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Summary Background: Crohn's disease and ulcerative colitis are the two major forms of inflammatory bowel disease; treatment strategies have historically been determined by this binary categorisation. Genetic studies have identified 163 susceptibility loci for inflammatory bowel disease, mostly shared between Crohn's disease and ulcerative colitis. We undertook the largest genotype association study, to date, in widely used clinical subphenotypes of inflammatory bowel disease with the goal of further understanding the biological relations between diseases. Methods: This study included patients from 49 centres in 16 countries in Europe, North America, and Australasia. We applied the Montreal classification system of inflammatory bowel disease subphenotypes to 34 819 patients (19 713 with Crohn's disease, 14 683 with ulcerative colitis) genotyped on the Immunochip array. We tested for genotype–phenotype associations across 156 154 genetic variants. We generated genetic risk scores by combining information from all known inflammatory bowel disease associations to summarise the total load of genetic risk for a particular phenotype. We used these risk scores to test the hypothesis that colonic Crohn's disease, ileal Crohn's disease, and ulcerative colitis are all genetically distinct from each other, and to attempt to identify patients with a mismatch between clinical diagnosis and genetic risk profile. Findings: After quality control, the primary analysis included 29 838 patients (16 902 with Crohn's disease, 12 597 with ulcerative colitis). Three loci (NOD2, MHC, and MST1 3p21) were associated with subphenotypes of inflammatory bowel disease, mainly disease location (essentially fixed over time; median follow-up of 10·5 years). Little or no genetic association with disease behaviour (which changed dramatically over time) remained after conditioning on disease location and age at onset. The genetic risk score representing all known risk alleles for inflammatory bowel disease showed strong association with disease subphenotype (p=1·65 × 10−78), even after exclusion of NOD2, MHC, and 3p21 (p=9·23 × 10−18). Predictive models based on the genetic risk score strongly distinguished colonic from ileal Crohn's disease. Our genetic risk score could also identify a small number of patients with discrepant genetic risk profiles who were significantly more likely to have a revised diagnosis after follow-up (p=6·8 × 10−4). Interpretation Our data support a continuum of disorders within inflammatory bowel disease, much better explained by three groups (ileal Crohn's disease, colonic Crohn's disease, and ulcerative colitis) than by Crohn's disease and ulcerative colitis as currently defined. Disease location is an intrinsic aspect of a patient's disease, in part genetically determined, and the major driver to changes in disease behaviour over time. Funding International Inflammatory Bowel Disease Genetics Consortium members funding sources (see Acknowledgments for full list).

Background: A major reason of the poor control of asthma is that patients fail to adhere to their treatment. The aim of the study was to identify factors affecting changes in asthma treatment adherence in an international cohort., Methods: A follow-up study was carried out by means of a structured clinical interview in 971 subjects with asthma from 12 countries who participated in both the European Community Respiratory Health Survey: ECRHS-I (1990-94) and ECRHS-II (1998-2002). Subjects were considered adherent if they reported they normally took all the prescribed drugs. A logistic model was used to study the adjusted effect of the determinants., Results: The net change in adherence to anti-asthmatic treatment per 10 years of follow-up was -2% (95% CI: -9.5, 5.5), 7.5% (-2.6, 17.6), 15.0% (6.6, 23.5) and 19.8% (4.1, 35.5), respectively, in Nordic, Mediterranean, Continental and extra-European areas. Among the 428 non-adherent subjects in ECRHS-I, having regular consultations with health care professionals was the strongest predictor of increased adherence (OR 3.32; 95% CI: 1.08-10.17). Among the 543 adherent subjects in ECRHS-I, using inhaled corticosteroids significantly predicted a persistence of adherence (OR 2.04; 95% CI: 1.11-3.75). No effect of gender, age, duration of the disease, smoking habit and educational level was observed., Conclusions: Our findings highlight the key role of doctors and nurses in educating and regularly reviewing the patients and support the efforts for an improvement of clinical communication.

