Methodology for Constructing a Short-Term Event Risk Score in Heart Failure Patients

We present a methodology for constructing a short-term event risk score in heart failure patients from an ensemble predictor, using bootstrap samples, two different classification rules, logistic regression and linear discriminant analysis for mixed data, continuous or categorical, and random selection of explanatory variables to build individual predictors. We define a measure of the importance of each variable in the score and an event risk measure by an odds-ratio. Moreover, we establish a property of linear discriminant analysis for mixed data. This methodology is applied to EPHESUS trial patients on whom biological, clinical and medical history variables were measured.

Construction of Parsimonious Event Risk Scores by an Ensemble Method. An Illustration for Short-Term Predictions in Chronic Heart Failure Patients from the GISSI-HF Trial

Selecting which explanatory variables to include in a given score is a common difficulty, as a balance must be found between statistical fit and practical application. This article presents a methodology for constructing parsimonious event risk scores combining a stepwise selection of variables with ensemble scores obtained by aggregation of several scores, using several classifiers, bootstrap samples and various modalities of random selection of variables. Selection methods based on a probabilistic model can be used to achieve a stepwise selection for a given classifier such as logistic regression, but not directly for an ensemble classifier constructed by aggregation of several classifiers. Three selection methods are proposed in this framework, two involving a backward selection of the variables based on their coefficients in an ensemble score and the third involving a forward selection of the variables maximizing the AUC. The stepwise selection allows constructing a succession of scores, with the practitioner able to choose which score best fits his needs. These three methods are compared in an application to construct parsimonious short-term event risk scores in chronic HF patients, using as event the composite endpoint of death or hospitalization for worsening HF within 180 days of a visit. Focusing on the fastest method, four scores are constructed, yielding out-of-bag AUCs ranging from 0.81 (26 variables) to 0.76 (2 variables).

Allogeneic stem cell transplantation-A curative treatment for paroxysmal nocturnal hemoglobinuria with PIGT mutation:A case report

BACKGROUND Patients with paroxysmal nocturnal hemoglobinuria(PNH)have a clonal population of blood cells deficient in glycosylphosphatidylinositol-anchored(GPIanchored)proteins,most of the time resulting from a mutation in the X-linked gene PIGA.We report a patient with PNH resulting from a rare biallelic PIGT mutation on chromosome 20.CASE SUMMARY A 47-year-old man was referred to our hospital for febrile pancytopenia.The patient reported a history of recurrent urticaria and arthralgia and he presented during 3 mo recurrent acute dermo-hypodermitis and aseptic meningitidis.Based on clinical cases published with PIGT-PNH,with clinically typical PNH and autoinflammatory symptoms,we treated our patients with repeated infusions of eculizumab to decrease autoinflammatory symptoms and then we performed an allogeneic stem cell transplantation(allo-SCT)with a mismatched unrelated donor.Our patient experienced no acute Graft vs Host disease(GvHD)and a moderate chronic GvHD and is now considered cured at 24 mo after allo-SCT.CONCLUSION This case report suggests that allo-SCT should be considered to cure PIGT-PNH patients.

Construction and Update of an Online Ensemble Score Involving Linear Discriminant Analysis and Logistic Regression

The present aim is to update, upon arrival of new learning data, the parameters of a score constructed with an ensemble method involving linear discriminant analysis and logistic regression in an online setting, without the need to store all of the previously obtained data. Poisson bootstrap and stochastic approximation processes were used with online standardized data to avoid numerical explosions, the convergence of which has been established theoretically. This empirical convergence of online ensemble scores to a reference “batch” score was studied on five different datasets from which data streams were simulated, comparing six different processes to construct the online scores. For each score, 50 replications using a total of 10N observations (N being the size of the dataset) were performed to assess the convergence and the stability of the method, computing the mean and standard deviation of a convergence criterion. A complementary study using 100N observations was also performed. All tested processes on all datasets converged after N iterations, except for one process on one dataset. The best processes were averaged processes using online standardized data and a piecewise constant step-size.

