failure with an odds ratio of ≥1.10 for common variants (allele frequency ≥ 0.05) and ≥1.20 for low-frequency variants (allele frequency 0.01-0.05) at P < 5 × 10 -8 under an additive genetic model., Conclusions: HERMES is a global collaboration aiming to (i) identify the genetic determinants of heart failure; (ii) generate insights into the causal pathways leading to heart failure and enable genetic approaches to target prioritization; and (iii) develop genomic tools for disease stratification and risk prediction., (© 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Objectives: The aim of the study was to describe renal pelvis (RP) and ureteral ultrasonographic measurements in a population of cats with confirmed benign ureteral obstruction (UO) by antegrade pyelography. The secondary objective was to further describe clinical findings associated with minimally dilated obstructed kidneys in an attempt to better understand its occurrence., Methods: Retrospective case series of cats diagnosed with benign UO were confirmed by antegrade pyelography. Medical records were reviewed and signalment, diagnostic imaging results, serum creatinine (SCr) concentration and urine culture results were recorded. Each obstructed kidney was categorized into two groups: group 1 included all RP measurements ⩽4 mm and group 2 included all RP measurements >4 mm., Results: A total of 82 cats with 114 obstructed ureters met the inclusion criteria. Fifty (61%) cats had a unilateral UO and 32 (39%) had a bilateral UO. Thirty (26%) kidneys were included in group 1 while 84 (74%) were included in group 2. Nine (8%) kidneys had an RP dilation ⩽2 mm. Median RP and ureteral diameters were 6.6 mm (range 1.1-37.0 mm) and 3.2 mm (range 0.0-11.0 mm), respectively. RP size correlated positively with ureteral diameter in the study population ( P <0.0001), but not in group 1 when analyzed separately ( P  = 0.47). UO was secondary to stones in 80 (70%) ureters. Seventeen (21%) cats had a positive urine culture. At admission, 79 (96%) cats were azotemic with a median preoperative SCr concentration of 444 µmol/l (range 108-1326 μmol/l). The mean (95% confidence interval [CI]) preoperative SCr concentration was significantly higher in group 1 (762 µmol/l [498-1165 μmol/l]) than in group 2 (409 µmol/l [333-502 μmol/l]). RP size in the two groups correlated negatively with preoperative SCr concentration ( P  = 0.0002)., Conclusions and Relevance: Feline UO may be associated with minimal RP dilation and the severity of RP and ureteral dilation can be highly variable. Absence of significant RP dilation does not rule out UO in cats.

Reconsolidation is a process by which memories are destabilized, updated, and then restabilized. Strong memories are resistant to undergoing reconsolidation. Here, we addressed whether an overtrained fear memory could be made susceptible to reconsolidation by first extinguishing, and then renewing, the memory. Rats were trained with ten tone-footshock pairings, followed by eight days of tone extinction in the training context. The next day, rats were placed into a second context and memory for the tone was renewed/reactivated with a single tone presentation. Immediately following reactivation, rats received an injection of midazolam or vehicle. Rats were then tested for freezing to the tone in a third context. Midazolam had no effect in rats that did not undergo tone extinction, but significantly attenuated freezing to the tone in extinguished rats. Thus, rats that received tone extinction underwent tone memory reconsolidation following its renewal. In a second experiment, we administered the reactivation session and midazolam injections prior to extinction. Midazolam had no effect and rats extinguished at a rate similar to controls. These data suggest that strong emotional memories are capable of updating following weakening of memory expression through extinction.

Alcohol expectancies have been linked to the development of alcohol pathology. Research has shown college drinkers can be classified into unique drinking profiles that vary by use and related problems. The current study examines paths of alcohol expectancy activation as a function of drinking profile. College student drinkers (n = 1,226; 60.77% female) completed assessments of alcohol involvement and alcohol expectancies. Latent profile analysis (LPA) was used to classify drinking profiles. Multidimensional scaling (MDS) techniques were then applied to examine differences in the likely activation of alcohol expectancies as a function of drinking profile. LPA identified 6 classes of college student drinkers: light drinkers with minor problems, moderate drinkers with mild problems, moderate drinkers with severe problems, heavy drinkers with mild problems, heavy drinkers with severe problems, and heavy drinkers with physical dependence. MDS was used to develop a hypothetical memory network of alcohol expectancies. Preference mapping was then used to plot paths of expectancy activation through the hypothetical memory network for each drinking profile. Light drinkers showed expectancy activation along a prosocial-antisocial dimension. As use patterns became increasingly pathological, paths of activation shifted toward arousal-sedation. The shift in activation paths from prosocial-antisocial to arousal-sedation was driven more by alcohol-related pathology than by consumption. This suggests that individuals high in arousal-sedation expectancies may be at an increased risk for more severe alcohol pathology. Further, individuals high in arousal-sedation expectancies may benefit most from programs that restructure expectancy pathways away from arousal-sedation. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

This study examines the role of anxiety and depression symptoms in predicting dietary choices in emerging adults while accounting for sex differences in these relationships. Participants were 225 English speaking undergraduates enrolled in a university in southeastern United States. Participants were recruited through an online research recruitment application utilized by the university. Participants volunteered for a two-phased anonymous survey monitoring the effects of eating habits and gastrointestinal health in young adults. As part of this effort, participants completed self-reporting measures related to anxiety and depression, as well as an automated, self-administered 24-h diet recall. Multigroup path analysis was used to test primary hypotheses. Overall, a decrease in total caloric intake and an increase in sugar consumption were found as self-reported symptoms of anxiety and depression increased. In addition, there were sex differences in the relationship between depression and food choices. Men consumed more saturated fat as well as less fruits and vegetables as self-reported symptoms of depression increased. Results suggest symptoms of depression are a greater risk factor for poor nutrition in male college students than females. The findings provide another justification to screen for psychological distress in student health services given the implications on behavioral lifestyle and health.

