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Introduction: Trough blood levels (C0) of tacrolimus are used to adjust drug dosage, but they do not consistently correlate with clinical outcomes. Measurement of residual gene expression of nuclear factor of activated T cell (NFAT)-regulated genes (NFAT-RGE) has been proposed as a pharmacodynamic biomarker to assess the degree of immunosuppression in certain solid organ transplantations, but little is known regarding lung transplant recipients (LTR). Our primary objective is to correlate tacrolimus blood levels with NFAT-RGE. Methods: NFAT-RGE and tacrolimus C0 and peak (C1.5) levels were determined in 42 patients at three, six and 12 months post-transplantation. Results: Tacrolimus C0 did not exhibit a correlation with NFAT-RGE, whereas C1.5 did. Besides, over 20% of measurements indicated high levels of immunosuppression based on the below 30% NFAT-RGE threshold observed in many studies. Among those measurements within the therapeutic range, 19% had an NFAT-RGE<30%. Conclusion: Consequently, a subset of patients within the tacrolimus therapeutic range may be more susceptible to infection or cancer, potentially benefiting from NFAT-RGE and tacrolimus peak level monitoring to tailor their dosage. Further quantitative risk assessment studies are needed to elucidate the relationship between NFAT-RGE and the risk of infection, cancer, or rejection. [ABSTRACT FROM AUTHOR]

Background and Purpose: Reperfusion therapy is the standard of care for ischaemic stroke; however, there is a need to identify new therapeutic targets able to ameliorate cerebral damage. Neutrophil β1 adrenoceptors (β1AR) have been linked to neutrophil migration during exacerbated inflammation. Given the central role of neutrophils in cerebral damage during stroke, we hypothesize that β1AR blockade will improve stroke outcomes. Experimental Approach: Rats were subjected to middle cerebral artery occlusion–reperfusion to evaluate the effect on stroke of the selective β1AR blocker metoprolol (12.5 mg·kg−1) when injected i.v. 10 min before reperfusion. Key Results: Magnetic resonance imaging and histopathology analysis showed that pre‐reperfusion i.v. metoprolol reduced infarct size. This effect was accompanied by reduced cytotoxic oedema at 24 h and vasogenic oedema at 7 days. Metoprolol‐treated rats showed reduced brain neutrophil infiltration and those which infiltrated displayed a high proportion of anti‐inflammatory phenotype (N2, YM1+). Additional inflammatory models demonstrated that metoprolol specifically blocked neutrophil migration via β1AR and excluded a significant effect on the glia compartment. Consistently, metoprolol did not protect the brain in neutrophil‐depleted rats upon stroke. In patients suffering an ischaemic stroke, β1AR blockade by metoprolol reduced circulating neutrophil–platelet co‐aggregates. Conclusions and Implications: Our findings describe that β1AR blockade ameliorates cerebral damage by targeting neutrophils, identifying a novel therapeutic target to improve outcomes in patients with stroke. This therapeutic strategy is in the earliest stages of the translational pathway and should be further explored. [ABSTRACT FROM AUTHOR]

Background: Mechanical ventilation increases the risk of lung injury (VILI). Some authors propose that the way to reduce VILI is to find the threshold of driving pressure below which VILI is minimized. In this study, we propose a method to titrate the driving pressure to pulmonary elastance in an acute respiratory distress syndrome model using Young's modulus and its consequences on ventilatory-induced lung injury.Material and Methods: 20 Wistar Han male rats were used. After generating an acute respiratory distress syndrome, two groups were studied: (a) standard protective mechanical ventilation: 10 rats received 150 min of mechanical ventilation with driving pressure = 14 cm H2O, tidal volume < 6 mL/kg) and (b) individualized mechanical ventilation: 10 rats received 150 min of mechanical ventilation with an individualized driving pressure according to their Young's modulus. In both groups, an individualized PEEP was programmed in the same manner. We analyzed the concentration of IL-6, TNF-α, and IL-1ß in BAL and the acute lung injury score in lung tissue postmortem.Results: Global driving pressure was different between the groups (14 vs 11 cm H2O, p = 0.03). The individualized mechanical ventilation group had lower concentrations in bronchoalveolar lavage of IL-6 (270 pg/mL vs 155 pg/mL, p = 0.02), TNF-α (292 pg/mL vs 139 pg/mL, p < 0.01) and IL-1ß (563 pg/mL vs 131 pg/mL, p = 0.05). They presented lower proportion of lymphocytes (96% vs 79%, p = 0.05) as well as lower lung injury score (6.0 points vs 2.0 points, p = 0.02).Conclusion: In our model, individualization of DP to pulmonary elastance through Young's modulus decreases lung inflammation and structural lung injury without a significant impact on oxygenation. [ABSTRACT FROM AUTHOR]

