Determinants of the willingness to get the third COVID-19 vaccine dose among health care workers.

OBJECTIVE: To characterize the willingness to get the third COVID-19 vaccine dose among health care workers (HCWs). METHODS: A cross-sectional study using a self-administered questionnaire proposed on a voluntary basis to all HCWs of a French teaching hospital in October and November 2021. RESULTS: Of 1,655 HCWs who completed the questionnaire, 64.2% were willing to receive the third dose, 20.1% were hesitant, and 15.7% were reluctant. On multivariate analysis, older age (P<0.0001), medical and executive staff, willingness to receive the flu vaccine (OR=5.72 [4.24-7.64]), previous vaccine scheme with ChAdOx1 nCoV-19 (AstraZeneca) (OR=2.13 [1.58-2.87]), and history of COVID-19 with a complete COVID-19 vaccine scheme (OR=2.77 [1.04-7.41]) were independent predictors of HCWs' willingness to get the third dose. CONCLUSIONS: One third of HCWs were hesitant or opposed to a third COVID-19 vaccine dose. Better knowledge of determinants of the willingness to get this third dose may improve communication and vaccine strategy.

[Targeted screening of COPD in primary care: Feasibility and effectiveness]. / Détection précoce de la BPCO en soins primaires : un essai contrôlé randomisé.

INTRODUCTION: Chronic obstructive pulmonary disease (COPD) is a common but under-diagnosed pathology in primary care. The objective was to study the feasibility of a randomized controlled trial in general practice to detect new cases of COPD at an earlier stage. METHODS: A cluster randomized, controlled, multicenter intervention study comparing, according to a 2×2 factorial plan, two case finding strategies: a systematic GOLD-HAS hetero-questionnaire and coordination of the patient's path to facilitate access to spirometry. The PIL-DISCO pilot study took place in 2017. Patients between 40 and 80 years old, with no previous history of COPD, consulting their GP on a given day regardless of the reason, were included. RESULTS: 176 patients were included in 1.5 days. Spirometry was performed in none of the control arm, in 13 (29.5%) of the questionnaire arm, in 22 (50%) in the coordination arm and in 32 (72.7%) with the combination of the two strategies. Two cases of stage 2 COPD and thirteen other respiratory diseases were diagnosed. CONCLUSIONS: This study confirms the feasibility of the protocol in primary care in terms of speed of inclusion and acceptability. An extension phase aiming to include 3200 patients will assess the diagnostic value of the two strategies tested in general practice.

[Suitability of red blood cell transfusion: a multicenter study]. / Évaluation multicentrique de la pertinence des prescriptions de concentrés de globules rouges.

The purpose of this retrospective observational multicenter study was to assess appropriateness of red blood cell (RBC) transfusion, according to the French national guidelines (Agence française de sécurité sanitaire des produits de santé) published in 2002. Six hundred and thirty-nine RBC transfusions from nine institutions have been randomly selected and analysed. The data collected are issued from different specialities. Patients' characteristics, occurrences of transfusion, admission, pre-transfusion, post-transfusion and discharge haemoglobin concentrations have been collected. Two physicians (who are in charge) must evaluate the appropriateness of pre-transfusion, discharged haemoglobin concentrations, quantity and quality of transfused RBC. The mean pre-transfusion haemoglobin concentration was 7.89 ± 1.24, the median number of transfused RBC was two (extremes: 1-16), the mean discharge haemoglobin concentration was 10.14 ± 1.30 (-5 days after the end of transfusion). The pre-transfusion and discharge haemoglobin concentrations were higher if the patient presented a co-morbidity factor. Ninety-three percent of pre-transfusion and 79% of discharge haemoglobin concentrations are in accordance with the guidelines. According to the physicians, the RBC transfusions are too "precocious" when pre-transfusion haemoglobin concentration is above nine and the anaemia is asymptomatic. 50% of RBC transfusion with discharge haemoglobin concentration above 10 is not excessive. In case of acute anaemia, the pre-transfusion and discharge haemoglobin concentrations are higher and RBC transfusion excessive. In this study, the trigger haemoglobin concentration is "restrictive", but the target haemoglobin concentration is "liberal" with a high-discharge haemoglobin concentration. Inappropriate RBC transfusions are mainly due to over-transfusion.

Alveolar macrophages from allergic lungs are not committed to a pro-allergic response and can reduce airway hyperresponsiveness following ex vivo culture.

