In light of the increasing rate of dengue infections throughout the world despite vector-control measures, several dengue vaccine candidates are in development.
In a phase 3 efficacy trial of a ...tetravalent dengue vaccine in five Latin American countries where dengue is endemic, we randomly assigned healthy children between the ages of 9 and 16 years in a 2:1 ratio to receive three injections of recombinant, live, attenuated, tetravalent dengue vaccine (CYD-TDV) or placebo at months 0, 6, and 12 under blinded conditions. The children were then followed for 25 months. The primary outcome was vaccine efficacy against symptomatic, virologically confirmed dengue (VCD), regardless of disease severity or serotype, occurring more than 28 days after the third injection.
A total of 20,869 healthy children received either vaccine or placebo. At baseline, 79.4% of an immunogenicity subgroup of 1944 children had seropositive status for one or more dengue serotypes. In the per-protocol population, there were 176 VCD cases (with 11,793 person-years at risk) in the vaccine group and 221 VCD cases (with 5809 person-years at risk) in the control group, for a vaccine efficacy of 60.8% (95% confidence interval CI, 52.0 to 68.0). In the intention-to-treat population (those who received at least one injection), vaccine efficacy was 64.7% (95% CI, 58.7 to 69.8). Serotype-specific vaccine efficacy was 50.3% for serotype 1, 42.3% for serotype 2, 74.0% for serotype 3, and 77.7% for serotype 4. Among the severe VCD cases, 1 of 12 was in the vaccine group, for an intention-to-treat vaccine efficacy of 95.5%. Vaccine efficacy against hospitalization for dengue was 80.3%. The safety profile for the CYD-TDV vaccine was similar to that for placebo, with no marked difference in rates of adverse events.
The CYD-TDV dengue vaccine was efficacious against VCD and severe VCD and led to fewer hospitalizations for VCD in five Latin American countries where dengue is endemic. (Funded by Sanofi Pasteur; ClinicalTrials.gov number, NCT01374516.).
Abstract
Human malaria is a devastating disease and a major cause of poverty in resource-limited countries. To develop and adapt within hosts Plasmodium falciparum undergoes drastic switches in gene ...expression. To identify regulatory regions in the parasite genome, we performed genome-wide profiling of chromatin accessibility in two culture-adapted isogenic subclones at four developmental stages during the intraerythrocytic cycle by using the Assay for Transposase-Accessible Chromatin by sequencing (ATAC-seq). Tn5 transposase hypersensitivity sites (THSSs) localize preferentially at transcriptional start sites (TSSs). Chromatin accessibility by ATAC-seq is predictive of active transcription and of the levels of histone marks H3K9ac and H3K4me3. Our assay allows the identification of novel regulatory regions including TSS and enhancer-like elements. We show that the dynamics in the accessible chromatin profile matches temporal transcription during development. Motif analysis of stage-specific ATAC-seq sites predicts the in vivo binding sites and function of multiple ApiAP2 transcription factors. At last, the alternative expression states of some clonally variant genes (CVGs), including eba, phist, var and clag genes, associate with a differential ATAC-seq signal at their promoters. Altogether, this study identifies genome-wide regulatory regions likely to play an essential function in the developmental transitions and in CVG expression in P. falciparum.
Real‐space tools were employed to show that the chemical bonding scenario used routinely to understand ground states lacks the necessary flexibility in excited states. It is shown that, even for ...two‐center, two‐electron bonds, the real‐space bond orders have exotic values that have never been reported. The nature of these situations was uncovered by using electron‐counting techniques that provide an appealing statistical interpretation of bonding descriptors, together with simple physical models. Bond orders greater than one as well as negative bond orders for a single bonding electron pair emerge in situations in which the electrons in the pair show a gregarious (bosonic) instead of the usual lonely (fermionic) behavior. In the first case the gregarious pair is intra‐atomic, whereas the coupling is interatomic in the second. A number of examples are used to substantiate these claims.
Real‐space tools were employed to show that the chemical bonding scenario used routinely to understand ground states lacks the required flexibility for excited states. Real‐space bond orders can have previously unreported exotic values, and bond orders greater than one and negative bond orders for a single electron pair emerge in situations in which the electrons in a bonding pair show a gregarious (bosonic) instead of the usual lonely (fermionic) behavior (see figure).
Multisystem inflammatory syndrome temporally associated with COVID-19 (MIS-C) has been described as a novel and often severe presentation of SARS-CoV-2 infection in children. We aimed to describe the ...characteristics of children admitted to Pediatric Intensive Care Units (PICUs) presenting with MIS-C in comparison with those admitted with SARS-CoV-2 infection with other features such as COVID-19 pneumonia.
A multicentric prospective national registry including 47 PICUs was carried out. Data from children admitted with confirmed SARS-CoV-2 infection or fulfilling MIS-C criteria (with or without SARS-CoV-2 PCR confirmation) were collected. Clinical, laboratory and therapeutic features between MIS-C and non-MIS-C patients were compared.
