Abstract
Many COVID-19 vaccines are proving to be highly effective to prevent severe disease and to diminish infections. Their uneven geographical distribution favors the appearance of new variants ...of concern, as the highly transmissible Delta variant, affecting particularly non-vaccinated people. It is important to device reliable models to analyze the spread of the different variants. A key factor is to consider the effects of vaccination as well as other measures used to contain the pandemic like social behaviour. The stochastic geographical model presented here, fulfills these requirements. It is based on an extended compartmental model that includes various strains and vaccination strategies, allowing to study the emergence and dynamics of the new COVID-19 variants. The model conveniently separates the parameters related to the disease from the ones related to social behavior and mobility restrictions. We applied the model to the United Kingdom by using available data to fit the recurrence of the currently prevalent variants. Our computer simulations allow to describe the appearance of periodic waves and the features that determine the prevalence of certain variants. They also provide useful predictions to help planning future vaccination boosters. We stress that the model could be applied to any other country of interest.
This study investigates the potentiality of nanosphere colloidal suspensions as sustained release systems for intravenous administration of docetaxel (DTX). Nanospheres were prepared by solvent ...displacement method using polylactic acids (PLA) at different molecular weight and polylactic-co-glycolic (PLGA) as biodegradable matrices. The systems were characterized by light scattering analysis for their mean size, size distribution and zeta potential and by scanning electron microscopy (SEM) for surface morphology. The average diameters of the nanoparticles ranged from 100 to 200
nm. Negative zeta potential values were observed for all systems, particularly the nanospheres produced with the lowest molecular weight PLA showed a zeta potential value of −28
mV. Differential scanning calorimetry analysis (DSC) suggested that DTX was molecularly dispersed in the polymeric matrices. A biphasic release of DTX was observed for all colloidal suspensions, after a burst effect in which about 50% (w/w) of the loaded drug was released a sustained release profile for about 10 days was observed. To evaluate the influence of the polymeric carrier on the interaction of DTX with biological membranes, we performed an
in vitro study using lipid vesicles made of dipalmitoylphosphatidylcholine (DPPC) as a biomembrane model. DSC was used as a simple and not invasive technique of analysis. DTX produced a depression of DPPC pretransition peak, no variation of the main phase transition temperature and a significative increase of Δ
H value, showing a superficial penetration of the drug into DPPC bilayer. Kinetic experiments demonstrated that the release process of DTX form nanospheres is affected by the molecular weight of the employed polymers.
OBJECTIVES:The primary outcome was to compare the effects of dopamine or epinephrine in severe sepsis on 28-day mortality; secondary outcomes were the rate of healthcare–associated infection, the ...need for other vasoactive drugs, and the multiple organ dysfunction score.
DESIGN:Double-blind, prospective, randomized controlled trial from February 1, 2009, to July 31, 2013.
SETTING:PICU, Hospital Universitário da Universidade de São Paulo, Brazil.
PATIENTS:Consecutive children who are 1 month to 15 years old and met the clinical criteria for fluid-refractory septic shock. Exclusions were receiving vasoactive drug(s) prior to hospital admission, having known cardiac disease, having already participated in the trial during the same hospital stay, refusing to participate, or having do-not-resuscitate orders.
INTERVENTIONS:Patients were randomly assigned to receive either dopamine (5–10 μg/kg/min) or epinephrine (0.1–0.3 μg/kg/min) through a peripheral or intraosseous line. Patients not reaching predefined stabilization criteria after the maximum dose were classified as treatment failure, at which point the attending physician gradually stopped the study drug and started another catecholamine.
MEASUREMENTS AND MAIN RESULTS:Physiologic and laboratory data were recorded. Baseline characteristics were described as proportions and mean (± SD) and compared using appropriate statistical tests. Multiple regression analysis was performed, and statistical significance was defined as a p value of less than 0.05. Baseline characteristics and therapeutic interventions for the 120 children enrolled (63, dopamine; 57, epinephrine) were similar. There were 17 deaths (14.2%)13 (20.6%) in the dopamine group and four (7%) in the epinephrine group (p = 0.033). Dopamine was associated with death (odds ratio, 6.5; 95% CI, 1.1–37.8; p = 0.037) and healthcare–associated infection (odds ratio, 67.7; 95% CI, 5.0–910.8; p = 0.001). The use of epinephrine was associated with a survival odds ratio of 6.49.
