Thomas Rothe

Acquired Resistance to Bedaquiline and Delamanid in Therapy for Tuberculosis

Treatment of multidrug-resistant Mycobacterium tuberculosis is a challenge. This letter describes the emergence of resistance to new therapies, bedaquiline and delamanid.

Occupational Exposure to Dusts, Gases, and Fumes and Incidence of Chronic Obstructive Pulmonary Disease in the Swiss Cohort Study on Air Pollution and Lung and Heart Diseases in Adults

RATIONALE There is limited evidence from population-based studies demonstrating incidence of spirometric-defined chronic obstructive pulmonary disease (COPD) in association with occupational exposures. OBJECTIVES We evaluated the association between occupational exposures and incidence of COPD in the Swiss Cohort Study on Air Pollution and Lung and Heart Diseases in Adults (SAPALDIA). MEASUREMENTS AND MAIN RESULTS Prebronchodilator ratio of forced expiratory volume in 1 second over forced vital capacity (FEV(1)/FVC) was measured in 4,267 nonasthmatic SAPALDIA participants ages 18-62 at baseline in 1991 and at follow-up in 2001-2003. COPD was defined by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) criterion (FEV(1)/FVC < 0.70) and Quanjer reference equation (FEV(1)/FVC < lower limit of normal [LLN]), and categorized by severity (≥ 80% and <80% predicted FEV(1) for stage I and stage II+, respectively). Using a job-exposure matrix, self-reported occupations at baseline were assigned exposures to biological dusts, mineral dusts, gases/fumes, and vapors, gases, dusts, or fumes (VGDF) (high, low, or unexposed as reference). Adjusted incident rate ratios (IRRs) of stage I and stage II+ COPD were estimated in mixed Poisson regression models. Statistically significant (P < 0.05) IRRs of stage II+ GOLD and LLN-COPD, indicating risks between two- and fivefold, were observed for all occupational exposures at high levels. Occupational exposure-associated risk of stage II+ COPD was observed mainly in males and ages ≥ 40 years, and remained elevated when restricted to nonsmokers. CONCLUSIONS In a Swiss working adult population, occupational exposures to biological dusts, mineral dusts, gases/fumes, and VGDF were associated with incidence of COPD of at least moderate severity.

Long-Term Exposure to Ambient Air Pollution and Metabolic Syndrome in Adults

Air pollutants (AP) play a role in subclinical inflammation, and are associated with cardiovascular morbidity and mortality. Metabolic syndrome (MetS) is inflammatory and precedes cardiovascular morbidity and type 2 diabetes. Thus, a positive association between AP and MetS may be hypothesized. We explored this association, (taking into account, pathway-specific MetS definitions), and its potential modifiers in Swiss adults. We studied 3769 participants of the Swiss Cohort Study on Air Pollution and Lung and Heart Diseases in Adults, reporting at least four-hour fasting time before venepuncture. AP exposures were 10-year mean residential PM10 (particulate matter <10μm in diameter) and NO2 (nitrogen dioxide). Outcomes included MetS defined by World Health Organization (MetS-W), International Diabetes Federation (MetS-I) and Adult Treatment Panel-III (MetS-A) using four- and eight-hour fasting time limits. We also explored associations with individual components of MetS. We applied mixed logistic regression models to explore these associations. The prevalence of MetS-W, MetS-I and MetS-A were 10%, 22% and 18% respectively. Odds of MetS-W, MetS-I and MetS-A increased by 72% (51-102%), 31% (11-54%) and 18% (4-34%) per 10μg/m3 increase in 10-year mean PM10. We observed weaker associations with NO2. Associations were stronger among physically-active, ever-smokers and non-diabetic participants especially with PM10 (p<0.05). Associations remained robust across various sensitivity analyses including ten imputations of missing observations and exclusion of diabetes cases. The observed associations between AP exposure and MetS were sensitive to MetS definitions. Regarding the MetS components, we observed strongest associations with impaired fasting glycemia, and positive but weaker associations with hypertension and waist-circumference-based obesity. Cardio-metabolic effects of AP may be majorly driven by impairment of glucose homeostasis, and to a less-strong extent, visceral adiposity. Well-designed prospective studies are needed to confirm these findings.

