Personalized pathology test for Cardio-vascular disease: Approximate Bayesian computation with discriminative summary statistics learning.

Cardio/cerebrovascular diseases (CVD) have become one of the major health issue in our societies. But recent studies show that the present pathology tests to detect CVD are ineffectual as they do not consider different stages of platelet activation or the molecular dynamics involved in platelet interactions and are incapable to consider inter-individual variability. Here we propose a stochastic platelet deposition model and an inferential scheme to estimate the biologically meaningful model parameters using approximate Bayesian computation with a summary statistic that maximally discriminates between different types of patients. Inferred parameters from data collected on healthy volunteers and different patient types help us to identify specific biological parameters and hence biological reasoning behind the dysfunction for each type of patients. This work opens up an unprecedented opportunity of personalized pathology test for CVD detection and medical treatment.

Systematic qualitative review of randomised trials conducted in nonsmall cell lung cancer with a noninferiority or equivalence design.

The use of noninferiority randomised trials for patients with advanced non-small cell lung cancer has emerged during the past 10-15 years but has raised some issues related to their justification and methodology. The present systematic review aimed to assess trial characteristics and methodological aspects. All randomised clinical trials with a hypothesis of noninferiority/equivalence, published in English, were identified. Several readers extracted a priori defined methodological information. A qualitative analysis was then performed. We identified 20 randomised clinical trials (three phase II and 17 phase III), 11 of them being conducted in strong collaboration with industry. We highlighted some deficiencies in the reports like the lack of justification for both the noninferiority assumption and the definition of the noninferiority margin, as well as inconsistencies between the results and the authors' conclusions. CONSORT guidelines were better followed for general items than for specific items (p<0.001). Improvement in the reporting of the meth"odology of noninferiority/equivalence trials is needed to avoid misleading interpretation and to allow readers to be fully aware of the assumptions underlying the trial designs. They should be restricted to limited specific situations with a strong justification why a noninferiority hypothesis is acceptable.

Myeloperoxidase-dependent LDL modifications in bloodstream are mainly predicted by angiotensin II, adiponectin, and myeloperoxidase activity: a cross-sectional study in men.

The present paradigm of atherogenesis proposes that low density lipoproteins (LDLs) are trapped in subendothelial space of the vascular wall where they are oxidized. Previously, we showed that oxidation is not restricted to the subendothelial location. Myeloperoxidase (MPO), an enzyme secreted by neutrophils and macrophages, can modify LDL (Mox-LDL) at the surface of endothelial cells. In addition we observed that the activation of the endothelial cells by angiotensin II amplifies this process. We suggested that induction of the NADPH oxidase complex was a major step in the oxidative process. Based on these data, we asked whether there was an independent association, in 121 patients, between NADPH oxidase modulators, such as angiotensin II, adiponectin, and levels of circulating Mox-LDL. Our observations suggest that the combination of blood angiotensin II, MPO activity, and adiponectin explains, at least partially, serum Mox-LDL levels.

Spherization of red blood cells and platelet margination in COPD patients.

Red blood cells (RBCs) in pathological situations undergo biochemical and conformational changes, leading to alterations in rheology involved in cardiovascular events. The shape of RBCs in volunteers and stable and exacerbated chronic obstructive pulmonary disease (COPD) patients was analyzed. The effects of RBC spherization on platelet transport (displacement in the flow field caused by their interaction with RBCs) were studied in vitro and by numerical simulations. RBC spherization was observed in COPD patients compared with volunteers. In in vitro experiments at a shear rate of 100 s-1 , treatment of RBCs with neuraminidase induced greater sphericity, which mainly affected platelet aggregates without changing aggregate size. At 400 s-1 , neuraminidase treatment changes both the size of the aggregates and the number of platelet aggregates. Numerical simulations indicated that RBC spherization induces an increase of the platelet mean square displacement, which is traditionally linked to the platelet diffusion coefficient. RBCs of COPD patients are more spherical than healthy volunteers. Experimentally, RBC spherization induces increased platelet transport to the wall. Additional studies are needed to understand the link between the effect of RBCs on platelet transport and the increased cardiovascular events observed in COPD patients.

Heme oxygenase-1 (HO-1) cytoprotective pathway: A potential treatment strategy against coronavirus disease 2019 (COVID-19)-induced cytokine storm syndrome.

The outbreak of coronavirus disease 2019 (COVID-19) requires urgent need for effective treatment. Severe COVID-19 is characterized by a cytokine storm syndrome with subsequent multiple organ failure (MOF) and acute respiratory distress syndrome (ARDS), which may lead to intensive care unit and increased risk of death. While awaiting a vaccine, targeting COVID-19-induced cytokine storm syndrome appears currently as the efficient strategy to reduce the mortality of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The stress-responsive enzyme, heme oxygenase-1 (HO-1) is largely known to protect against inflammatory response in animal models. HO-1 is induced by hemin, a well-tolerated molecule, used for decades in the treatment of acute intermittent porphyria. Experimental studies showed that hemin-induced HO-1 mitigates cytokine storm and lung injury in mouse models of sepsis and renal ischemia-reperfusion injury. Furthermore, HO-1 may also control numerous viral infections by inhibiting virus replication. In this context, we suggest the hypothesis that HO-1 cytoprotective pathway might be a promising target to control SARS-CoV-2 infection and mitigate COVID-19-induced cytokine storm and subsequent ARDS.

