Tripartite Genuine Non-Gaussian Entanglement in Three-Mode Spontaneous Parametric Down-Conversion.

We show that the states generated by a three-mode spontaneous parametric down-conversion (SPDC) interaction Hamiltonian possess tripartite entanglement of a different nature to other paradigmatic three-mode entangled states generated by the combination of two-mode SPDC interactions. While two-mode SPDC generates Gaussian states whose entanglement can be characterized by standard criteria based on two-mode quantum correlations, these criteria fail to capture the entanglement generated by three-mode SPDC. We use criteria built from three-mode correlation functions to show that the class of states recently generated in a superconducting-circuit implementation of three-mode SPDC ideally have tripartite entanglement, contrary to recent claims in the literature. These criteria are suitable for triple SPDC but we show that they fail to detect tripartite entanglement in other states which are known to possess it, which illustrates the existence of two fundamentally different notions of tripartite entanglement in three-mode continuous-variable systems.

Hurdles of environmental risk assessment procedures for advanced therapy medicinal products: comparison between the European Union and the United States.

An environmental risk assessment (ERA) consists of an analysis of the risks to human health and the environment that a medicinal product may cause due to its release during clinical development or after entering the market. Regulators in European Union (EU) and the United States (US) require that advanced therapy medicinal products (ATMPs) that are also genetically modified organisms (GMOs) undergo an ERA in order to be approved for marketing authorization. This work aims to review the regulatory issues that need to be taken into consideration for carrying out an ERA, comparing the EU and the US. The European regulatory framework for environmental procedures and the dissimilarities in its implementation across the Member States and its implications at a logistical level are analyzed in detail. In addition, this review provides a brief insight into the non-clinical and clinical assessments that should be carried out during the development of the product in order to conduct a successful ERA, and thus facilitate its marketing authorization and post-marketing monitoring. Finally, the need for a European harmonization regarding environmental procedures for ATMPs is discussed.

Early Life Origins of Asthma: A Review of Potential Effectors.

There is growing evidence that events occurring early in life, both before and after birth, are significantly associated with the risk of asthma, chronic obstructive pulmonary disease, and diminished lung function later in life. In fact, from conception to death, a series of continuous, dynamic gene-environment interactions determine 2 fundamental biological processes, namely, lung development and lung aging. Over 130 birth cohorts have been initiated in the last 30 years. Data from these cohorts have improved our understanding of the inception, progression, and persistency of asthma. In this review, we summarize the main data for the early life events proven to determine later development and persistence of asthma, such as maternal atopy and smoking, preterm birth/bronchopulmonary dysplasia, infections, nutrition, obesity, smoking, and other environmental exposures in childhood and adolescence. While some of these factors are obviously impossible to prevent or eliminate, others have been proven to have a protective role, and current research is aimed optimizing them. Available prophylactic measures are also reviewed. In the case of environmental pollution, large scale political interventions successfully managed to decrease contamination levels, leading to improved lung function and lower asthma prevalence in the respective geographical areas. Future research should focus on better understanding these complex interactions in order to develop and enhance effective preventive therapeutic measures.

INTEND II randomized clinical trial of intraoperative duct endoscopy in pathological nipple discharge.

