The fluctuation behavior of heart and respiratory system signals as a quantitative tool for studying long-term environmental exposures and chronic diseases

Background: Several studies over the last decades have suggested that a wide range of disease states, as well as the aging process itself, are marked by progressive impairment of the involved physiological processes to adapt, resulting in a loss of complexity in the dynamics of physiological functions. Therefore, measuring complexity from physiological system signals holds enormous promise for providing a new understanding of the mechanisms underlying physiological systems and how they change with diseases and aging. Furthermore, since physiological systems are continuously exposed to environmental factors, measuring how physiological complexity changes during exposure to environmental elements might also provide new insights into their effects. Indeed, this approach may be able to unveil subtle but important changes in the regulatory mechanisms of physiological systems not detectable by traditional analysis methods. Objectives: The overall objective of this PhD thesis was to quantify the complexity of the dynamics of heart and respiratory system signals, in order to investigate how this complexity changes with long-term environmental exposures and chronic diseases, using data from large epidemiological and clinical studies, in order to control for most potential confounders of the fluctuation behavior of systems signals (e.g., demographic, environmental, clinical, and lifestyle factors). We specifically aimed (1) at assessing the influence, first, of long-term smoking cessation, and second, of long-term exposure to traffic-related particulate matter of less than 10 micrometers in diameter (TPM10), on the regulation of the autonomic cardiovascular system and heart rate dynamics in an aging general population, using data from the SAPALDIA cohort study; (2) to assess whether the subgrouping of patients with recurrent obstructive airway diseases, including mild-to-moderate asthma, severe asthma, and COPD, according to their pattern of lung function fluctuation, allows for the identification of phenotypes with specific treatable traits, using data from the BIOAIR study. Methods: In the SAPALDIA cohort, a population-based Swiss cohort, 1608 participants ≥ 50 years of age underwent ambulatory 24-hr electrocardiogram monitoring and reported on lifestyle and medical history. In each participant, heart rate variability and heart rate dynamics were characterized by means of various quantitative analyses of the inter-beat interval time series generated from 24-hour electrocardiogram recordings. Each parameter obtained was then used as the outcome variable in multivariable linear regression models in order to evaluate the association with (1) smoking status and time elapsed since smoking cessation; (2) long-term exposure to TPM10. The models were adjusted for known confounding factors. In the BIOAIR study, we conducted a time series clustering analysis based on the fluctuation of twice-daily FEV1 measurements recorded over a one year period in a mixed group of 134 adults with mild-to-moderate asthma, severe asthma, or COPD from the longitudinal Pan-European BIOAIR study. Results: In the SAPALDIA cohort, our findings indicate that smoking triggers adverse changes in the regulation of the cardiovascular system, even at low levels of exposure since current light smokers exhibited significant changes as compared to lifelong non-smokers. Moreover, there was evidence for a dose-response effect. Furthermore, full recovery was achieved in former smokers (i.e., normalization to the level of lifelong non-smokers). However, while light smokers fully recovered within the 15 first years of cessation, heavy former smokers might need up to 15-25 years to fully recover. Regarding long-term exposure to TPM10, we did not observe an overall association with heart rate variability/heart rate dynamics in the entire study population. However, significant changes in the heart rate dynamics were found in subjects without cardiovascular morbidity and significant changes, both in the heart rate dynamics and in the heart rate variability, were found in non-obese subjects without cardiovascular morbidity. Furthermore, subjects with homozygous GSTM1 gene deletion appeared to be more susceptible to the effects of TPM10. In the BIOAIR study, we identified five phenotypes, of those three distinct phenotypes of severe asthma, in which the progressive functional alteration of the lung corresponded to a gradually increasing clinical severity and translated into specific risks of exacerbation and treatment response features. Conclusions: This thesis hopes to demonstrate the importance of multidimensional approaches to gain understanding in the complex functioning of the human physiological system and of disease processes. Characterization of the complexity in the fluctuation behavior of system signals holds enormous promise for providing new understandings of the regulatory mechanisms of physiological systems and how they change with diseases. However, it is important to combine this kind of approach with classical epidemiological approaches in order to disentangle the various contributions of the intrinsic physiological dynamics, aging, diseases and comorbidities, lifestyle, and environment. In the SAPALDIA cohort study, we were able to disentangle the influence of specific environmental exposures, such as particulate matter air pollution and smoking exposure, on the heart rate variability and heart rate dynamics, and thus to unveil long-term alterations in former heavy smokers, as well as adverse effects of low level, but long-term, exposure to TPM10 in healthy subjects and in subjects with homozygous GSTM1 gene deletion. In the BIOAIR study, we provide evidence that airway dynamics contain substantial information, which enables the identification of clinically meaningful phenotypes, in which the functional alteration of the lung translates into specific treatable traits

Prevalence, specific and non-specific determinants of complementary medicine use in Switzerland: Data from the 2017 Swiss Health Survey.

