The sympathetic nervous system (SNS) serves to maintain homeostasis of vital organ systems throughout the body, and its dysfunction plays a major role in human disease. The SNS also links the central nervous system to the immune system during different types of stress via innervation of the lymph nodes, spleen, thymus, and bone marrow. Previous studies have shown that pituitary adenylate cyclase-activating polypeptide (PACAP, gene name adcyap1) exhibits anti-inflammatory properties in the experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis. Because PACAP is known to regulate SNS function, we hypothesized that part of the immunoprotective action of PACAP is due to its neuromodulatory effects on sympathetic neurons. To examine this, we used an inducible, targeted approach to conditionally disrupt not only the PACAP-preferring PAC1 receptor gene (adcyap1r1) in dopamine β-hydroxylase-expressing cells, which includes postganglionic sympathetic neurons, but also catecholaminergic neurons in the brain and adrenomedullary chromaffin cells. In contrast to our previous EAE studies using PACAP global knockout mice which developed severe and prolonged EAE, we found that mice with conditional loss of PAC1 receptors in catecholaminergic cells developed a delayed time course of EAE with reduced helper T cell type 1 (Th1) and Th17 and enhanced Th2 cell polarization. At later time points, similar to mice with global PACAP loss, mice with conditional loss of PAC1 exhibited more severe clinical disease than controls. The latter was associated with a reduction in the abundance of thymic regulatory T cells (Tregs). These studies indicate that PAC1 receptor signaling acts in catecholaminergic cells in a time-dependent manner. At early stages of disease development, it enhances the ability of the SNS to polarize the Th response towards a more inflammatory state. Then, after disease is established, it enhances the ability of the SNS to dampen the inflammatory response via T. The lack of concordance in results between global PACAP KO mice and mice with the PAC1 deletion targeted to catecholaminergic cells during early EAE may be explained by the fact that PACAP acts to regulate inflammation via multiple receptor subtypes and multiple targets, including inflammatory cells.

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Multiple public health and medical research studies have applied matched‐pair cluster randomization design to the evaluation of the intervention and/or prevention effects. One of the most common and severe problems faced by researchers when conducting cluster randomized trials (CRTs) is incomplete observations, which are associated with various reasons causing the individuals to discontinue participating in the trials. Although statistical methods to remedy the problems of missing data have already been proposed, there are still methodological gaps in research concerning the determination of sample size in matched‐pair CRTs with incomplete binary outcomes. One conventional method for adjusting for missing data in the sample size determination is to divide the sample size under complete data by the expected follow‐up rate. However, such crude adjustment ignores the impact of the structure and strength of correlations regarding both outcome data and missing data mechanism. This article provides a closed‐form sample size formula for matched‐pair CRTs with incomplete binary outcomes, which appropriately accounts for different missing patterns and magnitudes as well as the effects of matching and clustering on the outcome and missing data. The generalized estimating equation (GEE) approach treats incomplete observations as missing data in a marginal logistic regression model, which flexibly accommodates various types of intraclass correlation, missing patterns, and missing proportions. In the presence of missing data, the proposed GEE sample size method provides higher accuracy as compared with the conventional method. The performance of the proposed method is assessed by simulation studies. This article also illustrates how the proposed method can be used to design a real‐world matched‐pair CRT to examine the effect of a team‐based approach on controlling blood pressure (BP).

The original version of this article unfortunately contained mistakes. The captured article title and corresponding author were incorrect. The correct information are as follows: 1. The article title should be: BPACAP/PAC1 Regulation of Inflammation via Catecholaminergic Neurons in a Model of Multiple Sclerosis2 .