Innate immunity is highly conserved and relies on pattern recognition receptors (PRRs) such as Toll-like receptors (identified through their homology to Drosophila Toll) for pathogen recognition. ...Although Drosophila Toll is vital for immune recognition and defense, roles for the other eight Drosophila Tolls in immunity have remained elusive. Here we have shown that Toll-7 is a PRR both in vitro and in adult flies; loss of Toll-7 led to increased vesicular stomatitis virus (VSV) replication and mortality. Toll-7, along with additional uncharacterized Drosophila Tolls, was transcriptionally induced by VSV infection. Furthermore, Toll-7 interacted with VSV at the plasma membrane and induced antiviral autophagy independently of the canonical Toll signaling pathway. These data uncover an evolutionarily conserved role for a second Drosophila Toll receptor that links viral recognition to autophagy and defense and suggest that other Drosophila Tolls may restrict specific as yet untested pathogens, perhaps via noncanonical signaling pathways.
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► Toll-7 is required for antiviral defense in cells and animals ► Toll-7 interacts with VSV at the plasma membrane ► Toll-7 is required for autophagy in response to VSV ► Toll-7 along with additional Tolls is transcriptionally induced by VSV infection
The use of peripheral nerve blocks for anesthesia and postoperative analgesia has increased significantly in recent years. Adjuvants are frequently added to local anesthetics to prolong analgesia ...following peripheral nerve blockade. Numerous randomized controlled trials and meta-analyses have examined the pros and cons of the use of various individual adjuvants.
To systematically review adjuvant-related randomized controlled trials and meta-analyses and provide clinical recommendations for the use of adjuvants in peripheral nerve blocks.
Randomized controlled trials and meta-analyses that were published between 1990 and 2014 were included in the initial bibliographic search, which was conducted using Medline/PubMed, Cochrane Central Register of Controlled Trials, and EMBASE. Only studies that were published in English and listed block analgesic duration as an outcome were included. Trials that had already been published in the identified meta-analyses and included adjuvants not in widespread use and published without an Investigational New Drug application or equivalent status were excluded.
Sixty one novel clinical trials and meta-analyses were identified and included in this review. The clinical trials reported analgesic duration data for the following adjuvants: buprenorphine (6), morphine (6), fentanyl (10), epinephrine (3), clonidine (7), dexmedetomidine (7), dexamethasone (7), tramadol (8), and magnesium (4). Studies of perineural buprenorphine, clonidine, dexamethasone, dexmedetomidine, and magnesium most consistently demonstrated prolongation of peripheral nerve blocks.
Buprenorphine, clonidine, dexamethasone, magnesium, and dexmedetomidine are promising agents for use in prolongation of local anesthetic peripheral nerve blocks, and further studies of safety and efficacy are merited. However, caution is recommended with use of any perineural adjuvant, as none have Food and Drug Administration approval, and concerns for side effects and potential toxicity persist.
The nucleus accumbens is a major input structure of the basal ganglia and integrates information from cortical and limbic structures to mediate goal-directed behaviors. Chronic exposure to several ...classes of drugs of abuse disrupts plasticity in this region, allowing drug-associated cues to engender a pathologic motivation for drug seeking. A number of alterations in glutamatergic transmission occur within the nucleus accumbens after withdrawal from chronic drug exposure. These drug-induced neuroadaptations serve as the molecular basis for relapse vulnerability. In this review, we focus on the role that glutamate signal transduction in the nucleus accumbens plays in addiction-related behaviors. First, we explore the nucleus accumbens, including the cell types and neuronal populations present as well as afferent and efferent connections. Next we discuss rodent models of addiction and assess the viability of these models for testing candidate pharmacotherapies for the prevention of relapse. Then we provide a review of the literature describing how synaptic plasticity in the accumbens is altered after exposure to drugs of abuse and withdrawal and also how pharmacological manipulation of glutamate systems in the accumbens can inhibit drug seeking in the laboratory setting. Finally, we examine results from clinical trials in which pharmacotherapies designed to manipulate glutamate systems have been effective in treating relapse in human patients. Further elucidation of how drugs of abuse alter glutamatergic plasticity within the accumbens will be necessary for the development of new therapeutics for the treatment of addiction across all classes of addictive substances.
