Left Ventricular Dysfunction and Plasmatic NT-proBNP Are Associated with Adverse Evolution in Respiratory Syncytial Virus Bronchiolitis

Aim: To investigate whether the presence of left ventricular myocardial dysfunction (LVMD) assessed by Tei index (LVTX) impacts the outcomes of healthy infants with Respiratory Syncytial Virus Bronchiolitis (RSVB). To explore whether N-terminal pro-B-type natriuretic peptide (NT-proBNP) increases the accuracy of traditional clinical markers in predicting the outcomes. Methods: A single-centre, prospective, cohort study including healthy infants aged 1–12 months old admitted for RSVB between 1 October 2016 and 1 April 2017. All patients underwent clinical, laboratory and echocardiographic evaluation within 24 h of admission. Paediatric intensive care unit (PICU) admission was defined as severe disease. Results: We enrolled 50 cases of RSVB (median age of 2 (1–6.5) months; 40% female) and 50 age-matched controls. We observed higher values of LVTX in infants with RSVB than in controls (0.42 vs. 0.36; p = 0.008). Up to nine (18%) children presented with LVMD (LVTX > 0.5), with a higher incidence of PICU admission (89% vs. 5%; p < 0.001). The diagnostic performance of NT-proBNP in predicting LVMD was high (area under the receiver operator characteristic curve (AUC) 0.95, CI 95% 0.90–1). The diagnostic yield of the predictive model for PICU admission that included NT-proBNP was excellent (AUC 0.945, CI 95% 0.880–1), and significantly higher than the model without NT-proBNP (p = 0.026). Conclusions: LVMD could be present in healthy infants with RSVB who develop severe disease. NT-proBNP seems to improve traditional clinical markers for outcomes

Lipid profile, cardiovascular disease and mortality in a Mediterranean high-risk population: The ESCARVAL-RISK study.

The potential impact of targeting different components of an adverse lipid profile in populations with multiple cardiovascular risk factors is not completely clear. This study aims to assess the association between different components of the standard lipid profile with all-cause mortality and hospitalization due to cardiovascular events in a high-risk population. This prospective registry included high risk adults over 30 years old free of cardiovascular disease (2008-2012). Diagnosis of hypertension, dyslipidemia or diabetes mellitus was inclusion criterion. Lipid biomarkers were evaluated. Primary endpoints were all-cause mortality and hospital admission due to coronary heart disease or stroke. We estimated adjusted rate ratios (aRR), absolute risk differences and population attributable risk associated with adverse lipid profiles. 51,462 subjects were included with a mean age of 62.6 years (47.6% men). During an average follow-up of 3.2 years, 919 deaths, 1666 hospitalizations for coronary heart disease and 1510 hospitalizations for stroke were recorded. The parameters that showed an increased rate for total mortality, coronary heart disease and stroke hospitalization were, respectively, low HDL-Cholesterol: aRR 1.25, 1.29 and 1.23; high Total/HDL-Cholesterol: aRR 1.22, 1.38 and 1.25; and high Triglycerides/HDL-Cholesterol: aRR 1.21, 1.30, 1.09. The parameters that showed highest population attributable risk (%) were, respectively, low HDL-Cholesterol: 7.70, 11.42, 8.40; high Total/HDL-Cholesterol: 6.55, 12.47, 8.73; and high Triglycerides/HDL-Cholesterol: 8.94, 15.09, 6.92. In a population with cardiovascular risk factors, HDL-cholesterol, Total/HDL-cholesterol and triglycerides/HDL-cholesterol ratios were associated with a higher population attributable risk for cardiovascular disease compared to other common biomarkers.S

Discovery of first-in-class reversible dual small molecule inhibitors against G9a and DNMTs in hematological malignancies