We aimed to evaluate the clinical outcome of Systemic Autoimmune Diseases (SADs) patients hospitalized with COVID-19 in Spain, before the introduction of SARS-CoV-2 vaccines. A nationwide, retrospective and observational analysis of the patients admitted during 2020, based on the ICD10 codes in the National Registry of Hospital Discharges, was performed. Among 117,694 patients, only 892 (0.8%) presented any type of SAD before COVID-19-related admission: Sjogren's Syndrome constituted 25%, Systemic Vasculitides 21%, Systemic Lupus Erythematosus 19%, Sarcoidosis 17%, Systemic Sclerosis 11%, Mixed and Undifferentiated Connective Tissue Disease 4%, Behçet's Disease 4% and Inflammatory Myopathies 2%. The in-hospital mortality rate was higher in SAD individuals (20% vs. 16%, p < 0.001). After adjustment by baseline conditions, SADs were not associated with a higher mortality risk (OR = 0.93, 95% CI 0.78–1.11). Mortality in the SADs patients was determined by age (OR = 1.05, 95% CI 1.04–1.07), heart failure (OR = 1.67, 95% CI 1.10–2.49), chronic kidney disease (OR = 1.29, 95% CI 1.05–1.59) and liver disease (OR = 1.97, 95% CI 1.13–3.44). In conclusion, the higher COVID-19 mortality rate seen in SADs patients hospitalized in Spain in 2020 was related to the higher burden of comorbidities, secondary to direct organ damage and sequelae of their condition. Whilst further studies should evaluate the impact of baseline immunosuppression on COVID-19 outcomes in this population, efforts should be focused on the optimal management of SAD to minimize the impact of the organ damage that has been shown to determine COVID-19 prognosis. [ABSTRACT FROM AUTHOR]

We aimed to explore the role of interleukin (IL)‐6, interferon‐gamma (IFNγ), IL‐10, and tumor necrosis factor (TNF) as predictors of systemic lupus erythematosus (SLE) clinical and serological activity, and their correlation with the treatment received. We performed a retrospective analysis of 77 patients with SLE according to the 2012 Systemic Lupus International Collaborative Clinics (SLICC) criteria. The outcomes were serological activity (SA), active disease (AD), complete remission (CR), the low‐disease activity state (LDAS), and immunosuppressive treatment. SA was present in 17.1%, AD in 17.3%, CR in 13%, and LDAS in 64.9% of patients. IL‐6 values were higher in patients in SA, in AD, in those receiving steroids alone, and in patients without CR or LDAS (p < 0.05). IFNγ was associated with anti‐double stranded DNA (dsDNA) antibodies positivity and immunosuppression, whereas IL‐10 values were higher in patients with CR (p < 0.05). The IL6‐IFN product was able to predict anti‐double stranded DNA (anti‐dsDNA) antibodies positivity (area under the receiver operating characteristic curve [AUC‐ROC] = 0.705, 95% confidence interval [CI] 0.563–0.847), SA (AUC‐ROC = 0.720, 95% CI 0.542–0.899), AD (AUC‐ROC = 0.701, 95% CI 0.520–0.882), steroid treatment (AUC‐ROC = 0.751, 95% CI 0.622–0.879), and the absence of LDAS (AUC‐ROC = 0.700, 95% CI 0.558–0.834). The IL6‐IFN/IL10 ratio predicted AD (AUC‐ROC = 0.742, 955 CI 0.540–0.944), steroid treatment (AUC‐ROC = 0.721, 95% CI 0.572–0.870), and the absence of LDAS (AUC‐ROC = 0.694, 95% CI 0.536–0.853). In conclusion, IL‐6, IL‐10, and IFNγ might help to assess SLE serological and clinical activity. Their combination in the IL‐6‐IFN product and the IL‐6xIFN to IL‐10 ratio results in novel tools to determine and predict SA, AD, and LDAS. Prompt detection of SLE activity might allow a rapid intervention to avoid established or chronic damage. [ABSTRACT FROM AUTHOR]