A team of RAND Corporation researchers projected in 2005 that rapid adoption of health information technology (IT) could save the United States more than $81 billion annually. Seven years later the ...empirical data on the technology's impact on health care efficiency and safety are mixed, and annual health care expenditures in the United States have grown by $800 billion. In our view, the disappointing performance of health IT to date can be largely attributed to several factors: sluggish adoption of health IT systems, coupled with the choice of systems that are neither interoperable nor easy to use; and the failure of health care providers and institutions to reengineer care processes to reap the full benefits of health IT. We believe that the original promise of health IT can be met if the systems are redesigned to address these flaws by creating more-standardized systems that are easier to use, are truly interoperable, and afford patients more access to and control over their health data. Providers must do their part by reengineering care processes to take full advantage of efficiencies offered by health IT, in the context of redesigned payment models that favor value over volume.
Incentives offered by the U.S. government have spurred marked increases in use of health information technology (IT).
To update previous reviews and examine recent evidence that relates health IT ...functionalities prescribed in meaningful use regulations to key aspects of health care.
English-language articles in PubMed from January 2010 to August 2013.
236 studies, including pre-post and time-series designs and clinical trials that related the use of health IT to quality, safety, or efficiency.
Two independent reviewers extracted data on functionality, study outcomes, and context.
Fifty-seven percent of the 236 studies evaluated clinical decision support and computerized provider order entry, whereas other meaningful use functionalities were rarely evaluated. Fifty-six percent of studies reported uniformly positive results, and an additional 21% reported mixed-positive effects. Reporting of context and implementation details was poor, and 61% of studies did not report any contextual details beyond basic information.
Potential for publication bias, and evaluated health IT systems and outcomes were heterogeneous and incompletely described.
Strong evidence supports the use of clinical decision support and computerized provider order entry. However, insufficient reporting of implementation and context of use makes it impossible to determine why some health IT implementations are successful and others are not. The most important improvement that can be made in health IT evaluations is increased reporting of the effects of implementation and context.
Office of the National Coordinator.
Novel methodology is presented for indexing the relative potential of hosts to function as resources. A Host Potential Index (HPI) was developed as a practical framework to express relative host ...potential based on combining results from one or more independent studies, such as those examining host selection, utilization, and physiological development of the organism resourcing the host. Several aspects of the HPI are addressed including: 1) model derivation; 2) influence of experimental design on establishing host rankings for a study type (no choice, two-choice, and multiple-choice); and, 3) variable selection and weighting associated with combining multiple studies. To demonstrate application of the HPI, results from the interactions of spotted wing drosophila (SWD), Drosophila suzukii Matsumura (Diptera: Drosophilidae), with seven “reported” hosts (blackberries, blueberries, sweet cherries, table grapes, peaches, raspberries, and strawberries) in a postharvest scenario were analyzed. Four aspects of SWD-host interaction were examined: attraction to host volatiles; population-level oviposition performance; individual-level oviposition performance; and key developmental factors. Application of HPI methodology indicated that raspberries (mean HPI varied = 301.9±8.39; rank 1 of 7) have the greatest potential to serve as a postharvest host for SWD relative to the other fruit hosts, with grapes (mean HPI varied = 232.4±3.21; rank 7 of 7) having the least potential.
The Third International Consensus Definitions (Sepsis-3) Task Force recommended the use of the quick Sequential Sepsis-related Organ Failure Assessment (qSOFA) score to screen patients for sepsis ...outside of the ICU. However, subsequent studies raise concerns about the sensitivity of qSOFA as a screening tool. We aim to use machine learning to develop a new sepsis screening tool, the Risk of Sepsis (RoS) score, and compare it with a slate of benchmark sepsis-screening tools, including the Systemic Inflammatory Response Syndrome, Sequential Organ Failure Assessment (SOFA), qSOFA, Modified Early Warning Score, and National Early Warning Score.