BACKGROUND: We already demonstrated that adoptive transfer of alveolar macrophages (AMs) from non-allergic rats into AM-depleted allergic rats prevents airway hyperresponsiveness (AHR). We also showed that AMs from non-sensitized, but not from sensitized, allergy-prone rats can prevent AHR following allergen challenge in sensitized allergic animals, establishing the importance of rat immunological status on the modulation of AM functions and suggesting that an allergic lung environment alters AM functions. OBJECTIVE: We investigated how the activation of allergic AMs can be modulated to reinstitute them with their capacity to reduce AHR. METHODS: AMs from sensitized Brown Norway rats were cultured ex vivo for up to 18 h in culture media to deprogram them from the influence of the allergic lung before being reintroduced into the lung of AM-depleted sensitized recipient. AHR and cytokines in bronchoalveolar lavage (BAL) were measured following allergen challenge. AMs stimulated ex vivo with Bacillus Calmette-Guerin (BCG) were used as positive controls as BCG induces a T-helper type 1 activation in AMs. RESULTS: AMs ex vivo cultured for 4-18 h reduced AHR to normal level. Interestingly, pro-allergic functions of AMs were dampened by 18 h culture and they reduced AHR even after spending 48 h in an allergic lung microenvironment. Furthermore, transfer of cultured AMs caused an increase in the levels of IFN-gamma and IL-12 in BAL when compared with their ovalbumin control. After 18 h of ex vivo culture, AMs expressed reduced levels of TNF, IL-1alpha, IL-6, and Arginase-2 mRNAs compared with freshly isolated AMs, suggesting that ex vivo culture exempted AMs from lung stimuli that affected their functions. CONCLUSIONS: There is a significant crosstalk between lung microenvironment and AMs, affecting their functions. It is also the first report showing that sensitized AMs can be modulated ex vivo to reduce lung pro-allergic environment, opening the way to therapies targetting AMs.

Serotonin modulates the cytokine network in the lung: involvement of prostaglandin E2.

Serotonin, well known for its role in depression, has been shown to modulate immune responses. Interestingly, the plasma level of serotonin is increased in symptomatic asthmatic patients and the use of anti-depressants, known to reduce serotonin levels, provokes a decrease in asthma symptoms and an increase in pulmonary function. Thus, we tested the hypothesis that serotonin affects alveolar macrophage (AM) cytokine production, altering the cytokine network in the lung and contributing to asthma pathogenesis. AMs were treated with different concentrations of serotonin (10(-11)-10(-9) M) or 5-HT(1) and 5-HT(2) receptor agonists for 2 h prior stimulation. T helper 1 (Th1) and Th2 cytokines, prostaglandin-E(2) (PGE(2)) and nitric oxide (NO) were measured in cell-free supernatants. Serotonin significantly inhibited the production of tumour necrosis factor (TNF) and interleukin (IL)-12, whereas IL-10, NO and PGE(2) production were increased. These immunomodulatory effects of serotonin were mimicked by 5-HT(2) receptor agonist but were not abrogated by 5-HT(2) receptor antagonist, suggesting the implication of other 5-HT receptors. Inhibitors of cyclooxygenase and antibody to PGE(2) abrogated the inhibitory and stimulatory effect of serotonin on TNF and IL-10 production, respectively, whereas NO synthase inhibitor eliminated serotonin-stimulated IL-10 increase. Furthermore, PGE(2) significantly increased AM IL-10 and NO production. These results suggest that serotonin alters the cytokine network in the lung through the production of PGE(2). The reduction of Th1-type cytokine by serotonin may contribute to asthma pathogenesis.

[Assessment of knowledge in blood transfusion of medical staff in 14 state-run hospitals]. / Evaluation des connaissances médicales transfusionnelles dans 14 établissements publics de santé

