Publications by authors named "Sarah R Haile"

65 Publications

Reference values and validation of the 1-minute sit-to-stand test in healthy 5-16-year-old youth: a cross-sectional study.

BMJ Open 2021 05 7;11(5):e049143. Epub 2021 May 7.

Epidemiology, Biostatistics and Prevention Institute, University of Zurich, Zurich, Switzerland

Objectives: It is essential to have simple, reliable and valid tests to measure children's functional capacity in schools or medical practice. The 1-minute sit-to-stand (STS) test is a quick fitness test requiring little equipment or space that is increasingly used in both healthy populations and those with chronic disease. We aimed to provide age-specific and sex-specific reference values of STS test in healthy children and adolescents and to evaluate its short-term reliability and construct validity.

Design Setting And Participants: Cross-sectional convenience sample from six public schools and one science fair in central Europe. Overall, 587 healthy participants aged 5-16 years were recruited and divided into age groups of 3 years each.

Outcomes: 1-minute STS. To evaluate short-term reliability, some children performed the STS test twice. To evaluate construct validity, some children also performed a standing long jump (SLJ) and a maximal incremental exercise test.

Results: Data from 547 youth aged 5-16 years were finally included in the analyses. The median number of repetitions in 1 min in males (females) ranged from 55 [95% CI: 38 to 72] (53 [95% CI: 35 to 76]) in 14-16-year olds to 59 [95% CI: 41 to 77] (60 [95% CI: 38 to 77]) in 8-10-year olds. Children who repeated STS showed a learning effect of on average 4.8 repetitions more than the first test (95% limits of agreement: -6.7 to 16.4). Moderate correlations were observed between the STS and the SLJ (r=0.48) tests and the maximal exercise test (r=0.43).

Conclusions: The reported STS reference values can be used to interpret STS test performance in children and adolescents. The STS appears to have good test-retest reliability, but a learning effect of about 10%. The association of STS with other measures of physical fitness should be further explored in a larger study and technical standards for its conduct are needed.
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http://dx.doi.org/10.1136/bmjopen-2021-049143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8108674PMC
May 2021

Clustering and longitudinal change in SARS-CoV-2 seroprevalence in school children in the canton of Zurich, Switzerland: prospective cohort study of 55 schools.

BMJ 2021 03 17;372:n616. Epub 2021 Mar 17.

Epidemiology, Biostatistics and Prevention Institute (EBPI), University of Zurich, Hirschengraben 84, 8001 Zurich, Switzerland

Objectives: To examine longitudinal changes in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) seroprevalence and to determine the clustering of children who were seropositive within school classes in the canton of Zurich, Switzerland from June to November 2020.

Design: Prospective cohort study.

Setting: Switzerland had one of the highest second waves of the SARS-CoV-2 pandemic in Europe in autumn 2020. Keeping schools open provided a moderate to high exposure environment to study SARS-CoV-2 infections. Children from randomly selected schools and classes, stratified by district, were invited for serological testing of SARS-CoV-2. Parents completed questionnaires on sociodemographic and health related questions.

Participants: 275 classes in 55 schools; 2603 children participated in June-July 2020 and 2552 in October-November 2020 (age range 6-16 years).

Main Outcome Measures: Serology of SARS-CoV-2 in June-July and October-November 2020, clustering of children who were seropositive within classes, and symptoms in children.

Results: In June-July, 74 of 2496 children with serological results were seropositive; in October-November, the number had increased to 173 of 2503. Overall SARS-CoV-2 seroprevalence was 2.4% (95% credible interval 1.4% to 3.6%) in the summer and 4.5% (3.2% to 6.0%) in late autumn in children who were not previously seropositive, leading to an estimated 7.8% (6.2% to 9.5%) of children who were ever seropositive. Seroprevalence varied across districts (in the autumn, 1.7-15.0%). No significant differences were found among lower, middle, and upper school levels (children aged 6-9 years, 9-13 years, and 12-16 years, respectively). Among the 2223 children who had serology tests at both testing rounds, 28/70 (40%) who were previously seropositive became seronegative, and 109/2153 (5%) who were previously seronegative became seropositive. Symptoms were reported for 22% of children who were seronegative and 29% of children who were newly seropositive since the summer. Between July and November 2020, the ratio of children diagnosed with SARS-CoV-2 infection to those who were seropositive was 1 to 8. At least one child who was newly seropositive was detected in 47 of 55 schools and in 90 of 275 classes. Among 130 classes with a high participation rate, no children who were seropositive were found in 73 (56%) classes, one or two children were seropositive in 50 (38%) classes, and at least three children were seropositive in 7 (5%) classes. Class level explained 24% and school level 8% of variance in seropositivity in the multilevel logistic regression models.

Conclusions: With schools open since August 2020 and some preventive measures in place, clustering of children who were seropositive occurred in only a few classes despite an increase in overall seroprevalence during a period of moderate to high transmission of SARS-CoV-2 in the community. Uncertainty remains as to whether these findings will change with the new variants of SARS-CoV-2 and dynamic levels of community transmission.

Trial Registration: NCT04448717.
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http://dx.doi.org/10.1136/bmj.n616DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7966948PMC
March 2021

and Exposures and Lung Function in Swiss Adults: Estimated Effects of Short-Term Exposures and Long-Term Exposures with and without Adjustment for Short-Term Deviations.

Environ Health Perspect 2021 Jan 27;129(1):17009. Epub 2021 Jan 27.

Epidemiology, Biostatistics and Prevention Institute, University of Zurich, Zurich, Switzerland.

Background: The impact of nitrogen dioxide () and particulate matter with an aerodynamic diameter of less than or equal to 2.5. microns () exposures on lung function has been investigated mainly in children and less in adults. Furthermore, it is unclear whether short-term deviations of air pollutant concentration need to be considered in long-term exposure models.

Objectives: The aims of this study were to investigate the association between short-term air pollution exposure and lung function and to assess whether short-term deviations of air pollutant concentration should be integrated into long-term exposure models.

Methods: Short-term (daily averages 0-7 d prior) and long-term (1- and 4-y means) and concentrations were modeled using satellite, land use, and meteorological data calibrated on ground measurements. Forced expiratory volume within the first second (FEV1) of forced exhalation and forced vital capacity (FVC) were measured during a LuftiBus assessment (2003-2012) and linked to exposure information from the Swiss National Cohort for 36,085 adults (ages 18-95 y). We used multiple linear regression to estimate adjusted associations, and additionally adjusted models of long-term exposures for short-term deviations in air pollutant concentrations.

Results: A increase in and on the day of the pulmonary function test was associated with lower FEV1 and FVC (: FEV1 [95% confidence interval: , ], FVC [, ]; : FEV1 [, ], FVC [, ]). A increase in 1-y mean was also associated with lower FEV1 (; , 0.5) and FVC (; , ), as was a increase in 1-y mean (FEV1: ; , ; FVC: ; , ). These associations were robust to adjustment for short-term deviations in the concentration of each air pollutant.

Conclusions: Short- and long-term air pollution exposures were negatively associated with lung function, in particular long-term exposure with FVC. Our findings contribute substantially to the evidence of adverse associations between air pollution and lung function in adults. https://doi.org/10.1289/EHP7529.
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http://dx.doi.org/10.1289/EHP7529DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7839986PMC
January 2021

TOURIST2 - Tracking of urgent risks in swiss travellers to the 6 main travel destinations - Feasibility and ethical considerations of a smartphone application-based study.