Measuring 1,2-o-dilauryl-rac-glycero-3-glutaric acid-(6'-methylresorufin) ester (DGGR) lipase activity is a cost-effective test for diagnosing pancreatitis compared to the feline pancreas-specific lipase (Spec fPL) test. However, little is known about the influence of renal insufficiency on DGGR lipase in cats. This study evaluated the influence of renal function on serum DGGR lipase in the cat. Serum samples from 49 cats with normal pancreas-specific lipase immunoreactivity were analyzed for DGGR lipase activity and serum creatinine. Median serum DGGR lipase activity for cats with kidney disease (KD+) was 22 IU/L (range: 9 to 29 IU/L), whereas for cats without kidney disease (KD-) and healthy cats, the medians were 16 IU/L (range: 6 to 32 IUI/L), and 15 IU/L (range: 9 to 23 IU/L), respectively. The KD+ group had significantly higher DGGR lipase concentrations compared to the healthy group ( P = 0.030), but most results were within the reference range. There was a weak positive correlation between creatinine and DGGR lipase values ( R 2 = 19.6%; P = 0.0014) and no significant correlation between symmetric dimethylarginine (SDMA) and DGGR lipase. Key clinical message: Although cats with kidney disease had significantly higher serum DGGR lipase concentrations than the healthy controls, the difference was small and does not appear to be clinically relevant., (Copyright and/or publishing rights held by the Canadian Veterinary Medical Association.)

In this randomized trial, 121 mandated college students (33% female, 74% Caucasian, M age = 19.42 years) received either a Brief Motivational Intervention (BMI) with personalized normative feedback (PNF) or the Expectancy Challenge Alcohol Literacy Curriculum (ECALC) to compare effectiveness in reducing alcohol use and associated harms. All participants received either BMI content (n = 63) or ECALC (n = 58). ECALC was delivered as a web-based program with clinician assistance. Measures of alcohol use and harms were completed at baseline and 4 weeks postintervention. ECALC produced significant reductions on all 4 positive expectancy subscales of the Comprehensive Effects of Alcohol Scale (CEOA). Both programs were associated with significant reductions on all alcohol use variables and harms, and expectancies significantly mediated the intervention to outcome relationship in the ECALC condition. There were no significant gender differences. Two one-sided equivalence test indicated superior effects for ECALC compared to BMI on four alcohol use variables (mean blood alcohol concentration, peak blood alcohol concentration, peak drinks per sitting, and drinking days per month), and noninferior to BMI in reducing others (mean drinks per sitting, mean drinks per week, & binge drinking). Superior effects of ECALC versus BMI are based on a short-term follow-up, and longevity of ECALC effects have yet to be established. ECALC has previously been found to be effective as a group-delivered program for male fraternity members, and these findings provide preliminary support for effectiveness for both males and females when delivered individually using a web-based clinician-assisted format. (PsycINFO Database Record (c) 2020 APA, all rights reserved).

Heart failure (HF) is a leading cause of morbidity and mortality worldwide. A small proportion of HF cases are attributable to monogenic cardiomyopathies and existing genome-wide association studies (GWAS) have yielded only limited insights, leaving the observed heritability of HF largely unexplained. We report results from a GWAS meta-analysis of HF comprising 47,309 cases and 930,014 controls. Twelve independent variants at 11 genomic loci are associated with HF, all of which demonstrate one or more associations with coronary artery disease (CAD), atrial fibrillation, or reduced left ventricular function, suggesting shared genetic aetiology. Functional analysis of non-CAD-associated loci implicate genes involved in cardiac development (MYOZ1, SYNPO2L), protein homoeostasis (BAG3), and cellular senescence (CDKN1A). Mendelian randomisation analysis supports causal roles for several HF risk factors, and demonstrates CAD-independent effects for atrial fibrillation, body mass index, and hypertension. These findings extend our knowledge of the pathways underlying HF and may inform new therapeutic strategies.

The objective of this study was to document tidal variations in tracheal height during normal respiration in 19 healthy adult (> 1 y old) small-breed dogs (< 10 kg) using fluoroscopy and radiography. Each dog underwent tracheal fluoroscopic examination on inspiration and expiration while in a standing position (F-S) and in right lateral recumbency (F-RL), followed by radiographic projections obtained in right lateral recumbency. The percent variation in tracheal height during maximal inspiration and expiration was determined at 3 different locations [cervical region (CR), thoracic inlet (TI), and intrathoracic (IT) region]. When all imaging procedures and sites of measurement were considered, tracheal height varied during physiologic inspiration and expiration from 0% to 21.1%, with a mean of 4.5%. The mean percent variation in tracheal height was not significantly different among imaging modalities (F-S versus F-RL versus radiography) ( P = 0.16) or measurement sites (CR versus TI versus IT) ( P = 0.89). The body condition score (BCS) ( P = 0.96), age ( P = 0.95), and breed ( P = 0.19) did not significantly influence the mean percent variation in tracheal height. The average variation in tracheal height during maximal physiological inspiration and expiration is small (< 6%) in most healthy adult small-breed dogs as assessed by fluoroscopy and radiography, although tracheal height may vary by as much as 21.1% in some healthy individuals. Inspiratory and expiratory radiographs acquired in right lateral recumbency provide an accurate assessment of tracheal height as an alternative to fluoroscopy., Competing Interests: The authors declare that there was no conflict of interest and no off-label use of antimicrobials involved in this study., (Copyright and/or publishing rights held by the Canadian Veterinary Medical Association.)

