Analysis of vancomycin use and associated risk factors in a university teaching hospital: a prospective cohort study

Background  

Vancomycin use is considered inappropriate in most hospitals. A particular concern is the recent emergence of S. aureus with decreased susceptibility to vancomycin, making it important to reduce overall exposure to vancomycin to minimize the incidence of VRE (vancomycin-resistant enterococci). The aim of this work was to analyze the use of vancomycin and the risk factors associated with inappropriate treatment.     

去氢甲基睾丸素的合成工艺研究

目的 :研究蛋白同化激素去氢甲基睾丸素的合成工艺。方法 :以去氢表雄酮醋酸酯为原料 ,经格氏反应 ,水解 ,沃氏氧化 ,DDQ脱氢等四步反应制得。结果 :该合成路线不仅收率高 ,产品纯 ,而且无需过柱分离。结论 :该工艺路线适合工业化生产。     

Fractionated total body irradiation and high-dose etoposide as a preparatory regimen for bone marrow transplantation for 99 patients with acute leukemia in first complete remission

Ninety-nine consecutive patients with acute leukemia in first complete remission under age 50 (median age 27 years; age range 1 to 47 years) with a histocompatible sibling donor were treated with fractionated total body irradiation (1,320 cGy) and high-dose etoposide (60 mg/kg) followed by allogeneic bone marrow transplantation. Sixty-one patients were diagnosed with acute myelogenous leukemia (AML), 34 patients with acute lymphoblastic leukemia (ALL), 3 patients with biphenotypic acute leukemia, and 1 patient with acute undifferentiated leukemia. Thirty of the 34 patients with ALL had at least one of the following high-risk factors: age greater than 30, white blood cell count at presentation > 25,000/microL, extramedullary disease, certain chromosomal translocations, or the need for greater than 4 weeks of induction chemotherapy to achieve first complete remission. Cumulative probabilities of disease-free survival and relapse at 3 years were 61% and 12%, respectively, for the 61 patients with AML and 64% and 12%, respectively, for the 34 patients with ALL. By stepwise Cox regression analysis, significant prognostic variables for patients with acute myelogenous leukemia were the presence of acute graft-versus-host disease and increasing age, whereas for patients with acute lymphoblastic leukemia, significant variables were age and the development of cytomegalovirus-associated interstitial pneumonia. Complications related to graft-versus-host disease and relapse of leukemia were the major causes of death.     

Dissociation of human mid-dorsolateral from posterior dorsolateral frontal cortex in memory processing.

Work with non-human primates had previously demonstrated that the mid-dorsolateral frontal cortex, which comprises cytoarchitectonic areas 46 and 9, plays a critical role in the performance of non-spatial self-ordered working memory tasks, whereas the immediately adjacent posterior dorsolateral frontal cortex (area 8) is critical for the learning and performance of visual conditional associative tasks. The present study used positron emission tomography with magnetic resonance imaging to demonstrate the existence, within the human brain, of these two functionally distinct subdivisions of the lateral frontal cortex. These findings provide direct evidence that, just as the monkey brain, the human lateral frontal cortex is functionally heterogeneous and that comparable anatomical areas underlie similar functions in the two species.     

Course and prognostic factors of disability in community‐dwelling older people with mild disability: The Rotterdam Study

Aim: To study the prognosis of disability of community‐dwelling older people with mild disability at baseline. Methods: We used data from the Rotterdam Study: a community‐based prospective cohort study of community‐dwelling older people. We evaluated sociodemographic factors, lifestyle variables, health conditions and disability status at baseline and follow‐up after 6 years. Disability was defined as a score on the Health Assessment Questionnaire. Results: At baseline the population consisted of 1166 older people with mild disability with a mean age of 69.7 (55–93) years. At follow‐up 18% of the study population recovered from mild disability, 20% stayed mildly disabled, 31% became severely disabled, while 32% were deceased. At follow‐up relatively more men died while more women had a worsened disability. Age and income were predictors of disability decrease. Alcohol use seemed to be significantly protective against death. Conclusion: Just a few prognostic factors appeared to be related to disability 6 years later.     

