Effects of short- and long-acting beta-agonists on asthma exacerbations: a prospective cohort.

BACKGROUND: In asthma, short- and long-acting ß-agonists (SABAs and LABAs) should be used together with inhaled corticosteroids (ICS), and regular use is inappropriate. OBJECTIVE: To assess the relationship between patterns of use of therapy and asthma exacerbations (AEx). METHODS: Patients with asthma (6-40 years) were enrolled in France and the United Kingdom. Prescribing data, computer-assisted telephone interviews (CATIs), and text messages assessed medication use and AEx over a maximum period of 24 months. Generalized linear mixed models provided AEx risks associated with therapy. RESULTS: Among the 908 patients (median age: 20.0 years, 46.6% women, 24.5% children) answering a total of 4248 CATIs over 486 (±235) days, regular (ie, daily) use was more frequent for single LABAs and fixed dose combinations (FDCs) than for single ICS (75.6%, 70.1%, and 65.4% of investigated periods of use, respectively). Regular (ie, daily or almost daily) SABA use was observed for 21.1% of periods of use. Altogether, 265 patients (29.2%) experienced 1 or more AEx. The ORs for AEx risk related to regular vs no use of FDCs, single ICS, and single LABAs were 0.98 (95% CI = [0.73-1.33]), 0.90 (95% CI = [0.61-1.33]), and 1.29 (95% CI = [0.76-2.17]), respectively, after adjustment for cotherapy, sociodemographic, and disease characteristics. The OR was 2.09 (95% CI = [1.36-3.21]) in regular SABA users. CONCLUSION: Inhaled corticosteroids and FDCs were often used intermittently, whereas SABAs and LABAs could be used regularly, and exacerbations were frequent. Compared with non-users, the risk of exacerbation increased moderately under regular use of single LABAs, whereas it doubled, significantly, in regular SABA users, likely in relationship with poor overall asthma control.

EuroQol (EQ-5D-5L) Validity in Assessing the Quality of Life in Adults With Asthma: Cross-Sectional Study.

BACKGROUND: The EuroQol-5 Dimension (EQ-5D), developed in 1990, is a most widely used generic tool to measure the health-related quality of life (HRQoL) and considered suitable for patients with asthma. In 2009, the EuroQol Group developed a new EQ-5D version to overcome limitations related to its consistently reported high ceiling effect. To enhance the sensitivity for assessing the HRQoL in further patient populations, the number of responses of EQ-5D was increased from 3 to 5 levels (EQ-5D-5L). Moreover, the availability of well-defined requirements for its Web-based administration allows EQ-5D-5L use to monitor the HRQoL in electronic health (eHealth) programs. No study has evaluated the metric properties of the new EQ-5D-5L in patients with asthma yet. OBJECTIVE: This study aims to examine the distribution, construct validity, and reliability of the new EQ-5D-5L questionnaire administered online to adults with asthma. METHODS: We evaluated patients with asthma (age: 18-40 years) from a primary care setting in France and England, who self-completed the EQ-5D-5L questionnaire online. The inclusion criteria were persistent asthma defined as >6 months of prescribed inhaled corticosteroids and long-acting beta-agonists or inhaled corticosteroids alone during the 12 months prior to inclusion. The EQ-5D index was obtained by applying the English preference value set for the new EQ-5D-5L and the French 3L-5L crosswalk value set. Both value sets produced single preference-based indices ranging from 1 (best health state) to negative values (health states valued as worse than death), where 0=death, allowing the calculation of quality-adjusted life years. Responses to dimensions and index distribution, including ceiling and floor effects, were examined. The construct validity was assessed by comparing the means of known groups by analyses of variance and calculation of effect sizes. RESULTS: Of 312 patients answering the baseline Web-based survey, 290 completed the EQ-5D-5L (93%). The floor effect was null, and the ceiling effect was 26.5% (74/279). The mean EQ-5D-5L index was 0.88 (SD 0.14) with the English value set and 0.83 (SD 0.19) with the French 3L-5L crosswalk value set. In both indices, large effect sizes were observed for known groups defined by the Asthma Control Questionnaire (1.06 and 1.04, P<.001). Differences between extreme groups defined by chronic conditions (P=.002 and P=.003 for the English value set and French 3L-5L crosswalk value set, respectively), short-acting beta-agonists (SABAs) canisters in the last 12 months (P=.02 and P=.03), or SABA use during the previous 4 weeks (P=.03 and P=.01) were of moderate magnitude with effect sizes around 0.5. CONCLUSIONS: The new EQ-5D-5L questionnaire has an acceptable ceiling effect, a good construct validity based on the discriminant ability for distinguishing among health-related known groups, and high reliability, supporting its adequacy for assessing the HRQoL in patients with asthma. EQ-5D-5L completion by most Web-based respondents supports the feasibility of this administration form.

