Effect of an eight-week high-intensity interval training programme on circulating sphingolipid levels in middle-aged adults at elevated cardiometabolic risk (SphingoFIT)-Protocol for a randomised controlled exercise trial.

INTRODUCTION: Evidence indicates that sphingolipid accumulation drives complex molecular alterations promoting cardiometabolic diseases. Clinically, it was shown that sphingolipids predict cardiometabolic risk independently of and beyond traditional biomarkers such as low-density lipoprotein cholesterol. To date, little is known about therapeutic modalities to lower sphingolipid levels. Exercise, a powerful means to prevent and treat cardiometabolic diseases, is a promising modality to mitigate sphingolipid levels in a cost-effective, safe, and patient-empowering manner. METHODS: This randomised controlled trial will explore whether and to what extent an 8-week fitness-enhancing training programme can lower serum sphingolipid levels of middle-aged adults at elevated cardiometabolic risk (n = 98, 50% females). The exercise intervention will consist of supervised high-intensity interval training (three sessions weekly), while the control group will receive physical activity counselling based on current guidelines. Blood will be sampled early in the morning in a fasted state before and after the 8-week programme. Participants will be provided with individualised, pre-packaged meals for the two days preceding blood sampling to minimise potential confounding. An 'omic-scale sphingolipid profiling, using high-coverage reversed-phase liquid chromatography coupled to tandem mass spectrometry, will be applied to capture the circulating sphingolipidome. Maximal cardiopulmonary exercise tests will be performed before and after the 8-week programme to assess patient fitness changes. Cholesterol, triglycerides, glycated haemoglobin, the homeostatic model assessment for insulin resistance, static retinal vessel analysis, flow-mediated dilatation, and strain analysis of the heart cavities will also be assessed pre- and post-intervention. This study shall inform whether and to what extent exercise can be used as an evidence-based treatment to lower circulating sphingolipid levels. TRIAL REGISTRATION: The trial was registered on www.clinicaltrials.gov (NCT06024291) on August 28, 2023.

Agricultural SandboxNL: A national-scale database of parcel-level processed Sentinel-1 SAR data.

Synthetic Aperture Radar (SAR) data handling, processing, and interpretation are barriers preventing a rapid uptake of SAR data by application specialists and non-expert domain users in the field of agricultural monitoring. To improve the accessibility of Sentinel-1 data, we have generated a reduced-volume, multi-year Sentinel-1 SAR database. It includes mean and standard deviation of VV, VH and VH/VV backscatter, pixel counts, geometry, crop type, local incidence angle and azimuth angle at parcel-level. The database uses around 3100 Sentinel-1 images (5 TB) to produce a 12 GB time series database for approximately 770,000 crop parcels over the Netherlands for a period of three years. The database can be queried by Sentinel-1 system parameters (e.g. relative orbit) or user application-specific parameters (e.g. crop type, spatial extent, time period) for parcel level assessment. The database can be used to accelerate the development of new tools, applications and methodologies for agricultural and water related applications, such as parcel-level crop bio-geophysical parameter estimation, inter-annual variability analysis, drought monitoring, grassland monitoring and agricultural management decision-support.

Long-term weight gain in obese COPD patients participating in a disease management program: a risk factor for reduced health-related quality of life.

BACKGROUND: Little is known about how long-term weight gain affects the health perception of COPD patients. OBJECTIVES: The aim is to evaluate the long-term association of BMI change and health-related quality of life (HRQoL) in obese COPD patients. METHODS: Claims and survey data from a COPD disease management program were used to match two groups of COPD patients with BMI ≥ 30 who have differing weight trajectories over a 5-year timespan via propensity score and genetic matching. EQ-5D-5L, including visual analog scale (VAS) and COPD Assessment Test (CAT), were used as outcomes of interest. Sociodemographic and disease-based variables were matched. RESULTS: Out of 1202 obese COPD patients, 126 with a weight increase of four or more BMI points were matched separately with 252 (propensity score matching) and 197 (genetic matching) control subjects who had relatively stable BMI. For the EQ-5D-5L, patients with BMI increase reported significantly worse health perception for VAS and all descriptive dimensions except pain/discomfort. For the CAT, especially the perception of ability to complete daily activities and overall energy results were significantly worse. VAS differences reach the range of minimal important differences. Stopping smoking and already being in obesity class II were the most influential risk factors for BMI increase. CONCLUSION: Obese COPD patients who gain four or more BMI points over 5 years report significantly lower results in different dimensions of generic and disease-specific HRQoL than their peers with stable BMI. To improve real-world outcomes, tracking and preventing specific BMI trajectories could constitute a clinically relevant aspect of managing COPD patients.