CONCLUSIONS:Dopamine was associated with an increased risk of death and healthcare–associated infection. Early administration of peripheral or intraosseous epinephrine was associated with increased survival in this population. Limitations should be observed while interpreting these results.
Context.
The binary star
α
Aurigae (otherwise known as Capella) is extremely important to understanding the core hydrogen and helium burning phases of stars, as its primary star is likely evolving ...through the core helium burning phase. Moreover, the masses of the star’s two components are ∼2.5
M
⊙
and ∼2.6
M
⊙
, meaning they fall into a mass range in which the extension of the core overshoot during the main sequence phase is uncertain.
Aims.
We aim to derive the extent of the core overshoot experienced during the core burning phases and to test the efficiency of the convective transport of energy in the external envelope of Capella by comparing results from stellar evolution modelling with the results from observations.
Methods.
We considered evolutionary tracks calculated expressly for the present work, that is, for the primary and secondary stars of Capella. We determined the extent of the extra mixing from the core during the main sequence evolution and the age of the system by requiring that the effective temperatures and surface gravities of the model stars reproduce those derived from the observations at the same epoch. We further checked the consistency between the observed and predicted surface chemistry of the stars.
Results.
The consistency between results from stellar evolution modelling and the observations of Capella is found when extra mixing from the core is assumed, the extent of the extra-mixed zone being of the order of 0.25
H
P
. The age of the system is estimated to be 710 Myr. These results allow the observed surface chemistry to be well reproduced, particularly the recent determination of the
12
C/
13
C ratio based on Large Binocular Telescope and Vatican Advanced Technology Telescope observations.
This study aimed to address the
Ophiothela
species distribution worldwide, report invasive populations, and investigate their association with benthic organisms through an extensive review of the ...scientific literature. All six
Ophiothela
species occur between latitudes 33º S and 38º N and, together, are dispersed across 75% of the marine realms. Spread throughout more than 6700 km of the Western Atlantic Ocean coastline,
O. mirabilis
is the only species recorded as invasive. Higher plasticity in substrate use was detected in invaded areas than in native ones, which indicates that substrate availability does not limit the invasive potential of
O. mirabilis
. The colonization affinity of
Ophiothela
species is high for Cnidaria species, irrespective of population origin. High densities (
e.g.,
up to 2.8 brittle stars cm
−2
per gorgonian surface) and opportunistic habitat colonization pattern found for
O. mirabilis
invasive populations suggest fast dispersion rates along the Atlantic coast. Therefore, the expansion of this species to nearby systems is likely, and the potential to damage native host species is high.
In a world being hit by waves of COVID-19, vaccination is a light on the horizon. However, the roll-out of vaccination strategies and their influence on the pandemic are still open questions. In ...order to compare the effect of various strategies proposed by the World Health Organization and other authorities, a previously developed SEIRS stochastic model of geographical spreading of the virus is extended by adding a compartment for vaccinated people. The parameters of the model were fitted to describe the pandemic evolution in Argentina, Mexico and Spain to analyze the effect of the proposed vaccination strategies. The mobility parameters allow to simulate different social behaviors (e.g. lock-down interventions). Schemes in which vaccines are applied homogeneously in all the country, or limited to the most densely-populated areas, are simulated and compared. The second strategy is found to be more effective. Moreover, under the current global shortage of vaccines, it should be remarked that immunization is enhanced when mobility is reduced. Additionally, repetition of vaccination campaigns should be timed considering the immunity lapse of the vaccinated (and recovered) people. Finally, the model is extended to include the effect of isolation of detected positive cases, shown to be important to reduce infections.