BACKGROUND: The majority of lesions resulting in pathological nipple discharge are benign. Conventional surgery is undirected and targeting the causative lesion by duct endoscopy may enable more accurate surgery with fewer complications. METHODS: Patients requiring microdochectomy and/or major duct excision were randomized to duct endoscopy or no duct endoscopy before surgery. Primary endpoints were successful visualization of the pathological lesion in patients randomized to duct endoscopy, and a comparison of the causative pathology between the two groups. The secondary endpoint was to compare the specimen size between groups. RESULTS: A total of 68 breasts were studied in 66 patients; there were 31 breasts in the duct endoscopy group and 37 in the no-endoscopy group. Median age was 49 (range 19-81) years. Follow-up was 5·4 (i.q.r. 3·3-8·9) years in the duct endoscopy group and 5·7 (3·1-9·0) years in no-endoscopy group. Duct endoscopy had a sensitivity of 80 (95 per cent c.i. 52 to 96) per cent, specificity of 71 (44 to 90) per cent, positive predictive value of 71 (44 to 90) per cent and negative predictive value of 80 (52 to 96) per cent in identifying any lesion. There was no difference in causative pathology between the groups. Median volume of the surgical resection specimen did not differ between groups. CONCLUSION: Diagnostic duct endoscopy is useful for identifying causative lesions of nipple discharge. Duct endoscopy did not influence the pathological yield of benign or malignant diagnoses nor surgical resection volumes. Registered as INTEND II in CancerHelp UK clinical trials database (https://www.cancerresearchuk.org/about-cancer/find-a-clinical-trial/a-study-looking-at-changes-inside-the-breast-ducts-of-women-who-have-nipple-discharge).

A genome-wide analysis of the response to inhaled ß2-agonists in chronic obstructive pulmonary disease.

Short-acting ß2-agonist bronchodilators are the most common medications used in treating chronic obstructive pulmonary disease (COPD). Genetic variants determining bronchodilator responsiveness (BDR) in COPD have not been identified. We performed a genome-wide association study (GWAS) of BDR in 5789 current or former smokers with COPD in one African-American and four white populations. BDR was defined as the quantitative spirometric response to inhaled ß2-agonists. We combined results in a meta-analysis. In the meta-analysis, single-nucleotide polymorphisms (SNPs) in the genes KCNK1 (P=2.02 × 10(-7)) and KCNJ2 (P=1.79 × 10(-7)) were the top associations with BDR. Among African Americans, SNPs in CDH13 were significantly associated with BDR (P=5.1 × 10(-9)). A nominal association with CDH13 was identified in a gene-based analysis in all subjects. We identified suggestive association with BDR among COPD subjects for variants near two potassium channel genes (KCNK1 and KCNJ2). SNPs in CDH13 were significantly associated with BDR in African Americans.The Pharmacogenomics Journal advance online publication, 27 October 2015; doi:10.1038/tpj.2015.65.

Inappropriate prescribing in elderly people with diabetes admitted to hospital.

AIMS: To assess inappropriate prescribing in older people with diabetes mellitus during the month prior to a hospitalization, using tools on potentially inappropriate medicines (PIMs) and potential prescribing omissions (PPOs) and comparing inappropriate prescribing in patients with without diabetes. METHODS: In an observational, prospective multicentric study, we assessed inappropriate prescribing in 672 patients aged 75 years and older during hospital admission. The Beers, Screening Tool of Older Person's Prescriptions (STOPP) and Screening Tool to Alert Doctors to Right Treatment (START) criteria and Assessing Care of Vulnerable Elders (ACOVE-3) medicine quality indicators were used. We analysed demographic and clinical factors associated with inappropriate prescribing. RESULTS: Of 672 patients, 249 (mean age 82.4 years, 62.9% female) had a diagnosis of diabetes mellitus. The mean number of prescribing drugs per patient with diabetes was 12.6 (4.5) vs. 9.4 (4.3) in patients without diabetes (P < 0.001). Of those patients with diabetes, 74.2% used 10 or more medications; 54.5% of patients with diabetes had at least one Beers-listed PIM, 68.1% had at least one STOPP-listed PIM, 64.6% had at least one START-listed PPO and 62.8% had at least one ACOVE-3-listed PPO. Except for the Beers criteria, these prevalences were significantly higher in patients with diabetes than in those without. After excluding diabetes-related items from these tools, only STOPP-listed PIMs remained significantly higher among patients with diabetes (P = 0.04). CONCLUSIONS: Polypharmacy is common among older patients with diabetes mellitus. Inappropriate prescribing is higher in older patients with diabetes, even when diabetes-related treatment is excluded from the inappropriate prescribing evaluation.

