Do long delay conditioned stimuli develop inhibitory properties?

In long-delay conditioning, a long conditioned stimulus (CS) is paired in its final segments with an unconditioned stimulus. With sufficient training, this procedure usually results in conditioned responding being delayed until the final segment of the CS, a pattern of responding known as inhibition of delay. However, there have been no systematic investigations of the associative structure of long delay conditioning, and whether the initial segment of a long delay CS actually becomes inhibitory is debatable. In an appetitive preparation with rat subjects, the initial segment of long delay CS A passed a retardation (Experiment 1a) but not a summation (Experiment 1b) test for conditioned inhibition. Furthermore, retardation was observed only if long delay conditioning and retardation training occurred in the same context (Experiment 2). Thus, the initial segment of a long delay CS appears to share more characteristics with a latent inhibitor than a conditioned inhibitor. Componential theories of conditioning appear best suited to account for these results

Sex differences in a mouse model of multiple sclerosis: neuropathic pain behavior in females but not males and protection from neurological deficits during proestrus

BACKGROUND: Multiple sclerosis (MS), a demyelinating disease of the central nervous system, is one of the most prevalent neurological disorders in the industrialized world. This disease afflicts more than two million people worldwide, over two thirds of which are women. MS is typically diagnosed between the ages of 20–40 and can produce debilitating neurological impairments including muscle spasticity, muscle paralysis, and chronic pain. Despite the large sex disparity in MS prevalence, clinical and basic research investigations of how sex and estrous cycle impact development, duration, and severity of neurological impairments and pain symptoms are limited. To help address these questions, we evaluated behavioral signs of sensory and motor functions in one of the most widely characterized animal models of MS, the experimental autoimmune encephalomyelitis (EAE) model. METHODS: C57BL/6 male and female mice received flank injection of complete Freund’s adjuvant (CFA) or CFA plus myelin oligodendrocyte glycoprotein 35-55 (MOG(35-55)) to induce EAE. Experiment 1 evaluated sex differences of EAE-induced neurological motor deficits and neuropathic pain-like behavior over 3 weeks, while experiment 2 evaluated the effect of estrous phase in female mice on the same behavioral measures for 3 months. EAE-induced neurological motor deficits including gait analysis and forelimb grip strength were assessed. Neuropathic pain-like behaviors evaluated included sensitivity to mechanical, cold, and heat stimulations. Estrous cycle was determined daily via vaginal lavage. RESULTS: MOG(35-55)-induced EAE produced neurological impairments (i.e., motor dysfunction) including mild paralysis and decreases in grip strength in both females and males. MOG(35-55) produced behavioral signs of neuropathic pain—mechanical and cold hypersensitivity—in females, but not males. MOG(35-55) did not change cutaneous heat sensitivity in either sex. Administration of CFA or CFA + MOG(35-55) prolonged the time spent in diestrus for 2 weeks, after which normal cycling returned. MOG(35-55) produced fewer neurological motor deficits when mice were in proestrus relative to non-proestrus phases. CONCLUSIONS: We conclude that female mice are superior to males for the study of neuropathic pain-like behaviors associated with MOG(35-55)-induced EAE. Further, proestrus may be protective against EAE-induced neurological deficits, thus necessitating further investigation into the impact that estrous cycle exerts on MS symptoms

Simulation-based power and sample size calculation for designing interrupted time series analyses of count outcomes in evaluation of health policy interventions

Objective: The purpose of this study was to present the design, model, and data analysis of an interrupted time series (ITS) model applied to evaluate the impact of health policy, systems, or environmental interventions using count outcomes. Simulation methods were used to conduct power and sample size calculations for these studies. Methods: We proposed the models and analyses of ITS designs for count outcomes using the Strengthening Translational Research in Diverse Enrollment (STRIDE) study as an example. The models we used were observation-driven models, which bundle a lagged term on the conditional mean of the outcome for a time series of count outcomes. Results: A simulation-based approach with ready-to-use computer programs was developed to calculate the sample size and power of two types of ITS models, Poisson and negative binomial, for count outcomes. Simulations were conducted to estimate the power of segmented autoregressive (AR) error models when autocorrelation ranged from -0.9 to 0.9, with various effect sizes. The power to detect the same magnitude of parameters varied largely, depending on the testing level change, the trend change, or both. The relationships between power and sample size and the values of the parameters were different between the two models. Conclusion: This article provides a convenient tool to allow investigators to generate sample sizes that will ensure sufficient statistical power when the ITS study design of count outcomes is implemented

Sex Differences in a Mouse Model of Multiple Sclerosis: Neuropathic Pain Behavior in Females but not Males and Protection from Neurological Deficits During Proestrus