OBJECTIVES To determine the prevalence of use of complementary medicine (CM) in Switzerland in 2017, its development since the 2012 Swiss Health Survey, and to examine specific and non-specific sociodemographic, lifestyle and health-related determinants of CM use as compared to determinants of conventional health care use. MATERIALS AND METHODS We used data of 18,832 participants from the cross-sectional Swiss Health Survey conducted by the Swiss Federal Statistical Office in 2017 and compared these data with those from 2012. We defined four CM categories: (1) traditional Chinese medicine, including acupuncture; (2) homeopathy; (3) herbal medicine; (4) other CM therapies (shiatsu, reflexology, osteopathy, Ayurveda, naturopathy, kinesiology, Feldenkrais, autogenic training, neural therapy, bioresonance therapy, anthroposophic medicine). Independent determinants of CM use and of conventional health care use were assessed using multivariate weighted logistic regression models. RESULTS Prevalence of CM use significantly increased between 2012 and 2017 from 24.7% (95% CI: 23.9-25.4%) to 28.9% (95% CI: 28.1-29.7%), respectively, p<0.001). We identified the following independent specific determinants of CM use: gender, nationality, age, lifestyle and BMI. Female gender and nationality were the most specific determinants of CM use. Current smoking, being overweight and obesity were determinants of non-use of CM, while regular consumption of fruits and/or vegetables and regular physical activity were determinants of CM use. CONCLUSION Prevalence of CM use significantly increased in Switzerland from 2012 to 2017. Gender, nationality, age, lifestyle and BMI were independent specific determinants of CM use as compared to conventional health care use. Healthier lifestyle was associated with CM use, which may have potentially significant implications for public health and preventive medicine initiatives. The nationality of CM users underlines the role of culture in driving the choice to use CM but also raises the question of whether all populations have equal access to CM within a same country

Euphrasia Eye Drops in Preterm Neonates With Ocular Discharge: A Randomized Double-Blind Placebo-Controlled Trial

Aim: To investigate whether the early administration of Euphrasia eye drops® in preterm neonates presenting with ocular discharge fosters the resolution of the ocular discharge and reduces the need for topical antibiotic therapy, as compared to placebo. Methods: We conducted a randomized double-blind placebo-controlled trial at the University Children's Hospital Bern, Switzerland. Preterm neonates with white, yellow, or green ocular discharge were included. Infants were randomly assigned (1:1) to the Euphrasia arm (Euphrasia eye drops®, Weleda AG, Arlesheim) or the placebo arm (NaCl 0.9%). Euphrasia or placebo was administrated at a dose of one drop in each eye four times a day over a period of 96 h. The primary outcome was the treatment success, defined as no ocular discharge at 96 h and no use of topical antibiotic therapy during the 96-h intervention. Results: A total of 114 neonates were screened and 84 were randomized. Among neonates in the Euphrasia arm, 22 (55.0%) achieved our primary outcome compared to 21 (51.2%) in the placebo arm (p = 0.85). In the Euphrasia arm, time to resolution of reddening tended to fall within the shorter bracket of 24 to 48 h (24 (92.3%) vs. 12 (80.0%) in the placebo arm, p = 0.34) and relapse or first signs of reddening during the 96-h intervention tended to be lower [3 (7.9%) eyes vs. 8 (18.2%) eyes in the placebo arm, p = 0.17]. Tearing at 96 h tended to be lower in the Euphrasia arm [5 (12.8%) eyes in the Euphrasia arm vs. 12 (27.3%) eyes in the placebo arm, p = 0.10]. Discussion: Euphrasia did not significantly improve treatment success, defined as no ocular discharge at 96 h and no use of topical antibiotic therapy during the 96-h intervention. However, results suggest that Euphrasia may be of benefit for symptoms such as reddening and tearing, and thus improve the comfort of patients. Trial Registration: The trial is registered at the US National Institutes of Health (ClinicalTrials.gov) NCT04122300 and at the portal for human research in Switzerland SNCTP000003490. Keywords: Euphrasia drops; complementary medicine; congenital nasolacrimal duct obstruction; ocular discharge; preterm neonate

Association of long-term exposure to traffic-related PM; 10; with heart rate variability and heart rate dynamics in healthy subjects

