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There are multiple FDA-approved biologics to treat poorly controlled moderate-to-severe asthma. Given the heterogeneity of asthma and the lack of head-to-head data between biologics, selecting the best biologic for a patient can be difficult. This review summarizes the key literature to date, in hopes of facilitating an evidence-based approach to selecting the most appropriate biologic for patients with asthma.In addition to unique mechanisms of action, there is increasing literature on predictors of response to each biologic, such as sensitizations to aeroallergens, peripheral eosinophil count, total serum IgE, and exhaled nitric oxide. Biologics available for asthma are also being increasingly studied in comorbid conditions with asthma, and this may facilitate selecting the most appropriate biologic for a patient. In the absence of head-to-head studies, there is literature of switching between biologics whenever necessary.The authors outline an approach to selecting a biologic based on various considerations, and hope this suggested approach facilitates selecting the biologic most suitable for each individual with poorly controlled moderate-to-severe asthma.

Background: The fractional exhaled nitric oxide (FENO) test is a point-of-care test that is used in the assessment of asthma.Objective: To provide evidence-based clinical guidance on whether FENO testing is indicated to optimize asthma treatment in patients with asthma in whom treatment is being considered.Methods: An international, multidisciplinary panel of experts was convened to form a consensus document regarding a single question relevant to the use of FENO. The question was selected from three potential questions based on the greatest perceived impact on clinical practice and the unmet need for evidencebased answers related to this question. The panel performed systematic reviews of published randomized controlled trials between 2004 and 2019 and followed the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) evidence-to-decision framework to develop recommendations. All panel members evaluated and approved the recommendations.Main Results: After considering the overall low quality of the evidence, the panel made a conditional recommendation for FENO-based care. In patients with asthma in whom treatment is being considered, we suggest that FENO is beneficial and should be used in addition to usual care. This judgment is based on a balance of effects that probably favors the intervention; the moderate costs and availability of resources, which probably favors the intervention; and the perceived acceptability and feasibility of the intervention in daily practice.Conclusions: Clinicians should consider this recommendation to measure FENO in patients with asthma in whom treatment is being considered based on current best available evidence.

Oral corticosteroid (OCS) use in severe asthma remains all too common despite advances in asthma treatment. Use of OCS is associated with significant toxicity that can have a lasting adverse impact on a patient's overall health. Monoclonal antibodies have been developed that reduce both the rate of occurrence of OCS-treated exacerbations and the OCS requirements in patients with oral corticosteroid-dependent asthma. This article describes strategies to prevent and best manage endocrine complications associated with OCS use and provides guidance on OCS dose management after the introduction of steroid-sparing therapies. (1) We identify OCS-dependent patients and assess for comorbidities including bone health, glycemic control, and adrenal function; (2) we begin attempts at OCS dose optimization before or soon after introducing a steroid-sparing biologic therapy; (3) we taper OCS, using explicit criteria for asthma control; (4) we assess hypothalamic-pituitary-adrenal axis integrity once a physiologic dose of OCS is achieved to guide further the rate of OCS taper; and (5) we manage corticosteroid-related comorbidities as detailed in this article.

This document provides clinical recommendations for the management of severe asthma. Comprehensive evidence syntheses, including metaanalyses, were performed to summarise all available evidence relevant to the European Respiratory Society/American Thoracic Society Task Force’s questions. The evidence was appraised using the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach and the results were summarised in evidence profiles. The evidence syntheses were discussed and recommendations formulated by a multidisciplinary Task Force of asthma experts, who made specific recommendations on six specific questions. After considering the balance of desirable and undesirable consequences, quality of evidence, feasibility, and acceptability of various interventions, the Task Force made the following recommendations:• suggest using anti-interleukin (IL)-5 and anti-IL-5 receptor α for severe uncontrolled adult eosinophilic asthma phenotypes;• suggest using a blood eosinophil cut-point ≥150 μL−1 to guide anti-IL-5 initiation in adult patients with severe asthma;• suggest considering specific eosinophil (≥260 μL−1) and exhaled nitric oxide fraction (≥19.5 ppb) cut-offs to identify adolescents or adults with the greatest likelihood of response to anti-IgE therapy;• suggest using inhaled tiotropium for adolescents and adults with severe uncontrolled asthma despite Global Initiative for Asthma (GINA) step 4 – 5 or National Asthma Education and Prevention Program (NAEPP) step 5 therapies;• suggest a trial of chronic macrolide therapy to reduce asthma exacerbations in persistently symptomatic or uncontrolled patients on GINA step 5 or NAEPP step 5 therapies, irrespective of asthma phenotype;• suggest using anti-IL-4/13 for adult patients with severe eosinophilic asthma and for those with severe corticosteroid-dependent asthma regardless of blood eosinophil levels.These recommendations should be reconsidered as new evidence becomes available.