UNLABELLED: This multi-centre study aimed to assess the knowledge in blood transfusion of medical staff in 14 state-run hospitals. MATERIALS AND METHODS: A questionnaire was distributed to all potential prescribers of blood products. It contained 35 questions concerning various subjects: blood products, immuno-haematology, prescription of blood products, transfusion practice, interpretation of the final bedside controls. The rate of correct answers (RCA) was obtained for each question, for each subject, and for nine questions defined as essential for patient safety. A weighted score was also calculated by ranking each question between one and six according to its importance. RESULTS: Six hundred and ninety four questionnaires were analysed (rate of return 15%). The RCA ranged from 14 to 89%, according to the questions. The RCA ranged from 47 to 78% for seven of the nine essential safety questions, and 82% and 83% for the two questions concerning the interpretation of incompatible final bedside controls: there were 9% of wrong answers, which validated an incompatible blood transfusion. The mean weighted score was 62%. Both the RCA and the weighted score were higher for those that regularly prescribe blood products than for that only prescribe them occasionally. There were no significant differences between hospitals. CONCLUSION: This study has confirmed that medical staff have deficiencies in their knowledge of blood transfusion, deficiencies which are acknowledged by medical staff. These first results will help the members of the study group to develop and prioritize various actions to improve this state of affairs, and to follow the effects of the training given.

Effects of phlebotomy therapy on cytochrome P450 2e1 activity and oxidative stress markers in dysmetabolic iron overload syndrome: a randomized trial.

AIM: To assess the effects of iron removal on cytochrome P450 2E1 activity and oxidative stress in dysmetabolic iron overload syndrome. METHODS: Forty-eight patients were randomized to phlebotomy therapy consisting of removal of 300-500 mL of blood every 14 days until serum ferritin levels dropped under 100 microg/L or to follow-up without phlebotomy therapy. Cytochrome P450 2E1 activity was measured at baseline and at the end of treatment by using the 6-hydroxychlorzoxazone/chlorzoxazone blood metabolic ratio, 2 h after the intake of 500 mg of chlorzoxazone. RESULTS: In the treatment group, a mean of 3.9 +/- 1.3 L of blood was removed and serum ferritin levels dropped from 715 +/- 397 to 74 +/- 34 microg/L. Variation of cytochrome P450 2E1 activity was not significantly different between the 2 groups (0.07 +/- 0.26 vs. 0.03 +/- 0.19, P = 0.36). In the treatment group, low-density lipoprotein cholesterol and vitamin E were lowered after treatment compared with control group (-0.15 +/- 0.51 vs. 0.24 +/- 0.58, P = 0.002 and -1.3 +/- 4.4 vs. 2.3 +/- 5.2, P = 0.03, respectively). Inversely, vitamin C was increased (0.5 +/- 3.5 vs. -1.8 +/- 3.9, P = 0.03). CONCLUSIONS: In dysmetabolic iron overload syndrome, reduction of iron stores does not significantly influence cytochrome P450 2E1 activity but is associated with a significant decrease of low-density lipoprotein cholesterol, suggesting that venesection therapy may be a suitable option in these patients.

Interleukin-4 production by human alveolar macrophages.

BACKGROUND: IL-4 is a key factor for T helper type 2 (Th2) differentiation and Ig class switching to IgE and IgG(4) during the development of immune responses. IL-4 is produced by T cells, mast cells, basophils, and eosinophils. However, there is also evidence suggesting that rat alveolar macrophages (AMs) produce IL-4. OBJECTIVE: Given the importance of AMs and Th2-related diseases in the lung, we investigated the production of IL-4 by human AMs. METHODS: Human AMs were isolated from bronchoalveolar lavage, purified, and IL-4 production was investigated at mRNA and protein levels using real-time PCR, flow cytometry, immunocytochemistry, and ELISA. The presence of IL-4 was investigated in subjects with asthma or asymptomatic airway hyper-responsiveness, and in normal non-smokers. RESULTS: IL-4 and IL-4delta2 (a splice variant found in other IL-4 producing cells) mRNAs were found in all these subjects, but IL-4 expression could not be correlated with a particular disease. Protein production was verified by immunocytochemistry and flow cytometry analysis demonstrating, respectively, up to 69% and 59% positive AMs, regardless of the subject condition. Furthermore, phorbol-12-myristate-13-acetate and calcium ionophore stimulated the release of IL-4 after 48 h treatment in the presence of anti-IL-4 receptor antibody. CONCLUSION: Our results show for the first time that IL-4 and IL-4delta2 mRNA are expressed and IL-4 protein produced and released by human AMs, suggesting a contribution of these cells in the modulation of Th2 immune response.

4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone, a component of tobacco smoke, modulates mediator release from human bronchial and alveolar epithelial cells.

