The cost of changing physical activity behaviour: Evidence from a "physical activity pathway" in the primary care setting

Copyright @ 2011 Boehler et al.BACKGROUND: The ‘Physical Activity Care Pathway’ (a Pilot for the ‘Let’s Get Moving’ policy) is a systematic approach to integrating physical activity promotion into the primary care setting. It combines several methods reported to support behavioural change, including brief interventions, motivational interviewing, goal setting, providing written resources, and follow-up support. This paper compares costs falling on the UK National Health Service (NHS) of implementing the care pathway using two different recruitment strategies and provides initial insights into the cost of changing physical activity behaviour. METHODS: A combination of a time driven variant of activity based costing, audit data through EMIS and a survey of practice managers provided patient-level cost data for 411 screened individuals. Self reported physical activity data of 70 people completing the care pathway at three month was compared with baseline using a regression based ‘difference in differences’ approach. Deterministic and probabilistic sensitivity analyses in combination with hypothesis testing were used to judge how robust findings are to key assumptions and to assess the uncertainty around estimates of the cost of changing physical activity behaviour. RESULTS: It cost £53 (SD 7.8) per patient completing the PACP in opportunistic centres and £191 (SD 39) at disease register sites. The completer rate was higher in disease register centres (27.3% vs. 16.2%) and the difference in differences in time spent on physical activity was 81.32 (SE 17.16) minutes/week in patients completing the PACP; so that the incremental cost of converting one sedentary adult to an ‘active state’ of 150 minutes of moderate intensity physical activity per week amounts to £ 886.50 in disease register practices, compared to opportunistic screening. CONCLUSIONS: Disease register screening is more costly than opportunistic patient recruitment. However, additional costs come with a higher completion rate and better outcomes in terms of behavioural change in patients completing the care pathway. Further research is needed to rigorously evaluate intervention efficiency and to assess the link between behavioural change and changes in quality adjusted life years (QALYs).This article is available through the Brunel Open Access Publishing Fund

Fabry Disease in Latin America: Data from the Fabry Registry

The purpose of these analyses was to characterize demographic and baseline clinical characteristics of Latin American patients with Fabry disease compared to that of patients in the rest of the world. Observational data reported to the Fabry Registry were obtained from untreated patients or prior to treatment with enzyme replacement therapy. As of October 1, 2010, 3,752 patients were enrolled in the Fabry Registry worldwide, including 333 patients within Latin America. Latin American patients tended to be younger than Fabry Registry patients enrolled in the rest of the world: mean current age 35.5 years versus 39.2 years for men (p < 0.05 by t-test), mean age 37.8 years versus 43.6 years for women (p < 0.05 by t-test). A smaller percentage of Latin American patients have received enzyme replacement therapy, compared to patients in the rest of the world: 67% versus 80% for men, and 19% versus 39% of women, respectively. Thirty-one percent of men and 22% of women in Latin America reported experiencing a significant cardiovascular, renal, or cerebrovascular event, at a mean age of 35 ± 12.6 years in men and 44 ± 12.3 years in women. Cardiovascular events were the most common type of initial clinical event among men and women in Latin America. The medical community in Latin America should be aware of Fabry disease as a possible cause of renal or cardiac dysfunction. Increased awareness will facilitate prompt diagnosis and initiation of treatment

Diagnostic value of plasma phosphorylated tau181 in Alzheimer's disease and frontotemporal lobar degeneration

With the potential development of new disease-modifying Alzheimer’s disease (AD) therapies, simple, widely available screening tests are needed to identify which individuals, who are experiencing symptoms of cognitive or behavioral decline, should be further evaluated for initiation of treatment. A blood-based test for AD would be a less invasive and less expensive screening tool than the currently approved cerebrospinal fluid or amyloid β positron emission tomography (PET) diagnostic tests. We examined whether plasma tau phosphorylated at residue 181 (pTau181) could differentiate between clinically diagnosed or autopsy-confirmed AD and frontotemporal lobar degeneration. Plasma pTau181 concentrations were increased by 3.5-fold in AD compared to controls and differentiated AD from both clinically diagnosed (receiver operating characteristic area under the curve of 0.894) and autopsy-confirmed frontotemporal lobar degeneration (area under the curve of 0.878). Plasma pTau181 identified individuals who were amyloid β-PET-positive regardless of clinical diagnosis and correlated with cortical tau protein deposition measured by 18F-flortaucipir PET. Plasma pTau181 may be useful to screen for tau pathology associated with AD

