An online supported self-management toolkit for relatives of people with psychosis or bipolar experiences: the IMPART multiple case study

Background Digital health interventions have the potential to improve the delivery of psychoeducation to people with mental health problems and their relatives. Despite substantial investment in the development of digital health interventions, successful implementation into routine clinical practice is rare. Objectives Use the implementation of the Relatives’ Education And Coping Toolkit (REACT) for psychosis/bipolar disorder to identify critical factors affecting uptake and use, and develop an implementation plan to support the delivery of REACT. Design This was an implementation study using a mixed-methods, theory-driven, multiple case study approach. A study-specific implementation theory for REACT based on normalisation process theory was developed and tested, and iterations of an implementation plan to address the key factors affecting implementation were developed. Setting Early-intervention teams in six NHS mental health trusts in England (three in the north and three in the south). Participants In total, 281 staff accounts and 159 relatives’ accounts were created, 129 staff and 23 relatives took part in qualitative interviews about their experiences, and 132 relatives provided demographic data, 56 provided baseline data, 21 provided data at 12 weeks’ follow-up and 20 provided data at 24 weeks’ follow-up. Interventions REACT is an online supported self-management toolkit, offering 12 evidence-based psychoeducation modules and support via a forum, and a confidential direct messaging service for relatives of people with psychosis or bipolar disorder. The implementation intervention was developed with staff and iteratively adapted to address identified barriers. Adaptations included modifications to the toolkit and how it was delivered by teams. Main outcome measures The main outcome was factors affecting implementation of REACT, assessed primarily through in-depth interviews with staff and relatives. We also assessed quantitative measures of delivery (staff accounts and relatives’ invitations), use of REACT (relatives’ logins and time spent on the website) and the impact of REACT [relatives’ distress (General Health Questionnaire-28), and carer well-being and support (Carer Well-being and Support Scale questionnaire)]. Results Staff and relatives were generally positive about the content of REACT, seeing it as a valuable resource that could help services improve support and meet clinical targets, but only within a comprehensive service that included face-to-face support, and with some additional content. Barriers to implementation included high staff caseloads and difficulties with prioritising supporting relatives; technical difficulties of using REACT; poor interoperability with trust information technology systems and care pathways; lack of access to mobile technology and information technology training; restricted forum populations leading to low levels of use; staff fears of managing risk, online trolling, or replacement by technology; and uncertainty around REACT’s long-term availability. There was no evidence that REACT would reduce staff time supporting relatives (which was already very low), and might increase it by facilitating communication. In all, 281 staff accounts were created, but only 57 staff sent relatives invitations. In total, 355 relatives’ invitations were sent to 310 unique relatives, leading to the creation of 159 relatives’ accounts. The mean number of logins for relatives was 3.78 (standard deviation 4.43), but with wide variation from 0 to 31 (median 2, interquartile range 1–8). The mean total time spent on the website was 40.6 minutes (standard deviation 54.54 minutes), with a range of 0–298 minutes (median 20.1 minutes, interquartile range 4.9–57.5 minutes). There was a pattern of declining mean scores for distress, social dysfunction, depression, anxiety and insomnia, and increases in relatives’ well-being and eHealth literacy, but no changes were statistically significant. Conclusions Digital health interventions, such as REACT, should be iteratively developed, evaluated, adapted and implemented, with staff and service user input, as part of a long-term strategy to develop integrated technology-enabled services. Implementation strategies must instil a sense of ownership for staff and ensure that they have adequate training, risk protocols and resources to deliver the technology. Cost-effectiveness and impact on workload and inequalities in accessing health care need further testing, along with the generalisability of our findings to other digital health interventions. Limitations REACT was offered by the same team running the IMPlementation of A Relatives’ Toolkit (IMPART) study, and was perceived by staff and relatives as a time-limited research study rather than ongoing clinical service, which affected engagement. Access to observational data was limited. Trial registration Current Controlled Trials ISRCTN16267685. Funding This project was funded by the National Institute for Health Research (NIHR) Health Services and Delivery Research programme and will be published in full in Health Services and Delivery Research; Vol. 8, No. 37. See the NIHR Journals Library website for further project information

Construction of Modern Robust Nodal Discontinuous Galerkin Spectral Element Methods for the Compressible Navier-Stokes Equations

