Cost-effectiveness of structured group psychoeducation versus unstructured group support for bipolar disorder: results from a multi-centre pragmatic randomised controlled trial

Background Bipolar disorder (BD) costs the English economy an estimated £5.2billion/year, largely through incomplete recovery. This analysis estimated the cost-effectiveness of group psychoeducation (PEd), versus group peer support (PS), for treating BD. Methods A 96-week pragmatic randomised controlled trial (RCT), conducted in NHS primary care. The primary analysis compared PEd with PS, using multiple imputed datasets for missing values. An economic model was used to compare PEd with treatment as usual (TAU). The perspective was Health and Personal Social Services. Results Participants receiving PEd (n=153) used more (costly) health-related resources than PS (n=151) (net cost per person £1098 (95% CI, £252-£1943)), with a quality-adjusted life year (QALY) gain of 0.023 (95% CI, 0.001-0.056). The cost per QALY gained was £47,739. PEd may be cost-effective (versus PS) if decision makers are willing to pay at least £37,500 per QALY gained. PEd costs £10,765 more than PS to avoid one relapse. The economic model indicates that PEd may be cost-effective versus TAU if it reduces the probability of relapse (by 15%) or reduces the probability of and increases time to relapse (by 10%). Limitations Participants were generally inconsistent in attending treatment sessions and low numbers had complete cost/QALY data. Factors contributing to pervasive uncertainty of the results are discussed. Conclusions This is the first economic evaluation of PEd versus PS in a pragmatic trial. PEd is associated with a modest improvement in health status and higher costs than PS. There is a high level of uncertainty in the data and results

Evaluation of the Delivery of a Live Attenuated Porcine Reproductive and Respiratory Syndrome Virus as a Unit Solid Dose Injectable Vaccine

Solid dose vaccine formulation and delivery systems offer potential advantages over traditional liquid vaccine formulations. In addition to enhanced thermostability, needle-free delivery of unit solid dose injectable (USDI) vaccines offers safe, rapid, and error-free administration, with applicability to both human and animal health. Solid dose formulation technologies can be adapted for delivery of different vaccine formats including live attenuated vaccines, which remain the 'gold standard' for many disease targets. Porcine reproductive and respiratory syndrome viruses (PRRSV) cause one of the most economically important diseases affecting the global pig industry. Despite several shortcomings, live attenuated vaccines are widely used to control PRRSV. We optimised a freeze-dried USDI formulation of live attenuated PRRSV-1, which fully retained infectious titre, and evaluated its immunogenicity in comparison to virus delivered in liquid suspension via intramuscular and subcutaneous needle inoculation. Pigs vaccinated with the USDI formulation displayed vaccine viraemia, and PRRSV-specific antibody and T cell responses comparable to animals immunised with the liquid vaccine. The USDI vaccine formulation was stable for at least 6 months when stored refrigerated. These data demonstrate the potential for a solid dose vaccine delivery system as an alternative to conventional needle-syringe delivery of live attenuated PRRSV vaccines.Peer reviewe

Scalar nanostructure of the <i>Candida albicans</i> cell wall; a molecular, cellular and ultrastructural analysis and interpretation

Funding Information: We thank the Wellcome Trust (086827, 075470, 099215, 099197, 101873 and 097377), the European Research Council (HEALTH-F2-2010-260338-ALLFUN), the Medical Research Council UK (MR/J008230/1 MR/M026663/1 and MR/N006364/1), the University of Aberdeen and the University of New South Wales for funding.Peer reviewedPublisher PD

Human cytomegalovirus immediate-early 1 protein rewires upstream STAT3 to downstream STAT1 signaling switching an IL6-type to an IFNγ-like response