Purpose: Central cancer registries collect data and provide population-level statistics that can be tracked over time; yet registries may not capture the full range of clinically relevant outcomes. Patient-generated health data (PGHD) include health/treatment history, biometrics, and patient-reported outcomes (PROs). Collection of PGHD would broaden registry outcomes to better inform research, policy, and care. However, this is dependent on the willingness of patients to share such data. This study examines cancer survivors' perspectives about sharing PGHD with central cancer registries., Methods: Three U.S. central registries sampled colorectal, non-Hodgkin lymphoma, and metastatic breast cancer survivors 1-4 years after diagnosis, recruiting them via mail to participate in one of seven focus groups (n = 52). Group discussions were recorded, transcribed, and thematically analyzed., Results: Most survivor-participants were unaware of the existence of registries. After having registries explained, all participants expressed their willingness to share PGHD with them if treated confidentially. Participants were willing to provide information on a variety of topics (e.g., medical history, medications, symptoms, financial difficulties, quality of life, biometrics, nutrition, exercise, and mental health), with a focus on long-term effects of cancer and its treatment. Participants' preferred mode for providing data varied. Participants were also interested in receiving information from registries., Conclusions: Our results suggest that registry-based collection of PGHD is acceptable to most cancer survivors and could facilitate registry-based efforts to collect PGHD/PROs. Central cancer registry-based collection of PGHD/PROs, especially on long-term effects, could enhance registry support of cancer control efforts including research and population health management.

Between-subjects literature has established that trait-like negative mood predicts coping motives, which predict alcohol-related problems and that trait-like positive mood predicts mood enhancement motives, which then predict alcohol consumption. However, there is considerable within-person variation in drinking motives, and the relationship between mood, motives, and alcohol outcomes must be more closely examined at a daily level. The current study used ecological momentary assessment (EMA) to measure mood, motives, alcohol use, and alcohol consequences in 101 college drinkers over a 15-day period. At the between-subjects level, positive mood predicted enhancement motives, which in turn predicted alcohol consumption and consequences. Negative mood predicted coping motives, which were associated with only alcohol-related consequences. At the within-subjects level, daily anxious and depressed mood were associated with endorsing coping motives, but coping motives were not associated with alcohol consumption or problems. Positive mood was associated with enhancement motives, which was associated with both daily alcohol consumption and problems. These results corroborate previous findings that enhancement motives are most predictive of outcomes in the college population and highlight the importance of considering within-subject variance in drinking motives. The relationships between mood, motives, and alcohol outcomes differ when examined as between-subjects versus within-subject constructs. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

A lithotripsy and percutaneous cystolithotomy (PCCL) were performed on a 5-year-old intact male English bulldog. The composition of the uroliths was 100% cystine. When a second PCCL was performed 2 months later, the nidus of the largest urolith was a segment of an optical fiber broken off during laser lithotripsy.

Several theories posit problematic alcohol use develops through mechanisms of positive and negative reinforcement. However, the literature on these mechanisms remains inconsistent. This may be due to a number of issues including a failure to disaggregate negative mood or a failure to account for mood functioning (i.e., stability in mood). Alternatively, there may be differences in typical postdrinking/evening mood on drinking and nondrinking days, however, this has yet to be fully explored. We examined multiple indices of distinct mood states prior to and after typical drinking onset times on drinking and nondrinking days using ecological momentary assessment. College student drinkers ( n = 102) carried personal data devices for 15 days. They reported on mood and alcohol use several times per day. Tonic positive mood was higher on drinking days than nondrinking days prior to typical drinking initiation. After typical drinking times, positive mood was higher on drinking days than nondrinking days. Similarly, negative moods (anxiety, stress, anger, and stress instability) indicated a pattern of lower levels relative to both predrinking mood on drinking days, and matched mood time-points on nondrinking days; though, not all of these differences were statistically different. Results suggest positive and negative reinforcing mechanisms may be at play-though the negative reinforcement effects may manifest through subjectively "better" mood on drinking versus nondrinking days. (PsycINFO Database Record, ((c) 2018 APA, all rights reserved).)

Background The rate of notifications of sexually transmissible infections (STIs) in Australians has increased dramatically, especially in those aged 16-30 years. This age bracket, typical of university students, is the most likely to report multiple sexual partners in the previous year. Individuals who have sex with multiple partners in a year have a significantly increased chance of contracting an STI, making them an important audience for sexual health promotion. This study aimed to determine how university sexual health promotion events can better reach this higher-risk subset of the population., Methods: Two anonymous cross-sectional surveys were used to understand current and ideal sexual health promotion events through the perspectives of student leaders (n=62) and general university students (n=502)., Results: Students who had more than one sexual partner in the previous year (the higher-risk group) made up 22.7% of the students sampled. Higher-risk students differed substantially from lower-risk students in terms of preferred event types, incentives and topics to be covered, often prioritising those rarely used in current university sexual health events., Conclusion: While current university sexual health events include some features that align with student priorities, elements beyond sexual health information, such as social activity, alcohol incentives and on-site sexual health testing, can be helpful tools to attract students with higher numbers of sexual partners.

Background: The calibrated automated thrombogram (CAT) is a functional thrombin generation (TG) assay that may provide a new approach for monitoring anticoagulant therapy in dogs. The effects of dalteparin on TG variables in dogs are unknown., Objectives: Objectives were to establish normal TG variable ranges in dogs and measure the in vitro TG variables in canine pooled platelet-poor plasma (PPP) spiked with different dalteparin concentrations., Methods: In the first experiment, plasma samples from 25 adult healthy Beagle dogs and 11 client-owned healthy dogs of multiple breeds was measured individually for obtaining normal TG values. In the second experiment, separate pools of the remaining PPP from 24 of the 25 previous adult Beagles and from 45 different client-owned dogs were spiked with dalteparin at 9 concentrations with increasing anti-factor Xa (anti-FXa) activity. Activated partial thromboplastin time, tissue factor-induced TG, and anti-FXa activity were measured for each concentration. Concentration-response relationships were determined with ADAPT v.5, using various nonlinear regression models for stimulatory or inhibitory effects., Results: Thrombin generation ranges of client-owned dogs and Beagles were equivalent only for time-to-peak (P < .05). In vitro dalteparin resulted in a concentration-dependent decrease in endogenous thrombin potential (ETP) in pooled PPP. The estimated dalteparin concentration that produced half the maximal inhibition of baseline ETP (IC 50 ) was 0.289 U/mL. Thrombin generation and anti-FXa activity were more sensitive than APTT to detect the effects of dalteparin., Conclusions: The CAT assay can measure the effects of dalteparin in canine plasma, resulting in significant dose-dependent decreases in ETP, prompting further in vivo investigation., (© 2017 American Society for Veterinary Clinical Pathology.)

