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Purpose: COPD has large impact on patient morbidity and mortality worldwide. Acute exacerbations (AECOPD) are mostly triggered by respiratory infections including influenza. While corticosteroids are strongly recommended in AECOPD, they are potentially harmful during influenza. We aimed to evaluate if steroid treatment for AECOPD due to influenza may worsen outcomes., Methods: A retrospective analysis of a Swiss nation-wide hospitalization database was conducted identifying all AECOPD hospitalisations between 2012 and 2017. In separate analyses, outcomes concerning length-of-stay (LOS), in-hospital mortality, rehospitalisation rate, empyema and aspergillosis were compared between AECOPD during and outside influenza season; AECOPD with and without laboratory-confirmed influenza; and AECOPD plus pneumonia with and without laboratory-confirmed influenza., Results: Patients hospitalized for AECOPD during influenza season showed shorter LOS (11.3 vs. 11.6 day, p < 0.001) but higher rehospitalisation rates (33 vs 31%, p < 0.001) compared to those hospitalized outside influenza season. Patients with confirmed influenza infection had lower in-hospital mortality (3.3 vs. 5.5%, p = 0.010) and rehospitalisation rates (29 vs. 37%, p < 0.001) than those without confirmed influenza., Conclusion: Using different indicators for influenza as the likely cause of AECOPD, we found no consistent evidence of worse outcomes of AECOPD due to influenza for hospitalized patients. Assuming that most of these patients received corticosteroids, as it is accepted standard of care in Switzerland, this study gives no evidence to change the current practice of using corticosteroids for hospitalized AECOPD independent of the influenza status., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Background: The Clinical Frailty Scale (CFS) is increasingly used for clinical decision making in acute care but little is known about frailty after COVID-19., Objectives: To investigate frailty and the CFS for post-COVID-19 follow-up., Methods: This prospective multicentre cohort study included COVID-19 survivors aged ≥50 years presenting for a follow-up visit ≥3 months after the acute illness. Nine centres retrospectively collected pre-COVID-19 CFS and prospectively CFS at follow-up. Three centres completed the Frailty Index (FI), the short physical performance battery (SPPB), 30 s sit-to-stand test and handgrip strength measurements. Mixed effect logistic regression models accounting for repeated measurements and potential confounders were used to investigate factors associated with post-COVID-19 CFS. Criterion and construct validity were determined by correlating the CFS to other concurrently assessed frailty measurements and measures of respiratory impairment, respectively., Results: Of the 288 participants 65% were men, mean (SD) age was 65.1 (9) years. Median (IQR) CFS at follow-up was 3 (2-3), 21% were vulnerable or frail (CFS ≥4). The CFS was responsive to change, correlated with the FI (r=0.69, p<0.001), the SPPB score (r=-0.48, p<0.001) (criterion validity) and with the St George's Respiratory Questionnaire score (r=0.59, p<0.001), forced vital capacity %-predicted (r=-0.25, p<0.001), 6 min walk distance (r=-0.39, p<0.001) and modified Medical Research Council (mMRC) (r=0.59, p<0.001). Dyspnoea was significantly associated with a higher odds for vulnerability/frailty (per one mMRC adjusted OR 2.01 (95% CI 1.13 to 3.58), p=0.02)., Conclusions: The CFS significantly increases with COVID-19, and dyspnoea is an important risk factor for post-COVID-19 frailty and should be addressed thoroughly., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Airflow reversibility criteria in COPD are still debated - especially in situations of co-existing COPD and asthma. Bronchodilator response (BDR) is usually assessed by spirometric parameters. Changes assessed by plethysmographic parameters such as the effective, specific airway conductance (sG eff ), and changes in end-expiratory resting level at functional residual capacity (FRC pleth ) are rarely appreciated. We aimed to assess BDR by spirometric and concomitantly measured plethysmographic parameters. Moreover, BDR on the specific aerodynamic work of breathing (sWOB) was evaluated., Methods: From databases of 3 pulmonary centers, BDR to 200 g salbutamol was retrospectively evaluated by spirometric (∆FEV 1 and ∆FEF 25-75 ), and plethysmographic (∆sG eff , ∆FRC pleth , and ∆sWOB) parameters in a total of 843 patients diagnosed as COPD (478 = 57%), asthma-COPD-overlap (ACO) (139 = 17%), or asthma (226 = 27%), encountering 1686 BDR-measurement-sets (COPD n = 958; ACO n = 276; asthma n = 452)., Results: Evaluating z-score improvement taking into consideration the whole pre-test z-score range, highest BDR was achieved by combining ∆sG eff and ∆FRC detecting BDR in 62.2% (asthma: 71.4%; ACO: 56.7%; COPD: 59.8%), by ∆sG eff in 53.4% (asthma: 69.1%; ACO: 51.6%; COPD: 47.4%), whereas ∆FEV 1 only distinguished in 10.6% (asthma: 21.8%; ACO: 18.6%; COPD: 4.2%). Remarkably, ∆sWOB detected BDR in 49.4% (asthma: 76.2%; ACO: 47.8%; COPD: 46.9%)., Conclusion: BDR largely depends on the pre-test functional severity and, therefore, should be evaluated in relation to the pre-test conditions expressed as ∆z-scores, considering changes in airway dynamics, changes in static lung volumes and changes in small airway function. Plethysmographic parameters demonstrated BDR at a significant higher rate than spirometric parameters., Competing Interests: The authors report no conflicts of interest in this work., (© 2021 Kraemer et al.)