Epidemiological evidence on the influence of long-term exposure to traffic-related particulate matter (TPM; 10; ) on heart rate variability (HRV) is weak.; To evaluate the association of long-term exposure (10 years) with TPM; 10; on the regulation of the autonomic cardiovascular system and heart rate dynamics (HRD) in an aging general population, as well as potential modifying effects by the a priori selected factors sex, smoking status, obesity, and gene variation in selected glutathione S-transferases (GSTs).; We analyzed data from 1593 SAPALDIA cohort participants aged ≥ 50 years. For each participant, various HRV and HRD parameters were derived from 24-hour electrocardiogram recordings. Each parameter obtained was then used as the outcome variable in multivariable mixed linear regression models in order to evaluate the association with TPM; 10; . Potential modifying effects were assessed using interaction terms.; No association between long-term exposure to TPM; 10; and HRV/HRD was observed in the entire study population. However, HRD changes were found in subjects without cardiovascular morbidity and both HRD and HRV changes in non-obese subjects without cardiovascular morbidity. Subjects without cardiovascular morbidity with homozygous GSTM1 gene deletion appeared to be more susceptible to the effects of TPM; 10; .; This study suggests that long-term exposure to TPM; 10; triggers adverse changes in the regulation of the cardiovascular system. These adverse effects were more visible in the subjects without cardiovascular disease, in whom the overall relationship between TPM; 10; and HRV/HRD could not be masked by underlying morbidities and the potential counteracting effects of related drug treatments

Eurythmy therapy versus slow movement fitness in the treatment of fatigue in metastatic breast cancer patients: study protocol for a randomized controlled trial

Background: Cancer-related fatigue (CRF) is the most taxing symptom for many breast cancer patients during and after therapy. In patients with metastatic disease, the prevalence of CRF exceeds 75%. Currently, there is no gold standard for the treatment of CRF. Physical activity can reduce CRF and is recommended during and after cancer treatment, but may be too burdensome for patients with metastatic breast cancer. The aim of this study is to assess the effect on fatigue of eurythmy therapy (ERYT) compared to slow movement fitness (CoordiFit) in metastatic breast cancer patients. Methods: The ERYT/CoordiFit study is a randomized controlled, open label, two-arm, multi-center Swiss clinical trial. A sample of 196 patients presenting with CRF will be recruited by oncologists from the departments of clinical oncology at each local study site. All participants will be randomly allocated to the intervention or control group in a 1:1 ratio. The control group is an active control intervention (CoordiFit) in order to control for potential non-intended effects such as therapist-patient interaction and participation in a program. Both ERYT and CoordiFit exercises are easy to learn, and the training sessions will follow the same frequency and duration schedule, i.e. 13 standardized therapy sessions of 45 minutes (once a week for 6 weeks and then once every second week) during the total intervention period of 20 weeks. The primary endpoint of the study is the change from baseline over the whole intervention period (i.e. including measurements at baseline, weeks 8, 14, and 20) in the Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F) subscale score. Discussion: This study is the first-known randomized clinical trial assessing eurythmy therapy in the treatment of fatigue in metastatic breast cancer patients. Given the distress that fatigue causes patients, it is important to validate treatment options. If eurythmy therapy proves beneficial in CRF as part of this randomized controlled clinical trial, the study may be very impactful with implications not only for metastatic breast cancer patients but also for other cancer patients, health care personnel, scientists, and funding and regulatory bodies

Euphrasia eye drops in preterm neonates with ocular discharge: a randomized double-blind placebo-controlled trial

Aim: To investigate whether the early administration of Euphrasia eye drops® in preterm neonates presenting with ocular discharge fosters the resolution of the ocular discharge and reduces the need for topical antibiotic therapy, as compared to placebo. Methods: We conducted a randomized double-blind placebo-controlled trial at the University Children’s Hospital Bern, Switzerland. Preterm neonates with white, yellow, or green ocular discharge were included. Infants were randomly assigned (1:1) to the Euphrasia arm (Euphrasia eye drops®, Weleda AG, Arlesheim) or the placebo arm (NaCl 0.9%). Euphrasia or placebo was administrated at a dose of one drop in each eye four times a day over a period of 96 hours. The primary outcome was the treatment success, defined as no ocular discharge at 96 hours and no use of topical antibiotic therapy during the 96-hour intervention. Results: A total of 114 neonates were screened and 84 were randomized. Among neonates in the Euphrasia arm, 22 (55.0%) achieved our primary outcome compared to 21 (51.2%) in the placebo arm (p=0.85). In the Euphrasia arm, time to resolution of reddening tended to fall within the shorter bracket of 24 to 48 hours (24 (92.3%) versus 12 (80.0%) in the placebo arm, p=0.34) and relapse or first signs of reddening during the 96-hour intervention tended to be lower (3 (7.9%) eyes versus 8 (18.2%) eyes in the placebo arm, p=0.17). Tearing at 96 hours tended to be lower in the Euphrasia arm (5 (12.8%) eyes in the Euphrasia arm versus 12 (27.3%) eyes in the placebo arm, p=0.10). Discussion: Euphrasia did not significantly improve treatment success, defined as no ocular discharge at 96 hours and no use of topical antibiotic therapy during the 96-hour intervention. However, results suggest that Euphrasia may be of benefit for symptoms such as reddening and tearing, and thus improve the comfort of patients