Travel Med Infect Dis 2021 Jan-Feb;39:101912. Epub 2020 Nov 7.

Department of Public Health & Global Health, Division of Infectious Diseases, Epidemiology, Biostatistics and Prevention Institute, University of Zurich, 8001, Zurich, Switzerland; Department of Tropical Medicine, Bernhard Nocht Institute for Tropical Medicine, 20359, Hamburg, Germany; Division of Hygiene and Infectious Diseases, Institute of Hygiene and Environment, 20539 Hamburg, Germany. Electronic address:

Background: The adoption of mHealth technology in travel medicine is a relatively new and unexplored field. We have further developed a TRAVEL application (app) for real-time data monitoring during travel. In this manuscript we report on the feasibility using this new app in a large and diverse cohort of travellers to three continents.

Methods: We enrolled 1000 participants from the travel clinics of Zurich and Basel, Switzerland, aged ≥18 years, travelling to Thailand, India, China, Tanzania, Brazil and Peru between 09/2017-01/2019. Participants included healthy travellers, individuals with pre-existing chronic diseases and elderly travellers (≥60 years). Participants completed an app-based daily survey on risk behaviours/health incidents pre-, during and after travel. Simultaneously, GPS locations were tightly collected and linked to environmental data.

Results: 793 (79%) travellers answered at least one questionnaire during their trip. Participants' median age was 34 years (range 18-84 years); 8% were aged ≥60 years; 55% female; 32% had pre-existing chronic diseases. Completion rates were similar in younger and elderly travellers and in those with and without pre-existing diseases.

Conclusions: The use of a smartphone app is a feasible method for collecting behavioural and health data in elderly travellers and individuals with chronic diseases travelling to three continents.
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http://dx.doi.org/10.1016/j.tmaid.2020.101912DOI Listing
November 2020

Seroprevalence and immunity of SARS-CoV-2 infection in children and adolescents in schools in Switzerland: design for a longitudinal, school-based prospective cohort study.

Int J Public Health 2020 Dec 15;65(9):1549-1557. Epub 2020 Oct 15.

Epidemiology, Biostatistics and Prevention Institute (EBPI), University of Zurich, Hirschengraben 84, 8001, Zurich, Switzerland.

Objectives: This longitudinal cohort study aims to assess the extent and patterns of seroprevalence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies in school-attending children, and their parents and school personnel. It will examine risk factors for infection, the relationship between seropositivity and symptoms, and temporal persistence of antibodies.

Methods: The study (Ciao Corona) will enroll a regionally representative, random sample of schools in the canton of Zurich, where 18% of the Swiss population live. Children aged 5-16 years, attending primary and secondary schools, and their parents and school personnel are invited. Venous blood and saliva samples are collected for serological testing in June/July 2020, in October/November 2020, and in March/April 2021. Bi-monthly questionnaires will cover SARS-CoV-2 symptoms and tests, health, preventive behavior, and lifestyle information. Hierarchical Bayesian logistic regression models will account for sensitivity and specificity of the serological tests in the analyses and complex sampling structure, i.e., clustering within classes and schools.

Results And Conclusions: This unique school-based study will allow describing temporal trends of immunity, evaluate effects of preventive measures and will inform goal-oriented policy decisions during subsequent outbreaks. Trial registration ClinicalTrials.gov Identifier: NCT04448717, registered June 26, 2020. https://clinicaltrials.gov/ct2/show/NCT04448717 .
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http://dx.doi.org/10.1007/s00038-020-01495-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7561232PMC
December 2020

Global variation of risk thresholds for initiating statins for primary prevention of cardiovascular disease: a benefit-harm balance modelling study.

BMC Cardiovasc Disord 2020 09 17;20(1):418. Epub 2020 Sep 17.

Department of Epidemiology, Epidemiology, Biostatistics and Prevention Institute, University of Zurich, Hirschengraben 84, CH-8001, Zurich, Switzerland.

Background: We previously showed that the 10-year cardiovascular disease (CVD) risk threshold to initiate statins for primary prevention depends on the baseline CVD risk, age, sex, and the incidence of statin-related harm outcome and competing risk for non-CVD death. As these factors appear to vary across countries, we aimed in this study to determine country-specific thresholds and provide guidelines a quantitative benefit-harm assessment method for local adaptation.

Methods: For each of the 186 countries included, we replicated the benefit-harm balance analysis using an exponential model to determine the thresholds to initiate statin use for populations aged 40 to 75 years, with no history of CVD. The analyses took data inputs from a priori studies, including statin effect estimates (network meta-analysis), patient preferences (survey), and baseline incidence of harm outcomes and competing risk for non-CVD (global burden of disease study). We estimated the risk thresholds above which the benefits of statins were more likely to outweigh the harms using a stochastic approach to account for statistical uncertainty of the input parameters.

Results: The 5 and 95 percentiles of the 10-year risk thresholds above which the benefits of statins outweigh the harms across 186 countries ranged between 14 and 20% in men and 19-24% in women, depending on age (i.e., 90% of the country-specific thresholds were in the ranges stated). The median risk thresholds varied from 14 to 18.5% in men and 19 to 22% in women. The between-country variability of the thresholds was slightly attenuated when further adjusted for age resulting, for example, in a 5 and 95 percentiles of 14-16% for ages 40-44 years and 17-21% for ages 70-74 years in men. Some countries, especially the islands of the Western Pacific Region, had higher thresholds to achieve net benefit of statins at 25-36% 10-year CVD risks.

Conclusions: This extensive benefit-harm analysis modeling shows that a single CVD risk threshold, irrespective of age, sex and country, is not appropriate to initiate statin use globally. Instead, countries need to carefully determine thresholds, considering the national or subnational contexts, to optimize benefits of statins while minimizing related harms and economic burden.
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http://dx.doi.org/10.1186/s12872-020-01697-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7495829PMC
September 2020

Recommended shielding against COVID-19 impacts physical activity levels in adults with cystic fibrosis.

J Cyst Fibros 2020 11 28;19(6):875-879. Epub 2020 Aug 28.

Swisstransplant, Berne, Switzerland; Faculty of Medicine, University of Zurich, Zurich, Switzerland. Electronic address:

Background: Severe acute respiratory syndrome - coronavirus-2 (SARS-CoV-2) has caused a pandemic threatening the life of people with chronic respiratory diseases including cystic fibrosis (CF). This study was designed to investigate health-related aspects of individuals with CF, with and without lung transplantation (LTX), their communication with their specialist healthcare providers during the pandemic, potential changes in peoples' individual therapy regimes and daily physical activity levels.

Methods: A web-based survey was conducted among Swiss adults with CF with and without LTX, study period from March 16th, 2020 - the day the "extraordinary situation" was officially declared in Switzerland introducing stringent measures protecting the public - until May 16, 2020.

Results: 327 individuals (25% LTX recipients) were included, 45 individuals reported coronavirus-2019 disease (COVID-19) like symptoms. Of 28 subjects tested, only three subjects were tested positive, all with mild symptoms, no hospitalization required. Almost half of the survey respondents (45%) reported undertaking less physical activity during the lockdown, while 79% and 91% of participants reported no change in traditional airway clearance and inhalation therapies, respectively. Distress regarding a potential SARS-CoV-2 infection or worsening of lung disease were no major concerns for subjects.

