Age-dependent effect of the IFIH1/MDA5 gene variants on the risk of critical COVID-19.

MDA5, encoded by the IFIH1gene, is a cytoplasmic sensor of viral RNAs that triggers interferon (IFN) antiviral responses. Common and rare IFIH1 variants have been associated with the risk of type 1 diabetes and other immune-mediated disorders, and with the outcome of viral diseases. Variants associated with reduced IFN expression would increase the risk for severe viral disease. The MDA5/IFN pathway would play a critical role in the response to SARS-CoV-2 infection mediating the extent and severity of COVID-19. Here, we genotyped a cohort of 477 patients with critical ICU COVID-19 (109 death) for three IFIH1 functional variants: rs1990760 (p.Ala946Thr), rs35337543 (splicing variant, intron 8 + 1G > C), and rs35744605 (p.Glu627Stop). The main finding of our study was a significant increased frequency of rs1990760 C-carriers in early-onset patients (< 65 years) (p = 0.01; OR = 1.64, 95%CI = 1.18-2.43). This variant was also increased in critical vs. no-ICU patients and in critical vs. asymptomatic controls. The rs35744605 C variant was associated with increased blood IL6 levels at ICU admission. The rare rs35337543 splicing variant showed a trend toward protection from early-onset critical COVID-19. In conclusion, IFIH1 variants associated with reduced gene expression and lower IFN response might contribute to develop critical COVID-19 with an age-dependent effect.

IGHG3 hinge length variation was associated with the risk of critical disease and death in a Spanish COVID-19 cohort.

IgG3 would play an important role in the immune adaptive response against SARS-CoV-2, and low plasma levels might increase the risk of COVID-19 severity and mortality. The IgG3 hinge sequence has a variable repeat of a 15 amino acid exon with common 4-repeats (M) and 3-repeats (S). This length IGHG3 polymorphism might affect the IgG3 effector functions. The short hinge length would reduce the IgG3 flexibility and impairs the neutralization and phagocytosis compared to larger length-isoforms. We genotyped the IGHG3 length polymorphism in patients with critical COVID-19 (N = 516; 107 death) and 152 moderate-severe but no-critical cases. Carriers of the S allele had an increased risk of critical ICU and mortality (p < 0.001, OR = 2.79, 95% CI = 1.66-4.65). This adverse effect might be explained by a less flexibility and reduced ability to induce phagocytosis or viral neutralization for the short length allele. We concluded that the IgG3 hinge length polymorphism could be a predictor of critical COVID-19 and the risk of death. This study was based on a limited number of patients from a single population, and requires validation in larger cohorts.

Association between the interferon-induced transmembrane protein 3 gene (IFITM3) rs34481144 / rs12252 haplotypes and COVID-19.

The interferon induced transmembrane-protein 3 (IFITM3) plays an important role in the defence against viral infection. IFITM3 gene variants have been linked to differences in expression and associated with the risk of severe influenza by some authors. More recently, these variants have been associated with the risk of COVID-19 after SARS-CoV-2 infection. We determined the effect of two common IFITM3 polymorphisms (rs34481144 â€‹C/T and rs12252 A/G) on the risk of hospitalization due to COVID-19 by comparing 484 patients (152 required support in thr intensive care unit, ICU) and 182 age and sex matched controls (no disease symptoms). We found significantly higher frequencies of rs34481144 â€‹T and rs12252 â€‹G carriers among the patients (OR â€‹= â€‹2.02 and OR â€‹= â€‹1.51, respectively). None of the two variants were associated with ICU-admission or death. We found a significantly higher frequency of rs34481144 CC â€‹+ â€‹rs12252 AA genotype carriers among the controls, suggesting a protective effect (p = 0.001, OR = 0.56, 95%CI = 0.40-0.80). Moreover, haplotype rs34481144 â€‹C - rs12252 A was significantly increased in the controls (p â€‹= â€‹0.008, OR â€‹= â€‹0.71, 95%CI â€‹= â€‹0.55-0.91). Our results showed a significant effect of the IFITM3 variants in the risk for hospitalization after SARS-CoV-2 infection.

Magnesium Deintercalation From the Spinel-Type MgMn2-y Fey O4 (0.4≤y≤2.0) by Acid-Treatment and Electrochemistry.