Purpose To compare biometry measurements and intraocular lens (IOL) power calculations obtained by a new optical A-scan interferometer biometer (Galilei G6) (new biometer) and a partial coherence ...interferometer biometer (IOLMaster 500) (reference biometer). Setting Private practice, Recife, Brazil. Design Retrospective comparative study. Methods Cataract patients who had biometric measurements with the new biometer and the reference biometer were included in the study. Comparisons were performed for axial length (AL), keratometry (K), anterior chamber depth (ACD), and IOL power calculation to reach emmetropia with an Acrysof SN60WF IOL using the Haigis formula. The Pearson correlation coefficient and the 95% limits of agreement (LoA) were calculated. The paired Student t test and the Wilcoxon test were used to assess differences between devices. Results Eighty-eight eyes (88 patients) were studied. Both biometers provided statistically similar mean IOL power to reach emmetropia, AL, keratometry, and ACD measurements ( P > .05). The differences in these variables did not vary as their mean values increased, and there was a strong positive correlation between the values obtained by both devices for each variable. The 95% LoA values for AL, mean keratometry, ACD, and IOL power were 0.27 mm, 1.08 diopters (D), 0.66 mm, and 1.56 D, respectively. Conclusions The 2 devices were comparable with regard to mean IOL power, mean AL, K, and ACD measurements. However, the wide range of differences between the devices suggests they should not be used interchangeably.
In this article, we consider a double phosphorylation cycle, a ubiquitous signaling component, having the ability to display bistability, a behavior strongly related to the existence of positive ...feedback loops. If this component is connected to other signaling elements, it very likely undergoes some sort of protein-protein interaction. In several cases, these interactions result in a non-explicit negative feedback effect, leading to interlinked positive and negative feedbacks. This combination was studied in the literature as a way to generate relaxation-type oscillations. Here, we show that the two feedbacks together ensure two types of oscillations, the relaxation-type ones and a smoother type of oscillations functioning in a very narrow range of frequencies, in such a way that outside that range, the amplitude of the oscillations is severely compromised. Even more, we show that the two feedbacks are essential for both oscillatory types to emerge, and it is their hierarchy what determines the type of oscillation at work. We used bifurcation analyses and amplitude vs. frequency curves to characterize and classify the oscillations. We also applied the same ideas to another simple model, with the goal of generalizing what we learned from signaling models. The results obtained display the wealth of oscillatory dynamics that exists in a system with a bistable module nested within a negative feedback loop, showing how to transition between different types of oscillations and other dynamical behaviors such as excitability. Our work provides a framework for the study of other oscillatory systems based on bistable modules, from simple two-component models to more complex examples like the MAPK cascade and experimental cases like cell cycle oscillators.
Increased levels of enhancer of zeste homolog 2 (EZH2), a critical regulator of cellular memory, are associated with negative estrogen receptor (ER) expression and disease progression in breast ...cancer. High levels of EZH2 signal the presence of metastasis and poor outcome in breast cancer patients. To test the hypothesis that deregulation of EZH2 contributes to ER-negative breast cancer progression, EZH2 expression was inhibited in ER-negative breast cancer cells MDA-MB-231 and CAL51 using a lentivirus system. EZH2 knockdown decreased proliferation and delayed the G(2)/M cell-cycle transition, although not affecting apoptosis. In vivo, EZH2 downregulation significantly decreased breast xenograft growth and improved survival. EZH2 knockdown upregulated BRCA1 protein. Of note, BRCA1 knockdown was sufficient to rescue the effects of EZH2 downregulation on proliferation, G(2)/M arrest, and on the levels of hyperphosphorylated mitotic Cdc25C and Cyclin B1 proteins, crucial for entry into mitosis. Invasive ER-negative breast carcinomas show significant overexpression of EZH2 and downregulation of BRCA1 proteins. Taken together, we show that EZH2 is important in ER-negative breast cancer growth in vivo and in vitro, and that BRCA1 is required for the proliferative effects of EZH2. Blockade of EZH2 may provide a prime target to prevent and/or halt ER-negative breast cancer progression.
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