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Pain after cancer remains underestimated and undertreated. Precision medicine is a recent concept that refers to the ability to classify patients into subgroups that differ in their susceptibility to, biology, or prognosis of a particular disease, or in their response to a specific treatment, and thus to tailor treatment to the individual patient characteristics. Applying this to pain after cancer, the ability to classify post-cancer pain into the three major pain phenotypes (i.e. nociceptive, neuropathic, and nociplastic pain) and tailor pain treatment accordingly, is an emerging issue. This is especially relevant because available evidence suggests that nociplastic pain is present in an important subgroup of those patients experiencing post-cancer pain. The 2021 International Association for the Study of Pain (IASP) clinical criteria and grading system for nociplastic pain account for the need to identify and correctly classify patients according to the pain phenotype early in their treatment. These criteria are an important step towards precision pain medicine with great potential for the field of clinical oncology. Within this framework, the Cancer Pain Phenotyping (CANPPHE) Network, an international and interdisciplinary group of oncology clinicians and researchers from seven countries, applied the 2021 IASP clinical criteria for nociplastic pain to the growing population of those experiencing post-cancer pain. A manual is provided to allow clinicians to differentiate between predominant nociceptive, neuropathic, or nociplastic pain after cancer. A seven-step diagnostic approach is presented and illustrated using cases to enhance understanding and encourage effective implementation of this approach in clinical practice. The Research Foundation Flanders (FWO), Belgium (11B1920N to AL, 1108621N to EH, G040919N to LL; and AP, a postdoctoral fellow). Stand Up To Cancer (Kom op tegen Kanker) (ANI25 to ER, KM, and LL), a Belgian cancer charity. FWO (G040919N to LL). JN holds a Chair in oncological rehabilitation funded by the Berekuyl Academy, the Netherlands. Grant support for ER was provided by a Chair funded by the Berekuyl Academy/European College for Decongestive Lymphatic Therapy, the Netherlands, and awarded to the Vrije Universiteit Brussel, Belgium. PB is funded by the Research, Innovation and Excellence Structure (DEKA) of the University of Thessaly.

Background Non-vitamin K antagonist oral anticoagulants (NOACs) are increasingly preferred over vitamin K antagonists (VKAs) in atrial fibrillation (AF) management. However, differences in oral anticoagulant (OAC) prescribing according to patient's age, patient's sex and physician's specialty may be present. Purpose To investigate the incident and prevalent use of OACs, NOACs and VKAs, stratified by age, sex and prescriber, and factors associated with the choice of OAC on a full-population scale. Methods Using two Belgian nationwide healthcare databases, AF patients ≥45 years old with ≥1 OAC prescription claim between January 1st, 2013 and December 31st, 2019 were identified. OAC use was investigated per half-year with a repeated cross-sectional design, based on medication prescription claims on a day-to-day basis. Incident use was defined as the first OAC use during the study period in OAC-naïve AF patients, whereas prevalent OAC use was defined as at least 1 OAC dispensing during a specific half-year. Factors influencing NOAC versus VKA initiation were identified by multivariable logistic regression models. Results Among 448,661 included OAC-treated AF patients (260,184 prevalent NOAC and 188,477 prevalent VKA users), 297,818 were newly-treated (232,739 incident NOAC and 65,079 incident VKA users). The mean age of incident NOAC and VKA users was 76±10 and 71±12 years, and 48% and 47% were female, respectively. Incident OAC use ranged from 45–49 to 42–44 users/10,000 persons between 2013–2019, whereas prevalent OAC use increased from 337 to 435 users/10,000 persons. Incident and prevalent NOAC use exceeded VKA use since 2013 and 2015 respectively, and NOACs represented 92% of incident and 81% of prevalent OAC users in 2019. Apixaban was the most frequently used NOAC since 2016. NOACs were significantly more prescribed by cardiologists and to older patients, whereas VKAs were more initiated in patients with cardiovascular, renal and hepatic comorbidities. Prevalent OAC use increased less in women than men (+25% versus +33% between 2013–2019) and female subjects had a 5% significantly lower odds of NOAC versus VKA initiation than men after multivariable adjustment. Conclusions Prevalent anticoagulant use increased with 29% in Belgium between 2013 and 2019. However, potential (N)OAC underuse among female AF patients was observed. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Research Foundation Flanders (FWO)

Funder: British Lung Foundation, Funder: National Institute for Health Research (NIHR), Lung-function impairment underlies chronic obstructive pulmonary disease (COPD) and predicts mortality. In the largest multi-ancestry genome-wide association meta-analysis of lung function to date, comprising 580,869 participants, we identified 1,020 independent association signals implicating 559 genes supported by ≥2 criteria from a systematic variant-to-gene mapping framework. These genes were enriched in 29 pathways. Individual variants showed heterogeneity across ancestries, age and smoking groups, and collectively as a genetic risk score showed strong association with COPD across ancestry groups. We undertook phenome-wide association studies for selected associated variants as well as trait and pathway-specific genetic risk scores to infer possible consequences of intervening in pathways underlying lung function. We highlight new putative causal variants, genes, proteins and pathways, including those targeted by existing drugs. These findings bring us closer to understanding the mechanisms underlying lung function and COPD, and should inform functional genomics experiments and potentially future COPD therapies.