Does the COPD assessment test (CAT(TM)) questionnaire produce similar results when self- or interviewer administered?

PURPOSE: The COPD assessment test (CAT) is a questionnaire that assesses the impact of chronic obstructive pulmonary disease (COPD) on health status, but some patients have difficulties filling it up by themselves. We examined whether the mode of administration of the Spanish version of CAT (self vs. interviewer) influences its scores and/or psychometric properties. METHODS: Observational, prospective study in 49 Spanish centers that includes clinically stable COPD patients (n = 153) and patients hospitalized because of an exacerbation (ECOPD; n = 224). The CAT was self-administered (CAT-SA) or administered by an interviewer (CAT-IA) based on the investigator judgment of the patient's capacity. To assess convergent validity, the Saint George's Respiratory Disease Questionnaire (SGRQ) and the London Chest Activity of Daily Living (LCADL) instrument were also administered. Psychometric properties were compared across modes of administration. RESULTS: A total of 118 patients (31 %) completed the CAT-SA and 259 (69 %) CAT-IA. Multiple regression analysis showed that mode of administration did not affect CAT scores. The CAT showed excellent psychometric properties in both modes of administration. Internal consistency coefficients (Cronbach's alpha) were high (0.86 for CAT-SA and 0.85 for CAT-IA) as was test-retest reliability (intraclass correlation coefficients of 0.83 for CAT-SA and CAT-IA). Correlations with SGRQ and LCADL were moderate to strong both in CAT-SA and CAT-IA, indicating good convergent validity. Similar results were observed when testing longitudinal validity. CONCLUSIONS: The mode of administration does not influence CAT scores or its psychometric properties. Hence, both modes of administration can be used in clinical practice depending on the physician judgment of patient's capacity.

Inflammatory Asthma Phenotype Discrimination Using an Electronic Nose Breath Analyzer.

BACKGROUND AND OBJECTIVE: Patients with persistent asthma have different inflammatory phenotypes. The electronic nose is a new technology capable of distinguishing volatile organic compound (VOC) breath-prints in exhaled breath. The aim of the study was to investigate the capacity of electronic nose breath-print analysis to discriminate between different inflammatory asthma phenotypes (eosinophilic, neutrophilic, paucigranulocytic) determined by induced sputum in patients with persistent asthma. METHODS: Fifty-two patients with persistent asthma were consecutively included in a cross-sectional proof-of-concept study. Inflammatory asthma phenotypes (eosinophilic, neutrophilic and paucigranulocytic) were recognized by inflammatory cell counts in induced sputum. VOC breath-prints were analyzed using the electronic nose Cyranose 320 and assessed by discriminant analysis on principal component reduction, resulting in cross-validated accuracy values. Receiver operating characteristic (ROC) curves were calculated. RESULTS: VOC breath-prints were different in eosinophilic asthmatics compared with both neutrophilic asthmatics (accuracy 73%; P=.008; area under ROC, 0.92) and paucigranulocytic asthmatics (accuracy 74%; P=.004; area under ROC, 0.79). Likewise, neutrophilic and paucigranulocytic breath-prints were also different (accuracy 89%; P=.001; area under ROC, 0.88). CONCLUSION: An electronic nose can discriminate inflammatory phenotypes in patients with persistent asthma in a regular clinical setting. ClinicalTrials.gov identifier: NCT02026336.

Determinants of between-hospital variations in outcomes for patients admitted with COPD exacerbations: findings from a nationwide clinical audit (AUDIPOC) in Spain.

