Impact of common mental disorders on sickness absence in an occupational cohort study

g The work presented in this paper was supported by a grant from the Department of Health (grant number 121/5044). The Whitehall II study has been supported by grants from the Medical Research Council, British Heart Foundation, Health and Safety Executive and Department of Health; the US National Heart Lung and Blood Institute (HL36310), National Institute on Ageing (AG13196) and Agency for Health Care Policy Research (HS06516); and the John D and Catherine T MacArthur Foundation Research Networks on Successful Midlife Development and Socio-economic Status and Healt

ImpRess: an Implementation Readiness checklist developed using a systematic review of randomised controlled trials assessing cognitive stimulation for dementia

Background Research reporting results of clinical trials, psychosocial or technological interventions frequently omit critical details needed to inform implementation in practice. The aim of this article is to develop an Implementation Readiness (ImpRess) checklist, that includes criteria deemed useful in measuring readiness for implementation and apply it to trials of cognitive stimulation in dementia, providing a systematic review of their readiness for widespread implementation. Methods Five electronic databases were searched. After initial screening of papers, two reviewers assessed quality and scored the included studies based on the ImpRess checklist specifically developed for this review. Results Twenty studies met the inclusion criteria. As determined by the ImpRess checklist, scores ranged from 11 to 29 out of 52. According to the checklist the most comprehensive and ready to implement version of cognitive stimulation was Cognitive Stimulation Therapy. Conclusions Reports of interventions rarely include consideration of implementation in practice. Contrary to the growing number of reporting guidelines, crucial items within the ImpRess checklist have been frequently overlooked. This study was able to show that the ImpRess checklist was feasible in practice and reliable. The checklist may be useful in evaluating readiness for implementation for other manualised interventions

Negative Aspects of Close Relationships as Risk Factors for Cognitive Aging

The extent to which social relationships influence cognitive aging is unclear. In this study, we investigated the association of midlife quality of close relationships with subsequent cognitive decline. Participants in the Whitehall II Study (n = 5,873; ages 45-69 years at first cognitive assessment) underwent executive function and memory tests 3 times over a period of 10 years (1997-1999 to 2007-2009). Midlife negative and positive aspects of close relationships were assessed twice using the Close Persons Questionnaire during the 8 years preceding cognitive assessment. Negative aspects of close relationships, but not positive aspects, were associated with accelerated cognitive aging. Participants in the top third of reported negative aspects of close relationships experienced a faster 10-year change in executive function (-0.04 standard deviation, 95% confidence interval: -0.08, -0.01) than those in the bottom third, which was comparable with 1 extra year of cognitive decline for participants aged 60 years after adjustment for sociodemographic and health status. Longitudinal analysis found no evidence of reverse causality. This study highlights the importance of differentiating aspects of social relationships to evaluate their unique associations with cognitive aging

Structure and dynamics of the E. coli chemotaxis core signaling complex by cryo-electron tomography and molecular simulations

To enable the processing of chemical gradients, chemotactic bacteria possess large arrays of transmembrane chemoreceptors, the histidine kinase CheA, and the adaptor protein CheW, organized as coupled core-signaling units (CSU). Despite decades of study, important questions surrounding the molecular mechanisms of sensory signal transduction remain unresolved, owing especially to the lack of a high-resolution CSU structure. Here, we use cryo-electron tomography and sub-tomogram averaging to determine a structure of the Escherichia coli CSU at sub-nanometer resolution. Based on our experimental data, we use molecular simulations to construct an atomistic model of the CSU, enabling a detailed characterization of CheA conformational dynamics in its native structural context. We identify multiple, distinct conformations of the critical P4 domain as well as asymmetries in the localization of the P3 bundle, offering several novel insights into the CheA signaling mechanism

