The effects of roflumilast, a phosphodiesterase type-4 inhibitor, on EEG biomarkers in schizophrenia: A randomised controlled trial

Background: Patients with schizophrenia have significant cognitive deficits, which may profoundly impair quality of life. These deficits are also evident at the neurophysiological level with patients demonstrating altered event-related potential in several stages of cognitive processing compared to healthy controls; within the auditory domain, for example, there are replicated alterations in Mismatch Negativity, P300 and Auditory Steady State Response. However, there are no approved pharmacological treatments for cognitive deficits in schizophrenia. Aims: Here we examine whether the phosphodiesterase-4 inhibitor, roflumilast, can improve neurophysiological deficits in schizophrenia. Methods: Using a randomised, double-blind, placebo-controlled, crossover design study in 18 patients with schizophrenia, the effect of the phosphodiesterase-4 inhibitor, roflumilast (100 µg and 250 µg) on auditory steady state response (early stage), mismatch negativity and theta (intermediate stage) and P300 (late stage) was examined using electroencephalogram. A total of 18 subjects were randomised and included in the analysis. Results: Roflumilast 250 µg significantly enhanced the amplitude of both the mismatch negativity (p=0.04) and working memory-related theta oscillations (p=0.02) compared to placebo but not in the other (early- or late-stage) cognitive markers. Conclusions: The results suggest that phosphodiesterase-4 inhibition, with roflumilast, can improve electroencephalogram cognitive markers, which are impaired in schizophrenia, and that phosphodiesterase-4 inhibition acts at an intermediate rather than early or late cognitive processing stage. This study also underlines the use of neurophysiological measures as cognitive biomarkers in experimental medicine

Strain specific maturation of Dendritic cells and production of IL-1β controls CD40-driven colitis

Intestinal integrity is maintained by balanced numbers of CD103 + Dendritic cells (DCs), which generate peripherally induced regulatory T cells (iTregs). We have developed a mouse model where DC-specific constitutive CD40 signals caused a strong reduction of CD103 + DCs in the lamina propria (LP) and intestinal lymph nodes (LN). As a consequence, also iTregs were strongly reduced and transgenic mice on the C57Bl/6-background (B6) developed fatal colitis. Here we describe that transgenic mice on a pure Balb/c-background (B/c) do not show any pathologies, while transgenic C57Bl/6 x Balb/c (F1) mice develop weak colon inflammation, without fatal colitis. This graded pathology correlated with the effects of CD40-signalling on DCs in each background, with striking loss of CD103 + DCs in B6, but reduced in F1 and diminished in B/c background. We further show direct correlation of CD103 + DC-numbers with numbers of iTregs, the frequencies of which behave correspondingly. Striking effects on B6-DCs reflected robust loss of surface MHCII, known to be crucial for iTreg induction. Furthermore, elevated levels of IL-23 together with IL-1, found only in B6 mice, support generation of intestinal IFN-γ + IL-17 + Th17 cells and IFN-γ + Th1 cells, responsible for onset of disease. Together, this demonstrates a novel aspect of colitis-control, depending on genetic background. Moreover, strain-specific environmental sensing might alter the CD103 + DC/iTreg-axis to tip intestinal homeostatic balance to pathology

Publication Guidelines for Quality Improvement Studies in Health Care: Evolution of the SQUIRE Project

In 2005 we published draft guidelines for reporting studies of quality improvement interventions as the initial step in a consensus process for development of a more definitive version. The current article contains the revised version, which we refer to as SQUIRE (Standards for QUality Improvement Reporting Excellence). We describe the consensus process, which included informal feedback, formal written commentaries, input from publication guideline developers, review of the literature on the epistemology of improvement and on methods for evaluating complex social programs, and a meeting of stakeholders for critical review of the guidelines’ content and wording, followed by commentary on sequential versions from an expert consultant group. Finally, we examine major differences between SQUIRE and the initial draft, and consider limitations of and unresolved questions about SQUIRE; we also describe ancillary supporting documents and alternative versions under development, and plans for dissemination, testing, and further development of SQUIRE