The exposure of ionizing radiation during early gestation often leads to deleterious and even lethal effects; however, few extensive studies have been conducted on late gestational exposures. This research examined the behavior al effects of C57Bl/6J mouse offspring exposed to low dose ionizing gamma irradiation during the equivalent third trimester. Pregnant dams were randomly assigned to sham or exposed groups to either low dose or sublethal dose radiation (50, 300, or 1000 mGy) at gestational day 15. Adult offspring underwent a behavioral and genetic analysis after being raised under normal murine housing conditions. Our results indicate very little change in the behavioral tasks measuring general anxiety, social anxiety, and stress-management in animals exposed prenatally across the low dose radiation conditions. Quantitative real-time polymerase chain reactions were conducted on the cerebral cortex, hippocampus, and cerebellum of each animal; results indicate some dysregulation in markers of DNA damage, synaptic activity, reactive oxygen species (ROS) regulation, and methylation pathways in the offspring. Together, our results provide evidence in the C57Bl/6J strain, that exposure to sublethal dose radiation (

Confirmation of effectiveness of asthma biologics in the real world is desirable because patient characteristics and experiences may differ from those included in randomized controlled trials.To evaluate real-world effectiveness of asthma biologics and identify predictors of response.We performed a retrospective study in patients with severe asthma receiving biologics. The primary outcome was change in clinically significant exacerbations at 12 months after starting biologic therapy, compared with 12 months before. Secondary outcomes were change in severe exacerbations, maintenance oral corticosteroid (OCS) dose, prebronchodilator forced expiratory volume in 1 second (FEV1), and asthma control test scores. Subgroup analyses were performed for subjects who were biologic naive or not. A stepwise logistic regression model was performed to compare responders to nonresponders.A total of 112 patients were included. Biologic therapy was associated with a 59% reduction in clinically significant exacerbations (P.001), 65% reduction in severe exacerbations (P.001), and 54% reduction in maintenance OCS dose (P = .001) in the 12 months after starting therapy. Biologics also resulted in improvement in prebronchodilator FEV1 (P = .002) and Asthma Control Test score (P.001). Subjects who were previously on another biologic also experienced significant improvements in exacerbation frequency, maintenance OCS dose, and asthma control. Responders were more likely to be nonsmokers and have higher baseline FEV1, gastroesophageal reflux disease, and eosinophil counts greater than 500 cells/μL.In a real-world setting, biologic therapy in asthma is effective in improving exacerbations, asthma control, and lung function. Patients who have a suboptimal response to 1 biologic can still benefit from treatment with a different biologic.

Respiratory symptoms are common reasons for patients to seek care and contribute significantly to use of health care resources. Identifying the underlying etiology of a respiratory symptom is key to management; yet, pinpointing the cause can be a challenge. Familiarity with the tools available to help discern between the various contributing etiologies is crucial in guiding management. Assessment and quantification of pulmonary function can provide an objective measure to guide diagnosis and therapy. We review key points of pulmonary function evaluation, highlighting indications and contraindications, fundamentals of interpretation, and the limitations of each individual component.