Background. Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-COV-2) infection elicits inflammatory manifestations that relate with a "cytokine storm." Objective. The aim of this research was to assess the role of circulating interleukin 6 (IL-6) levels and other inflammatory markers in patients with coronavirus disease 2019 (COVID-19) on metabolic functions and accompanying clinical complications. Patients and Methods. A total of 165 patients diagnosed with COVID-19 pneumonia were examined for medical features and inflammatory markers such as blood IL-6, CRP, ferritin, LDH, neutrophil/lymphocyte index (NLI), D-Dimer, and Red Cell Distribution Width (RDW). Regression analyses concerning electronically collected medical data were adjusted by appropriate factors and confounding variables. Results. Plasma IL-6 determinations evidenced a consistent association with hospital stay days, Intensive Care Unit (ICU) admission, and mortality rates. Similar trends were found for other proinflammatory variables, where ferritin and NLI showed a remarkable value as surrogates. Hyperglycaemia and the Charlson Comorbidity Index Score were positively associated with the inflammatory response induced by the SARS-COV-2 infection. An unhealthy lifestyle such as smoking and alcoholic drinks consumption as well as excessive body adiposity influenced inflammatory-related outcomes in the screened patients. Conclusion. IL-6 together with other inflammatory biomarkers accompanied poor clinical and metabolic outcomes in COVID-19-infected patients. IL-6 may result in a suitable proxy to individually categorise patients in order to manage this infectious pandemic. [ABSTRACT FROM AUTHOR]

A large number of prognostic factors are available to help predict the course of the disease for patients with B-cell chronic lymphocytic leukemia (B-CLL). However, it is not clear the involvement of these well established prognostic factors in the clinical response of the patients with B-CLL to the chemotherapy. The possible association of the patient clinical-biological characteristics and the in vitro response to chemotherapic agents may serve to provide powerful predictive information to identify optimum treatment for patients. An apoptosis induction assay displays the patient in vitro responses to chemotherapy and the possible association with their clinical-biological characteristics. In this study, patients showed a significant better in vitro response to drugs when they were in the initial stages of the disease or with low β2 microglobulin serum level. Response to purine analogues was significantly higher in patients with long lymphocyte doubling time (LDT), few cells expressing CD38, normal karyotype or no p53 deletion, whereas there was no correspondence with ZAP-70 expression. Furthermore, a good correlation was shown between in vitro apoptosis induction assay and the patient clinical response to purine analogues. In conclusion, association between in vitro drug sensitivity and some of the markers considered as prognostic factors could help to develop personalised therapeutic regimens for patients with B-CLL. [ABSTRACT FROM AUTHOR]

