[Early effect of vaccination on the positivity rate of salivary tests performed on nursing home staff in the Walloon Region]. / Face à la COVID-19. Effet précoce de la vaccination sur le taux de positivité des tests salivaires réalisés chez le personnel des maisons de repos en Région wallonne.

In Belgium, nursing homes (NH) were disproportionately affected by the SARS-CoV-2 pandemic. The objective of this study was to compare the risk of SARS-CoV-2 infection in vaccinated and unvaccinated staff members. METHODS: This was a prospective cohort study conducted between February 1 and April 02, 2021, in 99 nursing homes (NHs) in the Walloon Region, a few weeks after the start of the vaccination campaign. A mixed-effects logistic regression analysis was performed to assess the relationship between COVID results of molecular tests on saliva samples of the NHs' staff and their vaccination status. RESULTS: Only 32 (0,1 %) of 39 267 saliva tests were positive. Logistic analysis showed that unvaccinated nursing home staff were 4 times more likely to develop COVID-19 than vaccinated staff during the study period. CONCLUSION: This study demonstrated an early decreased risk of infection in vaccinated NHs staff. Saliva tests were designed to be convenient, less expensive and non-invasive, and could be considered as an alternative to nasopharyngeal tests.

En Belgique, les maisons de repos ont été touchées de manière disproportionnée par la pandémie de SARS-CoV-2. L'objectif de cette étude était de comparer le risque d'infection par le SARS-CoV-2 chez les membres du personnel vaccinés et non vaccinés. Méthodes : Il s'agit d'une étude de cohorte prospective qui s'est déroulée entre le 1er février et le 02 avril 2021 dans 99 maisons de repos (MR) en Région wallonne, quelques semaines après le début de la campagne de vaccination. Une analyse de régression logistique à effets mixtes a été effectuée pour évaluer la relation entre les résultats COVID des tests moléculaires sur des échantillons de salive du personnel des maisons de repos et leur statut vaccinal. Résultats : Seuls 32 (0,1 %) des 39.267 tests salivaires étaient positifs. L'analyse logistique montre que le personnel des maisons de repos non vacciné était 4 fois plus susceptible de développer la COVID-19 que le personnel vacciné pendant la période d'étude. Conclusion : cette étude a mis en évidence une réduction précoce du risque d'infection chez le personnel vacciné des maisons de repos. Les tests salivaires ont été conçus pour être pratiques, moins coûteux et non invasifs, ils pourraient être considérés comme une alternative aux tests nasopharyngés.

Using geographically weighted Poisson regression to examine the association between socioeconomic factors and hysterectomy incidence in Wallonia, Belgium.

BACKGROUND: Various studies have investigated geographical variations in the incidence of hysterectomy in Western countries and analyzed socioeconomic factors to explain those variations. However, few studies have used spatial analysis to characterize them. Geographically weighted Poisson regression (GWPR) explores the spatially varying impacts of covariates across a study area and focuses attention on local variations. Given the potential of GWPR to guide decision-making, this study aimed to describe the geographical distribution of hysterectomy incidence for benign indications in women older than 15 years old (15+) at the municipal level in Wallonia (southern region of Belgium) and to analyze potential associations with socioeconomic factors ('Education/training', 'Income and purchasing power' and 'Health and care') influencing the use of this surgery. METHODS: We carried out an ecological study on data for women aged 15+ living in one of the 262 Walloon municipalities who underwent hysterectomies for benign indications between 2012 and 2014. We linked standardized hysterectomy rates to three municipal-level socioeconomic factors ('Education/training', 'Income and purchasing power' and 'Health and care'). Then, a Poisson regression model and a GWPR were applied to study the relationships between hysterectomy incidence and socioeconomic covariates in Wallonia. RESULTS: The hysterectomy rate varied across the region. The Poisson regression revealed a positive and significant association between the hysterectomy rate and 'Income and purchasing power', and a negative and significant association between hysterectomies and 'Health and care'. The same associations were seen in the GWPR model. The latter demonstrated that the association between hysterectomies and 'Education and training' ranged from negative to positive over the study area. CONCLUSIONS: Hysterectomy incidence was shown to have nonstationary relationships with socioeconomic factors. These results support the development of targeted interventions for a more appropriate use of this surgery.

