C. Elizabeth Boudreau

This paper outlines the design features, data collection methods and analytic strategies of the International Tobacco Control (ITC) Four Country Survey, a prospective study of more than 2000 longitudinal respondents per country with yearly replenishments. This survey possesses unique features that sets it apart among surveys on tobacco use and cessation. One of these features is the use of theory-driven conceptual models. In this paper, however, the focus is on the two key statistical features of the survey: longitudinal and "quasi-experimental" designs. Although it is often possible to address the same scientific questions with a cross-sectional or a longitudinal study, the latter has the major advantage of being able to distinguish changes over time within individuals from differences among people at baseline (that is, differences between age and cohort effects). Furthermore, quasi-experiments, where countries not implementing a given new tobacco control policy act as the control group to which the country implementing such a policy will be compared, provide much stronger evidence than observational studies on the effects of national-level tobacco control policies. In summary, application of rigorous research methods enables this survey to be a rich data resource, not only to evaluate policies, but also to gain new insights into the natural history of smoking cessation, through longitudinal analyses of smoker behaviour.

The updated VCOG-CTCAE v2 guidelines contain several important updates and additions since the last update (v1.1) was released in 2011 and published within Veterinary and Comparative Oncology in 2016. As the Veterinary Cooperative Oncology Group (VCOG) is no longer an active entity, the original authors and contributors to the VCOG-CTCAE v1.0 and v1.1 were consulted for input, and additional co-authors sought for expansion and refinement of the adverse event (AE) categories. VCOG-CTCAE v2 includes expanded neurology, cardiac and immunologic AE sections, and the addition of procedural-specific AEs. It is our intent that, through inclusion of additional authors from ACVIM subspecialties and the American College of Veterinary Surgery, that we can more comprehensively capture AEs that are observed during clinical studies conducted across a variety of disease states, clinical scenarios, and body systems. It is also our intent that these updated veterinary CTCAE guidelines will offer improved application and ease of use within veterinary practice in general, as well as within clinical trials that assess new therapeutic strategies for animals with a variety of diseases. Throughout the revision process, we strived to ensure the grading structure for each AE category was reflective of the decision-making process applied to determination of dose-limiting events. As phase I trial decisions are based on these criteria and ultimately determine the maximally tolerated dose, there is impact on standard dosing recommendations for any new drug registration or application. This document should be updated regularly to reflect ongoing application to clinical studies carried out in veterinary patients.

Neurons in primary visual cortex exhibit several nonlinearities in their responses to visual stimuli, including response decrements to repeated stimuli, contrast-dependent phase advance, contrast saturation, and cross-orientation suppression. Thalamocortical synaptic depression has been implicated in these phenomena but has not been examined directly in visual cortex in vivo. We assessed depression of visual thalamocortical synapses in vivo using 20-100 Hz trains of electrical stimuli delivered to the LGN. Cortical cells receiving direct input from the LGN, identified by short latency and low jitter of LGN-evoked PSPs, showed moderate reductions in PSP amplitude during the fastest trains. Cells receiving indirect input from the thalamus via other cortical excitatory neurons show a marked reduction in PSP amplitude during a train, which could be explained either by synaptic depression in corticocortical synapses or by an inhibition-mediated suppression of the firing of their afferents. Reducing spontaneous activity in the LGN (by retinal blockade) unmasked additional depression at the thalamocortical synapse but only for the first stimulus in the train. That is, the first PSP was increased in amplitude relative to the unblocked condition, but subsequent responses were essentially unchanged. Thus, the synapses are maintained at significant levels of depression by spontaneous activity. These findings constrain the role that thalamocortical depression can play in shaping cortical responses to visual stimuli.

Spatial attention improves performance at attended locations and correspondingly modulates firing rates of cortical neurons. The size of these behavioral and neuronal effects depends on the difficulty of the task performed at the attended location. Psychological theorists have attributed this to a tighter focus of a fixed amount of processing resource at the attended location, but the effects of task difficulty on the distribution of neuronal effects of attention across the visual field have not been fully explored. We trained rhesus monkeys to do a detection task in which difficulty and spatial attention were manipulated independently. Probe stimuli were used to measure behavioral performance in different conditions of attention and difficulty. Animals performed better at attended locations and this advantage increased with difficulty, consistent with data from human psychophysics. Neuronal modulation by spatial attention was larger with greater difficulty. In two animals, increasing difficulty caused a modest increase in neuronal responses to visual stimuli regardless of the locus of spatial attention. In a third animal, which was previously trained to ignore multiple distracting stimuli, increasing task difficulty increased responses at the focus of attention and suppressed responses away from the focus of attention. The results show that difficulty can modulate effects of spatial attention in V4; it can alter the distribution of sensory responses across the visual scene in ways that may depend on the subject's behavioral strategy.