Funder: British Lung Foundation (BLF); doi: https://doi.org/10.13039/501100000351, Funder: DH | National Institute for Health Research (NIHR); doi: https://doi.org/10.13039/501100000272, Lung-function impairment underlies chronic obstructive pulmonary disease (COPD) and predicts mortality. In the largest multi-ancestry genome-wide association meta-analysis of lung function to date, comprising 580,869 participants, we identified 1,020 independent association signals implicating 559 genes supported by ≥2 criteria from a systematic variant-to-gene mapping framework. These genes were enriched in 29 pathways. Individual variants showed heterogeneity across ancestries, age and smoking groups, and collectively as a genetic risk score showed strong association with COPD across ancestry groups. We undertook phenome-wide association studies for selected associated variants as well as trait and pathway-specific genetic risk scores to infer possible consequences of intervening in pathways underlying lung function. We highlight new putative causal variants, genes, proteins and pathways, including those targeted by existing drugs. These findings bring us closer to understanding the mechanisms underlying lung function and COPD, and should inform functional genomics experiments and potentially future COPD therapies.

Background The aging population and its burden on health care systems warrant early detection of patients at risk of functional decline and mortality. We aimed to assess frailty transitions and its accuracy for mortality prediction in participants with impaired spirometry (Preserved Ratio Impaired Spirometry [PRISm] or chronic obstructive pulmonary disease [COPD]). Methods In participants from the population-based Rotterdam Study (mean age 69.1 ± 8.9 years), we examined whether PRISm (forced expiratory volume in 1 second [FEV1]/forced vital capacity [FVC] ≥ 70% and FEV1 < 80%) or COPD (FEV1/FVC < 70%) affected frailty transitions (progression/recovery between frailty states [robust, prefrailty, and frailty], lost to follow-up, or death) using age-, sex- and smoking state-adjusted multinomial regression models yielding odds ratios (OR). Second, we assessed the diagnostic accuracy of frailty score for predicting mortality in participants with COPD using c-statistics. Results Compared to participants with normal spirometry, participants with PRISm were more likely to transit from robust (OR 2.2 [1.2–4.2], p < .05) or prefrailty (OR 2.6 [1.3–5.5], p < .01) toward frailty. Participants with PRISm (OR 0.4 [0.2–0.8], p < .05) and COPD (OR 0.6 [0.4–1.0], NS) were less likely to recover from their frail state, and were more likely to progress from any frailty state toward death (OR between 1.1 and 2.8, p < .01). Accuracy for predicting mortality in participants with COPD significantly improved when adding frailty score to age, sex, and smoking status (90.5 [82.3–89.8] vs 77.9 [67.2–88.6], p < .05). Conclusion Participants with PRISm or COPD more often developed frailty with poor reversibility. Assessing physical frailty improved risk stratification for participants with impaired spirometry for predicting increased life years.

Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease with variable mortality risk. The aim of our investigation was to validate a simple clinical algorithm for long-term mortality previously proposed by Burgel et al. in 2017. Subjects with COPD from two cohorts, the Swedish PRAXIS study (n = 784, mean age (standard deviation (SD)) 64.0 years (7.5), 42% males) and the Rotterdam Study (n = 735, mean age (SD) 72 years (9.2), 57% males), were included. Five clinical clusters were derived from baseline data on age, body mass index, dyspnoea grade, pulmonary function and comorbidity (cardiovascular disease/diabetes). Cox models were used to study associations with 9-year mortality. The distribution of clinical clusters (1-5) was 29%/45%/8%/6%/12% in the PRAXIS study and 23%/26%/36%/0%/15% in the Rotterdam Study. The cumulative proportion of deaths at the 9-year follow-up was highest in clusters 1 (65%) and 4 (72%), and lowest in cluster 5 (10%) in the PRAXIS study. In the Rotterdam Study, cluster 1 (44%) had the highest cumulative mortality and cluster 5 (5%) the lowest. Compared with cluster 5, the meta-analysed age- and sex-adjusted hazard ratio (95% confidence interval) for cluster 1 was 6.37 (3.94-10.32) and those for clusters 2 and 3 were 2.61 (1.58-4.32) and 3.06 (1.82-5.13), respectively. Burgel's clinical clusters can be used to predict long-term mortality risk. Clusters 1 and 4 are associated with the poorest prognosis, cluster 5 with the best prognosis and clusters 2 and 3 with intermediate prognosis in two independent cohorts from Sweden and the Netherlands.

In this article I provide an analysis of XVS order in (Modern) standard French, and reconcile it with comparative analyses of XVS in (Modern) Romance by taking into account recent conceptual accounts for topic and focus. I concentrate on XVS clauses in Modern standard French where X is an adverbial or an adjectival phrase, and provide empirical evidence for the assumption that – contrary to what is often assumed – these are similar to XVS clauses in Romance and not subject to a special syntactic licensing constraint distinguishing them from other Romance languages. I claim that XVS clauses in (Modern) standard French display systematicity in that the initial element X is either [+anaphoric] or [+scalar] and that this is the result of micro-parametric rather than nano-parametric variation: the sentence-initial AdjPs and AdvPs in XVS are no individual lexical items but belong to a lexically defined subset of AdvPs and AdjPs. Instances of XVS introduced by a [+scalar] constituent are argued to be subsets of Romance mirative focus fronting, while those introduced by a [+anaphoric] constituent are subsets of Romance resumptive preposing. I argue that XVS in standard French is productive with fronted rare ‘rare’ and nombreux ‘numerous’, because these adjectives are both [+anaphoric] and [+scalar]. This shows that V2 is still active in standard French.

Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Research Foundation Flanders (Fonds Wetenschappelijk Onderzoek, FWO). Background Although non-vitamin K antagonist oral anticoagulants (NOACs) are recommended over vitamin K antagonists (VKAs) in atrial fibrillation (AF) management, direct head-to-head comparisons are lacking and the long-term effectiveness and safety are less well established in real life. Purpose We aimed to investigate the risk-benefit profiles of dabigatran, rivaroxaban, apixaban and edoxaban in direct head-to-head comparisons with VKAs and between NOACs. Methods Using two Belgian nationwide healthcare databases, AF patients ≥45 years old initiating anticoagulation between January 1st, 2013 and January 1st, 2019 were included. Outcomes were identified using International Classification of Diseases-coded hospital discharge diagnoses (e.g. cerebral infarction) and medical procedure codes in hospital care (e.g. intracranial mechanical thrombectomy). Patients were followed from anticoagulant initiation until the first occurrence of the investigated outcome, discontinuation or switch of treatment, death, emigration or end of the study period, whichever came first (on-treatment analysis). Inverse probability of treatment weighted Cox regression was used to investigate effectiveness and safety outcomes. Results A total of 254,478 newly-treated AF patients were included during a mean follow-up of 1.3 ± 1.5 years (328,796 person-years of on-treatment follow-up). Before weighting, the 193,072 NOAC and 61,406 VKA users were on average 76.3 ± 10.1 and 70.9 ± 12.1 years old, and had a mean CHA2DS2-VASc score of 3.6 ± 1.8 and 3.2 ± 2.0, respectively. After multivariable adjustment, 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 with apixaban in some risk groups including 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 associated with a more favorable safety profile for most patients, followed by dabigatran.

Objective: To investigate the association of chronic obstructive pulmonary disease (COPD) and Preserved Ratio Impaired Spirometry (PRISm) with cognitive performance and presence of vascular brain lesions (VBL). Methods: We determined both cross-sectional and longitudinal association of lung function impairment with cognition, as well as cross-sectional association of lung function impairment with VBL, in the general population. Between 2009 and 2014 we included 3,941 participants from the Rotterdam Study with spirometry tests, brain MRI scans and cognition tests, of whom 1815 had follow-up data on cognition. Results: Our finding indicated that cross-sectionally, participants with PRISm or COPD GOLD2-4 had a worse global cognitive performance. We did not find differences in cognition over time between those with normal spirometry versus those with lung function impairment. In addition, PRISm and COPD GOLD2-4 were associated with a higher prevalence of lacunar infarcts compared to normal spirometry. Conclusions: This study suggests that persons with COPD GOLD2-4 or restrictive lung function, defined as PRISm, are characterized by poorer global cognitive function and a higher prevalence of lacunar infarcts.

Asthma exacerbations reflect disease severity, affect morbidity and mortality, and may lead to declining lung function. Inflammatory endotypes (e.g.:T2-high (eosinophilic)) may play a key role in asthma exacerbations. We aimed to assess whether genetic susceptibility underlies asthma exacerbation risk and additionally tested for an interaction between genetic variants and eosinophilia on exacerbation risk.UK Biobank data were used to perform a GWAS study of individuals with asthma and at least one exacerbation compared to individuals with asthma and no history of exacerbations. Individuals with asthma were identified using self-reported data, hospitalization data and General Practitioners (GP) records. Exacerbations were identified as either asthma–related hospitalization, GP record of asthma exacerbation, or an oral corticosteroid (OCS) burst prescription. A logistic regression model adjusted for age, sex, smoking status, and genetic ancestry via principal components was used to assess the association between genetic variants and asthma exacerbations. We sought replication for suggestive associations (P-6) in the GERA cohort.In the UK Biobank, we identified 11,604 cases, and 37,890 controls. While no variants reached genome wide significance (P-8) in the primary analysis, 116 signals were suggestively significant (P-6). In GERA, two SNPs (rs34643691 and rs149721630) were nominally significant and showed the same direction of effect.Two novel genetic loci-(NTRK3 and ABCA13)-that are reproducibly associated with asthma exacerbation in participants with asthma were identified. Confirmation of these findings in different asthma (or ancestry) sub-populations and functional investigation will be required to understand their mechanisms of action and potentially inform therapeutic development.

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.

Background: During the past century, socioeconomic and scientific advances have resulted in changes in the health and physique of European populations. Accompanying improvements in lung function, if unrecognised, could result in the misclassification of lung function measurements and misdiagnosis of lung diseases. We therefore investigated changes in population lung function with birth year across the past century, accounting for increasing population height, and examined how such changes might influence the interpretation of lung function measurements. Methods: In our analyses of cross-sectional data from ten European population-based studies, we included individuals aged 20–94 years who were born between 1884 and 1996, regardless of previous respiratory diagnoses or symptoms. FEV1, forced vital capacity (FVC), height, weight, and smoking behaviour were measured between 1965 and 2016. We used meta-regression to investigate how FEV1 and FVC (adjusting for age, study, height, sex, smoking status, smoking pack-years, and weight) and the FEV1/FVC ratio (adjusting for age, study, sex, and smoking status) changed with birth year. Using estimates from these models, we graphically explored how mean lung function values would be expected to progressively deviate from predicted values. To substantiate our findings, we used linear regression to investigate how the FEV1 and FVC values predicted by 32 reference equations published between 1961 and 2015 changed with estimated birth year. Findings: Across the ten included studies, we included 243 465 European participants (mean age 51·4 years, 95% CI 51·4–51·5) in our analysis, of whom 136 275 (56·0%) were female and 107 190 (44·0%) were male. After full adjustment, FEV1 increased by 4·8 mL/birth year (95% CI 2·6–7·0; p1 and FVC values predicted by published reference equations corroborated these findings. This height-independent increase in FEV1 and FVC across the last century will have caused mean population values to progressively exceed previously predicted values. However, the population mean adjusted FEV1/FVC ratio decreased by 0·11 per 100 birth years (95% CI 0·09–0·14; p