Concentration-response curve and cumulative effects between ozone and daily mortality: an analysis in Wallonia, Belgium.

Many studies have shown an association between ozone and mortality. However, little data is available on the cumulative effects of ozone on health. A time-series analysis using a Poisson regression was used to measure the impact of ozone on non-traumatic mortality in Wallonia over the period 2000-2012. Initially, a single-lag model was tested. Then a distributed-lag non-linear model was used in order to verify the cumulative effects of ozone on mortality. Our study confirms the existence of an association between ozone and mortality. The linear model without threshold shows a higher sensitivity in persons aged 75 and over (ERR = 0.7, 95 % CI: 0.4; 1.0 %) compared to younger people (ages 25-74) (ERR = 0.2, 95 % CI: - 0.2; 0.6 %). Taking cumulative effects into account, men and women aged 25-74 have an ozone sensitivity equivalent to those over 75.

Short-term effects of air pollution on hospitalization for acute myocardial infarction: age effect on lag pattern.

The aim of the present study is to analyse the age effect on the lag patterns of relative risk of hospitalization for acute myocardial infarction and NO2, PM10 and O3. Daily hospitalizations for AMI during the period 2008-2011 were extracted from administrative data. Analyses were performed using the quasi-Poisson regression model adjusted for seasonality, long-term trend, day of the week and temperature. We observed very different patterns depending on age. For NO2 and PM10, the younger group (25-54 years) shows a more delayed effect in comparison with the two older age groups (55-64 and ≥ 65 years). Overall, the associations between NO2 and AMI are higher compared to PM10. There are no associations between O3 and AMI. This study indicates that age plays a major role in the lag pattern. Younger people have delayed effects, but they are nevertheless sensitive to air pollution.

Comparison of four case-crossover study designs to analyze the association between air pollution exposure and acute myocardial infarction.

The case-crossover design is frequently used for analyzing the acute health effects of air pollution. Nevertheless, only a few studies compared different methods for selecting control periods. In this study, the bidirectional method and three time-stratified methods were used to estimate the association between air pollution and acute myocardial infarction (AMI) in Charleroi, Belgium, during 1999-2008. The strongest associations between air pollution and AMI were observed for PM10 and NO(2) during the warm period, OR = 1.095 (95 % CI: 1.003-1.169) and OR = 1.120 (95 % CI: 1.001-1.255), respectively. The results of this study reinforce the evidence of the acute effects of air pollution on AMI, especially during the warm season. This study suggests that the different methods of case-crossover study design are suitable to studying the association between acute events and air pollution. The temperature-stratified design is useful to exclude temperature as a potential confounder.

Day-of-the-week variations in myocardial infarction onset over a 27-year period: the importance of age and other risk factors.

INTRODUCTION: The aim of this study was to analyze the day-of-the-week variations of acute myocardial infarction (AMI) over a 27-year period. The effects of sex, age, history of AMI, hypertension, fatality, and temporal changes over the 27-year period were also investigated. METHODS: The Charleroi register of ischemic cardiopathies is the oldest register of infarctions in the French-speaking community of Belgium and is one of the very rare registers that can track trends over 27 years. The analyses presented in our study relate only to patients in the 25- to 69-year age range over time from 1983 to 2009. The χ2 test for goodness of fit was used to test the difference among the frequencies of AMI events over 7 days during the week. RESULTS: Data from 9732 cases of AMI were analyzed. Overall, there was a significant day-of-the-week variation (P<.001), with an excess of AMI observed on Mondays (n=1495) and a minimum on Saturdays (n=1259), corresponding to a relative increase in AMI of 18.2% over the 2 days. The Monday peak is more pronounced for the 35- to 44-year (P=.045) age bracket than for the 45- to 54-year (P=.27) and the 55- to 64-year (P=.032) brackets. The cases with (n=2713) and without (n=4931) arterial hypertension exhibited the same day-of-the-week variation. In contrast, the cases with antecedent AMI (n=1888) exhibited a less pronounced excess of MI incidence on Mondays compared with the cases without antecedent (n=5970). CONCLUSIONS: The present study demonstrates that there is a marked incidence peak in AMI on Mondays. This peak is similar for men and women but varies according to age. The Monday peak is not observed in subjects previously admitted for AMI or in fatal cases. The organization of the emergency medical services could take into account the day-of-the-week pattern of AMI to adapt emergency medical service capacity to needs.