SQUIRE 2.0 (Standards for QUality Improvement Reporting Excellence) : Revised publication guidelines from a detailed consensus process

Since the publication of Standards for QUality Improvement Reporting Excellence (SQUIRE 1.0) guidelines in 2008, the science of the field has advanced considerably. In this manuscript, we describe the development of SQUIRE 2.0 and its key components. We undertook the revision between 2012 and 2015 using (1) semistructured interviews and focus groups to evaluate SQUIRE 1.0 plus feedback from an international steering group, (2) two face-to-face consensus meetings to develop interim drafts and (3) pilot testing with authors and a public comment period. SQUIRE 2.0 emphasises the reporting of three key components of systematic efforts to improve the quality, value and safety of healthcare: the use of formal and informal theory in planning, implementing and evaluating improvement work; the context in which the work is done and the study of the intervention(s). SQUIRE 2.0 is intended for reporting the range of methods used to improve healthcare, recognising that they can be complex and multidimensional. It provides common ground to share these discoveries in the scholarly literature (http://www.squire-statement.org). © Published by the BMJ Publishing Group Limited

Standards for QUality Improvement Reporting Excellence 2.0 : revised publication guidelines from a detailed consensus process

Since the publication of Standards for QUality Improvement Reporting Excellence (SQUIRE 1.0) guidelines in 2008, the science of the field has advanced considerably. In this article, we describe the development of SQUIRE 2.0 and its key components. We undertook the revision between 2012 and 2015 using (1) semistructured interviews and focus groups to evaluate SQUIRE 1.0 plus feedback from an international steering group, (2) two face-to-face consensus meetings to develop interim drafts, and (3) pilot testing with authors and a public comment period. SQUIRE 2.0 emphasizes the reporting of three key components of systematic efforts to improve the quality, value, and safety of health care: the use of formal and informal theory in planning, implementing, and evaluating improvement work; the context in which the work is done; and the study of the intervention(s). SQUIRE 2.0 is intended for reporting the range of methods used to improve health care, recognizing that they can be complex and multidimensional. It provides common ground to share these discoveries in the scholarly literature (www.squire-statement.org)

The effects of roflumilast, a phosphodiesterase type-4 inhibitor, on EEG biomarkers in schizophrenia: A randomised controlled trial

Background: Patients with schizophrenia have significant cognitive deficits, which may profoundly impair quality of life. These deficits are also evident at the neurophysiological level with patients demonstrating altered event-related potential in several stages of cognitive processing compared to healthy controls; within the auditory domain, for example, there are replicated alterations in Mismatch Negativity, P300 and Auditory Steady State Response. However, there are no approved pharmacological treatments for cognitive deficits in schizophrenia. Aims: Here we examine whether the phosphodiesterase-4 inhibitor, roflumilast, can improve neurophysiological deficits in schizophrenia. Methods: Using a randomised, double-blind, placebo-controlled, crossover design study in 18 patients with schizophrenia, the effect of the phosphodiesterase-4 inhibitor, roflumilast (100 µg and 250 µg) on auditory steady state response (early stage), mismatch negativity and theta (intermediate stage) and P300 (late stage) was examined using electroencephalogram. A total of 18 subjects were randomised and included in the analysis. Results: Roflumilast 250 µg significantly enhanced the amplitude of both the mismatch negativity (p=0.04) and working memory-related theta oscillations (p=0.02) compared to placebo but not in the other (early- or late-stage) cognitive markers. Conclusions: The results suggest that phosphodiesterase-4 inhibition, with roflumilast, can improve electroencephalogram cognitive markers, which are impaired in schizophrenia, and that phosphodiesterase-4 inhibition acts at an intermediate rather than early or late cognitive processing stage. This study also underlines the use of neurophysiological measures as cognitive biomarkers in experimental medicine