Discontinuous Galerkin (DG) methods have a long history in computational physics and engineering to approximate solutions of partial differential equations due to their high-order accuracy and geometric flexibility. However, DG is not perfect and there remain some issues. Concerning robustness, DG has undergone an extensive transformation over the past seven years into its modern form that provides statements on solution boundedness for linear and nonlinear problems. This chapter takes a constructive approach to introduce a modern incarnation of the DG spectral element method for the compressible Navier-Stokes equations in a three-dimensional curvilinear context. The groundwork of the numerical scheme comes from classic principles of spectral methods including polynomial approximations and Gauss-type quadratures. We identify aliasing as one underlying cause of the robustness issues for classical DG spectral methods. Removing said aliasing errors requires a particular differentiation matrix and careful discretization of the advective flux terms in the governing equations.Comment: 85 pages, 2 figures, book chapte

Complete hepatitis B virus genome analysis in HBsAg positive mothers and their infants with fulminant hepatitis B

BACKGROUND: After perinatal transmission of hepatitis B virus, infants of anti-HBe positive HBsAg carrier mothers may develop fulminant hepatitis B. Previously it has been suggested, that fulminant hepatitis B in adults was associated with specific mutations in the HBV-genome. The aim of this study was to investigate, whether specific viral variants are associated with fulminant hepatitis B in young infants. METHODS: The complete HBV-genomes of five mothers and their infants with fulminant hepatitis were isolated from the sera, amplified and directly sequenced. RESULTS: Between 6 and 43 base pair exchanges between the HBV genomes of the infants and their mothers were identified. The mutations spread over the entire virus genome. Nucleotide exchanges in the basic core promotor and precore region were identified in all cases. A heterogeneous virus population was detected in four mothers. CONCLUSIONS: Many new mutations were proved to emerge during fulminant hepatitis B in infants, who had been perinatally infected. HBeAg negative variants were the predominant population in all children, whereas these mutants could only be detected as subpopulations in four mothers. The data suggest that the selection of a specific HBeAg negative viral strain may be associated with the development of fulminant hepatitis B in children

The Cryo-EM Structure of a Complete 30S Translation Initiation Complex from Escherichia coli

Formation of the 30S initiation complex (30S IC) is an important checkpoint in regulation of gene expression. The selection of mRNA, correct start codon, and the initiator fMet-tRNAfMet requires the presence of three initiation factors (IF1, IF2, IF3) of which IF3 and IF1 control the fidelity of the process, while IF2 recruits fMet-tRNAfMet. Here we present a cryo-EM reconstruction of the complete 30S IC, containing mRNA, fMet-tRNAfMet, IF1, IF2, and IF3. In the 30S IC, IF2 contacts IF1, the 30S subunit shoulder, and the CCA end of fMet-tRNAfMet, which occupies a novel P/I position (P/I1). The N-terminal domain of IF3 contacts the tRNA, whereas the C-terminal domain is bound to the platform of the 30S subunit. Binding of initiation factors and fMet-tRNAfMet induces a rotation of the head relative to the body of the 30S subunit, which is likely to prevail through 50S subunit joining until GTP hydrolysis and dissociation of IF2 take place. The structure provides insights into the mechanism of mRNA selection during translation initiation

Phase I Hydroxylated Metabolites of the K2 Synthetic Cannabinoid JWH-018 Retain In Vitro and In Vivo Cannabinoid 1 Receptor Affinity and Activity