Essential versus accessory aspects of cell death: recommendations of the NCCD 2015

Cells exposed to extreme physicochemical or mechanical stimuli die in an uncontrollable manner, as a result of their immediate structural breakdown. Such an unavoidable variant of cellular demise is generally referred to as ‘accidental cell death’ (ACD). In most settings, however, cell death is initiated by a genetically encoded apparatus, correlating with the fact that its course can be altered by pharmacologic or genetic interventions. ‘Regulated cell death’ (RCD) can occur as part of physiologic programs or can be activated once adaptive responses to perturbations of the extracellular or intracellular microenvironment fail. The biochemical phenomena that accompany RCD may be harnessed to classify it into a few subtypes, which often (but not always) exhibit stereotyped morphologic features. Nonetheless, efficiently inhibiting the processes that are commonly thought to cause RCD, such as the activation of executioner caspases in the course of apoptosis, does not exert true cytoprotective effects in the mammalian system, but simply alters the kinetics of cellular demise as it shifts its morphologic and biochemical correlates. Conversely, bona fide cytoprotection can be achieved by inhibiting the transduction of lethal signals in the early phases of the process, when adaptive responses are still operational. Thus, the mechanisms that truly execute RCD may be less understood, less inhibitable and perhaps more homogeneous than previously thought. Here, the Nomenclature Committee on Cell Death formulates a set of recommendations to help scientists and researchers to discriminate between essential and accessory aspects of cell death

Runx Expression Is Mitogenic and Mutually Linked to Wnt Activity in Blastula-Stage Sea Urchin Embryos

The Runt homology domain (Runx) defines a metazoan family of sequence-specific transcriptional regulatory proteins that are critical for animal development and causally associated with a variety of mammalian cancers. The sea urchin Runx gene SpRunt-1 is expressed throughout the blastula stage embryo, and is required globally during embryogenesis for cell survival and differentiation.Depletion of SpRunt-1 by morpholino antisense-mediated knockdown causes a blastula stage deficit in cell proliferation, as shown by bromodeoxyuridine (BrdU) incorporation and direct cell counts. Reverse transcription coupled polymerase chain reaction (RT-PCR) studies show that the cell proliferation deficit is presaged by a deficit in the expression of several zygotic wnt genes, including wnt8, a key regulator of endomesoderm development. In addition, SpRunt-1-depleted blastulae underexpress cyclinD, an effector of mitogenic Wnt signaling. Blastula stage cell proliferation is also impeded by knockdown of either wnt8 or cyclinD. Chromatin immunoprecipitation (ChIP) indicates that Runx target sites within 5′ sequences flanking cyclinD, wnt6 and wnt8 are directly bound by SpRunt-1 protein at late blastula stage. Furthermore, experiments using a green fluorescent protein (GFP) reporter transgene show that the blastula-stage operation of a cis-regulatory module previously shown to be required for wnt8 expression (Minokawa et al., Dev. Biol. 288: 545–558, 2005) is dependent on its direct sequence-specific interaction with SpRunt-1. Finally, inhibitor studies and immunoblot analysis show that SpRunt-1 protein levels are negatively regulated by glycogen synthase kinase (GSK)-3.These results suggest that Runx expression and Wnt signaling are mutually linked in a feedback circuit that controls cell proliferation during development

Increased autophagy in EphrinB2-deficient osteocytes is associated with elevated secondary mineralization and brittle bone

