A care bundle approach for prevention of ventilator-associated pneumonia

AbstractImplementation of care bundles for prevention of ventilator-associated pneumonia (VAP) and its impact on patient outcomes requires validation with long-term follow-up. A collaborative multi-centre cohort study was conducted in five Spanish adult intensive-care units. A care bundle approach based on five measures was implemented after a 3-month baseline period, and compliance, VAP rates, intensive-care unit length of stay (ICU LOS) and duration of mechanical ventilation were prospectively recorded for 16 months. There were 149 patients in the baseline period and 885 after the intervention. Compliance with all measures after intervention was <30% (264/885). In spite of this, VAP incidence decreased from 15.5% (23/149) to 11.7% (104/885), after the intervention (p <0.05). This reduction was significantly associated with hand hygiene (OR = 0.35), intra-cuff pressure control (OR = 0.21), oral hygiene (OR = 0.23) and sedation control (OR = 0.51). Use of the care bundle was associated with an incidence risk ratio of VAP of 0.78 (95% CI 0.15–0.99). We documented a reduction of median ICU LOS (from 10 to 6 days) and duration of mechanical ventilation (from 8 to 4 days) for patients with full bundle compliance (intervention period). Efforts on VAP prevention and outcome improvement should focus on achieving higher compliance in hand and oral hygiene, sedation protocols and intracuff pressure control

Phosphotyrosine proteins in platelets from patients with storage pool disease: direct relation between granule defects and defective signal transduction

Background and objectives: storage pool diseases (SPD) are heterogeneous disorders associated with an abnormal presence of intraplatelet granules, which cause mild to moderate bleeding diathesis. We investigated signaling through tyrosine phosphorylation of proteins occurring in platelets with total or partial absence of dense- and alpha-granules in response to activation. Design and methods: we included a patient with severe delta-SPD, a patient with severe alpha-SPD or gray platelet syndrome, and six patients with partial deficiency of dense or a-granules. SPD was confirmed by electron microscopy evaluation of platelet ultrastructure. Platelet function was evaluated by bleeding time determination and conventional aggregometry. Platelet suspensions were activated with collagen and thrombin to analyze changes in tyrosine phosphorylation of proteins by electrophoresis and Western-blotting. Results: bleeding times were prolonged in all the patients included. Aggregation responses were slightly decreased in delta-SPD and normal in the rest of patients. Tyrosine phosphorylation in platelets from patients with partial forms of SPD was equivalent to that observed in control platelets, absent in response to collagen and thrombin activation in delta-SPD, and deficient only to thrombin activation in alpha-SPD. Interpretation and conclusions: tyrosine phosphorylation of proteins in activated platelets is highly dependent on the substances contained in the dense-granules and moderately dependent on those contained in the alpha-granules. A minimum amount of intraplatelet granules ensures signaling through tyrosine phosphorylation of proteins

TMAO and Gut Microbial-Derived Metabolites TML and γBB Are Not Associated with Thrombotic Risk in Patients with Venous Thromboembolism

Background: The present work evaluates the association between circulating concentrations of Trimethylamine-N-oxide (TMAO), gamma butyrobetaine (gamma BB), and trimetyllisine (TML) in controls and patients with venous thromboembolism (VTE) with coagulation parameters. Methods: The study involved 54 VTE patients and 57 controls. Platelet function, platelet hyperreactivity, platelet adhesiveness, thrombosis-associated parameters, and thrombin generation parameters were studied. Plasma TMAO, gamma BB, and TML determination was performed using an ultra-high-performance liquid chromatography system coupled with mass spectrometry. Results: No differences were found for TMAO, gamma BB, or TML concentrations between controls and VTE patients. In thrombin generation tests, TMAO, gamma BB, and TML showed a positive correlation with lag time and time to peak. TMAO, gamma BB, and TML negatively correlated with peak height. No significant differences were observed regarding TMAO, gamma BB, and TML concentrations between the two blood withdrawals, nor when the control and VTE patients were analyzed separately. No correlation was observed between these gut metabolites and platelet function parameters. Conclusions: No differences were found regarding TMAO, gamma BB, and TML concentrations between the control and VTE groups. Some correlations were found; however, they were mild or went in the opposite direction of what would be expected if TMAO and its derivatives were related to VTE risk

