Clinical pharmacokinetics of leriglitazone and a translational approach using PBPK modeling to guide the selection of the starting dose in children.

Leriglitazone is a unique peroxisome proliferator-activated receptor-gamma (PPARγ) agonist that crosses the blood-brain barrier in humans and clinical trials have shown evidence of efficacy in neurodegenerative diseases. At clinical doses which are well-tolerated, leriglitazone reaches the target central nervous system (CNS) concentrations that are needed for PPARγ engagement and efficacy; PPARγ engagement is also supported by clinical and anti-inflammatory biomarker changes in the Cerebrospinal fluid in the CNS. Plasma pharmacokinetics (PK) of leriglitazone were determined in a phase 1 study in male healthy volunteers comprising a single ascending dose (SAD) and a multiple ascending dose (MAD) at oral doses of 30, 90, and 270 mg and 135 and 270 mg, respectively. Leriglitazone was rapidly absorbed with no food effect on overall exposure and showed a linear PK profile with dose-exposure correlation. A physiologically based pharmacokinetic (PBPK) model was developed for leriglitazone based on phase 1 data (SAD part) and incorporated CYP3A4 (fmCYP3A4 = 24%) and CYP2C8-mediated (fmCYP2C8 = 45%) metabolism, as well as biliary clearance (feBIL = 19.5%) derived from in vitro data, and was verified by comparing the observed versus predicted concentration-time profiles from the MAD part. The PBPK model was prospectively applied to predict the starting pediatric doses and was preliminarily verified with data from five pediatric patients.

Safety and efficacy of leriglitazone for preventing disease progression in men with adrenomyeloneuropathy (ADVANCE): a randomised, double-blind, multi-centre, placebo-controlled phase 2-3 trial.

BACKGROUND: Adult patients with adrenoleukodystrophy have a poor prognosis owing to development of adrenomyeloneuropathy. Additionally, a large proportion of patients with adrenomyeloneuropathy develop life-threatening progressive cerebral adrenoleukodystrophy. Leriglitazone is a novel selective peroxisome proliferator-activated receptor gamma agonist that regulates expression of key genes that contribute to neuroinflammatory and neurodegenerative processes implicated in adrenoleukodystrophy disease progression. We aimed to assess the effect of leriglitazone on clinical, imaging, and biochemical markers of disease progression in adults with adrenomyeloneuropathy. METHODS: ADVANCE was a 96-week, randomised, double-blind, placebo-controlled, phase 2-3 trial done at ten hospitals in France, Germany, Hungary, Italy, the Netherlands, Spain, the UK, and the USA. Ambulatory men aged 18-65 years with adrenomyeloneuropathy without gadolinium enhancing lesions suggestive of progressive cerebral adrenoleukodystrophy were randomly assigned (2:1 without stratification) to receive daily oral suspensions of leriglitazone (150 mg starting dose; between baseline and week 12, doses were increased or decreased to achieve plasma concentrations of 200 µg·h/mL [SD 20%]) or placebo by means of an interactive response system and a computer-generated sequence. Investigators and patients were masked to group assignment. The primary efficacy endpoint was change from baseline in the Six-Minute Walk Test distance at week 96, analysed in the full-analysis set by means of a mixed model for repeated measures with restricted maximum likelihood and baseline value as a covariate. Adverse events were also assessed in the full-analysis set. This study was registered with ClinicalTrials.gov, NCT03231878; the primary study is complete; patients had the option to continue treatment in an open-label extension, which is ongoing. FINDINGS: Between Dec 8, 2017, and Oct 16, 2018, of 136 patients screened, 116 were randomly assigned; 62 [81%] of 77 patients receiving leriglitazone and 34 [87%] of 39 receiving placebo completed treatment. There was no between-group difference in the primary endpoint (mean [SD] change from baseline leriglitazone: -27·7 [41·4] m; placebo: -30·3 [60·5] m; least-squares mean difference -1·2 m; 95% CI -22·6 to 20·2; p=0·91). The most common treatment emergent adverse events in both the leriglitazone and placebo groups were weight gain (54 [70%] of 77 vs nine [23%] of 39 patients, respectively) and peripheral oedema (49 [64%] of 77 vs seven [18%] of 39). There were no deaths. Serious treatment-emergent adverse events occurred in 14 (18%) of 77 patients receiving leriglitazone and ten (26%) of 39 patients receiving placebo. The most common serious treatment emergent adverse event, clinically progressive cerebral adrenoleukodystrophy, occurred in six [5%] of 116 patients, all of whom were in the placebo group. INTERPRETATION: The primary endpoint was not met, but leriglitazone was generally well tolerated and rates of adverse events were in line with the expected safety profile for this drug class. The finding that cerebral adrenoleukodystrophy, a life-threatening event for patients with adrenomyeloneuropathy, occurred only in patients in the placebo group supports further investigation of whether leriglitazone might slow the progression of cerebral adrenoleukodystrophy. FUNDING: Minoryx Therapeutics.