Background: Dalteparin is used to prevent thrombotic complications in dogs. Measurement of anti-factor Xa (anti-FXa) activity is currently used for monitoring therapy, but remains a nonfunctional test. The calibrated automated thrombogram (CAT) could be a suitable approach for functional monitoring., Objectives: We hypothesized that the CAT will detect decreased endogenous thrombin potential (ETP) in healthy dogs receiving dalteparin., Methods: Twenty-four healthy adult Beagles were randomly allocated to 4 equal groups. A single subcutaneous (SC) dose of 50 U/kg, 100 U/kg, or 150 U/kg of dalteparin was given. Platelet-poor plasma (PPP) was collected over a 24-hour period and evaluated by thrombin generation (TG) via CAT, anti-FXa activity, and APTT. Analysis was performed with a repeated-measures general linear mixed model, and the treated groups were compared to a placebo group., Results: Time, dose, and time-dose interaction significantly affected ETP (P < .0001 for all effects), peak (P < .0001 for all effects), rate index (P < .0006 for all effects), and anti-FXa activity (P < .0001 for all effects). No significant time trend was detected in the control group. Dogs receiving the 100 U/kg dalteparin SC injection showed the most homogeneous response of ETP inhibition among treated groups. The % inhibition of ETP from baseline increased nonlinearly as a function of anti-FXa activity (r 2 = .8186)., Conclusions: The CAT assay can be employed to measure the effects of dalteparin at different doses in healthy dogs, showing sensitivity to time- and dose-dependent changes in ETP and other TG variables. Further investigation of the CAT as a tool for monitoring low molecular weight heparin therapy in dogs is warranted., (© 2017 American Society for Veterinary Clinical Pathology.)

Given the proven utility of natriuretic peptides as serum biomarkers of cardiovascular maladaptation and dysfunction in humans and the high cross-species sequence conservation of atrial natriuretic peptides, natriuretic peptides have the potential to serve as translational biomarkers for the identification of cardiotoxic compounds during multiple phases of drug development. This work evaluated and compared the response of N-terminal proatrial natriuretic peptide (NT-proANP) and N-terminal probrain natriuretic peptide (NT-proBNP) in rats during exercise-induced and drug-induced increases in cardiac mass after chronic swimming or daily oral dosing with a peroxisome proliferator-activated receptor γ agonist. Male Sprague-Dawley rats aged 8 to 10 weeks were assigned to control, active control, swimming, or drug-induced cardiac hypertrophy groups. While the relative heart weights from both the swimming and drug-induced cardiac hypertrophy groups were increased 15% after 28 days of dosing, the serum NT-proANP and NT-proBNP values were only increased in association with cardiac hypertrophy caused by compound administration. Serum natriuretic peptide concentrations did not change in response to adaptive physiologic cardiac hypertrophy induced by a 28-day swimming protocol. These data support the use of natriuretic peptides as fluid biomarkers for the distinction between physiological and drug-induced cardiac hypertrophy.

Background: Evaluation of underlying hemostatic function is challenging when feline patients are receiving an anticoagulant medication. Discontinuing the anticoagulant to obtain accurate results for hemostatic testing may lead to thrombotic complications. The addition of heparinase to blood samples may mitigate the effects of exogenous heparin and allow hemostatic testing., Methods: Tissue factor (TF)-activated thromboelastography (TEG) was performed using citrated whole blood from 19 cats. Assays were performed using citrated whole blood, with and without addition of unfractionated heparin to a concentration of 0.2 U/mL. For each blood sample, TEG assays were performed using a standard cup and a heparinase-coated cup., Key Findings: For TEG variables R, k, α-angle, and MA, mean values were not statistically different when citrated blood was used with standard or heparinase-coated cups. Heparinized blood assayed in standard cups displayed a significantly increased R and k, and significantly decreased α-angle and MA when compared to heparinized blood assayed in heparinase-coated cups. TEG variables for heparinized blood assayed in heparinase cups was not statistically different from those of the citrated whole blood without added heparin., Significance: Heparinase modified, TF-activated, TEG reverses heparin effects in feline-citrated blood., (© Veterinary Emergency and Critical Care Society 2016.)

G protein-coupled receptors (GPCRs) activate PI3K/v-AKT thymoma viral oncoprotein (AKT) to regulate many cellular functions that promote cell survival, proliferation, and growth. However, the mechanism by which GPCRs activate PI3K/AKT remains poorly understood. We used ovarian preantral granulosa cells (GCs) to elucidate the mechanism by which the GPCR agonist FSH via PKA activates the PI3K/AKT cascade. Insulin-like growth factor 1 (IGF1) is secreted in an autocrine/paracrine manner by GCs and activates the IGF1 receptor (IGF1R) but, in the absence of FSH, fails to stimulate YXXM phosphorylation of IRS1 (insulin receptor substrate 1) required for PI3K/AKT activation. We show that PKA directly phosphorylates the protein phosphatase 1 (PP1) regulatory subunit myosin phosphatase targeting subunit 1 (MYPT1) to activate PP1 associated with the IGF1R-IRS1 complex. Activated PP1 is sufficient to dephosphorylate at least four IRS1 Ser residues, Ser 318 , Ser 346 , Ser 612 , and Ser 789 , and promotes IRS1 YXXM phosphorylation by the IGF1R to activate the PI3K/AKT cascade. Additional experiments indicate that this mechanism also occurs in breast cancer, thyroid, and preovulatory granulosa cells, suggesting that the PKA-dependent dephosphorylation of IRS1 Ser/Thr residues is a conserved mechanism by which GPCRs signal to activate the PI3K/AKT pathway downstream of the IGF1R., (© 2016 by The American Society for Biochemistry and Molecular Biology, Inc.)

