Uncertainty model for rate of change of frequency analysis with high renewable energy participation

Large-scale integration of inverter-based renewables is displacing synchronous machine generation, causing a reduction in the inertia of electrical power systems. This reduction is reflected in an increase in the rate of change of frequency (RoCoF). Additionally, the variation of the RoCoF will depend on the uncertainty associated with the generation of non-conventional renewable energy sources. For the planning of the operation of the system, it is essential to know the range of variation of the RoCoF when there are disturbances in the system and uncertainties in the generation of non-conventional sources of renewable energy. This paper proposes to establish the calculation of a confidence interval of the RoCoF variation that considers these uncertainties. So, this paper proposes a method to consider these uncertainties based on the probabilistic point estimate method (PEM); considering multiple renewable non-conventional sources with correlated or uncorrelated behavior in their powers injected into the system. On the other hand, as there are different proposals to calculate the RoCoF, this paper presents the application of the uncertainty model with three different RoCoF proposed calculation methods

Exploring a Tetrahydroquinoline Antimalarial Hit from the Medicines for Malaria Pathogen Box and Identification of its Mode of Resistance as PfeEF2

New antimalarial treatments with novel mechanism of action are needed to tackle Plasmodium falciparum infections that are resistant to first-line therapeutics. Here we report the exploration of MMV692140 ( 2 ) from the Pathogen Box, a collection of 400 compounds that was made available by Medicines for Malaria Venture (MMV) in 2015. Compound 2 was profiled in in vitro models of malaria and was found to be active against multiple life-cycle stages of Plasmodium parasites. The mode of resistance, and putatively its mode of action, was identified as Plasmodium falciparum translation elongation factor 2 ( Pf eEF2), which is responsible for the GTP-dependent translocation of the ribosome along mRNA. The compound maintains activity against a series of drug-resistant parasite strains. The structural motif of the tetrahydroquinoline ( 2 ) was explored in a chemistry program with its structure-activity relationships examined, resulting in the identification of an analog with 30-fold improvement of antimalarial asexual blood stage potency

Preclinical characterization and target validation of the antimalarial pantothenamide MMV693183.

Drug resistance and a dire lack of transmission-blocking antimalarials hamper malaria elimination. Here, we present the pantothenamide MMV693183 as a first-in-class acetyl-CoA synthetase (AcAS) inhibitor to enter preclinical development. Our studies demonstrate attractive drug-like properties and in vivo efficacy in a humanized mouse model of Plasmodium falciparum infection. The compound shows single digit nanomolar in vitro activity against P. falciparum and P. vivax clinical isolates, and potently blocks P. falciparum transmission to Anopheles mosquitoes. Genetic and biochemical studies identify AcAS as the target of the MMV693183-derived antimetabolite, CoA-MMV693183. Pharmacokinetic-pharmacodynamic modelling predict that a single 30 mg oral dose is sufficient to cure a malaria infection in humans. Toxicology studies in rats indicate a \u3e 30-fold safety margin in relation to the predicted human efficacious exposure. In conclusion, MMV693183 represents a promising candidate for further (pre)clinical development with a novel mode of action for treatment of malaria and blocking transmission

The antimalarial MMV688533 provides potential for single-dose cures with a high barrier to

The emergence and spread of Plasmodium falciparum resistance to first-line antimalarials creates an imperative to identify and develop potent preclinical candidates with distinct modes of action. Here, we report the identification of MMV688533, an acylguanidine that was developed following a whole-cell screen with compounds known to hit high-value targets in human cells. MMV688533 displays fast parasite clearance in vitro and is not cross-resistant with known antimalarials. In a P. falciparum NSG mouse model, MMV688533 displays a long-lasting pharmacokinetic profile and excellent safety. Selection studies reveal a low propensity for resistance, with modest loss of potency mediated by point mutations in PfACG1 and PfEHD. These proteins are implicated in intracellular trafficking, lipid utilization, and endocytosis, suggesting interference with these pathways as a potential mode of action. This preclinical candidate may offer the potential for a single low-dose cure for malaria

The antimalarial MMV688533 provides potential for single-dose cures with a high barrier to

The emergence and spread of Plasmodium falciparum resistance to first-line antimalarials creates an imperative to identify and develop potent preclinical candidates with distinct modes of action. Here, we report the identification of MMV688533, an acylguanidine that was developed following a whole-cell screen with compounds known to hit high-value targets in human cells. MMV688533 displays fast parasite clearance in vitro and is not cross-resistant with known antimalarials. In a P. falciparum NSG mouse model, MMV688533 displays a long-lasting pharmacokinetic profile and excellent safety. Selection studies reveal a low propensity for resistance, with modest loss of potency mediated by point mutations in PfACG1 and PfEHD. These proteins are implicated in intracellular trafficking, lipid utilization, and endocytosis, suggesting interference with these pathways as a potential mode of action. This preclinical candidate may offer the potential for a single low-dose cure for malaria