Clinical burden related to oral corticosteroid treatment of severe asthma in Spain: LEVANTE study.

BACKGROUND: Severe asthma treatment with oral corticosteroids (OCS) added to inhaled corticosteroids and a long-acting ß2-agonist (ICS-LABA) may result in more treatment burden and increased adverse effects. OBJECTIVE AND METHODS: This ambispective multicenter observational study aimed at describing the clinical burden in patients with severe asthma on stable high-dose ICS-LABA who received OCS during ≥6 months (maintenance group) or ≥2 cycles in the previous 12 months (bursts group). Data collection comprised a retrospective 12-month baseline period and 2 follow-up visits at 3 and 6 months. RESULTS: Eighty-nine patients were evaluable (30 on maintenance, 59 on bursts). At baseline, mean (SD) daily prednisone equivalent exposure in the total population was 24.6 (14.7) mg: 13.8 (9.4) mg on maintenance and 29.9 (14.3) mg on bursts. During the 6-month follow-up period, mean (SD) daily dose in the total cohort was 22.5 (18.8) mg: 17.2 (18.6) mg on maintenance and 28.4 (20.6) mg on bursts. The overall annual severe exacerbations rate during the 12-month baseline period was 2.05 per patient-year and 1.5 per patient-year over the 6-month follow-up, and frequency of hospitalizations and emergency department visits were similar on both maintenance and bursts use. CONCLUSIONS: Results show a suboptimal control of severe asthma despite such high doses of OCS and persistence of disease burden regardless of the prescribing pattern in maintenance or bursts. There is therapeutic inertia to continue using OCS despite the increased risk of adverse effects and the availability of biologics.

Efficacy and Safety of Leriglitazone in Patients With Friedreich Ataxia: A Phase 2 Double-Blind, Randomized Controlled Trial (FRAMES).

Background and Objectives: Friedreich ataxia (FRDA) is an autosomal recessive ataxia with no approved treatments. Leriglitazone is a selective peroxisome proliferator-activated receptor γ agonist that crosses the blood-brain barrier and, in preclinical models, improved mitochondrial function and energy production. We assessed effects of leriglitazone in patients with FRDA in a proof-of-concept study. Methods: In this double-blind, randomized controlled trial, eligible participants (age 12-60 years) had genetically confirmed FRDA, a Scale for the Assessment and Rating of Ataxia (SARA) total score <25, and a SARA item 1 score of 2-6, inclusive. Key exclusion criteria were age at FRDA onset ≥25 years and history of cardiac dysfunction. Participants were randomly assigned (2:1) to receive a daily, oral, individualized dose of leriglitazone or placebo for 48 weeks. The primary endpoint was the change from baseline to week 48 in spinal cord area (C2-C3) (measured by MRI). Secondary endpoints included the change from baseline to week 48 in iron accumulation in the dentate nucleus (quantitative susceptibility mapping) and total N-acetylaspartate to myo-inositol (tNAA/mIns) ratio. Results: Overall, 39 patients were enrolled (mean age 24 years; 43.6% women; mean time since symptom onset 10.5 years): 26 patients received leriglitazone (20 completed) and 13 received placebo (12 completed). There was no difference between groups in spinal cord area from baseline to week 48 (least-squares [LS] mean change [standard error (SE)]: leriglitazone, -0.39 [0.55] mm2; placebo, 0.08 [0.72] mm2; p = 0.61). Iron accumulation in the dentate nucleus was greater with placebo (LS mean change [SE]: leriglitazone, 0.10 [1.33] ppb; placebo, 4.86 [1.84] ppb; p = 0.05), and a numerical difference was seen in tNAA/mIns ratio (LS mean change [SE]: leriglitazone, 0.03 [0.02]; placebo, -0.02 [0.03]; p = 0.25). The most frequent adverse event was peripheral edema (leriglitazone 73.1%, placebo 0%). Discussion: The primary endpoint of change in spinal cord area was not met. Secondary endpoints provide evidence supporting proof of concept for leriglitazone mode of action and, with acceptable safety data, support larger studies in patients with FRDA. Trial Registration Information: ClinicalTrials.gov: NCT03917225; EudraCT: 2018-004405-64; submitted April 17, 2019; first patient enrolled April 2, 2019. clinicaltrials.gov/ct2/show/NCT03917225?term=NCT03917225&draw=2&rank=1. Classification of Evidence: This study provides Class I evidence that individualized dosing of leriglitazone, compared with placebo, is not associated with changes in spinal cord area in patients with FRDA.