Purpose This systematic review and meta-analysis aimed to determine the effectiveness of psychologically informed practice (PIP) with behavioural graded activity (BGA) compared to (1) waitlist controls (WLC), (2) other interventions (OI), (3) PIP alone or (4) BGA alone in cancer patients and survivors (CPaS). Methods PubMed, Web of Science and Embase were screened for randomised controlled trials encompassing BGA + PIP in CPaS. Effect sizes were inventoried for outcomes regarding physical activity (PA), quality of life (QoL) and debilitating symptoms (DS), which were assessed at four time points: post-intervention (PI), follow-up F1 (1 to 3 months), F2 (4 to 6 months) and F3 (> 6 months). The quality of the evidence was classified by the GRADE approach. Results Thirty-three studies were found eligible, comprising 4330 participants. Significant effects with low heterogeneity of PIP + BGA comparing to WLC were found for anxiety (SMD − 1.29 [−1.71; − 0.86]), depression (SMD − 0.79 [− 1.10; − 0.48]), functional impairment (SMD − 0.72 [− 0.95; − 0.50]), PA (self-reported: (SMD − 0.58 [− 0.84; − 0.32]) and objectively measured: (SMD − 0.51 [− 0.90; − 0.13])) and social impairment (SMD − 0.33 [− 0.58; − 0.08]). When comparing PIP + BGA to OI, fatigue (SMD − 0.35 [− 0.51; − 0.20]) and PA (SMD − 0.26 [− 0.41; − 0.11]) at PI, and fatigue (SMD − 0.34 [− 0.58; − 0.10]) at F1 were found significant with low heterogeneity. No significant effects were observed in the meta-analyses of studies comparing PIP + BGA to BGA or PIP alone. Conclusions PIP with BGA has a favourable effect on DS, PA and QoL in CPaS when compared to non-behavioural interventions such as WLC, usual care and education. However, further research is needed on ‘how’ and ‘when’ PIP + BGA should be provided in cancer rehabilitation. Implications for Cancer Survivors PIP + BGA has the potential to facilitate CPaS to reach the recommended amount of PA and reduce DS.

Additional file 2: Fig. S1. Provides the distribution of the top 10 significantly associated miRNAs with current versus never smoking status; Fig. S2. Provides a Volcano plot depicting the results from current versus former smokers analysis, where current smoking was a reference; Fig. S3. Depicts boxplots of all 41 smoking miRNAs with their expression levels across different smoking cessation categories, while Fig. S4. Depicts the enrichment plot for the smoking associated miRNAs in the KEGG pathways.

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Background: Data on non-vitamin K antagonist oral anticoagulant (NOAC) use in patients with atrial fibrillation (AF) and a history of falls are limited. Therefore, we investigated the impact of a history of falls on AF-related outcomes, and the benefit-risk profiles of NOACs in patients with a history of falls. Methods: Using Belgian nationwide data, AF patients initiating anticoagulation between 2013 and 2019 were included. Previous falls that occurred ≤ 1 year before anticoagulant initiation were identified. Results: Among 254,478 AF patients, 18,947 (7.4%) subjects had a history of falls, which was associated with higher risks of all-cause mortality (adjusted hazard ratio (aHR) 1.11, 95%CI (1.06–1.15)), major bleeding (aHR 1.07, 95%CI (1.01–1.14)), intracranial bleeding (aHR 1.30, 95%CI (1.16–1.47)) and new falls (aHR 1.63, 95%CI (1.55–1.71)), but not with thromboembolism. Among subjects with a history of falls, NOACs were associated with lower risks of stroke or systemic embolism (aHR 0.70, 95%CI (0.57–0.87)), ischemic stroke (aHR 0.59, 95%CI (0.45–0.77)) and all-cause mortality (aHR 0.83, 95%CI (0.75–0.92)) compared to vitamin K antagonists (VKAs), while major, intracranial, and gastrointestinal bleeding risks were not significantly different. Major bleeding risks were significantly lower with apixaban (aHR 0.77, 95%CI (0.63–0.94)), but similar with other NOACs compared to VKAs. Apixaban was associated with lower major bleeding risks compared to dabigatran (aHR 0.78, 95%CI (0.62–0.98)), rivaroxaban (aHR 0.78, 95%CI (0.68–0.91)) and edoxaban (aHR 0.74, 95%CI (0.59–0.92)), but mortality risks were higher compared to dabigatran and edoxaban. Conclusions: A history of falls was an independent predictor of bleeding and death. NOACs had better benefit-risk profiles than VKAs in patients with a history of falls, especially apixaban.

