A Physiologically-Based Pharmacokinetic Model for the Antibiotic Ertapenem

Ertapenem is an antibiotic commonly used to treat a broad spectrum of infections, which is part of a broader class of antibiotics called carbapenem. Unlike other carbapenems, ertapenem has a longer half-life and thus only has to be administered once a day. A physiologically-based pharmacokinetic (PBPK) model was developed to investigate the uptake, distribution, and elimination of ertapenem following a single one gram dose. PBPK modeling incorporates known physiological parameters such as body weight, organ volumes, and blood ow rates in particular tissues. Furthermore, ertapenem is highly bound in human blood plasma; therefore, nonlinear binding is incorporated in the model since only the free portion of the drug can saturate tissues and, hence, is the only portion of the drug considered to be medicinally effective. Parameters in the model were estimated using a least squares inverse problem formulation with published data for blood concentrations of ertapenem for normal height, normal weight males. Finally, an uncertainty analysis of the parameter estimation and model predictions is presented

Evolution Of A Higher Intracellular Oxidizing Environment In Caenorhabditis Elegans Under Relaxed Selection

We explored the relationship between relaxed selection, oxidative stress, and spontaneous mutation in a set of mutation-accumulation (MA) lines of the nematode Caenorhabditis elegans and in their common ancestor. We measured steady-state levels of free radicals and oxidatively damaged guanosine nucleosides in the somatic tissues of five MA lines for which nuclear genome base substitution and GC-TA transversion frequencies are known. The two markers of oxidative stress are highly correlated and are elevated in the MA lines relative to the ancestor; point estimates of the per-generation rate of mutational decay (DM) of these measures of oxidative stress are similar to those reported for fitness-related traits. Conversely, there is no significant relationship between either marker of oxidative stress and the per-generation frequencies of base substitution or GC-TA transversion. Although these results provide no direct evidence for a causative relationship between oxidative damage and base substitution mutations, to the extent that oxidative damage may be weakly mutagenic in the germline, the case for condition-dependent mutation is advanced

Evaluation of an Artificial Intelligence Coronary Artery Calcium Scoring Model from Computed Tomography

OBJECTIVES: Coronary artery calcium (CAC) scores derived from computed tomography (CT) scans are used for cardiovascular risk stratification. Artificial intelligence (AI) can assist in CAC quantification and potentially reduce the time required for human analysis. This study aimed to develop and evaluate a fully automated model that identifies and quantifies CAC. METHODS: Fully convolutional neural networks for automated CAC scoring were developed and trained on 2439 cardiac CT scans and validated using 771 scans. The model was tested on an independent set of 1849 cardiac CT scans. Agatston CAC scores were further categorised into five risk categories (0, 1–10, 11–100, 101–400, and > 400). Automated scores were compared to the manual reference standard (level 3 expert readers). RESULTS: Of 1849 scans used for model testing (mean age 55.7 ± 10.5 years, 49% males), the automated model detected the presence of CAC in 867 (47%) scans compared with 815 (44%) by human readers (p = 0.09). CAC scores from the model correlated very strongly with the manual score (Spearman’s r = 0.90, 95% confidence interval [CI] 0.89–0.91, p < 0.001 and intraclass correlation coefficient = 0.98, 95% CI 0.98–0.99, p < 0.001). The model classified 1646 (89%) into the same risk category as human observers. The Bland–Altman analysis demonstrated little difference (1.69, 95% limits of agreement: −41.22, 44.60) and there was almost excellent agreement (Cohen’s κ = 0.90, 95% CI 0.88–0.91, p < 0.001). Model analysis time was 13.1 ± 3.2 s/scan. CONCLUSIONS: This artificial intelligence–based fully automated CAC scoring model shows high accuracy and low analysis times. Its potential to optimise clinical workflow efficiency and patient outcomes requires evaluation. KEY POINTS: • Coronary artery calcium (CAC) scores are traditionally assessed using cardiac computed tomography and require manual input by human operators to identify calcified lesions. • A novel artificial intelligence (AI)–based model for fully automated CAC scoring was developed and tested on an independent dataset of computed tomography scans, showing very high levels of correlation and agreement with manual measurements as a reference standard. • AI has the potential to assist in the identification and quantification of CAC, thereby reducing the time required for human analysis. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00330-022-09028-3

Evolution of a Higher Intracellular Oxidizing Environment in Caenorhabditis elegans under Relaxed Selection

We explored the relationship between relaxed selection, oxidative stress, and spontaneous mutation in a set of mutation-accumulation (MA) lines of the nematode Caenorhabditis elegans and in their common ancestor. We measured steady-state levels of free radicals and oxidatively damaged guanosine nucleosides in the somatic tissues of five MA lines for which nuclear genome base substitution and GC-TA transversion frequencies are known. The two markers of oxidative stress are highly correlated and are elevated in the MA lines relative to the ancestor; point estimates of the per-generation rate of mutational decay (DM) of these measures of oxidative stress are similar to those reported for fitness-related traits. Conversely, there is no significant relationship between either marker of oxidative stress and the per-generation frequencies of base substitution or GC-TA transversion. Although these results provide no direct evidence for a causative relationship between oxidative damage and base substitution mutations, to the extent that oxidative damage may be weakly mutagenic in the germline, the case for condition-dependent mutation is advanced