Introduction Electromagnetic navigation bronchoscopy (ENB) is a minimally invasive technology that guides endoscopic tools to pulmonary lesions. ENB has been evaluated primarily in small, single-center studies; thus, the diagnostic yield in a generalizable setting is unknown. Methods NAVIGATE is a prospective, multicenter, cohort study that evaluated ENB using the superDimension navigation system (Medtronic, Minneapolis, Minnesota). In this United States cohort analysis, 1215 consecutive subjects were enrolled at 29 academic and community sites from April 2015 to August 2016. Results The median lesion size was 20.0 mm. Fluoroscopy was used in 91% of cases (lesions visible in 60%) and radial endobronchial ultrasound in 57%. The median ENB planning time was 5 minutes; the ENB-specific procedure time was 25 minutes. Among 1157 subjects undergoing ENB-guided biopsy, 94% (1092 of 1157) had navigation completed and tissue obtained. Follow-up was completed in 99% of subjects at 1 month and 80% at 12 months. The 12-month diagnostic yield was 73%. Pathology results of the ENB-aided tissue samples showed malignancy in 44% (484 of 1092). Sensitivity, specificity, positive predictive value, and negative predictive value for malignancy were 69%, 100%, 100%, and 56%, respectively. ENB-related Common Terminology Criteria for Adverse Events grade 2 or higher pneumothoraces (requiring admission or chest tube placement) occurred in 2.9%. The ENB-related Common Terminology Criteria for Adverse Events grade 2 or higher bronchopulmonary hemorrhage and grade 4 or higher respiratory failure rates were 1.5% and 0.7%, respectively. Conclusions NAVIGATE shows that an ENB-aided diagnosis can be obtained in approximately three-quarters of evaluable patients across a generalizable cohort based on prospective 12-month follow-up in a pragmatic setting with a low procedural complication rate.

Introduction Fetal programming was characterized a few decades ago, explaining the correlation of physiological phenotypes of offspring exposed to early‐life stress. High acute or chronic prenatal stress can overwhelm the enzymatic placental barrier, inducing transcriptional changes in the fetus that can result in different adverse behavioral and physiological phenotypes. The current study investigates the impact of exposure to the synthetic glucocorticoid, dexamethasone, during late gestation on behavioral outcomes. Methods Pregnant Wistar Kyoto rats were given daily subcutaneous injections from gestational days 15–21 of either dexamethasone (0.9% NaCl, 4% EtOH, 100 µg kg−1 day−1) or were physically manipulated as naïve controls. Pups were raised normally until 17 weeks of age and underwent the Porsolt swim task and elevated plus maze for depressive and anxiety‐like behaviors, respectively. Neural tissue was preserved for genetic analysis using quantitative real‐time polymerase chain reaction. Results Statistical analyses show significant disruption of behavior and genetic profiles of offspring exposed to dexamethasone in‐utero. Exposed animals spent more time immobile on the swim task and entered open arms of the elevated plus maze more often than their naïve counterparts. In the prefrontal cortex, there was a sex by treatment interaction on gene expression relevant to neural transmission in ryanodine receptor 2, as well as increased gene expression in SNAP25, COMT, and LSAMP in males prenatally exposed to dexamethasone compared with controls. Both dysregulated genes and behavior are linked to decreased anxiety and fear inhibition. Conclusion Our results indicate adult offspring exposed to dexamethasone in‐utero have a tendency toward passive stress‐coping strategies and an inhibition of anxiety on behavioral tasks. Methyltransferase activity, synaptic activity, and cellular processes were disrupted in the prefrontal cortices of these animals. Specifically, genes involved in emotional response pathways were overexpressed, supporting the link between the behavioral and genetic profiles. Combined, we determine that dexamethasone offspring have adaptive predispositions when faced with novel situations, with increased immobility in the swim task and increased exploration on the elevated plus maze., This study examined the impact of prenatal exposure to the synthetic glucocorticoids on postnatal adult behavior. Behavioral tasks used to examine the anxiety and stress‐coping strategies. (A) Elevated plus maze. (B) Porsolt swim task.

The field of cardiovascular fetal programming has emphasized the importance of the uterine environment on postnatal cardiovascular health. Studies have linked increased fetal glucocorticoid exposure, either from exogenous sources (such as dexamethasone (Dex) injections), or from maternal stress, to the development of adult cardiovascular pathologies. Although the mechanisms are not fully understood, alterations in gene expression driven by altered oxidative stress and epigenetic pathways are implicated in glucocorticoid-mediated cardiovascular programming. Antioxidants, such as the naturally occurring polyphenol epigallocatechin gallate (EGCG), or the superoxide dismutase (SOD) 4-hydroxy-TEMPO (TEMPOL), have shown promise in the prevention of cardiovascular dysfunction and programming. This study investigated maternal antioxidant administration with EGCG or TEMPOL and their ability to attenuate the fetal programming of hypertension via Dex injections in WKY rats. Results from this study indicate that, while Dex-programming increased blood pressure in male and female adult offspring, administration of EGCG or TEMPOL via maternal drinking water attenuated Dex-programmed increases in blood pressure, as well as changes in adrenal mRNA and protein levels of catecholamine biosynthetic enzymes phenylalanine hydroxylase (PAH), tyrosine hydroxylase (TH), dopamine beta hydroxylase (DBH), and phenylethanolamine N-methyltransferase (PNMT), in a sex-specific manner. Furthermore, programmed male offspring displayed reduced antioxidant glutathione peroxidase 1 (Gpx1) expression, increased superoxide dismutase 1 (SOD1) and catalase (CAT) expression, and increased pro-oxidant NADPH oxidase activator 1 (Noxa1) expression in the adrenal glands. In addition, prenatal Dex exposure alters expression of epigenetic regulators histone deacetylase (HDAC) 1, 5, 6, 7, 11, in male and HDAC7 in female offspring. These results suggest that glucocorticoids may mediate the fetal programming of hypertension via alteration of epigenetic machinery and oxidative stress pathways.