FinanceColombia

Las asesorías financieras debido al sector son de las empresas más sólidas del país debido a que existe gente que desconoce muchos aspectos y temas financieros, es por esto que acuden a ellas buscando asesorías en temas que en otros países son de conocimiento de todos, por eso innovando a través de las asesorías financieras se desarrolla este plan de negocio buscando estructurar un excelente servicio para las personas que necesitan una asesoría financiera y no la utilizan debido a que tienen ciertos paradigmas a cerca los sectores financieros del país, esta plan de negocios estructura los aspectos más importantes para elaborar una empresa para conocer qué tan viable es el proyecto de emprendimiento sobre una asesoría financiera innovadora.Financial advice due to the sector are of the strongest companies in the country because there are people who know many aspects and financial issues, which is why they come to them seeking advice on issues in other countries are known to all, so innovating through financial advice this business plan is developed looking to structure an excellent service for people who need financial advice and not use it because they have certain paradigms about the financial sectors of the country, this business plan structure the most important to develop a company to know how viable is the project of entrepreneurship on an innovative financial advisory aspects.Profesional en Finanzas y Comercio Exterio

Difference in the duration of pediatric diabetic ketoacidosis: Comparison of new-onset to known type 1 diabetes

Objective: To compare the duration (hours until (Formula presented.) ? 15 mmol/L) of diabetic ketoacidosis (DKA) episodes that are the first manifestation of new type 1 diabetes (NT1D) and those that are a complication in patients with previously diagnosed type 1 diabetes (PT1D). Methods: A multicenter retrospective cohort study was designed. The duration of DKA was measured from the start of the treatment. The primary outcome was the comparison of the time needed in each group to reach (Formula presented.) ? 15 mmol/L. The secondary outcomes were the comparison of the time to reach pH ? 7.3 and length of hospital stay in each group. Data were analyzed with a bivariate analysis of the variables vs primary outcome. Then, a regression model was analyzed. Results There were 305 episodes included (NT1D: 115, PT1D: 190). DKA in the NT1D group lasted longer (NT1D 20 (16-19) vs PT1D 12 (8-16), hours, P less than .01) with a significant difference in each level of DKA severity. This group also took longer to reach pH ? 7.3 (NT1D 16 (12-22) vs PT1D 9 (6-12), hours, P less than .01) and had a longer hospital stay (NT1D 9 (6-12) vs PT1D 7 (4-10), hours, P less than .01). Conclusion: The duration of DKA is longer in patients with NT1D regardless of characteristics like DKA severity, duration of symptoms, and type of treatments received. © 2020 John Wiley and Sons A/S. Published by John Wiley and Sons Lt

Difference in the duration of pediatric diabetic ketoacidosis: Comparison of new-onset to known type 1 diabetes

Objective: To compare the duration (hours until (Formula presented.) ? 15 mmol/L) of diabetic ketoacidosis (DKA) episodes that are the first manifestation of new type 1 diabetes (NT1D) and those that are a complication in patients with previously diagnosed type 1 diabetes (PT1D). Methods: A multicenter retrospective cohort study was designed. The duration of DKA was measured from the start of the treatment. The primary outcome was the comparison of the time needed in each group to reach (Formula presented.) ? 15 mmol/L. The secondary outcomes were the comparison of the time to reach pH ? 7.3 and length of hospital stay in each group. Data were analyzed with a bivariate analysis of the variables vs primary outcome. Then, a regression model was analyzed. Results There were 305 episodes included (NT1D: 115, PT1D: 190). DKA in the NT1D group lasted longer (NT1D 20 (16-19) vs PT1D 12 (8-16), hours, P less than .01) with a significant difference in each level of DKA severity. This group also took longer to reach pH ? 7.3 (NT1D 16 (12-22) vs PT1D 9 (6-12), hours, P less than .01) and had a longer hospital stay (NT1D 9 (6-12) vs PT1D 7 (4-10), hours, P less than .01). Conclusion: The duration of DKA is longer in patients with NT1D regardless of characteristics like DKA severity, duration of symptoms, and type of treatments received. © 2020 John Wiley and Sons A/S. Published by John Wiley and Sons Lt

Plasmodium falciparum K13 mutations in Africa and Asia impact artemisinin resistance and parasite fitness

The emergence of mutant K13-mediated artemisinin (ART) resistance in Plasmodium falciparum malaria parasites has led to widespread treatment failures across Southeast Asia. In Africa, K13-propeller genotyping confirms the emergence of the R561H mutation in Rwanda and highlights the continuing dominance of wild-type K13 elsewhere. Using gene editing, we show that R561H, along with C580Y and M579I, confer elevated in vitro ART resistance in some African strains, contrasting with minimal changes in ART susceptibility in others. C580Y and M579I cause substantial fitness costs, which may slow their dissemination in high-transmission settings, in contrast with R561H that in African 3D7 parasites is fitness neutral. In Cambodia, K13 genotyping highlights the increasing spatio-temporal dominance of C580Y. Editing multiple K13 mutations into a panel of Southeast Asian strains reveals that only the R561H variant yields ART resistance comparable to C580Y. In Asian Dd2 parasites C580Y shows no fitness cost, in contrast with most other K13 mutations tested, including R561H. Editing of point mutations in ferredoxin or mdr2, earlier associated with resistance, has no impact on ART susceptibility or parasite fitness. These data underline the complex interplay between K13 mutations, parasite survival, growth and genetic background in contributing to the spread of ART resistance