In this article I provide an analysis of XVS order in (Modern) standard French, and reconcile it with comparative analyses of XVS in (Modern) Romance by taking into account recent conceptual accounts for topic and focus. I concentrate on XVS clauses in Modern standard French where X is an adverbial or an adjectival phrase, and provide empirical evidence for the assumption that – contrary to what is often assumed – these are similar to XVS clauses in Romance and not subject to a special syntactic licensing constraint distinguishing them from other Romance languages. I claim that XVS clauses in (Modern) standard French display systematicity in that the initial element X is either [+anaphoric] or [+scalar] and that this is the result of micro-parametric rather than nano-parametric variation: the sentence-initial AdjPs and AdvPs in XVS are no individual lexical items but belong to a lexically defined subset of AdvPs and AdjPs. Instances of XVS introduced by a [+scalar] constituent are argued to be subsets of Romance mirative focus fronting, while those introduced by a [+anaphoric] constituent are subsets of Romance resumptive preposing. I argue that XVS in standard French is productive with fronted rare ‘rare’ and nombreux ‘numerous’, because these adjectives are both [+anaphoric] and [+scalar]. This shows that V2 is still active in standard French. ispartof: Isogloss vol:8 issue:3 pages:1-30 status: Published online

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 con-verted 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 in-creased (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.

Background This study aimed to evaluate the prevalence of potential drug-drug interactions (DDIs) and the appropriateness of direct oral anticoagulant (DOAC) dosing according to both the Summary of Product Characteristics (SmPC) and the European Heart Rhythm Association (EHRA) Practical Guide in a ‘real-world’ sample of non-valvular atrial fibrillation (NVAF) patients. Methods and results Data of a cross-sectional observational study in a primary care sample of 654 long-term DOAC users were used for this sub-analysis. A total of 262 potential DDIs were identified in 220 patients (33.6%). Pharmacodynamic DDIs were present in 163 patients (24.9%) and pharmacokinetic DDIs in 82 patients (12.5%). One-third of patients (33.8%) received reduced DOAC dose. According to the dosing recommendations in the SmPC, 81.7% of DOACs were dosed appropriately. According to the EHRA recommendations, 76.6% of DOACs were dosed appropriately. Dosing recommendations were consistent for 90.7% of patients, with both the SmPC and EHRA Practical Guide considering DOACs dosed appropriately in 74.5% of patients, overdosed in 7.8%, underdosed in 7.6% and contraindicated in 0.8%. However, for the remaining 9.3% dosing recommendations differed between SmPC and EHRA. Conclusions This ‘real-world’ analysis of DOAC dosing demonstrated that in about one-third of NVAF patients potential DDIs were present. In 18.3% and 23.4% of patients, DOACs were dosed inappropriately according to the SmPC and EHRA Practical Guide respectively. In almost 10% of the study population dosing advice was inconsistent between both references. More research is needed to ensure appropriate DOAC dosing in this ‘grey zone’ population.

Observational studies report a reduction of COPD exacerbations in patients treated with β-blockers. In contrast, the Beta-Blockers for the Prevention of Acute Exacerbations of Chronic Obstructive Pulmonary Disease (BLOCK COPD) randomised controlled trial which excluded COPD patients with cardiovascular conditions showed an increase in COPD exacerbations. It is unclear whether this discrepancy could be explained by underlying cardiovascular comorbidity. We examined whether the association between use of β-blockers and risk of COPD exacerbations differed between patients with and without a cardiovascular indication for β-blockers use. Within the Rotterdam Study, we followed COPD subjects until the first COPD exacerbation, or end of follow-up. Cardiovascular indication for β-blockers use was defined as a history of hypertension, coronary heart disease, atrial fibrillation and/or heart failure at baseline. The association between β-blockers use and COPD exacerbations was assessed using Cox proportional hazards models adjusted for age, sex, smoking, incident cardiovascular disease (i.e. heart failure, hypertension, atrial fibrillation and/or coronary heart disease during follow-up), respiratory drugs and nitrates. In total, 1312 COPD patients with a mean age of 69.7±9.2 years were included. In patients with a cardiovascular indication (n=755, mean age of 70.4±8.8 years), current use of cardioselective β-blockers was significantly associated with a reduced risk of COPD exacerbations (HR 0.69, 95% CI 0.57–0.85). In contrast, in subjects without a cardiovascular indication (n=557, mean age of 68.8±9.7 years), current use of cardioselective β-blockers was not associated with an altered risk of COPD exacerbations (HR 0.94, 95% CI 0.55–1.62). Use of cardioselective β-blockers reduced the risk of exacerbations in COPD patients with concomitant cardiovascular disease. Therefore, the potential benefits of β-blockers might be confined to COPD patients with cardiovascular disease., Use of cardioselective β-blockers reduces the risk of COPD exacerbations in patients with concomitant cardiovascular disease. The potential benefits of β-blockers might be restricted to COPD patients with cardiovascular disease. https://bit.ly/3bB1RGg

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. ispartof: Environment International vol:170 ispartof: location:Netherlands status: Published online

Wastewater-based surveillance was conducted by the national public health authority to monitor SARS-CoV-2 circulation in the Belgian population. Over 5 million inhabitants representing 45% of the Belgian population were monitored throughout 42 wastewater treatment plants for 15 months comprising three major virus waves. During the entire period, a high correlation was observed between the daily new COVID-19 cases and the SARS-CoV-2 concentration in wastewater corrected for rain impact and covered population size. Three alerting indicators were included in the weekly epidemiological assessment: High Circulation, Fast Increase, and Increasing Trend. These indicators were computed on normalized concentrations per individual treatment plant to allow for a comparison with a reference period as well as between analyses performed by distinct laboratories. When the indicators were not corrected for rain impact, rainy events caused an underestimation of the indicators. Despite this negative impact, the indicators permitted us to effectively monitor the evolution of the fourth virus wave and were considered complementary and valuable information to conventional epidemiological indicators in the weekly wastewater reports communicated to the National Risk Assessment Group.