The energetics of protein-lipid interactions as viewed by molecular simulations

Membranes are formed from a bilayer containing diverse lipid species with which membrane proteins interact. Thus, integral membrane proteins are embedded in a bilayer, where they interact with lipids from their surroundings, whilst peripheral membrane proteins bind to lipids at the surface of membranes. Lipid interactions can influence the function of membrane proteins, either directly or allosterically. Both experimental (structural) and computational approaches can reveal lipid binding sites on membrane proteins. It is therefore important to understand the free energies of these interactions. This affords a more complete view of the engagement of a particular protein with the biological membrane surrounding it. Here, we describe a number of computational approaches currently in use for this purpose, including recent advances using both free energy and unbiased simulation methods. In particular we focus on interactions of integral membrane proteins with cholesterol, and with anionic lipids such as phosphatidylinositol 4,5-bisphosphate and cardiolipin. Peripheral membrane proteins are exemplified via interactions of PH domains with phosphoinositide-containing membranes. We summarise the current state of the field and provide an outlook on likely future directions of investigation

Structural basis for substrate specificity and regulation of nucleotide sugar transporters in the lipid bilayer

Nucleotide sugars are the activated form of monosaccharides used by glycosyltransferases during glycosylation. In eukaryotes the SLC35 family of solute carriers are responsible for their selective uptake into the Endoplasmic Reticulum or Golgi apparatus. The structure of the yeast GDP-mannose transporter, Vrg4, revealed a requirement for short chain lipids and a marked difference in transport rate between the nucleotide sugar and nucleoside monophosphate, suggesting a complex network of regulatory elements control transport into these organelles. Here we report the crystal structure of the GMP bound complex of Vrg4, revealing the molecular basis for GMP recognition and transport. Molecular dynamics, combined with biochemical analysis, reveal a lipid mediated dimer interface and mechanism for coordinating structural rearrangements during transport. Together these results provide further insight into how SLC35 family transporters function within the secretory pathway and sheds light onto the role that membrane lipids play in regulating transport across the membrane

Structural basis of proton-coupled potassium transport in the KUP family

Potassium homeostasis is vital for all organisms, but is challenging in single-celled organisms like bacteria and yeast and immobile organisms like plants that constantly need to adapt to changing external conditions. KUP transporters facilitate potassium uptake by the co-transport of protons. Here, we uncover the molecular basis for transport in this widely distributed family. We identify the potassium importer KimA from Bacillus subtilis as a member of the KUP family, demonstrate that it functions as a K+/H+ symporter and report a 3.7 Å cryo-EM structure of the KimA homodimer in an inward-occluded, trans-inhibited conformation. By introducing point mutations, we identify key residues for potassium and proton binding, which are conserved among other KUP proteins

A Synthesis of the Evidence for Managing Stress at Work: A Review of the Reviews Reporting on Anxiety, Depression, and Absenteeism

Background. Psychosocial stressors in the workplace are a cause of anxiety and depressive illnesses, suicide and family disruption. Methods. The present review synthesizes the evidence from existing systematic reviews published between 1990 and July 2011. We assessed the effectiveness of individual, organisational and mixed interventions on two outcomes: mental health and absenteeism. Results. In total, 23 systematic reviews included 499 primary studies; there were 11 meta-analyses and 12 narrative reviews. Meta-analytic studies found a greater effect size of individual interventions on individual outcomes. Organisational interventions showed mixed evidence of benefit. Organisational programmes for physical activity showed a reduction in absenteeism. The findings from the meta-analytic reviews were consistent with the findings from the narrative reviews. Specifically, cognitive-behavioural programmes produced larger effects at the individual level compared with other interventions. Some interventions appeared to lead to deterioration in mental health and absenteeism outcomes.Gaps in the literature include studies of organisational outcomes like absenteeism, the influence of specific occupations and size of organisations, and studies of the comparative effectiveness of primary, secondary and tertiary prevention. Conclusions. Individual interventions (like CBT) improve individuals' mental health. Physical activity as an organisational intervention reduces absenteeism. Research needs to target gaps in the evidence