Early vascular endothelial complications after hematopoietic cell transplantation: Role of the endotheliopathy in biomarkers and target therapies development

This work aims to review the role of endothelial dysfunction underlying the main complications appearing early after autologous and allogeneic hematopoietic cell transplantation (HCT). The endothelial damage as the pathophysiological substrate of sinusoidal obstruction syndrome (SOS) is well established. However, there is growing evidence of the involvement of endothelial dysfunction in other complications, such as acute graft-versus-host disease (aGVHD) and transplant-associated thrombotic microangiopathy (TA-TMAs). Moreover, HCT-related endotheliopathy is not only limited to the HCT setting, as there is increasing evidence of its implication in complications derived from other cellular therapies. We also review the incidence and the risk factors of the main HCT complications and the biological evidence of the endothelial involvement and other linked pathways in their development. In addition, we cover the state of the art regarding the potential use of the biomarkers of endotheliopathy in the prediction, the early diagnosis, and the follow-up of the HCT complications and summarize current knowledge points to the endothelium and the other linked pathways described as potential targets for the prevention and treatment of HCT-complications. Lastly, the endothelium-focused therapeutic strategies that are emerging and might have a potential impact on the survival and quality of life of post-HCT-patients are additionally reviewed.Copyright © 2022 Moreno-Castaño, Salas, Palomo, Martinez-Sanchez, Rovira, Fernández-Avilés, Martínez, Cid, Castro, Escolar, Carreras and Diaz-Ricart

Endothelial damage, inflammation and immunity in chronic kidney disease

Chronic kidney disease (CKD) patients have an accelerated atherosclerosis, increased risk of thrombotic-ischemic complications, and excessive mortality rates when compared with the general population. There is also evidence of an endothelial damage in which the proinflammatory state, the enhanced oxidative stress, or the accumulation of toxins due to their reduced renal clearance in uremia play a role. Further, there is evidence that uremic endothelial cells are both involved in and victims of the activation of the innate immunity. Uremic endothelial cells produce danger associated molecular patterns (DAMPS), which by binding to specific pattern recognition receptors expressed in multiple cells, including endothelial cells, induce the expression of adhesion molecules, the production of proinflammatory cytokines and an enhanced production of reactive oxygen species in endothelial cells, which constitute a link between immunity and inflammation. The connection between endothelial damage, inflammation and defective immunity in uremia will be reviewed here

NFkB in the development of endothelial activation and damage in uremia: an in vitro approach

Impaired hemostasis coexists with accelerated atherosclerosis in patients with chronic kidney disease (CKD). The elevated frequency of atherothrombotic events has been associated with endothelial dysfunction. The relative contribution of the uremic state and the impact of the renal replacement therapies have been often disregarded. Plasma markers of endothelial activation and damage were evaluated in three groups of patients with CKD: under conservative treatment (predialysis), on hemodialysis, and on peritoneal dialysis. Activation of p38 MAPK and the transcription factor NFκB was assessed in endothelial cell (EC) cultures exposed to pooled sera from each group of patients. Most of the markers evaluated (VCAM-1, ICAM-1, VWF, circulating endothelial cells) were significantly higher in CDK patients than in controls, being significantly more increased in the group of peritoneal dialysis patients. These results correlated with the activation of both p38 MAPK and NFκB in EC cells exposed to the same sera samples, and also to the peritoneal dialysis fluids. Hemodialysis did not further contribute to the endothelial damage induced by the uremic state observed in predialysis patients, probably due to the improved biocompatibility of the hemodialysis technique in recent years, resulting in lower cellular activation. However, peritoneal dialysis seemed to exert a significant proinflammatory effect on the endothelium that could be related to the high glucose concentrations and glucose degradation products present in the dialysis fluid. Although peritoneal dialysis has been traditionally considered a more physiological technique, our results raise some doubts with respect to inflammation and EC damage

Genome-wide DNA methylation pattern in visceral adipose tissue differentiates insulin-resistant from insulin-sensitive obese subject