Mineralized bone forms when collagen-containing osteoid accrues mineral crystals. This is initiated rapidly (primary mineralization), and continues slowly (secondary mineralization) until bone is remodeled. The interconnected osteocyte network within the bone matrix differentiates from bone-forming osteoblasts; although osteoblast differentiation requires EphrinB2, osteocytes retain its expression. Here we report brittle bones in mice with osteocyte-targeted EphrinB2 deletion. This is not caused by low bone mass, but by defective bone material. While osteoid mineralization is initiated at normal rate, mineral accrual is accelerated, indicating that EphrinB2 in osteocytes limits mineral accumulation. No known regulators of mineralization are modified in the brittle cortical bone but a cluster of autophagy-associated genes are dysregulated. EphrinB2-deficient osteocytes displayed more autophagosomes in vivo and in vitro, and EphrinB2-Fc treatment suppresses autophagy in a RhoA-ROCK dependent manner. We conclude that secondary mineralization involves EphrinB2-RhoA-limited autophagy in osteocytes, and disruption leads to a bone fragility independent of bone mass

Reducing repeat pregnancies in adolescence: applying realist principles as part of a mixed-methods systematic review to explore what works, for whom, how and under what circumstances

BACKGROUND: Previous research has demonstrated emotional, psychological and educational harm to young mothers following unintended conceptions. The UK has one of the highest rates of pregnancies in adolescence in Western Europe with a high proportion of these being repeat pregnancies, making it a topic of interest for public health policy makers, and health and social care practitioners. As part of a wider mixed-methods systematic review, realist principles were applied to synthesise evidence about interventions aiming to reduce repeat pregnancies in adolescence.METHODS: A multi-streamed, mixed-methods systematic review was conducted searching 11 major electronic databases and 9 additional databases from 1995 onwards, using key terms such as pregnancy, teen or adolescent. The principles of realist synthesis were applied to all included literature to uncover theories about what works, for whom, how and in what context. Initial theory areas were developed through evidence scoping, group discussion by the authors and stakeholder engagement to uncover context + mechanism = outcome (CMO) configurations and related narratives.RESULTS: The searches identified 8,664 documents initially, and 403 in repeat searches, filtering to 81 included studies, including qualitative studies, randomised controlled trials, quantitative studies and grey literature. Three CMO configurations were developed. The individual experiences of young mothers' triggered self-efficacy, notions of perceived risks, susceptibility and benefits of pregnancy, resulting in the adolescent taking control of their fertility and sexual encounters. The choice between motherhood and other goals triggered notions of motivations, resulting in the adolescent managing their expectations of motherhood and controlling their fertility and sexual encounters. Barriers and facilitators to accessing services triggered notions of connectedness and self-determination; resulting in interventions that are tailored so they are relevant to young persons, and improve access to services and engagement with the issue of pregnancy in adolescence.CONCLUSIONS: Pregnancy in adolescence is a complex issue with many factors to consider. The conceptual platform described here could help guide policy makers and professionals towards a number of areas that need to be attended to in order to increase the likelihood of an intervention working to prevent rapid repeat pregnancy in adolescence.TRIAL REGISTRATION: PROSPERO CRD42012003168

Finding one's way in proteomics: a protein species nomenclature

Our knowledge of proteins has greatly improved in recent years, driven by new technologies in the fields of molecular biology and proteome research. It has become clear that from a single gene not only one single gene product but many different ones - termed protein species - are generated, all of which may be associated with different functions. Nonetheless, an unambiguous nomenclature for describing individual protein species is still lacking. With the present paper we therefore propose a systematic nomenclature for the comprehensive description of protein species. The protein species nomenclature is flexible and adaptable to every level of knowledge and of experimental data in accordance with the exact chemical composition of individual protein species. As a minimum description the entry name (gene name + species according to the UniProt knowledgebase) can be used, if no analytical data about the target protein species are available

Acute Effects of Sex Steroid Hormones on Susceptibility to Cardiac Arrhythmias: A Simulation Study