Conclusions: Our study reveals that the direct impact of SARS-CoV-2 on clinical outcomes of individuals with CF was mild although people with chronic lung diseases like CF are considered a high-risk population; overall, this is reassuring. However, strict lockdown measures substantially affected peoples' physical activity levels, a vital cornerstone of CF therapy; and this is worrisome.
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http://dx.doi.org/10.1016/j.jcf.2020.08.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7455146PMC
November 2020

Effects of suboptimal adherence of CPAP therapy on symptoms of obstructive sleep apnoea: a randomised, double-blind, controlled trial.

Eur Respir J 2020 03 20;55(3). Epub 2020 Mar 20.

Dept of Pulmonology, University Hospital Zurich, Zurich, Switzerland

Introduction: Continuous positive airway pressure (CPAP) is currently the treatment of choice for sleepiness in patients with obstructive sleep apnoea (OSA); however, adherence is often thought to be suboptimal. We investigated the effects of suboptimal CPAP usage on objective and subjective sleepiness parameters in patients with OSA.

Material And Methods: In this 2-week, parallel, double-blind, randomised controlled trial we enrolled moderate-to-severe OSA patients with excessive pre-treatment daytime sleepiness (Epworth sleepiness scale (ESS) score >10 points) who had suboptimal CPAP adherence over ≥12 months (mean nightly usage time 3-4 h). Patients were allocated through minimisation to either subtherapeutic CPAP ("sham CPAP") or continuation of CPAP ("therapeutic CPAP"). A Bayesian analysis with historical priors calculated the posterior probability of superiority.

Results: Between May, 2016 and November, 2018, 57 patients (aged 60±8 years, 79% male, 93% Caucasian) were allocated in total, and 52 who completed the study (50% in each arm) were included in the final analysis. The unadjusted ESS score increase was 2.4 points (95% CI 0.6-4.2, p=0.01) in the sham-CPAP group when compared to continuing therapeutic CPAP. The probability of superiority of therapeutic CPAP over sham CPAP was 90.4% for ESS, 90.1% for systolic blood pressure and 80.3% for diastolic blood pressure.

Conclusions: Patients with moderate-to-severe OSA and daytime sleepiness are still getting a substantial benefit from suboptimal CPAP adherence, albeit not as much as they might get if they adhered more. Whether a similar statement can be made for even lower adherence levels remains to be established in future trials.
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http://dx.doi.org/10.1183/13993003.01526-2019DOI Listing
March 2020

Effect of Treatment of Central Sleep Apnea/Cheyne-Stokes Respiration on Left Ventricular Ejection Fraction in Heart Failure: A Network Meta-Analysis.

J Clin Sleep Med 2019 12 30;15(12):1817-1825. Epub 2019 Oct 30.

Department of Pulmonology and Sleep Disorders Centre, University Hospital of Zurich, Zurich, Switzerland.

Study Objectives: Patients who have experienced heart failure with central sleep apnea/Cheyne-Stokes respiration (CSA/CSR) have an impaired prognosis. Continuous positive airway pressure (CPAP) and adaptive servoventilation (ASV) as well as nocturnal oxygen (O₂) are proposed treatment modalities of CSA/CSR. The goal of the study is to assess whether and how different treatments of CSA/CSR affect cardiac function.

Methods: Databases were searched up to December 2017 for randomized controlled trials (RCTs) comparing the effect of any combination of CPAP, ASV, O₂ or an inactive control on left ventricular ejection fraction (LVEF) in patients with heart failure and CSA/CSR. A systematic review and network meta-analysis using multivariate random-effects meta-regression were performed.

Results: Twenty-four RCTs (1,289 patients) were included in the systematic review and data of 16 RCTs (951 patients; apnea-hypopnea-index 38 ± 3/h, LVEF 29 ± 3%) could be pooled in a network meta-analysis. Compared to an inactive control, both CPAP and ASV significantly improved LVEF by 4.4% (95% confidence interval 0.3-8.5%, P = 0.036) and 3.8% (95% confidence interval 0.6-7.0%, P = 0.025), respectively, whereas O₂ had no effect on LVEF (P = 0.35). There was no difference in treatment effects on LVEF between CPAP and ASV (P = 0.76). The treatment effect of positive pressure ventilation was larger when baseline LVEF was lower in systolic heart failure.

Conclusions: CPAP and ASV are effective in improving LVEF in patients with heart failure and CSA/CSR to a clinically relevant amount, whereas nocturnal O₂ is not. There is no difference between CPAP and ASV in the comparative beneficial effect on cardiac function.
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http://dx.doi.org/10.5664/jcsm.8092DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7099193PMC
December 2019

Endocrine responses during CPAP withdrawal in obstructive sleep apnoea: data from two randomised controlled trials.

Thorax 2019 11 29;74(11):1102-1105. Epub 2019 Aug 29.

Department of Pulmonology and Sleep Disorders Centre, University Hospital Zurich, Zurich, Switzerland

The aim of this investigation was to elucidate the effect of CPAP withdrawal on neurometabolic and cardiometabolic markers in patients with obstructive sleep apnoea. We evaluated 70 patients (mean age 61±10 years, 82% men) treated with CPAP in two 2-week, parallel, randomised controlled trials. CPAP withdrawal resulted in elevated 3,4-dihydroxyphenylglycol, norepinephrine and cortisol after 2 weeks of CPAP withdrawal; however, no statistically significant changes of the renin-angiotensin-aldosterone system (RAAS) determinants were documented. In summary, CPAP withdrawal may be more prominently linked to short-term increases in sympathetic activation than hypothalamic-pituitary-adrenal axis or RAAS activation. ClinicalTrials.gov Identifier: NCT02493673 and NCT02050425.
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http://dx.doi.org/10.1136/thoraxjnl-2019-213522DOI Listing
November 2019

Bronchoalveolar lavage cytokines are of minor value to diagnose complications following lung transplantation.

Cytokine 2020 01 7;125:154794. Epub 2019 Aug 7.

Division of Pulmonology, University Hospital Zurich, Rämistrasse 100, CH-8091 Zurich, Switzerland. Electronic address:

Early diagnosis and treatment of acute cellular rejection (ACR) may improve long-term outcome for lung transplant recipients (LTRs). Cytokines have become valuable diagnostic tools in many medical fields. The role of bronchoalveolar lavage (BAL) cytokines is of unknown value to diagnose ACR and distinguish rejection from infection. We hypothesized that distinct cytokine patterns obtained by surveillance bronchoscopies during the first year after transplantation are associated with ACR and microbiologic findings. We retrospectively analyzed data from 319 patients undergoing lung transplantation at University Hospital Zurich from 1998 to 2016. We compared levels of IL-6, IL-8, IFN-γ and TNF-α in 747 BAL samples with transbronchial biopsies (TBB) and microbiologic results from surveillance bronchoscopies. We aimed to define reference values that would allow distinction between four specific groups "ACR", "infection", "combined ACR and infection" and "no pathologic process". No definitive pattern was identified. Given the overlap between groups, these four cytokines are not suitable diagnostic markers for ACR or infection after lung transplantation.
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http://dx.doi.org/10.1016/j.cyto.2019.154794DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7128992PMC
January 2020

Efficacy of pharmacotherapy for OSA in adults: A systematic review and network meta-analysis.

Sleep Med Rev 2019 08 19;46:74-86. Epub 2019 Apr 19.