BACKGROUND: Previous studies have demonstrated significant variability in the processes of care and outcomes of chronic obstructive pulmonary disease (COPD) exacerbations. The AUDIPOC is a Spanish nationwide clinical audit that identified large between-hospital variations in care and clinical outcomes. Here, we test the hypothesis that these variations can be attributed to either patient characteristics, hospital characteristics and/or the so-called hospital-clustering effect, which indicates that patients with similar characteristics may experience different processes of care and outcomes depending on the hospital to which they are admitted. METHODS: A clinical audit of 5178 COPD patients consecutively admitted to 129 Spanish public hospitals was performed, with a 90-day follow-up. Multilevel regression analysis was conducted to model the probability of patients experiencing adverse outcomes. For each outcome, an empty model (with no independent variables) was fitted to assess the clustering effect, followed by a model adjusted for the patient- and hospital-level covariables. The hospital-clustering effect was estimated using the intracluster correlation coefficient (ICC); the cluster heterogeneity was estimated with the median odds ratio (MOR), and the coefficients of predictors were estimated with the odds ratio (OR). RESULTS: In the empty models, the ICC (MOR) for inpatient mortality and the follow-up mortality and readmission were 0.10 (1.80), 0.08 (1.65) and 0.01 (1.24), respectively. In the adjusted models, the variables that most represented the patients' clinical conditions and interventions were identified as outcome predictors and further reduced the hospital variations. By contrast, the resource factors were primarily unrelated with outcomes. CONCLUSIONS: This study demonstrates a noteworthy reduction in the observed crude between-hospital variation in outcomes after accounting for the hospital-cluster effect and the variables representing patient's clinical conditions. This emphasises the predictor importance of the patients' clinical conditions and interventions, and understates the impacts of hospital resources and organisational factors.

Integrated care pathways for airway diseases (AIRWAYS-ICPs).

The objective of Integrated Care Pathways for Airway Diseases (AIRWAYS-ICPs) is to launch a collaboration to develop multi-sectoral care pathways for chronic respiratory diseases in European countries and regions. AIRWAYS-ICPs has strategic relevance to the European Union Health Strategy and will add value to existing public health knowledge by: 1) proposing a common framework of care pathways for chronic respiratory diseases, which will facilitate comparability and trans-national initiatives; 2) informing cost-effective policy development, strengthening in particular those on smoking and environmental exposure; 3) aiding risk stratification in chronic disease patients, using a common strategy; 4) having a significant impact on the health of citizens in the short term (reduction of morbidity, improvement of education in children and of work in adults) and in the long-term (healthy ageing); 5) proposing a common simulation tool to assist physicians; and 6) ultimately reducing the healthcare burden (emergency visits, avoidable hospitalisations, disability and costs) while improving quality of life. In the longer term, the incidence of disease may be reduced by innovative prevention strategies. AIRWAYSICPs was initiated by Area 5 of the Action Plan B3 of the European Innovation Partnership on Active and Healthy Ageing. All stakeholders are involved (health and social care, patients, and policy makers).

Prevalence of and risk factors for pulmonary abnormalities in HIV-infected patients treated with antiretroviral therapy.

BACKGROUND: Pulmonary abnormalities are often present in patients infected with the human immunodeficiency virus (HIV). OBJECTIVES: The aim of the study was to determine the prevalence and characteristics of, and risk factors for, pulmonary abnormalities in HIV-positive patients. METHODS: A total of 275 HIV-positive patients [mean (± standard deviation) age 48.5 ± 6.6 years] were included in the study, of whom 95.6% had been receiving highly active antiretroviral therapy (HAART) for a mean (± standard deviation) duration of 11.9 ± 5.4 years. The median (interquartile range) CD4 lymphocyte count was 541 (392-813) cells/µL, and 92% of the patients had an undetectable viral load. We determined: (1) spirometry, static lung volumes, lung diffusing capacity, pulmonary gas exchange and exercise tolerance, and (2) the amount of emphysema via a computed tomography (CT) scan. RESULTS: Chronic cough and expectoration (47%) and breathlessness during exercise (33.9%) were commonly reported. Airflow limitation (AL) was present in 17.2%, low pulmonary diffusing capacity in 52.2% and emphysema in 10.5-37.7% of patients, depending on the method used for quantification. Most of these abnormalities had not been diagnosed or treated previously. Smoking exposure and previous tuberculosis were the main risk factors for AL, whereas smoking exposure and several variables related to HIV infection appeared to contribute to the risk of emphysema and low diffusing capacity. CONCLUSIONS: Despite HAART, pulmonary structural and functional abnormalities are frequent in HIV-positive patients. They are probably attributable to both environmental (smoking and tuberculosis) and HIV-related factors. Most of these abnormalities remain unnoticed and untreated. Given the relatively young age of these patients, these results anticipate a significant health problem in the next few years as, thanks to the efficacy of HAART, patients survive longer and experience the effects of aging.