Rechargeable magnesium batteries attract lots of attention because of their high safety and low cost compared to lithium batteries, and it is needed to develop more efficient electrode materials. Although MgMn2 O4 is a promising material for the positive electrode in Mg rechargeable batteries, it usually exhibits poor cyclability. To improve the electrochemical behavior, we have prepared nanoparticles of MgMn2-y Fey O4 . The XRD results have confirmed that when Mn3+ (Jahn-Teller ion) ions are replaced by Fe3+ (non-Jahn-Teller ion), the resulting MgMn2-y Fey O4 is a cubic phase. The structure and theoretical voltage are theoretically calculated by using the DFT method. The obtained samples have been chemically treated in acid solution for partial demagnesiation, and it is observed that the presence of iron inhibits the deinsertion of Mg through disproportionation and favors the exchange reaction. The electrochemical behavior in non-aqueous magnesium cells has been explored.

Testing the reversible insertion of magnesium in a cation-deficient manganese oxy-spinel through a concentration cell.

Magnesium-ion batteries could be competitive with lithium-ion batteries, but the reversible intercalation of magnesium in the framework of the host material needs to be verified. A concentration cell was built by using electrodes with different concentrations of magnesium ions in the cubic spinel MgxMn2O4. For this purpose, firstly cations were partially extracted from MgMn2O4 by acid-treatment. This concentration cell was used to test the reversible intercalation of magnesium and the effect of the cationic vacancies. The theoretical results of the percolation energy can explain the lower polarization experimentally observed in the voltage curve of the acid-treated sample. The reversible capacity (ca. 115 mA h g-1) is preserved after charge-discharge cycling.

Temporal Changes in Platelet Response in Acute Coronary Syndrome Patients With Prasugrel and Clopidogrel After Stent Implantation.

BACKGROUND: Prasugrel has been shown to provide more potency and less variability than clopidogrel, but its potential temporal variability has not been described.Methods and Results:We conducted a prospective open-label study, evaluating platelet reactivity overtime in acute coronary syndrome (ACS) patients on aspirin and clopidogrel (n=60) or prasugrel (n=61), after a percutaneous coronary intervention (PCI). Blood samples were taken at discharge and at 3 and 6 months. Platelet function tests included VerifyNow (VN-P2Y12), and Multiplate Aggregometry (MEA). By means of VN-P2Y12, prasugrel patients displayed significantly (P<0.001) higher platelet inhibition than clopidogrel patients over time, although there were not significant differences using MEA. Prasugrel patients showed higher platelet inhibition at baseline than at 3 months (59.3±8.1 vs. 105.0±49.2; P<0.001), without significant change at 6 months (107.9±72.0; P=0.919 vs. 3 months). Clopidogrel patients showed a similar trend (160.1±65.1, 184.8±62.7 and 185.0±53.3; baseline vs. 3 months P=0.060; 3 months vs. 6 months P=0.974). High platelet reactivity (HPR) was shown in 16.3% prasugrel patients, with no patient consistently remaining in HPR over time. HPR was detected in 36.6% of the clopidogrel patients, being consistently observed in 15.0% of them. Low platelet reactivity (LPR) was detected in 60.5% prasugrel and 9.8% clopidogrel patients. CONCLUSIONS: Prasugrel patients showed less temporal variation than patients on clopidogrel in terms of HPR. In contrast, higher variability in LPR was detected in prasugrel patients for up to 6 months' follow-up.

Consumer Behavior in the Choice of Mode of Transport: A Case Study in the Toledo-Madrid Corridor.

Within the context of the consumption of goods or services the decisions made by individuals involve the choice between a set of discrete alternatives, such as the choice of mode of transport. The methodology for analyzing the consumer behavior are the models of discrete choice based on the Theory of Random Utility. These models are based on the definition of preferences through a utility function that is maximized. These models also denominated of disaggregated demand derived from the decision of a set of individuals, who are formalized by the application of probabilistic models. The objective of this study is to determine the behavior of the consumer in the choice of a service, namely of transport services and in a short-distance corridor, such as Toledo-Madrid. The Toledo-Madrid corridor is characterized by being short distance, with high speed train available within the choice options to get the airport, along with the bus and the car. And where offers of HST and aircraft services can be proposed as complementary modes. By applying disaggregated transport models with revealed preference survey data and declared preferences, one can determine the most important variables involved in the choice and determine the arrangements for payment of individuals. These payment provisions may condition the use of certain transport policies to promote the use of efficient transportation.

Meat quality, free fatty acid concentration, and oxidative stability of pork from animals fed diets containing different sources of selenium.

This study evaluates the effect of the source of dietary selenium supplementation (organic versus mineral) and the combined effect of organic selenium and vitamin E on the fatty acid composition and lipolysis in pork intramuscular fat and other meat quality characteristics such as drip loss and lipid stability. Higher vitamin E deposition, lower drip loss, and higher stability against oxidation were detected in muscle from pigs fed organic selenium. Also higher proportion of free fatty acids was observed in intramuscular fat from pigs fed organic selenium than those fed inorganic selenium, being these mainly coming from neutral lipid fraction. In addition, the inclusion of vitamin E in the diet enhanced such effect. Dietary organic selenium also increased Δ9-desaturase and elongase indexes and C18:1n-9 concentration. A related decrease of C18:0 concentration was also observed. Described differences in the lipid fraction composition could affect sensory characteristics of meat and meat products.

