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One of the challenges with initiating long-acting injectable (LAI) antipsychotic regimens is achieving relevant drug levels quickly. After first injection of the LAI antipsychotic aripiprazole lauroxil (AL), the lag to reaching relevant plasma aripiprazole levels was initially addressed using supplemental oral aripiprazole for 21 days. A 1-day AL initiation regimen using a NanoCrystal® Dispersion formulation of AL (ALNCD; Aristada Initio®) combined with a single 30 mg dose of oral aripiprazole has been developed as an alternative approach. We compared the 1-day AL initiation regimen (ALNCD + 30 mg oral aripiprazole for 1 day) with the 21-day AL initiation regimen (AL + 15 mg/day of oral aripiprazole for 21 days) using kinetic modeling. Observed and modeled data demonstrate that the 1-day AL initiation regimen provides continuous aripiprazole exposure comparable to the 21-day AL initiation regimen. Each component of the 1-day AL initiation regimen (30 mg oral aripiprazole, ALNCD, and AL) contributes to aripiprazole plasma levels at different times, with oral aripiprazole predominating in the first week, then ALNCD and AL over time. In a double-blind, placebo-controlled, phase 1 study in patients with schizophrenia, the 1-day initiation regimen resulted in rapid achievement of relevant plasma aripiprazole levels comparable to those from the 21-day initiation regimen. Safety and tolerability of the 1-day regimen were consistent with the known profile of aripiprazole. Each part of the 1-day initiation regimen, together with AL, is necessary for continuous aripiprazole exposure from treatment initiation until the next regularly scheduled AL injection is administered.
Background: Safety behaviours are ubiquitous across anxiety disorders and are associated with the aetiology, maintenance and exacerbation of anxiety. Cognitive behavioural models posit that beliefs about safety behaviours directly influence their use. Therefore, beliefs about safety behaviours may be an important component in decreasing safety behaviour use. Unfortunately, little empirical research has evaluated this theorized relationship.
Aims: The present study aimed to examine the predictive relationship between beliefs about safety behaviours and safety behaviour use while controlling for anxiety severity.
Method: Adults with clinically elevated levels of social anxiety (n = 145) and anxiety sensitivity (n = 109) completed an online survey that included established measures of safety behaviour use, quality of life, and anxiety severity. Participants also completed the Safety Behaviour Scale (SBS), a measure created for the current study which includes a transdiagnostic checklist of safety behaviours, as well as questions related to safety behaviour use and beliefs about safety behaviours.
Results: Within both the social anxiety and anxiety sensitivity groups, positive beliefs about safety behaviours predicted greater safety behaviour use, even when controlling for anxiety severity. Certain beliefs were particularly relevant in predicting safety behaviour use within each of the clinical analogue groups.
Conclusions: Findings suggest that efforts to decrease safety behaviour use during anxiety treatment may benefit from identifying and modifying positive beliefs about safety behaviours.
Slow release is a fundamental feature of long-acting injectable (LAI) antipsychotics. This property allows continuous drug exposure between dosing intervals. However, there can be a significant delay between giving the first LAI dose and achievement of efficacious plasma concentrations. This time period requires additional pharmacologic intervention. Until now, this delay was addressed with one of two strategies: 1) continuing with supplemental oral antipsychotic, or 2) giving more LAI up front (e.g. loading dose). A third strategy has now been developed to reduce the time needed for oral supplementation when starting the LAI aripiprazole lauroxil (AL) from 21days to 1day. A nano-crystalline milled dispersion of AL (ALNCD; brand name ARISTADA INITIO™) was formulated by reducing the AL particle diameter from micron-size particles to nanometer- sized particles. ALNCD has faster dissolution and a shorter half-life than AL and is designed to be used as a single injection along with a single oral aripiprazole dose of 30mg as a 1-day alternative to the 21days of oral aripiprazole supplementation. Here we provide an overview of the new 1-day initiation regimen for starting AL treatment, and demonstrate the relative contributions of each of its components.
A blinded, randomized, phase 1, pharmacokinetic (PK), and safety study compared the 1-day initiation regimen with the 21-day oral aripiprazole regimen. A combination of observed data, and population pharmacokinetic model–based simulations were used to plot plasma aripiprazole concentrations of single doses of ALNCD, 30mg oral aripiprazole, and AL, individually, and all three combined.
The PK profiles of the 1-day and 21-day initiation regimens (both in conjunction with either 441mg or 882mg doses of AL) were comparable, with therapeutically relevant aripiprazole levels achieved within 4days of treatment initiation. The safety profile of the 1-day initiation regimen was similar to the 21-day initiation regimen, and consistent with that of AL. Aripiprazole concentration–time profiles demonstrated that each component delivered aripiprazole to the systemic circulation at different time periods, with the 30mg dose of oral aripiprazole predominant in the first week, followed by ALNCD, and then AL.