Outcomes of off-label drug uses in hospitals: a multicentric prospective study.

PURPOSE: The study aims to assess the clinical evidence, outcome and cost of off-label use of medicines in the hospital setting. METHODS: A multicentric prospective cohort study of patients treated with off-label medicines was carried out in five tertiary hospitals from May 2011 to May 2012. Information on clinical characteristics of patients, drugs, outcomes and costs was collected. Patients were followed up to 6 months, and information was assessed by reviewing clinical records and interviewing physicians. RESULTS: A total of 226 patients were included. The median (interquartile range (IQR)) age of patients was 46 (33-62) years; 59 % were women. Patients had received a median of three previous treatments, and a lack of response (or suboptimal) was the main reason for off-label use (72.1 %). A total of 232 off-label medicines were administered for 102 different indications. The most frequent medicines were rituximab (49; 21.1 %), botulinum toxin (25; 10.7 %) and omalizumab (14; 6.0 %). In 117 (51.8 %) cases, the level of clinical evidence for their use was low. A partial clinical response was observed in 82 patients (36.3 %), complete response in 71 (31.4 %) and stabilization in 11 (4.9 %). A total of 58 (26.5 %) patients had adverse effects, which in 11 (4.9 %) were severe. The median (IQR) cost per patient was 2,943.07 (541.9-5,872.54). CONCLUSIONS: There was a high variability of off-label medicines and indications. Although the clinical evidence of off-label medicines was often low, clinical response was observed in many patients with previous multiple treatment failure, but at the expense of some adverse effects and a high cost. Registers of patients would be helpful for clinical decisions, although clinical trials are needed.

Available evidence and outcome of off-label use of rituximab in clinical practice.

PURPOSE: To analyze the therapeutic indications for off-label use of rituximab, the available evidence for its use, the outcomes, and the cost. METHODS: This was a retrospective analysis of patients treated with rituximab for off-label indications from January 2007 to December 2009 in two tertiary hospitals. Information on patient characteristics, medical conditions, and therapeutic responses was collected from medical records. Available evidence for the efficacy of rituximab in each condition was reviewed, and the cost of treatment was calculated. RESULTS: A total of 101 cases of off-label rituximab use were analyzed. The median age of the patients involved was 53 [interquartile range (IQR) 37.5-68.0] years; 55.4 % were women. The indications for prescribing rituximab were primarily hematological diseases (46 %), systemic connective tissue disorders (27 %), and kidney diseases (20 %). Available evidence supporting rituximab treatment for these indications mainly came from individual cohort studies (53.5 % of cases) and case series (25.7 %). The short-term outcome (median 3 months, IQR 2-4 months) was a complete response in 38 % of cases and partial response in 32.6 %. The highest short-term responses were observed for systemic lupus erythematosus and membranous glomerulonephritis, and the lowest was for neuromyelitis optica, idiopathic thrombocytopenic purpura, and miscellaneous indications. Some response was maintained in long-term follow-up (median 23 months IQR 12-30 months) in 69.2 % of patients showing a short-term response. Median cost per patient was €5,187.5 (IQR €5,187.5-7,781.3). CONCLUSIONS: In our study, off-label rituximab was mainly used for the treatment of hematological, kidney, and systemic connective tissue disorders, and the response among our patient cohort was variable depending on the specific disease. The level of evidence supporting the use of rituximab for these indications was low and the cost was very high. We conclude that more clinical trials on the off-label use of rituximab are needed, although these may be difficult to conduct in some rare diseases. Data from observational studies may provide useful information to assist prescribing in clinical practice.