Real-life effectiveness of omalizumab in difficult-to-treat versus severe asthma: a national cohort study in Belgium.

BACKGROUND: Guidelines recommend omalizumab in patients with uncontrolled severe allergic asthma. We investigated real-life use of omalizumab, the proportion of patients fulfilling eligibility criteria, its costs and its effectiveness. METHOD: In a cohort of asthma patients initiating treatment with omalizumab in Belgium between 2010 and 2016, we investigated fulfilment of eligibility criteria (chronic use of high-dose inhaled corticosteroids (ICSs) plus long-acting ß2-agonists (LABAs) and ≥2 severe asthma exacerbations in previous year), and compared hospitalisations and systemic corticosteroid consumption in the year before and after omalizumab initiation. We computed healthcare costs in the respective time periods and compared the cost per prevented hospitalisation in patients fulfilling eligibility criteria versus those who did not. RESULTS: Between 2010 and 2016, omalizumab treatment was initiated in 2068 patients with asthma; only 24% fulfilled the eligibility criteria, mainly due to nonadherence to high-dose ICSs + LABAs. The proportion of patients hospitalised for asthma decreased from 41% to 21% in eligible patients (absolute risk reduction, 20%), whereas the absolute risk reduction was 5% (from 19% to 14%) in noneligible patients. The cost per prevented hospitalisation was €44 238 versus €139 495, respectively. Chronic use of systemic corticosteroids was discontinued in 35% of eligible patients versus 15% of noneligible patients. CONCLUSION: In Belgium, omalizumab is mostly initiated in uncontrolled asthma patients who are nonadherent to ICSs + LABAs. Omalizumab decreases hospitalisations and the use of systemic corticosteroids, but at a high cost. Careful management of patients with difficult-to-treat asthma should be a priority before prescribing omalizumab.

The impact of continuous positive airway pressure on blood pressure in patients with obstructive sleep apnea syndrome: evidence from a meta-analysis of placebo-controlled randomized trials.

BACKGROUND: Continuous positive airway pressure (CPAP) in patients with obstructive sleep apnea syndrome (OSAS) might lower blood pressure, but evidence from clinical studies is inconsistent, perhaps as a result of small sample size or heterogeneity in study design. This study aimed to assess whether CPAP reduces ambulatory blood pressure in patients with OSAS, to quantify the effect size with precision, and to identify trial characteristics associated with the greatest blood pressure reductions. METHODS: We identified randomized controlled trials of CPAP vs placebo in patients with OSAS specifically reporting 24-hour ambulatory mean blood pressure (MBP). RESULTS: We included a total of 572 patients from 12 randomized controlled trials. According to a random-effects model, the pooled estimate of the effect of the CPAP intervention was a net decrease of 1.69 mm Hg in 24-hour MBP (95% confidence interval, -2.69 to -0.69). Statistical heterogeneity was moderate (I(2) = 41%). Predefined metaregression analyses estimated that 24-hour MBP would decrease by 0.89 mm Hg per 10-point increase in apnea-hypopnea index at entry (P = .006), by 0.74 mm Hg for each increase of 10 arousal events per hour slept (P = .008), and by 1.39 mm Hg for each 1-hour increase in effective nightly use of the CPAP device (P = .01). CONCLUSIONS: Among patients with OSAS, CPAP reduces 24-hour ambulatory MBP, with greater treatment-related reductions in ambulatory MBP among patients with a more severe degree of OSAS and a better effective nightly use of the CPAP device. These reductions in blood pressure are likely to contribute to a better prognosis in terms of adverse cardiovascular events.

Tracheotomy: clinical review and guidelines.

Tracheotomy is a commonly performed procedure. The Belgian Society of Pneumology (BVP-SBP) and the Belgian Association for Cardiothoracic Surgery (BACTS) developed guidelines on tracheotomy for mechanical ventilation in adults. The levels of evidence as developed by the American College of Chest Physicians (ACCP) were used. The members of the guideline committee reviewed peer-reviewed publications on this subject. After discussion, a proposal of guidelines was placed on the website for remarks and suggestions of the members. Remarks and suggestions were discussed and used to adapt the guidelines when judged necessary. The different techniques of tracheotomy are described. The potential advantages and disadvantages of surgical and percutaneous tracheotomy versus endotracheal intubation are discussed. An overview of early and late complications is given. Low-pressure, high-volume cuffs should be used. The cuff pressure should be monitored with calibrated devices and recorded at least once every nursing shift and after manipulation of the tracheotomy tubes. Inspired gas should be humidified and heated. Regarding the timing of tracheotomy there are not enough well-designed studies to establish clear guidelines. Therefore, the timing of tracheotomy should be individualised. In critically ill adult patients requiring prolonged mechanical ventilation, tracheotomy performed at an early stage (within the first week) may shorten the duration of artificial ventilation and length of stay in intensive care. Percutaneous dilatational tracheotomy (PDT) appears to be at least as safe as surgical tracheotomy (ST) as measured in terms of peri-procedural complications. With PDT, less wound infection is observed. When PDT is compared to ST performed in the operating room, PDT is less expensive, reduces the time between the decision and the performance of tracheotomy and has a lower mortality rate. Different techniques of PDT are discussed. We recommend performing PDT under bronchoscopic guidance. Because of its technical simplicity and short procedure time, the modified Ciaglia Blue Rhino technique is advocated as technique of choice. PDT should be considered the procedure of choice in elective non-urgent tracheotomy. There are some relative contraindications for PDT, but with growing experience, they become less frequent.