Particulate matter and subclinical atherosclerosis : associations between different particle sizes and sources with carotid intima-media thickness in the SAPALDIA study

Background: Subclinical atherosclerosis has been associated with long-term exposure to particulate matter (PM), but the relevance of particle size and sources of exposure remains unclear. Objectives: We investigated the association of long-term exposure to PM10 (≤ 10 μm), PM2.5 (≤ 2.5 μm: total mass, vehicular, and crustal sources), and ultrafine particles [UFP < 0.1 μm: particle number concentration (PNC) and lung-deposited surface area (LDSA)] with carotid intima-media thickness (CIMT). Methods: We used data from 1,503 participants ≥ 50 years old who participated in the third examination of the Swiss SAPALDIA cohort. Exposures were obtained from dispersion models and land-use regression models. Covariate information, including previous cardiovascular risk factors, was obtained from the second and third SAPALDIA examinations. Results: The adjusted percent difference in CIMT associated with an exposure contrast between the 10th and 90th percentile was 1.58% (95% CI: –0.30, 3.47%) for PM10, 2.10% (95% CI: 0.04, 4.16%) for PM2.5, 1.67% (95% CI: –0.13, 3.48%) for the vehicular source of PM2.5, –0.58% (95% CI: –3.95, 2.79%) for the crustal source of PM2.5, 2.06% (95% CI: 0.03, 4.10%) for PNC, and 2.32% (95% CI: 0.23, 4.40%) for LDSA. Stronger associations were observed among diabetics, subjects with low-educational level, and those at higher cardiovascular risk. Conclusions: CIMT was associated with exposure to PM10, PM2.5, and UFP. The PM2.5 source-specific analysis showed a positive association for the vehicular source but not for the crustal source. Although the effects of PNC and LDSA were similar in magnitude, two-pollutant and residual-based models suggested that LDSA may be a better marker for the health relevance of UFP. Citation: Aguilera I, Dratva J, Caviezel S, Burdet L, de Groot E, Ducret-Stich RE, Eeftens M, Keidel D, Meier R, Perez L, Rothe T, Schaffner E, Schmit-Trucksäss A, Tsai MY, Schindler C, Künzli N, Probst-Hensch N. 2016. Particulate matter and subclinical atherosclerosis: associations between different particle sizes and sources with carotid intima-media thickness in the SAPALDIA study. Environ Health Perspect 124:1700–1706; http://dx.doi.org/10.1289/EHP161

Variability and reproducibility of carotid structural and functional parameters assessed with transcutaneous ultrasound - results from the SAPALDIA Cohort Study

OBJECTIVE Carotid intima media thickness (CIMT) and local stiffness are vascular biomarkers of atherosclerotic burden. We investigated the variability and reproducibility of clinically relevant structural (CIMT, lumen diameter) and functional parameters (strain, distensibility, compliance, β-stiffness index, Petersons elastic modulus and Youngs elastic modulus) measured in B-mode ultrasound sequences of the common carotid artery in the second follow up of the Swiss Cohort Study on Air Pollution and Lung and Heart Diseases In Adults (SAPALDIA3). METHODS Ultrasound sequential images were examined twice over a 1 cm segment across at least one heart cycle in 165 SAPALDIA3 participants. To assess variability and reproducibility of structural and functional parameters, individual coefficients of variation (CV), intraclass correlation (ICC), Bland-Altman plots and mixed effect regressions were used. RESULTS ICCs of repeated examinations ranged between 0.67 and 0.77 for blood pressure indices, between 0.87 and 0.97 for structural properties and between 0.75 and 0.79 for functional parameters. CV was lowest in structural parameters (1.6-4.6%), followed by blood pressure (5.1-7.9%) and functional indices (11.0-13.1%). Variations in all parameters were predominantly explained by subjects (>74% in functional, >82% in structural properties). Bland-Altman plots for functional indices showed mean and standard deviation of the respective mean value of 4.2(19.6)% for strain, 1.9(24.4)% for distensibility, 2.4(22.2)% for compliance, 3.0(24.4)% for β-stiffness index, 0.9(25.7)% for Petersons elastic modulus and 1.2(27.9)% for Youngs elastic modulus. CONCLUSION The results show that SAPALDIA3 measurements of transcutaneous ultrasound examinations have an excellent reproducibility of structural parameters and a good reproducibility of functional indices.