Effect of dietary selenium source (organic vs. mineral) and muscle pH on meat quality characteristics of pigs.

This study evaluates the effect of organic (Se-enriched yeast; SeY) versus inorganic selenium (sodium selenite; SeS) supplementation and the different response of selenium source according to muscle pH on pork meat quality characteristics. Pigs (n = 30) were fed the Se-supplemented diets (0.3 mg/kg) for 65 days. Neither electric conductivity (EC) nor drip loss were affected by the selenium source. The SeY group had lower TBARS in muscle samples after day 7 of refrigerated storage and higher a* values on days 1 and 7 than the SeS group. The effect of dietary selenium source on some meat quality characteristics was affected by muscle pH. Hence, as the muscle pH increases, the drip loss decreases but this effect is more marked with the dietary organic Se enrichment. Muscle pH seems to modulate the action of selenium in pork, especially some meat characteristics such as drip loss.

Differences of Perceived Image Generated through the Web Site: Empirical Evidence Obtained in Spanish Destinations.

In this paper, a study of the perceived destination image created by promotional Web Pages is expounded in an attempt to identify their differences as generators of destination image in the consumers' mind. Specifically, it seeks to analyse whether the web sites of different Spanish regions improve the image that consumers have of the destination, identifying their main dimensions and analysing its effect on satisfaction and intentions of the future behavior of potential visitors. To achieve these objectives and verify the hypotheses, a laboratory experiment was performed, where it was determined what changes are produced in the tourist's previous image after browsing the tourist webs of three different regions. Moreover, it analyses the differences in the effect of the perceived image on satisfaction and potential visitors' future behavioral intentions. The results obtained enable us to identify differences in the composition of the perceived image according to the destination, while confirming the significant effect of different perceived image dimensions regarding satisfaction. The results allow managers to gain a better understanding of the effectiveness of their sites from a consumer perspective as well as suggestions to follow in order to achieve greater efficiency in their communication actions in order to improve the motivation of visitors to go to the destination.

Cardiac Relapse of Acute Myeloid Leukemia after Allogeneic Hematopoietic Stem Cell Transplantation.

Secondary or metastatic cardiac tumors are much more common than primary benign or malignant cardiac tumors. Any tumor can cause myocardial or pericardial metastasis, although isolated or combined tumor invasion of the pericardium is more common. Types of neoplasia with the highest rates of cardiac or pericardial involvement are melanoma, lung cancer, and breast and mediastinal carcinomas. Acute myeloid leukemia (AML) is the most common type of acute leukemia in adults. Initial treatment involves chemotherapy followed by consolidation treatment to reduce the risk of relapse. In high-risk patients, the treatment of choice for consolidation is hematopoietic stem cell transplantation (HSCT). Relapse of AML is the most common cause of HSCT failure. Extramedullary relapse is rare. The organs most frequently affected, called "sanctuaries," are the testes, ovaries, and central nervous system. We present a case with extramedullary relapse in the form of a solid cardiac mass.

Clinical and radiographic outcomes of the use of four dressing materials in pulpotomized primary molars: a randomized clinical trial with 2-year follow-up.

BACKGROUND: Although multiple materials have been suggested for pulpotomized primary molars, there is no reliable evidence of the superiority of one particular type. AIM: To compare the effectiveness of formocresol (FC), mineral trioxide aggregate (MTA), ferric sulphate, and sodium hypochlorite (NaOCl) as pulp dressing agents in primary molars after 2 years. DESIGN: One hundred primary molars requiring pulp treatment were allocated randomly to the control (FC) and experimental groups (MTA, ferric sulphate, and NaOCl). Clinical and radiographic evaluations were performed at 6, 12, 18, and 24 months. Statistical analysis using Fischer's exact test was performed to determine the significant differences between groups. RESULTS: In the FC and MTA groups, 100% of the available teeth were clinically successful at all follow-up appointments. In the NaOCl group, one clinical failure was found at 18 months, and two clinical failures in the ferric sulphate group were noted at 12 and 24 months, but no significant differences were found among the groups (P = 0.41). No significant differences in radiographic success were found among all the groups at 24 months of follow-up (P = 0.303). CONCLUSIONS: No statistically significant differences among the four materials were found at 24 months suggesting that NaOCl may be an appropriate substitute for FC.

