Incident venous thromboembolic events in the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER)

<p>Background: Venous thromboembolic events (VTE), including deep venous thrombosis and pulmonary embolism, are common in older age. It has been suggested that statins might reduce the risk of VTE however positive results from studies of middle aged subjects may not be generalisable to elderly people. We aimed to determine the effect of pravastatin on incident VTE in older people; we also studied the impact of clinical and plasma risk variables.</p> <p>Methods: This study was an analysis of incident VTE using data from the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER), a randomized, double-blind, placebo-controlled trial of pravastatin in men and women aged 70-82. Mean follow-up was 3.2 years. Risk for VTE was examined in non-warfarin treated pravastatin (n = 2834) and placebo (n = 2865) patients using a Cox's proportional hazard model, and the impact of other risk factors assessed in a multivariate forward stepwise regression analysis. Baseline clinical characteristics, blood biochemistry and hematology variables, plasma levels of lipids and lipoproteins, and plasma markers of inflammation and adiposity were compared. Plasma markers of thrombosis and hemostasis were assessed in a nested case (n = 48) control (n = 93) study where the cohort was those participants, not on warfarin, for whom data were available.</p> <p>Results: There were 28 definite cases (1.0%) of incident VTE in the pravastatin group recipients and 20 cases (0.70%) in placebo recipients. Pravastatin did not reduce VTE in PROSPER compared to placebo [unadjusted hazard ratio (95% confidence interval) 1.42 (0.80, 2.52) p = 0.23]. Higher body mass index (BMI) [1.09 (1.02, 1.15) p = 0.0075], country [Scotland vs Netherlands 4.26 (1.00, 18.21) p = 0.050 and Ireland vs Netherlands 6.16 (1.46, 26.00) p = 0.013], lower systolic blood pressure [1.35 (1.03, 1.75) p = 0.027] and lower baseline Mini Mental State Examination (MMSE) score [1.19 (1.01, 1.41) p = 0.034] were associated with an increased risk of VTE, however only BMI, country and systolic blood pressure remained significant on multivariate analysis. In a nested case control study of definite VTE, plasma Factor VIII levels were associated with VTE [1.52 (1.01, 2.28), p = 0.044]. However no other measure of thrombosis and haemostasis was associated with increased risk of VTE.</p> <p>Conclusions: Pravastatin does not prevent VTE in elderly people at risk of vascular disease. Blood markers of haemostasis and inflammation are not strongly predictive of VTE in older age however BMI, country and lower systolic blood pressure are independently associated with VTE risk.</p&gt

Metabolic, inflammatory and haemostatic effects of a low-dose continuous combined HRT in women with type 2 diabetes: potentially safer with respect to vascular risk?

BACKGROUND Conventional hormone replacement therapy (HRT) containing conjugated equine oestrogen (CEE) and medroxyprogesterone acetate (MPA) increases triglyceride, C- reactive protein (CRP) and coagulation Factor VII concentrations, potentially explaining their increased coronary heart disease (CHD) and stroke risk. OBJECTIVE To assess the metabolic effects of a continuous combined HRT containing 1 mg oestradiol and 0.5 mg norethisterone or matching placebo. DESIGN Double-blind, randomized placebo-controlled trial. PATIENTS Fifty women with type 2 diabetes. MEASUREMENTS Classical and novel risk factors for vascular disease. RESULTS Triglyceride concentration was not altered (P = 0.31, change in active arm relative to placebo) and low-density lipoprotein (LDL) cholesterol concentration declined 13% (P = 0.018). IL-6 concentration (mean difference -1.42 pg/ml, 95% CI: -2.55 to - 0.29 IU/dl, P = 0.015), Factor VII (-32 IU/dl, -43 to -21 IU/l, P lt 0.001) and tissue plasminogen activator antigen (by 13%, P = 0.005) concentrations fell, but CRP was not significantly altered (P = 0.62). Fasting glucose (P = 0.026) also declined significantly, but there are no significant effects on HBA1c, Factor IX or APC resistance. CONCLUSIONS HRT containing 1 mg oestradiol and 0.5 mg norethisterone may avoid the adverse metabolic effects potentially implicated in the elevated CHD and stroke risk induced by conventional higher dose HRT. This type of preparation may therefore be more suitable than conventional HRT for women at elevated CHD risk such as those with type 2 diabetes. Large randomized controlled trials of such low dose preparations, powered for cardiovascular end points, are now needed