Tumour neoantigens arising from cancer-specific mutations generate a molecular fingerprint that has a definite specificity for cancer. Although this fingerprint perfectly discriminates cancer from healthy somatic and germline cells, and is therefore therapeutically exploitable using immune checkpoint blockade, gut and extra-gut microbial species can independently produce epitopes that resemble tumour neoantigens as part of their natural gene expression programmes. Such tumour molecular mimicry is likely not only to influence the quality and strength of the body's anti-cancer immune response, but could also explain why certain patients show favourable long-term responses to immune checkpoint blockade while others do not benefit at all from this treatment. This article outlines the requirement for tumour neoantigens in successful cancer immunotherapy and draws attention to the emerging role of microbiome-mediated tumour neoantigen mimicry in determining checkpoint immunotherapy outcome, with far-reaching implications for the future of cancer immunotherapy., (© 2021. The Author(s).)

Background and Objective: Reduced physical capacity (PC) and physical activity (PA) are common in COPD patients and associated with poor outcome. However, they represent different aspects of physical functioning and interventions do not affect them in the same manner. To address this, a new PC-PA quadrant concept was recently generated to identify clinical characteristics of sub-groups of physical functioning. The objective of this study was to I) proof the new concept and to verify their differentiating clinical characteristics, II) evaluate the consistency of the concept over time, III) assess whether patients changed their quadrant affiliation over time, IV) and to test if changes in quadrant affiliations are associated with changes in clinical characteristics., Methods: In a longitudinal, prospective, non-interventional cohort with mild to very severe COPD patients, PC and PA as well as respiratory variables, COPD-specific health status, comorbidities, survival, and exacerbations were yearly assessed., Results: Data from 283 patients were analysed at baseline. Mean (min/max) follow-up time was 2.4 (0.5/6.8) years. The PC-PA quadrants could be characterized as follows: I) "can't do, don't do": most severe and symptomatic, several comorbidities II) "can do, don't do": severe but less symptomatic, several comorbidities III) "can't do, do do": few patients, severe and symptomatic, less comorbidities IV) "can do, do do": mildest and less symptomatic, less comorbidities, lowest exacerbation frequency. Of the 172 patients with at least one follow-up, 58% patients never changed their quadrant affiliation, while 17% declined either PC, PA or both, 11% improved their PC, PA or both, and 14% showed improvement and decline in PC, PA or both during study period. None of the clinical characteristics or their annual changes showed consistent significant and relevant differences between all individual sub-groups., Conclusion: Our findings suggest that there are no clinical characteristics allowing to distinguish between the PC-PA quadrants and the concept seems not able to illustrate disease process. However, the already low PA but preserved PC in the "can do, don't do" quadrant raises the question if regularly assessment of PA in clinical practice would be more sensitive to detect progressive deterioration of COPD compared to the commonly used PC., Clinical Trial Registration: www.ClinicalTrials.gov, NCT01527773.

