Management of varices and variceal hemorrhage in liver cirrhosis: a recent update.

Cirrhosis consists of two main stages: compensated (asymptomatic) and decompensated, the latter with a higher mortality. Variceal hemorrhage, together with ascites or encephalopathy, or both, are events that define cirrhosis decompensation and are driven by portal hypertension. The approach and management of patients with compensated cirrhosis has been mostly focused on preventing variceal hemorrhage in those who have high-risk varices on endoscopy. Recent studies suggest a paradigm shift aimed at preventing all decompensating events, not only variceal hemorrhage, in patients with cirrhosis and clinically significant portal hypertension identified via noninvasive measures such as liver stiffness and platelet count. In these patients, nonselective beta-blockers have been shown to prevent ascites (the most common decompensating event) and variceal growth. Variceal hemorrhage has a high mortality rate and even though advances in diagnostic approach and standard of care over the past decades have led to a decrease in mortality, it is still high with a 6-week mortality rate of 15-20%. Survival has improved with the preemptive placement of the transjugular intrahepatic portosystemic shunt in patients at high risk of failing standard therapy. In this review, we provide an overview of the pathophysiology and bases for therapy of portal hypertension and varices, the diagnostic approach and management of compensated cirrhosis with clinically significant portal hypertension, and the management of acute variceal hemorrhage as well as prevention strategies for variceal hemorrhage recurrence.

Single-cell characterization of a model of poly I:C-stimulated peripheral blood mononuclear cells in severe asthma.

BACKGROUND: Asthma has been associated with impaired interferon response. Multiple cell types have been implicated in such response impairment and may be responsible for asthma immunopathology. However, existing models to study the immune response in asthma are limited by bulk profiling of cells. Our objective was to Characterize a model of peripheral blood mononuclear cells (PBMCs) of patients with severe asthma (SA) and its response to the TLR3 agonist Poly I:C using two single-cell methods. METHODS: Two complementary single-cell methods, DropSeq for single-cell RNA sequencing (scRNA-Seq) and mass cytometry (CyTOF), were used to profile PBMCs of SA patients and healthy controls (HC). Poly I:C-stimulated and unstimulated cells were analyzed in this study. RESULTS: PBMCs (n = 9414) from five SA (n = 6099) and three HC (n = 3315) were profiled using scRNA-Seq. Six main cell subsets, namely CD4 + T cells, CD8 + T cells, natural killer (NK) cells, B cells, dendritic cells (DCs), and monocytes, were identified. CD4 + T cells were the main cell type in SA and demonstrated a pro-inflammatory profile characterized by increased JAK1 expression. Following Poly I:C stimulation, PBMCs from SA had a robust induction of interferon pathways compared with HC. CyTOF profiling of Poly I:C stimulated and unstimulated PBMCs (n = 160,000) from the same individuals (SA = 5; HC = 3) demonstrated higher CD8 + and CD8 + effector T cells in SA at baseline, followed by a decrease of CD8 + effector T cells after poly I:C stimulation. CONCLUSIONS: Single-cell profiling of an in vitro model using PBMCs in patients with SA identified activation of pro-inflammatory pathways at baseline and strong response to Poly I:C, as well as quantitative changes in CD8 + effector cells. Thus, transcriptomic and cell quantitative changes are associated with immune cell heterogeneity in this model to evaluate interferon responses in severe asthma.

Premature, Opportune, and Delayed Weaning in Mechanically Ventilated Patients: A Call for Implementation of Weaning Protocols in Low- and Middle-Income Countries.

OBJECTIVES: Weaning protocols establish readiness-to-wean criteria to determine the opportune moment to conduct a spontaneous breathing trial. Weaning protocols have not been widely adopted or evaluated in ICUs in low- and middle-income countries. We sought to compare clinical outcomes between participants whose weaning trials were retrospectively determined to have been premature, opportune, or delayed based on when they met readiness-to-wean criteria. DESIGN: Prospective, multicenter observational study. SETTING: Five medical ICUs in four public hospitals in Lima, Perú. SUBJECTS: Adults with acute respiratory failure and at least 24 hours of invasive mechanical ventilation (n = 1,657). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We established six readiness-to-wean criteria and retrospectively categorized our sample into three weaning groups: 1) premature: if the weaning trial took place before fulfilling all criteria, 2) opportune: if the weaning trial took place within 24 hours after fulfilling the criteria, and 3) delayed: if the weaning trial took place over 24 hours after fulfilling criteria. We compared 90-day mortality, ventilator-free days, ICU-free days, and hospital-free days between premature, opportune, and delayed weaning groups. In our sample, 761 participants (60.8%) were classified as having a premature weaning trial, 196 underwent opportune weaning (15.7%), and 295 experienced delayed weaning (23.6%). There was no significant difference in 90-day mortality between the groups. Both the premature and delayed weaning groups had poorer clinical outcomes with fewer ventilator-free days (-2.18, p = 0.008) and (-3.49, p < 0.001), ICU-free days (-2.25, p = 0.001) and (-3.72, p < 0.001), and hospital-free days (-2.76, p = 0.044) and (-4.53, p = 0.004), respectively, compared with the opportune weaning group. CONCLUSIONS: Better clinical outcomes occur with opportune weaning compared with premature and delayed weaning. If readiness-to-wean criteria can be applied in resource-limited settings, it may improve ICU outcomes associated with opportune weaning.