BackgroundLung ultrasound (LUS) is feasible for assessing lung injury caused by COVID-19. However, the prognostic meaning and time-line changes of lung injury assessed by LUS in COVID-19 hospitalised patients, is unknown.MethodsProspective cohort study designed to analyse prognostic value of LUS in COVID-19 patients by using a quantitative scale (LUZ-score) during the first 72 h after admission. Primary endpoint was in-hospital death and/or admission to the intensive care unit. Total length of hospital stay, increase of oxygen flow or escalate medical treatment during the first 72 h, were secondary endpoints.Results130 patients were included in the final analysis; mean age was 56.7±13.5 years. Time since the beginning of symptoms until admission was 6 days (4–9). Lung injury assessed by LUZ-score did not differ during the first 72 h (21 points [16–26] at admission versus 20 points [16–27] at 72 h; p=0.183). In univariable logistic regression analysis estimated PaO2/FiO2 (HR 0.99 [0.98–0.99]; p=0.027) and LUZ-score>22 points (5.45 (1.42–20.90); p=0.013) were predictors for the primary endpoint.ConclusionsLUZ-score is an easy, simple and fast point of care ultrasound tool to identify patients with severe lung injury due to COVID-19, upon admission. Baseline score is predictive of severity along the whole period of hospitalisation. The score facilitates early implementation or intensification of treatment for COVID-19 infection. LUZ-score may be combined with clinical variables (as estimated PAFI) to further refine risk stratification.

Sepsis is a serious global health problem. In addition to a high incidence, this syndrome has a high mortality and is responsible for huge health expenditure. The pathophysiology of sepsis is very complex and it is not well-understood yet. However, it is widely accepted that the initial phase of sepsis is characterized by a hyperinflammatory response while the late phase is characterized by immunosuppression and immune anergy, increasing the risk of secondary infections. Granzymes (Gzms) are a family of serine proteases classified according to their cleavage specificity. Traditionally, it was assumed that all Gzms acted as cytotoxic proteases. However, recent evidence suggests that GzmB is the one with the greatest cytotoxic capacity, while the cytotoxicity of others such as GzmA and GzmK is not clear. Recent studies have found that GzmA, GzmB, GzmK, and GzmM act as pro-inflammatory mediators. Specially, solid evidences show that GzmA and GzmK function as extracellular proteases that regulate the inflammatory response irrespectively of its ability to induce cell death. Indeed, studies in animal models indicate that GzmA is involved in the cytokine release syndrome characteristic of sepsis. Moreover, the GZM family also could regulate other biological processes involved in sepsis pathophysiology like the coagulation cascade, platelet function, endothelial barrier permeability, and, in addition, could be involved in the immunosuppressive stage of sepsis. In this review, we provide a comprehensive overview on the contribution of these novel functions of Gzms to sepsis and the new therapeutic opportunities emerging from targeting these proteases for the treatment of this serious health problem.

