Arachidonic acid-stimulated platelet tests: Identification of patients less sensitive to aspirin treatment

Serum thromboxane-B2 (TxB2), together with arachidonic acid (AA)-induced platelet aggregation, are, at the moment, the most used tests to identify patients displaying high on-aspirin treatment platelet reactivity (HAPR). Both tests are specific for aspirin action on cyclooxygenase-1. While the correlation between serum TxB2 assay and clinical outcome is established, data are conflicting with regard to aspirin treatment and a possible association with AA-stimulated platelet markers and clinical outcome. To understand such discrepancy, we performed a retrospective study to compare both assays. We collected data from 132 patients receiving a daily dose of aspirin (100?mg/day) and data from 48 patients receiving aspirin on alternate days. All Patients who received a daily dose of aspirin were studied for AA-induced platelet aggregation together with serum TxB2 levels and AA-induced TxB2 formation was also studied in 71 patients out of entire population. Consistent with recommendations in the literature, we defined HAPR by setting a cut-off point at 3.1?ng/ml for serum levels of thromboxane B2 and 20% for AA-induced platelet aggregation. According to this cut-off point, we divided our overall population into two groups: (1) TxB2?<?3.1?ng/ml and (2) TxB2?>?3.1?ng/ml. We found low agreement between such tests to identify patients displaying HAPR. Our results show that AA-induced platelet aggregation >20% identify a smaller number of HAPR patients in comparison with TxB2. A good correlation between serum TxB2 and arachidonic acid-induced TxB2 production was found (r?=?0.76619).     

The association between the decreased expression levels of FOXJ1 and the activation of NF-κB pathway in interstitial lung disease of MRL/Lpr mice

Background: Pulmonary manifestations of systemic lupus erythematosus (SLE) are appearing in 4-5% of patients involving lung in almost half of the cases during the disease course. Objective: We compared the autoimmune pulmonary inflammation in the lung tissue of mice to determine the association between decreased expression levels of Forkhead Box J1 (FOXJ1) and the activation of the NF-κB pathway in autoimmune pulmonary inflammation of MRL/Lpr mice. Methods: The female BALB/c mice (n=6) and MRL/Lpr mice (n=30) were divided into 5 groups including a control group (BALB/c), and five MRL/Lpr mice groups (8W, 12W, 16W, 24W, and 32W). The infiltration of the inflammatory cells was determined in lung tissue by performing the histological analysis. The western blotting was used to examine the expression levels of the age-related FOXJ1, and p50 and p65 proteins in the lungs of MRL/Lpr mice. The expression levels of MMP2 and MMP9 were determined via immunohistochemistry and immunofluorescence. Results: There were severe infiltrates of lung cells with high levels of tracheal damage, perivascular injury and interstitial inflammatory cell infiltration when the MRL/Lpr mice from 16w to 32w comparing to the 8w old healthy MRL/Lpr mice in the control group (p <0.05). Moreover, the reduced expression levels of FOXJ1 were associated with the activation of the NF-κB pathway in interstitial lung disease of MRL/Lpr mice via the modulation of p50 and p65. In addition, the expression levels of MMP2 and MMP9 pro-inflammation factors increased in the lungs of the MRL/Lpr mice from 16w to 32w. Conclusions: The expression level of FOXJ1 might be an indicator of the degree of lung disease in lupus-prone mice.     

Programmed Cell Death Ligand 1 Expression in Untreated EGFR Mutated Advanced NSCLC and Response to Osimertinib Versus Comparator in FLAURA

IntroductionEGFR mutated (EGFRm) NSCLC tumors occasionally express programmed cell death ligand 1 (PD-L1), although frequency and clinical relevance are not fully characterized. We report PD-L1 expression in patients with EGFRm advanced NSCLC and association with clinical outcomes following treatment with osimertinib or comparator EGFR tyrosine kinase inhibitors in the FLAURA trial (phase III, NCT02296125).MethodsOf 231 tissue blocks available from the screened population (including EGFRm-positive and -negative samples), 197 had sufficient tissue for PD-L1 testing using the SP263 (Ventana, Tucson, Arizona) immunohistochemical assay. Tumor cell (TC) staining thresholds of PD-L1 TC greater than or equal to 1%, TC greater than or equal to 25%, and TC greater than or equal to 50% were applied. Progression-free survival (PFS) was investigator-assessed, per Response Evaluation Criteria in Solid Tumor, version 1.1, according to PD-L1 expressors (TC ≥ 1%) or negatives (TC < 1%) in randomized patients.ResultsPD-L1 staining was successful in 193 of 197 patient formalin-fixed paraffin-embedded blocks; of these, 128 of 193 were EGFRm-positive and 106 of 128 patients were randomized to treatment (osimertinib: 54; comparator: 52). At the PD-L1 TC greater than or equal to 25% threshold, 8% (10 of 128) of EGFRm-positive tumors expressed PD-L1 versus 35% (23 of 65) of EGFRm-negative tumors. With the TC greater than or equal to 1% threshold, 51% (65 of 128) versus 68% (44 of 65) were mutation-positive and –negative, respectively, and with the TC greater than or equal to 50% threshold, 5% (7 of 128) versus 28% (18 of 65), were mutation-positive and -negative, respectively. For PD-L1 expressors (TC ≥ 1%), median PFS was 18.4 months with osimertinib and 6.9 months with comparator (hazard ratio = 0.30; 95% confidence interval: 0.15–0.60). For PD-L1–negative patients (TC < 1%), median PFS was 18.9 months with osimertinib and 10.9 months with comparator (hazard ratio = 0.37; 95% confidence interval: 0.17–0.74).ConclusionsClinical benefit with osimertinib was unaffected by PD-L1 expression status.     

