Omineca Herald, May, 23, 1924

Background: LKB1 mutations are the underlying genetic abnormality causing Peutz-Jeghers syndrome (PJS) and are a potential target for everolimus. In this phase II study, the efficacy of everolimus on polyp and tumor growth in PJS patients was investigated. Methods: Adult patients with a proven LKB1 mutation and who were suitable for everolimus treatment were included in two different PJS cohorts: (a) patients with unresectable malignancies and (b) patients with high-risk polyps. Treatment in both groups was oral everolimus, 10 mg daily. Response rates were primary endpoints for both cohorts. Results: Between October 2011 and April 2016, only two patients were enrolled, one in each cohort. A 49-year-old patient with advanced pancreatic cancer in cohort 1 was progressive after 2 months. A 52-year-old male patient in cohort 2 experienced severe toxicity and refused treatment after 4 months, even though endoscopy suggested stabilization of polyps. Adverse

Monocyte state 1 (MS1) cells in critically ill patients with sepsis or non-infectious conditions: association with disease course and host response

Background: Sepsis is a life-threatening condition arising from an aberrant host response to infection. Recent single-cell RNA sequencing investigations identified an immature bone-marrow-derived CD14+ monocyte phenotype with immune suppressive properties termed “monocyte state 1” (MS1) in patients with sepsis. Our objective was to determine the association of MS1 cell profiles with disease presentation, outcomes, and host response characteristics. Methods: We used the transcriptome deconvolution method (CIBERSORTx) to estimate the percentage of MS1 cells from blood RNA profiles of patients with sepsis admitted to the intensive care unit (ICU). We compared these profiles to ICU patients without infection and to healthy controls. Host response dysregulation was further studied by gene co-expression network and gene set enrichment analyses of blood leukocytes, and measurement of 15 plasma biomarkers indicative of pathways implicated in sepsis pathogenesis. Results: Sepsis patients (n = 332) were divided into three equally-sized groups based on their MS1 cell levels (low, intermediate, and high). MS1 groups did not differ in demographics or comorbidities. The intermediate and high MS1 groups presented with higher disease severity and more often had shock. MS1 cell abundance did not differ between survivors and non-survivors, or between patients who did or did not acquire a secondary infection. Higher MS1 cell percentages were associated with downregulation of lymphocyte-related and interferon response genes in blood leukocytes, with concurrent upregulation of inflammatory response pathways, including tumor necrosis factor signaling via nuclear factor-κB. Previously described sepsis host response transcriptomic subtypes showed different MS1 cell abundances, and MS1 cell percentages positively correlated with the “quantitative sepsis response signature” and “molecular degree of perturbation” scores. Plasma biomarker levels, indicative of inflammation, endothelial cell activation, and coagulation activation, were largely similar between MS1 groups. In ICU patients without infection (n = 215), MS1 cell percentages and their relation with disease severity, shock, and host response dysregulation were highly similar to those in sepsis patients. Conclusions: High MS1 cell percentages are associated with increased disease severity and shock in critically ill patients with sepsis or a non-infectious condition. High MS1 cell abundance likely indicates broad immune dysregulation, entailing not only immunosuppression but also anomalies reflecting exaggerated inflammatory responses. Graphical abstract: (Figure presented.

Pre-PCI versus immediate post-PCI Impella initiation in acute myocardial infarction complicated by cardiogenic shock

BACKGROUND: In selected patients with an acute myocardial infarction (AMI) complicated by Cardiogenic shock (CS), mechanical circulatory support with Impella may be beneficial, although conclusive evidence is still lacking. Nevertheless, it has been suggested that Impella initiation prior to primary PCI might improve survival. OBJECTIVE: To investigate the effect pre-PCI versus immediate post-PCI Impella initiation on short term mortality. METHODS: A prospective, single center, observational study, was performed including all patients with STEMI complicated by CS, treated with primary PCI and Impella. Thirty day mortality was compared between patients with Impella initiation pre-PCI and immediately post-PCI. RESULTS: A total of 88 patients were included. In the pre-PCI group (n = 21), admission heart rate was lower (84 versus 94 bpm, p = 0.04) and no IABP was implanted before Impella initiation, versus 17.9% in post-PCI group (n = 67), p = 0.04. Total 30-day all-cause mortality was 58%, and was lower in pre-PCI group, 47.6% versus 61.2% in the post-PCI group, however not statistically significant (HR 0.7, 95% CI 0.3-1.3, p = 0.21). Thirty-day cardiac mortality was significantly lower in the pre-PCI group, 19% versus 44.7% in the post-PCI group (HR 0.3, 95% CI 0.09-0.96, p = 0.042). CONCLUSION: Pre-PCI Impella initiation in AMICS patients was not associated with a statistically significant difference in 30-day all-cause mortality, compared to post-PCI Impella initiation

A multicentre point prevalence survey of patterns and quality of antibiotic prescribing in Indonesian hospitals