When GETomics meets aging and exercise in COPD.

The term GETomics has been recently proposed to illustrate that human health and disease are actually the final outcome of many dynamic, interacting and cumulative gene (G) - environment (E) interactions that occur through the lifetime (T) of the individual. According to this new paradigm, the final outcome of any GxE interactions depends on both the age of the individual at which such GxE interaction occurs as well as on the previous, cumulative history of previous GxE interactions through the induction of epigenetic changes and immune memory (both lasting overtime). Following this conceptual approach, our understanding of the pathogenesis of chronic obstructive pulmonary disease (COPD) has changed dramatically. Traditionally believed to be a self-inflicted disease induced by tobacco smoking occurring in older men and characterized by an accelerated decline of lung function with age, now we understand that there are many other risk factors associated with COPD, that it occurs also in females and young individuals, that there are different lung function trajectories through life, and that COPD is not always characterized by accelerated lung function decline. In this paper we discuss how a GETomics approach to COPD may open new perspectives to better understand its relationship with exercise limitation and the ageing process.

[Esclerosis multiple. Lactancia. Lactante. Planificacion familiar. Posparto. Tratamiento modificador de la enfermedad.] / Fármacos modificadores de la enfermedad en la esclerosis múltiple durante la lactancia: revisión de la evidencia actual.

INTRODUCTION: Multiple sclerosis mainly affects women of childbearing age, and the pregnancy and postpartum period is of special interest because of the peculiarities of the disease course and the therapeutic consequences that derive from it. During the period of breastfeeding (BF), the choice of treatment strategy must weigh up the well-established benefits of BF for both the newborn and the mother against the safety profile and potential adverse effects on the infant resulting from exposure to disease-modifying drugs transferred through breast milk. DEVELOPMENT: The study reviews the current evidence on the safety of disease-modifying drugs available for the treatment of multiple sclerosis during the BF period, and gathers data on the transfer of the different drugs into breast milk, as well as the potential adverse effects described in the infant. The drugs of first choice during this period are interferon beta and glatiramer acetate. The rest of the disease modifying drugs are not accepted for use in the BF period according to their summary of product characteristics. However, in recent years, data from studies of clinical practice and case series have been published suggesting that some of these drugs could be used safely during this period. CONCLUSIONS: Given the recognised health benefits of BF for both mother and infant, exclusive breastfeeding is recommended whenever possible. It is essential to carry out an individualised assessment prior to pregnancy and to evaluate the different treatment options depending on each patient.

TITLE: Fármacos modificadores de la enfermedad en la esclerosis múltiple durante la lactancia: revisión de la evidencia actual.Introducción. La esclerosis múltiple afecta principalmente a mujeres en edad fértil, y el período de gestación y posparto es de especial interés por las peculiaridades que comporta en cuanto a evolución de la enfermedad y por las consecuencias terapéuticas que se derivan. En el período de lactancia materna (LM), la elección de la estrategia de tratamiento debe poner en una balanza, por un lado, los beneficios bien establecidos de la LM para el recién nacido y su madre y, por el otro, el perfil de seguridad y potenciales efectos adversos en el lactante derivados de la exposición a los fármacos modificadores de la enfermedad, por transferencia a través de leche materna. Desarrollo. Se realiza una revisión de la evidencia actual acerca de la seguridad de los fármacos modificadores de la enfermedad disponibles para el tratamiento de la esclerosis múltiple durante el período de LM, y se recogen datos de transferencia de los diferentes fármacos a la leche materna, así como los potenciales efectos adversos descritos en el lactante. Los fármacos considerados de primera elección durante este período son el interferón beta y el acetato de glatiramer. El resto de los fármacos modificadores de la enfermedad no están aceptados para su utilización en el período de LM por ficha técnica. Sin embargo, en los últimos años, se han publicado datos de estudios de práctica clínica y series de casos que indican que algunos de estos fármacos podrían utilizarse con seguridad durante este período. Conclusiones. Teniendo en cuenta los beneficios reconocidos de la LM para la salud tanto de la madre como del lactante, se debe recomendar la LM exclusiva a las pacientes con esclerosis múltiple siempre que sea posible. Es fundamental realizar una evaluación individualizada previa al embarazo y valorar las diferentes opciones de tratamiento en función de cada paciente.