The relationship between body mass index and health-related quality of life in COPD: real-world evidence based on claims and survey data.

BACKGROUND: Body mass index (BMI) is an important parameter associated with mortality and health-related quality of life (HRQoL) in chronic obstructive pulmonary disease (COPD). However, informed guidance on stratified weight recommendations for COPD is still lacking. This study aims to determine the association between BMI and HRQoL across different severity grades of COPD to support patient management. METHODS: We use conjunct analysis of claims and survey data based on a German COPD disease management program from 2016 to 2017. The EQ-5D-5L visual analog scale (VAS) and COPD Assessment Test (CAT) are used to measure generic and disease-specific HRQoL. Generalized additive models with smooth functions are implemented to evaluate the relationship between BMI and HRQoL, stratified by COPD severity. RESULTS: 11,577 patients were included in this study. Mean age was 69.4 years and 59% of patients were male. In GOLD grades 1-3, patients with BMI of around 25 had the best generic and disease-specific HRQoL, whereas in GOLD grade 4, obese patients had the best HRQoL using both instruments when controlled for several variables including smoking status, income, COPD severity, comorbidities, emphysema, corticosteroid use, and days spent in hospital. CONCLUSION: This real-world analysis shows the non-linear relationship between BMI and HRQoL in COPD. HRQoL of obese patients with mild to severe COPD might improve following weight reduction. For very severe COPD, a negative association of obesity and HRQoL could not be confirmed. The results hint at the need to stratify COPD patients by disease stage for optimal BMI management.

Effect of BMI on health care expenditures stratified by COPD GOLD severity grades: Results from the LQ-DMP study.

Chronic Obstructive Pulmonary Disease (COPD) is characterized by persistent respiratory symptoms and airflow limitation, which is progressive and not fully reversible. In patients with COPD, body mass index (BMI) is an important parameter associated with health outcomes, e.g. mortality and health-related quality of life. However, so far no study evaluated the association of BMI and health care expenditures across different COPD severity grades. We used claims data and documentation data of a Disease Management Program (DMP) from a statutory health insurance fund (AOK Bayern). Patients were excluded if they had less than 4 observations in the 8 years observational period. Generalized additive mixed models with smooth functions were used to evaluate the association between BMI and health care expenditures, stratified by severity of COPD, indicated by GOLD grades 1-4. We included 30,682 patients with overall 188,725 observations. In GOLD grades 1-3 we found an u-shaped relation of BMI and expenditures, where patients with a BMI of 30 or slightly above had the lowest and underweight and obese patients had the highest health care expenditures. Contrarily, in GOLD grade 4 we found an almost linear decline of health care expenditures with increasing BMI. In terms of expenditures, the often reported obesity paradox in patients with COPD was clearly reflected in GOLD grade 4, while in all other severity grades underweight as well as severely obese patients caused the highest health care expenditures. Reduction of obesity may thus reduce health care expenditures in GOLD grades 1-3.

Plasma proteomic profiling suggests an association between antigen driven clonal B cell expansion and ME/CFS.

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is an unexplained chronic, debilitating illness characterized by fatigue, sleep disturbances, cognitive dysfunction, orthostatic intolerance and gastrointestinal problems. Using ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS), we analyzed the plasma proteomes of 39 ME/CFS patients and 41 healthy controls. Logistic regression models, with both linear and quadratic terms of the protein levels as independent variables, revealed a significant association between ME/CFS and the immunoglobulin heavy variable (IGHV) region 3-23/30. Stratifying the ME/CFS group based on self-reported irritable bowel syndrome (sr-IBS) status revealed a significant quadratic effect of immunoglobulin lambda constant region 7 on its association with ME/CFS with sr-IBS whilst IGHV3-23/30 and immunoglobulin kappa variable region 3-11 were significantly associated with ME/CFS without sr-IBS. In addition, we were able to predict ME/CFS status with a high degree of accuracy (AUC = 0.774-0.838) using a panel of proteins selected by 3 different machine learning algorithms: Lasso, Random Forests, and XGBoost. These algorithms also identified proteomic profiles that predicted the status of ME/CFS patients with sr-IBS (AUC = 0.806-0.846) and ME/CFS without sr-IBS (AUC = 0.754-0.780). Our findings are consistent with a significant association of ME/CFS with immune dysregulation and highlight the potential use of the plasma proteome as a source of biomarkers for disease.