Immuno-Diagnosis of Active Tuberculosis by a Combination of Cytokines/Chemokines Induced by Two Stage-Specific Mycobacterial Antigens: A Pilot Study in a Low TB Incidence Country.

Active tuberculosis (aTB) remains a major killer from infectious disease, partially due to delayed diagnosis and hence treatment. Classical microbiological methods are slow and lack sensitivity, molecular techniques are costly and often unavailable. Moreover, available immuno-diagnostic tests lack sensitivity and do not differentiate between aTB and latent TB infection (LTBI). Here, we evaluated the performance of the combined measurement of different chemokines/cytokines induced by two different stage-specific mycobacterial antigens, Early-secreted-antigenic target-6 (ESAT-6) and Heparin-binding-haemagglutinin (HBHA), after a short in vitro incubation of either peripheral blood mononuclear cells (PBMC) or whole blood (WB). Blood samples were collected from a training cohort comprising 22 aTB patients, 22 LTBI subjects and 17 non-infected controls. The concentrations of 13 cytokines were measured in the supernatants. Random forest analysis identified the best markers to differentiate M. tuberculosis-infected from non-infected subjects, and the most appropriate markers to differentiate aTB from LTBI. Logistic regression defined predictive abilities of selected combinations of cytokines, first on the training and then on a validation cohort (17 aTB, 27 LTBI, 25 controls). Combining HBHA- and ESAT-6-induced IFN-γ concentrations produced by PBMC was optimal to differentiate infected from non-infected individuals in the training cohort (100% correct classification), but 2/16 (13%) patients with aTB were misclassified in the validation cohort. ESAT-6-induced-IP-10 combined with HBHA-induced-IFN-γ concentrations was selected to differentiate aTB from LTBI, and correctly classified 82%/77% of infected subjects as aTB or LTBI in the training/validation cohorts, respectively. Results obtained on WB also selected ESAT-6- and HBHA-induced IFN-γ concentrations to provided discrimination between infected and non-infected subjects (89%/90% correct classification in the training/validation cohorts). Further identification of aTB patients among infected subjects was best achieved by combining ESAT-6-induced IP-10 with HBHA-induced IL-2 and GM-CSF. Among infected subjects, 90%/93% of the aTB patients were correctly identified in the training/validation cohorts. We therefore propose a two steps strategy performed on 1 mL WB for a rapid identification of patients with aTB. After elimination of most non-infected subjects by combining ESAT-6 and HBHA-induced IFN-γ, the combination of IP-10, IL-2 and GM-CSF released by either ESAT-6 or HBHA correctly identifies most patients with aTB.

Specific Host Signatures for the Detection of Tuberculosis Infection in Children in a Low TB Incidence Country.