Validity of the EQ-5D-5L and reference norms for the Spanish population.

BACKGROUND AND OBJECTIVE: The EuroQol 5 dimensions 5 levels (EQ-5D-5L) is the new version of EQ-5D, developed to improve its discriminatory capacity. This study aims to evaluate the construct validity of the Spanish version and provide index and dimension population-based reference norms for the new EQ-5D-5L. METHODS: Data were obtained from the 2011/2012 Spanish National Health Survey, with a representative sample (n = 20,587) of non-institutionalized Spanish adults (≥ 18 years). The EQ-5D-5L index was calculated by using the Spanish value set. Construct validity was evaluated by comparing known groups with estimators obtained through regression models, adjusted by age and gender. Sampling weights were applied to restore the representativeness of the sample and to calculate the norms stratified by gender and age groups. We calculated the percentages and standard errors of dimensions, and the deciles, percentiles 5 and 95, means, and 95% confidence intervals of the health index. RESULTS: All the hypotheses established a priori for known groups were confirmed (P < 0.001). The EQ-5D-5L index indicated worse health in groups with lower education level (from 0.94 to 0.87), higher number of chronic conditions (0.96-0.79), probable psychiatric disorder (0.94 vs 0.80), strong limitations (0.96-0.46), higher number of days of restriction (0.93-0.64) or confinement to bed (0.92-0.49), and hospitalized in the previous 12 months (0.92 vs 0.81). CONCLUSIONS: The EQ-5D-5L is a valid instrument to measure perceived health in the Spanish-speaking population. The representative population-based norms provided here will help improve the interpretation of results obtained with the new EQ-5D-5L.

Prevalence of prenatal exposure to substances of abuse: questionnaire versus biomarkers.

Alcohol and drugs of abuse consumption in young adults, including women of childbearing age, has experienced significant increase over the past two decades. The use of questionnaires as the only measure to investigate prenatal alcohol and drugs of abuse exposure underestimates the real prevalence of exposure and could mislead to wrong conclusions. Therefore, the aim of this article was to compare reported rates of prenatal alcohol and drugs of abuse consumption with biomarkers of exposure by a comprehensive review of the available literature. We searched MEDLINE and EMBASE databases for articles catalogued between 1992 and 2015. We identified relevant published studies that assessed the comparison between prenatal exposure to alcohol and drugs of abuse assessed by self-reported questionnaire of consumption versus biomarkers of exposure. Thirteen studies were included regarding alcohol consumption, and seven of them about drugs of abuse. Women who admitted consumption during pregnancy by questionnaire varied from 0 to 37% for alcohol, from 0 to 4.3% for cocaine, and 2.9% for tetrahydrocannabinol (THC). Positive biomarkers results ranged from 16 to 44% for alcohol, 15.4% for cocaine, and from 4 to 12.4% for THC. Biomarkers should always complement questionnaires, as it has been shown that self-report may underestimate prenatal exposure to substances of abuse.

Asthma inhaler adherence determinants in adults: systematic review of observational data.