The brain penetrant PPARγ agonist leriglitazone restores multiple altered pathways in models of X-linked adrenoleukodystrophy.

X-linked adrenoleukodystrophy (X-ALD), a potentially fatal neurometabolic disorder with no effective pharmacological treatment, is characterized by clinical manifestations ranging from progressive spinal cord axonopathy [adrenomyeloneuropathy (AMN)] to severe demyelination and neuroinflammation (cerebral ALD-cALD), for which molecular mechanisms are not well known. Leriglitazone is a recently developed brain penetrant full PPARγ agonist that could modulate multiple biological pathways relevant for neuroinflammatory and neurodegenerative diseases, and particularly for X-ALD. We found that leriglitazone decreased oxidative stress, increased adenosine 5'-triphosphate concentration, and exerted neuroprotective effects in primary rodent neurons and astrocytes after very long chain fatty acid-induced toxicity simulating X-ALD. In addition, leriglitazone improved motor function; restored markers of oxidative stress, mitochondrial function, and inflammation in spinal cord tissues from AMN mouse models; and decreased the neurological disability in the EAE neuroinflammatory mouse model. X-ALD monocyte-derived patient macrophages treated with leriglitazone were less skewed toward an inflammatory phenotype, and the adhesion of human X-ALD monocytes to brain endothelial cells decreased after treatment, suggesting the potential of leriglitazone to prevent the progression to pathologically disrupted blood-brain barrier. Leriglitazone increased myelin debris clearance in vitro and increased myelination and oligodendrocyte survival in demyelination-remyelination in vivo models, thus promoting remyelination. Last, leriglitazone was clinically tested in a phase 1 study showing central nervous system target engagement (adiponectin increase) and changes on inflammatory biomarkers in plasma and cerebrospinal fluid. The results of our study support the use of leriglitazone in X-ALD and, more generally, in other neuroinflammatory and neurodegenerative conditions.

Association of the CFTR gene with asthma and airway mucus hypersecretion.