Cell integrity indicators assessed by bioelectrical impedance: A systematic review of studies involving athletes

IntroductionBioelectrical impedance analysis (BIA) has been used to evaluate cellular health and integrity through bioelectrical indicators. In the sporting context, monitoring these indicators can be useful to assess the quality and vitality of cells and body tissues.ObjectiveThe aim of this systematic review was to investigate indicators of cellular health and integrity evaluated by BIA in athletes.MethodsSearches were performed in December 2017 in the Lilacs, Medline, PubMed, Science Direct, Scielo, Scopus, SPORTDiscus, and Web of Science databases, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.ResultsThe searches retrieved 31 articles (30 involving professional athletes and one involving university athletes). In longitudinal studies (n = 15), the bioelectrical parameters directly associated with cellular health and integrity were extracellular water (ECW), phase angle (PA), BIA vector analysis (BIVA), crude reactance data (Xc), resistance (R), and ECW/BCM ratio. Regarding the findings of cross-sectional studies (n = 16), the investigated parameters (ECW, PA, BIVA, Z, BCM, and ECW/BCM) were directly associated with gender, age, sports performance level, modality, and game position.ConclusionsIn the included studies, the cellular health and integrity indicators were: Z, Xc, R, total water, intracellular water, ECW, PA, BIVA, BCM, and ECW/BCM.     

Factors associated with clinically significant hypoglycemia in patients with type 1 diabetes using sensor-augmented pump therapy with predictive low-glucose management: A multicentric study on iberoamerica

Background and aimsDespite using sensor-augmented pump therapy (SAPT) with predictive low-glucose management (PLGM), hypoglycemia is still an issue in patients with type 1 Diabetes (T1D). Our aim was to determine factors associated with clinically significant hypoglycemia (<54 mg/dl) in persons with T1D treated with PLGM-SAPT.Methodology: This is a multicentric prospective real-life study performed in Colombia, Chile and Spain. Patients with T1D treated with PLGM-SAPT, using sensor ≥70% of time, were included. Data regarding pump and sensor use patterns and carbohydrate intake from 28 consecutive days were collected. A bivariate and multivariate Poisson regression analysis was carried out, to evaluate the association between the number of events of <54 mg/dl with the clinical variables and patterns of sensor and pump use.Results188 subjects were included (41 ± 13.8 years-old, 23 ± 12 years disease duration, A1c 7.2% ± 0.9). The median of events <54 mg/dl was four events/patient/month (IQR 1–10), 77% of these events occurred during day time. Multivariate analysis showed that the number of events of hypoglycemia were higher in patients with previous severe hypoglycemia (IRR1.38; 95% CI 1.19–1.61; p < 0.001), high glycemic variability defined as Coefficient of Variation (CV%) > 36% (IRR 2.09; 95%CI 1.79–2.45; p < 0.001) and hypoglycemia unawareness. A protector effect was identified for adequate sensor calibration (IRR 0.77; 95%CI 0.66–0.90; p:0.001), and the use of bolus wizard >60% (IRR 0.74; 95%CI 0.58–0.95; p:0.017).ConclusionIn spite of using advanced SAPT, clinically significant hypoglycemia is still a non-negligible risk. Only the identification and intervention of modifiable factors could help to prevent and reduce hypoglycemia in clinical practice.     

Predictive value of HbA1c for in-hospital adverse prognosis in COVID-19: A systematic review and meta-analysis

Background and aimsClinical and laboratory predictors of adverse clinical course and death in COVID-19 patients urgently need to be identified. So far, the association between HbA1c and in-hospital mortality of COVID-19 remains a controversial issue. The aim of this study is to analyze predictive value of HbA1c for adverse prognosis in COVID-19.MethodsBoth Chinese and English databases were systematically searched using specific keywords associated with the aims until November 21th, 2020. The Newcastle-Ottawa Scale (NOS) was used for quality assessment. A Statistical analysis was carried out using Review Manager 5.3 and STATA 15.1.ResultsNine clinical trials were included in this study involving 2577 subjects. The results indicate that the association between elevated HbA1c referred as a continuous variable and adverse prognosis of COVID-19 was not significant (OR, 1.02; 95%CI, 0.95–1.09). However, higher HbA1c levels regarded as a dichotomous variable contributed to an increase mortality of COVID-19 (OR, 2.300; 95%CI, 1.679–3.150). Results were stable in a sensitivity analysis. More studies are needed to demonstrate the effect of HbA1c on hospital mortality.ConclusionProlonged uncontrolled hyperglycemia increases the risk of adverse prognosis in COVID-19. Patients with higher HbA1c should be monitored strictly to minimize the risk of adverse prognosis in COVID-19.     

1p31.1 microdeletion including only NEGR1 gene in two patients

Neuronal growth regulator 1 (NEGR1), a member of the immunoglobulin superfamily cell adhesion molecule subgroup IgLON, has been involved in neuronal growth and connectivity. Genetic variants, in or near the NEGR1 locus, have been associated with obesity and, more recently, with learning difficulties, intellectual disability, and psychiatric disorders.Here, we described the only second report of NEGR1 gene disruption in 1p31.1 microdeletion in two patients. Patient 1 is a 14-year-old female with neurological and psychiatric features present also in her family. Patient 2 is a 5-month-old infant showing global hypotonia as unique neurological features till now. This patient also carries 7p22.1 duplication, of paternal origin, that could be responsible for some malformations present in the child.We hypothesize a role of NEGR1 in producing the phenotype of our patients and compare them with other cases previously reported in the literature and DECIPHER database to better identify a possible genotype-phenotype correlation.