The functional importance of the tumor stroma for cancer growth and progression is increasingly recognized, but has not resulted in notable therapeutic developments yet. Within the mesenchymal tumor microenvironment, cancer-associated fibroblasts take the center stage and fuel tumor progression in various ways including malignant cell potentiation, immune regulation and fibrosis. However, recent studies have demonstrated pronounced heterogeneity of the fibroblastic tumor stroma, which comprises a plethora of individual cell subsets with varying phenotypes and functions, some of which suppress malignant growth through immune engagement or crosstalk with the tumor vasculature. This article summarizes the various levels at which the fibroblastic tumor stroma may impact cancer progression and highlights potential target structures for future therapeutic intervention(s)., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background and Objective: Daily physical activity (PA) and exercise capacity are reduced in patients with COPD. Whether the natural longitudinal course of both appears synchronically or one precedes the other is currently unclear. The aim was to assess the longitudinal relationship between exercise capacity and physical activity and their changes over time in patients with COPD., Methods: In a longitudinal observation-study of heterogeneous COPD patients, recruited from pulmonary outpatient clinics or hospital settings, we annually investigated two exercise capacity tests (1-min sit to stand test (STS) and 6 min walking test (6MWT)) and daily physical activity assessed by number of steps per day for minimum one, up to seven years. Univariable and multivariable mixed effect models were used to investigate the annual change in STS, 6MWD and number of steps per day., Results: 202 COPD patients (17% COPD risk group (considers symptoms and future exacerbation risk to grade disease severity) A, 49% B, 4% C and 34% D) with a mean (min/max) follow-up time of 2.4 (0.9/6.8) years were annually assessed. The number of steps per day decreased significantly over time (annual mean (95% CI) of -451.0 (-605.3/-296.6) steps, p < 0.001) while STS and 6MWD remained stable., Conclusion: Our findings suggest that COPD patients are increasingly impaired in their daily PA while exercise capacity remains stable during the study period. Thus, the longitudinal decline in PA seems not to be explained by a concomitant reduction in exercise tolerance., Clinical Trial Registration: www.Clinicaltrials.Gov, NCT01527773., (Copyright © 2018. Published by Elsevier Ltd.)

Purpose: Only a few studies have examined the effect of public smoking bans on respiratory conditions. These showed reduced admission rates for different respiratory diseases., Objective: The objective of the present study was to evaluate the effect of the public smoking ban implemented in Graubünden, Switzerland, on the incidence of acute hospital admissions for acute exacerbated chronic obstructive pulmonary disease (AECOPD)., Methods: We searched a database, including all nationwide hospitalisations in Switzerland, for AECOPD and analysed incidence rates before and after introduction of the smoking ban using Poisson regression and incidence rate ratios (IRRs)., Results: After introduction of the smoking ban, we observed a significant 22.4% decrease in the incidence of AECOPD hospitalisations in Graubünden (IRR=0.78 (0.68 to 0.88), p<0.001). In the same period, the incidence of AECOPD hospitalisations only slightly decreased by 7.0% in the rest of Switzerland (IRR=0.93 (0.91 to 0.95), p<0.001). The observed reduction in AECOPD hospitalisation incidence was significantly greater in GR than in the rest of CH (p=0.008)., Conclusions: Our study supports the limited body of evidence demonstrating that a reduction of secondhand smoke by legislated bans on smoking is associated with reduced rates of admission to hospital for respiratory conditions, hereby shown for AECOPD, in addition to the meanwhile well-documented impact on cardiovascular disease., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Dyspnoea is a common symptom of exercice intolerance. Tests performed at rest often leave the reason open. Cardiopulmonary exercise testing (CPET) is a tool for the qualitative and quantitative assessment of the cardio-circulatory, pulmonary and metabolic response to exercise. It is the gold-standard in the evaluation of dyspnoea and identifying its etiology (obstructive/restrictive lung disease, heart failure, physical fitness …). CPET is particularly useful, if previous evaluations including history, physical examination, ECG, pulmonary function testing (PFT), X-ray, blood tests, and blood gases do not lead to a decisive diagnosis. The measurement of peak oxygen consumption, carbon dioxide production, minute ventilation and heart rate provides substantial diagnostic and prognostic information in a wide variety of clinical settings. Interpreting CPET requires pathophysiological knowledge and can sometimes be challenging. An easy-to-use algorithm may provide a useful assistance for interpretation the results. In addition to its use as a diagnostic tool, CPET can be used to support sportsmen reaching their training goals and evaluate subject's ability to work.