Respiratory epithelial cells are known to contribute to immune responses through the release of mediators. The aim of this study was to characterize the immunomodulatory effects of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a tobacco carcinogen, on respiratory epithelial cells and to compare two metabolic pathways, alpha-methylhydroxylation and alpha-methylenehydroxylation, involved in these effects using selective precursors, 4-(acetoxy-methylnitrosamino)-1-(3-pyridil)-1-butanone (NNKOAc) and N-nitroso (acetoxymethyl) methylamine (NDMAOAc), respectively. Human bronchial and alveolar epithelial cell lines, BEAS-2B and A549, respectively, were treated with NNK, NNKOAc and NDMAOAc for 24 h with and without tumour necrosis factor (TNF) and mediators released in cell-free supernatants were measured by enzyme-linked immunosorbent assay (ELISA). NNK significantly inhibited interleukin (IL)-8, IL-6 and monocyte chemoattractant protein-1 (MCP-1) production in both cell types. Similar results were observed with primary bronchial and alveolar epithelial cells. Although NNK increased prostaglandin E(2) (PGE(2)) production by A549 cells, its immunomodulatory effects were not mediated by PGE(2) according to the results with cyclo-oxygenase inhibitors. NNKOAc mimicked NNK effects, whereas NDMAOAc significantly inhibited IL-8 production in BEAS-2B cells and MCP-1 in both cell types. These results demonstrate that NNK and its reactive metabolites have immunosuppressive effects on respiratory epithelial cells, which could contribute to the increased respiratory infections observed in smokers and the development and/or the progression of lung cancer.

PCT-233, a novel modulator of pro- and anti-inflammatory cytokine production.

Plant extracts have been implicated in various immunoregulatory effects that are poorly understood. Thus, we investigated the modulatory activity of PureCell Complex (PCT)-233, an active molecular complex from mesophyll tissue of Spinacia oleacea on the inflammatory process. Alveolar macrophages (AM) were treated with PCT-233 and/or budesonide, a well-known anti-inflammatory agent, before or after being stimulated with lipopolysaccharides (LPS). Pro- and anti-inflammatory cytokine production, tumour necrosis factor (TNF) and interleukin (IL)-10, respectively, were measured in cell-free supernatants at different times after the treatment. PCT-233 increased unstimulated AM release of both TNF and IL-10, whereas heat- and light-inactivated PCT-233 stimulated only the release of TNF without affecting IL-10 production, suggesting that different mechanisms are involved in the modulation of TNF and IL-10 release by PCT-233. The presence of LPS did not modify PCT-233-stimulated TNF production, but the ratio TNF/IL-10 production by LPS-stimulated AM was reduced significantly in the presence of PCT-233. Pretreatment of AM with PCT-233 and budesonide before LPS stimulation reduced TNF production at both protein and mRNA levels, whereas IL-10 production was increased. Moreover, TNF/IL-10 ratio was reduced further with the combination PCT-233/budesonide. Interestingly, AM treatment with PCT-233 and budesonide 18 h after LPS stimulation did not modulate TNF release significantly but it did increase IL-10 production, and a synergistic effect was observed with the combination PCT-233/budesonide. These exciting data suggest that PCT-233 possesses some anti-inflammatory properties, even when added during the inflammatory process, and could potentiate the effect of other anti-inflammatory agents.

Microbiological and inflammatory factors associated with the development of pneumococcal pneumonia.

Pneumococcal pneumonia still is associated with a high mortality rate, despite appropriate antimicrobial therapy. Many gaps remain in the understanding of the pathogenesis of this deadly infection. The microbial and inflammatory events that characterize survival or death after intranasal inoculation of mice with an LD(50) inoculum of Streptococcus pneumoniae were investigated. Survival was associated with rapid bacterial clearance and low inflammation (surfactant and red blood cells in alveoli), but no neutrophil recruitment or lung tissue injury was noted. By contrast, death was preceded by strong bacterial growth that peaked 48 h after the infection and was associated with gradual increases in pulmonary levels of interleukin-6, macrophage inflammatory protein (MIP)-1alpha, MIP-2, monocyte chemoattractant protein-1, KC, and neutrophil recruitment. The injection of tumor necrosis factor-alpha or the addition of lipopolysaccharide or heat-killed S. pneumoniae to the inoculum enhanced early host response and survival. These observations may help develop appropriate markers of evolution of pneumonia, as well as new therapeutic strategies.