Background: Only one population-based study in one country has reported effects of smoking cessation and weight change on lung function, and none has reported the net effect. We estimated the net benefit of smoking cessation, and the independent effects of smoking and weight change on change in ventilatory lung function in the international European Community Respiratory Health Survey., Methods: 6654 participants in 27 centres had lung function measured in 1991-93, when aged 20-44 years, and in 1998-2002. Smoking information was obtained from detailed questionnaires. Changes in lung function were analysed by change in smoking and weight, adjusted for age and height, in men and women separately and together with interaction terms., Findings: Compared with those who had never smoked, decline in FEV1 was lower in male sustained quitters (mean difference 5.4 mL per year, 95% CI 1.7 to 9.1) and those who quit between surveys (2.5 mL, -1.9 to 7.0), and greater in smokers (-4.8 mL, -7.9 to -1.6). In women, estimates were 1.3 mL per year (-1.5 to 4.1), 2.8 mL (-0.8 to 6.3) and -5.1 mL (-7.5 to -2.8), respectively. These sex differences were not significant. FEV1 changed by -11.5 mL (-13.3 to -9.6) per kg weight gained in men, and by -3.7 mL per kg (-5.0 to -2.5) in women, which diminished the benefit of quitting by 38% in men, and by 17% in women., Interpretation: Smoking cessation is beneficial for lung function, but maximum benefit needs control of weight gain, especially in men.

Chronic obstructive pulmonary disease (COPD) is a disease state characterized by chronic airflow limitation that is not fully reversible, with a precise definition varying between different management guidelines. The burden of COPD is considerable from all relevant viewpoints. From the perspective of society, the mortality is already considerable, and it is likely to increase from the sixth to the third most common cause of death worldwide by 2020. From the patient's perspective, COPD is responsible for disability that restricts many everyday activities, such as walking up stairs. The burden of COPD on physicians includes increasing consultations for the condition. From the perspective of healthcare payers, COPD represents an increasing burden, primarily due to the costs incurred when exacerbations require hospital treatment. Despite this considerable burden, there are many signs that the impact of COPD is not recognized. Research on COPD is currently underfunded in relation to the impact of the disease; patients only present late with symptoms; physicians may fail to diagnose the condition and healthcare payers may be failing to support treatment approaches that could reduce the number of costly hospital exacerbations. Reasons for this overall poor recognition of the burden of COPD include lack of recognition of the disease, difficulties in diagnosis, poor knowledge of COPD and nihilistic attitudes towards the condition and its treatment. Awareness of COPD could be improved with education of the public and healthcare professionals. Long-term epidemiological studies showing the impact on morbidity and mortality of different treatment approaches would also influence the setting of priorities by healthcare payers.

Failure to follow asthma management guidelines may result in poor asthma control for many patients. The Asthma Insights and Reality in Europe (AIRE) survey, a multi-national survey assessing the level of asthma control from the patients perspective in seven Western European countries, previously demonstrated that the Global Initiative for Asthma (GINA) guideline goals were not achieved in Western Europe and that both adults and children with asthma were poorly controlled. Using additional data on asthma management practices from each of the seven countries in the AIRE survey, we compared variations in asthma morbidity and asthma management practices across countries to provide insight into the reasons for poor asthma control. Asthma management practices and asthma control among adults and children with current asthma were suboptimal in each of seven countries surveyed. Among patients with symptoms of severe persistent asthma, over 40% reported their asthma was well or completely controlled. School absence due to asthma was reported by upto 52.7% of children and up to 27.6% of adult reported work absence due to asthma. Lung function testing in the past year was uncommon: ranging from 13.5% of children in the U.K. to 68.8% of adults in Germany. Written asthma management plans were used by less than 50% of adults and less than 61% of children in all seven countries. Most adults (49.5-73.0%) and a large proportion of children (38.4-70.6%) had follow-up visits for their asthma only when problems developed. The ratio of recent inhaled corticosteroid use to recent short-acting beta-agonist use was inappropriate (<1) among patients with symptoms of severe asthma in all countries. This disparity was greatest among adults in Italy and France, where recent inhaled corticosteroid use was reported by less than one in nine patients reporting recent use of short-acting bronchodialators (IS:SAB <0.11). Management practices differ between countries and additional public health interventions and resources may be necessary to reduce patient suffering. Further efforts to fully implement asthma management guidelines are required to improve asthma control in Europe.