Nonadherence to inhaled medication leads to poor asthma control and increased healthcare utilisation. Many studies exploring adherence determinants have been conducted, but summaries of the evidence are scarce. We performed a systematic review of observational research on determinants of asthma inhaler adherence among adults. We searched for articles in English reporting quantitative observational studies on inhaler adherence correlates among adults in developed countries, published in EMBASE, Medline, PsychInfo and PsychArticles in 1990-2014. Two coders independently assessed eligibility and extracted data, and assessed study quality. Results were summarised qualitatively into social and economic, and healthcare-, therapy-, condition- and patient-related factors. The 51 studies included mainly examined patient-related factors and found consistent links between adherence and stronger inhaler-necessity beliefs, and possibly older age. There was limited evidence on the relevance of other determinants, partly due to study heterogeneity regarding the types of determinants examined. Methodological quality varied considerably and studies performed generally poorly on their definitions of variables and measures, risk of bias, sample size and data analysis. A broader adoption of common methodological standards and health behaviour theories is needed before cumulative science on the determinants of adherence to asthma inhalers among adults can develop further.

Long-acting beta-agonists plus inhaled corticosteroids safety: a systematic review and meta-analysis of non-randomized studies.

BACKGROUND: Although several systematic reviews investigated the safety of long-acting beta-agonists (LABAs) in asthma, they mainly addressed randomized clinical trials while evidence from non-randomized studies has been mostly neglected. We aim to assess the risk of serious adverse events in adults and children with asthma treated with LABAs and Inhaled Corticosteroids (ICs), compared to patients treated only with ICs, from published non-randomized studies. METHODS: The protocol registration number was CRD42012003387 (http://www.crd.york.ac.uk/Prospero). Literature search for articles published since 1990 was performed in MEDLINE and EMBASE. Two authors selected studies independently for inclusion and extracted the data. A third reviewer resolved discrepancies. To assess the risk of serious adverse events, meta-analyses were performed calculating odds ratio summary estimators using random effect models when heterogeneity was found, and fixed effect models otherwise. RESULTS: Of 4,415 candidate articles, 1,759 abstracts were reviewed and 220 articles were fully read. Finally, 19 studies met the inclusion criteria. Most of them were retrospective observational cohorts. Sample sizes varied from 50 to 514,216. The meta-analyses performed (69,939-624,303 participants according to the outcome considered) showed that odds ratio of the LABAs and ICs combined treatment when compared with ICs alone was: 0.88 (95% CI 0.69-1.12) for asthma-related hospitalization; 0.75 (95% CI 0.66-0.84) for asthma-related emergency visits; 1.02 (95% CI 0.94-1.10) for systemic corticosteroids; and 0.95 (95% CI 0.9-1.0) for the combined outcome. CONCLUSIONS: Evidence from observational studies shows that the combined treatment of LABAs and ICs is not associated with a higher risk of serious adverse events, compared to ICs alone. Major gaps identified were prospective design, paediatric population and inclusion of mortality as a primary outcome.

Health Inequalities by Sexual Orientation: Results from the 2016-2017 Barcelona Health Survey.

Purpose: The aim of this study was to assess health inequalities by sexual attraction in the 2016-2017 Barcelona population, stratifying by sex. Methods: Data came from the 2016-2017 Barcelona Health Survey, where 3362 adults answered among other instruments the EuroQol-5 dimensions-5 levels (EQ-5D-5L), which measures five dimensions and summarizes health-related quality of life into a single utility index score. To assess health differences by sexual attraction, we constructed Tobit models for the EQ-5D index score and Poisson regression models for the EQ-5D dimensions. Nested models were constructed to examine the mediating role of discrimination and health-related variables. Results: After adjusting for sociodemographic variables, women feeling attraction to more than one sex showed a lower EQ-5D index score (worse health) than those with only other sex attraction (-0.042, p = 0.012), and higher prevalence of problems with mobility, usual activities, and anxiety/depression with the following adjusted prevalence ratios (aPR) and confidence intervals (CIs): 1.79 (95% CI 1.05-3.05), 1.84 (95% CI 1.05-3.21), and 1.76 (95% CI 1.27-2.43). Women feeling attraction only to their same sex also presented higher prevalence of anxiety/depression (aPR = 1.46, CI 95% 1.10-1.92). In contrast, differences were not observed for men. Conclusion: Women, but not men, feeling attraction to more than one sex and only same-sex attraction in Barcelona in 2016-2017 presented worse health than those feeling only other sex attraction, with discrimination playing a mediating role in explaining such inequalities. These results among women indicate the need to develop public health strategies in Barcelona addressed to lesbian and bisexual women, considering the intersection of gender and sexual orientation.