We used retrospective electronic health record data from adult patients who presented to 49 urban community hospital emergency departments during a 22-month period (N=2,759,529). We used the Rhee clinical surveillance criteria as our standard definition of sepsis and as the primary target for developing our model. The data were randomly split into training and test cohorts to derive and then evaluate the model. A feature selection process was carried out in 3 stages: first, we reviewed existing models for sepsis screening; second, we consulted with local subject matter experts; and third, we used a supervised machine learning called gradient boosting. Key metrics of performance included alert rate, area under the receiver operating characteristic curve, sensitivity, specificity, and precision. Performance was assessed at 1, 3, 6, 12, and 24 hours after an index time.
The RoS score was the most discriminant screening tool at all time thresholds (area under the receiver operating characteristic curve 0.93 to 0.97). Compared with the next most discriminant benchmark (Sequential Organ Failure Assessment), RoS was significantly more sensitive (67.7% versus 49.2% at 1 hour and 84.6% versus 80.4% at 24 hours) and precise (27.6% versus 12.2% at 1 hour and 28.8% versus 11.4% at 24 hours). The sensitivity of qSOFA was relatively low (3.7% at 1 hour and 23.5% at 24 hours).
In this retrospective study, RoS was more timely and discriminant than benchmark screening tools, including those recommend by the Sepsis-3 Task Force. Further study is needed to validate the RoS score at independent sites.
Astrocytes provide support for neurons, regulate metabolic processes, and influence neuronal communication in a variety of ways, including through the homeostatic regulation of glutamate. Following ...2-h cocaine or methamphetamine self-administration (SA) and extinction, rodents display decreased levels of basal glutamate in the nucleus accumbens core (NAcore), which transitions to elevated glutamate levels during drug seeking. We hypothesized that, like cocaine, this glutamate ‘overflow’ during methamphetamine seeking arises via decreased expression of the astroglial glutamate transporter GLT-1, and withdrawal of perisynaptic astroglial processes (PAPs) from synapses. As expected, methamphetamine self-administration and extinction decreased the level of contact made by PAPs in the NAcore, yet did not impact glutamate uptake, GLT-1 expression, or the general structural characteristics of astrocytes. Interestingly, systemic administration of N-acetylcysteine (NAC), a drug that both upregulates GLT-1 and promotes glial-glutamate release, reduced cued methamphetamine seeking. In order to test the impact of astrocyte activation and the induction of glial glutamate release within the NAcore, we employed astrocyte-specific expression of designer receptors exclusively activated by designer drugs (DREADDs). We show here that acute activation of Gq-coupled DREADDs in this region inhibited cued methamphetamine seeking. Taken together, these data indicate that cued methamphetamine seeking following two-hour SA is not mediated by deficient glutamate clearance in the NAcore, yet can be inhibited by engaging NAcore astrocytes.
•Two-hour methamphetamine self-administration and extinction does not alter glutamate uptake in the NAcore.•Two-hour methamphetamine self-administration and extinction decreases astrocytic insulation of NAcore synapses.•Chronic NAC treatment inhibits cued-methamphetamine seeking.•Acute activation of Gq-DREADD, specifically in NAcore astrocytes, inhibits cued-methamphetamine seeking.
How the immune system adapts to malnutrition to sustain immunity at barrier surfaces, such as the intestine, remains unclear. Vitamin A deficiency is one of the most common micronutrient deficiencies ...and is associated with profound defects in adaptive immunity. Here, we found that type 3 innate lymphoid cells (ILC3s) are severely diminished in vitamin A–deficient settings, which results in compromised immunity to acute bacterial infection. However, vitamin A deprivation paradoxically resulted in dramatic expansion of interleukin-13 (IL-13)–producing ILC2s and resistance to nematode infection in mice, which revealed that ILCs are primary sensors of dietary stress. Further, these data indicate that, during malnutrition, a switch to innate type 2 immunity may represent a powerful adaptation of the immune system to promote host survival in the face of ongoing barrier challenges.
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