Study Objective: To estimate the possible association between reported symptoms of gastroesophageal reflux (GER) after bedtime, sleep-disordered breathing, respiratory symptoms, and asthma., Design: Cross-sectional international population survey., Participants: Participants consisted of 2,661 subjects (age range, 20 to 48 years) from three countries (Iceland, Belgium, and Sweden), of whom 2,202 were randomly selected from the general population and 459 were added because of reported asthma., Measurements: The investigation included a structured interview, spirometry, methacholine challenge, peak flow diary, skin-prick tests, and a questionnaire on sleep disturbances., Results: In the random population sample, 101 subjects (4.6%) reported GER, which was defined as the occurrence of heartburn or belching after going to bed at least once per week. Subjects with nocturnal GER more often were overweight and had symptoms of sleep-disordered breathing than participants not reporting GER. Participants with GER were more likely to report wheezing (adjusted odds ratio [OR], 2.5), breathlessness at rest (adjusted OR, 2.8), and nocturnal breathlessness (adjusted OR, 2.9), and they had increased peak flow variability compared to the subjects without GER. Physician-diagnosed current asthma was reported by 9% of subjects with GER compared to 4% of those not reporting GER (p < 0.05). Subjects with the combination of asthma and GER had a higher prevalence of nocturnal cough, morning phlegm, sleep-related symptoms, and higher peak flow variability than subjects with asthma alone., Conclusion: The occurrence of GER after bedtime is strongly associated with both asthma and respiratory symptoms, as well as symptoms of obstructive sleep apnea syndrome. The partial narrowing or occlusion of the upper airway during sleep, followed by an increase in intrathoracic pressure, might predispose the patient to nocturnal GER and, consequently, to respiratory symptoms.

Compliance by patients to prescribed treatment regimens can be considered as the interface between effective therapy and effective disease management. Compliance can be affected by the nature of the relationship between the practitioner and the patient, and their attitudes towards each other. It has also been suggested that practitioner behaviour can influence patient behaviour and health status. However, each individual patient is influenced in his or her attitudes, and reactions to disease and its management, by a wide variety of patient-related factors. These include psychological variables such as mood, beliefs, and the knowledge, motivation and ability of the patient. Social factors may also play a role: these include age, marital and socioeconomic status and level of education. Results from a range of studies in patients with pulmonary or other diseases show that the psychosocial determinants of compliance are only poorly understood, and suggest that compliance cannot be predicted from patients' health status and that social factors are weak indicators only. Furthermore, it appears from available data that patients' beliefs about health issues are not as useful as indicators of likely compliance as was previously believed.

A 28-year-old woman presented with monthly returning thoracic pain and cough. Catamenial pneumothorax was diagnosed. Thoracoscopy showed multiple nodules on the diaphragm, parietal pleura and lung itself, which proved to be thoracic endometriosis. Thoracoscopy is a useful procedure for diagnosis and treatment of this rare condition.

Background: This study investigated the feasibility and efficacy of doxorubicin dose-escalated chemotherapy in combination with ifosfamide in patients with malignant mesothelioma., Patients and Methods: In this single institution phase II study, 24 chemotherapy-naive, eligible patients were entered. The chemotherapy regimen consisted of doxorubicin 75 mg/m2 in combination with ifosfamide 5 gr/m2 given as a continuous 24 hour infusion, every 21 days with either rhG-CSF (5 micrograms/kg) or rhGM-CSF (250 micrograms/m2) as haematopoietic support from d3 to d14. Cycles were repeated every 3 weeks., Results: We treated 24 patients, of whom 22 are evaluable for tumour response. One of the two inevaluable patients died from a cerebral haemorrhage during a period of grade III thrombocytopenia after the second course. In 7 patients a partial response was observed, resulting in a response rate of 32% (95% confidence interval 13%-51%). Median response duration was 6 months (range 1-13) and median survival was 7 months (range 1-18)., Conclusions: The high-dose regimen with growth factor support is feasible in this group of patients and leads to an interesting response rate. The limiting toxicity for further dose increments and more courses of treatment, was cumulative thrombocytopenia. There seems to be a subgroup of patients with malignant mesothelioma which is less susceptible to develop thrombocytopenia. However, the overall toxicity and the poor response duration limit the use of this schedule in the treatment of malignant mesothelioma.

Pulmonary vascular reactivity was assessed during diagnostic heart catheterization in two patients with pulmonary hypertension unexplained by pulmonary or cardiac disease and in five patients with atypical chest pain and normal coronary arteriograms. Acetylcholine, an endothelium-dependent vasodilator that also has a direct contracting effect on vascular smooth muscle cells, was infused in the right atrium in a step-wise increasing dose in order to obtain final blood concentrations in the pulmonary circulation ranging from 10(-6) mol/L to 10(-4) mol/L. In the five control patients, acetylcholine induced a dose-related decrease of pulmonary vascular resistance (-52 percent +/- 9 percent). In the patients with primary pulmonary arterial hypertension, however, acetylcholine caused a paradoxic increase of pulmonary arterial pressure and of pulmonary vascular resistance. Thus, it appears that endothelium-dependent vasodilation is impaired in the pulmonary circulation of patients with primary pulmonary arterial hypertension. Endothelial dysfunction in the pulmonary circulation may play a role in the pathophysiology of this disease.