Spirometer Replacement and Serial Lung Function Measurements in Population Studies: Results From the SAPALDIA Study

The Swiss Cohort Study on Air Pollution and Lung and Heart Disease in Adults (SAPALDIA), a population cohort study, used heated-wire spirometers in 1991 and 2002 and then ultrasonic spirometers in 2010 revealing measurement bias in healthy never smokers. To provide a practical method to control for measurement bias given the replacement of spirometer in long-term population studies, we built spirometer-specific reference equations from healthy never smokers participating in 1991, 2002, and 2010 to derive individualized corrections terms. We compared yearly lung function decline without corrections terms with fixed terms that were obtained from a quasi-experimental study and individualized terms. Compared with baseline reference equations, spirometer-specific reference equations predicted lower lung function. The mean measurement bias increased with age and height. The decline in forced expiratory volume in 1 second during the reference period of 1991-2002 was 31.5 (standard deviation (SD), 28.7) mL/year while, after spirometer replacement, uncorrected, corrected by fixed term, and individualized term, the declines were 47.0 (SD, 30.1), 40.4 (SD, 30.1), and 30.4 (SD, 29.9) mL/year, respectively. In healthy never smokers, ultrasonic spirometers record lower lung function values than heated-wire spirometers. This measurement bias is sizeable enough to be relevant for researchers and clinicians. Future reference equations should account for not only anthropometric variables but also spirometer type. We provide a novel method to address spirometer replacement in cohort studies.

Reproducibility of oscillometrically measured arterial stiffness indices: Results of the SAPALDIA 3 cohort study

Abstract Background. There is an increasing interest in oscillometric arterial stiffness measurement for cardiovascular risk stratification. We assessed reproducibility of the cuff-based arterial stiffness measures cardio-ankle vascular index (CAVI), brachial-ankle pulse wave velocity (baPWV) and peripheral augmentation index (pAI) in a subsample of the second follow-up of the Swiss Cohort Study on Air Pollution and Lung and Heart Diseases in Adults (SAPALDIA 3). Methods. CAVI, baPWV and pAI were measured twice within 90 days in a representative subsample (n = 105) of SAPALDIA 3 with a mean age of 63 years (52.4% female). Results. The mean coefficient of variation for CAVI was 4.4%, baPWV 3.9%, and pAI 7.4%. The intraclass correlation coefficient ranged from 0.6 for pAI to 0.8 for CAVI, and 0.9 for baPWV. The mixed linear model revealed that 68.7%/80.1%/55.0% of the CAVI/baPWV/pAI variance was accounted for by the subject, 5.2%/8.1%/ < 0.01% by the fieldworker, 6.7%/7.8%/28.5% by variation between measurement days, and 19.4%/4%/16.5% by measurement error. Bland-Altman plots showed no particular dispersion patterns except for pAI. Conclusions. Oscillometric arterial stiffness measurement by CAVI and baPWV has proved to be highly reproducible in Caucasians. Results of the pAI showed lower reproducibility. CAVI and baPWV can be implemented as easy-to-apply arterial stiffness measures in population wide cardiovascular risk assessment in Caucasians.

