Multicentre, non-interventional study to assess the profile of patients with uncontrolled rhinitis prescribed a novel formulation of azelastine hydrochloride and fluticasone propionate in a single spray in routine clinical practice in the UK

OBJECTIVE: The aims of this study were (1) to characterise the type of patient prescribed MP-AzeFlu (Dymista, a novel formulation of azelastine hydrochloride, fluticasone propionate and excipients in a single spray) in real life in the UK and physicians' reasons for prescribing it and (2) to quantify the personal and societal burden of allergic rhinitis (AR) in the UK prior to MP-AzeFlu prescription. DESIGN, SETTING AND PARTICIPANTS: This multicentre, non-interventional study enrolled patients (n=193) with moderate-to-severe AR and acute symptoms who were eligible to receive treatment with MP-AzeFlu according to its licensed indications. Information was gathered on patient demographics, AR history and symptom severity, symptomatology and AR treatments in the previous calendar year (prior to MP-AzeFlu prescription). Physicians also recorded the number of previous AR visits, specific reasons for these visits and their reason for prescribing MP-AzeFlu. RESULTS: Most patients had seasonal AR either alone (10.4%) or in combination with perennial AR (35.2%), but many had AR of unknown origin (35.8%). Prior to MP-AzeFlu prescription, patients reported troublesome symptoms (78.2%) and sleep disturbance (64.8%), with congestion considered the most bothersome (54.4%) and ocular symptoms reported by 68.4% of patients. The most frequent reason for MP-AzeFlu prescription was that other therapies were not sufficient in the past (78.8%) or not sufficient to treat acute symptoms (16.1%). 79.3% of patients reported using ≥2 AR therapies in the past year. An average of 1.6 (SD 1.9) doctor visits due to AR were reported prior to MP-AzeFlu prescription. CONCLUSIONS: In the UK, MP-AzeFlu was prescribed for individuals (≥12 years) with moderate/severe AR irrespective of (1) previous AR treatment (mono or multiple), (2) previous or likely treatment failure, (3) phenotype, (4) number of previous physician visits for AR and (5) for the relief of both acute symptoms and in anticipation of allergen exposure