Background and Objective: Both comorbidities and physical inactivity have been shown to impair quality of life and contribute to hospital admissions and mortality in chronic obstructive pulmonary disease (COPD) patients. We hypothesized that the comorbid status predicts the level of daily physical activity (PA) in COPD., Methods: In 228 patients with COPD (76% men; median (quartiles) age: 64 (59/69) years; percentage of predicted forced expiratory volume in 1 s (FEV1 % pred): 44 (31/63)), comorbidities were assessed by medical history, clinical interviews, examination and blood analysis. PA level (PAL) was measured by an activity monitor (SenseWear Pro, Bodymedia Inc., Pittsburgh, PA, USA). The association between PAL and comorbidities was investigated by univariate and multivariate regression analysis., Results: Seventy-nine percent of the COPD patients had at least one additional chronic comorbidity, 56% had two or more comorbidities and 35% had three or more comorbidities. In univariate analysis body mass index, the number of pack years and having at least one additional comorbidity was negatively associated with PAL while there was a positive nonlinear association between FEV1 and PAL. The presence of at least one additional comorbidity was independently associated with PAL irrespective of airflow limitation., Conclusions: In this cohort, almost 80% of COPD patients had at least one additional chronic comorbidity. The level of daily PA seems to be significantly impaired by the presence of comorbidities irrespective of the type of comorbidity and independent of the degree of airflow limitation., Clinical Trial Registration: NCT01527773 at http://www.clinicalTrials.gov., (© 2015 Asian Pacific Society of Respirology.)

Purpose: Midregional pro-adrenomedullin (MR-proADM) and C-terminal pro-vasopressin (copeptin) are novel biomarkers providing prognostic information in various settings. We aimed to (1) assess the kinetics of MR-proADM and copeptin during cardiopulmonary exercise testing (CPET); (2) assess the relationship of MR-proADM and copeptin measured at rest with peak oxygen consumption (peak VO2) and other key CPET parameters; (3) compare this relationship to that of B-type natriuretic peptide (BNP)., Methods: In 162 patients undergoing symptom-limited CPET for evaluation of exercise intolerance, MR-proADM, copeptin, and BNP were measured at rest and peak exercise., Results: There was a significant rise in copeptin and BNP (p < 0.001) but not in MR-proADM (p = 0.60) from rest to peak exercise. MR-proADM (r = -0.57; p < 0.001) and BNP (r = -0.49; p < 0.001) but not copeptin were significantly and inversely related to peak VO2. MR-proADM was inversely correlated to the percentage of predicted heart rate achieved and peak oxygen pulse and directly related to the peak ventilation/carbon dioxide production relationship, the physiological dead space-to-tidal volume ratio, and the alveolo-arterial oxygen gradient (p ≤ 0.01 for all), and these associations were at least as strong as for BNP. In contrast, copeptin was not significantly related to any of these parameters (p > 0.05 for all)., Conclusion: In contrast to BNP and copeptin, MR-proADM is not immediately affected by a maximal exercise test. MR-proADM but not copeptin is at least as good an indicator of low peak VO2 and CPET parameters reflecting an impaired cardiac output reserve, ventilatory efficiency and diffusion capacity as BNP, and thereby a global cardiopulmonary stress marker.

Sarcoidosis is a chronic granulomatous inflammatory disorder of unknown origin with heterogeneous outcome. In most cases the disease is self-limited, others progress or die from organ involvement, which is often associated with extensive scarring. Although often the primarily affected sites are the lungs and thoracic lymph nodes patients with sarcoidosis must be staged for multiorgan involvement. Modern treatment strategies appraise a critical awareness for the side-effect-ratio of long-term medication. A main interest of research is to identify those patients with unfavourable outcome.

Background and Aim of the Work: Sarcoidosis is a chronic granulomatous disorder of unknown etiology. In most patients the disease is self-limited, although for reasons unclear, others progress or die from progressive organ fibrosis. Growth factors have been implicated in the pathogenesis of other fibrotic lung conditions. We have, therefore, examined the relationship between growth factor expression and disease phenotype in sarcoidosis., Methods: Adopting a target gene approach utilizing gene expression arrays, growth factor gene expression profile was analyzed in the peripheral blood of 12 patients and 12 healthy controls. Expression, functional activity and the effect of oligonucleotide antisense treatment on selected proteins differentially expressed in progressive sarcoidosis were then tested in vitro on primary human lung fibroblasts., Results: Genes regulating angiogenesis were preferentially upregulated in the self-limited form of disease, while early growth response-1 and interleukin-6 were predominantly activated in progressive sarcoidosis. Increased expression of early growth response-1 in sarcoid lung was confirmed by immunohistochemistry. Stimulated human fibroblasts also rapidly expressed interleukin-6 and early growth response-1 and these proteins were found to mediate serum-induced fibroblast proliferation as proliferation could be significantly abrogated with interleukin-6 and early growth response-1 antisense oligonucelotides., Conclusion: We conclude that progressive pulmonary sarcoidosis is characterized by a fibroproliferative dysregulation potentially triggered by early growth response-1 and interleukin-6. Our disease model underlines the inability of steroids to prevent ongoing fibroproliferation in the lung.