Department of Pulmonology, University Hospital Zurich, Zurich, Switzerland. Electronic address:

Pharmacotherapy represents a desirable potential therapeutic alternative for patients with obstructive sleep apnoea (OSA). We aimed to summarize evidence on the efficacy of pharmacotherapy in adults with OSA and delineate the underlying mechanisms. Seven databases were systematically screened for randomised controlled trials (RCTs) from their inception to September 2018. According to a pre-registered study protocol (PROSPERO-ID-CRD42018086446) network meta-analysis was performed to obtain intervention effects on the apnoea-hypopnoea-index (AHI) based on data extracted from published reports. We identified 58 RCTs (n = 1710 patients) investigating 44 different drugs or drug-combinations. Interventions were classified into seven pathomechanism-groups and summarized narratively. A meta-analysis of 17 trials for seven drugs (acetazolamide, donepezil, mirtazapine, ondansetron, paroxetine, protriptyline, theophylline) indicated a small effect for acetazolamide (mean difference in AHI -9.6/h [-17.7; -1.4]; p = 0.02). In the network meta-analysis (I = 50%) nine drugs (tramazoline, liraglutide, spironolactone/furosemide, acetazolamide, dronabinol, zonisamide, phentermine, spironolactone, and ondansetron/fluoxetine) significantly lowered the AHI compared to placebo. Although some trials indicate favorable outcomes, these results are only valid for distinctive OSA-phenotypes or were not clinically significant. The effect sizes were small, the majority of trials were not adequately powered. There is currently insufficient evidence to recommend any pharmacotherapy for OSA and no phase-III trials are available.
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http://dx.doi.org/10.1016/j.smrv.2019.04.009DOI Listing
August 2019

Effects of short-term continuous positive airway pressure withdrawal on cerebral vascular reactivity measured by blood oxygen level-dependent magnetic resonance imaging in obstructive sleep apnoea: a randomised controlled trial.

Eur Respir J 2019 02 21;53(2). Epub 2019 Feb 21.

Dept of Pulmonology and Sleep Disorders Centre, University Hospital Zurich, Zurich, Switzerland.

Impaired cerebral vascular reactivity (CVR) increases long-term stroke risk. Obstructive sleep apnoea (OSA) is associated with peripheral vascular dysfunction and vascular events. The aim of this trial was to evaluate the effect of continuous positive airway pressure (CPAP) withdrawal on CVR.41 OSA patients (88% male, mean age 57±10 years) were randomised to either subtherapeutic or continuation of therapeutic CPAP. At baseline and after 2 weeks, patients underwent a sleep study and magnetic resonance imaging (MRI). CVR was estimated by quantifying the blood oxygen level-dependent (BOLD) MRI response to breathing stimuli.OSA did recur in the subtherapeutic CPAP group (mean treatment effect apnoea-hypopnoea index +38.0 events·h, 95% CI 24.2-52.0; p<0.001) but remained controlled in the therapeutic group. Although there was a significant increase in blood pressure upon CPAP withdrawal (mean treatment effect +9.37 mmHg, 95% CI 1.36-17.39; p=0.023), there was no significant effect of CPAP withdrawal on CVR assessed BOLD MRI under either hyperoxic or hypercapnic conditions.Short-term CPAP withdrawal did not result in statistically significant changes in CVR as assessed by functional MRI, despite the recurrence of OSA. We thus conclude that, unlike peripheral endothelial function, CVR is not affected by short-term CPAP withdrawal.
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http://dx.doi.org/10.1183/13993003.01854-2018DOI Listing
February 2019

Clinical and radiographic course of early undifferentiated arthritis under treatment is not dependent on the number of joints with erosions at diagnosis: results from the Swiss prospective observational cohort.

RMD Open 2018 6;4(1):e000673. Epub 2018 Jun 6.

Division of Rheumatology and Immunology, Kantonsspital St. Gallen, St. Gallen, Switzerland.

Objective: To analyse whether early arthritis patients who do not fulfil the American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) 2010 classification criteria for rheumatoid arthritis (RA) have a different course of the disease dependent on whether they can or cannot be classified as RA because of radiographic disease (EULAR task force) at diagnosis.

Methods: For this observational study within the Swiss RA cohort SCQM, we included patients with early undifferentiated arthritis (disease duration ≤1 year), who had not received any previous disease-modifying antirheumatic drugs (DMARDs). 2010 ACR/EULAR criteria negative patients were separated into two groups (radiographic vs non-radiographic arthritis) depending on whether or not they had radiographic changes defined as erosive disease by a EULAR task force (≥3 joints with erosions). The primary outcome measure was the radiographic progression detected employing the Ratingen erosion score. Health Assessment Questionnaire (HAQ) and DAS-28 were used as secondary outcome measures. The average observation period was 4 years.

Results: A total of 592 patients were analysed. 240 were not classifiable as RA by application of the 2010 ACR/EULAR criteria at baseline. In 57 patients, radiographs at the first visit were not available. 133 patients had radiographic arthritis and 50 non-radiographic arthritis. Treatment was initiated in all patients with DMARDs, mostly methotrexate. No differences in DAS-28 and HAQ scores were found during follow-up. The average erosion scores were higher among patients with initially radiographic arthritis throughout the study. The progression of erosion scores over time, however, was higher in patients with initially non-radiographic arthritis with less subsequent radiological progression (3.3 erosions/year vs 0.4, respectively, p<0.0001).

Conclusions: The clinical and radiographic course of early undifferentiated arthritis under treatment was not dependent on the presence of erosions in three or more joints (ie, the definition of radiographic disease by the EULAR task force) at diagnosis in our cohort.
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http://dx.doi.org/10.1136/rmdopen-2018-000673DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6018869PMC
June 2018

BMI-mortality association: shape independent of smoking status but different for chronic lung disease and lung cancer.

Int J Chron Obstruct Pulmon Dis 2018 6;13:1851-1855. Epub 2018 Jun 6.

Epidemiology, Biostatistics and Prevention Institute (EBPI), University of Zurich, Zurich, Switzerland.

Background: Besides smoking, low or high body mass index (BMI) is associated with chronic lung disease (CLD). It is unclear how CLD is associated with BMI, whether smoking interacts with this association, and how the associations differ from the patterns known for lung cancer.

Population And Methods: Our population comprised 35,212 individuals aged 14-99, who participated in population-based surveys conducted in 1977-1993 in Switzerland (mortality follow-up until 2014). We categorized smokers into never, former, light, and heavy; and BMI into underweight, normal weight, overweight, and obese. Hazard ratios (HRs) were obtained with multivariable Cox proportional hazards models.

Results: CLD mortality was strongly associated with being underweight. This was mainly due to the effect in men (HR 5.04 [2.63-9.66]) and also prevailed in never smokers (HR 1.81 [1.11-3.00]). Obesity was also associated with CLD mortality (HR men: 1.37 [1.01-1.86], women: 1.39 [0.90-2.17]), but not with lung cancer mortality. In line with lung cancer, for CLD, the BMI-mortality association followed the same shape in all smoking categories, suggesting that this association was largely independent of smoking status.

Conclusion: The shape of the BMI-mortality association was inversely linear for lung cancer but followed a U-shape for CLD. Further research should examine the potentially protective effect of obesity on lung cancer occurrence and the possibly hazardous impact of underweight on CLD development.
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http://dx.doi.org/10.2147/COPD.S157629DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5995287PMC
January 2019

Pulmonary involvement in Fabry disease: effect of plasma globotriaosylsphingosine and time to initiation of enzyme replacement therapy.