Direct and indirect costs of COPD progression and its comorbidities in a structured disease management program: results from the LQ-DMP study.

BACKGROUND: Evidence on the economic impact of chronic obstructive pulmonary disease (COPD) for third-party payers and society based on large real world datasets are still scarce. Therefore, the aim of this study was to estimate the economic impact of COPD severity and its comorbidities, stratified by GOLD grade, on direct and indirect costs for an unselected population enrolled in the structured German Disease Management Program (DMP) for COPD. METHODS: All individuals enrolled in the DMP COPD were included in the analysis. Patients were only excluded if they were not insured or not enrolled in the DMP COPD the complete year before the last DMP documentation (at physician visit), had a missing forced expiratory volume in 1 s (FEV1) measurement or other missing values in covariates. The final dataset included 39,307 patients in GOLD grade 1 to 4. We used multiple generalized linear models to analyze the association of COPD severity with direct and indirect costs, while adjusting for sex, age, income, smoking status, body mass index, and comorbidities. RESULTS: More severe COPD was significantly associated with higher healthcare utilization, work absence, and premature retirement. Adjusted annual costs for GOLD grade 1 to 4 amounted to €3809 [€3691-€3935], €4284 [€4176-€4394], €5548 [€5328-€5774], and €8309 [€7583-9065] for direct costs, and €11,784 [€11,257-€12,318], €12,985 [€12,531-13,443], €15,805 [€15,034-€16,584], and €19,402 [€17,853-€21,017] for indirect costs. Comorbidities had significant additional effects on direct and indirect costs with factors ranging from 1.19 (arthritis) to 1.51 (myocardial infarction) in direct and from 1.16 (myocardial infarction) to 1.27 (cancer) in indirect costs. CONCLUSION: The findings indicate that more severe GOLD grades in an unselected COPD population enrolled in a structured DMP are associated with tremendous additional direct and indirect costs, with comorbidities significantly increase costs. In direct cost category hospitalization and in indirect cost category premature retirement were the main cost driver. From a societal perspective prevention and interventions focusing on disease control, and slowing down disease progression and strengthening the ability to work would be beneficial in order to realize cost savings in COPD.

Predicting patient-reported outcomes following hip and knee replacement surgery using supervised machine learning.

BACKGROUND: Machine-learning classifiers mostly offer good predictive performance and are increasingly used to support shared decision-making in clinical practice. Focusing on performance and practicability, this study evaluates prediction of patient-reported outcomes (PROs) by eight supervised classifiers including a linear model, following hip and knee replacement surgery. METHODS: NHS PRO data (130,945 observations) from April 2015 to April 2017 were used to train and test eight classifiers to predict binary postoperative improvement based on minimal important differences. Area under the receiver operating characteristic, J-statistic and several other metrics were calculated. The dependent outcomes were generic and disease-specific improvement based on the EQ-5D-3L visual analogue scale (VAS) as well as the Oxford Hip and Knee Score (Q score). RESULTS: The area under the receiver operating characteristic of the best training models was around 0.87 (VAS) and 0.78 (Q score) for hip replacement, while it was around 0.86 (VAS) and 0.70 (Q score) for knee replacement surgery. Extreme gradient boosting, random forests, multistep elastic net and linear model provided the highest overall J-statistics. Based on variable importance, the most important predictors for post-operative outcomes were preoperative VAS, Q score and single Q score dimensions. Sensitivity analysis for hip replacement VAS evaluated the influence of minimal important difference, patient selection criteria as well as additional data years. Together with a small benchmark of the NHS prediction model, robustness of our results was confirmed. CONCLUSIONS: Supervised machine-learning implementations, like extreme gradient boosting, can provide better performance than linear models and should be considered, when high predictive performance is needed. Preoperative VAS, Q score and specific dimensions like limping are the most important predictors for postoperative hip and knee PROMs.