Serum bilirubin is associated with lung function in a Swiss general population sample

Bilirubin is a strong antioxidant. Increased serum levels have been associated with lower respiratory disease and mortality risk. We studied the association of bilirubin with lung function in the Swiss study on Air Pollution and Lung Disease in adults (SAPALDIA) cohort. Associations between natural logarithmised bilirubin and forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), FEV1/FVC and mean forced expiratory flow between 25%–75% of FVC (FEF25–75%) were tested using multiple linear regression in the whole study population (n=4195) and strata of ever-smoking and high body mass index (BMI, defined by the highest distribution quartile). Associations were retested with single nucleotide polymorphism rs6742078, a genetic determinant of bilirubin. High bilirubin levels were significantly associated with higher FEV1/FVC and FEF25–75% overall. Upon stratification, significant associations persisted in ever-smokers, amounting to 1.1% (95% CI 0.1–2.2%) increase in FEV1/FVC, and 116.2 mL·s−1 (95% CI -15.9–248.4 mL·s−1) in FEF25–75% per interquartile range of bilirubin exposure in smokers with high BMI. Associations were positive but nonsignificant in never-smokers with high BMI. Similarly, rs6742078 genotype TT was associated with increased FEV1/FVC and FEF25–75%. Our results suggest a possible protective role of bilirubin on lung tissue, which could be important for prevention and therapy. Serum bilirubin is associated with lung function in subjects with low-grade inflammation from the general population http://ow.ly/tD3FP

Accuracy of the Piko-1 Pocket Spirometer

Background. Good asthma control is the main goal of long-term asthma treatment. According to the Global Initiative for Asthma (GINA) guidelines (www.ginasthma.com), medical professionals assess asthma control based on specific questions regarding asthma symptoms and by spirometry measuring forced expiratory volume in 1 second (FEV1). Patients trained in early self-detection of asthma exacerbations use a symptom-based questionnaire, such as the Asthma Control Test (ACT) [Nathan RA, Sorkness CA, Kosinski M, et al. Development of the Asthma Control Test. A survey for assessing asthma control. J Allergy Clin Immunol 2004; 113:59–64]. However, some patients may prefer harder indicators, like peak flow values, when considering how to act within their regular asthma self-management plan. Objectives. Monitoring of FEV1 at home could be an even more valuable alternative to recording peak flow values. The inexpensive handheld pocket spirometer “Piko-1®” offers the opportunity to monitor and store consecutive FEV1 values. This study assesses the accuracy of the Piko-1 device. Methods. Twenty volunteers tested 20 Piko-1 devices over five consecutive days. All results were compared to daily FEV1 values, as measured by a calibrated reference spirometer. Results. Overall, the accuracy was acceptable, although Piko-1 tended to underestimate FEV1 in the lower range. Moreover, there was no evidence of major heterogeneity between Piko-1 devices. Conclusion. The Piko-1 FEV1 measurements are sufficiently accurate to start a clinical trial to compare the detection of asthma exacerbations with this device and based on asthma symptoms alone.

A single dose of Sildenafil does not enhance FeNO: A randomised, cross-over and placebo-controlled study

Monitoring of asthma control can be performed with different means including measurement of the concentration of nitric oxide (NO) in exhaled air. Due to its action on the NO-metabolism; we hypothesized that the intake of Sildenafil might augment and falsify the NO-values in exhaled air of subjects taking the drug to treat erectile dysfunction. This randomised, placebo-controlled cross-over study including 10 male non-asthmatic volunteers taking a single dose of 50 mg Sildenafil did not confirm this assumption in non-asthmatic subjects. We cannot think of any reason why asthmatics should behave differently. On the basis of these results, it does not seem necessary to ask asthma patients with elevated NO-values if they had taken any selective inhibitor of the cGMP-specific phosphodiesterase Type 5 as Sildenafil prior to the test.