BMJ Open Respir Res 2018 21;5(1):e000277. Epub 2018 Apr 21.

University Heart Center, University Hospital Zurich, Zurich, Switzerland.

Introduction: Anderson-Fabry disease (AFD) is an X-linked lysosomal storage disorder caused by mutations of gene leading to reduced α-galactosidase activity and resulting in a progressive accumulation of globotriaosylceramide (Gb3) and its deacylated derivative, globotriaosyl-sphingosine (Lyso-Gb3). Plasma Lyso-Gb3 levels serve as a disease severity and treatment monitoring marker during enzyme replacement therapy (ERT).

Methods: Adult patients with AFD who had yearly pulmonary function tests between 1999 and 2015 were eligible for this observational study. Primary outcome measures were the change in z-score of forced expiratory volume in the first second (FEV) and FEV/FVC over time. Plasma Lyso-Gb3 levels and the age of ERT initiation were investigated for their association with lung function decline.

Results: Fifty-three patients (42% male, median (range) age at diagnosis of AFD 34 (6-61) years in men, 34 (13-67) in women) were included. The greatest decrease of FEV/FVC z-scores was observed in Classic men (-0.048 per year, 95% CI -0.081 to -0.014), compared with the Later-Onset men (+0.013,95% CI -0.055 to 0.082), Classic women (-0.008, 95% CI -0.035 to +0.020) and Later-Onset women (-0.013, 95% CI -0.084 to +0.058). Cigarette smoking (P=0.022) and late ERT initiation (P=0.041) were independently associated with faster FEV decline. FEV/FVC z-score decrease was significantly reduced after initiation of ERT initiation (-0.045 compared with -0.015, P=0.014). Furthermore, there was a trend towards a relevant influence of Lyso-Gb3 (P=0.098) on airflow limitation with age.

Conclusion: Early ERT initiation seems to preserve pulmonary function. Plasma Lyso-Gb3 is maybe a useful predictor for airflow limitation. Classic men need a closer monitoring of the lung function.
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http://dx.doi.org/10.1136/bmjresp-2018-000277DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5922571PMC
April 2018

Physical activity and sedentary behavior in preschoolers: a longitudinal assessment of trajectories and determinants.

Int J Behav Nutr Phys Act 2018 04 4;15(1):35. Epub 2018 Apr 4.

Epidemiology, Biostatistics and Prevention Institute, University of Zurich, Hirschengraben 84, 8001, Zurich, Switzerland.

Background: Despite physical activity (PA) being recognized as a critically important factor for good physical and mental health already early in life and throughout the life course, prospective data on activity behavior during the preschool years remains scarce. This study examined trajectories and determinants of levels and change in total PA (TPA), moderate-to-vigorous PA (MVPA) and sedentary behavior (SB) in a representative sample of Swiss preschoolers.

Methods: Data were drawn from the Swiss Preschoolers' Health Study (SPLASHY), a multi-site prospective cohort study including 555 children (53% boys) aged 2-to-6 years at baseline. A follow-up was conducted after 12 months. Activity behavior was measured using accelerometers. Information on 35 potential determinants from different socio-ecological domains was either directly measured or parent-reported. Trajectories of TPA, MVPA and SB over time were described for boys and girls. Linear mixed models were used to investigate factors that predicted levels and change in TPA, MVPA and SB.

Results: All children were sufficiently physically active according to published recommendations for preschoolers. Trajectory profiles revealed a marked increase in TPA and MVPA in boys and girls whereas SB remained fairly stable over time. Mixed modeling demonstrated that variables most relevant to determining PA levels were sex, age and activity temperament (all positively associated). Together with gross motor skills, birth weight, family structure (only for TPA) and season (only for MVPA), these factors accounted for 26 and 32% of total variance explained in TPA and MVPA, respectively. Activity temperament emerged as the strongest determinant of SB (negative association) and explained with sex, season and family structure 20% of total variance in SB. The presence of older siblings was the only factor that predicted change in PA over time.

Conclusions: In this healthy physically active cohort of preschoolers, non-modifiable individual-level factors had the greatest influence on PA. The limited success of this and previous studies to identify modifiable determinants and the finding that most preschoolers were sufficiently active suggest that future attempts should provide insights into how preschoolers' activity levels can be maintained and fostered to prevent subsequent harmful declines attributable, amongst others, to educational transitions. Thus, good-quality longitudinal studies are needed.

Trial Registration: Current Controlled Trials ISRCTN41045021 (date of registration: 21.03.14).
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http://dx.doi.org/10.1186/s12966-018-0670-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5885465PMC
April 2018

Large-scale external validation and comparison of prognostic models: an application to chronic obstructive pulmonary disease.

BMC Med 2018 03 2;16(1):33. Epub 2018 Mar 2.

Universidad Nacional de la Plata, Hospital San Juan de Dios de La Plata, Buenos Aires, Argentina.

Background: External validations and comparisons of prognostic models or scores are a prerequisite for their use in routine clinical care but are lacking in most medical fields including chronic obstructive pulmonary disease (COPD). Our aim was to externally validate and concurrently compare prognostic scores for 3-year all-cause mortality in mostly multimorbid patients with COPD.

Methods: We relied on 24 cohort studies of the COPD Cohorts Collaborative International Assessment consortium, corresponding to primary, secondary, and tertiary care in Europe, the Americas, and Japan. These studies include globally 15,762 patients with COPD (1871 deaths and 42,203 person years of follow-up). We used network meta-analysis adapted to multiple score comparison (MSC), following a frequentist two-stage approach; thus, we were able to compare all scores in a single analytical framework accounting for correlations among scores within cohorts. We assessed transitivity, heterogeneity, and inconsistency and provided a performance ranking of the prognostic scores.

Results: Depending on data availability, between two and nine prognostic scores could be calculated for each cohort. The BODE score (body mass index, airflow obstruction, dyspnea, and exercise capacity) had a median area under the curve (AUC) of 0.679 [1st quartile-3rd quartile = 0.655-0.733] across cohorts. The ADO score (age, dyspnea, and airflow obstruction) showed the best performance for predicting mortality (difference AUC - AUC = 0.015 [95% confidence interval (CI) = -0.002 to 0.032]; p = 0.08) followed by the updated BODE (AUC - AUC = 0.008 [95% CI = -0.005 to +0.022]; p = 0.23). The assumption of transitivity was not violated. Heterogeneity across direct comparisons was small, and we did not identify any local or global inconsistency.

Conclusions: Our analyses showed best discriminatory performance for the ADO and updated BODE scores in patients with COPD. A limitation to be addressed in future studies is the extension of MSC network meta-analysis to measures of calibration. MSC network meta-analysis can be applied to prognostic scores in any medical field to identify the best scores, possibly paving the way for stratified medicine, public health, and research.
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http://dx.doi.org/10.1186/s12916-018-1013-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5833113PMC
March 2018

Correction to: Multiple Score Comparison: a network meta-analysis approach to comparison and external validation of prognostic scores.

BMC Med Res Methodol 2018 02 12;18(1):21. Epub 2018 Feb 12.

Epidemiology, Biostatistics and Prevention Institute, University of Zurich, Zurich, Switzerland.