Protocol for the development of guidance for stakeholder engagement in health and healthcare guideline development and implementation

Stakeholder engagement has become widely accepted as a necessary component of guideline development and implementation. While frameworks for developing guidelines express the need for those potentially affected by guideline recommendations to be involved in their development, there is a lack of consensus on how this should be done in practice. Further, there is a lack of guidance on how to equitably and meaningfully engage multiple stakeholders. We aim to develop guidance for the meaningful and equitable engagement of multiple stakeholders in guideline development and implementation. METHODS: This will be a multi-stage project. The first stage is to conduct a series of four systematic reviews. These will (1) describe existing guidance and methods for stakeholder engagement in guideline development and implementation, (2) characterize barriers and facilitators to stakeholder engagement in guideline development and implementation, (3) explore the impact of stakeholder engagement on guideline development and implementation, and (4) identify issues related to conflicts of interest when engaging multiple stakeholders in guideline development and implementation. DISCUSSION: We will collaborate with our multiple and diverse stakeholders to develop guidance for multi-stakeholder engagement in guideline development and implementation. We will use the results of the systematic reviews to develop a candidate list of draft guidance recommendations and will seek broad feedback on the draft guidance via an online survey of guideline developers and external stakeholders. An invited group of representatives from all stakeholder groups will discuss the results of the survey at a consensus meeting which will inform the development of the final guidance papers. Our overall goal is to improve the development of guidelines through meaningful and equitable multi-stakeholder engagement, and subsequently to improve health outcomes and reduce inequities in health

A retrospective analysis of ezrin protein and mRNA expression in breast cancer: Ezrin expression is associated with patient survival and survival of patients with receptor‐positive disease

Introduction: The cytoskeletal protein ezrin is upregulated in many cancer types and is strongly associated with poor patient outcome. While the clinical and prognostic value of ezrin has been previously evaluated in breast cancer, most studies to date have been conducted in smaller cohorts (less than 500 cases) or have focused on specific disease characteristics. The current study is the largest of its kind to evaluate ezrin both at the protein and mRNA levels in early‐stage breast cancer patients using the Nottingham (n = 1094) and METABRIC (n = 1980) cohorts, respectively. Results: High expression of ezrin was significantly associated with larger tumour size (p = 0.027), higher tumour grade (p < 0.001), worse Nottingham Prognostic Index prognostic group (p = 0.011) and HER2‐positive status (p = 0.001). High ezrin expression was significantly associated with adverse survival of breast cancer patients (p < 0.001) and remained associated with survival in multivariate Cox‐regression analysis (p = 0.018, hazard ratio (HR) = 1.343, 95% confidence interval (CI) = 1.051–1.716) when potentially confounding factors were included. High ezrin expression was significantly associated with adverse survival of patients whose tumours were categorised as receptor (oestrogen receptor (ER), progesterone receptor (PgR) or HER2) positive (p < 0.001) in comparison to those categorised as triple‐negative breast cancer (p = 0.889). High expression of ezrin mRNA (VIL2) in the METABRIC cohort was also significantly associated with adverse survival of breast cancer patients (p < 0.001). Conclusion: Retrospective analyses show that ezrin is an independent prognostic marker, with higher expression associated with shortened survival in receptor‐positive (ER, PgR or HER2) patients. Ezrin expression is associated with more aggressive disease and may have clinical utility as a biomarker of patient prognosis in early‐stage breast cancer

