Clinical relevance of lung function trajectory clusters in middle-aged and older adults.

Background: The determinants and health outcomes of lung function trajectories in adults among the general population are poorly understood. We aimed to identify and characterise clusters of lung function trajectories in adults aged ≥45 years. Methods: Gaussian finite-mixture modelling was applied to baseline and annualised change of forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and FEV1/FVC ratio z-scores in participants of the Rotterdam Study, a prospective population-based cohort study, with repeated spirometry (n=3884; mean±sd age 64.7±8.9 years). Longitudinal outcomes were all-cause mortality, respiratory outcomes (symptoms, COPD (FEV1/FVC <0.7 in absence of asthma), preserved ratio impaired spirometry (PRISm; FEV1/FVC ≥0.7 and FEV1 or FVC <80%)), smoking cessation and weight changes. Independent risk factors, including genetics, were identified by multiple logistic regression. Results: We identified eight trajectory clusters, with the reference group having persistently normal spirometry (prevalence 42.8%). Three clusters showed higher mortality, adjusted for confounders: 1) the persistently low FEV1 cluster (prevalence 6.8%, hazard ratio (HR) 1.71, 95% CI 1.37-2.13); 2) rapid FEV1 decliners (prevalence 4.6%, HR 1.48, 95% CI 1.10-1.99); and 3) FVC decliners (prevalence 3.7%, HR 1.49, 95% CI 1.09-2.03). In contrast, FVC improvers (prevalence 6.7%, HR 0.61, 95% CI 0.41-0.90) and persistently high FEV1 (prevalence 29.2%, HR 0.82, 95% CI 0.69-0.98) were protective trajectory clusters. Clusters were characterised by differences in genetic predisposition (polygenic scores of FEV1 and FEV1/FVC), demographics, cigarette smoking, respiratory symptoms (chronic cough, wheezing and dyspnoea), cardiovascular factors (body mass index, hypertension and heart failure) and serum C-reactive protein levels. Frailty, weight changes and the development of respiratory symptoms, COPD and PRISm were significantly associated with trajectory clusters. Conclusions: This study reveals clinically relevant lung function trajectory clusters in older adults of the general population.

Phenotyping asthma with airflow obstruction in middle-aged and older adults: a CADSET clinical research collaboration.

BACKGROUND: The prevalence and clinical profile of asthma with airflow obstruction (AO) remain uncertain. We aimed to phenotype AO in population- and clinic-based cohorts. METHODS: This cross-sectional multicohort study included adults ≥50 years from nine CADSET cohorts with spirometry data (N=69 789). AO was defined as ever diagnosed asthma with pre-BD or post-BD FEV1/FVC <0.7 in population-based and clinic-based cohorts, respectively. Clinical characteristics and comorbidities of AO were compared with asthma without airflow obstruction (asthma-only) and chronic obstructive pulmonary disease (COPD) without asthma history (COPD-only). ORs for comorbidities adjusted for age, sex, smoking status and body mass index (BMI) were meta-analysed using a random effects model. RESULTS: The prevalence of AO was 2.1% (95% CI 2.0% to 2.2%) in population-based, 21.1% (95% CI 18.6% to 23.8%) in asthma-based and 16.9% (95% CI 15.8% to 17.9%) in COPD-based cohorts. AO patients had more often clinically relevant dyspnoea (modified Medical Research Council score ≥2) than asthma-only (+14.4 and +14.7 percentage points) and COPD-only (+24.0 and +5.0 percentage points) in population-based and clinic-based cohorts, respectively. AO patients had more often elevated blood eosinophil counts (>300 cells/µL), although only significant in population-based cohorts. Compared with asthma-only, AO patients were more often men, current smokers, with a lower BMI, had less often obesity and had more often chronic bronchitis. Compared with COPD-only, AO patients were younger, less often current smokers and had less pack-years. In the general population, AO patients had a higher risk of coronary artery disease than asthma-only and COPD-only (OR=2.09 (95% CI 1.26 to 3.47) and OR=1.89 (95% CI 1.10 to 3.24), respectively) and of depression (OR=1.41 (95% CI 1.19 to 1.67)), osteoporosis (OR=2.30 (95% CI 1.43 to 3.72)) and gastro-oesophageal reflux disease (OR=1.68 (95% CI 1.06 to 2.68)) than COPD-only, independent of age, sex, smoking status and BMI. CONCLUSIONS: AO is a relatively prevalent respiratory phenotype associated with more dyspnoea and a higher risk of coronary artery disease and elevated blood eosinophil counts in the general population compared with both asthma-only and COPD-only.

Time series modelling for wastewater-based epidemiology of COVID-19: A nationwide study in 40 wastewater treatment plants of Belgium, February 2021 to June 2022.