Questions Under Study: Evaluation of cardiopulmonary capacity and work ability is often done by cardiopulmonary exercise testing under laboratory conditions. Mobile CPET devices allow measurements under specific real-life conditions, i.e.: at the patient's workplace. We investigated the feasibility and validity of mobile CPET in healthy controls., Method: We compared oxygen uptake measured by mobile CPET (MCPET) with that by standard CPET (LCPET), and we compared oxygen uptake with markers of self-reported physical exhaustion. Twenty-two healthy subjects (15 male, 21-49 years) underwent LCPET and 6 outdoors 12-min running tests (MCPETs) at different intensities. Physical exhaustion and the time they could continue exercising (T(EX)) was reported for each level. Standard descriptive statistics were applied., Results: Of 132 MCPETs, performed in 22 subjects, 128 (97%) were of suitable quality. The facemask was well tolerated and nobody felt uncomfortable at any time. On average VO2 [peak] was 21% (SD 9%) higher with MCPET compared to LCPET (median 3.60, range [2.22, 5.14] versus median 2.63, range [1.67, 4.16] L*min(-1)), but showed a strong correlation (r2 = 0.90). MCPET-VO2 at steady state correlated with subjectively rated physical exhaustion, and with TEX., Conclusions: Out-of-laboratory MCPET was feasible, correlated with parameters of standard CPET, and correlated with markers of physical exhaustion. After validation in patients, MCPET could be used for a rational evaluation of cardiopulmonary capacity and work ability in selected patients.

Background: HLA-DR2 (15) and 14 (6) have been recently proposed as susceptibility alleles for the development of sarcoidosis and HLA-DR15 as a marker of poor outcome, but validation in other populations is necessary., Methods: Employing serological techniques, we HLA-typed 103 Irish sarcoidosis patients and 105 ethnically-matched healthy controls for class I A and B and II DR and DQ alleles., Results: HLA-B5 (10% vs. 2%, p = 0.018) and DR2 (45% vs. 27%, p = 0.007) were positively associated and B15 (0% vs. 7%, p = 0.01) negatively associated with sarcoidosis compared to control subjects. Seventy-five patients were followed > 2 years and 47 (63%) had chronic and 28 (37%) non-chronic disease. HLA-DR2 (55% vs. 27%, p = 0.001) and DR11 (26% vs. 5%, p<0.0001) were significantly more frequent in chronic disease vs. controls, in contrast to HLA-DR3 (13% vs. 38%, p = 0.002), which had a significant negative association. HLA-B5 (11% vs. 2%, p = 0.029) and DR3 (64% vs. 38%, p = 0.005) were significantly more frequent in non-chronic disease. Of the 29 patients achieving spontaneous remission, 24 (83%) were HLA-DR3 -positive and DR3-positivity was associated with significantly greater carbon monoxide diffusion at follow-up compared to DR3-negative patients (90% vs. 82% predicted, p = 0.027)., Conclusions: This study supports the role of HLA-DR2 (15) as both a susceptibility and poor prognostic marker in sarcoidosis and DR2 positive patients may particularly benefit from close follow-up and early treatment. In contrast, DR3 positive patients are at a much lesser risk of chronic disease. Studies for long-term treatment effects require stratification for HLA-DR2 and DR3 status.

Background: Atopic disorders have been associated with a Th-2 cytokine predominance. This study investigated Th1- and Th2-related gene expression in asthmatics, atopics and healthy individuals., Methods: We compared Th1- and Th2-related in vivo-signals using gene expression arrays in 18 atopic asthmatics, 8 atopic non-asthmatic and 14 healthy control subjects. Purified mRNA from peripheral blood mononuclear cells was reverse-transcribed and hybridised to cDNA membranes. Group differences were assessed after standardisation with Mann-Whitney U-test., Results: Atopic individuals had upregulated lymphotoxin-alpha and downregulated IFNGR1. On the other hand, they had particularly high IL-4, IL-5 and IL4R levels, together with significantly upregulated IL10. Asthmatic individuals had normal Th1-gene expression, but an upregulation og Th-2 genes. Atopic individuals had high, asthmatic individuals excessively high IL12RB1-levels. No Th-2 gene was downregulated in both atopic phenotypes. The expression of IL6R correlated with the daily dose of inhaled corticosteroids., Conclusions: Atopic individuals had a down regulation of key TH1- and Th2-genes, resulting in a balanced upregulation of Th-specific genes. In contrast, asthmatic subjects had normal Th1-gene expression but a constant upregulation of Th2-specific genes, leading to Th2-predominance.