BACKGROUND: Multiple sclerosis (MS), a demyelinating disease of the central nervous system, is one of the most prevalent neurological disorders in the industrialized world. This disease afflicts more than two million people worldwide, over two thirds of which are women. MS is typically diagnosed between the ages of 20-40 and can produce debilitating neurological impairments including muscle spasticity, muscle paralysis, and chronic pain. Despite the large sex disparity in MS prevalence, clinical and basic research investigations of how sex and estrous cycle impact development, duration, and severity of neurological impairments and pain symptoms are limited. To help address these questions, we evaluated behavioral signs of sensory and motor functions in one of the most widely characterized animal models of MS, the experimental autoimmune encephalomyelitis (EAE) model. METHODS: C57BL/6 male and female mice received flank injection of complete Freund\u27s adjuvant (CFA) or CFA plus myelin oligodendrocyte glycoprotein 35-55 (MOG35-55) to induce EAE. Experiment 1 evaluated sex differences of EAE-induced neurological motor deficits and neuropathic pain-like behavior over 3 weeks, while experiment 2 evaluated the effect of estrous phase in female mice on the same behavioral measures for 3 months. EAE-induced neurological motor deficits including gait analysis and forelimb grip strength were assessed. Neuropathic pain-like behaviors evaluated included sensitivity to mechanical, cold, and heat stimulations. Estrous cycle was determined daily via vaginal lavage. RESULTS: MOG35-55-induced EAE produced neurological impairments (i.e., motor dysfunction) including mild paralysis and decreases in grip strength in both females and males. MOG35-55 produced behavioral signs of neuropathic pain-mechanical and cold hypersensitivity-in females, but not males. MOG35-55 did not change cutaneous heat sensitivity in either sex. Administration of CFA or CFA + MOG35-55 prolonged the time spent in diestrus for 2 weeks, after which normal cycling returned. MOG35-55 produced fewer neurological motor deficits when mice were in proestrus relative to non-proestrus phases. CONCLUSIONS: We conclude that female mice are superior to males for the study of neuropathic pain-like behaviors associated with MOG35-55-induced EAE. Further, proestrus may be protective against EAE-induced neurological deficits, thus necessitating further investigation into the impact that estrous cycle exerts on MS symptoms

Design, analysis, power, and sample size calculation for three-phase interrupted time series analysis in evaluation of health policy interventions

OBJECTIVE: To discuss the study design and data analysis for three-phase interrupted time series (ITS) studies to evaluate the impact of health policy, systems, or environmental interventions. Simulation methods are used to conduct power and sample size calculation for these studies. METHODS: We consider the design and analysis of three-phase ITS studies using a study funded by National Institutes of Health as an exemplar. The design and analysis of both one-arm and two-arm three-phase ITS studies are introduced. RESULTS: A simulation-based approach, with ready-to-use computer programs, was developed to determine the power for two types of three-phase ITS studies. Simulations were conducted to estimate the power of segmented autoregressive (AR) error models when autocorrelation ranged from -0.9 to 0.9 with various effect sizes. The power increased as the sample size or the effect size increased. The power to detect the same effect sizes varied largely, depending on testing level change, trend changes, or both. CONCLUSION: This article provides a convenient tool for investigators to generate sample sizes to ensure sufficient statistical power when three-phase ITS study design is implemented

Education and Training of Non-Genetics Providers on the Return of Genome Sequencing Results in a NICU Setting

To meet current and expected future demand for genome sequencing in the neonatal intensive care unit (NICU), adjustments to traditional service delivery models are necessary. Effective programs for the training of non-genetics providers (NGPs) may address the known barriers to providing genetic services including limited genetics knowledge and lack of confidence. The SouthSeq project aims to use genome sequencing to make genomic diagnoses in the neonatal period and evaluate a scalable approach to delivering genome sequencing results to populations with limited access to genetics professionals. Thirty-three SouthSeq NGPs participated in a live, interactive training intervention and completed surveys before and after participation. Here, we describe the protocol for the provider training intervention utilized in the SouthSeq study and the associated impact on NGP knowledge and confidence in reviewing, interpreting, and using genome sequencing results. Participation in the live training intervention led to an increased level of confidence in critical skills needed for real-world implementation of genome sequencing. Providers reported a significant increase in confidence level in their ability to review, understand, and use genome sequencing result reports to guide patient care. Reported barriers to implementation of genome sequencing in a NICU setting included test cost, lack of insurance coverage, and turn around time. As implementation of genome sequencing in this setting progresses, effective education of NGPs is critical to provide access to high-quality and timely genomic medicine care