INTRODUCTION: Asthma with airway mucus hypersecretion is an inadequately characterized variant of asthma. While several studies have reported that hypersecreting patients may carry genetic variants in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, many of those studies have been questioned for their numerous limitations and contradictory results. OBJECTIVES: (1) To determine the presence of genetic variants of the CFTR gene in patients with asthma with and without airway mucus hypersecretion. (2) To identify the clinical, inflammatory and functional characteristics of the asthma phenotype with airway mucus hypersecretion. METHOD: Comparative multicentre cross-sectional descriptive study that included 100 patients with asthma (39 hypersecretors and 61 non-hypersecretors). Asthmatic hypersecretion was defined as the presence of cough productive of sputum on most days for at least 3 months in 2 successive years. The patients were tested for fractional exhaled nitric oxide, spirometry, induced sputum cell count, total immunoglobulin E (IgE), peripheral blood eosinophil count, C-reactive protein, blood fibrinogen and blood albumin and underwent a skin prick test. Asthma control and quality of life were assessed by the Asthma Control Test and Mini Asthma Quality of Life questionnaires, respectively. Blood DNA samples were collected from the patients and next-generation sequencing using a MiSeq sequencer and the Illumina platform was used for the CFTR gene analysis. RESULTS: Genetic differences were observed in the c.1680-870T>A polymorphism of the CFTR gene, significantly more evident in hypersecretors than in non-hypersecretors: 78.94% vs. 59.32% in the majority allele and 21.05% vs. 40.67% in the minority allele (p = 0.036). Clinically, asthma hypersecretors compared to non-hypersecretors were older (57.4 years vs. 49.4 years; p = 0.004); had greater asthma severity (58.9% vs. 23.7%; p = 0.005); experienced greater airway obstruction (FEV1/FVC% 64.3 vs. 69.5; p = 0.041); had poorer asthma control (60% vs. 29%; p = 0.021); had lower IgE levels (126.4 IU/mL vs. 407.6 IU/mL; p = 0.003); and were less likely to have a positive prick test (37.5% vs. 68.85%; p = 0.011). CONCLUSION: The results suggest that patients with asthma and with mucus hypersecretion (1) may have a different phenotype and disease mechanism produced by an intronic polymorphism in the CFTR gene (NM_000492.3:c.1680-870T>A), and (2) may have a poorer clinical outcome characterized by severe disease and poorer asthma control with a non-allergic inflammatory phenotype.

Effects of smoking bans on passive smoking exposure at work and at home. The European Community respiratory health survey.

This longitudinal study investigated whether smoking bans influence passive smoking at work and/or at home in the same subjects. Passive smoking at work and/or at home was investigated in random population samples (European Community Respiratory Health Survey) in 1990-1995, with follow-up interviews in 1998-2003 and 2010-2014. National smoking bans were classified as partial (restricted to public workplaces) or global (extended to private workplaces). Multivariable analysis was accomplished by three-level logistic regression models, where level-1, level-2, and level-3 units were, respectively, questionnaire responses, subjects, and centers. Passive smoking at work was reported by 31.9% in 1990-1995, 17.5% in 1998-2003, and 2.5% in 2010-2014. Concurrently, passive smoking at home decreased from 28.9% to 18.2% and 8.8%. When controlling for sex, age, education, smoking status, and ECHRS wave, the odds of passive smoking at work was markedly reduced after global smoking bans (OR = 0.45, 95% CI 0.25-0.81), particularly among non-smokers, while the protective effect of global smoking bans on passive smoking at home was only detected in non-smokers. Smoking bans both in public and private workplaces were effective in reducing passive smoking at work in Europe. However, given the inefficacy of smoking bans in current smokers' dwellings, better strategies are needed to avoid smoking indoors.

Restrictive spirometry pattern is associated with low physical activity levels. A population based international study.

INTRODUCTION: Restrictive spirometry pattern is an under-recognised disorder with a poor morbidity and mortality prognosis. We compared physical activity levels between adults with a restrictive spirometry pattern and with normal spirometry. METHODS: Restrictive spirometry pattern was defined as a having post-bronchodilator FEV1/FVC ≥ Lower Limit of Normal and a FVC<80% predicted in two population-based studies (ECRHS-III and SAPALDIA3). Physical activity was measured using the International Physical Activity Questionnaire. The odds of having low physical activity (<1st study-specific tertile) was evaluated using adjusted logistic regression models. RESULTS: Subjects with a restrictive spirometry pattern (n = 280/4721 in ECRHS, n = 143/3570 in SAPALDIA) reported lower levels of physical activity than those with normal spirometry (median of 1770 vs 2253 MET·min/week in ECRHS, and 3519 vs 3945 MET·min/week in SAPALDIA). Subjects with a restrictive spirometry pattern were more likely to report low physical activity (meta-analysis odds ratio: 1.41 [95%CI 1.07-1.86]) than those with a normal spirometry. Obesity, respiratory symptoms, co-morbidities and previous physical activity levels did not fully explain this finding. CONCLUSION: Adults with a restrictive spirometry pattern were more likely to report low levels of physical activity than those with normal spirometry. These results highlight the need to identify and act on this understudied but prevalent condition.

Residential air pollution does not modify the positive association between physical activity and lung function in current smokers in the ECRHS study.

