Recently Published Documents
Abstract Background Vestibular syndrome is often accompanied by nausea. Drugs currently approved for its treatment have been developed to stop vomiting but not nausea. The efficacy of 5-HT3 receptor antagonists to reduce nausea has been described for chemotherapy, but not for nausea secondary to vestibular disorders. Methods Sixteen dogs with vestibular syndrome-associated nausea were included in the open-label, multicentre study. The intensity of nausea-like behaviour was analysed before ondansetron administration (0.5 mg/kg i.v.) and 2 h afterwards, using a validated 5-point-scale. The occurrence and frequency of salivation, lip licking, restlessness, vocalisation, lethargy, and vomiting were assessed. Results All dogs initially showed signs of nausea, whereas only 31% showed vomitus. The intensity of nausea was significantly reduced in all dogs (p ≤ 0.0001) 2 h after ondansetron administration, including the clinical signs of nausea analysed in 11 dogs (salivation [p = 0.0078], lip licking [p = 0.0078], restlessness [p = 0.0039], and lethargy [p = 0.0078]) except for vocalisation (p > 0.9999). Conclusions The results provide preliminary evidence of the potential benefit of ondansetron in the treatment of nausea, which was present in all examined dogs. Vomiting was only observed in 5 dogs indicating that nausea can occur separately and should not be perceived only as a preceding stimulation of the vomiting centre.
Pharmacokinetic–pharmacodynamic guided optimisation of dose and schedule of CGM097, an HDM2 inhibitor, in preclinical and clinical studies
Abstract Background CGM097 inhibits the p53-HDM2 interaction leading to downstream p53 activation. Preclinical in vivo studies support clinical exploration while providing preliminary evidence for dosing regimens. This first-in-human phase I study aimed at assessing the safety, MTD, PK/PD and preliminary antitumor activity of CGM097 in advanced solid tumour patients (NCT01760525). Methods Fifty-one patients received oral treatment with CGM097 10–400 mg 3qw (n = 31) or 300–700 mg 3qw 2 weeks on/1 week off (n = 20). Choice of dose regimen was guided by PD biomarkers, and quantitative models describing the effect of CGM097 on circulating platelet and PD kinetics. Results No dose-limiting toxicities were reported in any regimens. The most common treatment-related grade 3/4 AEs were haematologic events. PK/PD models well described the time course of platelet and serum GDF-15 changes, providing a tool to predict response to CGM097 for dose-limiting thrombocytopenia and GDF-15 biomarker. The disease control rate was 39%, including one partial response and 19 patients in stable disease. Twenty patients had a cumulative treatment duration of >16 weeks, with eight patients on treatment for >32 weeks. The MTD was not determined. Conclusions Despite delayed-onset thrombocytopenia frequently observed, the tolerability of CGM097 appears manageable. This study provided insights on dosing optimisation for next-generation HDM2 inhibitors. Translational relevance Haematologic toxicity with delayed thrombocytopenia is a well-known on-target effect of HDM2 inhibitors. Here we have developed a PK/PD guided approach to optimise the dose and schedule of CGM097, a novel HDM2 inhibitor, using exposure, platelets and GDF-15, a known p53 downstream target to predict patients at higher risk to develop thrombocytopenia. While CGM097 had shown limited activity, with disease control rate of 39% and only one patient in partial response, the preliminary data from the first-in-human escalation study together with the PK/PD modeling provide important insights on how to optimize dosing of next generation HDM2 inhibitors to mitigate hematologic toxicity.
Methods to Address Self-Selection and Reverse Causation in Studies of Neighborhood Environments and Brain Health
Preliminary evidence suggests that neighborhood environments, such as socioeconomic disadvantage, pedestrian and physical activity infrastructure, and availability of neighborhood destinations (e.g., parks), may be associated with late-life cognitive functioning and risk of Alzheimer’s disease and related disorders (ADRD). The supposition is that these neighborhood characteristics are associated with factors such as mental health, environmental exposures, health behaviors, and social determinants of health that in turn promote or diminish cognitive reserve and resilience in later life. However, observed associations may be biased by self-selection or reverse causation, such as when individuals with better cognition move to denser neighborhoods because they prefer many destinations within walking distance of home, or when individuals with deteriorating health choose residences offering health services in neighborhoods in rural or suburban areas (e.g., assisted living). Research on neighborhood environments and ADRD has typically focused on late-life brain health outcomes, which makes it difficult to disentangle true associations from associations that result from reverse causality. In this paper, we review study designs and methods to help reduce bias due to reverse causality and self-selection, while drawing attention to the unique aspects of these approaches when conducting research on neighborhoods and brain aging.
AbstractDust and grit are ingested by herbivores in their natural habitats along with the plants that represent their selected diet. Among the functions of the rumen, a washing of ingesta from adhering dust and grit has recently been demonstrated. The putative consequence is a less strenuous wear on ruminant teeth by external abrasives during rumination. The same function should theoretically apply to camelids, but has not been investigated so far. We fed six llamas (Lama glama) a diet of grass hay and a lucerne-based pelleted food in which fine sand had been included at about 8% of ingredients, for ad libitum consumption for 6 weeks. Subsequently, animals were slaughtered and content of the different sections of the gastrointestinal tract was sampled for the analysis of dry matter (DM), total ash, and acid detergent insoluble ash (ADIA, a measure for silica). Additionally, two of the animals were subjected to whole-body computer tomography (CT) after death in the natural sternal resting position. No clinical problems or macroscopic changes in the faeces were observed during the experimental period. The results indicate an accumulation of ADIA in the C3 compartment of the stomach complex, in particular in the posterior portion that is the equivalent of the abomasum in ruminants. By contrast, contents of the C1, from which material is recruited for regurgitation and rumination, were depleted of ADIA, indicating that the contents had largely been washed free of sand. The washing effect is an unavoidable side effect of the flotation- and sedimentation-based sorting mechanisms in the ruminant and the camelid forestomachs. In theory, this should allow ruminants and camelids to live in similar habitats as nonruminant herbivores at lower degrees of hypsodonty.