Within the ovarian follicle, granulosa cells (GCs) surround and support immature oocytes. FSH promotes the differentiation and proliferation of GCs and is essential for fertility. We recently reported that ERK activation is necessary for FSH to induce key genes that define the preovulatory GC. This research focused on the phosphoregulation by FSH of ERK within GCs. FSH-stimulated ERK phosphorylation on Thr(202)/Tyr(204) was PKA-dependent, but MEK(Ser(217)/Ser(221)) phosphorylation was not regulated; rather, MEK was already active. However, treatment of GCs with the EGF receptor inhibitor AG1478, a dominant-negative RAS, an Src homology 2 domain-containing Tyr phosphatase inhibitor (NSC 87877), or the MEK inhibitor PD98059 blocked FSH-dependent ERK(Thr(202)/Tyr(204)) phosphorylation, demonstrating the requirement for upstream pathway components. We hypothesized that FSH via PKA enhances ERK phosphorylation by inhibiting the activity of a protein phosphatase that constitutively dephosphorylates ERK in the absence of FSH, allowing MEK-phosphorylated ERK to accumulate in the presence of FSH because of inactivation of the phosphatase. GCs treated with different phosphatase inhibitors permitted elimination of both Ser/Thr and Tyr phosphatases and implicated dual specificity phosphatases (DUSPs) in the dephosphorylation of ERK. Treatment with MAP kinase phosphatase (MKP3, DUSP6) inhibitors increased ERK(Thr(202)/Tyr(204)) phosphorylation in the absence of FSH to levels comparable with ERK phosphorylated in the presence of FSH. ERK co-immunoprecipitated with Myc-FLAG-tagged MKP3(DUSP6). GCs treated with MKP3(DUSP6) inhibitors blocked and PKA inhibitors enhanced dephosphorylation of recombinant ERK2-GST in an in vitro phosphatase assay. Together, these results suggest that FSH-stimulated ERK activation in GCs requires the PKA-dependent inactivation of MKP3(DUSP6)., (© 2016 by The American Society for Biochemistry and Molecular Biology, Inc.)

Within the ovarian follicle, immature oocytes are surrounded and supported by granulosa cells (GCs). Stimulation of GCs by FSH leads to their proliferation and differentiation, events that are necessary for fertility. FSH activates multiple signaling pathways to regulate genes necessary for follicular maturation. Herein, we investigated the role of Y-box-binding protein-1 (YB-1) within GCs. YB-1 is a nucleic acid binding protein that regulates transcription and translation. Our results show that FSH promotes an increase in the phosphorylation of YB-1 on Ser(102) within 15 min that is maintained at significantly increased levels until ∼8 h post treatment. FSH-stimulated phosphorylation of YB-1(Ser(102)) is prevented by pretreatment of GCs with the PKA-selective inhibitor PKA inhibitor (PKI), the MEK inhibitor PD98059, or the ribosomal S6 kinase-2 (RSK-2) inhibitor BI-D1870. Thus, phosphorylation of YB-1 on Ser(102) is PKA-, ERK-, and RSK-2-dependent. However, pretreatment of GCs with the protein phosphatase 1 (PP1) inhibitor tautomycin increased phosphorylation of YB-1(Ser(102)) in the absence of FSH; FSH did not further increase YB-1(Ser(102)) phosphorylation. This result suggests that the major effect of RSK-2 is to inhibit PP1 rather than to directly phosphorylate YB-1 on Ser(102) YB-1 coimmunoprecipitated with PP1β catalytic subunit and RSK-2. Transduction of GCs with the dephospho-adenoviral-YB-1(S102A) mutant prevented the induction by FSH of Egfr, Cyp19a1, Inha, Lhcgr, Cyp11a1, Hsd17b1, and Pappa mRNAs and estradiol-17β production. Collectively, our results reveal that phosphorylation of YB-1 on Ser(102) via the ERK/RSK-2 signaling pathway is necessary for FSH-mediated expression of target genes required for maturation of follicles to a preovulatory phenotype., (© 2016 by The American Society for Biochemistry and Molecular Biology, Inc.)

The ubiquitous phosphatidylinositol 3-kinase (PI3K) signaling pathway regulates many cellular functions. However, the mechanism by which G protein-coupled receptors (GPCRs) signal to activate PI3K is poorly understood. We have used ovarian granulosa cells as a model to investigate this pathway, based on evidence that the GPCR agonist follicle-stimulating hormone (FSH) promotes the protein kinase A (PKA)-dependent phosphorylation of insulin receptor substrate 1 (IRS1) on tyrosine residues that activate PI3K. We report that in the absence of FSH, granulosa cells secrete a subthreshold concentration of insulin-like growth factor-1 (IGF-1) that primes the IGF-1 receptor (IGF-1R) but fails to promote tyrosine phosphorylation of IRS1. FSH via PKA acts to sensitize IRS1 to the tyrosine kinase activity of the IGF-1R by activating protein phosphatase 1 (PP1) to promote dephosphorylation of inhibitory Ser/Thr residues on IRS1, including Ser(789). Knockdown of PP1β blocks the ability of FSH to activate PI3K in the presence of endogenous IGF-1. Activation of PI3K thus requires both PKA-mediated relief of IRS1 inhibition and IGF-1R-dependent tyrosine phosphorylation of IRS1. Treatment with FSH and increasing concentrations of exogenous IGF-1 triggers synergistic IRS1 tyrosine phosphorylation at PI3K-activating residues that persists downstream through protein kinase B (AKT) and FOXO1 (forkhead box protein O1) to drive synergistic expression of genes that underlies follicle maturation. Based on the ability of GPCR agonists to synergize with IGFs to enhance gene expression in other cell types, PP1 activation to relieve IRS1 inhibition may be a more general mechanism by which GPCRs act with the IGF-1R to activate PI3K/AKT., (© 2016 by The American Society for Biochemistry and Molecular Biology, Inc.)