Sustained elevation of intracellular cyclic 3'-5' adenosine monophosphate is necessary for preservation of platelet integrity during long-term storage at 22 degrees C

Preservation of platelet integrity and responsiveness was examined in platelet concentrates prepared in the presence of various formulations and combinations of platelet-activation inhibitors affecting intracellular levels of cyclic 3'-5' adenosine monophosphate (cAMP). Platelet concentrates were prepared and stored in an artificial medium for two weeks at 22 degrees C. Markers of metabolic activity (pH, lactate, pO2, pCO2 in the medium), aggregation response, hypotonic shock response, and glycoprotein Ib (GPIb) expression were assessed along with direct measurements of cAMP in platelet pellets and thromboxane B2 (TxB2) in the supernate. The platelet concentrates prepared with only adenylate-cyclase stimulators (prostaglandin E-1 or forskolin) showed less maintenance of the integrity and responsiveness markers and greater loss of GPIb than concentrates prepared with phosphodiesterase inhibitors (theophylline or caffeine) or combinations with the above. These results were correlated with the ability of these compounds to sustain elevation of cAMP above basal level during the entire extended-storage period. The strong correlation (rs = -0.67) between elevation of cAMP levels and suppression of TxB2 production suggests that the phosphodiesterase inhibitors provided better protection than stimulators of adenylate cyclase alone through a reduction in platelet activation and its deleterious effects on preservation of platelets during storage.     

Anomalous nanoparticle surface diffusion in LCTEM is revealed by deep learning-assisted analysis

The motion of nanoparticles near surfaces is of fundamental importance in physics, biology, and chemistry. Liquid cell transmission electron microscopy (LCTEM) is a promising technique for studying motion of nanoparticles with high spatial resolution. Yet, the lack of understanding of how the electron beam of the microscope affects the particle motion has held back advancement in using LCTEM for in situ single nanoparticle and macromolecule tracking at interfaces. Here, we experimentally studied the motion of a model system of gold nanoparticles dispersed in water and moving adjacent to the silicon nitride membrane of a commercial LC in a broad range of electron beam dose rates. We find that the nanoparticles exhibit anomalous diffusive behavior modulated by the electron beam dose rate. We characterized the anomalous diffusion of nanoparticles in LCTEM using a convolutional deep neural-network model and canonical statistical tests. The results demonstrate that the nanoparticle motion is governed by fractional Brownian motion at low dose rates, resembling diffusion in a viscoelastic medium, and continuous-time random walk at high dose rates, resembling diffusion on an energy landscape with pinning sites. Both behaviors can be explained by the presence of silanol molecular species on the surface of the silicon nitride membrane and the ionic species in solution formed by radiolysis of water in presence of the electron beam.