A phase 1, randomized double-blind, placebo controlled trial to evaluate safety and efficacy of epigallocatechin-3-gallate and cognitive training in adults with Fragile X syndrome.

BACKGROUND & AIMS: Despite the wide spectrum of experimental compounds tested in clinical trials, there is still no proven pharmacological treatment available for Fragile-X syndrome (FXS), since several targeted clinical trials with high expectations of success have failed to demonstrate significant improvements. Here we tested epigallocatechin-3-gallate (EGCG) as a treatment option for ameliorating core cognitive and behavioral features in FXS. METHODS: We conducted preclinical studies in Fmr1 knockout mice (Fmr1-/y) using novel object-recognition memory paradigm upon acute EGCG (10 mg/kg) administration. Furthermore we conducted a double-blind placebo-controlled phase I clinical trial (TESXF; NCT01855971). Twenty-seven subjects with FXS (18-55 years) were administered of EGCG (5-7 mg/kg/day) combined with cognitive training (CT) during 3 months with 3 months of follow-up after treatment discontinuation. RESULTS: Preclinical studies showed an improvement in memory using the Novel Object Recognition paradigm. We found that FXS patients receiving EGCG + CT significantly improved cognition (visual episodic memory) and functional competence (ABAS II-Home Living skills) in everyday life compared to subjects receiving Placebo + CT. CONCLUSIONS: Phase 2 clinical trials in larger groups of subjects are necessary to establish the therapeutic potential of EGCG for the improvement of cognition and daily life competences in FXS.

Impact of asthma on women and men: Comparison with the general population using the EQ-5D-5L questionnaire.

BACKGROUND: The aim was to evaluate the impact of asthma on patients' Health-Related Quality of Life (HRQoL) by comparing asthmatic women and men with reference norms, to examine the factors which contributed to an impaired HRQoL, and to identify groups at higher risk. METHODS: Cross-sectional evaluation of 222 primary care patients with persistent asthma (18-40 years old). HRQoL impact was estimated with the EuroQol-5 Dimensions (EQ-5D), which allows calculating Quality-Adjusted Life-Years (QALYs) by applying society preferences. Participants self-completed the EQ-5D questionnaire online. Telephonic interviews collected information on medication and adherence, and administered the Asthma Control Questionnaire. Severity markers included asthma-related comorbidity, previous oral corticosteroids course prescription, and inhaled corticosteroids daily dose. After bivariate analyses, multiple linear regression models were constructed to examine the relations between HRQoL asthma impact and socio-demographic and clinical variables, using as dependent variable the deviation from general population-based EQ-5D reference norms. RESULTS: Deviation from the EQ-5D index norms was moderate in most age/gender groups (-0.1, which corresponds to 0.6 standard deviations), while it was large in women aged 18-24 years (-0.18, corresponding to 1.1 standard deviations). In regression models, a poor asthma control was the only factor independently associated to HRQoL impact in both women and men: ß -0.18 (p<0.001) and -0.15 (p = 0.01) respectively. Translating these ß coefficients to QALYs, they are interpretable as 66 fewer days of full health per year in women with uncontrolled asthma and 55 for men, compared with those with controlled asthma. CONCLUSION: Persistent asthma has a moderately negative HRQoL impact on patients of both genders, and the youngest women have been identified as a high risk group which merits further research. We identified asthma control as the major contributor to impaired HRQoL in patients, regardless of their gender, suggesting that asthma HRQoL impact could be alleviated by achieving a good control of symptoms.