Diagnosis of tuberculosis (TB) in children remains challenging due to unspecific clinical presentation and low bacillary load. In low TB incidence countries, most cases are diagnosed by a contact screening strategy after exposure to an index TB case. Due to the severity of TB in young children, the priority is to determine whether a child is infected or not, whereas differential diagnosis between active TB (aTB) and latent TB constitutes a second step. In Belgium, a low TB incidence country, we prospectively included 47 children with a defined M. tuberculosis infection status (12 children with aTB, 18 with latent TB, and 17 uninfected) (exploratory cohort), and determined the optimal combinations of cytokines secreted by their peripheral blood mononuclear cells in response to a 5-days in vitro stimulation with four different mycobacterial antigens, in an attempt to classify the children according to their infectious status. Correct identification of all infected children was obtained by several combinations of two purified protein derivative (PPD)-induced cytokines (IFN-γ and either GM-CSF, MIP-1α, sCD40L or TNF-α), or by combining PPD-induced IFN-γ with culture-filtrate protein-10 (CFP-10)-induced TNF-α. Alternatively, combining CFP-10-induced TNF-α and IP-10 with heparin-binding haemagglutinin (HBHA)-induced-IFN-γ was more effective in testing recently BCG-vaccinated children or those suspected to be infected with non-tuberculous mycobacteria, providing a correct classification of 97% of the M. tuberculosis-infected children. This combination also correctly classified 98% of the children from a validation cohort comprising 40 M. tuberculosis infected children and 20 non-infected children. Further differentiation between aTB and children with latent TB was more difficult. Combining ESAT-6-induced MIP1-α and IP-10, CFP-10-induced MIG, and HBHA-induced MIG provided a correct classification of 77% of the children from the exploratory cohort but only of 57.5% of those from the validation cohort. We conclude that combining the measurement of 2-4 cytokines induced by three different mycobacterial antigens allows an excellent identification of M. tuberculosis-infected children, whereas differentiating children with aTB from those with latent TB remains far from perfect.

Impact of COVID-19-related public containment measures on the ST elevation myocardial infarction epidemic in Belgium: a nationwide, serial, cross-sectional study.

AIMS: The current study assessed the impact of COVID-19-related public containment measures (i.e. lockdown) on the ST elevation myocardial infarction (STEMI) epidemic in Belgium. METHODS AND RESULTS: Clinical characteristics, reperfusion therapy modalities, COVID-19 status and in-hospital mortality of consecutive STEMI patients who were admitted to Belgian hospitals for percutaneous coronary intervention (PCI) were recorded during a three-week period starting at the beginning of the lockdown period on 13 March 2020. Similar data were collected for the same time period for 2017-2019. An evaluation of air quality revealed a 32% decrease in ambient NO2 concentrations during lockdown (19.5 µg/m³ versus 13.2 µg/m³, p < .001). During the three-week period, there were 188 STEMI patients admitted for PCI during the lockdown versus an average 254 STEMI patients before the lockdown period (incidence rate ratio = 0.74, p = .001). Reperfusion strategy was predominantly primary PCI in both time periods (96% versus 95%). However, there was a significant delay in treatment during the lockdown period, with more late presentations (>12 h after onset of pain) (14% versus 7.6%, p = .04) and with longer door-to-balloon times (median of 45 versus 39 min, p = .02). Although the in-hospital mortality between the two periods was comparable (5.9% versus 6.7%), 5 of the 7 (71%) COVID-19-positive STEMI patients died. CONCLUSION: The present study revealed a 26% reduction in STEMI admissions and a delay in treatment of STEMI patients. Less exposure to external STEMI triggers (such as ambient air pollution) and/or reluctance to seek medical care are possible explanations of this observation.

Benzyl prolinate derivatives as novel selective KCC2 blockers.

The discovery and optimization of a novel class of selective submicromolar KCC2 blockers is described. Details of synthesis and SAR are given together with ADME properties of selected compounds. A methylsulfone residue on the R(1) phenyl group improved the overall general profile of these prolinate derivatives.

4-benzyl-1H-imidazoles with oxazoline termini as histamine H3 receptor agonists.