Acute effects of sex steroid hormones likely contribute to the observation that post-pubescent males have shorter QT intervals than females. However, the specific role for hormones in modulating cardiac electrophysiological parameters and arrhythmia vulnerability is unclear. Here we use a computational modeling approach to incorporate experimentally measured effects of physiological concentrations of testosterone, estrogen and progesterone on cardiac ion channel targets. We then study the hormone effects on ventricular cell and tissue dynamics comprised of Faber-Rudy computational models. The “female” model predicts changes in action potential duration (APD) at different stages of the menstrual cycle that are consistent with clinically observed QT interval fluctuations. The “male” model predicts shortening of APD and QT interval at physiological testosterone concentrations. The model suggests increased susceptibility to drug-induced arrhythmia when estradiol levels are high, while testosterone and progesterone are apparently protective. Simulations predict the effects of sex steroid hormones on clinically observed QT intervals and reveal mechanisms of estrogen-mediated susceptibility to prolongation of QT interval. The simulations also indicate that acute effects of estrogen are not alone sufficient to cause arrhythmia triggers and explain the increased risk of females to Torsades de Pointes. Our results suggest that acute effects of sex steroid hormones on cardiac ion channels are sufficient to account for some aspects of gender specific susceptibility to long-QT linked arrhythmias

Mantle Pb paradoxes : the sulfide solution

Author Posting. © Springer, 2006. This is the author's version of the work. It is posted here by permission of Springer for personal use, not for redistribution. The definitive version was published in Contributions to Mineralogy and Petrology 152 (2006): 295-308, doi:10.1007/s00410-006-0108-1.There is growing evidence that the budget of Pb in mantle peridotites is largely contained in sulfide, and that Pb partitions strongly into sulfide relative to silicate melt. In addition, there is evidence to suggest that diffusion rates of Pb in sulfide (solid or melt) are very fast. Given the possibility that sulfide melt ‘wets’ sub-solidus mantle silicates, and has very low viscosity, the implications for Pb behavior during mantle melting are profound. There is only sparse experimental data relating to Pb partitioning between sulfide and silicate, and no data on Pb diffusion rates in sulfides. A full understanding of Pb behavior in sulfide may hold the key to several long-standing and important Pb paradoxes and enigmas. The classical Pb isotope paradox arises from the fact that all known mantle reservoirs lie to the right of the Geochron, with no consensus as to the identity of the “balancing” reservoir. We propose that long-term segregation of sulfide (containing Pb) to the core may resolve this paradox. Another Pb paradox arises from the fact that the Ce/Pb ratio of both OIB and MORB is greater than bulk earth, and constant at a value of 25. The constancy of this “canonical ratio” implies similar partition coefficients for Ce and Pb during magmatic processes (Hofmann et al. 1986), whereas most experimental studies show that Pb is more incompatible in silicates than Ce. Retention of Pb in residual mantle sulfide during melting has the potential to bring the bulk partitioning of Ce into equality with Pb if the sulfide melt/silicate melt partition coefficient for Pb has a value of ~ 14. Modeling shows that the Ce/Pb (or Nd/Pb) of such melts will still accurately reflect that of the source, thus enforcing the paradox that OIB and MORB mantles have markedly higher Ce/Pb (and Nd/Pb) than the bulk silicate earth. This implies large deficiencies of Pb in the mantle sources for these basalts. Sulfide may play other important roles during magmagenesis: 1). advective/diffusive sulfide networks may form potent metasomatic agents (in both introducing and obliterating Pb isotopic heterogeneities in the mantle); 2). silicate melt networks may easily exchange Pb with ambient mantle sulfides (by diffusion or assimilation), thus ‘sampling’ Pb in isotopically heterogeneous mantle domains differently from the silicate-controlled isotope tracer systems (Sr, Nd, Hf), with an apparent ‘de-coupling’ of these systems.Our intemperance should not be blamed on the support we gratefully acknowledge from NSF: EAR- 0125917 to SRH and OCE-0118198 to GAG