Association of low-density neutrophils with lung function and disease progression in adult cystic fibrosis.

BACKGROUND: Cystic fibrosis (CF) neutrophils fail to eradicate infection despite their massive recruitment into the lung. While studies mostly focus on pathogen clearance by normal density neutrophils in CF, the contribution of low-density neutrophil (LDNs) subpopulations to disease pathogenesis remains unclear. METHODS: LDNs were isolated from whole blood donations of clinically stable adult CF patients and from healthy donors. LDN proportion and immunophenotype was assessed by flow cytometry. Associations of LDNs with clinical parameters were determined. RESULTS: LDN proportion was increased in CF patients' circulation compared with healthy donors. LDNs are a heterogeneous population of both mature and immature cells in CF and in healthy individuals. Moreover, a higher proportion of mature LDN correlates with a gradual decline in lung function and repeated pulmonary exacerbations in CF patients. CONCLUSIONS: Collectively, our observations suggest that low-density neutrophils are linked to CF pathogenesis and underscore the potential clinical relevance of neutrophil subpopulations in CF.

A Precision Medicine Approach to Optimize Modulator Therapy for Rare CFTR Folding Mutants.

Trikafta, a triple-combination drug, consisting of folding correctors VX-661 (tezacaftor), VX-445 (elexacaftor) and the gating potentiator VX-770 (ivacaftor) provided unprecedented clinical benefits for patients with the most common cystic fibrosis (CF) mutation, F508del. Trikafta indications were recently expanded to additional 177 mutations in the CF transmembrane conductance regulator (CFTR). To minimize life-long pharmacological and financial burden of drug administration, if possible, we determined the necessary and sufficient modulator combination that can achieve maximal benefit in preclinical setting for selected mutants. To this end, the biochemical and functional rescue of single corrector-responsive rare mutants were investigated in a bronchial epithelial cell line and patient-derived human primary nasal epithelia (HNE), respectively. The plasma membrane density of P67L-, L206W- or S549R-CFTR corrected by VX-661 or other type I correctors was moderately increased by VX-445. Short-circuit current measurements of HNE, however, uncovered that correction comparable to Trikafta was achieved for S549R-CFTR by VX-661 + VX-770 and for P67L- and L206W-CFTR by the VX-661 + VX-445 combination. Thus, introduction of a third modulator may not provide additional benefit for patients with a subset of rare CFTR missense mutations. These results also underscore that HNE, as a precision medicine model, enable the optimization of mutation-specific modulator combinations to maximize their efficacy and minimize life-long drug exposure of CF patients.

Cystic fibrosis-related diabetes onset can be predicted using biomarkers measured at birth.

PURPOSE: Cystic fibrosis (CF), caused by pathogenic variants in the CF transmembrane conductance regulator (CFTR), affects multiple organs including the exocrine pancreas, which is a causal contributor to cystic fibrosis-related diabetes (CFRD). Untreated CFRD causes increased CF-related mortality whereas early detection can improve outcomes. METHODS: Using genetic and easily accessible clinical measures available at birth, we constructed a CFRD prediction model using the Canadian CF Gene Modifier Study (CGS; n = 1,958) and validated it in the French CF Gene Modifier Study (FGMS; n = 1,003). We investigated genetic variants shown to associate with CF disease severity across multiple organs in genome-wide association studies. RESULTS: The strongest predictors included sex, CFTR severity score, and several genetic variants including one annotated to PRSS1, which encodes cationic trypsinogen. The final model defined in the CGS shows excellent agreement when validated on the FGMS, and the risk classifier shows slightly better performance at predicting CFRD risk later in life in both studies. CONCLUSION: We demonstrated clinical utility by comparing CFRD prevalence rates between the top 10% of individuals with the highest risk and the bottom 10% with the lowest risk. A web-based application was developed to provide practitioners with patient-specific CFRD risk to guide CFRD monitoring and treatment.

Assessment of management of cardiovascular risk factors in patients with thoracic aortic disease.

BACKGROUND: Cardiovascular risk profiles and adiposity assessment data in patients with thoracic aortic disease (TAD) are sparse. HYPOTHESIS: Despite the fact that TAD patients are considered as a high-risk population, they will not be managed as aggressively as they should in terms of their cardiovascular risk profile. MATERIALS AND METHODS: Anthropometric, blood pressure (BP) data, and blood samples were collected prospectively from patients followed at our TAD dedicated clinic. The same measures have been taken in a control group initiating a cardiac rehabilitation program. RESULTS: In all, 286 patients with TAD and 116 controls were recruited. BMI was higher among the controls than the patients with TAD (30.0±6.1 vs. 27.2±4.9 kg/m(2), respectively; P<0.001). We found no statistical difference between the groups for waist circumference (TAD: 93.1±15.2 and 103.6±14.5 cm, control: 95.0±13.4 and 106.3±14.8 cm, respectively, for women and men; P=0.06). In terms of lipid profile, low-density lipoprotein cholesterol was 2.44±0.88 in patients with TAD and 2.09±0.82 mmol/l in the controls (P<0.001). A higher percentage of patients with TAD had low-density lipoprotein cholesterol values that were beyond the target (63.3% in TAD vs. 46.1% in control; P<0.01). The values of apolipoprotein-B were similar between groups (P=0.41). BP was higher in patients with TAD (135±19/76±11 mmHg) versus the controls (129±17/71±11 mmHg; P<0.01). On the basis of ambulatory BP monitoring, 49.3% of patients with TAD were not well controlled for daytime and/or night-time BP. CONCLUSION: Cardiovascular risk factors, particularly BP, are not well controlled in patients with TAD followed in a dedicated clinic when compared with another high-risk control group in a cardiac rehabilitation program.