Background Treatments for long-term control of asthma have improved and include a promising but expensive class of biologic therapies. However, the clinical trials evaluating these and other novel treatments have used a variety of different outcomes to evaluate efficacy. The evolution of asthma care calls for a re-examination of outcomes that are most important to patients and other stakeholders. Objective To develop a core set of outcomes to be measured in phase 3 and phase 4 clinical drug trials in patients with moderate-to-severe asthma. Methods We used a robust and in-depth multistakeholder consensus process bringing together patients, clinicians, regulators, payers, health technology assessors, researchers, and product developers to reach consensus on outcomes. We used a modified Delphi method to reach consensus, an approach adapted from the Core Outcome Measures in Effectiveness Trials Initiative aligned with contemporary methodological standards for core outcome set development. Results The following outcomes were included in the final core set: severe asthma exacerbation, change in asthma control, asthma-specific or severe asthma-specific quality of life, asthma-specific hospital stay (ie, >24-hour stays at any level of care) or admission, and asthma-specific emergency department visit. Conclusion These 5 outcomes represent a minimum set of core outcomes for use in phase 3 and phase 4 clinical drug trials in moderate-to-severe asthma. Consistent collection of these outcomes as minimum, independent of whether additional heterogeneous primary or secondary outcomes are included, will allow for meaningful comparisons of the effect of asthma therapies across clinical trials.

Prenatal glucocorticoid exposure is associated with the development of hypertension in adults. We have previously demonstrated that antenatal dexamethosone (DEX) administration in Wistar-Kyoto dams results in offspring with increased blood pressure coupled with elevated plasma epinephrine levels. In order to elucidate the molecular mechanisms responsible for prenatal DEX-mediated programming of hypertension, a whole-transcriptome analysis was performed on DEX programmed WKY male adrenal glands using the Rat Gene 2.0 microarray. Differential gene expression (DEG) analysis of DEX-exposed offspring compared with saline-treated controls revealed 142 significant DEGs (109 upregulated and 33 downregulated genes). DEG pathway enrichment analysis demonstrated that genes involved in circadian rhythm signaling were most robustly dysregulated. RT-qPCR analysis confirmed the increased expression of circadian genes Bmal1 and Npas2, while Per2, Per3, Cry2 and Bhlhe41 were significantly downregulated. In contrast, gene expression profiling of Spontaneously Hypertensive (SHR) rats, a genetic model of hypertension, demonstrated decreased expression of Bmal1 and Npas2, while Per1, Per2, Per3, Cry1, Cry2, Bhlhe41 and Csnk1D were all upregulated compared to naïve WKY controls. Taken together, this study establishes that glucocorticoid programmed adrenals have impaired circadian signaling and that changes in adrenal circadian rhythm may be an underlying molecular mechanism responsible for the development of hypertension.

Asthma-chronic obstructive pulmonary disease (COPD) overlap (ACO) defines a subgroup of patients with asthma who have persistent airflow obstruction or patients with COPD who may exhibit variable airflow limitation and/or evidence of type 2 inflammation. Additional investigations are needed to determine whether ACO represents a distinct disorder with unique underlying pathophysiology, whether ACO patients should be managed differently from those with asthma or COPD, and whether the diagnosis affects long-term outcomes. This article presents the data about the clinical features of ACO, the current information regarding the underlying pathophysiology of the syndrome, and current understanding of therapeutic options.

