Modeling Cues May Reduce Sway Following Sit-To-Stand Transfer for People with Parkinson's Disease.

Cues are commonly used to overcome the effects of motor symptoms associated with Parkinson's disease. Little is known about the impact of cues on postural sway during transfers. The objective of this study was to identify if three different types of explicit cues provided during transfers of people with Parkinson's disease results in postural sway more similar to healthy controls. This crossover study had 13 subjects in both the Parkinson's and healthy control groups. All subjects completed three trials of uncued sit to stand transfers. The Parkinson's group additionally completed three trials of sit to stand transfers in three conditions: external attentional focus of reaching to targets, external attentional focus of concurrent modeling, and explicit cue for internal attentional focus. Body worn sensors collected sway data, which was compared between groups with Mann Whitney U tests and between conditions with Friedman's Tests. Sway normalized with modeling but was unchanged in the other conditions. Losses of balance presented with reaching towards targets and cueing for an internal attentional focus. Modeling during sit to stand of people with Parkinson's disease may safely reduce sway more than other common cues.

Implementing Full Practice Authority for Advanced Practice Registered Nurses: A Case for Mitigating Critical Mental Health Services.

The COVID-19 pandemic has highlighted some perverse health disparities that we know have long existed in the United States. Disparities related to access, affordability, and cultural appropriateness of care cannot be overemphasized. More importantly, disparities related to provider shortages continue to contribute to adverse patient outcomes, particularly in rural areas and other socioeconomically deprived communities. Despite the push from the National Council of State Boards of Nursing (NCSBN) to ensure adoption and implementation of full practice authority (FPA) of advanced practice registered nurses (APRNs), currently only 28 states in the United States have achieved this goal. In addition, there are some states such as Florida that recently passed legislation supporting FPA for primary care APRNs, yet still have practice restrictions for specialty APRNs, such as mental health. The evidence is clear that patients managed by APRNs have better or comparable outcomes to those managed by physicians; thus, more advocacy is needed to ensure that all states and territories achieve this very important milestone for the profession as it has the potential to foster a collaborative interdisciplinary approach to patient care, which at the same time produces positive patient outcomes, employee satisfaction, and a work environment in which all members of the care team feel valued and autonomous.

Emergency medical care of incarcerated patients: Opportunities for improvement and cost savings.

In the United States (US), the lifetime incidence of incarceration is 6.6%, exceeding that of any other nation. Compared to the general US population, incarcerated individuals are disproportionally affected by chronic health conditions, mental illness, and substance use disorders. Barriers to accessing medical care are common in correctional facilities. We sought to characterize the local incarcerated patient population and explore barriers to medical care in these patients. We conducted a retrospective, observational cohort study by reviewing the medical records of incarcerated patients presenting to the adult emergency department (ED) of a single academic, tertiary care facility with medical or psychiatric (med/psych) and trauma-related emergencies between January 2012 and December 2014. Data on demographics, medical complexity, trauma intentionality, and barriers to medical care were analyzed using descriptive statistics, unpaired student's t-test or one-way analysis of variance for continuous variables, and chi-square analysis or Fisher's exact test as appropriate. Trauma patients were younger with fewer medical comorbidities and were less likely to be admitted to the hospital than med/psych patients. 47.8% of injuries resulted from violence or were self-inflicted. Most trauma-related complaints were managed by the emergency medicine physician in the ED. While barriers to medical care were not correlated with hospital admission, 5.4% of med/psych and 2.9% of trauma patients reported barriers as a contributing factor to the ED encounter. Med/psych patients commonly reported a lack of access to medications, while trauma patients reported a delay in medical care. Trauma-related presentations were less medically complex than med/psych-related complaints. Medical management of most injuries required no hospital resources outside of the ED, indicating a potential role for outpatient management of trauma-related complaints. Additional opportunities for health care improvement and cost savings include the implementation of programs that target violence, prevent injuries, and promote the continuity of medical care while incarcerated.

Aligning mouse models of asthma to human endotypes of disease.