MN and CP were supported by the Wellcome Trust (www.wellcome.ac.uk) Institutional Strategic Support Fund and CP was supported by the Deutsche Forschungsgemeinschaft (PA 815/2-1; www.dfg.de).The human cytomegalovirus (hCMV) major immediate-early 1 protein (IE1) is best known for activating transcription to facilitate viral replication. Here we present transcriptome data indicating that IE1 is as significant a repressor as it is an activator of host gene expression. Human cells induced to express IE1 exhibit global repression of IL6- and oncostatin M-responsive STAT3 target genes. This repression is followed by STAT1 phosphorylation and activation of STAT1 target genes normally induced by IFNγ. The observed repression and subsequent activation are both mediated through the same region (amino acids 410 to 445) in the C-terminal domain of IE1, and this region serves as a binding site for STAT3. Depletion of STAT3 phenocopies the STAT1-dependent IFNγ-like response to IE1. In contrast, depletion of the IL6 receptor (IL6ST) or the STAT kinase JAK1 prevents this response. Accordingly, treatment with IL6 leads to prolonged STAT1 instead of STAT3 activation in wild-type IE1 expressing cells, but not in cells expressing a mutant protein (IE1dl410-420) deficient for STAT3 binding. A very similar STAT1-directed response to IL6 is also present in cells infected with a wild-type or revertant hCMV, but not an IE1dl410-420 mutant virus, and this response results in restricted viral replication. We conclude that IE1 is sufficient and necessary to rewire upstream IL6-type to downstream IFNγ-like signaling, two pathways linked to opposing actions, resulting in repressed STAT3- and activated STAT1-responsive genes. These findings relate transcriptional repressor and activator functions of IE1 and suggest unexpected outcomes relevant to viral pathogenesis in response to cytokines or growth factors that signal through the IL6ST-JAK1-STAT3 axis in hCMV-infected cells. Our results also reveal that IE1, a protein considered to be a key activator of the hCMV productive cycle, has an unanticipated role in tempering viral replication.Publisher PDFPeer reviewe

Human Cytomegalovirus IE1 Protein Elicits a Type II Interferon-Like Host Cell Response That Depends on Activated STAT1 but Not Interferon-γ

Human cytomegalovirus (hCMV) is a highly prevalent pathogen that, upon primary infection, establishes life-long persistence in all infected individuals. Acute hCMV infections cause a variety of diseases in humans with developmental or acquired immune deficits. In addition, persistent hCMV infection may contribute to various chronic disease conditions even in immunologically normal people. The pathogenesis of hCMV disease has been frequently linked to inflammatory host immune responses triggered by virus-infected cells. Moreover, hCMV infection activates numerous host genes many of which encode pro-inflammatory proteins. However, little is known about the relative contributions of individual viral gene products to these changes in cellular transcription. We systematically analyzed the effects of the hCMV 72-kDa immediate-early 1 (IE1) protein, a major transcriptional activator and antagonist of type I interferon (IFN) signaling, on the human transcriptome. Following expression under conditions closely mimicking the situation during productive infection, IE1 elicits a global type II IFN-like host cell response. This response is dominated by the selective up-regulation of immune stimulatory genes normally controlled by IFN-γ and includes the synthesis and secretion of pro-inflammatory chemokines. IE1-mediated induction of IFN-stimulated genes strictly depends on tyrosine-phosphorylated signal transducer and activator of transcription 1 (STAT1) and correlates with the nuclear accumulation and sequence-specific binding of STAT1 to IFN-γ-responsive promoters. However, neither synthesis nor secretion of IFN-γ or other IFNs seems to be required for the IE1-dependent effects on cellular gene expression. Our results demonstrate that a single hCMV protein can trigger a pro-inflammatory host transcriptional response via an unexpected STAT1-dependent but IFN-independent mechanism and identify IE1 as a candidate determinant of hCMV pathogenicity

The Coactivator PGC-1 Is Involved in the Regulation of the Liver Carnitine Palmitoyltransferase I Gene Expression by cAMP in Combination with HNF4α and cAMP-response Element-binding Protein (CREB)