BACKGROUND: Wastewater-based epidemiology (WBE) has been implemented to monitor surges of COVID-19. Yet, multiple factors impede the usefulness of WBE and quantitative adjustment may be required. AIM: We aimed to model the relationship between WBE data and incident COVID-19 cases, while adjusting for confounders and autocorrelation. METHODS: This nationwide WBE study includes data from 40 wastewater treatment plants (WWTPs) in Belgium (02/2021-06/2022). We applied ARIMA-based modelling to assess the effect of daily flow rate, pepper mild mottle virus (PMMoV) concentration, a measure of human faeces in wastewater, and variants (alpha, delta, and omicron strains) on SARS-CoV-2 RNA levels in wastewater. Secondly, adjusted WBE metrics at different lag times were used to predict incident COVID-19 cases. Model selection was based on AICc minimization. RESULTS: In 33/40 WWTPs, RNA levels were best explained by incident cases, flow rate, and PMMoV. Flow rate and PMMoV were associated with -13.0 % (95 % prediction interval: -26.1 to +0.2 %) and +13.0 % (95 % prediction interval: +5.1 to +21.0 %) change in RNA levels per SD increase, respectively. In 38/40 WWTPs, variants did not explain variability in RNA levels independent of cases. Furthermore, our study shows that RNA levels can lead incident cases by at least one week in 15/40 WWTPs. The median population size of leading WWTPs was 85.1 % larger than that of non­leading WWTPs. In 17/40 WWTPs, however, RNA levels did not lead or explain incident cases in addition to autocorrelation. CONCLUSION: This study provides quantitative insights into key determinants of WBE, including the effects of wastewater flow rate, PMMoV, and variants. Substantial inter-WWTP variability was observed in terms of explaining incident cases. These findings are of practical importance to WBE practitioners and show that the early-warning potential of WBE is WWTP-specific and needs validation.

Do the lockdown-imposed changes in a wastewater treatment plant catchment's socio-demographics impact longitudinal temporal trends in psychoactive pharmaceutical use?

Wastewater-based epidemiology (WBE) includes the analysis of human metabolic biomarkers of xenobiotics in influent wastewater. WBE complements existing drug utilization approaches and provides objective, spatio-temporal information on the consumption of pharmaceuticals in the general population. This approach was applied to 24-h composite influent wastewater samples from Leuven, Belgium. Daily samples were analysed from September 2019 to December 2019 (n = 76), and on three days of the week (Monday, Wednesday, Saturday) from January 2020 to April 2022 (n = 367). Sample analysis consisted of 96-well solid-phase extraction and liquid chromatography coupled to tandem mass spectrometry. Measured concentrations of 21 biomarkers for antidepressant and opioid use were converted to population-normalized mass loads (PNML) by considering the flow rate and catchment population. To capture population movements, mobile phone data was used. Amitriptyline, hydroxy-bupropion, norcitalopram, citalopram, normirtazapine, trazodone, O-desmethylvenlafaxine, codeine, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP), methadone, morphine, O-desmethyltramadol, and tramadol were included in the temporal assessment since concentrations were above the lower limit of quantification. The PNML of most biomarkers increased (with 3-119 %) throughout the sampling period. The population disruption during the COVID-19 pandemic led to a major change in the socio-demographics of the catchment area, resulting in temporal differences in the PNML of the different biomarkers. As such, higher PNML were observed during the different lockdown phases, which were characterized by the outflow of university students and a decreasing commuting in and out the catchment area. The effects of the fluctuating socio-demographics of the catchment population were further evidenced by the different week-weekend pattern of PNMLs over the course of the sampling campaign. Mean parent/metabolite ratios (i.e., citalopram/norcitalopram, tramadol/O-desmethyltramadol, venlafaxine/O-desmethylvenlafaxine, and methadone/EDDP) remained relatively stable throughout the entire sampling campaign (RSD% below 25 % for all ratios, except for methadone/EDDP) and therefore were not affected by this population change.

Long-term comparative effectiveness and safety of dabigatran, rivaroxaban, apixaban and edoxaban in patients with atrial fibrillation: A nationwide cohort study.

Background: Although non-vitamin K antagonist oral anticoagulants (NOACs) are recommended over vitamin K antagonists (VKAs) in atrial fibrillation (AF) management, direct long-term head-to-head comparisons are lacking. Therefore, their risk-benefit profiles were investigated compared to VKAs and between NOACs. Methods: AF patients initiating anticoagulation between 2013-2019 were identified in Belgian nationwide data. Inverse probability of treatment weighted Cox regression was used to investigate effectiveness and safety outcomes and were additionally stratified by NOAC dose. Results: Among 254,478 AF patients (328,796 person-years of follow-up), NOACs were associated with significantly lower risks of stroke or systemic embolism (stroke/SE) (hazard ratio (HR) 0.68, 95% confidence interval (CI) (0.64-0.72)), all-cause mortality (HR 0.76, 95%CI (0.74-0.79)), major or clinically relevant non-major bleeding (MB/CRNMB) (HR 0.94, 95%CI (0.91-0.98)) and intracranial hemorrhage (HR 0.73, 95%CI (0.66-0.79)), but non-significantly different risks of myocardial infarction, gastrointestinal and urogenital bleeding compared to VKAs. Despite similar stroke/SE risks, dabigatran and apixaban were associated with significantly lower MB/CRNMB risks compared to rivaroxaban (HR 0.86, 95%CI (0.83-0.90); HR 0.86, 95%CI (0.83-0.89), respectively) and edoxaban (HR 0.91, 95%CI (0.83-0.99); HR 0.86, 95%CI (0.81-0.91), respectively), and apixaban with significantly lower major bleeding risks compared to dabigatran (HR 0.86, 95%CI (0.80-0.92)) and edoxaban (HR 0.79, 95%CI (0.72-0.86)). However, higher mortality risks were observed in some risk groups including with apixaban in patients with diabetes or concomitantly using digoxin compared to dabigatran and edoxaban, respectively. Conclusion: NOACs had better long-term risk-benefit profiles than VKAs. While effectiveness was comparable, apixaban was overall associated with a more favorable safety profile followed by dabigatran.