The medical treatment of cardiogenic shock

Cardiogenic shock (CS) is a leading cause of mortality worldwide. CS presentation and management in the current era have been widely depicted in epidemiological studies. Its treatment is codified and relies on medical care and extracorporeal life support (ECLS) in the bridge to recovery, chronic mechanical device therapy, or transplantation. Recent improvements have changed the landscape of CS. The present analysis aims to review current medical treatments of CS in light of recent literature, including addressing excitation–contraction coupling and specific physiology on applied hemodynamics. Inotropism, vasopressor use, and immunomodulation are discussed as pre-clinical and clinical studies have focused on new therapeutic options to improve patient outcomes. Certain underlying conditions of CS, such as hypertrophic or Takotsubo cardiomyopathy, warrant specifically tailored management that will be overviewed in this review.

Potentiation of NETs release is novel characteristic of TREM-1 activation and the pharmacological inhibition of TREM-1 could prevent from the deleterious consequences of NETs release in sepsis

During sepsis,neutrophil activation induces endothelial cell(EC)dysfunction partly through neutrophil extracellular trap(NET)release.The triggering receptor expressed on myeloid cell-1(TREM-1)is an orphan immune receptor that amplifies the inflammatory response mediated by Toll-like receptor-4(TLR4)engagement.Although the key role of TLR4 signaling in NETosis is known,the role of TREM-1 in this process has not yet been investigated.Here,we report that TREM-1 potentiates NET release by human and murine neutrophils and is a component of the NET structure.In contrast,pharmacologic inhibition or genetic ablation of TREM-1 decreased NETosis in vitro and during experimental septic shock in vivo.Moreover,isolated NETs were able to activate ECs and impair vascular reactivity,and these deleterious effects were dampened by TREM-1 inhibition.TREM-1 may,therefore,constitute a new therapeutic target to prevent NETosis and associated endothelial dysfunction.

sTREM-1 is a specific biomarker of TREM-1 pathway activation

TREM-1(triggering receptor expressed on myeloid cells-1)is a transmembrane receptor expressed by innate immune cells,including endothelial cells and platelets.TREM-1 is a crucial mediator of septic shock that acts by synergizing with Toll-like receptors(TLRs)to amplify the inflammatory responses to pathogens,thus promoting sepsis-induced immune dysregulation and organ dysfunction[1,2,3].

Advanced nonmetastatic hepatocellular carcinoma: curative surgery may be an option

In this multicentric retrospective study(1),the authors aimed to compare surgery versus Sorafenib(SOR)for the treatment of advanced nonmetastatic hepatocellular carcinoma(HCC).Data were collected from two Italian registries,between 2008 and 2019.

Beta-blockers in septic shock: What is new?

The use of beta(β)-blockers during septic shock aimed at countering peripheral adrenergic stress may be justified by the early reduction in deleterious effects resulting from sympathetic overactivation,and could improve the prognosis of patients in septic shock.Animal studies have demonstrated either a maintenance or increase in cardiac output(CO)despite the decrease in heart rate(HR)associated with improved myocardial performance.The mechanism by which𝛽-blockers alter hemodynamics in septic shock is debated;however,preclinical and clinical data show that𝛽-blockers are safe when started at a low dose.Recent publications(2019-2021)on adrenergic𝛽1 receptor antagonists used in septic shock indicate that esmolol and landiolol should not be used in the early phase.While there is no optimal timing for their administration,a minimum of 12 h after the initiation of vasopressor therapy in stabilized euvolemic patients is a reasonable option.Patients should have a normal cardiac function,although a slight depression is compatible with landiolol use under hemodynamic monitoring.Slow titration in patients who remain tachycardic is preferable to rapid titration.When used to decrease HR,landiolol is also effective in reducing the incidence of new arrhythmias.Results of a well-performed and well-powered randomized controlled trial(RCT)demonstrating a positive effect on survival-or at least on hard surrogates such as the incidence/duration of organ failure-are pending.