Substantial gains in understanding the pathophysiologic mechanisms underlying asthma have been made using preclinical mouse models. However, because asthma is a complex, heterogeneous syndrome that is rarely due to a single allergen and that often presents in the absence of atopy, few of the promising therapeutics that demonstrated effectiveness in mouse models have translated into new treatments for patients. This has resulted in an urgent need to characterize T helper (Th) 2-low, non-eosinophilic subsets of asthma, to study models that are resistant to conventional treatments such as corticosteroids and to develop therapies targeting patients with severe disease. Classifying asthma based on underlying pathophysiologic mechanisms, known as endotyping, offers a stratified approach for the development of new therapies for asthma. In preclinical research, new models of asthma are being utilized that more closely resemble the clinical features of different asthma endotypes, including the presence of interleukin-17 and a Th17 response, a biomarker of severe disease. These models utilize more physiologically relevant sensitizing agents, exacerbating factors and allergens, as well as incorporate time points that better reflect the natural history and chronicity of clinical asthma. Importantly, some models better represent non-classical asthma endotypes that facilitate the study of non-Th2-driven pathology and resemble the complex nature of clinical asthma, including corticosteroid resistance. Placing mouse asthma models into the context of human asthma endotypes will afford a more relevant approach to the understanding of pathophysiological mechanisms of disease that will afford the development of new therapies for those asthmatics that remain difficult to treat.

Inflammasome Activity in Non-Microbial Lung Inflammation.

The understanding of interleukin-1 (IL-1) family cytokines in inflammatory disease has rapidly developed, due in part to the discovery and characterization of inflammasomes, which are multi-subunit intracellular protein scaffolds principally enabling recognition of a myriad of cellular stimuli, leading to the activation of caspase-1 and the processing of IL-1ß and IL-18. Studies continue to elucidate the role of inflammasomes in immune responses induced by both microbes and environmental factors. This review focuses on the current understanding of inflammasome activity in the lung, with particular focus on the non-microbial instigators of inflammasome activation, including inhaled antigens, oxidants, cigarette smoke, diesel exhaust particles, mineral fibers, and engineered nanomaterials, as well as exposure to trauma and pre-existing inflammatory conditions such as metabolic syndrome. Inflammasome activity in these sterile inflammatory states contribute to diseases including asthma, chronic obstructive disease, acute lung injury, ventilator-induced lung injury, pulmonary fibrosis, and lung cancer.

Antigen-induced mast cell expansion and bronchoconstriction in a mouse model of asthma.

Lung mastocytosis and antigen-induced bronchoconstriction are common features in allergic asthmatics. It is therefore important that animal models of asthma show similar features of mast cell inflammation and reactivity to inhaled allergen. We hypothesized that house dust mite (HDM) would induce mastocytosis in the lung and that inhalation of HDM would trigger bronchoconstriction. Mice were sensitized with intranasal HDM extract, and the acute response to nebulized HDM or the mast cell degranulating compound 48/80 was measured with respiratory input impedance. Using the constant-phase model we calculated Newtonian resistance (Rn) reflecting the conducting airways, tissue dampening (G), and lung elastance (H). Bronchoalveolar lavage fluid was analyzed for mouse mast cell protease-1 (mMCP-1). Lung tissue was analyzed for cytokines, histamine, and α-smooth muscle actin (α-SMA), and histological slides were stained for mast cells. HDM significantly increased Rn but H and G remained unchanged. HDM significantly expanded mast cells compared with control mice; at the same time mMCP-1, α-SMA, Th2 cytokines, and histamine were significantly increased. Compound 48/80 inhalation caused bronchoconstriction and mMCP-1 elevation similarly to HDM inhalation. Bronchoconstriction was eliminated in mast cell-deficient mice. We found that antigen-induced acute bronchoconstriction has a distinct phenotype in mice. HDM sensitization caused lung mastocytosis, and we conclude that inhalation of HDM caused degranulation of mast cells leading to an acute bronchoconstriction without affecting the lung periphery and that mast cell-derived mediators are responsible for the development of the HDM-induced bronchoconstriction in this model.

The endogenous Th17 response in NO2-promoted allergic airway disease is dispensable for airway hyperresponsiveness and distinct from Th17 adoptive transfer.