Understanding the motion of nanoparticles in boundary layers is of fundamental importance in scientific fields such as biophysics and colloidal self-assembly, and of practical importance in technological applications such as drug delivery and additive manufacturing. The physics behind the motion of nanoparticles is particularly challenging to understand due to the multitude of effects including particle–-particle interactions, particle–surface interactions, and changes in the rheological properties in boundary layers close to a liquid–solid interface.The common technique to study the motion of particles has been optical microscopy, which has limitations in terms of spatial resolution. The advent of in situ liquid cell transmission electron microscopy (LCTEM) has now made it possible to visualize the motion of nanoparticles near a surface with an unprecedented spatial resolution at the nanometer length scale (1–3). However, the electron beam of a transmission electron microscope (TEM), which is the key acquisition tool to enable nanoscale visualization, can significantly influence both interactions and dynamics of nanoparticles (4–6). Previous literature has reported that the motion of nanoparticles near the surface of an LC and in the presence of the electron beam is subdiffusive (i.e., non-Brownian, or “anomalous”) (7–16). Such subdiffusive motion suggests that the nanoparticle motion is significantly influenced by interactions with the nearby substrate or interface, but what precisely is the nature of these interactions and the forces that create them? Are they stable or fluctuating? Do they arise because of the electron beam or are they native to the system? How do the changes in rheology within a few nanometers of the interface figure into the picture? The nature of the observed anomalies are still very much under debate as the new technique of LCTEM continues to be developed (7–12, 14–16).Two canonical processes that describe anomalous motion are continuous-time random walk (CTRW) and fractional Brownian motion (FBM) (17–20). In the context of particle diffusion, each of these types of subdiffusive motions implies a distinct physical picture of the environment. CTRW indicates a random energy landscape of potential wells, where the time a particle spends in any well diverges when averaged over all well depths. FBM, on the other hand, indicates a viscoelastic environment such as those found in crowded fluids (21–24). The goal of this work is to identify the type of anomalous motion of nanoparticles near the surface in LCTEM, elucidate the nanoscopic physical features in the system that give rise to this motion, and understand how the electron beam can influence them.A key challenge in studying the motion of nanoparticles under the effect of the electron beam is that one needs to resort to a limited number of short trajectories from a single in situ LCTEM experiment. This is because achieving high spatial resolution requires a relatively small field of view, which limits the number of nanoparticles accessible (experiments are done in dilute solutions to avoid interactions between nanoparticles). Moreover, state-of-the-art cameras on TEMs are limited by lower bounds on time resolution (hundreds of frames per second) and upper bounds on measurement time (minutes-long trajectories) (25). This limitation creates a challenge for canonical methods used to characterize diffusive particle dynamics such as the mean-squared displacement (MSD) analysis. These methods often rely on features of the trajectory that converge upon averaging over very long single-particle trajectories (for systems obeying ergodicity) or hundreds of medium-length trajectories collected under the same experimental conditions (20, 26, 27). Here, we show that physics-informed artificial intelligence can be used as a complementary tool for LCTEM to extract hidden features that exist in short trajectories of single nanoparticles in LCTEM in order to elucidate the type of anomalous diffusion.In this study, we collected a large dataset from a model system of gold nanoparticles dispersed in water and diffusing near a silicon nitride (SiN_x) membrane of a commercial LC irradiated by a broad range of electron beam dose rates. Inspired by the recent advances in using machine-learning tools to study the diffusion of single microparticles in biological media (26–29), we developed a convolutional deep neural-network model, dubbed MotionNet (MoNet), which solves an inverse problem of determining the underlying diffusion mechanism behind the anomalous motion of nanoparticles in LCTEM. The architecture of the neural network employed in MoNet is designed based on classical tests in statistics (30) and is trained on thousands of simulated short trajectories from three classes of diffusion, i.e., Brownian, FBM, and CTRW. Guided by MoNet, our analysis reveals that at low dose rates the anomalous diffusive motion of nanoparticles in LCTEM is governed by viscoelasticity-dominated FBM, while at high dose rates the motion is governed by a pinning-site-mediated CTRW process (24). The prediction results were benchmarked against the statistical p-variation test (30) to confirm the behavior in low and high dose-rate limits.The dose-rate-dependent transition can be explained by the existence of silanol molecular groups on the surface of the SiN_x membrane, which act as pinning sites and exhibit a broad distribution of restoring forces (15, 31). At low dose rates, the binding strength of these pinning sites is high compared to the thermal energy and their effective restoring force acts similar to the effect of a viscoelastic environment. This results in nanoparticle motion confined to the local vicinity of a pinning site. Upon increasing the dose rate and thus passivating the charges on the pinning sites, the binding strength decreases, making nanoparticles more mobile, which allows them to diffuse over the SiN_x membrane only making intermittent stops on randomly distributed pinning sites. This understanding provides us with important insight into the mechanism of nanoparticle motion near a substrate in LCTEM and opens up the path to use in situ LCTEM as a technique for studying motions of nanoparticles in complex systems at the nanoscale. Furthermore, we show that neural networks can extract features to classify the underlying diffusive behavior of the system and determine the extent of anomaly, particularly when canonical statistical methods require extreme amounts of data and may not be able to classify the behavior of the system due to experimental limitations.