Intranasal steroids versus placebo or no intervention for chronic rhinosinusitis

BACKGROUND: This review is one of six looking at the primary medical management options for patients with chronic rhinosinusitis.Chronic rhinosinusitis is common and is characterised by inflammation of the lining of the nose and paranasal sinuses leading to nasal blockage, rhinorrhoea, facial pressure/pain and loss of sense of smell. The condition can occur with or without nasal polyps. The use of topical (intranasal) corticosteroids has been widely advocated for the treatment of chronic rhinosinusitis given the belief that inflammation is a major component of this condition.  OBJECTIVES: To assess the effects of intranasal corticosteroids in people with chronic rhinosinusitis.  SEARCH METHODS: The Cochrane ENT Information Specialist searched the Cochrane ENT Trials Register; Central Register of Controlled Trials (CENTRAL 2015, Issue 8); MEDLINE; EMBASE; ClinicalTrials.gov; ICTRP and additional sources for published and unpublished trials. The date of the search was 11 August 2015.  SELECTION CRITERIA: Randomised controlled trials (RCTs) with a follow-up period of at least three months comparing intranasal corticosteroids (e.g. beclomethasone dipropionate, triamcinolone acetonide, flunisolide, budesonide) against placebo or no treatment in patients with chronic rhinosinusitis.  DATA COLLECTION AND ANALYSIS: We used the standard methodological procedures expected by Cochrane. Our primary outcomes were disease-specific health-related quality of life (HRQL), patient-reported disease severity and the commonest adverse event - epistaxis. Secondary outcomes included general HRQL, endoscopic nasal polyp score, computerised tomography (CT) scan score and the adverse events of local irritation or other systemic adverse events. We used GRADE to assess the quality of the evidence for each outcome; this is indicated in italics.  MAIN RESULTS: We included 18 RCTs with a total of 2738 participants. Fourteen studies had participants with nasal polyps and four studies had participants without nasal polyps. Only one study was conducted in children. Intranasal corticosteroids versus placebo or no interventionOnly one study (20 adult participants without polyps) measured our primary outcome disease-specific HRQL using the Rhinosinusitis Outcome Measures-31 (RSOM-31). They reported no significant difference (numerical data not available) (very low quality evidence).Our second primary outcome, disease severity , was measured using the Chronic Sinusitis Survey in a second study (134 participants without polyps), which found no important difference (mean difference (MD) 2.84, 95% confidence interval (CI) -5.02 to 10.70; scale 0 to 100). Another study (chronic rhinosinusitis with nasal polyps) reported an increased chance of improvement in the intranasal corticosteroids group (RR 2.78, 95% CI 1.76 to 4.40; 109 participants). The quality of the evidence was low.Six studies provided data on at least two of the individualsymptoms used in the EPOS 2012 criteria to define chronic rhinosinusitis (nasal blockage, rhinorrhoea, loss of sense of smell and facial pain/pressure). When all four symptoms in the EPOS criteria were available on a scale of 0 to 3 (higher = more severe symptoms), the average MD in change from baseline was -0.26 (95% CI -0.37 to -0.15; 243 participants; two studies; low quality evidence). Although there were more studies and participants when only nasal blockage and rhinorrhoea were considered (MD -0.31, 95% CI -0.38 to -0.24; 1702 participants; six studies), the MD was almost identical to when loss of sense of smell was also considered (1345 participants, four studies; moderate quality evidence).When considering the results for the individual symptoms, benefit was shown in the intranasal corticosteroids group. The effect size was larger for nasal blockage (MD -0.40, 95% CI -0.52 to -0.29; 1702 participants; six studies) than for rhinorrhoea (MD -0.25, 95% CI -0.33 to -0.17; 1702 participants; six studies) or loss of sense of smell (MD -0.19, 95% CI -0.28 to -0.11; 1345 participants; four studies). There was heterogeneity in the analysis for facial pain/pressure (MD -0.27, 95% CI -0.56 to 0.02; 243 participants; two studies). The quality of the evidence was moderate for nasal blockage, rhinorrhoea and loss of sense of smell, but low for facial pain/pressure.There was an increased risk of epistaxis with intranasal corticosteroids (risk ratio (RR) 2.74, 95% CI 1.88 to 4.00; 2508 participants; 13 studies; high quality evidence).Considering our secondary outcome, general HRQL, one study (134 participants without polyps) measured this using the SF-36 and reported a statistically significant benefit only on the general health subscale. The quality of the evidence was very low.It is unclear whether there is a difference in the risk of local irritation (RR 0.94, 95% CI 0.53 to 1.64; 2124 participants; 11 studies) (low quality evidence).None of the studies treated or followed up patients long enough to provide meaningful data on the risk of osteoporosis or stunted growth (children). Other comparisonsWe identified no other studies that compared intranasal corticosteroids plus co-intervention A versus placebo plus co-intervention A.  AUTHORS' CONCLUSIONS: Most of the evidence available was from studies in patients with chronic rhinosinusitis with nasal polyps. There is little information about quality of life (very low quality evidence). For disease severity, there seems to be improvement for all symptoms (low quality evidence), a moderate-sized benefit for nasal blockage and a small benefit for rhinorrhoea (moderate quality evidence). The risk of epistaxis is increased (high quality evidence), but these data included all levels of severity; small streaks of blood may not be a major concern for patients. It is unclear whether there is a difference in the risk of local irritation (low quality evidence)