Safety and efficacy of cognitive training plus epigallocatechin-3-gallate in young adults with Down's syndrome (TESDAD): a double-blind, randomised, placebo-controlled, phase 2 trial.

BACKGROUND: Early cognitive intervention is the only routine therapeutic approach used for amelioration of intellectual deficits in individuals with Down's syndrome, but its effects are limited. We hypothesised that administration of a green tea extract containing epigallocatechin-3-gallate (EGCG) would improve the effects of non-pharmacological cognitive rehabilitation in young adults with Down's syndrome. METHODS: We enrolled adults (aged 16-34 years) with Down's syndrome from outpatient settings in Catalonia, Spain, with any of the Down's syndrome genetic variations (trisomy 21, partial trisomy, mosaic, or translocation) in a double-blind, placebo-controlled, phase 2, single centre trial (TESDAD). Participants were randomly assigned at the IMIM-Hospital del Mar Medical Research Institute to receive EGCG (9 mg/kg per day) or placebo and cognitive training for 12 months. We followed up participants for 6 months after treatment discontinuation. We randomly assigned participants using random-number tables and balanced allocation by sex and intellectual quotient. Participants, families, and researchers assessing the participants were masked to treatment allocation. The primary endpoint was cognitive improvement assessed by neuropsychologists with a battery of cognitive tests for episodic memory, executive function, and functional measurements. Analysis was on an intention-to-treat basis. This trial is registered with ClinicalTrials.gov, number NCT01699711. FINDINGS: The study was done between June 5, 2012, and June 6, 2014. 84 of 87 participants with Down's syndrome were included in the intention-to-treat analysis at 12 months (43 in the EGCG and cognitive training group and 41 in the placebo and cognitive training group). Differences between the groups were not significant on 13 of 15 tests in the TESDAD battery and eight of nine adaptive skills in the Adaptive Behavior Assessment System II (ABAS-II). At 12 months, participants treated with EGCG and cognitive training had significantly higher scores in visual recognition memory (Pattern Recognition Memory test immediate recall, adjusted mean difference: 6·23 percentage points [95% CI 0·31 to 12·14], p=0·039; d 0·4 [0·05 to 0·84]), inhibitory control (Cats and Dogs total score, adjusted mean difference: 0·48 [0·02 to 0·93], p=0·041; d 0·28 [0·19 to 0·74]; Cats and Dogs total response time, adjusted mean difference: -4·58 s [-8·54 to -0·62], p=0·024; d -0·27 [-0·72 to -0·20]), and adaptive behaviour (ABAS-II functional academics score, adjusted mean difference: 5·49 [2·13 to 8·86], p=0·002; d 0·39 [-0·06 to 0·84]). No differences were noted in adverse effects between the two treatment groups. INTERPRETATION: EGCG and cognitive training for 12 months was significantly more effective than placebo and cognitive training at improving visual recognition memory, inhibitory control, and adaptive behaviour. Phase 3 trials with a larger population of individuals with Down's syndrome will be needed to assess and confirm the long-term efficacy of EGCG and cognitive training. FUNDING: Jérôme Lejeune Foundation, Instituto de Salud Carlos III FEDER, MINECO, Generalitat de Catalunya.

A new cognitive evaluation battery for Down syndrome and its relevance for clinical trials.