Valuing health-related quality of life: systematic variation in health perception.

BACKGROUND: Population-based value sets are widely used to transform health states into utilities, but may deviate from actual patient experience. Whether this occurs in a systematic way can be analyzed, in a first step, for respondents who do not report problems on the five domains of the EQ-5D-5L instrument in population studies. METHODS: EQ-5D-5L results from three annual cross-sectional surveys (2012, 2013, and 2014) were filtered for participants who reported being problem-free. Continuous visual analog scale (VAS) scores, ranging from 0 (worst imaginable health) to 100 (best imaginable health) were then used to measure their actual health perception and to compare results with the proposed EQ-5D-5L value. A multiple linear regression model was used to identify possible risk factors for low VAS scores. RESULTS: Some 3739 (61.5%) participants reported being problem-free. Their mean age was 41.1 years and mean VAS score was 91.9. Age and BMI were significantly associated with lower VAS scores. Age groups from 50 years onwards reported VAS means of 90.0 and below. Female gender and low education also had small but significant negative effects on patient experience. The presence of BMI class III as well as diabetes had the greatest negative effect on VAS results (- 9.0 and - 8.4) and reached the range of minimally important differences. Heart disease (- 6.2) and musculoskeletal disease (- 3.4) also had strong negative effects. The 25th percentile of VAS scores in our sample was 90.0, and the 50th percentile was 95.0. CONCLUSIONS: For some groups in population studies, especially older people with high BMI and those affected by specific diseases, no problems on all five domains of the EQ-5D-5L fails to reflect the respondents' health perception as measured by the VAS.

Cost-effectiveness of possible future smoking cessation strategies in Hungary: results from the EQUIPTMOD.

AIMS: To evaluate potential health and economic returns from implementing smoking cessation interventions in Hungary. METHODS: The EQUIPTMOD, a Markov-based economic model, was used to assess the cost-effectiveness of three implementation scenarios: (a) introducing a social marketing campaign; (b) doubling the reach of existing group-based behavioural support therapies and proactive telephone support; and (c) a combination of the two scenarios. All three scenarios were compared with current practice. The scenarios were chosen as feasible options available for Hungary based on the outcome of interviews with local stakeholders. Life-time costs and quality-adjusted life years (QALYs) were calculated from a health-care perspective. The analyses used various return on investment (ROI) estimates, including incremental cost-effectiveness ratios (ICERs), to compare the scenarios. Probabilistic sensitivity analyses assessed the extent to which the estimated mean ICERs were sensitive to the model input values. RESULTS: Introducing a social marketing campaign resulted in an increase of 0.3014 additional quitters per 1 000 smokers, translating to health-care cost-savings of €0.6495 per smoker compared with current practice. When the value of QALY gains was considered, cost-savings increased to €14.1598 per smoker. Doubling the reach of existing group-based behavioural support therapies and proactive telephone support resulted in health-care savings of €0.2539 per smoker (€3.9620 with the value of QALY gains), compared with current practice. The respective figures for the combined scenario were €0.8960 and €18.0062. Results were sensitive to model input values. CONCLUSIONS: According to the EQUIPTMOD modelling tool, it would be cost-effective for the Hungarian authorities introduce a social marketing campaign and double the reach of existing group-based behavioural support therapies and proactive telephone support. Such policies would more than pay for themselves in the long term.

Cost-effectiveness of increasing the reach of smoking cessation interventions in Germany: results from the EQUIPTMOD.