Different types of intranasal steroids for chronic rhinosinusitis

BACKGROUND: This review is one of six looking at the primary medical management options for patients with chronic rhinosinusitis.Chronic rhinosinusitis is common and is characterised by inflammation of the lining of the nose and paranasal sinuses leading to nasal blockage, nasal discharge, facial pressure/pain and loss of sense of smell. The condition can occur with or without nasal polyps. Topical (intranasal) corticosteroids are used with the aim of reducing inflammation in the sinonasal mucosa in order to improve patient symptoms. OBJECTIVES: To assess the effects of different types of intranasal steroids in people with chronic rhinosinusitis. SEARCH METHODS: The Cochrane ENT Information Specialist searched the ENT Trials Register; Central Register of Controlled Trials (CENTRAL 2015, Issue 7); MEDLINE; EMBASE; ClinicalTrials.gov; ICTRP and additional sources for published and unpublished trials. The date of the search was 11 August 2015. SELECTION CRITERIA: Randomised controlled trials (RCTs) with a follow-up period of at least three months comparing first-generation intranasal corticosteroids (e.g. beclomethasone dipropionate, triamcinolone acetonide, flunisolide, budesonide) with second-generation intranasal corticosteroids (e.g. ciclesonide, fluticasone furoate, fluticasone propionate, mometasone furoate, betamethasone sodium phosphate), or sprays versus drops, or low-dose versus high-dose intranasal corticosteroids. DATA COLLECTION AND ANALYSIS: We used the standard methodological procedures expected by Cochrane. Our primary outcomes were disease-specific health-related quality of life (HRQL), patient-reported disease severity and the commonest adverse event - epistaxis (nosebleed). Secondary outcomes included general HRQL, endoscopic nasal polyp score, computerised tomography (CT) scan score and the adverse event of local irritation. We used GRADE to assess the quality of the evidence for each outcome; this is indicated in italics. MAIN RESULTS: We included nine RCTs (911 participants), including four different comparisons. None of the studies evaluated our first primary outcome measure, disease-specific HRQL. Fluticasone propionate versus beclomethasone dipropionateWe identified two small studies (56 participants with polyps) that evaluated disease severity and looked at the primary adverse effect: epistaxis , but no other outcomes. We cannot report any numerical data but the study authors reported no difference between the two steroids. The evidence was of very low quality. Fluticasone propionate versus mometasone furoateWe identified only one study (100 participants with polyps) that evaluated disease severity (nasal symptoms scores), which reported no difference (no numerical data available). The evidence was of very low quality. High-dose versus low-dose steroidsWe included five studies (663 participants with nasal polyps), three using mometasone furoate (400 µg versus 200 µg in adults and older children, 200 µg versus 100 µg in younger children) and two using fluticasone propionate drops (800 µg versus 400 µg). We found low quality evidence relating to disease severity and nasal polyps size, with results from the high-dose and low-dose groups being similar. Although all studies reported more improvement in polyp score in the high-dose group, the significance of this is unclear due to the small size of the improvements.The primary adverse effect, epistaxis , was more common when higher doses were used (risk ratio (RR) 2.06, 95% confidence interval (CI) 1.20 to 3.54, 637 participants, moderate quality evidence). Most of the studies that contributed data to this outcome used a broad definition of epistaxis, which ranged from frank bleeding to bloody nasal discharge to flecks of blood in the mucus. Aqueous nasal spray versus aerosol sprayWe identified only one poorly reported study (unclear number of participants for comparison of interest, 91 between three treatment arms), in which there were significant baseline differences between the participants in the two groups. We were unable to draw meaningful conclusions from the data. AUTHORS' CONCLUSIONS: We found insufficient evidence to suggest that one type of intranasal steroid is more effective than another in patients with chronic rhinosinusitis, nor that the effectiveness of a spray differs from an aerosol. We identified no studies that compared drops with spray.It is unclear if higher doses result in better symptom improvements (low quality evidence), but there was moderate quality evidence of an increased risk of epistaxis as an adverse effect of treatment when higher doses were used. This included all levels of severity of epistaxis and it is likely that the proportion of events that required patients to discontinue usage is low due to the low numbers of withdrawals attributed to it. If epistaxis is limited to streaks of blood in the mucus it may be tolerated by the patient and it may be safe to continue treatment. However, it may be a factor that affects compliance.There is insufficient evidence to suggest that the different types of corticosteroid molecule or spray versus aerosol have different effects. Lower doses have similar effectiveness but fewer side effects.Clearly more research in this area is needed, with specific attention given to trial design, disease-specific health-related quality of life outcomes and evaluation of longer-term outcomes and adverse effects

A prospective cohort study of neighborhood stress and ischemic heart disease in Japan: a multilevel analysis using the JACC study data