Correction: Following publication of the original article [1], a member of the writing group reported that his name is misspelt. The paper should appear in Pubmed under "Ter Riet G", bot as "Riet GT".
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http://dx.doi.org/10.1186/s12874-018-0481-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5808419PMC
February 2018

Multiple Score Comparison: a network meta-analysis approach to comparison and external validation of prognostic scores.

BMC Med Res Methodol 2017 12 21;17(1):172. Epub 2017 Dec 21.

Epidemiology, Biostatistics and Prevention Institute, University of Zurich, Zurich, Switzerland.

Background: Prediction models and prognostic scores have been increasingly popular in both clinical practice and clinical research settings, for example to aid in risk-based decision making or control for confounding. In many medical fields, a large number of prognostic scores are available, but practitioners may find it difficult to choose between them due to lack of external validation as well as lack of comparisons between them.

Methods: Borrowing methodology from network meta-analysis, we describe an approach to Multiple Score Comparison meta-analysis (MSC) which permits concurrent external validation and comparisons of prognostic scores using individual patient data (IPD) arising from a large-scale international collaboration. We describe the challenges in adapting network meta-analysis to the MSC setting, for instance the need to explicitly include correlations between the scores on a cohort level, and how to deal with many multi-score studies. We propose first using IPD to make cohort-level aggregate discrimination or calibration scores, comparing all to a common comparator. Then, standard network meta-analysis techniques can be applied, taking care to consider correlation structures in cohorts with multiple scores. Transitivity, consistency and heterogeneity are also examined.

Results: We provide a clinical application, comparing prognostic scores for 3-year mortality in patients with chronic obstructive pulmonary disease using data from a large-scale collaborative initiative. We focus on the discriminative properties of the prognostic scores. Our results show clear differences in performance, with ADO and eBODE showing higher discrimination with respect to mortality than other considered scores. The assumptions of transitivity and local and global consistency were not violated. Heterogeneity was small.

Conclusions: We applied a network meta-analytic methodology to externally validate and concurrently compare the prognostic properties of clinical scores. Our large-scale external validation indicates that the scores with the best discriminative properties to predict 3 year mortality in patients with COPD are ADO and eBODE.
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http://dx.doi.org/10.1186/s12874-017-0433-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5740913PMC
December 2017

Prognostic value of MIB-1 proliferation index in solitary fibrous tumors of the pleura implemented in a new score - a multicenter study.

Respir Res 2017 12 16;18(1):210. Epub 2017 Dec 16.

Department of Pulmonology, University Hospital Zurich, Raemistrasse 100, 8091, Zurich, Switzerland.

Background: Although the majority of solitary fibrous tumors of the pleura (SFTP) follow a benign course, 10-25% of patients suffer from recurrence or metastatic disease. Several scoring models have been proposed to predict the outcome. However, none of these included immunohistochemical (IHC) markers as possible prognosticators.

Methods: In this multicenter study, we collected clinical data and formalin-fixed and paraffin-embedded (FFPE) tissue blocks of patients with histologically proven SFTP which had been surgically resected between 2000 und 2015. After systematic and extensive IHC staining on tissue microarrays, the results were analyzed and compared to histomorphological and clinical data for their possible prognostic value.

Results: In total, 78 patients (mean age 61 ± 11 years) were included. Of these, 9 patients (11%) had an adverse outcome including SFTP recurrence (n = 6) or SFTP-related death (n = 3). Mean overall survival was 172 ± 13 months. 1 and 10-year event-free survival rates were 99% and 93%. In the multivariable analysis only MIB-1 proliferation index (Ki-67) ≥10% (HR 12.3, CI 1.1-139.5, p = 0.043), ≥4 mitoses per 10 high power fields (HR 36.5, CI 1.2-1103.7, p = 0.039) and tumor size larger than 10 cm (HR 81.8, CI 1.7-4016.8, p = 0.027) were independently associated with adverse outcome.

Conclusion: A high proliferation rate by MIB-1 IHC was associated with impaired outcome. Upon this, we established a new score using mitosis, necrosis, size of the tumor and MIB-1, which performed better than the traditional scores in our data set. This prognostic score could help to better evaluate outcome of SFTP, but requires external validation.
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http://dx.doi.org/10.1186/s12931-017-0693-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5732426PMC
December 2017

Commonly Used Patient-Reported Outcomes Do Not Improve Prediction of COPD Exacerbations: A Multicenter 4½ Year Prospective Cohort Study.

Chest 2017 12 18;152(6):1179-1187. Epub 2017 Sep 18.

Epidemiology, Biostatistics and Prevention Institute, University of Zurich, Zurich, Switzerland.

Background: Several cross-sectional and short-term studies suggest that patient-reported outcomes (PROs) may be useful to help predict COPD exacerbations, but evidence from long-term prospective cohort studies is lacking. Our aim was to assess if PROs add to the prediction of exacerbations.

Methods: Four hundred eight primary care patients with COPD participated in the multicenter prospective International Collaborative Effort on Chronic Obstructive Lung Disease: Exacerbation Risk Index Cohorts (ICE COLD ERIC) study. PROs included the Chronic Respiratory Disease Questionnaire, the Hospital Anxiety and Depression Scale, the Feeling Thermometer, and the LASA Physical Activity Questionnaire (LAPAQ). Exacerbations during 4½ years were adjudicated by experts. We used negative binomial regression to assess the association between PROs and exacerbations while considering age, sex, airflow obstruction, previous exacerbations, and smoking status. We then assessed if adding PROs improved the predictive properties of widely used indices.

Results: Lower levels of dyspnea, fatigue, and anxiety and higher levels of physical activity were associated with a lower risk of exacerbations (adjusted incidence rate ratio [IRR], 0.90; 95% CI, 0.84-0.97; P = .01; IRR, 0.93; 95% CI, 0.86-1.00; P = .04; IRR, 1.03; 95% CI, 1.00-1.06; P = .03; IRR, 0.93; 95% CI, 0.87-0.99; P = .04, respectively). The best prediction was when LAPAQ was added to the BMI, airflow obstruction, dyspnea, and previous exacerbations (BODEx) index (area under the curve Δ+0.02, from 0.72-0.74). However, this increase was not clinically relevant (net reclassification improvement, 0.03; 95% CI, -0.03 to 0.08).

Conclusions: Some domains of PROs are independently associated with exacerbations but do not lead to clearly improved prediction when added to established indices to predict exacerbations. There is still much room for improvement in the prediction of exacerbations.

Trial Registry: ClinicalTrials.gov; No.: NCT00706602.
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http://dx.doi.org/10.1016/j.chest.2017.09.003DOI Listing
December 2017

Long-term follow-up of pulmonary function in Fabry disease: A bi-center observational study.

PLoS One 2017 25;12(7):e0180437. Epub 2017 Jul 25.

Transplantation Centre, Lausanne University Hospital, Lausanne, Switzerland.

Introduction: Fabry disease (FD) is a lysosomal storage disorder leading to decreased α-galactosidase A enzyme activity and subsequent abnormal accumulation of glycosphingolipids in various organs. Although histological evidence of lung involvement has been demonstrated, the functional impact of these changes is less clear.

Materials And Methods: Adult patients with FD who had yearly pulmonary function tests (PFT) at two centers from 1999 thru 2015 were eligible for this observational study. Primary outcome measures were the change in forced expiratory volume in the first second (FEV1) and FEV1/FVC over time. As secondary outcome we investigated sex, smoking, enzyme replacement therapy (ERT), residual enzyme activity, and Mainz Severity Score Index as possible predictors.