Educational aims This article is mainly intended for trainees and specialists who are interested in the management of severe asthma. It aims to inform readers about the updated ERS/ATS recommendations for management of severe asthma, specifically on the topics of biologics, macrolides and long-acting muscarinic antagonists.It also provides guidance on utilisation of available biomarkers in selecting advanced therapies in severe asthma., This article summarises the 2019 @EuroRespSoc/@ATScommunity Severe Asthma Task Force recommendations on the use of anti-IL-5 strategy, anti-IL-4/13 antibody, tiotropium and macrolides in severe asthma, and the role of biomarkers in directing therapy https://bit.ly/3braK43

Extraction of RNA from neural sections and complimentary DNA synthesis. This technique has been replicated multiple times in our laboratory and produces high yield.

The causes of hypertension are complex and involve both genetic and environmental factors. Environment changes during fetal development have been linked to adult diseases including hypertension. Studies show that timed in utero exposure to the synthetic glucocorticoid (GC) dexamethasone (Dex) results in the development of hypertension in adult rats. Evidence suggests that in utero stress can alter patterns of gene expression, possibly a result of alterations in the topology of the genome by epigenetic markers such as DNA methyltransferases (DNMTs) and histone deacetylases (HDACs). The objective of this study was to determine the effects of epigenetic regulators in the fetal programming and the development of adult hypertension. Specifically, this research examined the effects of the HDAC inhibitor valproic acid (VPA) and the DNMT inhibitor 5-aza-2′-deoxycytidine (5aza2DC) on blood pressure (BP) and gene expression in prenatal Dex-programmed rats. Data suggest that both VPA and 5aza2DC attenuated the Dex-mediated development of hypertension and restored BP to control levels. Epigenetic DNMT inhibition (DNMTi) or HDAC inhibition (HDACi) also successfully attenuated elevations in the majority of altered catecholamine (CA) enzyme expression, phenylethanolamine N-methyltransferase (PNMT) protein, and elevated epinephrine (Epi) levels in males. Although females responded to HDACi similar to males, DNMTi drove increased glucocorticoid receptor (GR) and PNMT expression and elevations in circulating Epi in females despite showing normotensive BP.

Bronchial thermoplasty (BT) is a novel, Food and Drug Administration-approved nondrug treatment for patients whose asthma remains uncontrolled despite traditional pharmacotherapy. BT involves application of controlled radiofrequency energy to reduce airway smooth muscle in large- and medium-sized airways. Although BT is often performed under general anesthesia, anesthetic management strategies for BT are poorly described. We describe the anesthetic management of 7 patients who underwent 19 BT treatments in a tertiary academic medical center.

Epidemiological studies show a strong correlation between Obstructive Sleep Apnea (OSA) and cardiovascular disorders. OSA patients experience intermittent hypoxia (IH), characterized by brief, but recurring episodes of cessation in breathing. These patients have higher levels of circulating catecholamines and an increased incidence of hypertension; however the mechanisms defining this association are not clearly established. Genetic linkage studies have associated the phenylethanolamine N-methyltransferase (PNMT) gene to the development of hypertension. PNMT, the terminal enzyme in the catecholamine biosynthetic pathway, directly responsible for adrenaline synthesis, is elevated in hypertensive animals. Recent studies utilizing PC12 cells show an increase in the expression of PNMT and its regulatory transcription factors when exposed to continuous hypoxia. The current study examined the regulation of PNMT under conditions of IH. The mRNA of PNMT was analyzed to assess if the regulation of PNMT expression entails alternative splicing. The mRNA and protein of transcription factors HIF1α, Egr-1, GR, and Sp1, were analyzed to assess the cellular pathways involved in regulating PNMT expression. A PNMT promoter-driven luciferase assay was performed to evaluate promoter activity under IH. Preliminary results lay an antecedent for the regulation of PNMT by IH conceivably via an altered regulation of its transcription factors and establish a possible role for PNMT in IH mediated hypertension in OSA patients.