BACKGROUND: Very few studies have examined whether a long-term beneficial effect of physical activity on lung function can be influenced by living in polluted urban areas. OBJECTIVE: We assessed whether annual average residential concentrations of nitrogen dioxide (NO2) and particulate matter with aerodynamic diameters < 2.5 µm (PM2.5) and <10 µm (PM10) modify the effect of physical activity on lung function among never- (N = 2801) and current (N = 1719) smokers in the multi-center European Community Respiratory Health Survey. METHODS: Associations between repeated assessments (at 27-57 and 39-67 years) of being physically active (physical activity: ≥2 times and ≥1 h per week) and forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) were evaluated using adjusted mixed linear regression models. Models were conducted separately for never- and current smokers and stratified by residential long-term NO2, PM2.5 mass and PM10 mass concentrations (≤75th percentile (low/medium) versus >75th percentile (high)). RESULTS: Among current smokers, physical activity and lung function were positively associated regardless of air pollution levels. Among never-smokers, physical activity was associated with lung function in areas with low/medium NO2, PM2.5 mass and PM10 mass concentrations (e.g. mean difference in FVC between active and non-active subjects was 43.0 mL (13.6, 72.5), 49.5 mL (20.1, 78.8) and 49.7 mL (18.6, 80.7), respectively), but these associations were attenuated in high air pollution areas. Only the interaction term of physical activity and PM10 mass for FEV1 among never-smokers was significant (p-value = 0.03). CONCLUSIONS: Physical activity has beneficial effects on adult lung function in current smokers, irrespective of residential air pollution levels in Western Europe. Trends among never-smokers living in high air pollution areas are less clear.

Direct Evidence of the Presence of Cross-Linked Aß Dimers in the Brains of Alzheimer's Disease Patients.

Brain-derived amyloid-ß (Aß) dimers are associated with Alzheimer's disease (AD). However, their covalent nature remains controversial. This feature is relevant, as a covalent cross-link has been proposed to make brain-derived dimers (brain dimers) more synaptotoxic than Aß monomers and would also make them suitable candidates for biomarker development. To resolve this controversy, we here present a three-step approach. First, we validated a type of synthetic cross-linked Aß (CL Aß) dimers, obtained by means of the photoinduced cross-linking of unmodified proteins (PICUP) reaction, as well-defined mimics of putative brain CL Aß dimers. Second, we used these PICUP CL Aß dimers as standards to improve the isolation of brain Aß dimers and to develop state-of-the-art mass spectrometry (MS) strategies to allow their characterization. Third, we applied these MS methods to the analysis of brain Aß dimer samples allowing the detection of the CL [Aß(6-16)]2 peptide comprising a dityrosine cross-link. This result demonstrates the presence of CL Aß dimers in the brains of patients with AD and opens up avenues for establishing new therapeutic targets and developing novel biomarkers for this disease.

Predicting 1-year mortality after hospitalization for community-acquired pneumonia.

BACKGROUND: Community-acquired pneumonia (CAP) is a major public health problem with high short- and long-term mortality. The main aim of this study was to develop and validate a specific prognostic index for one-year mortality in patients admitted for CAP. METHODS: This was an observational, prospective study of adults aged ≥18 years admitted to Galdakao-Usansolo Hospital (Bizkaia, Spain) from January 2001 to July 2009 with a diagnosis of CAP surviving the first 15 days. The entire cohort was divided into two parts, in order to develop a one-year mortality predictive model in the derivation cohort, before validation using the second cohort. RESULTS: A total of 2351 patients were included and divided into a derivation and a validation cohort. After deaths within 15 days were excluded, one-year mortality was 10.63%. A predictive model was created in order to predict one-year mortality, with a weighted score that included: aged over 80 years (4 points), congestive heart failure (2 points), dementia (6 points), respiratory rate ≥30 breaths per minute (2 points) and blood urea nitrogen >30 mg/dL (3 points) as predictors of higher risk with C-index of 0.76. This new model showed better predictive ability than current risk scores, PSI, CURB65 and SCAP with C-index of 0.73, 0.69 and 0.70, respectively. CONCLUSIONS: An easy-to-use score, called the one-year CAPSI, may be useful for identifying patients with a high probability of dying after an episode of CAP.