The 1-day initiation regimen is well-tolerated and a suitable alternative to 21days of oral aripiprazole supplementation for starting AL. Each component of the 1-day initiation regimen, together with AL, is necessary to provide continuous coverage from treatment initiation until the next regularly scheduled AL injection.
Funding Acknowledgements: This study was funded by Alkermes Inc.
A constraint on Solar System formation is the high 26Al/27Al abundance ratio, 17 times higher than the average Galactic ratio, while the 60Fe/56Fe value was lower than the Galactic value. This challenges the assumption that a nearby supernova was responsible for the injection of these short-lived radionuclides into the early Solar System. We suggest that the Solar System was formed by triggered star formation at the edge of a Wolf-Rayet (W-R) bubble. We discuss the details of various processes within the model using numerical simulations, and analytic and semi-analytic calculations, and conclude that it is a viable model that can explain the initial abundances of 26Al and 60Fe. We estimate that 1%-16% of all Sun-like stars could have formed in such a setting.
Children with CHD and acquired heart disease have unique, high-risk physiology. They may have a higher risk of adverse tracheal-intubation-associated events, as compared with children with non-cardiac disease.
Materials and methods
We sought to evaluate the occurrence of adverse tracheal-intubation-associated events in children with cardiac disease compared to children with non-cardiac disease. A retrospective analysis of tracheal intubations from 38 international paediatric ICUs was performed using the National Emergency Airway Registry for Children (NEAR4KIDS) quality improvement registry. The primary outcome was the occurrence of any tracheal-intubation-associated event. Secondary outcomes included the occurrence of severe tracheal-intubation-associated events, multiple intubation attempts, and oxygen desaturation.
A total of 8851 intubations were reported between July, 2012 and March, 2016. Cardiac patients were younger, more likely to have haemodynamic instability, and less likely to have respiratory failure as an indication. The overall frequency of tracheal-intubation-associated events was not different (cardiac: 17% versus non-cardiac: 16%, p=0.13), nor was the rate of severe tracheal-intubation-associated events (cardiac: 7% versus non-cardiac: 6%, p=0.11). Tracheal-intubation-associated cardiac arrest occurred more often in cardiac patients (2.80 versus 1.28%; p<0.001), even after adjusting for patient and provider differences (adjusted odds ratio 1.79; p=0.03). Multiple intubation attempts occurred less often in cardiac patients (p=0.04), and oxygen desaturations occurred more often, even after excluding patients with cyanotic heart disease.
The overall incidence of adverse tracheal-intubation-associated events in cardiac patients was not different from that in non-cardiac patients. However, the presence of a cardiac diagnosis was associated with a higher occurrence of both tracheal-intubation-associated cardiac arrest and oxygen desaturation.
OBJECTIVES/SPECIFIC AIMS: To create a searchable public registry of all Quality Improvement (QI) projects. To incentivize the medical professionals at UF Health to initiate quality improvement projects by reducing startup burden and providing a path to publishing results. To reduce the review effort performed by the internal review board on projects that are quality improvement Versus research. To foster publication of completed quality improvement projects. To assist the UF Health Sebastian Ferrero Office of Clinical Quality & Patient Safety in managing quality improvement across the hospital system. METHODS/STUDY POPULATION: This project used a variant of the spiral software development model and principles from the ADDIE instructional design process for the creation of a registry that is web based. To understand the current registration process and management of quality projects in the UF Health system a needs assessment was performed with the UF Health Sebastian Ferrero Office of Clinical Quality & Patient Safety to gather project requirements. Biweekly meetings were held between the Quality Improvement office and the Clinical and Translational Science – Informatics and Technology teams during the entire project. Our primary goal was to collect just enough information to answer the basic questions of who is doing which QI project, what department are they from, what are the most basic details about the type of project and who is involved. We also wanted to create incentive in the user group to try to find an existing project to join or to commit the details of their proposed new project to a data registry for others to find to reduce the amount of duplicate QI projects. We created a series of design templates for further customization and feature discovery. We then proceed with the development of the registry using a Python web development framework called Django, which is a technology that powers Pinterest and the Washington Post Web sites. The application is broken down into 2 main components (i) data input, where information is collected from clinical staff, Nurses, Pharmacists, Residents, and Doctors on what quality improvement projects they intend to complete and (ii) project registry, where completed or “registered” projects can be viewed and searched publicly. The registry consists of a quality investigator profile that lists contact information, expertise, and areas of interest. A dashboard allows for the creation and review of quality improvement projects. A search function enables certain quality project details to be publicly accessible to encourage collaboration. We developed the Registry Matching Algorithm which is based on the Jaccard similarity coefficient that uses quality project features to find similar quality projects. The algorithm allows for quality investigators to find existing or previous quality improvement projects to encourage collaboration and to reduce repeat projects. We also developed the QIPR Approver Algorithm that guides the investigator through a series of questions that allows an appropriate quality project to get approved to start without the need for human intervention. RESULTS/ANTICIPATED RESULTS: A product of this project is an open source software package that is freely available on GitHub for distribution to other health systems under the Apache 2.0 open source license. Adoption of the Quality Improvement Project Registry and promotion of it to the intended audience are important factors for the success of this registry. Thanks goes to the UW-Madison and their QI/Program Evaluation Self-Certification Tool (https://uwmadison.co1.qualtrics.com/SE/?SID=SV_3lVeNuKe8FhKc73) used as example and inspiration for this project. DISCUSSION/SIGNIFICANCE OF IMPACT: This registry was created to help understand the impact of improved management of quality projects in a hospital system. The ultimate result will be to reduce time to approve quality improvement projects, increase collaboration across the UF Health Hospital system, reduce redundancy of quality improvement projects and translate more projects into publications.