Results: 95 patients (41% male, 38.2 ± 14.5 years) were included. The overall prevalence of bronchial obstruction (BO, (FEV1/FVC < 70%)) was 46%, with male sex, age and smoking as significant predictors. FEV1 decreased 29 ml per year (95% CI -36, -22 ml, p<0.0001). FEV1 decline was significantly higher in males (p = 0.009) and in patients on ERT (p = 0.004). Conclusion: Pulmonary involvement seems to be a relevant manifestation of Fabry disease, and routine PFTs should therefore be included in the multidisciplinary follow-up of these patients.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0180437PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5526574PMC
September 2017

Body height and mortality - mortality follow-up of four Swiss surveys.

Prev Med 2017 Aug 1;101:67-71. Epub 2017 Jun 1.

Division of Chronic Disease Epidemiology, Epidemiology, Biostatistics and Prevention Institute (EBPI), University of Zurich, Zurich, Switzerland; Bern University of Applied Sciences (BFH), Health Division - Nutrition and Dietetics, Bern, Switzerland.

Background: Adult body height is largely determined by genetics, but also by dietary factors, which in turn depend on socioeconomic status and lifestyle. We examined the association between adult body height and mortality in Switzerland, a country with three main language regions with different cultural background.

Methods: We included 16,831 men and 18,654 women, who participated in Swiss population-based health surveys conducted 1977-1993 and who were followed up until end of 2008. Multivariable Cox proportional hazards models were computed to examine the association of body height with overall, cardiovascular, and cancer mortality.

Results: We observed a positive association between adult body height and all-cause mortality in women (HR=1.34, 95% CI 1.10-1.62, tallest vs. average women). In men, mortality risk decreased with increasing height, with shortest men tending to have higher (1.06, 0.94-1.19) and tallest men a lower (0.94, 0.77-1.14) risk compared with men of average height (p-trend 0.0001). Body height was associated with cancer mortality in women, such that tallest women had a higher risk of dying from cancer than women of average height (1.37, 1.02-1.84), but there was no such association in men (0.95, 0.69-1.30). In both sexes, height was not associated with cardiovascular mortality in a statistically significant manner.

Conclusion: Our study does not support an inverse association of body height with all-cause mortality. On the contrary, our data suggests a higher overall risk in taller women, mainly driven by a positive association between body height and cancer mortality.
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http://dx.doi.org/10.1016/j.ypmed.2017.05.023DOI Listing
August 2017

Night-to-night variability of obstructive sleep apnea.

J Sleep Res 2017 12 26;26(6):782-788. Epub 2017 May 26.

Sleep Disorders Center and Pulmonary Division, University Hospital of Zurich, Zurich, Switzerland.

One night of a sleep study is the standard for diagnosis and exclusion of obstructive sleep apnea. Single testing requires high sensitivity of the test method and a stable disease of interest to warrant a low rate of false-negative tests. Obstructive sleep apnea is diagnosed and graded by conventional thresholds of apneas and hypopneas per hour of sleep, and treatment is usually initiated in the presence of symptoms. The aim of this study was to assess night-to-night variability of obstructive sleep apnea to reassess the current practice. Seventy-seven patients previously diagnosed with obstructive sleep apnea, randomised to continuous positive airway pressure withdrawal within four trials, performed nightly pulse-oximetry over 2 weeks while off continuous positive airway pressure. The main outcome of interest was the coefficient of variation of the oxygen desaturation index marking night-to-night variability in obstructive sleep apnea. Obstructive sleep apnea was categorised according to conventional thresholds using oxygen desaturation index (no obstructive sleep apnea: <5 per h; mild: 5-15 per h; moderate: 15-30 per h; and severe: >30 per h). High night-to-night variability of obstructive sleep apnea was evidenced by a coefficient of variation of oxygen desaturation index of 31.1% (SD 16.5). Differences in oxygen desaturation index of >10 per h between nights were found in 84.4% and shifts in obstructive sleep apnea severity category in 77.9% of patients. The probability of missing moderate obstructive sleep apnea was up to 60%. Variability was higher in less severe obstructive sleep apnea. Obstructive sleep apnea shows a considerable night-to-night variability. Single-night diagnostic sleep studies are prone to miscategorise obstructive sleep apnea if arbitrary thresholds are used. Thus, treatment decisions should be based less on the conventional derivatives from sleep studies, especially in patients with less severe obstructive sleep apnea.

Clinical Trial Registration: www.controlled-trials.com (ISRCTN 93153804, ISRCTN 73047833) and www.clinicaltrials.gov (NCT01332175 & NCT02050425).
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http://dx.doi.org/10.1111/jsr.12558DOI Listing
December 2017

Determinants of annual change in physical activity in COPD.

Respirology 2017 08 30;22(6):1133-1139. Epub 2017 Mar 30.

Pulmonary Division, University Hospital of Zurich, Zurich, Switzerland.

Background And Objective: Daily physical activity (PA) is reduced in patients with COPD. Previous cross-sectional analyses indicate various predictors for a low level of PA including airway obstruction, exacerbations and co-morbidities. However, information from longitudinal studies evaluating PA in the context of disease progression, survival and co-morbidities is scant.

Methods: In a heterogeneous cohort of COPD patients, we annually assessed the number of steps per day over 1 week and potential determinants including lung function, exacerbations and co-morbidities. Univariable and multivariable mixed effect models were used to investigate associations between the change in steps per day (dependent variable) and possible predictors and their annual changes.

Results: A total of 177 COPD patients (46% GOLD (Global Initiative for Chronic Obstructive Lung Disease) stage 1/2, 38% stage 3 and 16% stage 4) with a mean (min/max) follow-up time of 2.7 (1/5) years were annually assessed. The number of steps per day decreased significantly over time (P < 0.001) with a mean annual change of -508 steps. The decrease in activity was significantly associated with forced expiratory volume in 1 s (FEV ) % predicted (P = 0.020) but not with annual changes in FEV . Hyperinflation, exacerbations, co-morbidities and their annual changes, and survival did not significantly affect change in PA.

Conclusion: COPD patients have a substantial decrease of PA over time. This decrease seems to be determined by the degree of airflow limitation. However, patients with a greater annual decline in lung function did not show a greater decrease in PA. The rate of decline in PA did not differ between survivors and non-survivors in this cohort.
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http://dx.doi.org/10.1111/resp.13035DOI Listing
August 2017

Does addition of glucocorticoids to the initial therapy influence the later course of the disease in patients with early RA? Results from the Swiss prospective observational registry (SCQM).

Clin Rheumatol 2017 Jan 12;36(1):59-66. Epub 2016 Nov 12.

Division of Rheumatology, Immunology and Rehabilitation, Kantonsspital St. Gallen, Rorschacherstr. 95, 9007, St. Gallen, Switzerland.