BACKGROUND Confirmation of effectiveness of asthma biologics in the real world is desirable because patient characteristics and experiences may differ from those included in randomized controlled trials. OBJECTIVE To evaluate real-world effectiveness of asthma biologics and identify predictors of response. METHODS We performed a retrospective study in patients with severe asthma receiving biologics. The primary outcome was change in clinically significant exacerbations at 12 months after starting biologic therapy, compared with 12 months before. Secondary outcomes were change in severe exacerbations, maintenance oral corticosteroid (OCS) dose, prebronchodilator forced expiratory volume in 1 second (FEV1), and asthma control test scores. Subgroup analyses were performed for subjects who were biologic naive or not. A stepwise logistic regression model was performed to compare responders to nonresponders. RESULTS A total of 112 patients were included. Biologic therapy was associated with a 59% reduction in clinically significant exacerbations (P < .001), 65% reduction in severe exacerbations (P < .001), and 54% reduction in maintenance OCS dose (P = .001) in the 12 months after starting therapy. Biologics also resulted in improvement in prebronchodilator FEV1 (P = .002) and Asthma Control Test score (P < .001). Subjects who were previously on another biologic also experienced significant improvements in exacerbation frequency, maintenance OCS dose, and asthma control. Responders were more likely to be nonsmokers and have higher baseline FEV1, gastroesophageal reflux disease, and eosinophil counts greater than 500 cells/μL. CONCLUSION In a real-world setting, biologic therapy in asthma is effective in improving exacerbations, asthma control, and lung function. Patients who have a suboptimal response to 1 biologic can still benefit from treatment with a different biologic.

BACKGROUND The renal renin-angiotensin system (RAS) is physiologically important for blood pressure regulation. Altered regulation of RAS-related genes has been observed in an animal model of hypertension (spontaneously hypertensive rats - SHRs). The current understanding of certain RAS-related gene expression differences between Wistar-Kyoto rats (WKYs) and SHRs is either limited or has not been compared. The purpose of this study was to compare the regulation of key RAS-related genes in the kidneys of adult WKYs and SHRs. MATERIAL AND METHODS Coronal sections were dissected through the hilus of kidneys from 16-week-old male WKYs and SHRs. RT-PCR analysis was performed for Ace, Ace2, Agt, Agtr1a, Agtr1b, Agtr2, Atp6ap2 (PRR), Mas1, Ren, Rnls, and Slc12a3 (NCC). RESULTS Increased mRNA expression was observed for Ace, Ace2, Agt, Agtr1a, Agtr1b, and Atp6ap2 in SHRs compared to WKYs. Mas1, Ren, Slc12a3, and Rnls showed no difference in expression between animal types. CONCLUSIONS This study shows that the upregulation of several key RAS-related genes in the kidney may account for the increased blood pressure of adult SHRs.

Epinephrine is synthesised by the catecholamine biosynthetic enzyme, phenylethanolamine N-methyltransferase (PNMT), primarily in chromaffin cells of the adrenal medulla and secondarily in brainstem adrenergic neurons of the medulla oblongata. Epinephrine is an important neurotransmitter/neurohormone involved in cardiovascular regulation; however, overproduction is detrimental with negative outcomes such as cellular damage, cardiovascular dysfunction, and hypertension. Genetic mapping studies have linked elevated expression of PNMT to hypertension. Adrenergic neurons are responsible for blood pressure regulation and are the only PNMT containing neurons in the brainstem. The purpose of the current study was to determine whether elevated blood pressure found in adult spontaneously hypertensive rats (SHR) is associated with altered regulation of the PNMT gene in catecholaminergic neurons. C1, C2, and C3 adrenergic regions of 16 week old Wistar Kyoto (WKY) and SHR rats were excised using micropunch microdissection for mRNA expression analyses. Results from the current study confirm high PNMT mRNA expression in all three brainstem adrenergic regions (C1: 2.96-fold; C2: 2.17-fold; C3 1.20-fold) of the SHR compared to normotensive WKY rats. Furthermore, the immediate early gene transcription factor (Egr-1) mRNA was elevated in the C1 (1.84-fold), C2 (8.57-fold) and C3 (2.41-fold) regions in the brainstem of the SHR. Low mRNA expression for transcription factors Sp1 and GR was observed, while no change was observed for AP-2. The findings presented propose that alterations in the PNMT gene regulation in the brainstem contribute to enhanced PNMT production and epinephrine synthesis in the SHR, a genetic model of hypertension.

Severe asthma makes up for less than 10% of all asthma but is associated with disproportionately high healthcare costs. In 2019, asthma is not a one-size-fits-all disease. Heterogeneity in asthma is becoming increasingly evident. Not every patient with severe asthma has the same underlying pathophysiology or responds in a similar manner to targeted therapy. Keeping this in mind, a multidimensional and interdisciplinary approach to the management of severe asthma is desired. The role of patient-care teams in management of chronic diseases has become increasingly accepted, and this is particularly true for difficult or severe asthma. A high-risk asthma service can provide patients with state-of-the-art, evidence-based clinical management. This chapter provides an overview of complexities of “difficult-to-control” asthma and a practical systematic approach to its management.