Background: Norms clarification has been identified as an effective component of college student drinking interventions, prompting research on norms clarification as a single-component intervention known as Personalized Normative Feedback (PNF). Previous reviews have examined PNF in combination with other components but not as a stand-alone intervention., Objectives: To investigate the degree to which computer-delivered stand-alone personalized normative feedback interventions reduce alcohol consumption and alcohol-related harms among college students and to compare gender-neutral and gender-specific PNF., Data Sources: Electronic databases were searched systematically through November 2014. Reference lists were reviewed manually and forward and backward searches were conducted., Selection Criteria: Outcome studies that compared computer-delivered, stand-alone PNF intervention with an assessment only, attention-matched, or active treatment control and reported alcohol use and harms among college students., Methods: Between-group effect sizes were calculated as the standardized mean difference in change scores between treatment and control groups divided by pooled standard deviation. Within-group effect sizes were calculated as the raw mean difference between baseline and follow-up divided by pooled within-groups standard deviation., Results: Eight studies (13 interventions) with a total of 2,050 participants were included. Compared to control participants, students who received gender-neutral (dbetween = 0.291, 95% CI [0.159, 0.423]) and gender-specific PNF (dbetween = 0.284, 95% CI [0.117, 0.451]) reported greater reductions in drinking from baseline to follow-up. Students who received gender-neutral PNF reported 3.027 (95% CI [2.171, 3.882]) fewer drinks per week at first follow-up and gender-specific PNF reported 3.089 (95% CI [0.992, 5.186]) fewer drinks. Intervention effects were small for harms (dbetween = 0.157, 95% CI [0.037, 0.278])., Conclusions: Computer-delivered PNF is an effective stand-alone approach for reducing college student drinking and has a small impact on alcohol-related harms. Effects are small but clinically relevant when considered from a public health perspective. Additional research is needed to examine computer-delivered, stand-alone PNF as a population-level prevention program.

Objective: To determine the respective associations between ureteral obstruction and renomegaly, urine specific gravity (USG), and serum creatinine concentration and to assess the reliability of abdominal palpation for detection of renomegaly in cats., Design: Retrospective case series., Animals: 89 client-owned cats with (n = 29) or without ureteral obstruction and with (30) or without (30) kidney disease., Procedures: Medical records of cats that underwent abdominal ultrasonography at a veterinary teaching hospital from January 2006 through April 2013 were reviewed. Cats were categorized as having ureteral obstruction (obstructed group) or no ureteral obstruction with (KD group) or without kidney disease (NKD group). Renomegaly and renal asymmetry were defined on the basis of mean renal length for NKD cats. Prevalence of renomegaly and renal asymmetry, mean USG and serum creatinine concentration, and abdominal palpation and ultrasonographic findings were compared among the groups., Results: Renomegaly was identified in 2 obstructed cats and 1 KD cat and was not associated with ureteral obstruction. Renal asymmetry was detected in 18 obstructed cats and 11 KD cats. For obstructed and KD cats, the mean USG was significantly lower and the mean serum creatinine concentration was significantly greater than those for NKD cats. Twenty-eight of 29 cats with ureteral obstruction had hypercreatininemia. Abdominal palpation was not a reliable method for detection of renomegaly., Conclusions and Clinical Relevance: Results indicated renomegaly was not associated with ureteral obstruction in cats, and abdominal palpation was an unreliable method for detection of renomegaly. The most consistent abnormal finding for cats with ureteral obstruction was hypercreatininemia.

The development of a web-based parent-focused intervention to improve parental awareness and monitoring of adolescent alcohol use was preliminarily evaluated. Upon completion of baseline assessment, sixty-seven parents were randomly assigned to the experimental web-based parent-focused intervention or an assessment only control condition. Participants who completed the experimental program, relative to control participants, significantly improved knowledge of problems related to underage drinking (p < .01) while improvements in overall monitoring of their children approached significance (p = .08). Improvements in monitoring by experimental participants, relative to controls, were pronounced in phone monitoring (p < .01) and indirect monitoring (p = .05). Participants in this study improved their communication about alcohol from pre- to post-intervention regardless of intervention. There were no statistical between group differences found regarding underage drinking attitudes. This pilot evaluation demonstrates that this program warrants further examination in controlled trials with greater power. Study implications are discussed in light of results.

Serum cardiac troponins are the key biomarkers of myocardial necrosis in humans and in preclinical species. The use of ultrasensitive assays for serum cardiac troponin I (cTnI) as a biomarker in safety studies is hampered by interindividual differences. In this study, we investigated the effect of handling procedures on serum cTnI and explored modeling and simulation approaches to mitigate the impact of these interindividual differences. Femoral-catheterized male Crl:WI(Han) rats (n = 16/group) were left undisturbed in their cages with no handling; subjected to 5 min of isoflurane/O2 anesthesia (A); or placed into a rodent restrainer followed by simulated tail vein injection (RR). Serum cTnI concentrations were assessed over a 24-h period using an ultrasensitive assay, and the study was repeated for confirmation. The mean serum cTnI concentration pre-procedure was 4.2 pg/mL, and remained stable throughout the duration of the study in the rats submitted to the A procedure. Serum cTnI concentrations increased transiently after the RR procedure with a median time to maximum concentration (T max), of 1 and 2 h and a mean maximum value concentration (C max), of 53.0 and 7.2 pg/mL in the initial and repeat studies, respectively. A population pharmacodynamic model identified interindividual, procedure- and study-specific effects on serum cTnI concentrations in rats. It is concluded that a modeling and simulation approach more appropriately describes and statistically analyzes the data obtained with this ultrasensitive assays.