The main goal of this study was to analyse whether initial addition of glucocorticoid to DMARD therapy influences the long-term course of the disease in patients with early rheumatoid arthritis. All patients from the Swiss RA cohort SCQM with recent-onset arthritis (disease duration ≤1 year) were analysed. The exposure of interest was the use of glucocorticoids (GCs) at baseline. As primary outcome, we considered clinical and radiographic disease progression, assessed by the disease activity (disease activity score, DAS-28), function (health assessment questionnaire disability index, HAQ-DI) and structural joint damage (Ratingen erosion score). The baseline disease characteristics were compared using standard descriptive statistics. The effects of initial GC use on disease progression during follow-up were estimated using linear mixed models with random slope and random intercept, adjusted for potential confounders. In total, 592 patients with early disease were available, with 4.3 years of follow-up (average). Of these, 363 were initially treated with glucocorticoids (GC patients) and 228 were not (no-GC patients). DAS-28 (4.6 vs. 4.3, p = 0.01) and the HAQ-DI (0.94 vs. 0.82, p = 0.01) were higher at baseline in GC patients, while other prognostic factors were balanced at baseline. Neither the change of DAS-28, of HAQ-DI nor of the development of joint erosions differed between the two groups during follow-up. Escalation of treatment employing biologics was documented in 18.0% of the no-GC patients and 27.3% of the GC patients (p < 0.01). In this cohort, patients with early RA initially treated with GCs had higher measures of disease activity at baseline in comparison to no-GC patients. Despite a similar course of the disease in GC versus non-GC patients, the higher escalation rate to biologic agents in GC patients may reflect a disease less responsive to therapy in these patients. These data suggest that GC use as part of the initial therapeutic strategy in early RA may prevent a more severe course of the disease in patients with higher clinical disease measures at the start of therapy.
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http://dx.doi.org/10.1007/s10067-016-3468-6DOI Listing
January 2017

Follow-up practices for high-grade extremity Osteosarcoma.

BMC Cancer 2016 May 6;16:301. Epub 2016 May 6.

London Sarcoma Service, University College London Hospitals, London, NW1 2BU, UK.

Background: The optimal conduct of follow-up (FU) of patients with osteosarcoma is uncertain. In the absence of any formal validation of optimal timing and method of surveillance, guidance is provided by oncology societies' recommendations. FU is designed to detect either local recurrence or metastatic disease at a time when early treatment is still possible and might be effective.

Methods: We performed a retrospective analysis of 101 patients with high-grade extremity osteosarcoma in a single centre. Chest x-ray (CXR) was used as routine surveillance method; however patients with initial lung metastases or previous suspicious findings had computed tomography (CT) scans.

Results: With a median FU time of 30.7 months 34 patients relapsed. Relapse-free survival after 5 years was 61% (CI 52%; 73%), late relapses occurred in only two patients between 2 and 5 years of FU. Twenty-five of the 34 relapses were detected at routine FU appointments. All 8 local recurrences were noted clinically. Twenty-two patients had metastases confined to the lungs, either detected on CXR or CT. Thirty-two percent of patients with lung metastases only were salvaged successfully.

Conclusions: Routine FU in high-grade osteosarcoma results in clinical detection of local relapse, and detection of lung metastases by CXR at a time when metastatectomy is possible. The optimal time interval for FU appointments is not known, however we recommend more frequent surveillance visits during the two years after treatment. We hypothesize that routine CT scans are not required and propose CXR for detection of lung metastases.
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http://dx.doi.org/10.1186/s12885-016-2333-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4859955PMC
May 2016

Relationship of Serum Vitamin D Concentrations and Allostatic Load as a Measure of Cumulative Biological Risk among the US Population: A Cross-Sectional Study.

PLoS One 2015 9;10(10):e0139217. Epub 2015 Oct 9.

Division of Chronic Disease Epidemiology, Epidemiology, Biostatistics and Prevention Institute (EBPI), University of Zurich, Zurich, Switzerland.

Introduction: The allostatic load (AL) index is a multi-systemic measure of physiologic dysregulation known to be associated with chronic exposure to stress and adverse health outcomes. We examined the relationship between AL and serum 25-hydroxyvitamin D (25(OH)D) concentration in non-institutionalized US adults.

Methods: Data from the Third National Health and Nutrition Examination Survey (NHANES III, 1988-94) were used to calculate two versions of AL including 9 biomarkers and another two with 14 biomarkers (systolic and diastolic blood pressure, pulse rate, serum cholesterol, serum HDL-cholesterol, glycated hemoglobin, sex-specific waist-to-hip ratio, serum albumin, and serum C-reactive protein for AL1, and, additionally body mass index, serum triglyceride, serum creatinine, and serum herpes I & II antibodies for AL2), each set defined by predefined cut-offs or by quartiles. Serum vitamin D concentration was ranked into quartiles. Logistic regression, Poisson regression and linear regression were used to examine the association of serum 25(OH)D concentrations on AL, after adjusting for biological, physiological, socioeconomic, lifestyle, and health variables.

Results: Odds Ratios (OR) for high AL of the lowest 25(OH)D serum quartile were between 1.45 (95% CI: 1.28, 1.67) and 1.79 (95% CI: 1.39, 2.32) for the fully adjusted model, depending on AL version. Inverse relationships between vitamin D serum concentrations were observed for all AL versions and every adjustment. This relationship was consistent after stratification by sex, age or ethnic background. Sensitivity to low 25(OH)D concentrations was highest among the youngest group (20-39 years) with an OR of 2.11 (95% CI: 1.63, 2.73) for the lowest vitamin D quartile Q1.

Conclusions: Vitamin D had a consistent and statistically significant inverse association with all tested models of high AL, which remained consistent after adjusting for biological, socioeconomic, lifestyle and health variables. Our study adds evidence linking low 25(OH)D concentrations with poorer health, further-reaching than bone health.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0139217PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4599851PMC
June 2016

A basic model for training of microscopic and endoscopic transsphenoidal pituitary surgery: the Egghead.

Acta Neurochir (Wien) 2015 Oct 21;157(10):1771-7; discussion 1777. Epub 2015 Aug 21.

Department of Neurosurgery, Cantonal Hospital of St. Gall, St. Gall, Switzerland.

Background: Transsphenoidal endoscopic surgery has gained popularity in the last 2 decades and is becoming a standard technique for resection of pituitary adenomas. In contrast to their ENT colleagues, neurosurgical residents have practically no endoscopic experience when they reach the training stage for transsphenoidal procedures. We have developed an affordable method for repetitive training in endoscopic (and microscopic) work in a narrow channel, allowing training of the basic movements needed for resection of pituitary adenoma.

Methods: In collaboration with colleagues in the ENT Department, Cantonal Hospital St. Gall, and the Technical University of Zurich, a three-dimensional model of the nasal cavity was developed and patented. The Egghead model consists of a 3D synthetic reconstruction of the head nasal cavity and sphenoid sinus. A boiled egg represents the sella. For validation, 17 neurosurgical residents from the Department of Neurosurgery, University Hospital of Basel, and Department of Neurosurgery, Cantonal Hospital of St. Gall, St. Gall, Switzerland, and two experts performed a standardized procedure mimicking a transsphenoidal pituitary procedure by dissecting a corridor to the egg yolk and resecting it, respecting the surrounding egg white. This procedure was performed under both microscopic and video-endoscopic visualization. A score for the precision and speed of the surgical performance was developed and used.

Results: The model allows repetitive training of the resection of the egg yolk under sparing of the egg white after careful opening of the shell. The validation data showed a steeper learning curve using the endoscopic technique than performing the same task using the microscope. After three repetitions, the quality of resection was better with the endoscopic technique.

Conclusions: Our model, the Egghead, is affordable, offers tactile feedback and allows infinite repetitions in basic training for pituitary surgery. It can be used for training of advanced neurosurgical residents, who thus far have very few possibilities of acquiring endoscopic experience.
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http://dx.doi.org/10.1007/s00701-015-2544-zDOI Listing
October 2015