AIMS: To evaluate costs, effects and cost-effectiveness of increased reach of specific smoking cessation interventions in Germany. DESIGN: A Markov-based state transition return on investment model (EQUIPTMOD) was used to evaluate current smoking cessation interventions as well as two prospective investment scenarios. A health-care perspective (extended to include out-of-pocket payments) with life-time horizon was considered. A probabilistic analysis was used to assess uncertainty concerning predicted estimates. SETTING: Germany. PARTICIPANTS: Cohort of current smoking population (18+ years) in Germany. INTERVENTIONS: Interventions included group-based behavioural support, financial incentive programmes and varenicline. For prospective scenario 1 the reach of group-based behavioral support, financial incentive programme and varenicline was increased by 1% of yearly quit attempts (= 57 915 quit attempts), while prospective scenario 2 represented a higher reach, mirroring the levels observed in England. MEASUREMENTS: EQUIPTMOD considered reach, intervention cost, number of quitters, quality-of-life years (QALYs) gained, cost-effectiveness and return on investment. FINDINGS: The highest returns through reduction in smoking-related health-care costs were seen for the financial incentive programme (€2.71 per €1 invested), followed by that of group-based behavioural support (€1.63 per €1 invested), compared with no interventions. Varenicline had lower returns (€1.02 per €1 invested) than the other two interventions. At the population level, prospective scenario 1 led to 15 034 QALYs gained and €27 million cost-savings, compared with current investment. Intervention effects and reach contributed most to the uncertainty around the return-on-investment estimates. At a hypothetical willingness-to-pay threshold of only €5000, the probability of being cost-effective is approximately 75% for prospective scenario 1. CONCLUSIONS: Increasing the reach of group-based behavioural support, financial incentives and varenicline for smoking cessation by just 1% of current annual quit attempts provides a strategy to German policymakers that improves the population's health outcomes and that may be considered cost-effective.

Health-Related Quality of Life of the General German Population in 2015: Results from the EQ-5D-5L.

The EQ-5D-5L is a widely used generic instrument to measure health-related quality of life. This study evaluates health perception in a representative sample of the general German population from 2015. To compare results over time, a component analysis technique was used that separates changes in the description and valuation of health states. The whole sample and also subgroups, stratified by sociodemographic parameters as well as disease affliction, were analyzed. In total, 2040 questionnaires (48.4% male, mean age 47.3 year) were included. The dimension with the lowest number of reported problems was self-care (93.0% without problems), and the dimension with the highest proportion of impairment was pain/discomfort (71.2% without problems). Some 64.3% of the study population were identified as problem-free. The visual analog scale (VAS) mean for all participants was 85.1. Low education was connected with significantly lower VAS scores, but the effect was small. Depression, heart disease, and diabetes had a strong significant negative effect on reported VAS means. Results were slightly better than those in a similar 2012 survey; the most important driver was the increase in the share of the study population that reported to be problem-free. In international comparisons, health perception of the general German population is relatively high and, compared with previous German studies, fairly stable over recent years. Elderly and sick people continue to report significant reductions in perceived health states.

Connecting Artificial Brains to Robots in a Comprehensive Simulation Framework: The Neurorobotics Platform.

Combined efforts in the fields of neuroscience, computer science, and biology allowed to design biologically realistic models of the brain based on spiking neural networks. For a proper validation of these models, an embodiment in a dynamic and rich sensory environment, where the model is exposed to a realistic sensory-motor task, is needed. Due to the complexity of these brain models that, at the current stage, cannot deal with real-time constraints, it is not possible to embed them into a real-world task. Rather, the embodiment has to be simulated as well. While adequate tools exist to simulate either complex neural networks or robots and their environments, there is so far no tool that allows to easily establish a communication between brain and body models. The Neurorobotics Platform is a new web-based environment that aims to fill this gap by offering scientists and technology developers a software infrastructure allowing them to connect brain models to detailed simulations of robot bodies and environments and to use the resulting neurorobotic systems for in silico experimentation. In order to simplify the workflow and reduce the level of the required programming skills, the platform provides editors for the specification of experimental sequences and conditions, environments, robots, and brain-body connectors. In addition to that, a variety of existing robots and environments are provided. This work presents the architecture of the first release of the Neurorobotics Platform developed in subproject 10 "Neurorobotics" of the Human Brain Project (HBP). At the current state, the Neurorobotics Platform allows researchers to design and run basic experiments in neurorobotics using simulated robots and simulated environments linked to simplified versions of brain models. We illustrate the capabilities of the platform with three example experiments: a Braitenberg task implemented on a mobile robot, a sensory-motor learning task based on a robotic controller, and a visual tracking embedding a retina model on the iCub humanoid robot. These use-cases allow to assess the applicability of the Neurorobotics Platform for robotic tasks as well as in neuroscientific experiments.