The indisputable role of epigenetics in cancer and the fact that epigenetic alterations can be reversed have favoured development of epigenetic drugs. In this study, we design and synthesize potent novel, selective and reversible chemical probes that simultaneously inhibit the G9a and DNMTs methyltransferase activity. In vitro treatment of haematological neoplasia (acute myeloid leukaemia-AML, acute lymphoblastic leukaemia-ALL and diffuse large B-cell lymphoma-DLBCL) with the lead compound CM-272, inhibits cell proliferation and promotes apoptosis, inducing interferon-stimulated genes and immunogenic cell death. CM-272 significantly prolongs survival of AML, ALL and DLBCL xenogeneic models. Our results represent the discovery of first-in-class dual inhibitors of G9a/DNMTs and establish this chemical series as a promising therapeutic tool for unmet needs in haematological tumours.We particularly acknowledge the Biobank of the University of Navarra for its collaboration. We thank Dr Edorta Martínez de Marigorta and Dr Francisco Palacios from Departamento de Química Orgánica I, Facultad de Farmacia, Universidad del Pais Vasco for 13C NMR determination and Angel Irigoyen Barrio and Dr Ana Romo Hualde, from University of Navarra, for HRMS determination. Dr. Irene de Miguel Turrullols from Small Molecule Discovery Platform, CIMA, University of Navarra is acknowledged for NMR data interpretation. This work was funded by grants from Instituto de Salud Carlos III (ISCIII) PI10/01691, PI13/01469, PI14/01867, PI10/2983, TRASCAN (EPICA), CIBERONC, cofinanciacion FEDER, RTICC RD12/0036/0068, Fundació La Marató de TV3 (20132130-31-32) and ‘Fundación Fuentes Dutor’. B.P. is supported by a Sara Borrell fellowship CD13/00340 and X.A. is a Marie Curie researcher under contract ‘LincMHeM-330598’.S

Impact Of Antibiotic Resistance in Latin America in The Last Decade

Los antibióticos son medicamentos usados para tratar infecciones bacterianas, pero su uso indiscriminado, automedicación entre otras condiciones pueden llevar a un paciente a la resistencia a los antibióticos. Diferentes mecanismos pueden mediar la aparición de la resistencia a los antibióticos como por ejemplo su resistencia intrínseca. Por ello, hemos realizado una búsqueda bibliográfica de artículos en inglés y español en bases de datos nacionales e internacionales que nos dieron como resultados diferentes reportes de casos en los que se evidencia la resistencia a los antibióticos y el impacto en Latinoamérica en los últimos años. Por lo que nos lleva a concluir que la resistencia a los antibióticos es una de las mayores preocupaciones hoy en día debido a la disminución de la efectividad de un tratamiento.Antibiotics are medications used to treat bacterial infections, but their indiscriminate use, self-medication among other conditions can lead a patient to antibiotic resistance. Different mechanisms can mediate the emergence of resistance to antibiotics, such as intrinsic resistance. For this reason, we have carried out a bibliographic search of articles in English and Spanish in national and international databases that gave us different case reports in which resistance to antibiotics and the impact in Latin America in recent years is evident. Therefore, it leads us to conclude that antibiotic resistance is one of the biggest concerns today due to the decrease in the effectiveness of a treatment

Lipid profile, cardiovascular disease and mortality in a Mediterranean high-risk population: the ESCARVAL-RISK study