Is voluntary International Integrated Reporting Framework adoption a step on the sustainability road and does adoption matter to capital markets?
Purpose This paper aims to examine the type of firms that voluntarily adopt the International Integrated Reporting Framework (IIRF) and how markets respond to voluntary IIRF adherence. Design/methodology/approach Analysis of a matched global sample of listed firms that voluntarily adopt the IIRF (IIRF firms) and those that do not (non-IIRF firms). The samples range from 188 to 436 observations as alternative research designs, different matched samples and regression specifications, and several sensitivity analyses were conducted. Findings In markets where integrated reporting (IR) is not mainstream, voluntary IIRF adoption is more likely for firms with established sustainability practices. Such findings suggest that the IIRF is an incremental innovation for sustainability rather than an innovation that radically changes management and reporting practices. In Japan, where IR is mainstream, results show no observable differences between IIRF firms and non-IIRF firms. Consistent with the determinants results, this paper finds no evidence of associations between voluntary IIRF adoption and the information environment, the cost of equity or firm value. However, the additional analysis provides preliminary evidence suggesting capital market effects may differ for IIRF firms with higher sustainability or market performance. Practical implications This study offers useful insights into the current global debate on whether there is value in adopting the IIRF. Originality/value This study adds to the limited body of research on the determinants and consequences of voluntary IIRF adoption, offering insights for regulators, practitioners and proponents of IR. This study is the first to provide quantitative evidence of the influence sustainability practices have on voluntary IIRF adoption. Further, the results add to the current global debate on whether there is value in adopting the IIRF. This paper finds that voluntary IIRF adoption has no clear and distinct influence on disclosure practices and capital markets, suggesting there are no additional benefits from prioritising the promotion or adoption of the IIRF over other disclosure forms. Unless there are advancements supporting the implementation of integrated thinking and information connectivity, the potential for the IIRF to improve information quality may be limited to encouraging more non-financial disclosure and transparency in countries where integrated disclosures are not trending.
Three-dimensional mechanics of the rugby tackle, does the ball carrier alter their movement into contact in response to the tackler’s position?
In rugby league and rugby union, the ball carrier is vulnerable to injury during a tackle. The height of the tackle has been associated with injury risk. The extent to which a ball carrier may alter their approach entering a tackle in response the tackler’s body height is unknown. This exploratory study aimed to identify if, when and how, the ball carrier modified their motion when being tackled in response to tackling instructions given to the tackler. Three-dimensional analysis was completed on 15 adult male rugby union/league players performing a front-on, one-on-one tackle at differing tackle heights. Repeated measure factorial analyses of variance were used to test for differences (P < 0.05). The ball carrier used two movement strategies: (1) increasing their stability by flexing their trunk, knee, and hips more when entering mid/high torso tackles; (2) offloading the ball or performing an evasive movement strategy by positioning themselves in a more upright body position when being tackled at a lower torso tackle height. This preliminary evidence suggests it may be beneficial for a coach to provide different instructions to the ball carrier to modify their movement strategies when being tackled in response to the height of the tackler to improve their performance and decrease their potential injury risk.
The Differential Impact of Acute Exercise and Mindfulness Meditation on Executive Functioning and Psycho-Emotional Well-Being in Children and Youth With ADHD
This study investigated how acute exercise and mindfulness meditation impacts executive functioning and psycho-emotional well-being in 16 children and youth with ADHD aged 10–14 (male = 11; White = 80%). Participants completed three interventions: 10 min of exercise, 10 min of mindfulness meditation, and 10 min of reading (control). Before and after each intervention, executive functioning (inhibitory control, working memory, task-switching) and psycho-emotional well-being (mood, self-efficacy) were assessed. Mindfulness meditation increased performance on all executive functioning tasks whereas the other interventions did not (d = 0.55–0.86). Exercise enhanced positive mood and self-efficacy whereas the other interventions did not (d = 0.22–0.35). This work provides preliminary evidence for how acute exercise and mindfulness meditation can support differential aspects of executive and psycho-emotional functioning among children and youth with ADHD.
A Neurosociological Theory of Culturally and Structurally Situated Cognition and Ethno-Racial Stress
A longstanding body of literature reveals that experiences of discrimination and exclusion lead to health disadvantages by increasing physiological stress responses both in the body and the brain. However, a sociological view that takes into account structurally and culturally shaped biological processes is missing from the literature. Building on recent literature from the sociology of morality and values and the dual process model of culture, this paper proposes and provides preliminary evidence for an applied theory of culturally situated moral cognition as a coping mechanism with ethno-racial stress. I focus on values as they help cope with ethnicity and race related stress such as discrimination. Using functional neuroimaging data, I offer evidence that values operate through both explicit (controlled and conscious) processes recruiting brain regions like the dorsal prefrontal cortex, and implicit (automatic and non-conscious) processes recruiting regions like the ventromedial prefrontal cortex, to help cope with exclusion and discrimination.