Research on the therapeutic applications of the histamine H3 receptor (H3R) has traditionally focused on antagonists/inverse agonists. In contrast, H3R agonists have received less attention despite their potential use in several disease areas. The lower availability of H3R agonists not only hampers their full therapeutic exploration, it also prevents an unequivocal understanding of the structural requirements for H3R activation. In the light of these important issues, we present our findings on 4-benzyl-1H-imidazole-based H3R agonists. Starting from two high throughput screen hits (10 and 11), the benzyl side chain was altered with lipophilic groups using combinatorial and classical chemical approaches (compounds 12-31). Alkyne- or oxazolino-substituents gave excellent affinities and agonist activities up to the single digit nM range. Our findings further substantiate the growing notion that basic ligand sidechains are not necessary for H 3R activation and reveal the oxazolino group as a hitherto unexplored functional group in H3R research.

Short-term effects of nitrogen dioxide on hospital admissions for cardiovascular disease in Wallonia, Belgium.

Many studies have shown a short-term association between NO2 and cardiovascular disease. However, few data are available on the delay between exposure and a health-related event. The aim of the present study is to determine the strength of association between NO2 and cardiovascular health in Wallonia for the period 2008-2011. This study also seeks to evaluate the effects of age, gender, season and temperature on this association. The effect of the delay between exposure and health-related event was also investigated. The daily numbers of hospital admissions for arrhythmia, acute myocardial infarction, ischemic and haemorrhagic stroke were taken from a register kept by Belgian hospitals. Analyses were performed using the quasi-Poisson regression model adjusted for seasonality, long-term trend, day of the week, and temperature. Our study confirms the existence of an association between NO2 and cardiovascular disease. Apart from haemorrhagic stroke, the strongest association between NO2 concentrations and number of hospital admissions is observed at lag 0. For haemorrhagic stroke, the association is strongest with a delay of 2days. All associations calculated without stratification are statistically significant and range from an excess relative risk of 2.8% for myocardial infarction to 4.9% for haemorrhagic strokes. The results of this study reinforce the evidence of the short-term effects of NO2 on hospital admissions for cardiovascular disease. The different delay between exposure and health-related event for haemorrhagic stroke compared to ischemic stroke suggests different mechanisms of action.

Data on short-term effect of nitrogen dioxide on cardiovascular health in Wallonia, Belgium.

Data presented in this article are related to the research paper entitled "Short-term effects of nitrogen dioxide on hospital admissions for cardiovascular disease in Wallonia, Belgium." (Collart et al., in press) [1]. Nitrogen dioxide concentrations showed a strong seasonal pattern with higher levels in the cold period than in the warm period. A minimum of 13.1 µg/m3 in July and a maximum of 26.9 µg/m3 in January were observed. The coldest months are December, January and February and the hottest months are June, July and August. Temperature and nitrogen dioxide were negatively correlated in the cold period and positively correlated in the warm period. For the period 2008-2011 there were 113 147 hospital admissions for cardiovascular disease. Forty-five percent of patients were women and 66.5% were 65 and older. Heart rhythm disorders account for the majority of hospital admissions for cardiovascular disease. Our data confirms the existence of an association between NO2 and cardiovascular disease. Apart from haemorrhagic stroke, the strongest association between NO2 concentrations and number of hospital admissions is observed at lag 0. For haemorrhagic stroke, the association is strongest with a delay of 2 days. All associations calculated without stratification are statistically significant and range from an excess relative risk of 2.8% for myocardial infarction to 4.9% for haemorrhagic strokes.

Trends in acute myocardial infarction treatment between 1998 and 2007 in a Belgian area (Charleroi).