The potential impact of targeting different components of an adverse lipid profile in populations with multiple cardiovascular risk factors is not completely clear. This study aims to assess the association between different components of the standard lipid profile with all cause mortality and hospitalization due to cardiovascular events in a high-risk population. Methods This prospective registry included high risk adults over 30 years old free of cardiovascular disease (2008±2012). Diagnosis of hypertension, dyslipidemia or diabetes mellitus was inclusion criterion. Lipid biomarkers were evaluated. Primary endpoints were all-cause mortality and hospital admission due to coronary heart disease or stroke. We estimated adjusted rate ratios (aRR), absolute risk differences and population attributable risk associated with adverse lipid profiles. Results 51,462 subjects were included with a mean age of 62.6 years (47.6% men). During an average follow-up of 3.2 years, 919 deaths, 1666 hospitalizations for coronary heart disease and 1510 hospitalizations for stroke were recorded. The parameters that showed an increased rate for total mortality, coronary heart disease and stroke hospitalization were, respectively, low HDL-Cholesterol: aRR 1.25, 1.29 and 1.23; high Total/HDL-Cholesterol: aRR 1.22, 1.38 and 1.25; and high Triglycerides/HDL-Cholesterol: aRR 1.21, 1.30, 1.09. The parameters that showed highest population attributable risk (%) were, respectively, low HDL-Cholesterol: 7.70, 11.42, 8.40; high Total/HDL-Cholesterol: 6.55, 12.47, 8.73; and high Triglycerides/ HDL-Cholesterol: 8.94, 15.09, 6.92. Conclusions In a population with cardiovascular risk factors, HDL-cholesterol, Total/HDL-cholesterol and triglycerides/HDL-cholesterol ratios were associated with a higher population attributable risk for cardiovascular disease compared to other common biomarkers

Correction: Lipid profile, cardiovascular disease and mortality in a Mediterranean high-risk population: The ESCARVAL-RISK study.

The potential impact of targeting different components of an adverse lipid profile in populations with multiple cardiovascular risk factors is not completely clear. This study aims to assess the association between different components of the standard lipid profile with all-cause mortality and hospitalization due to cardiovascular events in a high-risk populatio

Exploring Cosmic Origins with CORE: Cosmological Parameters

We forecast the main cosmological parameter constraints achievable with theCORE space mission which is dedicated to mapping the polarisation of the CosmicMicrowave Background (CMB). CORE was recently submitted in response to ESA'sfifth call for medium-sized mission proposals (M5). Here we report the resultsfrom our pre-submission study of the impact of various instrumental options, inparticular the telescope size and sensitivity level, and review the great,transformative potential of the mission as proposed. Specifically, we assessthe impact on a broad range of fundamental parameters of our Universe as afunction of the expected CMB characteristics, with other papers in the seriesfocusing on controlling astrophysical and instrumental residual systematics. Inthis paper, we assume that only a few central CORE frequency channels areusable for our purpose, all others being devoted to the cleaning ofastrophysical contaminants. On the theoretical side, we assume LCDM as ourgeneral framework and quantify the improvement provided by CORE over thecurrent constraints from the Planck 2015 release. We also study the jointsensitivity of CORE and of future Baryon Acoustic Oscillation and Large ScaleStructure experiments like DESI and Euclid. Specific constraints on the physicsof inflation are presented in another paper of the series. In addition to thesix parameters of the base LCDM, which describe the matter content of aspatially flat universe with adiabatic and scalar primordial fluctuations frominflation, we derive the precision achievable on parameters like thosedescribing curvature, neutrino physics, extra light relics, primordial heliumabundance, dark matter annihilation, recombination physics, variation offundamental constants, dark energy, modified gravity, reionization and cosmicbirefringence. (ABRIDGED

Clonal chromosomal mosaicism and loss of chromosome Y in elderly men increase vulnerability for SARS-CoV-2

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) had an estimated overall case fatality ratio of 1.38% (pre-vaccination), being 53% higher in males and increasing exponentially with age. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, we found 133 cases (1.42%) with detectable clonal mosaicism for chromosome alterations (mCA) and 226 males (5.08%) with acquired loss of chromosome Y (LOY). Individuals with clonal mosaic events (mCA and/or LOY) showed a 54% increase in the risk of COVID-19 lethality. LOY is associated with transcriptomic biomarkers of immune dysfunction, pro-coagulation activity and cardiovascular risk. Interferon-induced genes involved in the initial immune response to SARS-CoV-2 are also down-regulated in LOY. Thus, mCA and LOY underlie at least part of the sex-biased severity and mortality of COVID-19 in aging patients. Given its potential therapeutic and prognostic relevance, evaluation of clonal mosaicism should be implemented as biomarker of COVID-19 severity in elderly people. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, individuals with clonal mosaic events (clonal mosaicism for chromosome alterations and/or loss of chromosome Y) showed an increased risk of COVID-19 lethality

Evaluating the Effects of SARS-CoV-2 Spike Mutation D614G on Transmissibility and Pathogenicity.