Evaluating the impact of COVID-19 countermeasures on alcohol consumption through wastewater-based epidemiology: A case study in Belgium.

Wastewater-based epidemiology (WBE) is a complementary approach to monitor alcohol consumption in the general population. This method measures concentrations of xenobiotic biomarkers (e.g., ethyl sulphate) in influent wastewater (IWW) and converts these to population-normalized mass loads (PNML, in g/day/1000 inhabitants) by multiplying with the flow rate and dividing by the catchment population. The aims of this case study were to: (i) investigate temporal trends in alcohol use during the COVID-19 pandemic; and (ii) measure the effect of policy measures on alcohol consumption. Daily 24-h composite IWW samples (n = 735) were collected in the wastewater treatment plant of the university city of Leuven (Belgium) starting from September 2019 to September 2021. This is the first study that investigates alcohol use through WBE for a continuous period of two years on a daily basis. Mobile phone data was used to accurately capture population fluxes in the catchment area. Data was evaluated using a time series based statistical framework to graphically and quantitatively assess temporal differences in the measured PNML. Different WBE studies observed temporal changes in alcohol use during the COVID-19 pandemic. In this study, the PNML of ethyl sulphate decreased during the first lockdown phase, potentially indicating that less alcohol was consumed at the Leuven area during home confinement. Contrastingly, alcohol use increased after the re-opening of the catering industry. Additionally, a decrease in alcohol use was observed during the exam periods at the University of Leuven and an increase during the holiday periods. The present study shows the potential of WBE to rapidly assess the impact of some policy measures on alcohol consumption in Belgium. This study also indicates that WBE could be employed as a complementary data source to fill in some of the current knowledge gaps linked to lifestyle behavior.

Factors influencing SARS-CoV-2 RNA concentrations in wastewater up to the sampling stage: A systematic review.

Wastewater-based surveillance (WBS) for SARS-CoV-2 RNA is a promising complementary approach to monitor community viral circulation. A myriad of factors, however, can influence RNA concentrations in wastewater, impeding its epidemiological value. This article aims to provide an overview and discussion of factors up to the sampling stage that impact SARS-CoV-2 RNA concentration estimates in wastewater. To this end, a systematic review was performed in three databases (MEDLINE, Web of Science and Embase) and two preprint servers (MedRxiv and BioRxiv). Two authors independently screened and selected articles published between January 1, 2019 and May 4, 2021. A total of 22 eligible articles were included in this systematic review. The following factors up to sampling were identified to have an influence on SARS-CoV-2 RNA concentrations in wastewater and its interpretation: (i) shedding-related factors, including faecal shedding parameters (i.e. shedding pattern, recovery, rate, and load distribution), (ii) population size, (iii) in-sewer factors, including solid particles, organic load, travel time, flow rate, wastewater pH and temperature, and (iv) sampling strategy. In conclusion, factors influencing SARS-CoV-2 RNA concentration estimates in wastewater were identified and research gaps were discussed. The identification of these factors supports the need for further research on WBS for COVID-19.

The implementation of risk minimization measures to prevent teratogenic pregnancy outcomes related to oral retinoid and valproate use in Belgium.

INTRODUCTION: Both oral retinoid and valproate containing medicines are highly teratogenic. Their use by women of childbearing age is controlled by risk minimization measures (RMMs) introduced by the European Medicine Agency, including the pregnancy prevention programme (PPP). In 2018, the RMMs were revised as previous measures were insufficient to prevent the use of these medicines during pregnancies. AIM & METHODS: A cross-sectional survey was conducted among patients, physicians and pharmacists to evaluate the implementation of the revised RMMs in Belgium. The primary outcome was compliance with key aspects of the PPP. Differences in compliance between oral retinoid and valproate stakeholders were investigated. The relationship between potential determinants (population characteristics and RMM usage) and compliance was studied via multiple logistic regression. RESULTS: A total of 317 eligible patients, physicians and pharmacists participated. The majority of the studied patients fail to comply with the PPP, mainly driven by poor implementation of pregnancy testing. A large number of healthcare providers is unaware of the available educational materials. CONCLUSION: It is likely that a substantial part of Belgian women of childbearing age using oral retinoids or valproate insufficiently meet the PPP requirements. We propose to better inform healthcare providers about the mandatory PPPs and available educational materials as well as to support them with the implementation of such programmes to improve the safe use of these teratogenic medicines.