A new device to mimic intermittent hypoxia in mice.

Intermittent hypoxia (hypoxia-reoxygenation) is often associated with cardiovascular morbidity and mortality. We describe a new device which can be used to submit cohorts of mice to controlled and standardised hypoxia-normoxia cycles at an individual level. Mice were placed in individual compartments to which similar gas flow parameters were provided using an open loop strategy. Evaluations made using computational fluid dynamics were confirmed by studying changes in haemoglobin oxygen saturation in vivo. We also modified the parameters of the system and demonstrated its ability to generate different severities of cyclic hypoxemia very precisely, even with very high frequency cycles of hypoxia-reoxygenation. The importance of the parameters on reoxygenation was shown. This device will allow investigators to assess the effects of hypoxia-reoxygenation on different pathological conditions, such as obstructive sleep apnoea or chronic obstructive pulmonary disease.

Subclinical thyroid dysfunction and mortality: an estimate of relative and absolute excess all-cause mortality based on time-to-event data from cohort studies.

OBJECTIVES: To what extent persons with subclinical hyper- or hypothyroidism are more (or less) likely to die than euthyroid control subjects remains a matter of controversy. METHODS: We searched electronic reference databases up to July 31, 2007. Three reviewers independently assessed eligibility. Cohort studies published in full that reported data on the hazard ratio (HR) for mortality from all causes in persons with subclinical thyroid dysfunction versus euthyroid controls were included. RESULTS: Based on seven cohorts including 290 participants with subclinical hyperthyroidism, random-effects models estimated that the pooled HR for all-cause mortality was 1.41 (95% confidence interval (CI), 1.12-1.79; P=0.004). Using the pooled HR and standard life-table methods applied to a US reference population, we estimated that a white US woman, when diagnosed with subclinical hyperthyroidism at age of 70, has an excess mortality of 1.5, 4.0, and 8.7% at 2, 5, and 10 years respectively after diagnosis. Likewise, a white US man has an excess mortality of 2.3, 5.7, and 10.7%. For the nine cohorts including 1580 participants with subclinical hypothyroidism, observed heterogeneity (Q test P=0.006; I(2)=63%) disappeared after pooling cohorts in predefined subgroups according to the presence or absence of a comorbid condition. In doing so, the pooled HR for all-cause mortality was 1.03 (95% CI, 0.78-1.35; P=0.83) in cohorts from the community and 1.76 (95% CI, 1.36-2.30; P<0.001) in cohorts of participants with comorbidities (P=0.014 for heterogeneity among study groups). CONCLUSIONS: Individuals with subclinical hyperthyroidism demonstrate a 41% increase in relative mortality from all causes versus euthyroid control subjects. Mathematical modeling suggests that absolute excess mortality after diagnosis might depend on age, with an increase beyond the age of 60, especially in aging men. For patients with subclinical hypothyroidism, the relative risk of all-cause mortality is increased only in patients with comorbid conditions.

Sleep apnoea-hypopnoea index is an independent predictor of high-sensitivity C-reactive protein elevation.

BACKGROUND: Recent reports have identified the apnoea and hypopnoea index (AHI) as an additional independent risk factor for cardiovascular morbidity and mortality. However, several studies reported contradictory results about the association between the serum C-reactive protein (CRP) level and the severity of apnoea. OBJECTIVE: The purpose of this work is to study this association in patients referred to the sleep laboratory for clinical suspicion of sleep apnoea and presenting a wide range of AHI. METHODS: Forty-nine consecutive patients were included in the study. The SigmaStat software package (Jandle Scientific) was used. Multilinear regression analysis was tested using a stepwise backward selection of the explicative variables. The clinical characteristics (diabetes, hypertension, smoking habits, gender) were treated as dichotomous variables, while all other data (age, BMI, lipids, white blood cells) were continuous ones; high-sensitivity (hs)-CRP was the dependent variable. RESULTS: In univariate analysis, AHI was correlated to hs-CRP: R = 0.43, p = 0.002. In multivariate analyses, we found an independent association between the AHI, adjusted for classical cardiovascular risk factors, and hs-CRP. CONCLUSION: In a sample of 49 patients, referred to the sleep laboratory for suspicion of sleep apnoea in routine practice, we observed an independent association between the AHI and hs-CRP.