Global dispersal and increasing frequency of the SARS-CoV-2 spike protein variant D614G are suggestive of a selective advantage but may also be due to a random founder effect. We investigate the hypothesis for positive selection of spike D614G in the United Kingdom using more than 25,000 whole genome SARS-CoV-2 sequences. Despite the availability of a large dataset, well represented by both spike 614 variants, not all approaches showed a conclusive signal of positive selection. Population genetic analysis indicates that 614G increases in frequency relative to 614D in a manner consistent with a selective advantage. We do not find any indication that patients infected with the spike 614G variant have higher COVID-19 mortality or clinical severity, but 614G is associated with higher viral load and younger age of patients. Significant differences in growth and size of 614G phylogenetic clusters indicate a need for continued study of this variant

Cardiovascular disease, chronic kidney disease, and diabetes mortality burden of cardiometabolic risk factors from 1980 to 2010: A comparative risk assessment

Background: High blood pressure, blood glucose, serum cholesterol, and BMI are risk factors for cardiovascular diseases and some of these factors also increase the risk of chronic kidney disease and diabetes. We estimated mortality from cardiovascular diseases, chronic kidney disease, and diabetes that was attributable to these four cardiometabolic risk factors for all countries and regions from 1980 to 2010. Methods: We used data for exposure to risk factors by country, age group, and sex from pooled analyses of population-based health surveys. We obtained relative risks for the effects of risk factors on cause-specific mortality from meta-analyses of large prospective studies. We calculated the population attributable fractions for each risk factor alone, and for the combination of all risk factors, accounting for multicausality and for mediation of the effects of BMI by the other three risks. We calculated attributable deaths by multiplying the cause-specific population attributable fractions by the number of disease-specific deaths. We obtained cause-specific mortality from the Global Burden of Diseases, Injuries, and Risk Factors 2010 Study. We propagated the uncertainties of all the inputs to the final estimates. Findings: In 2010, high blood pressure was the leading risk factor for deaths due to cardiovascular diseases, chronic kidney disease, and diabetes in every region, causing more than 40% of worldwide deaths from these diseases; high BMI and glucose were each responsible for about 15% of deaths, and high cholesterol for more than 10%. After accounting for multicausality, 63% (10·8 million deaths, 95% CI 10·1-11·5) of deaths from these diseases in 2010 were attributable to the combined effect of these four metabolic risk factors, compared with 67% (7·1 million deaths, 6·6-7·6) in 1980. The mortality burden of high BMI and glucose nearly doubled from 1980 to 2010. At the country level, age-standardised death rates from these diseases attributable to the combined effects of these four risk factors surpassed 925 deaths per 100 000 for men in Belarus, Kazakhstan, and Mongolia, but were less than 130 deaths per 100 000 for women and less than 200 for men in some high-income countries including Australia, Canada, France, Japan, the Netherlands, Singapore, South Korea, and Spain. Interpretation: The salient features of the cardiometabolic disease and risk factor epidemic at the beginning of the 21st century are high blood pressure and an increasing effect of obesity and diabetes. The mortality burden of cardiometabolic risk factors has shifted from high-income to low-income and middle-income countries. Lowering cardiometabolic risks through dietary, behavioural, and pharmacological interventions should be a part of the global response to non-communicable diseases. Funding: UK Medical Research Council, US National Institutes of Health. © 2014 Elsevier Ltd