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Background: Fluid therapy has a pivotal role in the management of acutely ill patients. However, whether or not a patient can tolerate additional intravascular volume is controversial and optimal strategy is unknown. Carotid femoral pulse wave velocity (cfPWV) evaluates arterial stiffness.Objective: To determine whether cfPWV can predict the ability of patients to tolerate clinically indicated acute fluid expansion.Methods: 50 consecutive patients requiring intravascular volume expansion were prospectively recruited in intensive care units. All subjects underwent transthoracic echocardiography, pulmonary ultrasound assessment, and a cfPWV study (S. Giovanni Bosco Hospital in Turin, Italy, between 2015 and 2016) at baseline and after 24 hours. Acute outcomes were registered at 24 hours ("soft" end points) and 30 days ('hard' end points: death, acute myocardial infarction, stroke, occurrence of atrial fibrillation, need for dialysis) after initial fluid therapy. Multivariate logistic regression was used to assess association of the initial cfPWV with outcomes.Results: cfPWV was significantly higher (10.6±3.6 vs 7.4±2.2 m/s, P<0.0001) in subjects who met the prespecified combined endpoints (hard or soft) than in those who did not. After adjustment for confounding factors, initial cfPWV was significantly and independently associated with the occurrence of hard events (OR=2.8 (95% CI 1.36 to 5.97), P=0.005; area under the receiver operating characteristic curve 84%). cfPWV of <9 m/s had a negative predictive value of 93%, excluding hard events associated with fluid expansion.Conclusion: cfPWV appears to reflect the ability of the patient to tolerate an intravascular fluid expansion when clinically indicated. Increased cfPWV could help to identify subjects at greater risk of developing signs and symptoms of fluid overload. [ABSTRACT FROM AUTHOR]

Abstract: Extracellular vesicles, released from cells, are important for intercellular communication. They are heterogeneous but fall into two broad categories based on origin and function: microvesicles formed by outward budding from the plasma membrane; and exosomes that originate as intraluminal vesicles in multivesicular endosomes that fuse with the plasma membrane to release them. Extracellular vesicles generally and exosomes in particular have powerful effects on specific immune responses, and recent advances highlight their potential therapeutic uses. Dendritic cells (DC) that have internalized antigen release exosomes that express MHC class II molecules loaded with antigenic peptides, co‐stimulatory molecules and intact antigen. Depending on the setting, these stimulate CD4 T‐cell proliferation either directly or only in the context of accessory antigen naïve DC. Here, we discuss the reasons for this; and review current knowledge about the loading of antigen, class II and other cargo into exosomes released by DC and other professional antigen‐presenting cells in the context of advances in exosome biology more generally. [ABSTRACT FROM AUTHOR]

Monitoring the cardiovascular health of patients and early diagnosis of heart diseases are highly sought after as they can represent a true cornerstone in tomorrow's healthcare surveillance. Here, an unprecedented non‐invasive device prototype is reported for pulse wave velocity (PWV) measurement based on a piezoelectric graphene pressure sensor. PWV is a critical health indicator that estimates arterial stiffness by measuring the velocity of arterial pulse flow through the circulatory system. The sensor incorporates advanced electronic components and data analysis tools, enabling the measurement of pulse transit time (PTT), that is the time required for the pulse wave to travel between carotid and femoral artery sites. Significantly, the outcomes obtained through the novel method, which involved monitoring 10 patients within clinical environment, show statistical similarity to results obtained using established technology for the PWV estimation such as SphygmoCor. In particular, the mean difference between measurements done with the two techniques resulted in 0.1 m s−1, that is <2%, underscoring the reliability of the novel device. The technology holds big promise for enhancing cardiovascular healthcare delivery: it is wearable, potentially exploitable by a non‐expert user, and it needs to be powered with just 0.2 V, thus it can become compatible even with applications in point‐of‐care settings. [ABSTRACT FROM AUTHOR]

Although great advances have been made in understanding the pathobiology of mixed lineage leukemia-rearranged (MLL-r) leukemias, therapies for this leukemia have remained limited, and clinical outcomes remain bleak. In order to identify novel targets for immunotherapy treatments, we compiled a lineage-independent MLL-r leukemia gene signature using publicly available data sets. Data from large leukemia repositories were filtered through the in silico human surfaceome, providing a list of highly predicted cell surface proteins overexpressed in MLL-r leukemias. LAMP5, a lysosomal associated membrane protein, is expressed highly and specifically in MLL-r leukemia. We found that LAMP5 is a direct target of the oncogenic MLL-fusion protein. LAMP5 depletion significantly inhibited leukemia cell growth in vitro and in vivo. Functional studies showed that LAMP-5 is a novel modulator of innate-immune pathways in MLL-r leukemias. Downregulation of LAMP5 led to inhibition of NF-kB signaling and increased activation of type-1 interferon signaling downstream of Toll-like receptor/interleukin 1 receptor activation. These effects were attributable to the critical role of LAMP-5 in transferring the signal flux from interferon signaling endosomes to pro-inflammatory signaling endosomes. Depletion of IRF7 was able to partially rescue the cell growth inhibition upon LAMP5 downregulation. Lastly, LAMP-5 was readily detected on the surface of MLL-r leukemia cells. Targeting surface LAMP-5 using an antibody-drug conjugate leads to significant cell viability decrease specifically in MLL-r leukemias. Overall, based on the limited expression throughout human tissues, we postulate that LAMP-5 could potentially serve as an immunotherapeutic target with a wide therapeutic window to treat MLL-r leukemias.

Background: Fluid therapy has a pivotal role in the management of acutely ill patients. However, whether or not a patient can tolerate additional intravascular volume is controversial and optimal strategy is unknown. Carotid femoral pulse wave velocity (cfPWV) evaluates arterial stiffness., Objective: To determine whether cfPWV can predict the ability of patients to tolerate clinically indicated acute fluid expansion., Methods: 50 consecutive patients requiring intravascular volume expansion were prospectively recruited in intensive care units. All subjects underwent transthoracic echocardiography, pulmonary ultrasound assessment, and a cfPWV study (S. Giovanni Bosco Hospital in Turin, Italy, between 2015 and 2016) at baseline and after 24 hours. Acute outcomes were registered at 24 hours ("soft" end points) and 30 days ('hard' end points: death, acute myocardial infarction, stroke, occurrence of atrial fibrillation, need for dialysis) after initial fluid therapy. Multivariate logistic regression was used to assess association of the initial cfPWV with outcomes., Results: cfPWV was significantly higher (10.6±3.6 vs 7.4±2.2 m/s, P<0.0001) in subjects who met the prespecified combined endpoints (hard or soft) than in those who did not. After adjustment for confounding factors, initial cfPWV was significantly and independently associated with the occurrence of hard events (OR=2.8 (95% CI 1.36 to 5.97), P=0.005; area under the receiver operating characteristic curve 84%). cfPWV of <9 m/s had a negative predictive value of 93%, excluding hard events associated with fluid expansion., Conclusion: cfPWV appears to reflect the ability of the patient to tolerate an intravascular fluid expansion when clinically indicated. Increased cfPWV could help to identify subjects at greater risk of developing signs and symptoms of fluid overload., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)