BACKGROUND/OBJECTIVES: To describe the evolution of the therapeutic practices over 10 years of follow-up of acute myocardial infarction (AMI) in Charleroi and to analyse the factors influencing the choice of treatments and the mortality of these patients. METHODS: The Charleroi register of ischaemic cardiopathies is the oldest register of infarctions in the French-speaking community of Belgium and is one of the very rare registers that allows identifying tendencies over 25 years. Analyses presented hereafter relate only patients in the 25-69-year age range over time from 1998 to 2007. The data were analysed in five periods of 2 years. Treatment evolutions over time were analysed using chi-squared tests for trend and logistic regression analyses identify factors influencing the type of treatment. RESULTS: The present study shows a marked increase in the utilization of percutaneous transluminal coronary angioplasty (PTCA) between 1998-1999 and 2006-2007. The use of thrombolytic agents on approximately one-third of the patients treated remained fairly stable between 1998 and 2007. A lower proportion of patients with a history of AMI received thrombolytic agents. Thrombolysis seems beneficial for men and without effect for women. The use of ß-blockers continued to increase until the 2000-2001 period and remained fairly stable for the two following periods. 42% of patients were administered three medications (angiotensin-converting enzyme inhibitors, antiplatelet drugs, and ß-blockers). Association of PTCA with antiplatelet drugs, ß-blockers, and thrombolysis was observed for 58.7, 50.6, and 25.7%, respectively. These associations were still observed after adjustment for gender, age, and comorbidity. The factors associated with fatality were specifically old-aged patients, antecedents of diabetes, hypercholesterolaemia and oral antiplatelet drugs, and ß-blockers therapies and PTCA. CONCLUSIONS: The evolution of the therapeutic data on AMI in this register confirms the use and the efficacy of thrombolytic therapy. PTCA becomes the main coronary reperfusion treatment with less risk of bleeding. Angiotensin-converting enzyme inhibitors were without effect on mortality.

Gender differences in acute myocardial infarction, twenty-five years registration.

BACKGROUND/OBJECTIVES: The French-speaking Community of Belgium has set up a register of ischaemic cardiopathies (1983-2007). The aim consists in analyzing the evolution of fatal and non-fatal acute coronary events rates as well as the 28 days case fatality on a 25-year period and examine sex differences in lethality. METHODS: This register assures a standardized procedure according to the MONICA criteria. For each period, we present attack rates and trends analysis. Hospital lethality takes again in-patients and community lethality is calculated starting from all the cases. RESULTS: The total attack rate is rather stable between 1983 and 2007 for women (from 12 to 19 per 10,000 residents). For men, there is a distinct decline of the total attack rate since 1991 till 1993 (63 to 43 per 10,000 residents). We systematically observe a reduction in risk between men and women according to the age. For each 5-year period, this risk decreases significantly with age and this difference is strongest during the periods 1993-1997 and 1998-2002. The analysis shows also a significant decline in lethality between the 1983-1987 and 1993-1997 periods. Among women, lethality is systematically higher than in men in spite of the presence or the absence of antecedents of myocardial infarction. CONCLUSIONS: Favourable evolutions in the attack rates of acute coronary events in the study population appear clearly on the 25-year period of observation. The whole lethality rates decreased during the first 15 years of the register; after that, it stabilized.

Discovery of a new class of non-imidazole oxazoline-based histamine H(3) receptor (H(3)R) inverse agonists.

H(3)R inverse agonists based on an aminopropoxy-phenyloxazoline framework constitute highly valuable druglike lead compounds that display efficacy in a mouse model of recognition memory.

Pyrazolone methylamino piperidine derivatives as novel CCR3 antagonists.

The discovery and optimization of a novel class of potent CCR3 antagonists is described. Details of synthesis and SAR are given together with some ADME properties of selected compounds. An optimal balance between activities, physicochemical properties, and in vitro metabolic stability was reached by the proper choice of substituents.

Discovery of new C3aR ligands. Part 1: arginine derivatives.

The synthesis and in vitro binding of several new arginine-containing C3aR ligands are reported. DMPK properties and functional activities of selected compounds have been evaluated. One compound is shown to be active in an in vivo model of airway inflammation after aerosol administration.

Discovery of new C3aR ligands. Part 2: amino-piperidine derivatives.

The synthesis and structure-activity relationships against the C3a receptor of a series of substituted aminopiperidine derivatives are reported. DMPK properties and functional activities of selected compounds are described. The compounds obtained are the first non-arginine ligands of C3aR.