Accreditation of specialized asthma units for adults in Spain: an applicable experience for the management of difficult-to-control asthma.

This paper, developed by consensus of staff physicians of accredited asthma units for the management of severe asthma, presents information on the process and requirements for already-existing asthma units to achieve official accreditation by the Spanish Society of Pneumology and Thoracic Surgery (SEPAR). Three levels of specialized asthma care have been established based on available resources, which include specialized units for highly complex asthma, specialized asthma units, and basic asthma units. Regardless of the level of accreditation obtained, the distinction of "excellence" could be granted when more requirements in the areas of provision of care, technical and human resources, training in asthma, and teaching and research activities were met at each level. The Spanish experience in the process of accreditation of specialized asthma units, particularly for the care of patients with difficult-to-control asthma, may be applicable to other health care settings.

SDS-PAGE analysis of Aß oligomers is disserving research into Alzheimer´s disease: appealing for ESI-IM-MS.

The characterization of amyloid-beta peptide (Aß) oligomer forms and structures is crucial to the advancement in the field of Alzheimer´s disease (AD). Here we report a critical evaluation of two methods used for this purpose, namely sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), extensively used in the field, and ion mobility coupled to electrospray ionization mass spectrometry (ESI-IM-MS), an emerging technique with great potential for oligomer characterization. To evaluate their performance, we first obtained pure cross-linked Aß40 and Aß42 oligomers of well-defined order. Analysis of these samples by SDS-PAGE revealed that SDS affects the oligomerization state of Aß42 oligomers, thus providing flawed information on their order and distribution. In contrast, ESI-IM-MS provided accurate information, while also reported on the chemical nature and on the structure of the oligomers. Our findings have important implications as they challenge scientific paradigms in the AD field built upon SDS-PAGE characterization of Aß oligomer samples.

Asthma control and concordance of opinions between patients and pulmonologists.

UNLABELLED: Patient-physician opinion concordance could play a key role in asthma control. There have been no studies evaluating this association in large samples of patients. OBJECTIVES: To determine opinion concordance between asthma patients and their pulmonologists on the impact of the disease and to correlate concordance to asthma control. METHODS: This was a cross-sectional multicentre study including 1160 patients and 300 pulmonologists. Patient-physician concordance rates were assessed by two semi-structured qualitative questionnaires: (1) impact of the disease and (2) treatment satisfaction. Subsequently, participating pulmonologists determined the concordance between their perceptions and their patient's. Sociodemographic and clinical data were recorded for all patients. RESULTS: In 53.6% of cases, asthma was controlled. The rate of patient-pulmonologist concordance on disease impact on patient daily life was 57%, with physicians underestimating the impact (compared to patients) in 26% of cases. Concordance on satisfaction with treatment was 56%, with physicians underestimating satisfaction in 26% of cases. Patient-physician discordance rates were significantly lower among patients with controlled asthma (29 and 32.1%) than those with poor control (73.7 and 73.1%). CONCLUSIONS: Patient-pulmonologist concordance on perceptions of disease impact is low, particularly in uncontrolled asthma. This poor concordance should be addressed in education programmes, particularly for patients with uncontrolled symptoms.

Pharmacokinetics and safety of aclidinium bromide in younger and elderly patients with chronic obstructive pulmonary disease.

OBJECTIVE: To investigate the pharmacokinetics, safety and tolerability of aclidinium bromide 200 µg and 400 µg after a single dose and repeated once-daily doses in younger and elderly patients with moderate or severe chronic obstructive pulmonary disease (COPD). METHODS: Younger (40-59 years; n = 12) and elderly (≥ 70 years; n = 12) patients were treated with aclidinium via the Genuair® inhaler. Patients received once-daily aclidinium 200 µg for 3 days; after a 7-day washout period, patients received once-daily aclidinium 400 µg for 3 days. Pharmacokinetic analyses were conducted on plasma and urine on Days 1 and 3 of both treatment periods. Safety and tolerability were assessed. RESULTS: Aclidinium showed similar linear and time-independent pharmacokinetics in younger and elderly patients at each dose level and day of treatment. For both age groups at each dose level and day, aclidinium appeared rapidly in the plasma with a median tmax between 10 and 15 min; concentrations of aclidinium in the plasma declined rapidly with a t1/2 between 1 and 3 h. Plasma exposure with the 400 µg dose was ~ 2-fold higher than for the 200 µg dose in both age groups on both days. For both age groups, urinary excretion of aclidinium over 24 h was < 0.15% of the dose at each dose and day. Aclidinium 200 µg and 400 µg were safe and well tolerated in both age groups. CONCLUSION: These data suggest that no dose adjustment of aclidinium is required when treating elderly patients with COPD.