EQ-5D-5L in the General German Population: Comparison and Evaluation of Three Yearly Cross-Section Surveys.

Health-related quality of life (HRQoL) is a key measure for evaluating health status in populations. Using the recent EQ-5D-5L for measurement, this study analyzed quality of life results and their stability over consecutive population surveys. Three cross-section surveys for representative samples of the general German population from 2012, 2013, and 2014 were evaluated using the EQ-5D-5L descriptive system and valuation by the Visual Analog Scale (VAS). Aggregated sample size reached 6074. The dimension with the highest prevalence of problems was pain/discomfort (31.7%). Compared with 2012 (59.3%), the percentage of participants in the best health state increased slightly in 2013 (63.4%) and 2014 (62%). Over the 3-year period, diabetes and heart disease had the strongest negative influence on mean VAS result. The number of reported chronic diseases cumulatively reduced mean VAS. Extreme problems in one or more dimensions were stated by only 0.1%-0.2% of patients. Of the potential 247 health states with a problem score ≥ 20, only six were observed in the aggregated sample. HRQoL results were fairly stable over the 3 years, but the share of the population with no problems was not. Results from the aggregated sample may serve as updated reference values for the general German population.

Comorbid Influences on Generic Health-Related Quality of Life in COPD: A Systematic Review.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a leading cause of mortality and of loss of disability-adjusted life years worldwide. It often is accompanied by the presence of comorbidity. OBJECTIVES: To systematically review the influence of COPD comorbidity on generic health-related quality of life (HRQoL). METHODS: A systematic review approach was used to search the databases Pubmed, Embase and Cochrane Library for studies evaluating the influence of comorbidity on HRQoL in COPD. Identified studies were analyzed according to study characteristics, generic HRQoL measurement instrument, COPD severity and comorbid HRQoL impact. Studies using only non-generic instruments were excluded. RESULTS: 25 studies met the selection criteria. Seven studies utilized the EQ-5D, six studies each used the SF-36 or SF-12. The remaining studies used one of six other instruments each. Utilities were calculated by four EQ-5D studies and one 15D study. Patient populations covered both early and advanced stages of COPD and ranged from populations with mostly stage 1 and 2 to studies with patients classified mainly stage 3 and 4. Evidence was mainly created for cardiovascular disease, depression and anxiety as well as diabetes but also for quantitative comorbid associations. Strong evidence is pointing towards the significant negative association of depression and anxiety on reduced HRQoL in COPD patients. While all studies found the occurrence of specific comorbidities to decrease HRQoL in COPD patients, the orders of magnitude diverged. Due to different patient populations, different measurement tools and different concomitant diseases the study heterogeneity was high. CONCLUSIONS: Facilitating multimorbid intervention guidance, instead of applying a parsimony based single disease paradigm, should constitute an important goal for improving HRQoL of COPD patients in research and in clinical practice.

Excess costs of comorbidities in chronic obstructive pulmonary disease: a systematic review.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide. Comorbidities are often reported in patients with COPD and may influence the cost of care. Yet, the extent by which comorbidities affect costs remains to be determined. OBJECTIVES: To review, quantify and evaluate excess costs of comorbidities in COPD. METHODS: Using a systematic review approach, Pubmed and Embase were searched for studies analyzing excess costs of comorbidities in COPD. Resulting studies were evaluated according to study characteristics, comorbidity measurement and cost indicators. Mark-up factors were calculated for respective excess costs. Furthermore, a checklist of quality criteria was applied. RESULTS: Twelve studies were included. Nine evaluated comorbidity specific costs; three examined index-based results. Pneumonia, cardiovascular disease and diabetes were associated with the highest excess costs. The mark-up factors for respective excess costs ranged between 1.5 and 2.5 in the majority of cases. On average the factors constituted a doubling of respective costs in the comorbid case. The main cost driver, among all studies, was inpatient cost. Indirect costs were not accounted for by the majority of studies. Study heterogeneity was high. CONCLUSIONS: The reviewed studies clearly show that comorbidities are associated with significant excess costs in COPD. The inclusion of comorbid costs and effects in future health economic evaluations of preventive or therapeutic COPD interventions seems highly advisable.