Regression of melanoma metastases after immunotherapy is associated with activation of antigen presentation and interferon-mediated rejection genes.

We present the results of a comparative gene expression analysis of 15 metastases (10 regressing and 5 progressing) obtained from 2 melanoma patients with mixed response following different forms of immunotherapy. Whole genome transcriptional analysis clearly indicate that regression of melanoma metastases is due to an acute immune rejection mediated by the upregulation of genes involved in antigen presentation and interferon mediated response (STAT-1/IRF-1) in all the regressing metastases from both patients. In contrast, progressing metastases showed low transcription levels of genes involved in these pathways. Histological analysis showed T cells and HLA-DR positive infiltrating cells in the regressing but not in the progressing metastases. Quantitative expression analysis of HLA-A,B and C genes on microdisected tumoral regions indicate higher HLA expression in regressing than in progressing metastases. The molecular signature obtained in melanoma rejection appeared to be similar to that observed in other forms of immune-mediated tissue-specific rejection such as allograft, pathogen clearance, graft versus host or autoimmune disease, supporting the immunological constant of rejection. We favor the idea that the major factor determining the success or failure of immunotherapy is the nature of HLA Class I alterations in tumor cells and not the type of immunotherapy used. If the molecular alteration is reversible by the immunotherapy, the HLA expression will be upregulated and the lesion will be recognized and rejected. In contrast, if the defect is structural the MHC Class I expression will remain unchanged and the lesion will progress.

Randomized clinical trial to assess the efficacy of a comprehensive programme of secondary prevention of cardiovascular disease in general practice: the PREseAP study.

INTRODUCTION AND OBJECTIVES: To assess the efficacy of a comprehensive program of secondary prevention of cardiovascular disease in general practice. METHODS: A cluster randomized clinical trial was carried out in a regular general practice setting. Male and female patients aged under 86 years with a diagnosis of ischemic heart disease, stroke or peripheral artery disease were recruited between January 2004 and May 2005. Study participants were seen at 42 health centers throughout the whole of Spain. The primary endpoint was the combination of all-cause mortality and hospital cardiovascular readmission at 3-year follow-up. RESULTS: In total, 1224 patients were recruited: 624 in the intervention group and 600 in the control group. The primary endpoint was observed in 29.9% (95% confidence interval [CI], 25.5-34.8%) in the intervention group and 25.6% (22.3-29.2%) in the control group (P=.15). At the end of follow-up, 8.5% (6.3-11.3%) in the intervention group and 11% (7.4-16%) in the control group were smokers (P=.07). The mean waist circumference of patients in the intervention and control groups was 100.44 cm (95% CI, 98.97-101.91 cm) and 102.58 cm (95% CI, 100.96-104.21 cm), respectively (P=.07). Overall, 20.9% (15.6-27.7%) of patients in the intervention group and 29.6% (23.9-36.1%) in the control group suffered from anxiety (P=.05), and 29.6% (22.4-37.9%) in the intervention group and 41.4% (35.8-47.3%) in the control group had depression (P=.02). CONCLUSIONS: A comprehensive program of secondary prevention of cardiovascular disease in general practice was not effective in reducing cardiovascular morbidity and mortality. However, some factors associated with a healthy lifestyle were improved and anxiety and depression were reduced.

[Factors affecting the control of blood pressure and lipid levels in patients with cardiovascular disease: the PREseAP Study]. / Determinantes del control de la presión arterial y los lípidos en pacientes con enfermedad cardiovascular (estudio PREseAP).

The aim of this observational study was to identify factors influencing the control of blood pressure (i.e., <140/90 mmHg, or <130/80 mmHg in diabetic patients) and low-density lipoprotein (LDL) cholesterol level (<100 mg/dL) in 1223 patients with cardiovascular disease. Overall, 70.2% of patients were men, and their mean age was 66.4 years. Blood pressure was poorly controlled in 50.9% (95% confidence interval [CI], 46.9%-54.8%) and the LDL cholesterol level was poorly controlled in 60.1% (95% CI, 56.3%-63.9%). Determinants of poor blood pressure control were diabetes, hypertension, no previous diagnosis of heart failure, previous diagnosis of peripheral artery disease or stroke, obesity, and no lipid-lowering treatment. Determinants of poor LDL cholesterol control were no lipid-lowering treatment, no previous diagnosis of ischemic heart disease, no antihypertensive treatment, and dyslipidemia. The factors affecting blood pressure control were different from those affecting LDL cholesterol control, an observation that should be taken into account when implementing treatment recommendations for achieving therapeutic objectives in secondary prevention.