Unlabelled: The present study used a randomized clinical trial design to examine the effectiveness of personalized alcohol feedback delivered individually, in a group and via computer on alcohol use and related negative consequences in a sample of 173 college students referred for alcohol-related violations. Findings revealed statistically significant reductions in alcohol use and related harms for the individually delivered intervention, with significant reductions in alcohol-related harms for the electronically delivered intervention. No statistically significant results were found for the group-delivered intervention or between groups, and a main effect of time was noted for all outcome variables. This study adds to the literature by being the first randomized clinical trial to include analyses of an empirically supported individually delivered personalized alcohol feedback intervention with more cost-effective group-delivered and electronically delivered feedback formats within a single research design, by expanding the range of participant drinking habits reported at baseline to include all drinking levels and not solely those classified as 'heavy drinking' and by providing anonymity pre-intervention and post-intervention given the potential demand characteristics to underreport illegal and/or illicit behaviours in this vulnerable population., Key Practitioner Message: Personalized alcohol feedback delivered in a one-on-one, face-to-face format serves to decrease both alcohol use and harms in mandated college students. The use of web-delivered personalized alcohol feedback may be clinically useful when working with a mandated student population to reduce alcohol-related harms. Personalized alcohol feedback delivered in a group setting may not be indicated for use with a mandated student population as it does not demonstrate decreases in either alcohol use or harms, possibly because of the normalization of deviant behaviour., (Copyright © 2012 John Wiley & Sons, Ltd.)

Background: Hyperadrenocorticism (HAC) has been associated with thrombotic disease in dogs., Hypothesis: The purpose of this study was to use thromboelastography (TEG) and measurement of thrombin generation (TG) to characterize the hypercoagulable state in dogs with HAC. We hypothesized that dogs with HAC would have a hypercoagulable profile on TEG tracings and an increase in thrombin generation as measured by endogenous thrombin potential (ETP)., Animals: Sixteen dogs with HAC. Dogs were compared with a population of normal dogs used to obtain reference intervals., Methods: TEG tracings on citrated whole blood were obtained from 15 dogs, and TG measurements on frozen-thawed platelet-poor plasma (PPP) were obtained from 15 dogs., Results: For the TEG analysis, when results of individual dogs were compared with the reference interval, 12/15 dogs had at least 1 parameter associated with hypercoagulability. When the population of HAC dogs was compared with a population of healthy dogs, HAC dogs had decreases in R and K and increases in α and MA values. The ETP was increased when the HAC group was compared with a population of normal dogs. However, only 3/15 dogs had an ETP above reference interval, and 1/15 had a decreased lag time., Conclusion and Clinical Importance: Of 16 dogs with HAC, 12/15 had evidence of hypercoagulability when evaluated by TEG, 4/15 when evaluated by TG, and 2 dogs had increases in ETP and MA., (Copyright © 2013 by the American College of Veterinary Internal Medicine.)

Controlled maturation of ovarian follicles is necessary for fertility. Follicles are restrained at an immature stage until stimulated by FSH secreted by pituitary gonadotropes. FSH acts on granulosa cells within the immature follicle to inhibit apoptosis, promote proliferation, stimulate production of steroid and protein hormones, and induce ligand receptors and signaling intermediates. The phosphoinositide 3-kinase (PI3K)/AKT (protein kinase B) pathway is a pivotal signaling corridor necessary for transducing the FSH signal. We report that protein kinase A (PKA) mediates the actions of FSH by signaling through multiple targets to activate PI3K/AKT. PKA uses a route that promotes phosphorylation of insulin receptor substrate-1 (IRS-1) on Tyr(989), a canonical binding site for the 85-kDa regulatory subunit of PI3K that allosterically activates the catalytic subunit. PI3K activation leads to activation of AKT through phosphorylation of AKT on Thr(308) and Ser(473). The adaptor growth factor receptor bound protein 2-associated binding protein 2 (GAB2) is present in a preformed complex with PI3K heterodimer and IRS-1, it is an A-kinase anchoring protein that binds the type I regulatory subunit of PKA, and it is phosphorylated by PKA on Ser(159). Overexpression of GAB2 enhances FSH-stimulated AKT phosphorylation. GAB2, thus, seems to coordinate signals from the FSH-stimulated rise in cAMP that leads to activation of PI3K/AKT. The ability of PKA to commandeer IRS-1 and GAB2, adaptors that normally integrate receptor/nonreceptor tyrosine kinase signaling into PI3K/AKT, reveals a previously unrecognized route for PKA to activate a pathway that promotes proliferation, inhibits apoptosis, enhances translation, and initiates differentiation of granulosa cells.

Cannabis is the most widely used illicit drug in the U.S., and the number of illicit and licit users is rising. Lasting neurocognitive changes or deficits as a result of use are frequently noted despite a lack of clarity in the scientific literature. In an effort to resolve inconsistencies in the evidence of lasting residual effects of cannabis use, we conducted two meta-analyses. First, we updated a previous meta-analysis on broad nonacute cognitive effects of cannabis use through inclusion of newer studies. In a second meta-analysis, we focused on evidence for lasting residual effects by including only studies that tested users after at least 25 days of abstinence. In the first meta-analysis, 33 studies met inclusion criteria. Results indicated a small negative effect for global neurocognitive performance as well for most cognitive domains assessed. Unfortunately, methodological limitations of these studies prevented the exclusion of withdrawal symptoms as an explanation for observed effects. In the second meta-analysis, 13 of the original 33 studies met inclusion criteria. Results indicated no significant effect of cannabis use on global neurocognitive performance or any effect on the eight assessed domains. Overall, these meta-analyses demonstrate that any negative residual effects on neurocognitive performance attributable to either cannabis residue or withdrawal symptoms are limited to the first 25 days of abstinence. Furthermore, there was no evidence for enduring negative effects of cannabis use.