Electron-beam (e-beam) irradiation damage is often regarded as a severe limitation to atomic-scale study of two-dimensional (2D) materials using electron microscopy techniques. However, energy transferred from the e-beam can also provide a way to modify 2D materials via defect engineering when the interaction of the beam with the sample is precisely controlled. In this article, we discuss the atomic geometry, formation mechanism, and properties of several types of structural defects, ranging from zero-dimensional point defects to extended domains, induced by an e-beam in a few representative 2D materials, including graphene, hexagonal boron nitride, transition-metal dichalcogenides, and phosphorene. We show that atomic as well as line defects and even novel nanostructures can be created and manipulated in 2D materials by an e-beam in a controllable manner. Phase transitions can also be induced. The e-beam in a (scanning) transmission electron microscope not only resolves the intrinsic atomic structure of materials with defects, but also provides new opportunities to modify the structure with subnanometer precision.
Cognitive behavioural therapy (CBT) for major depression is an effective treatment, but outcomes for complex cases, with co-occurring biological, psychological and social factors, are variable. Complexity factors can cause treatment to become diffuse, disorganized and over-complicated. At Step 3, disorder-specific protocols should be provided with therapy kept as simple as possible and delivered responsively, e.g. barriers to treatment should be tackled, ensure the client is well-prepared and seek to form a strong therapeutic alliance. At Step 4, if disorder-specific protocols have been ineffective, the priority is to formulate how complexity factors are interacting with the client's depression. An individualized formulation is used to carefully target these interactions. The treatment is still evidence-based and simple at the point of delivery, but there is greater emphasis on case-level interactions that are unique to each individual. Case examples are used to illustrate both approaches.
In this paper, we prove that if
is a postcritically finite rational map with Julia set homeomorphic to the Sierpiński carpet, then there is an integer
, such that, for any
, there exists an
-invariant Jordan curve
containing the postcritical set of
Shape grammars are rule-based formalisms for the specification of shape languages. Most of the existing shape grammars are developed on paper and have not been implemented computationally thus far. Nevertheless, the computer implementation of shape grammar is an important research question, not only to automate design analysis and generation, but also to extend the impact of shape grammars toward design practice and computer-aided design tools. In this paper, we investigate the implementation of shape grammars on a computer system, using a graph-theoretic representation. In particular, we describe and evaluate the implementation of the existing Rabo-de-Bacalhau transformation grammar. A practical step-by-step approach is presented, together with a discussion of important findings noticed during the implementation and evaluation. The proposed approach is shown to be both feasible and valuable in several aspects: we show how the attempt to implement a grammar on a computer system leads to a deeper understanding of that grammar, and might result in the further development of the grammar; we show how the proposed approach is embedded within a commercial computer-aided design environment to make the shape grammar formalism more accessible to students and practitioners, thereby increasing the impact of grammars on design practice; and the proposed step-by-step implementation approach has shown to be feasible for the implementation of the Rabo-de-Bacalhau transformation grammar, but can also be generalized using different ontologies for the implementation.
Patients with borderline personality disorder frequently show non-suicidal self-injury (NSSI). In these patients, NSSI often serves to reduce high levels of stress.
Investigation of neurobiological mechanisms of NSSI in borderline personality disorder
In total, 21 women with borderline personality disorder and 17 healthy controls underwent a stress induction, followed by either an incision into the forearm or a sham treatment. Afterwards participants underwent resting-state functional magnetic resonance imaging while aversive tension, heart rate and heart rate variability were assessed.
We found a significant influence of incision on subjective and objective stress levels with a stronger decrease of aversive tension in the borderline personality disorder group following incision than sham. Amygdala activity decreased more and functional connectivity with superior frontal gyrus normalised after incision in the borderline personality disorder group.