Background: the admission and death causes of SLE patients might have changed over the last years. Methods: Analysis of the Spanish National Hospital Discharge database. All individuals admitted with SLE, according to ICD-9, were selected. The following five admission categories were considered: SLE, cardiovascular disease (CVD), neoplasm, infection, and venous-thromboembolic disease (VTED), along four periods of time (1997–2000, 2001–2005, 2006–2010, and 2011–2015). Results: The admissions (99,859) from 43.432 patients with SLE were included. The absolute number of admissions increased from 15,807 in 1997–2000 to 31,977 in 2011–2015. SLE decreased as a cause of admission (from 47.1% to 20.8%, p < 0.001), while other categories increased over the time, as follows: 5% to 8.6% for CVD, 8.2% to 13% for infection, and 1.4% to 5.5% for neoplasm (p < 0.001 for all). The admission mortality rate rose from 2.22% to 3.06% (p < 0.001) and the causes of death evolved in parallel with the admission categories. A significant trend to older age was observed over time in the overall population and deceased patients (p < 0.001). Conclusions: Better control of SLE over the past two decades has led to a decrease in early admissions, and disease chronification. As a counterpart, CVD, infections, and neoplasm have become the main causes of admissions and mortality. [ABSTRACT FROM AUTHOR]

Background: There is increasing evidence that programmed cell death can be triggered during cardiopulmonary bypass (CPB) and may be involved in postoperative complications. The purpose of this study was to investigate whether apoptosis occurs during aortic valve surgery and whether modifying temperature during CPB has any influence on cardiomyocyte apoptotic death rate. Methods: 20 patients undergoing elective aortic valve replacement for aortic stenosis were randomly assigned to either moderate hypothermic (ModHT group, n = 10, 28±C) or mild hypothermic (MiHT group, n = 10, 34±C) CPB. Myocardial samples were obtained from the right atrium before and after weaning from CPB. Specimens were examined for apoptosis by flow cytometry analysis of annexin V-propidium iodide (PI) and Fas death receptor staining. Results: In the ModHT group, non apoptotic non necrotic cells (annexin negative, PI negative) decreased after CPB, while early apoptotic (annexin positive, PI negative) and late apoptotic or necrotic (PI positive) cells increased. In contrast, no change in the different cell populations was observed over time in the MiHT group. Fas expression rose after reperfusion in the ModHT group but not in MiHT patients, in which there was even a trend for a lower Fas staining after CPB (p = 0.08). In ModHT patients, a prolonged ischemic time tended to induce a higher increase of Fas (p = 0.061). Conclusion: Our data suggest that apoptosis signal cascade is activated at early stages during aortic valve replacement under ModHT CPB. This apoptosis induction can effectively be attenuated by a more normothermic procedure. [ABSTRACT FROM AUTHOR]

Background: For laryngeal carcinoma, the present TNM clinical staging system does not seem completely satisfactory as a guide for providing a prognosis for survival. We believe that natural killer cell activity would probably have a role in a more reliable system. Therefore, we analyzed the disease outcome with previously untreated epidermoid carcinoma of the larynx, evaluating classic clinical and pathologic factors, as well as natural killer cell activity in peripheral blood samples of the patients. Objectives: To determine the level of natural killer cell activity in patients with laryngeal carcinoma and to analyze the prognostic value of this finding when associated with other clinical and pathologic variables. Design: Prospective cohort study of surveillance of laryngeal cancer. Mean follow-up of 42.8 months. Settings: Tertiary care referral center and ambulatory and hospitalized care. Participants: We compared 81 men (mean age, 62.4 years; range, 35-89 years) with laryngeal carcinoma with 44 healthy men serving as control subjects (mean age, 57.6 years; range, 37-82 years). Results: Natural killer cell activity was significantly reduced in patients who had died of cancer-related causes in comparison with tumor-free survivors. Overall actuarial survival differed significantly in histologically assessed nodal involvement and low natural killer cell activity. Use of the Cox proportional hazards regression model showed that the factors that seem to have a prognostic effect on survival are histologically determined nodal involvement and low natural killer cell activity. Conclusions: These results support the prognostic significance of the determination of pretreatment natural killer cell activity in peripheral blood samples from patients with laryngeal carcinoma and suggest that assessment of adding such a determination to the current tumor staging system is advisable. [ABSTRACT FROM AUTHOR]