Impact of anxiety and depression on disease control and quality of life in asthma patients.

INTRODUCTION: Patients with asthma also tend to have anxiety and depression. These comorbidities may affect asthma control and quality of life. The objective of this study was to assess the impact of anxiety and depression on asthma control and quality of life. PATIENTS AND METHODS: Cross-sectional study of asthma outpatients was conducted at two hospitals in the Basque Country (northern Spain). Data collected included sociodemographic variables, asthma symptoms, treatment, number of exacerbations, level of control, quality of life, presence of psychological morbidities, and level of physical activity. Spirometry was performed in accordance with the recommendations of the Spanish Society of Pneumology and Thoracic Surgery. RESULTS: Among 354 asthmatics, 77% had poor or partial control of their condition, 31% had anxiety alone, 2% had depression alone, and 10% had anxiety plus depression. Poor asthma control was associated with anxiety plus depression (odds ratio (OR): 3.61; 95% confidence interval (CI): 1.05-12.41) as well as with female patients (OR: 1.85; 95% CI: 1.11-3.10). Anxiety had an independent effect on reduced quality of life across all domains; anxiety plus depression had an even greater effect. CONCLUSION: Among patients with asthma, anxiety and depression adversely affect asthma control and quality of life, raising the possibility that treating these psychological comorbidities could improve asthma control and quality of life.

Prevalencia de silicosis en una marmolería tras la exposición a conglomerados de cuarzo / Prevalence of silicosis in a marble factory after exposure to quartz conglomerates

En esta nota mostramos la elevada prevalencia de silicosis encontrada en una marmolería tras una exposición a una novedosa presentación de sílice.Se trata de un estudio observacional, prospectivo, en el que se han estudiado 11 trabajadores que se exponen desde 1995 a diversas presentaciones de superficies de cuarzo. Los puestos de trabajo se dividen en dos grupos: por una parte 4 sujetos desarrollan trabajos de corte en el taller; el resto de los trabajadores trabaja en el montaje. Hasta la fecha no han utilizado sistemas de protección respiratoria específicos.Se han diagnosticado 6 casos de silicosis, lo que supone una prevalencia de enfermedad para este ámbito del 54,5%. De los 6 afectados, 5 (83,33%) son montadores.Destacamos el elevado riesgo de desarrollo de silicosis en el manejo de los diversos productos que conforman la gama de superficies de cuarzo(AU)

In this note we present the increased prevalence of silicosis found in a marble factory after exposure to a new presentation of silica.A prospective, observational study was conducted on 11 workers who were exposed to different presentations of quartz surfaces since 1995. The jobs were divided into two groups: 4 subjects worked in the cutting workshop; the rest of the workers worked in assembly. Up to that date they had not used any specific respiratory protection apparatus.Six cases of silicosis have been diagnosed, which assumes a disease prevalence in this environment of 54.5%. Of the 6 affected, 5 (83.3% are assemblers.We highlight the high risk of developing silicosis in the handling of different products which make up the range of quartz surfaces(AU)

Prevalence of silicosis in a marble factory after exposure to quartz conglomerates.

In this note we present the increased prevalence of silicosis found in a marble factory after exposure to a new presentation of silica. A prospective, observational study was conducted on 11 workers who were exposed to different presentations of quartz surfaces since 1995. The jobs were divided into two groups: 4 subjects worked in the cutting workshop; the rest of the workers worked in assembly. Up to that date they had not used any specific respiratory protection apparatus. Six cases of silicosis have been diagnosed, which assumes a disease prevalence in this environment of 54.5%. Of the 6 affected, 5 (83.3% are assemblers. We highlight the high risk of developing silicosis in the handling of different products which make up the range of quartz surfaces.