Background: Sarcoidosis is a systemic disorder of unknown cause, highly variable phenotype and unpredictable outcome. Antigen processing, inflammatory response and immunomodulation appear critical to development and prognosis of the disease., Methods: We performed a comprehensive genomic analysis, applying high-density human GeneChip probe arrays (HUG95A, Affymetrix Inc.) for gene expression profiling from peripheral blood of patients with acute pulmonary sarcoidosis (n = 12) and matched healthy controls (n = 12), mean age 36 +/- 12 and 33 +/- 10 years respectively., Results: At follow-up (18 [15-24] months), 7 patients had self-limited disease and 5 had persistent disease. Significantly different expression comparing patients and controls was identified for 1,860 (14.9%) and 729 (5.8%) gene products at p = 0.05 and p = 0.01 levels respectively. Genes closely associated with persistent disease included HLA-DRB1*1501 DQB1*0602, TNFA, NFKB, cyclic AMP-responsive element modulator (CREM) and T-cell activation marker CD69. IL1B, IL8, growth related (GRO)-beta/-gamma and CCR 2,5,6 were closely associated with self-limited disease., Conclusion: We hypothesize that, in self-limited disease, greater effector cell activation leads to successful antigen elimination/tolerance, whereas HLA-DRB1*1501 DQBI*0602-mediated, probably defective/partial T-lymphocyte activation results in an inefficient primary immune response, antigen intolerance and persistent disease.

Principles: Current asthma management employing inhaled corticosteroids (ICS) and longacting b2-agonists (LABA) aims to rapidly achieve and then maintain overall asthma control including symptoms with minimal medication. This study compared self-guided adjustable maintenance dosing with budesonide/formoterol in a single inhaler with fixed dosing., Methods: In an open-label, parallel-group, multicentre study, 127 asthmatic patients, well controlled on ICS and LABA, were treated with budesonide/formoterol (Symbicort) Turbuhaler) 200/6 mg (equivalent to 160/4.5 mg delivered dose) 2 inhalations bid for 4 weeks, and were then randomised to budesonide/formoterol adjustable dosing (n = 69) (guided self-adjustment of dose: 1 inhalation bid or 2 inhalations at night with interim step ups to 2 inhalations bid and if not sufficient up to 4 inhalations bid for 14 days) or fixed dosing (2 inhalations bid) (n = 58) for 12 weeks., Results: Patients used adjustable dosing effectively; >50% used a decreased maintenance dose on >50% of the days. Seventy-two percent (50/69) from the adjustable-dosing group reduced their maintenance dose within the first 2 treatment weeks. Thirteen adjustable-dose patients (18.8%) never reduced their dose and 4 (5.8%) stepped up their dose. Symptom severity (NHLBI severity grade) decreased in both groups; however, the decrease was only statistically significant (p = 0.004) in the adjustable-dosing group. Treatment failures occurred in 17% and 24% of patients (adjustable and fixed dosing, respectively p = 0.35). Nocturnal awakenings (0.057 vs. 0.067/night, p = 0.006) and rescue medication use (0.15 vs. 0.23 inhalations/day, p <0.0001) were significantly less frequent with adjustable dosing, and the average daily medication dose was significantly reduced (3.0 vs. 3.9, p <0.0001) compared with fixed dosing. Lung function measurements (FEV1 and PEF) were not significantly different between groups during the study. There were no asthma-related hospital admissions., Conclusion: Asthma patients on adjustable maintenance dosing with budesonide/ formoterol maintained control of symptoms using significantly less medication overall than fixed dosing. Thus, adjustable maintenance dosing achieved guideline goals of effective asthma control at an appropriately low maintenance dose. However, larger studies on adjustable maintenance dosing are needed.

In the year 2000, the Human Genome Project Consortium presented the first complete draft of the human genome together with Celera Genetics. Since then, the so-called "post-genome era" has started. Microarrays are capable of profiling gene expression patterns of tens of thousands of genes in a single experiment and thus allow a systematic analysis of DNA and RNA variation. They seem likely to become a standard tool of both molecular biology research and clinical diagnostics. These prospects have attracted great interest and investment from both the public and private sectors. This review introduces the principle of microarray technology and gives an overview of its current and future potential in clinical medicine.