K2 products are synthetic cannabinoid-laced, marijuana-like drugs of abuse, use of which is often associated with clinical symptoms atypical of marijuana use, including hypertension, agitation, hallucinations, psychosis, seizures and panic attacks. JWH-018, a prevalent K2 synthetic cannabinoid, is structurally distinct from Δ(9)-THC, the main psychoactive ingredient in marijuana. Since even subtle structural differences can lead to differential metabolism, formation of novel, biologically active metabolites may be responsible for the distinct effects associated with K2 use. The present study proposes that K2's high adverse effect occurrence is due, at least in part, to distinct JWH-018 metabolite activity at the cannabinoid 1 receptor (CB1R).JWH-018, five potential monohydroxylated metabolites (M1-M5), and one carboxy metabolite (M6) were examined in mouse brain homogenates containing CB1Rs, first for CB1R affinity using a competition binding assay employing the cannabinoid receptor radioligand [(3)H]CP-55,940, and then for CB1R intrinsic efficacy using an [(35)S]GTPγS binding assay. JWH-018 and M1-M5 bound CB1Rs with high affinity, exhibiting K(i) values that were lower than or equivalent to Δ(9)-THC. These molecules also stimulated G-proteins with equal or greater efficacy relative to Δ(9)-THC, a CB1R partial agonist. Most importantly, JWH-018, M2, M3, and M5 produced full CB1R agonist levels of activation. CB1R-mediated activation was demonstrated by blockade with O-2050, a CB1R-selective neutral antagonist. Similar to Δ(9)-THC, JWH-018 and M1 produced a marked depression of locomotor activity and core body temperature in mice that were both blocked by the CB1R-preferring antagonist/inverse agonist AM251.Unlike metabolites of most drugs, the studied JWH-018 monohydroxylated compounds, but not the carboxy metabolite, retain in vitro and in vivo activity at CB1Rs. These observations, combined with higher CB1R affinity and activity relative to Δ(9)-THC, may contribute to the greater prevalence of adverse effects observed with JWH-018-containing products relative to cannabis

Entropy Stable Finite Volume Approximations for Ideal Magnetohydrodynamics

This article serves as a summary outlining the mathematical entropy analysis of the ideal magnetohydrodynamic (MHD) equations. We select the ideal MHD equations as they are particularly useful for mathematically modeling a wide variety of magnetized fluids. In order to be self-contained we first motivate the physical properties of a magnetic fluid and how it should behave under the laws of thermodynamics. Next, we introduce a mathematical model built from hyperbolic partial differential equations (PDEs) that translate physical laws into mathematical equations. After an overview of the continuous analysis, we thoroughly describe the derivation of a numerical approximation of the ideal MHD system that remains consistent to the continuous thermodynamic principles. The derivation of the method and the theorems contained within serve as the bulk of the review article. We demonstrate that the derived numerical approximation retains the correct entropic properties of the continuous model and show its applicability to a variety of standard numerical test cases for MHD schemes. We close with our conclusions and a brief discussion on future work in the area of entropy consistent numerical methods and the modeling of plasmas

Dual use of GTP hydrolysis by elongation factor G on the ribosome.

Elongation factor G (EF-G) is a GTPase that catalyzes tRNA and mRNA translocation during the elongation cycle of protein synthesis. The GTP-bound state of the factor on the ribosome has been studied mainly with non-hydrolyzable analogs of GTP, which led to controversial conclusions about the role of GTP hydrolysis in translocation. Here we describe a mutant of EF-G in which the catalytic His91 is replaced with Ala. The mutant EF-G does not hydrolyze GTP, but binds GTP with unchanged affinity, allowing us to study the function of the authentic GTP-bound form of EF-G in translocation. Utilizing fluorescent reporter groups attached to the tRNAs, mRNA, and the ribosome we compile the velocity map of translocation seen from different perspectives. The data suggest that GTP hydrolysis accelerates translocation up to 30-fold and facilitates conformational rearrangements of both 30S subunit (presumably the backward rotation of the 30S head) and EF-G that lead to the dissociation of the factor. Thus, EF-G combines the energy regime characteristic for motor proteins, accelerating movement by a conformational change induced by GTP hydrolysis, with that of a switch GTPase, which upon Pi release switches the conformations of EF-G and the ribosome to low affinity, allowing the dissociation of the factor

Choreography of molecular movements during ribosome progression along mRNA.

During translation elongation, ribosome translocation along an mRNA entails rotations of the ribosomal subunits, swiveling motions of the small subunit (SSU) head and stepwise movements of the tRNAs together with the mRNA. Here, we reconstructed the choreography of the collective motions of the Escherichia coli ribosome during translocation promoted by elongation factor EF-G, by recording the fluorescence signatures of nine different reporters placed on both ribosomal subunits, tRNA and mRNA. We captured an early forward swiveling of the SSU head taking place while the SSU body rotates in the opposite, clockwise direction. Backward swiveling of the SSU head starts upon tRNA translocation and continues until the post-translocation state is reached. This work places structures of translocation intermediates along a time axis and unravels principles of the motions of macromolecular machines