Day-night variations in endothelial dysfunction markers and haemostatic factors in sleep apnoea.

Patients with sleep apnoea have a significant alteration in the day-night pattern of myocardial infarction and sudden cardiac death observed in the general population. The aim of this study was to investigate the influence of sleep apnoea on the diurnal variations in various haemostatic parameters (factor VII, von Willebrand factor and plasminogen activator inhibitor (PAI)-1) and markers of endothelial dysfunction (asymmetric dimethylarginine (ADMA) and soluble CD40 ligand (sCD40L)). We studied 26 male patients with obstructive sleep apnoea syndrome (OSAS; 13 patients with severe OSAS (apnoea/hypopnoea index (AHI) >30 events · h(-1)) and 13 patients with mild-to-moderate OSAS (AHI <30 events · h(-1))) and 12 controls of similar body mass index (BMI) and waist circumference. In each subject, six different samples were obtained over 24 h. Although all the markers values tended to be higher in patients with severe OSAS, differences did not reach statistical significance at any time. PAI-1 levels were significantly related to BMI (p<0.001), mean (p<0.001) and minimal (p = 0.047) nocturnal oxygenation saturation. ADMA levels were significantly related to arousal index (p = 0.046). The results of this study suggest that day-night variations in factor VII:antigen (Ag), von Willebrand factor:Ag, PAI-1, sCD40L and ADMA levels may be dependent on either the obesity index or metabolic dysfunction rather than on sleep apnoea alone.

Exposure to medicines among patients admitted for hip fracture and the case-fatality rate at 1 year: a longitudinal study.

PURPOSE: To describe the demographic and clinical characteristics and the pre-fracture exposure to medicines of patients admitted for a hip fracture, and to explore their association with fatal outcome 1 year after the fracture. METHODS: All patients ≥ 65 years old admitted for a hip fracture in a tertiary hospital in Barcelona between January 1 and December 31 2007 were included. Data on the patients' clinical characteristics before and during hospital admission and on pre-fracture exposures to medicines were collected from the clinical records. One-year mortality was checked by approaching the patients and their families and was cross-checked with the national mortality statistics database. A Cox proportional hazards analysis was carried out. RESULTS: Four hundred and fifty-six patients [mean age (SD) 82.9 (7.2) years, 73.5 % female], were admitted with hip fracture during the study period. Almost 80 % of the patients (363, 79.6 %) had three or more associated conditions, and 41.7 % received pre-fracture treatment with five or more drugs. The case-fatality rate during hospital admission was 4.6 % (21 patients). One hundred and seven patients died within 1 year (23.5 %). Advanced age, male gender, two or more associated chronic conditions, cancer, severe cognitive impairment, and treatment with opiates before fracture were significantly associated with the risk of dying. An inverse association was recorded between mortality and pre-hospital exposure to medicines for osteoporosis. CONCLUSIONS: One-quarter of patients admitted for hip fracture died within 1 year after the fracture. Exposure to opiates before hip fracture was associated with an increased 1-year death rate, whereas treatment with drugs for osteoporosis was associated with a decrease in death rate. These results should be confirmed in studies with detailed prospective collection of information on exposure to medicines.

Distribution of chronic cough phenotypes in the general population: A cross-sectional analysis of the LEAD cohort in Austria.

