There has been extensive progress in understanding the cellular and molecular mechanisms of inflammation and immune regulation in allergic diseases of the skin and lungs during the last few years. Asthma and atopic dermatitis (AD) are typical diseases of type 2 immune responses. interleukin (IL)-25, IL-33, and thymic stromal lymphopoietin are essential cytokines of epithelial cells that are activated by allergens, pollutants, viruses, bacteria, and toxins that derive type 2 responses. Th2 cells and innate lymphoid cells (ILC) produce and secrete type 2 cytokines such as IL-4, IL-5, IL-9, and IL-13. IL-4 and IL-13 activate B cells to class-switch to IgE and also play a role in T-cell and eosinophil migration to allergic inflammatory tissues. IL-13 contributes to maturation, activation, nitric oxide production and differentiation of epithelia, production of mucus as well as smooth muscle contraction, and extracellular matrix generation. IL-4 and IL-13 open tight junction barrier and cause barrier leakiness in the skin and lungs. IL-5 acts on activation, recruitment, and survival of eosinophils. IL-9 contributes to general allergic phenotype by enhancing all of the aspects, such as IgE and eosinophilia. Type 2 ILC contribute to inflammation in AD and asthma by enhancing the activity of Th2 cells, eosinophils, and their cytokines. Currently, five biologics are licensed to suppress type 2 inflammation via IgE, IL-5 and | 1583 AKDIS et Al. 1 | INTRODUC TI ON Allergic diseases cause significant morbidity and mortality with almost one billion cases, accounting for a significant portion of overall healthcare costs. The dysregulated immune response, chronic inflammation, and remodeling in the affected tissues define a dynamic and heterogeneous spectrum of anaphylaxis, food allergy, asthma, allergic rhinitis, chronic rhinosinusitis with nasal polyposis (CRSwNP), and atopic dermatitis (AD). Two main subtypes of immune responses driving asthma and AD have been defined, namely type 2-high and type 2-low. 1-4 Precision medicine and biomarker discovery is important for the management of asthma and AD in the context of a better selection of good responders to treatment, prediction of outcomes, and design of disease-modifying strategies. Progress has been made in profiling the type 2 immune response-driven diseases. In contrast, the non-type 2 immune response in asthma and AD is insufficiently understood. The majority of patients with AD, CRS and asthma involve, or result from, an overexpression of type 2 inflammatory pathways (Figure 1). 5-7 A specific type 2 set of cytokines are produced during the induction and maintenance of allergic immune response with the contribution of epithelial cells, dendritic cells (DC), T cells, innate lymphoid cells (ILC), eosinophils, mast cells (MC), and basophils. Activation of Th2 and ILC2 pathways is at the core of type 2 inflammation. Th2 cytokines include interleukin (IL)-4, IL-5, IL-9, IL-13, and IL-31, and main type 2 cytokines of ILC2 are IL-5, IL-9, and IL-13. 8,9 IL-4 induces Th2 cell di...

MethodsLiterature search timeframe: The references cited in the previous guidelines [1] are not repeated here, except for some relevant publications, and only the previous guidelines are cited instead. All publications published after the previous guidelines (i.e., from January 2004 to December 2014), have been considered for the first draft of this manuscript. Randomized controlled trials (RCTs), review articles, prospective studies and meta-analyses published in 2015 and 2016, during the revision process, have also been considered.Type of publications: Original papers, meta-analyses and reviews.

Deep brain stimulation in the subthalamic nucleus is an effective and safe surgical procedure that has been shown to reduce the motor dysfunction of patients with advanced Parkinson's disease. Bilateral subthalamic nucleus deep brain stimulation, however, has been associated with declines in cognitive and cognitive-motor functioning. It has been hypothesized that spread of current to nonmotor areas of the subthalamic nucleus may be responsible for declines in cognitive and cognitive-motor functioning. The aim of this study was to assess the cognitive-motor performance in advanced Parkinson's disease patients with subthalamic nucleus deep brain stimulation parameters determined clinically (Clinical) to settings derived from a patient-specific computational model (Model). Data were collected from 10 patients with advanced Parkinson's disease bilaterally implanted with subthalamic nucleus deep brain stimulation systems. These patients were assessed off medication and under three deep brain stimulation conditions: Off, Clinical or Model based stimulation. Clinical stimulation parameters had been determined based on clinical evaluations and were stable for at least 6 months prior to study participation. Model-based parameters were selected to minimize the spread of current to nonmotor portions of the subthalamic nucleus using Cicerone Deep Brain Stimulation software. For each stimulation condition, participants performed a working memory (n-back task) and motor task (force tracking) under single- and dual-task settings. During the dual-task, participants performed the n-back and force-tracking tasks simultaneously. Clinical and Model parameters were equally effective in improving the Unified Parkinson's disease Rating Scale III scores relative to Off deep brain stimulation scores. Single-task working memory declines, in the 2-back condition, were significantly less under Model compared with Clinical deep brain stimulation settings. Under dual-task conditions, force tracking was significantly better with Model compared with Clinical deep brain stimulation. In addition to better overall cognitive-motor performance associated with Model parameters, the amount of power consumed was on average less than half that used with the Clinical settings. These results indicate that the cognitive and cognitive-motor declines associated with bilateral subthalamic nucleus deep brain stimulation may be reversed, without compromising motor benefits, by using model-based stimulation parameters that minimize current spread into nonmotor regions of the subthalamic nucleus.