Background: There are limited data that describe the association between markers of asthma control and depressive symptoms in severe asthma. Objective: To evaluate the association between depressive symptoms and markers of asthma control in patients with uncontrolled severe eosinophilic asthma. Methods: Baseline data from the MENSA and SIRIUS studies (N = 681) of mepolizumab intervention in severe eosinophilic asthma was used. We analyzed the relationships between depressive symptom severity by using the Beck Depression Inventory (BDI-II) and quality of life by using the St. George's Respiratory Questionnaire (SGRQ), asthma control questionnaire-5 (ACQ-5), polypharmacy, and sleep symptoms. Results: When compared with patients with less severe depressive symptoms, patients with more severe depressive symptoms were predominantly female (81% versus 54%), had a higher mean body mass index (30.56 versus 27.67 kg/m²), were more likely to have a blood eosinophil count of ≥300 cells/uL within the previous 12 months (81% versus 68%), and to have experienced a near-fatal asthma event (16% versus 7%). The mean SGRQ score was higher in the severe BDI-II category compared with the minimal depressive symptoms category, which indicated a worse quality of life (71.6 versus 41.4, p www.clinicaltrials.gov .

Purpose The goal of this study was to assess the long-term safety and efficacy of mepolizumab in patients with the most severe eosinophilic asthma. Methods This multicenter, open-label, long-term, Phase IIIb study (COSMEX [COSMOS Extension]; 201312/NCT02135692) enrolled patients from the 52-week, open-label extension study COSMOS (A Study to Determine Long-term Safety of Mepolizumab in Asthmatic Subjects) that previously enrolled patients from the double-blinded, placebo-controlled Phase III studies MENSA (Mepolizumab as Adjunctive Therapy in Patients with Severe Asthma) and SIRIUS (Steroid Reduction with Mepolizumab Study). To enter COSMEX, patients had to have life-threatening/seriously debilitating asthma before entering MENSA or SIRIUS and to have completed these previous studies with demonstrated improvement while receiving mepolizumab. In COSMEX, patients received mepolizumab 100 mg subcutaneously every 4 weeks as add-on therapy for up to 172 weeks. Primary endpoints were adverse event frequency and exacerbation rate per year; also assessed were forced expiratory volume in 1 s, Asthma Control Questionnaire-5 score, and daily oral corticosteroid (OCS) use. Findings Of the 340 patients enrolled, 339 received mepolizumab; median treatment duration within this extension study was 2.2 years, equating to 718 patient-years of additional exposure. No new safety signals were identified. Patients receiving mepolizumab throughout this study and previous studies had lasting reductions in exacerbation rate and daily OCS use and improvements in forced expiratory volume in 1 s and Asthma Control Questionnaire-5 score. In COSMEX, the on-treatment exacerbation rate (95% CI) was 0.93 (0.81–1.06) event/year for clinically significant exacerbations, 0.13 (0.10–0.18) event/year for exacerbations requiring hospitalization/emergency department visit, and 0.07 (0.05–0.10) event/year for exacerbations requiring hospitalization. In patients requiring systemic/oral corticosteroids with ≥128 weeks of continuous enrollment across SIRIUS, COSMOS, and COSMEX, mepolizumab maintained the median daily OCS dose at 1.3–2.8 mg during COSMEX, with additional patients no longer requiring OCS after extended mepolizumab treatment. Implications This study indicates that long-term mepolizumab treatment is well tolerated and associated with sustained clinical benefits in patients with severe eosinophilic asthma. ClinicalTrials.gov identifier: NCT02135692.

Asthma is a serious global health issue and asthma guidelines recommend a stepwise approach to management with goals to achieve control and minimize future risk. Prior to escalation of pharmacotherapy, steps to confirm accurate diagnosis as well as address comorbidities and triggers are critical to effective asthma management. This article provides readers with a structured approach to evaluation and management of asthma of varying severity.