<p>Abstract</p> <p>Background</p> <p>A body of research has shown that neighborhood environment may have an effect on a variety of health outcomes, including cardiovascular disease. One explanation for the mechanism of the effect of neighborhood on cardiovascular disease is psychosocial pathways. Direct evidence for an effect of neighborhood on cardiovascular disease with adjustment for perceived stress at the individual level has not been obtained, however. The Japan Collaborative Cohort Study for the Evaluation of Cancer Risk provides a unique dataset which has aggregated area-based cohorts from 45 areas throughout Japan. The purpose of the present study was to examine the contextual effect of area-level stress on ischemic heart disease using data from a large prospective cohort in Japan.</p> <p>Methods</p> <p>A baseline survey of 110,792 residents of 45 areas aged 40-79 years was conducted between 1988 and 1990. Analysis was restricted to subjects from the 33 of 45 areas providing information about self-rated stress (32183 men and 45896 women). Multilevel Poisson regression models were employed in a two-level structure of individuals nested within the 33 areas. Area-level stress was calculated by sex as the number of persons who rated their stress level as high divided by the total number of subjects in that area. Mortality rate ratios (MRRs) per 1 percentage point increase in area-level stress were estimated with adjustment for compositional individual factors.</p> <p>Results</p> <p>During 15 years of follow-up (1,116,895 person-years), 936 deaths due to ischemic heart disease were recorded. Area-level stress varied from 6% to 22%. In the multivariable models, MRRs of area-level stress were 1.06 (95% confidence interval: 1.00-1.12, p = 0.043) in men and 1.07 (95% confidence interval: 1.00-1.14, p = 0.057) in women.</p> <p>Conclusions</p> <p>Area-level stress affects the likelihood of death due to ischemic heart disease of individuals in men. The present findings may suggest that stress should be considered not only within the individual but also within the neighborhood context.</p

Area deprivation and its association with health in a cross-sectional study: are the results biased by recent migration?

<p>Abstract</p> <p>Background</p> <p>The association between area deprivation and health has mostly been examined in cross-sectional studies or prospective studies with short follow-up. These studies have rarely taken migration into account. This is a possible source of misclassification of exposure, i.e. an unknown number of study participants are attributed an exposure of area deprivation that they may have experienced too short for it to have any influence. The aim of this article was to examine to what extent associations between area deprivation and health outcomes were biased by recent migration.</p> <p>Methods</p> <p>Based on data from the Oslo Health Study, a cross-sectional study conducted in 2000 in Oslo, Norway, we used six health outcomes (self rated health, mental health, coronary heart disease, chronic obstructive pulmonary disease, smoking and exercise) and considered migration nine years prior to the study conduct. Migration into Oslo, between the areas of Oslo, and the changes in area deprivation during the period were taken into account. Associations were investigated by multilevel logistic regression analyses.</p> <p>Results</p> <p>After adjustment for individual socio-demographic variables we found significant associations between area deprivation and all health outcomes. Accounting for migration into Oslo and between areas of Oslo did not change these associations much. However, the people who migrated into Oslo were younger and had lower prevalences of unfavourable health outcomes than those who were already living in Oslo. But since they were evenly distributed across the area deprivation quintiles, they had little influence on the associations between area deprivation and health. Evidence of selective migration within Oslo was weak, as both moving up and down in the deprivation hierarchy was associated with significantly worse health than not moving.</p> <p>Conclusion</p> <p>We have documented significant associations between area deprivation and health outcomes in Oslo after adjustment for socio-demographic variables in a cross-sectional study. These associations were weakly biased by recent migration. From our results it still appears that migration prior to study conduct may be relevant to investigate even within a relatively short period of time, whereas changes in area deprivation during such a period is of limited interest.</p