Background: The global emergence of antimicrobial resistance is driven by antibiotic misuse and overuse. However, systematic data in Indonesian hospitals to adequately inform policy are scarce. Objectives: To evaluate patterns and quality indicators of antibiotic prescribing in six general hospitals in Jakarta, Indonesia. Methods: We conducted a hospital-wide point prevalence survey (PPS) between March and August 2019, using Global-PPS and WHO-PPS protocols. The analysis focused on antibacterials (antibiotics) for systemic use. Results: Of 1602 inpatients, 993 (62.0%) received ≥1 antimicrobial. Of 1666 antimicrobial prescriptions, 1273 (76.4%) were antibiotics. Indications comprised community-acquired infections (42.6%), surgical prophylaxis (22.6%), hospital-acquired infections (18.5%), medical prophylaxis (9.6%), unknown (4.6%) and other (2.1%). The most common reasons for antibiotic prescribing were pneumonia (27.7%), skin and soft tissue infections (8.3%), and gastrointestinal prophylaxis (7.9%). The most prescribed antibiotic classes were third-generation cephalosporins (44.3%), fluoroquinolones (13.5%), carbapenems (7.4%), and penicillins with β-lactamase inhibitor (6.8%). According to the WHO AWaRe classification, Watch antibiotics accounted for 67.4%, followed by 28.0% Access and 2.4% Reserve. Hospital antibiotic guidelines were not available for 28.1% of prescriptions, and, where available, guideline compliance was 52.2%. Reason for the antibiotic prescription, stop/review date and planned duration were poorly documented. Culture-guided prescriptions comprised 8.1% of community-acquired infections and 26.8% of hospital-acquired infections. Conclusions: Our data indicate a high rate of empirical use of broad-spectrum antibiotics in Indonesian hospitals, coupled with poor documentation and guideline adherence. The findings suggest important areas for antimicrobial stewardship interventions

Immunomodulation and endothelial barrier protection mediate the association between oral imatinib and mortality in hospitalised COVID-19 patients

INTRODUCTION: Imatinib reduced 90-day mortality in hospitalised COVID-19 patients in a recent clinical trial, but the biological effects that cause improved clinical outcomes are unknown. We aimed to determine the biological changes elicited by imatinib in patients with COVID-19, and what baseline biological profile moderates the effect of imatinib. METHODS: Secondary analysis of a randomised, double-blind, placebo-controlled trial of oral imatinib in hospitalised, hypoxemic COVID-19 patients. Mediating effects of changes in plasma concentration of 25 plasma host response biomarkers on the association between randomisation group and 90-day mortality were studied by combining linear mixed-effect modelling and joint modelling. Moderation of baseline biomarker concentrations was evaluated by Cox regression modelling. We identified subphenotypes using Ward's method clustering and evaluated moderation of these subphenotypes using the above-described method. RESULTS: 332 out of 385 participants had plasma samples available. Imatinib increased the concentration of surfactant protein D (SP-D), and decreased the concentration of interleukin-6, procalcitonin, angiopoietin 2 to 1 ratio, E-selectin, tumour necrosis factor (TNF)α, and TNF receptor I. The effect of imatinib on 90-day mortality was fully mediated by changes in these biomarkers.Cluster analysis revealed three host response subphenotypes. Mortality benefit of imatinib was only present in the subphenotype characterised by alveolar epithelial injury indicated by increased SP-D levels in the context of systemic inflammation and endothelial dysfunction (HR 0.29, 95%-CI: 0.10-0.92). CONCLUSIONS: The effect of imatinib on mortality in hospitalised COVID-19 patients is mediated through modulation of innate immune responses and reversal of endothelial dysfunction, and possibly moderated by biological subphenotypes

Immunomodulation and endothelial barrier protection mediate the association between oral imatinib and mortality in hospitalised COVID-19 patients

Background Imatinib reduced 90-day mortality in hospitalised coronavirus disease 2019 (COVID-19) patients in a recent clinical trial, but the biological effects that cause improved clinical outcomes are unknown. We aimed to determine the biological changes elicited by imatinib in patients with COVID-19 and what baseline biological profile moderates the effect of imatinib. Methods We undertook a secondary analysis of a randomised, double-blind, placebo-controlled trial of oral imatinib in hospitalised, hypoxaemic COVID-19 patients. Mediating effects of changes in plasma concentration of 25 plasma host response biomarkers on the association between randomisation group and 90-day mortality were studied by combining linear mixed effect modelling and joint modelling. Moderation of baseline biomarker concentrations was evaluated by Cox regression modelling. We identified subphenotypes using Ward's method clustering and evaluated moderation of these subphenotypes using the aforementioned method. Results 332 out of 385 participants had plasma samples available. Imatinib increased the concentration of surfactant protein D (SP-D), and decreased the concentration of interleukin-6, procalcitonin, angiopoietin (Ang)-2/Ang-1 ratio, E-selectin, tumour necrosis factor (TNF)-α, and TNF receptor I. The effect of imatinib on 90-day mortality was fully mediated by changes in these biomarkers. Cluster analysis revealed three host response subphenotypes. Mortality benefit of imatinib was only present in the subphenotype characterised by alveolar epithelial injury indicated by increased SP-D levels in the context of systemic inflammation and endothelial dysfunction (hazard ratio 0.30, 95% CI 0.10-0.92). Conclusions The effect of imatinib on mortality in hospitalised COVID-19 patients is mediated through modulation of innate immune responses and reversal of endothelial dysfunction, and possibly moderated by biological subphenotypes

Integrated single-cell analysis unveils diverging immune features of COVID-19, influenza, and other community-acquired pneumonia

The exact immunopathophysiology of community-acquired pneumonia (CAP) caused by SARS-CoV-2 (COVID-19) remains clouded by a general lack of relevant disease controls. The scarcity of single-cell investigations in the broader population of patients with CAP renders it difficult to distinguish immune features unique to COVID-19 from the common characteristics of a dysregulated host response to pneumonia. We performed integrated single-cell transcriptomic and proteomic analyses in peripheral blood mononuclear cells from a matched cohort of eight patients with COVID-19, eight patients with CAP caused by Influenza A or other pathogens, and four non-infectious control subjects. Using this balanced, multi-omics approach, we describe shared and diverging transcriptional and phenotypic patterns-including increased levels of type I interferon-stimulated natural killer cells in COVID-19, cytotoxic CD8 T EMRA cells in both COVID-19 and influenza, and distinctive monocyte compositions between all groups-and thereby expand our understanding of the peripheral immune response in different etiologies of pneumonia.peer-reviewe