Aims: Peritonitis is one of the most common causes of sepsis, a serious syndrome characterized by a dysregulated systemic inflammatory response. Recent evidence suggests that Granzyme A (GzmA), a serine protease mainly expressed by NK and T cells, could act as a proinflammatory mediator and could play an important role in the pathogenesis of sepsis. This work aims to analyze the role and the therapeutic potential of GzmA in the pathogenesis of peritoneal sepsis. Methods: The level of extracellular GzmA as well as GzmA activity were analyzed in serum from healthy volunteers and patients with confirmed peritonitis and were correlated with the Sequential Organ Failure Assessment (SOFA) score. Peritonitis was induced in C57Bl/6 (WT) and GzmA -/- mice by cecal ligation and puncture (CLP). Mice were treated intraperitoneally with antibiotics alone or in combination serpinb6b, a specific GzmA inhibitor, for 5 days. Mouse survival was monitored during 14 days, levels of some proinflammatory cytokines were measured in serum and bacterial load and diversity was analyzed in blood and spleen at different times. Results: Clinically, elevated GzmA was observed in serum from patients with abdominal sepsis suggesting that GzmA plays an important role in this pathology. In the CLP model GzmA deficient mice, or WT mice treated with an extracellular GzmA inhibitor, showed increased survival, which correlated with a reduction in proinflammatory markers in both serum and peritoneal lavage fluid. GzmA deficiency did not influence bacterial load in blood and spleen and GzmA did not affect bacterial replication in macrophages in vitro, indicating that GzmA has no role in bacterial control. Analysis of GzmA in lymphoid cells following CLP showed that it was mainly expressed by NK cells. Mechanistically, we found that extracellular active GzmA acts as a proinflammatory mediator in macrophages by inducing the TLR4-dependent expression of IL-6 and TNFα. Conclusions: Our findings implicate GzmA as a key regulator of the inflammatory response during abdominal sepsis and provide solid evidences about its therapeutic potential for the treatment of this severe pathology.

Managing the multisystemic symptoms of type I Gaucher Disease (GD) requires a multidisciplinary team approach that includes disease-specific treatments, as well as supportive care. This involves a range of medical specialists, general practitioners, supportive care providers, and patients. Phenotype classification and the setting of treatment goals are important for optimizing the management of type I GD, and for providing personalized care. The ability to classify disease severity using validated measurement tools allows the standardization of patient monitoring, and the measurement of disease progression and treatment response. Defining treatment goals is useful to provide a benchmark for assessing treatment response and managing the expectations of patients and their families. Although treatment goals will vary depending on disease severity, they include the stabilization, improvement or reversal (if possible) of clinical manifestations. Enzyme replacement therapy (ERT) is the standard care for patients with type I GD, but a novel substrate reduction therapy (SRT), Eliglustat, has demonstrated safety and efficacy in selected patients. To ensure that treatment goals are being achieved, regular and comprehensive follow up are necessary.

Background: Detecting and managing antimicrobial drug interactions (ADIs) is one of the facets of prudent antimicrobial prescribing. Our aim is to compare the capability of several electronic drug-drug interaction (DDI) checkers to detect and report ADIs. Methods: Six electronic DDI checking platforms were evaluated: Drugs.com ® , Medscape ® , Epocrates ® , Medimecum ® , iDoctus ® , and Guía IF ® . Lexicomp ® Drug Interactions was selected as the gold standard. Ten ADIs addressing different mechanisms were evaluated with every electronic DDI checker. For each ADI, we assessed five dimensions and calculated an overall performance score (maximum possible score: 10 points). The explored dimensions were sensitivity (capability to detect ADI), clinical effect (type and severity), mechanism of interaction, recommended action(s), and documentation (quality of evidence and availability of references). Results: The electronic DDI checkers did not detect a significant proportion of the ADI assessed. The overall performance score ranged between 4.4 (Medimecum) and 8.8 (Drugs.com). Drugs.com was the highest ranked platform in four out of five dimensions (sensitivity, effect, mechanism, and recommended action). Conclusions: There is significant variability in the performance of the available platforms in detecting and assessing ADI. Although some ADI checkers have proven to be very accurate, others missed almost half of the explored interactions.

ABSTRACT:Managing the multisystemic symptoms of type I Gaucher Disease (GD) requires a multidisciplinary team approach that includes disease-specific treatments, as well as supportive care. This involves a range of medical specialists, general practitioners, supportive care providers, and patients. Phenotype classification and the setting of treatment goals are important for optimizing the management of type I GD, and providing personalized care. The ability to classify disease severity using validated measurement tools allows the standardization of patient monitoring, and the measurement of disease progression and treatment response. Defining treatment goals is useful to provide a benchmark for assessing treatment response, and managing the expectations of patients and their families. Although treatment goals will vary depending on disease severity, they include the stabilization, improvement or reversal

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