The Expectancy Challenge Alcohol Literacy Curriculum (ECALC) is a single session group-delivered program designed to modify alcohol expectancy processes and reduce alcohol use among children and young adults. The objective of this study was to demonstrate the effectiveness of the ECALC in reducing risky alcohol use among heavy drinking college men. Four fraternities at a large state university were randomly assigned to receive either the single session ECALC or a control presentation (2 fraternity houses per condition, n=250). Alcohol expectancies were assessed before and immediately after program presentation. Results demonstrated significant changes on 5 of the 7 subscales of the Comprehensive Effects of Alcohol Scale (CEOA) among students who received the ECALC when compared with control participants. Alcohol use data were collected for 4 weeks before and 4 weeks after program presentation. Compared with those in the control condition, students who received the ECALC demonstrated significant reductions in all facets of alcohol use measured, including decreased mean and peak blood alcohol content (BAC), decreased mean number of days drinking per week, decreased mean drinks per sitting, and decreased number of binge-drinking episodes per month. This study represents 2 important advances. First is the significant reduction in risky alcohol use produced by a single session group-delivered program. The second important advance is the success in changing expectancy processes without using impractical elements common in previous expectancy challenge methods (e.g., a "barlab" environment and actual alcohol administration)., (PsycINFO Database Record (c) 2012 APA, all rights reserved.)

Myocardial mononuclear cell infiltrate is a spontaneous cardiac finding commonly identified in laboratory cynomolgus monkeys. The infiltrates are predominantly composed of macrophages with lesser lymphocytes and are not typically associated with histologically detectable cardiomyocyte degeneration. These infiltrates are of concern because they confound interpretation of test article-related histopathology findings in nonclinical safety toxicology studies. The interpretation of safety studies would be simplified by a biomarker that could identify myocardial infiltrates prior to animal placement on study. We hypothesized that monkeys with myocardial mononuclear cell infiltrates could be identified before necropsy using an ultrasensitive immunoassay for cardiac troponin I (cTnI). Serum cTnI concentrations in monkeys with myocardial infiltrates were not higher than those in monkeys without infiltrates at any of the sampling times before and on the day of necropsy. Increased serum cTnI levels are not suitable for screening monkeys with myocardial mononuclear cell infiltrates before placement in the study.

Methodology that has led to successful strategies to reduce alcohol use was applied to tobacco smoking expectancies. Individual differences scaling was used to empirically model a semantic network of associations stored in memory and preference mapping was used to model likely paths of expectancy activation for groups with different smoking histories. Smokers emphasized an external appearance-internal experience dimension and were more likely to activate expectancies of negative affect reduction. Nonsmokers emphasized a positive-negative dimension and were more likely to activate expectancies of health risks and reduced physical attractiveness. Proportionate frequencies of first associates' validated findings of the MDS-based solutions. Future efforts to alter likely activation patterns may successfully reduce the onset of smoking, enhance quit rates, and reduce relapse., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Background: Long-term corticosteroid therapy has been associated with increased risk of thrombotic disease in dogs., Objective: The purpose of this prospective study was to use thrombelastography (TEG) and thrombin generation (TG) to detect development of a hypercoagulable state in healthy Beagle dogs receiving oral prednisone. We hypothesized that administration of corticosteroids would result in a hypercoagulable profile on TEG tracings and an increase in TG., Methods: Six healthy adult Beagles from the University of Montreal's research colony were used to conduct a prospective longitudinal study in which all dogs received 1 mg/kg of prednisone orally once daily for 2 weeks, followed by a 6-week washout period, and then 4 mg/kg of prednisone orally once daily for 2 weeks. TEG tracings on citrated whole blood and TG measurements on frozen-thawed platelet-poor plasma were obtained before prednisone administration (baseline), at the end of the washout period, and at the end of both corticosteroid trials., Results: Significant differences compared with baseline values were obtained for K, α, and MA, with tracings compatible with a hypercoagulable profile following both corticosteroid trials. There was a significant increase in endogenous thrombin potential only after low-dose (1 mg/kg) prednisone., Conclusion: Administration of prednisone to healthy Beagles resulted in hypercoagulability as indicated by TEG tracings, whereas the effect on TG was more variable. Further studies are needed to determine the underlying mechanisms of hypercoagulability and its clinical impact., (© 2011 American Society for Veterinary Clinical Pathology.)

Background: Glycolytic flux in the mouse heart during the progression of left ventricular hypertrophy (LVH) and mechanical dysfunction has not been described., Methods: The main objectives of this study were to characterize the effects of thoracic aortic banding, of 3- and 6-week duration, on: (1) left ventricular (LV) systolic and diastolic function of perfused working hearts quantified by analysis of pressure-volume loops; (2) glycolytic flux in working hearts expressed as the rate of conversion of (3)H-glucose to (3)H(2)O, and (3) ultrastructure of LV biopsies assessed by quantitative and qualitative analysis of light and electron micrographs., Results: Results revealed that (1) indexes of systolic function, including LV end-systolic pressure, cardiac output, and rate of LV pressure development and decline, were depressed to similar degrees at 3 and 6 weeks post-banding; (2) diastolic dysfunction, represented by elevated LV end-diastolic pressure and volume, was more severe at 6 than at 3 weeks, consistent with a transition to failure; (3) a progressive decline in glycolytic flux that was roughly half the control rate by 6 weeks post-banding; and (4) structural derangements, manifested by increases in interstitial collagen content and myocyte Z-band disruption, that were more marked at 3 weeks than at 6 weeks., Conclusion: The results are consistent with the view that myocyte damage, fibrosis, and suppressed glycolytic flux represent maladaptive structural and metabolic remodeling that contribute to the development of failure in high pressure load-induced LVH in the mouse., (Published by Elsevier Inc.)