International audienceLiver carnitine palmitoyltransferase I catalyzes the transfer of long-chain fatty acids into mitochondria. L-CPT I is considered the rate-controlling enzyme in fatty acid oxidation. Expression of the L-CPT I gene is induced by starvation in response to glucagon secretion from the pancreas, an effect mediated by cAMP. Here, the molecular mechanisms underlying the induction of L-CPT I gene expression by cAMP were characterized. We demonstrate that the cAMP response unit of the L-CPT I gene is composed of a cAMP-response element motif and a DR1 sequence located 3 kb upstream of the transcription start site. Our data strongly suggest that the coactivator PGC-1 is involved in the regulation of this gene expression by cAMP in combination with HNF4α and cAMP-response element-binding protein (CREB). Indeed, (i) cotransfection of CREB or HNF4α dominant negative mutants completely abolishes the effect of cAMP on the L-CPT I promoter, and (ii) the cAMP-responsive unit binds HNF4α and CREB through the DR1 and the cAMP-response element sequences, respectively. Moreover, cotransfection of PGC-1 strongly activates the L-CPT I promoter through HNF4α bound at the DR1 element. Finally, we show that the transcriptional induction of the PGC-1 gene by glucagon through cAMP in hepatocytes precedes that of L-CPT-1. In addition to the key role that PGC-1 plays in glucose homeostasis, it may also be critical for lipid homeostasis. Taken together these observations suggest that PGC-1 acts to coordinate the process of metabolic adaptation in the liver

Short-Term Outcomes for Opiate and Crack Users Accessing Treatment:The Effects of Criminal Justice Referral and Crack Use

&lt;b&gt;&lt;i&gt;Background/Aims:&lt;/i&gt;&lt;/b&gt; The English drug treatment population doubled in size between 1998 and 2008, increasingly characterised by crack cocaine use and criminal justice system (CJS) referral. We assessed short-term (median 3.5 month) behaviour changes following participation in drug treatment and the moderating effect of CJS referral/crack use. &lt;b&gt;&lt;i&gt;Methods:&lt;/i&gt;&lt;/b&gt; Opiate and/or crack cocaine users (n = 1,267) were recruited from 342 agencies. Outcome effects were assessed via interaction term regression, clustered at participant level, controlling for client characteristics. Treatment retention effects were tested via Cox proportional hazard models. &lt;b&gt;&lt;i&gt;Results:&lt;/i&gt;&lt;/b&gt; Statistically significant improvements in health, drug use and offensive behaviour were observed (e.g. heroin use from 87 to 51%, acquisitive offending from 47 to 23%). Referral route was not associated with variation in outcomes. Crack use at baseline was associated with a greater chance of non-fatal overdose at follow-up (p = 0.035, 95% CI 1.08-8.20) but a greater reduction in offending income (p = 0.002, 95% CI £104-£419). &lt;b&gt;&lt;i&gt;Conclusion:&lt;/i&gt;&lt;/b&gt; Despite changes in the English drug treatment population, equivalent short-term improvements in client behaviour were observed a decade earlier. Outcomes for CJS-referred clients were comparable to non-CJS. Crack use at treatment entry offered some scope for greater improvements in offending but may be a barrier to cessation of mortality-associated risky behaviour.</jats:p

Validity of subjective versus objective quality of life assessment in people with schizophrenia

BACKGROUND: Quality of life (QoL) is considered an important outcome in health research. It can be rated by the patient, or by an external assessor. We wished to identify the predictors of any discrepancies between these two approaches in people with schizophrenia. METHODS: Patients with DSM schizophrenia and related disorders (N = 80) completed both patient-rated (Lancashire Quality of Life Profile; LQOLP) and assessor-rated (Heinrich’s Quality of Life Scale; QLS) measures of QoL. RESULTS: Patient-rated (LQOLP) and assessor-rated (QLS) measures showed a modest correlation (r = 0.38). In a regression analysis, independent predictors of subjectively-rated QoL being higher than objectively-assessed QoL in the same patient, were low insight score (BIS), negative symptoms (PANSS), absence of depression (CDSS), and less positive attitude toward prescribed treatment (DAI). CONCLUSIONS: In people with schizophrenia, scores on objectively- and subjectively-rated measures of quality of life can differ markedly. When comparing subjective to objective assessments, patients with depressive symptoms will value their QoL lower, and those with low insight will value their QoL higher. This has important implications for the utility and interpretation of QoL measures in schizophrenia