RATIONALE: Recent guidelines consider chronic cough to be a unique clinical entity with different phenotypes. We aimed to investigate them in a general population and to describe prevalence, distribution, and characteristics of these phenotypes within the Austrian general population. METHODS: From the LEAD study, a longitudinal observational population-based cohort, data from questionnaires and spirometry of 10,057 adult participants was analysed. Chronic cough was defined as coughing nearly every day during the last 12 months for at least 3 months (>12 weeks). RESULTS: The prevalence of chronic cough was 9% and increased with age. We found no sex predominance but a female preponderance (68%) in never smokers. A presumable cause was identified in 85% of which more than half (53.9%) had two phenotypes, 36.9% belonged to one only and 9.2% to three or more. Regarding the distribution of phenotypes, 40.8% were current smokers, 32.6% had an ACE inhibitor intake, 18.2% GERD, 17.6% asthmatic cough, 9.7% UACS and 28.3% other diseases associated with chronic cough. 15% had unexplained chronic cough with no identifiable phenotype. Current smoking, low socioeconomic status, obesity, COPD and obstructive sleep apnea were associated factors with chronic cough. CONCLUSION: Chronic cough is common among adults in Austria and highly prevalent in the older population. Most participants can be phenotyped with simple questionnaire-based assessment and can therefore potentially receive specific treatment without intensive clinical workup.

Candidate genes for COPD in two large data sets.

Lack of reproducibility of findings has been a criticism of genetic association studies on complex diseases, such as chronic obstructive pulmonary disease (COPD). We selected 257 polymorphisms of 16 genes with reported or potential relationships to COPD and genotyped these variants in a case-control study that included 953 COPD cases and 956 control subjects. We explored the association of these polymorphisms to three COPD phenotypes: a COPD binary phenotype and two quantitative traits (post-bronchodilator forced expiratory volume in 1 s (FEV1) % predicted and FEV1/forced vital capacity (FVC)). The polymorphisms significantly associated to these phenotypes in this first study were tested in a second, family-based study that included 635 pedigrees with 1,910 individuals. Significant associations to the binary COPD phenotype in both populations were seen for STAT1 (rs13010343) and NFKBIB/SIRT2 (rs2241704) (p<0.05). Single-nucleotide polymorphisms rs17467825 and rs1155563 of the GC gene were significantly associated with FEV1 % predicted and FEV1/FVC, respectively, in both populations (p<0.05). This study has replicated associations to COPD phenotypes in the STAT1, NFKBIB/SIRT2 and GC genes in two independent populations, the associations of the former two genes representing novel findings.

Five-year follow-up of patients with chronic C hepatitis and sustained virological response.

OBJECTIVE: to assess persistence of sustained viral response at 5 years of follow-up in patients with chronic viral hepatitis C treated with pegylated interferon and ribavirin. DESIGN: a descriptive study. PATIENTS: from August 2001 to May 2004, all patients treated at our center with pegylated interferon and ribavirin who achieved a sustained viral response were consecutively enrolled (93 patients). Demographic, histological, biochemical, and virological data were collected during treatment and 5 years after achievement of the sustained viral response. Eighty-six percent of patients enrolled (n = 80) attended the control visit at 5 years. RESULTS: mean age of enrolled patients was 41 years (standard deviation = 10 years), and 30.1% (n = 28) were women. Liver biopsy had been performed before treatment in 68.8% of patients (n = 64), showing no or mild fibrosis in 62.3% (F0 and F1) and significant fibrosis and cirrhosis in 37.7% (F ≥ 3). Genotype distribution was: 58.1% genotype 1 (n = 54); 8.6% genotype 2 (n = 8); 24.7% genotype 3 (n = 23); 7.5% genotype 4 (n = 7), and indeterminate in one patient. Only one patient experienced virological recurrence. All other patients had negative HCV RNA levels and, in the absence of other liver diseases, normal ALT levels. CONCLUSION: in patients treated with pegylated interferon and ribavirin with sustained viral response, long-term recurrence rate was very low.