Background Personalized medicine is an emerging field, aiming to improve the safety and efficacy of pharmacotherapy. The field’s implementation in clinical care is steadily increasing. Pharmacogenomics are one example of personalized approaches in the clinic and direct-to-consumer (DTC) pharmacogenomic tests have become publicly available. We aimed to assess public opinion on pharmacogenomic research and testing to foster integration within Belgian health care. Methods A cross-sectional survey was created and disseminated online, focusing on the citizen perspective. Participants’ willingness to engage in pharmacogenomic research was the primary outcome. In addition, their awareness, understanding, expectations and overall acceptance towards pharmacogenomic testing was investigated. Results A total of 156 participants (54.5% aged between 18 and 30 years, 45.5% > 30 years; 73.1% females) completed the survey. Half ever experienced side effects (46.2%) and treatment failure (52.6%). Up to 45.5% (n = 71) were willing to participate in pharmacogenomics research, and the majority (78.8%) were convinced that pharmacogenomic tests could help doctors to prescribe them the right medications. Additionally, 76.3% (n = 118) supported a partial reimbursement of pharmacogenomics tests. A minority (5.1%, n = 8) of participants showed interest in DTC tests, and 15.4% (n = 24) expressed privacy concerns regarding pharmacogenomics testing. Participants preferred their healthcare professionals’ to perform the test and access their data, but refused commercial providers. Conclusion Overall, participants showed a positive attitude towards precision medicine and pharmacogenomics research. Our findings may help guiding future pharmacogenomic implementation initiatives to optimize drug use by using pharmacogenomic information integrated within health care.

IntroductionImmunoglobulins (Igs) play a pivotal role in host defense and prevention of pneumonia. Aging influences serum Ig levels, but the association between Igs and pneumonia in community-dwelling older individuals remains unknown. We evaluated the association of serum IgA, IgG, and IgM with pneumonia and lung function in middle-aged and older individuals.MethodsWe performed Cox and negative binomial regression analyses for the association of Igs with incident pneumonia and pneumonia-related mortality, and recurrent pneumonia respectively. We performed logistic regression analyses for the association between Igs and lung function values. Associations were adjusted for age, sex, smoking, comorbidities, and serum C-reactive protein.ResultsWe included 8,766 participants (median age 62.2 years, 57% women, median follow-up 9.8 years). Higher IgA (hazard ratio [HR]: 1.15; 95% confidence interval [95% CI]: 1.00-1.32) and IgG (HR: 1.13; 95% CI: 1.06-1.19) were associated with an increased pneumonia risk. Higher IgG was associated with an increased risk of pneumonia-related mortality (HR: 1.08; 95% CI: 1.01-1.16) and recurrent pneumonia (incidence rate ratio: 1.04; 95% CI: 1.00-1.09). Higher IgA and IgG were also associated with lower forced expiratory volume in one second (FEV1), lower forced vital capacity (FVC), and an increased odds of preserved ratio impaired spirometry (PRISm, i.e. FEV1 1/FVC ratio ≥70%). No association was seen with an obstructive spirometry pattern.DiscussionHigher serum IgA and IgG levels were associated with pneumonia, pneumonia-related mortality, and PRISm in middle-aged and older individuals from the general population. Future studies should validate our findings and elucidate underlying pathophysiology.

Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Research Foundation Flanders (FWO) Background P-glycoprotein (P-gp) and CYP3A4-interacting drugs influence plasma levels of non-vitamin K antagonist oral anticoagulants (NOACs). However, the clinical relevance is questioned. Purpose A critical appraisal of the impact of pharmacokinetically-interacting drugs on the effectiveness and safety of NOACs in patients with atrial fibrillation (AF). Methods After searching Pubmed and Embase, phase III randomized controlled trials (RCTs) and longitudinal observational cohort studies on the impact of concomitantly used P-gp/CYP3A4-interacting drugs on the risk-benefit profile of NOACs in AF patients during a mean/median follow-up of ≥6 months were included. A fixed effects meta-analysis was performed with the Mantel-Haenszel method. Results Fifteen studies were included (10 post hoc analyses of RCTs, 5 observational studies), investigating 21,711 and 306,421 NOAC-treated AF patients with and without P-gp/CYP3A4 inhibitor use respectively, while only one study included P-gp/CYP3A4 inducers. In NOAC-treated AF patients, concomitant use of P-gp/CYP3A4 inhibitors was associated with significantly higher major bleeding (relative risk (RR) 1.10, 95% confidence interval (CI) (1.01-1.19)) and all-cause mortality risks (RR 1.14, 95%CI (1.05-1.23)) compared to not using P-gp/CYP3A4 inhibitors, while the risks of stroke/SE (RR 0.88, 95%CI (0.77-1.01)), intracranial bleeding (RR 0.89, 95%CI (0.68-1.15)) and gastro-intestinal bleeding (RR 1.09, 95%CI (0.91-1.30)) were not significantly different. Concomitant use of amiodarone with NOACs was associated with lower thromboembolic (RR 0.75, 95%CI (0.61-0.92)), but higher mortality risks (RR 1.21, 95%CI (1.05-1.39)). Co-administration of verapamil or diltiazem was associated with higher major bleeding risks (RR 1.64, 95%CI (1.31-2.06)), but no significantly different thromboembolic or mortality risks. Conclusions Given the higher bleeding and mortality risks in NOAC-treated AF patients concomitantly using P-gp/CYP3A4 inhibitors compared to NOAC users not taking interacting drugs, close monitoring of these patients is warranted, including regular medication review and addressing modifiable bleeding risk factors. Regarding P-gp/CYP3A4 inducers, a considerable research gap was identified, necessitating more research on their impact.