Severe, glucocorticoid-resistant asthma comprises 5-7% of patients with asthma. IL-17 is a biomarker of severe asthma, and the adoptive transfer of Th17 cells in mice is sufficient to induce glucocorticoid-resistant allergic airway disease. Nitrogen dioxide (NO2) is an environmental toxin that correlates with asthma severity, exacerbation, and risk of adverse outcomes. Mice that are allergically sensitized to the antigen ovalbumin by exposure to NO2 exhibit a mixed Th2/Th17 adaptive immune response and eosinophil and neutrophil recruitment to the airway following antigen challenge, a phenotype reminiscent of severe clinical asthma. Because IL-1 receptor (IL-1R) signaling is critical in the generation of the Th17 response in vivo, we hypothesized that the IL-1R/Th17 axis contributes to pulmonary inflammation and airway hyperresponsiveness (AHR) in NO2-promoted allergic airway disease and manifests in glucocorticoid-resistant cytokine production. IL-17A neutralization at the time of antigen challenge or genetic deficiency in IL-1R resulted in decreased neutrophil recruitment to the airway following antigen challenge but did not protect against the development of AHR. Instead, IL-1R-/- mice developed exacerbated AHR compared to WT mice. Lung cells from NO2-allergically inflamed mice that were treated in vitro with dexamethasone (Dex) during antigen restimulation exhibited reduced Th17 cytokine production, whereas Th17 cytokine production by lung cells from recipient mice of in vitro Th17-polarized OTII T-cells was resistant to Dex. These results demonstrate that the IL-1R/Th17 axis does not contribute to AHR development in NO2-promoted allergic airway disease, that Th17 adoptive transfer does not necessarily reflect an endogenously-generated Th17 response, and that functions of Th17 responses are contingent on the experimental conditions in which they are generated.

Histamine H(3) receptor integrates peripheral inflammatory signals in the neurogenic control of immune responses and autoimmune disease susceptibility.

Histamine H(3) receptor (Hrh3/H(3)R) is primarily expressed by neurons in the central nervous system (CNS) where it functions as a presynaptic inhibitory autoreceptor and heteroreceptor. Previously, we identified an H(3)R-mediated central component in susceptibility to experimental allergic encephalomyelitis (EAE), the principal autoimmune model of multiple sclerosis (MS), related to neurogenic control of blood brain barrier permeability and peripheral T cell effector responses. Furthermore, we identified Hrh3 as a positional candidate for the EAE susceptibility locus Eae8. Here, we characterize Hrh3 polymorphisms between EAE-susceptible and resistant SJL and B10.S mice, respectively, and show that Hrh3 isoform expression in the CNS is differentially regulated by acute peripheral inflammatory stimuli in an allele-specific fashion. Next, we show that Hrh3 is not expressed in any subpopulations of the immune compartment, and that secondary lymphoid tissue is anatomically poised to be regulated by central H(3)R signaling. Accordingly, using transcriptome analysis, we show that, inflammatory stimuli elicit unique transcriptional profiles in the lymph nodes of H(3)RKO mice compared to WT mice, which is indicative of negative regulation of peripheral immune responses by central H(3)R signaling. These results further support a functional link between the neurogenic control of T cell responses and susceptibility to CNS autoimmune disease coincident with acute and/or chronic peripheral inflammation. Pharmacological targeting of H(3)R may therefore be useful in preventing the development and formation of new lesions in MS, thereby limiting disease progression.

Interleukin-1 receptor and caspase-1 are required for the Th17 response in nitrogen dioxide-promoted allergic airway disease.

Nitrogen dioxide (NO2) is an environmental pollutant and endogenously generated oxidant associated with the development, severity, and exacerbation of asthma. NO2 exposure is capable of allergically sensitizing mice to the innocuous inhaled antigen ovalbumin (OVA), promoting neutrophil and eosinophil recruitment, and a mixed Th2/Th17 response upon antigen challenge that is reminiscent of severe asthma. However, the identity of IL-17A-producing cells and the mechanisms governing their ontogeny in NO2-promoted allergic airway disease remain unstudied. We measured the kinetics of lung inflammation after antigen challenge in NO2-promoted allergic airway disease, including inflammatory cells in bronchoalveolar lavage and antigen-specific IL-17A production from the lung. We determined that IL-17A(+) cells were predominately CD4(+)T cell receptor (TCR)ß(+) Th17 cells, and that a functional IL-1 receptor was required for Th17, but not Th2, cytokine production after in vitro antigen restimulation of lung cells. The absence of natural killer T cells, γδ T cells, or the inflammasome scaffold nucleotide-binding oligomerization domain, leucine rich repeat and pyrin domain (Nlrp)3 did not affect the development of NO2-promoted allergic inflammation or IL-17A production. Similarly, neutrophil depletion or the neutralization of IL-1α during sensitization exerted no effect on these parameters. However, the absence of caspase-1 significantly reduced IL-17A production from lung cells without affecting Th2 cytokines or lung inflammation. Finally, the intranasal administration of IL-1ß and the inhalation of antigen promoted allergic sensitization that was reflected by neutrophilic airway inflammation and IL-17A production from CD4(+)TCRß(+) Th17 cells subsequent to antigen challenge. These data implicate a role for caspase-1 and IL-1ß in the IL-1 receptor-dependent Th17 response manifest in NO2-promoted allergic airway disease.