Seventy-four children were recruited. Sixty-one percent met MIS-C definition. MIS-C patients were older than non-MIS-C patients (p = 0.002): 9.4 years (IQR 5.5-11.8) vs 3.4 years (IQR 0.4-9.4). A higher proportion of them had no previous medical history of interest (88.2% vs 51.7%, p = 0.005). Non-MIS-C patients presented more frequently with respiratory distress (60.7% vs 13.3%, p < 0.001). MIS-C patients showed higher prevalence of fever (95.6% vs 64.3%, p < 0.001), diarrhea (66.7% vs 11.5%, p < 0.001), vomits (71.1% vs 23.1%, p = 0.001), fatigue (65.9% vs 36%, p = 0.016), shock (84.4% vs 13.8%, p < 0.001) and cardiac dysfunction (53.3% vs 10.3%, p = 0.001). MIS-C group had a lower lymphocyte count (p < 0.001) and LDH (p = 0.001) but higher neutrophil count (p = 0.045), neutrophil/lymphocyte ratio (p < 0.001), C-reactive protein (p < 0.001) and procalcitonin (p < 0.001). Patients in the MIS-C group were less likely to receive invasive ventilation (13.3% vs 41.4%, p = 0.005) but were more often treated with vasoactive drugs (66.7% vs 24.1%, p < 0.001), corticosteroids (80% vs 44.8%, p = 0.003) and immunoglobulins (51.1% vs 6.9%, p < 0.001). Most patients were discharged from PICU by the end of data collection with a median length of stay of 5 days (IQR 2.5-8 days) in the MIS-C group. Three patients died, none of them belonged to the MIS-C group.
MIS-C seems to be the most frequent presentation among critically ill children with SARS-CoV-2 infection. MIS-C patients are older and usually healthy. They show a higher prevalence of gastrointestinal symptoms and shock and are more likely to receive vasoactive drugs and immunomodulators and less likely to need mechanical ventilation than non-MIS-C patients.
Natal dispersal, the movement between the birth and the first breeding site, has been rarely studied in long-lived territorial birds with a long-lasting pre-breeding stage. Here we benefited from the ...long-term monitoring programs of six populations of Egyptian vultures (Neophron percnopterus) from Spain and France to study how the rearing environment determines dispersal. For 124 vultures, we recorded a median dispersal distance of 48 km (range 0-656 km). Linear models were used to assess the effect of population and individual traits on dispersal distance at two spatial scales. Dispersal distances were inversely related to vulture density in the natal population, suggesting that birds perceive the abundance of conspecifics as a signal of habitat quality. This was particularly true for declining populations, so increasing levels of opportunistic philopatry seemed to arise in high density contexts as a consequence of vacancies created by human-induced adult mortality. Females dispersed further than males, but males were more sensitive to the social environment, indicating different dispersal tactics. Both sexes were affected by different individual attributes simultaneously and interactively with this social context. These results highlight that complex phenotype-by-environment interactions should be considered for advancing our understanding of dispersal dynamics in long-lived organisms.
Variation in offspring sex ratio, particularly in birds, has been frequently studied over the last century, although seldom using long‐term monitoring data. In raptors, the cost of raising males and ...females is not equal, and several variables have been found to have significant effects on sex ratio, including food availability, parental age, and hatching order. Sex ratio differences between island populations and their mainland counterparts have been poorly documented, despite broad scientific literature on the island syndrome reporting substantial differences in population demography and ecology. Here, we assessed individual and environmental factors potentially affecting the secondary sex ratio of the long‐lived Egyptian vulture Neophron percnopterus. We used data collected from Spanish mainland and island populations over a ca. 30‐year period (1995–2021) to assess the effects of insularity, parental age, breeding phenology, brood size, hatching order, type of breeding unit (pairs vs. trios), and spatial and temporal variability on offspring sex ratio. No sex bias was found at the population level, but two opposite trends were observed between mainland and island populations consistent with the island syndrome. Offspring sex ratio was nonsignificantly female‐biased in mainland Spain (0.47, n = 1112) but significantly male‐biased in the Canary Islands (0.55, n = 499), where a male‐biased mortality among immatures could be compensating for offspring biases and maintaining a paired adult sex ratio. Temporal and spatial variation in food availability might also have some influence on sex ratio, although the difficulties in quantifying them preclude us from determining the magnitude of such influence. This study shows that insularity influences the offspring sex ratio of the Egyptian vulture through several processes that can affect island and mainland populations differentially. Our research contributes to improving our understanding of sex allocation theory by investigating whether sex ratio deviations from parity are possible as a response to changing environments comprised by multiple and complexly interrelated factors.