Decreased stress levels and amygdala activity after incision support the assumption of an influence of NSSI on emotion regulation in individuals with borderline personality disorder and aids in understanding why these patients use self-inflicted pain to reduce inner tension.
This paper presents an assessment of the surplus grass production in the Region of Southern Denmark, and the perspectives of utilizing it in local biogas production. Grass production represents a significant role in the Danish agricultural sector. However, statistical data show an excess production of averagely 12% in the period 2006–2012. Based on spatial analyses and statistical data, the geographical distribution of grass production and consumption was estimated and mapped for the Region of Southern Denmark. An excess production of grass was estimated for several of the municipalities in the Region of Southern Denmark, but the excess production was found to be quite sensitive to the management practice of the grass fields and the productivity of the grass. The yields of excess grass estimated in the sensitive and conservative scenario were found to be sufficient to serve a sole co-substrate in 2–8 biogas plants using animal manure as primary feedstock. The yields in the intensive scenario were assessed to be sufficient to serve a sole co-substrate in 8–16 biogas plants. Alternatively, at least 31% of the regionally produced maize which is exported to the biogas sector could annually be substituted by methane produced from the production of excess grass. The intensive scenario was estimated to have significantly higher grass yields than the sensitive and conservative scenario. The environmental impacts of intensified agricultural management should, however, be assessed carefully in order to ensure that the ecosystems are not increasingly being burdened. The potential of utilizing residual grass for energy production in the region or as an alternative to the maize exported to Northern Germany, was concluded to seem as a promising possibility for a sustainable development of the regional biogas sector. Furthermore, it could provide incentives for establishing new biogas plants in the region and thereby increase the share of manure being digested anaerobically, which could help extrapolate the environmental and climate related benefits documented for the use of digested animal manure as fertilizer on agricultural land.
Despite immense achievements in the past century in hygiene control, and the development of vaccines and antibiotics, infectious diseases continue to pose a tremendous threat to public health globally. There are still devastating infections for which there are no effective vaccines or antimicrobial therapies. Moreover, the problem of drug resistance in bacteria and viral populations and the increasing appreciation that pathologies resulting from infections are responsible for a number of chronic conditions, are creating an ever-growing need for novel preventive and therapeutic approaches. In line with this, a new host-targeted approach has been suggested for antimicrobial drug research that exploits the central role of the host cell during infection. Decades of research have taught us that infections are supported by host cell functions, and that infection pathology is frequently host dependent. Accordingly, the pharmacological targeting of host cell factors promises novel opportunities to prevent and treat infectious disease. Such an approach may be anticipated to expand the number of druggable targets, produce broad-spectrum compounds and impede the generation of resistance. The discovery of RNA interference (RNAi) has created opportunities to explore gene functions in cellular systems in a targeted manner. RNAi loss-of-function approaches have proved invaluable for the identification of host proteins important for pathogen viability. These approaches can be applied on a high-throughput scale, which demands sophisticated liquid handling and high-content image analysis. Here, we provide an overview of the current status of high-content screening (HCS) in loss-of-function analyses in infectious disease research and discuss how these powerful techniques can be applied to identify host factors with previously unknown roles in infection and its pathology.
The challenge of fighting infectious diseases
Infections by pathogenic species of bacteria, viruses, fungi and protozoa have had considerable impact on mankind throughout history. Advances in our understanding of the importance of hygiene control, and later, improvements in diagnostics and the development and successful employment of vaccines and antimicrobial drugs, have substantially benefited human health, and provided social and economic benefits.
Metribuzin has a 60-d preharvest interval (PHI) in potato, which limits utility of metribuzin POST in potato. In certain years, the potato may not fully cover the area between the potato rows. This allows for late-season weed emergence and subsequent yield reduction through direct competition or harvest interference. Field experiments were conducted in 2011 at Castle Hayne, NC; Freeville, NY; Hasting, FL; and Plymouth, NC to determine the effect of a 30-d PHI on potato crop tolerance. The cultivars planted were ‘Superior' and ‘Yukon Gold' in Castle Hayne and Plymouth, ‘Castille' and Yukon Gold in Freeville, and ‘Atlantic' in Hastings. Treatments included metribuzin at 278 g ai ha−1 PRE, 30, and 60 d before harvest (DBH), and metribuzin at 556 g ha−1 at 30 and 60 DBH. Split application treatments included metribuzin at 556 g ha−1 at PRE followed by metribuzin at 556 g ha−1 30 or 60 DBH and metribuzin at 842 g ha−1 PRE followed by metribuzin at 278 g ha−1 at 30 or 60 DBH. Potato injury was ≤ 8% at all locations, and injury was transient. There were no differences observed between metribuzin rate or application date for individual potato grades or total yield. Reducing the PHI in potato to 30 d would have no effect on yield and would provide a longer period for controlling broadleaf weeds.