Quantitative Modeling of GRK-Mediated β2AR Regulation

We developed a unified model of the GRK-mediated β2 adrenergic receptor (β2AR) regulation that simultaneously accounts for six different biochemical measurements of the system obtained over a wide range of agonist concentrations. Using a single deterministic model we accounted for (1) GRK phosphorylation in response to various full and partial agonists; (2) dephosphorylation of the GRK site on the β2AR; (3) β2AR internalization; (4) recycling of the β2AR post isoproterenol treatment; (5) β2AR desensitization; and (6) β2AR resensitization. Simulations of our model show that plasma membrane dephosphorylation and recycling of the phosphorylated receptor are necessary to adequately account for the measured dephosphorylation kinetics. We further used the model to predict the consequences of (1) modifying rates such as GRK phosphorylation of the receptor, arrestin binding and dissociation from the receptor, and receptor dephosphorylation that should reflect effects of knockdowns and overexpressions of these components; and (2) varying concentration and frequency of agonist stimulation “seen” by the β2AR to better mimic hormonal, neurophysiological and pharmacological stimulations of the β2AR. Exploring the consequences of rapid pulsatile agonist stimulation, we found that although resensitization was rapid, the β2AR system retained the memory of the previous stimuli and desensitized faster and much more strongly in response to subsequent stimuli. The latent memory that we predict is due to slower membrane dephosphorylation, which allows for progressive accumulation of phosphorylated receptor on the surface. This primes the receptor for faster arrestin binding on subsequent agonist activation leading to a greater extent of desensitization. In summary, the model is unique in accounting for the behavior of the β2AR system across multiple types of biochemical measurements using a single set of experimentally constrained parameters. It also provides insight into how the signaling machinery can retain memory of prior stimulation long after near complete resensitization has been achieved

European Summit on the Prevention and Self-Management of Chronic Respiratory Diseases: report of the European Union Parliament Summit (29 March 2017)

On March 29, 2017, a European Summit on the Prevention and Self-Management of Chronic Respiratory Diseases (CRD) was organized by the European Forum for Research and Education in Allergy and Airway Diseases. The event took place in the European Parliament of Brussels and was hosted by MEP David Borrelli and MEP Sirpa Pietikainen. The aim of the Summit was to correspond to the needs of the European Commission and of patients suffering from CRD to join forces in Europe for the prevention and self-management. Delegates of the European Rhinologic Society, European Respiratory Society, European Academy of Allergy and Clinical Immunology, European Academy of Paediatrics, and European Patients Organization EFA all lectured on their vision and action plan to join forces in achieving adequate prevention and self-management of CRD in the context of Precision Medicine. Recent data highlight the preventive capacity of education on optimal care pathways for CRD. Self-management and patient empowerment can be achieved by novel educational on-line materials and by novel mobile health tools enabling patients and doctors to monitor and optimally treat CRDs based on the level of control. This report summarizes the contributions of the representatives of different European academic stakeholders in the field of CRD

Neighborhood disparities in stroke and myocardial infarction mortality: a GIS and spatial scan statistics approach

<p>Abstract</p> <p>Background</p> <p>Stroke and myocardial infarction (MI) are serious public health burdens in the US. These burdens vary by geographic location with the highest mortality risks reported in the southeastern US. While these disparities have been investigated at state and county levels, little is known regarding disparities in risk at lower levels of geography, such as neighborhoods. Therefore, the objective of this study was to investigate spatial patterns of stroke and MI mortality risks in the East Tennessee Appalachian Region so as to identify neighborhoods with the highest risks.</p> <p>Methods</p> <p>Stroke and MI mortality data for the period 1999-2007, obtained free of charge upon request from the Tennessee Department of Health, were aggregated to the census tract (neighborhood) level. Mortality risks were age-standardized by the direct method. To adjust for spatial autocorrelation, population heterogeneity, and variance instability, standardized risks were smoothed using Spatial Empirical Bayesian technique. Spatial clusters of high risks were identified using spatial scan statistics, with a discrete Poisson model adjusted for age and using a 5% scanning window. Significance testing was performed using 999 Monte Carlo permutations. Logistic models were used to investigate neighborhood level socioeconomic and demographic predictors of the identified spatial clusters.</p> <p>Results</p> <p>There were 3,824 stroke deaths and 5,018 MI deaths. Neighborhoods with significantly high mortality risks were identified. Annual stroke mortality risks ranged from 0 to 182 per 100,000 population (median: 55.6), while annual MI mortality risks ranged from 0 to 243 per 100,000 population (median: 65.5). Stroke and MI mortality risks exceeded the state risks of 67.5 and 85.5 in 28% and 32% of the neighborhoods, respectively. Six and ten significant (p < 0.001) spatial clusters of high risk of stroke and MI mortality were identified, respectively. Neighborhoods belonging to high risk clusters of stroke and MI mortality tended to have high proportions of the population with low education attainment.</p> <p>Conclusions</p> <p>These methods for identifying disparities in mortality risks across neighborhoods are useful for identifying high risk communities and for guiding population health programs aimed at addressing health disparities and improving population health.</p