Drug problems among homeless individuals in Toronto, Canada: prevalence, drugs of choice, and relation to health status

<p>Abstract</p> <p>Background</p> <p>Drug use is believed to be an important factor contributing to the poor health and increased mortality risk that has been widely observed among homeless individuals. The objective of this study was to determine the prevalence and characteristics of drug use among a representative sample of homeless individuals and to examine the association between drug problems and physical and mental health status.</p> <p>Methods</p> <p>Recruitment of 603 single men, 304 single women, and 284 adults with dependent children occurred at homeless shelters and meal programs in Toronto, Canada. Information was collected on demographic characteristics and patterns of drug use. The Addiction Severity Index was used to assess whether participants suffered from drug problems. Associations of drug problems with physical and mental health status (measured by the SF-12 scale) were examined using regression analyses.</p> <p>Results</p> <p>Forty percent of the study sample had drug problems in the last 30 days. These individuals were more likely to be single men and less educated than those without drug problems. They were also more likely to have become homeless at a younger age (mean 24.8 vs. 30.9 years) and for a longer duration (mean 4.8 vs. 2.9 years). Marijuana and cocaine were the most frequently used drugs in the past two years (40% and 27%, respectively). Drug problems within the last 30 days were associated with significantly poorer mental health status (-4.9 points, 95% CI -6.5 to -3.2) but not with poorer physical health status (-0.03 points, 95% CI -1.3 to 1.3)).</p> <p>Conclusions</p> <p>Drug use is common among homeless individuals in Toronto. Current drug problems are associated with poorer mental health status but not with poorer physical health status.</p

Examining Behavioral Phenotypes of Overeating and Obesity: Environmental, Psychological, and Neurobiological Influences on Food Motivation and Palatable Food Consumption

Obesity is a substantial problem in the U.S., with growing rates particularly at early developmental stages (e.g., childhood, adolescents). Several factors may contribute to the development of overeating and obesity, including elevated craving in response to food-related cues, individual susceptibility to food-related cues, and neural changes associated with behavioral phenotypes implicated in obesity. The current dissertation aims to shed light on these contributing factors, in an effort to better understand obesity risk and contribute to the development of effective interventions. Study 1 aimed to test the incentive-sensitization theory of addiction by examining food motivation, hunger, and consumption in a cue-rich compared to neutral environment. Participants (n = 126) were randomized to either a naturalistic fast-food laboratory or a neutral laboratory, where they provided self-reported ratings of “wanting,” “liking,” and hunger, and engaged in a task assessing food motivation and food consumption. Study 1 found that “wanting,” hunger, and consumption were greater in the cue-rich compared to neutral laboratory, while “liking” did not differ between conditions. This study provides support for the incentive-sensitization theory as applied to eating behavior. Study 2 developed and tested a novel paradigm for identifying two phenotypes of cue-responsivity, sign-tracking and goal-tracking. Children aged 5-7 (n = 64) engaged in a Pavlovian conditioning task designed to assess propensity to engage with a cue (sign-tracking) versus the location of a reward (goal-tracking). Children then engaged in tasks assessing food motivation and inhibitory control. Contrary to hypotheses, Study 1 did not find a distinct goal-tracking phenotype, and did not find sign-tracking behavior to be associated with either food motivation or inhibitory control. Considerations for how to examine these phenotypes in future research are discussed. Study 3 examined how resting state functional connectivity (rsFC) relates to obesity, food consumption, food motivation, and inhibitory control in adolescents (n = 164) aged 13-16 who ranged from lean to obese. Participants completed tasks assessing food motivation and inhibitory control, then on a second visit underwent a resting-state scan and then completed a food consumption task in a cue-rich environment. Obesity and elevated food motivation were found to be marked by altered connectivity in areas in the salience network (e.g., caudate, NAcc, OFC) and the default mode network (e.g., PCC, hippocampus). However, obesity was not found to be associated with behavioral outcomes, thus these behaviors were not found to mediate associations between obesity and rsFC patterns. These findings provide suggestions as to effective prevention and intervention targets. The current dissertation provides evidence for a strong role of elevated food motivation (especially in the context of food cues) in the overconsumption of palatable foods. Clinical implications and suggestions for intervention are discussed.PHDPsychologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttps://deepblue.lib.umich.edu/bitstream/2027.42/151531/1/majoyn_1.pd

“They’re coming to us and we don’t have any training” - Professional learning approaches for secondary Australian school year advisors: a call for support

Secondary school year advisors fulfil an important relationship-building, middle leadership position in schools. Although responsible for supporting the wellbeing of students with a range of academic, social, and emotional needs, there is limited research into year advisor’s role and the support provided for these educators. This qualitative study provides insight into year advisors’ perceptions of professional learning that prepared them to support student wellbeing. Semi-structured interviews were conducted with secondary school year advisors in New South Wales, Australia, investigating their training experiences and views on navigating the expectations of their role. Interpretive Phenomenological Analysis revealed key themes capturing the limited provision of formal training for year advisors and the perception that training was insufficient for responding to students’ mental health needs. Year advisors reported relying on self-sourced informal training methods including collaborative partnerships, practice-based learning and independent investigation, to manage situations encountered when supporting students. Findings reveal a disparity in formalised professional learning opportunities across schools and year advisors’ desire for systematic, role specific, formalised training, especially for supporting students’ mental health