Lung function impairment underlies chronic obstructive pulmonary disease (COPD) and predicts mortality. In the largest multi-ancestry GWAS meta-analysis of lung function to date, comprising 580,869 participants, 1020 independent association signals identified 559 genes supported by ≥2 criteria from a systematic variant-to-gene mapping framework. These genes were enriched in 29 pathways. Individual variants showed heterogeneity across ancestries, age and smoking groups, and collectively as a genetic risk score (GRS) showed strong association with COPD across ancestry groups. We undertook phenome-wide association studies (PheWAS) for selected associated variants, and trait and pathway-specific GRS to infer possible consequences of intervening in pathways underlying lung function. We highlight new putative causal variants, genes, proteins and pathways, including those targeted by existing drugs. These findings bring us closer to understanding the mechanisms underlying lung function and COPD, and should inform functional genomics experiments and potentially future COPD therapies.

BACKGROUND: Attenuation of transforming growth factor β by blocking angiotensin II has been shown to reduce emphysema in a murine model. General population studies have demonstrated that the use of angiotensin converting enzyme inhibitors (ACEis) and angiotensin-receptor blockers (ARBs) is associated with reduction of emphysema progression in former smokers and that the use of ACEis is associated with reduction of FEV(1) progression in current smokers. RESEARCH QUESTION: Is use of ACEi and ARB associated with less progression of emphysema and FEV(1) decline among individuals with COPD or baseline emphysema? METHODS: Former and current smokers from the Genetic Epidemiology of COPD Study who attended baseline and 5-year follow-up visits, did not change smoking status, and underwent chest CT imaging were included. Adjusted linear mixed models were used to evaluate progression of adjusted lung density (ALD), percent emphysema (%total lung volume

Background: Inhaled corticosteroids (ICS) are a cornerstone of asthma treatment. However, their efficacy is characterized by wide variability in individual responses. Objective: We investigated the association between genetic variants and risk of exacerbations in adults with asthma and how this association is affected by ICS treatment. Methods: We investigated the pharmacogenetic effect of 10 single nucleotide polymorphisms (SNPs) selected from the literature, including SNPs previously associated with response to ICS (assessed by change in lung function or exacerbations) and novel asthma risk alleles involved in inflammatory pathways, within all adults with asthma from the Dutch population–based Rotterdam study with replication in the American GERA cohort. The interaction effects of the SNPs with ICS on the incidence of asthma exacerbations were assessed using hurdle models adjusting for age, sex, BMI, smoking and treatment step according to the GINA guidelines. Haplotype analyses were also conducted for the SNPs located on the same chromosome. Results: rs242941 (CRHR1) homozygotes for the minor allele (A) showed a significant, replicated increased risk for frequent exacerbations (RR = 6.11, P

Purpose: Oral anticoagulants are crucial for preventing systemic thromboembolism in atrial fibrillation (AF), with guidelines preferring non-vitamin K antagonist oral anticoagulants (NOACs) over vitamin K antagonists (VKAs) in the general AF population. However, as NOACs are administered in fixed doses, concerns of unintentional underdosing in morbidly obese patients and unintentional overdosing in underweight patients have emerged. Therefore, a critical appraisal of the benefit-risk profile of NOACs in AF patients across the body weight spectrum is needed. Methods and results: After searching Medline, this systematic review discusses the impact of body weight on the risk-benefit profile of NOACs versus VKAs. The meta-analysis demonstrated that NOAC use in obese and class III obese AF patients (body mass index (BMI) ≥ 30 and ≥ 40 kg/m2, respectively) was associated with significantly lower stroke/systemic embolism (stroke/SE) risks (RR 0.82, 95%CI [0.71-0.96] and RR 0.75, 95%CI [0.64-0.87], respectively), similar to lower major bleeding risks (RR 0.83, 95%CI [0.69-1.00] and RR 0.74, 95%CI [0.57-0.95], respectively) and similar mortality risks (RR 0.92, 95%CI [0.73-1.15] and RR 1.17, 95%CI [0.83-1.64], respectively) compared to VKAs. In AF patients ≤ 60 kg, significantly lower stroke/SE (RR 0.63, 95%CI [0.56-0.71]) and major bleeding risks (RR 0.71, 95%CI [0.62-0.80]), but similar mortality risks (RR 0.68, 95%CI [0.42-1.10]), were observed for NOAC- versus VKA-treated patients. Conclusion: The benefit-risk profile of NOACs seems preserved in (morbidly) obese AF patients and patients with low body weight. However, more data are needed on underweight AF patients (BMI < 18.5 kg/m2) and on differences between NOACs in these patients.

Over the past decade, pharmacogenetics (PGx) became an essential tool for personalized medicine although its clinical implementation is still limited. We aimed to assess the current level of knowledge, applications, and expectations of Flemish pharmacists and physicians towards PGx and determine the factors that influence healthcare professionals' knowledge of PGx, aiming to guide future implementation initiatives. A web-based cross-sectional survey was conducted from 8 March 2019 to 8 April 2019, targeting pharmacists, physicians, and trainees of both professions. Ten questions were used to assess the participants' knowledge about PGx. Multivariable linear regression was used to assess the association of profession, experience, practice setting, and prior education with the level of PGx knowledge. In total, 201 Flemish healthcare providers participated, including 100 pharmacists, 73 physicians, and 28 trainees. The majority (78%) of participants were unfamiliar with the basic principles of PGx and its application in clinical practice. The mean percentage of correct answers achieved for the knowledge assessment questions was 34%. Only 9% had counseled patients, while 8% assisted other healthcare professionals on PGx tests the past year. Participants' PGx knowledge was significantly affected by their profession, practice setting, and level of prior education independent of years of experience. These findings provide insight into factors affecting the knowledge of PGx and the current level of PGx implementation in Flemish clinical practice. This may form a basis for developing educational initiatives to enhance the clinical application of PGx in Flanders.