Academic pediatric clinical research: factors associated with study implementation duration

International audienceAbstractBackgroundThe ethical, methodological, and technical aspects of pediatric research, often results in complications and delays in implementation. Our objective was to identify factors associated with the implementation duration of hospital-based pediatric studies.MethodsAll hospital-based pediatric studies sponsored by AP-HP between 2002 and 2008 were retrospectively identified. Association of the funding mechanism and methodological factors with the implementation duration was assessed using a multivariable mixed linear model. Pharmaceutical factors were explored as part of a subgroup analysis restricted to the studies involving drug therapy. Given that we took an exploratory approach, factors associated with implementation duration with p < 0.10 were kept in the final models.ResultsA total of 139 studies were evaluated. The median implementation duration was 17.1 months (range: 0.9-55.3 months), and tended to increase over time (from 14.9 [25th percentile-75th percentile: 11.5-19.9] months in 2002 to 23.7 [15.2-31.0] months in 2008, p = 0.01). External (coefficient [95 % confidence interval]: -7.7 [-11.9;-3.5] months, p < 0.001) and internal funding (-5.3 95 % CI [-9.8;-0.8], p = 0.02) compared to governmental funding and number of centers (-0.1 95 % CI[-0.2;0.02] months for 1 center increase, p = 0.07) were associated with reduced duration, whereas interventional study (either involving drug therapy (6.0 95 % CI[0.7;11.3] months, p = 0.03 or not (3.5 95 % CI[-0.3;7.3] months, p = 0.06) was associated with increased duration compared to observational study. Regarding the 35 studies involving drug therapy, external funding decreased duration (-6.7 95 % CI[-13.2;-0.2] months, p = 0.05), whereas studies involving solely a pediatric population (7.8 95 % CI[1.1;14.5] months, p = 0.01) (compared to mixed adult-pediatric population), a placebo-controlled design (6.6 95 % CI[0.9;12.3] months, p = 0.01), and inappropriate drug formulation for at least one drug used in the study (6.9 95 % CI[-0.2;14.0] months, p = 0.06) were associated with increased duration.ConclusionImplementation of hospital-based pediatric studies primarily faced delays when they were interventional and, in particular, when they involved drug therapy. Regarding the latter, difficulties that resulted in delayed studies arose with respect to the supply of drugs and placebo in age-appropriate dosages and route of administration. Therefore, difficulties related to the use of pharmaceuticals need to be anticipated earlier in order to avoid implementation delays

Physiological phenotyping of pediatric chronic obstructive airway diseases

Inert tracer gas washout (IGW) measurements detect increased ventilation inhomogeneity (VI) in chronic lung diseases. Their suitability for different diseases, such as cystic fibrosis (CF) and primary ciliary dyskinesia (PCD), has already been shown. However, it is still unclear if physiological phenotypes based on different IGW variables can be defined independently of underlying disease. Eighty school-age children, 20 with CF, 20 with PCD, 20 former preterm children, and 20 healthy children, performed nitrogen multiple-breath washout, double-tracer gas (DTG) single-breath washout, and spirometry. Our primary outcome was the definition of physiological phenotypes based on IGW variables. We applied principal component analysis, hierarchical Ward's clustering, and enrichment analysis to compare clinical characteristics between the clusters. IGW variables used for clustering were lung clearance index (LCI) and convection-dependent [conductive ventilation heterogeneity index (Scond)] and diffusion-convection-dependent variables [acinar ventilation heterogeneity index (Sacin) and carbon dioxide and DTG phase III slopes]. Three main phenotypes were identified. Phenotype I (n = 38) showed normal values in all IGW outcome variables. Phenotype II (n = 21) was characterized by pronounced global and convection-dependent VI while diffusion-dependent VI was normal. Phenotype III (n = 21) was characterized by increased global and diffusion- and convection-dependent VI. Enrichment analysis revealed an overrepresentation of healthy children and former preterm children in phenotype I and of CF and PCD in phenotypes II and III. Patients in phenotype III showed the highest proportion and frequency of exacerbations and hospitalization in the year prior to the measurement. IGW techniques allow identification of clinically meaningful, disease-independent physiological clusters. Their predictive value of future disease outcomes remains to be determined