We assessed individual and environmental factors potentially affecting the offspring sex ratio of the Egyptian vulture (Neophron percnopterus), collected from Spanish mainland and island populations over a ca. 30‐year period (1995–2021). Offspring sex ratio was nonsignificantly female‐biased in mainland Spain while significantly male‐biased in the Canary Islands, where a male‐biased mortality among immatures could be compensating for offspring biases and maintaining a paired adult sex ratio.
Transcutaneous electrical stimulation can depolarize nerve or muscle cells applying impulses through electrodes attached on the skin. For these applications, the electrode-skin impedance is an ...important factor which influences effectiveness. Various models describe the interface using constant or current-depending resistive-capacitive equivalent circuit. Here, we develop a dynamic impedance model valid for a wide range stimulation intensities. The model considers electroporation and charge-dependent effects to describe the impedance variation, which allows to describe high-charge pulses. The parameters were adjusted based on rectangular, biphasic stimulation pulses generated by a stimulator, providing optionally current or voltage-controlled impulses, and applied through electrodes of different sizes. Both control methods deliver a different electrical field to the tissue, which is constant throughout the impulse duration for current-controlled mode or have a very current peak for voltage-controlled. The results show a predominant dependence in the current intensity in the case of both stimulation techniques that allows to keep a simple model. A verification simulation using the proposed dynamic model shows coefficient of determination of around 0.99 in both stimulation types. The presented method for fitting electrode-skin impedance can be simple extended to other stimulation waveforms and electrode configuration. Therefore, it can be embedded in optimization algorithms for designing electrical stimulation applications even for pulses with high charges and high current spikes.
This work deals with educational text mining, a field of natural language processing applied to education. The objective is to classify the feedback generated by teachers in online courses to the ...activities sent by students according to the model of Hattie and Timperley (2007), considering that feedback may be at the levels task, process, regulation, praise and other. Four multi-label classification methods of the data transformation approach - binary relevance, classification chains, power labelset and rakel-d - are compared with the base algorithms SVM, Random Forest, Logistic Regression and Naive Bayes. The methodology was applied to a case study in which 11013 feedbacks written in Spanish language from 121 online courses of the Law degree from a public university in Mexico were collected from the Blackboard learning manager system. The results show that the random forests algorithms and vector support machines will have the best performance when using the binary relevance transformation and classifier chains methods.
En 1921 se celebró una subasta de antigüedades en Nueva York en la que se vendió un retablo de pequeño formato que pudo pertenecer a una capilla u oratorio privado. Un siglo después, en 2020, esta ...pieza ha sido adquirida por el Grupo Jorge y en la actualidad forma parte de su colección de arte medieval en Zaragoza. En este trabajo se ha reconstruido el periplo de esta pieza desde que salió de España en 1921 hasta la actualidad y, además gracias a una fotografía antigua, hemos podido identificar que este retablo perteneció a un personaje cercano al arzobispo Domingo Ram.
Hemp seeds (HS) constitute a rich nutrient source and contain γ‐linolenic acid (GLA, 18:3, n‐6), which is a healthy fatty acid (FA). The objectives of this research are i) to look for GLA‐rich ...varieties of unhusked hemp seeds (UHS) and commercial hulled hemp seeds (HHS); ii) to check the influence of different extracting systems on both oil yield and FA profiles; iii) to test a simultaneous oil extraction/GLA‐enrichment process looking to improve GLA content. Hop and European hackberry seeds (both from Cannabaceae family) are also analyzed for comparative purposes. GLA is the most discriminant FA among UHS varieties, ranging in both UHS and HHS seeds from 0.5% to 4.5% of total FA, while hop seeds are the richest GLA source from Cannabaceae (7.2% of total FA). The extraction system selected for hemp seeds processing has a clear influence on oil yields, although, the FA profiles are slightly modified. The use of n‐hexane and n‐hexane:acetone in extractions allows an improvement in oil yields at the same GLA percentage. A process comprising saponification and subsequent cooling allows the improvement of GLA percentage in both hemp and hop seeds extracts at values higher than 10% of total FA, at high yields (>70%).
Practical Applications: The global HS market increases significantly year after year and the demand of hemp products is increasing rapidly. The natural GLA sources in nature are limited, and although hemp contains GLA, this reaches low percentages in the oil. Hemp is a well‐established crop with highly standardized agricultural technologies, thus, the development of any well‐designed processes feasible for application in oil extraction industries, would allow the development of new GLA‐based functional seed oils. This would boost the development of the agricultural and food industries dedicated to revaluing hemp products.
In this study, gamma linolenic acid (GLA) occurrence is checked in hemp, hop, and European hackberry seeds. Different extracting systems are checked for oil extraction with the goal to improve GLA content. A process comprising saponification and subsequent cooling allowed improvement in GLA percentage in both hemp and hop seeds extracts at values higher than 10% of total FA, at high yields (>70%).
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