The aim of the present paper is to identify the contexts in which French children produce dislocated and non-dislocated subjects. For that purpose, we carried out a corpus study for 21 children between age 2 and 5 from the TCOF corpus, and extracted a total of 370 dislocated and 1029 non-dislocated subjects. We will show that, in child language, dislocated subjects (i) always correspond to the topic of the utterance, (ii) can express a contrastive topic and (iii) are used for referents which are less accessible for the interlocutor than non-dislocated subject pronouns. Lexical non-dislocated subjects are extremely rare, as we found only 11 instances of such subjects. However, almost all of them appear in a very different context from dislocated subjects: they are typically produced in all-focus utterances. These results suggest that children master the functions of dislocation from the onset of the acquisition of the construction. This result puts in question former studies claiming that the clitic pronoun in child language is a morphological marker and hence a compulsory element in French child grammar.

Background Coping with a chronic disease can be really challenging. Self-management represents a promising strategy to improve daily life experiences. The role of primary healthcare professionals cannot be underestimated in supporting self-management. Due to a shortage of theory, implementation of self-management support is hindered in primary care practice. The aim of this study is to create a conceptual model for self-management support by analysing patients’ care experiences towards self-management support. Methods An explorative-descriptive qualitative study was conducted in Flanders, Belgium. Semi-structured interviews were performed with 16 patients and their informal caregiver (dyads) using a purposive sampling strategy and processed by an inductive content analysis, according to Graneheim and Lundman. Results Interviews revealed in-depth insights into patients’ care experiences. A conceptual model was developed for primary care practice, including five fundamental tasks for healthcare professionals - Supporting, Involving, Listening, Coordinating and Questioning (SILCQ) – contributing to the support of self-management of chronic patients. Conclusions This qualitative paper emphasises the use of the SILCQ-model to develop optimal roadmaps and hands-on toolkits for healthcare professionals to support self-management. The model needs to be further explored by all stakeholders to support the development of self-management interventions in primary care practice.

Since the beginning of the COVID-19 pandemic, the wastewater-based epidemiology (WBE) of SARS-CoV-2 has been used as a complementary indicator to follow up on the trends in the COVID-19 spread in Belgium and in many other countries. To further develop the use of WBE, a multiplex digital polymerase chain reaction (dPCR) assay was optimized, validated and applied for the measurement of emerging SARS-CoV-2 variants of concern (VOC) in influent wastewater (IWW) samples. Key mutations were targeted in the different VOC strains, including SΔ69/70 deletion, N501Y, SΔ241 and SΔ157. The presented bioanalytical method was able to distinguish between SARS-CoV-2 RNA originating from the wild-type and B.1.1.7, B.1.351 and B.1.617.2 variants. The dPCR assay proved to be sensitive enough to detect low concentrations of SARS-CoV-2 RNA in IWW since the limit of detection of the different targets ranged between 0.3 and 2.9 copies/µL. This developed WBE approach was applied to IWW samples originating from different Belgian locations and was able to monitor spatio-temporal changes in the presence of targeted VOC strains in the investigated communities. The present dPCR assay developments were realized to bring added-value to the current national WBE of COVID-19 by also having the spatio-temporal proportions of the VoC in presence in the wastewaters.

Stress has been consistently linked to negative impacts on physical and mental health. More specifically, patients with chronic pain experience stress intolerance, which is an exacerbation or occurrence of symptoms in response to any type of stress. The pathophysiological mechanisms underlying this phenomenon remain unsolved. In this state-of-the-art paper, we summarised the role of the autonomic nervous system (ANS) and hypothalamus-pituitary-adrenal (HPA) axis, the two major stress response systems in stress intolerance. We provided insights into such mechanisms based on evidence from clinical studies in both patients with chronic pain, showing dysregulated stress systems, and healthy controls supported by preclinical studies, highlighting the link between these systems and symptoms of stress intolerance. Furthermore, we explored the possible regulating role for (epi)genetic mechanisms influencing the ANS and HPA axis. The link between stress and chronic pain has become an important area of research as it has the potential to inform the development of interventions to improve the quality of life for individuals living with chronic pain. As stress has become a prevalent concern in modern society, understanding the connection between stress, HPA axis, ANS, and chronic health conditions such as chronic pain is crucial to improve public health and well-being. ispartof: Journal Of Clinical Medicine vol:12 issue:6 ispartof: location:Switzerland status: Published online

Only a few therapies have been shown to prolong survival in specific patients with COPD. In recent years, the IMPACT and the ETHOS trials suggested that triple therapy (a combination of inhaled corticosteroid (ICS), long-acting muscarinic antagonist (LAMA) and long-acting β2-agonist (LABA) given in a single inhaler) may reduce mortality compared with dual bronchodilation.These results need however to be interpreted with caution. These trials were not powered by design to evaluate the impact of triple therapy on mortality as mortality was a secondary outcome. In addition, mortality reduction has to be put in perspective with the low mortality rate in both studies (There are no conclusive data yet that triple therapy reduces mortality in COPD. Future, well-designed and -powered trials are needed to validate the findings on mortality.