Effectiveness of a pedometer-based program using a socio-cognitive intervention on physical activity and quality of life in a setting of cardiac rehabilitation.

BACKGROUND: Physical activity contributes to improve health and quality of life. However, the prevalence of sedentary lifestyle is elevated after an acute coronary syndrome. METHODS: A randomized controlled trial was performed to evaluate the impact of a pedometer-based program associated with a socio-cognitive intervention on physical activity behaviour, cardiovascular risk factors, and quality of life during the year after an acute coronary syndrome event. During hospitalization, we randomized 32 patients to an experimental group and 33 patients to a usual care group. The experimental intervention included 6 consultations with a clinical nurse specialist during 12 months. RESULTS: Groups characteristics were comparable. At baseline, the percentage of participants considered in the active range category was similar between groups (31% vs 41%; P = 0.915). However, the proportion of participants who were still active was greater in the experimental group than in the usual care group at 6, 9, and 12 months follow-up (75% vs 41%; 68% vs 36%, and 83% vs 55%, respectively; P < 0.05). After 12 months, changes in overall quality of life and in health and the functioning scores were different between groups (interaction effects [groups by time] P = 0.048 and P = 0.036, respectively). CONCLUSIONS: The use of a pedometer concomitantly with a socio-cognitive intervention improves adherence to physical activity and quality of life during the year after an acute coronary syndrome event. This finding is relevant because physical activity and quality of life are a great concern in preventive cardiology. These results support applying this innovative approach in cardiac rehabilitation programs.

Innovative program to increase physical activity following an acute coronary syndrome: randomized controlled trial.

OBJECTIVE: To evaluate the impact of a socio-cognitive intervention associated with a pedometer-based program on physical activity, cardiovascular risk factors and self-efficacy expectation during one year following an acute coronary syndrome. METHODS: Sixty-five subjects were randomized during hospitalization in an experimental or a usual care group. Average steps/day was measured every 3 months until one year following discharge. Other dependent variables were measured at baseline, 6 and 12 months follow-up. RESULTS: There were 32 patients in the experimental group and 33 patients in the usual care group. Group characteristics were comparable. At baseline, averages steps/day were similar between groups (5845±3246 vs. 6097±3055 steps/day; p=0.812). At 3-month follow-up, both groups increased their averages steps/day (p<0.05). This increase was higher in the experimental group (3388±844 vs. 1934±889 steps/day; p<0.001). At 12-month, interaction effects (group×time) in physical activity and waist circumference were different between groups (p<0.05), whereas self-efficacy expectation increased in both groups similarly (p<0.05). CONCLUSION: The intervention is useful to improve average steps/day and waist circumference during the first year following an acute coronary syndrome. PRACTICE IMPLICATIONS: This study supports development of the home-based cardiac rehabilitation program using socio-cognitive intervention associated with a pedometer after an acute coronary syndrome.

Pro-inflammatory cytokine and chemokine release by human brain microvascular endothelial cells stimulated by Streptococcus suis serotype 2.

Streptococcus suis serotype 2 is a world-wide agent of diseases among pigs including meningitis, septicemia and arthritis. This microorganism is also recognized as an important zoonotic agent. The pathogenesis of the meningitis caused by S. suis is poorly understood. We have previously shown that S. suis is able to adhere to human brain microvascular endothelial cells (BMEC), but not to human umbilical vein endothelial cells (HUVEC). The objective of this work was to study the ability of S. suis serotype 2 to induce the release of the pro-inflammatory cytokines tumor necrosis factor alpha (TNF-alpha), interleukin-1 (IL-1); IL-6 and the chemokines IL-8 and monocyte chemotactic protein-1 (MCP-1) by human BMEC and HUVEC, using a sandwich enzyme-linked immunosorbent assay. S. suis was able to stimulate the production of IL-6, IL-8 and MCP-1 by BMEC but not HUVEC, in a time- and concentration-dependent manner. Bacterial cell wall components were largely responsible for such stimulation. The human and pig origin of strains does not seem to affect the intensity of the response; indeed, a very heterogeneous pattern of cytokine and chemokine production was observed for the different strains tested in this study. In situ production of cytokines and chemokines by BMEC may be the result of specific adhesion of S. suis to this cell type, with several consequences such as increased recruitment of leukocytes and an increase in the blood-brain barrier permeability.