Elucidating the potential mechanisms involved in the detrimental effect of excess body weight on insulin action is an important priority in counteracting obesity-associated diseases. The present study aimed to disentangle the epigenetic basis of insulin resistance by performing a genome-wide epigenetic analysis in visceral adipose tissue (VAT) from morbidly obese patients depending on the insulin sensitivity evaluated by the clamp technique. The global human methylome screening performed in VAT from 7 insulin-resistant (IR) and 5 insulin-sensitive (IS) morbidly obese patients (discovery cohort) analyzed using the Infinium HumanMethylation450 BeadChip array identified 982 CpG sites able to perfectly separate the IR and IS samples. The identified sites represented 538 unique genes, 10% of which were diabetes-associated genes. The current work identified novel IR-related genes epigenetically regulated in VAT, such as COL9A1, COL11A2, CD44, MUC4, ADAM2, IGF2BP1, GATA4, TET1, ZNF714, ADCY9, TBX5, and HDACM. The gene with the largest methylation fold-change and mapped by 5 differentially methylated CpG sites located in island/shore and promoter region was ZNF714. This gene presented lower methylation levels in IR than in IS patients in association with increased transcription levels, as further reflected in a validation cohort (n = 24; 11 IR and 13 IS). This study reveals, for the first time, a potential epigenetic regulation involved in the dysregulation of VAT that could predispose patients to insulin resistance and future type 2 diabetes in morbid obesity, providing a potential therapeutic target and biomarkers for counteracting this process

Response to Maccio et al, - Multifactorial pathogenesis of COVID- 19- related coagulopathy: Can defibrotide have a role in the early phases of coagulation disorders?-

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/163392/2/jth15088_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/163392/1/jth15088.pd

Antioxidant and Anti-Inflammatory Strategies Based on the Potentiation of Glutathione Peroxidase Activity Prevent Endothelial Dysfunction in Chronic Kidney Disease

BACKGROUND/AIMS: Accelerated atherosclerosis in chronic kidney disease (CKD) is preceded by endothelial dysfunction (ED), which exhibits a proinflammatory and prothrombotic phenotype and enhanced oxidative stress. In this study, the effect of several compounds with anti-inflammatory and/or antioxidant properties on uremia-induced endothelial dysfunction has been evaluated in an in vitro model. METHODS: Endothelial cells (ECs) were exposed to sera from uremic patients in the absence and presence of the flavonoids apigenin, genistein and quercetin, the antioxidant enzyme mimetics (AEM) ebselen (glutathione peroxidase mimetic), EUK-134 and EUK-118 (both superoxide dismutase mimetics), and the pharmacological drug N-acetylcysteine (NAC). We explored changes in the expression of adhesion receptors on the cell surface, by immunofluorescence, the production of radical oxygen species (ROS), by fluorescence detection, and the activation of signaling proteins related to inflammation, by both a phosphospecific antibody cell-based ELISA and immunoblotting techniques. RESULTS: Uremic media induced a significantly increased expression of ICAM-1, overproduction of radical oxygen species (ROS) and activation of p38 mitogen activated protein kinase (p38MAPK) and Nuclear Factor kB (NFkB) in ECs. Quercetin, the AEM and NAC showed a significant inhibitory effect on both ICAM-1 expression and ROS generation (p<0.05). All the compounds reduced p38MAPK activation, but only the AEM, especially ebselen, and NAC, both potentiating the glutathione peroxidase pathway, also inhibited NFkB activation. These two compounds were capable of increasing endothelial glutathione levels, especially in response to uremia. CONCLUSION: Our results indicate that the potentiation of the antioxidant pathways can be an effective strategy to improve endothelial dysfunction in uremia and a potential target to reduce the cardiovascular risk in this population

Endothelial damage, inflammation and immunity in chronic kidney disease

Chronic kidney disease (CKD) patients have an accelerated atherosclerosis, increased risk of thrombotic-ischemic complications, and excessive mortality rates when compared with the general population. There is also evidence of an endothelial damage in which the proinflammatory state, the enhanced oxidative stress, or the accumulation of toxins due to their reduced renal clearance in uremia play a role. Further, there is evidence that uremic endothelial cells are both involved in and victims of the activation of the innate immunity. Uremic endothelial cells produce danger associated molecular patterns (DAMPS), which by binding to specific pattern recognition receptors expressed in multiple cells, including endothelial cells, induce the expression of adhesion molecules, the production of proinflammatory cytokines and an enhanced production of reactive oxygen species in endothelial cells, which constitute a link between immunity and inflammation. The connection between endothelial damage, inflammation and defective immunity in uremia will be reviewed here