The recent prospect of pharmaceutical interventions for cognitive impairment of Down syndrome (DS) has boosted a number of clinical trials in this population. However, running the trials has raised some methodological challenges and questioned the prevailing methodology used to evaluate cognitive functioning of DS individuals. This is usually achieved by comparing DS individuals to matched healthy controls of the same mental age. We propose a new tool, the TESDAD Battery that uses comparison with age-matched typically developed adults. This is an advantageous method for probing the clinical efficacy of DS therapies, allowing the interpretation and prediction of functional outcomes in clinical trials. In our DS population the TESDAD battery permitted a quantitative assessment of cognitive defects, which indicated language dysfunction and deficits in executive function, as the most important contributors to other cognitive and adaptive behavior outcomes as predictors of functional change in DS. Concretely, auditory comprehension and functional academics showed the highest potential as end-point measures of therapeutic intervention for clinical trials: the former as a cognitive key target for therapeutic intervention, and the latter as a primary functional outcome measure of clinical efficacy. Our results also emphasize the need to explore the modulating effects of IQ, gender and age on cognitive enhancing treatments. Noticeably, women performed significantly better than men of the same age and IQ in most cognitive tests, with the most consistent differences occurring in memory and executive functioning and negative trends rarely emerged on quality of life linked to the effect of age after adjusting for IQ and gender. In sum, the TESDAD battery is a useful neurocognitive tool for probing the clinical efficacy of experimental therapies in interventional studies in the DS population suggesting that age-matched controls are advantageous for determining normalization of DS.

Diferencias en manifestaciones clínicas y gravedad en niños con tuberculosis menores y mayores de 1 año / Differences in clinical manifestations and severity in patients with tuberculosis in children under one year and older

Introducción: Debido a la inmadurez del sistema inmune en los primeros años de vida, la edad sería uno de los factores más importantes que determinaría progreso de infección tuberculosa a enfermedad en individuos inmunocompetentes. Evaluamos si pacientes con tuberculosis menores de un año tienen mayor riesgo de presentar manifestaciones clínicas extrapulmonares y mayor gravedad que los mayores de un año. Población y métodos: Estudio de casos y controles incluyendo niños con tuberculosis menores (n=30) y mayores (n=60) de 1 año de edad. Se analizaron manifestaciones clínicas (pulmonar/extrapulmonar) y gravedad (moderada/grave). Resultados: De acuerdo a la metodología utilizada y al análisis estadístico aplicado, no se encontraron diferencias significativas entre menores y mayores de un año en relación a proporción de manifestaciones extrapulmonares (23,3% vs. 8,3% p=0,09; OR=3,35 IC95=0,81-14,65), ni a la de formas graves (23,3% vs. 8,3%; p=0,09; OR=3,35 IC95%=0,81-14,65). Al excluir pacientes con comorbilidades (n=11) el análisis de la proporción de formas extrapulmonares entre los menores y mayores de 1 año fue el siguiente: 25,9% vs. 7,7% p=0,03; OR=4,2 IC95%=0,93-21,6. Los datos comparativos analizando la gravedad fueron: 25,9% vs. 7,7%; p=0,03; OR=4,2 IC95%=0,93-21,6. Conclusión: No encontramos diferencias significativas en manifestaciones clínicas ni gravedad de tuberculosis entre menores y mayores de un año. Es posible que este hecho se halle influenciado por un tamaño muestral insuficiente, particularmente en pacientes sin comorbilidades.

Introduction: Because of immature cell-mediated immunity in young children, age could be one of the most important factors determining progression of tuberculosis from infection to disease.We evaluated whether children with tuberculosis below one year of age had a greater risk for extrapulmonary or severe tuberculosis than older children.Population and methods: Case-control study including children with tuberculosis below one year of age (n=30) and older children (n=60). We analyzed clinical manifestations (pulmonary/extrapulmonary) and severity (moderate/severe).Results: There were no significant differences in the proportions of extrapulmonary manifestations (23.3% vs. 8.3%; p=0.09; OR=3.35; IC95=0.81-14.65), and the proportions of severe cases (23.3% vs. 8.3%; p=0.09; OR=3.35; IC95=0.81-14.65), between children with tuberculosis younger and older of one year. After controlling for comorbidities (n=11), the proportions of extrapulmonary manifestations between the two age groups were: 25.9% vs. 7.7% (p=0,03; OR=4.2; IC95%=0.93-21.6), and the proportions of severe cases were: 25.9% vs. 7.7% (p=0.03; OR=4.2; IC95%=0,93-21.6). Conclusion: There were no significant differences in prevalence of extrapulmonary manifestations or severe cases between children with tuberculosis younger and older of one year. These findings could be influenced by a limited sample size, especially regarding patients without comorbidities.