Biochemical changes in utero may alter normal fetal development, resulting in disease later in life, a phenomenon known as fetal programming. Recent epidemiological studies link fetal programming to negative health outcomes, such as low birth weight and hypertension in adulthood. Here, we used a WKY rat model and studied the molecular changes triggered by prenatal glucocorticoid (GC) exposure on the development of hypertension, and on the regulation of phenylethanolamine N-methyl transferase (PNMT), the enzyme responsible for biosynthesis of epinephrine, and a candidate gene linked to hypertension. Clinically, high doses of the synthetic GC dexamethasone (DEX) are used to treat infant respiratory distress syndrome. Elevated maternal GCs have been correlated with fetal programming of hypertension. The aim of this study was to determine if lower doses of DEX would not lead to detrimental fetal programming effects such as hypertension. Our data suggests that prenatal stress programs for increased expression of PNMT and altered regulation of PNMT in males and females. Importantly, we identified that DEX mediated programming was more apparent in the male rats, and the lower dose 10μg/kg/day of DEX did not lead to changes in blood pressure (BP) in female rats suggesting that this dose is below the threshold for programming of hypertension. Furthermore, sex-specific differences were observed in regards to programming mechanisms that may account for hypertension in males.

Objective: Asthma is a heterogeneous disease with varying clinical presentations, severity and ability to achieve asthma control. The present study aimed to characterize clinical phenotypes of asthma in an Indian cohort of subjects using a cluster analysis approach. Methods: Patients with confirmed asthma (N = 100) and at least 6-months of follow-up data, identified by retrospective chart review, were included in this study. Demographics, age at disease onset, disease duration, body mass index, serial spirometry and allergen sensitization were assessed. Asthma control was assessed prospectively using Global Initiative for Asthma and Asthma Control Test. R version 3.4.3 was used for statistical analysis. Ward’s minimum-variance hierarchical clustering method was performed using an agglomerative (bottom-up) approach. To compare differences between clusters, analysis of variance using Kruskal-Wallis test (continuous variables) and chi-square test (categorical variables) was used. Results: Cluster analysis of 100 treatment-naive patients with asthma identified four clusters. Cluster 1, (N = 40), childhood onset of disease, normal body weight, equal gender distribution and achieved normal lung function. Cluster 2 (N = 16) included adolescent disease-onset, obese, majority males and had poor attainment of maximum lung functions. Cluster 3 (N = 20) were older, late-onset of disease, obese, majority male and had poor attainment of maximum lung function. Cluster 4 (N = 24) had adult-onset of disease, obese, predominantly female and achieved normal lung function. Conclusions: In an Indian cohort of well-characterized patients with asthma, cluster analysis identified four distinct clinical phenotypes of asthma, two of which had poor attainment of maximum lung functions.

Exposure to ionizing radiation contributing to negative health outcomes is a widespread concern. However, the impact of low dose and sub-lethal dose radiation (SLDR) exposures remain contentious, particularly in pregnant women who represent a vulnerable group. The fetal programming hypothesis states that an adverse in utero environment or stress during development of an embryo or fetus can result in permanent physiologic changes often resulting in progressive metabolic dysfunction with age. To assess changes in gene expression profiles of glucose/insulin signaling and lipid metabolism caused by radiation exposure in utero, pregnant C57Bl/6J mice were irradiated using a dose response ranging from low dose to SLDR and compared to a Sham-irradiated group. mRNA expression analysis in 16 week old offspring (n = 84) revealed that genes involved in metabolic function including glucose metabolism, insulin signaling and lipid metabolism were unaffected by prenatal radiation exposures up to 300 mGy. However, female offspring of dams exposed to 1000 mGy had upregulated expression of genes contributing to insulin resistance and gluconeogenesis. In a second cohort of mice, the effects of SLDR on fetal programming of hepatic SOCS3 and PEPCK protein expression were assessed. 4 month old female offspring of dams irradiated at 1000 mGy had: 1) increased liver weights, 2) increased hepatic expression of proteins involved in glucose metabolism and 3) increased 18F-fluorodeoxyglucose (FDG) uptake in interscapular brown adipose tissue (IBAT) measured by positron emission tomography (PET) (n = 25). The results of this study indicate that prenatal radiation exposure does not affect metabolic function up to 300 mGy and 1000 mGy may be a threshold dose for sex-specific alterations in glucose uptake and hepatic gene and protein expression of SOCS3, PEPCK, PPARGC1A and PPARGC1B. These findings suggest that SLDR doses alter glucose uptake in IBAT and hepatic gene and protein expression of offspring and these changes may progress with age.