Reptile remains from Tiga (Tokanod), Loyalty Islands, New Caledonia

Archaeological excavations on Tiga provide the first vouchered herpetological records for this small island between Lifou and Maré in the Loyalty Islands. Eighty-three skeletal elements from four sites yielded material assignable to skinks (Emoia loyaltiensis, Lioscincus nigrofasciolatus), geckos (Bavayia crass i-collis, B. sp., Gehyra georgpotthasti, Nactus pelagicus), and a boid snake (Candoia bihroni) all known from elsewhere in the Loyalties, as well as undetermined material consistent with these and other Loyalties lizards. Diagnostic features of geckos versus skinks for elements commonly recovered from archaeological sites and from owl pellets are discussed. Gehyra georgpotthasti has a limited distribution in the Loyalties and its occurrence on Tiga clarifies its range. The boid snake is the only reptile likely to have been harvested by human inhabitants of Tiga. The presence of gekkonid geckos in pre-European times is confirmed and contrasts with the situation of Grande Terre fossil sites, where only diplodactylid geckos have been recovered. Although it is anticipated that all species recovered from archaeological sites are still present on the island, a modern herpetofaunal survey is needed

Centile charts for birthweight for gestational age for Scottish singleton births

<p>Abstract</p> <p>Background</p> <p>Centile charts of birthweight for gestational age are used to identify low birthweight babies. The charts currently used in Scotland are based on data from the 1970s and require updating given changes in birthweight and in the measurement of gestational age since then.</p> <p>Methods</p> <p>Routinely collected data of 100,133 singleton births occurring in Scotland from 1998–2003 were used to construct new centile charts using the LMS method.</p> <p>Results</p> <p>Centile charts for birthweight for sex and parity groupings were constructed for singleton birth and compared to existing charts used in Scottish hospitals.</p> <p>Conclusion</p> <p>Mean birthweight has been shown to have increased over recent decades. The differences shown between the new and currently used centiles confirm the need for more up-to-date centiles for birthweight for gestational age.</p

Alternating hemiplegia of childhood-related neural and behavioural phenotypes in Na+,K+-ATPase α3 missense mutant mice

Missense mutations in ATP1A3 encoding Na(+),K(+)-ATPase α3 have been identified as the primary cause of alternating hemiplegia of childhood (AHC), a motor disorder with onset typically before the age of 6 months. Affected children tend to be of short stature and can also have epilepsy, ataxia and learning disability. The Na(+),K(+)-ATPase has a well-known role in maintaining electrochemical gradients across cell membranes, but our understanding of how the mutations cause AHC is limited. Myshkin mutant mice carry an amino acid change (I810N) that affects the same position in Na(+),K(+)-ATPase α3 as I810S found in AHC. Using molecular modelling, we show that the Myshkin and AHC mutations display similarly severe structural impacts on Na(+),K(+)-ATPase α3, including upon the K(+) pore and predicted K(+) binding sites. Behavioural analysis of Myshkin mice revealed phenotypic abnormalities similar to symptoms of AHC, including motor dysfunction and cognitive impairment. 2-DG imaging of Myshkin mice identified compromised thalamocortical functioning that includes a deficit in frontal cortex functioning (hypofrontality), directly mirroring that reported in AHC, along with reduced thalamocortical functional connectivity. Our results thus provide validation for missense mutations in Na(+),K(+)-ATPase α3 as a cause of AHC, and highlight Myshkin mice as a starting point for the exploration of disease mechanisms and novel treatments in AHC

Welfare Reform, Precarity and the Re-Commodification of Labour

While welfare reform matters for workers and workplaces, it is peripheral in English-language sociology of work and industrial relations research. This article’s core proposition is that active labour market policies (ALMPs) are altering the institutional constitution of the labour market by intensifying market discipline within the workforce. This re-commodification effect is specified drawing on Marxism, comparative institutionalism, German-language sociology, and English-language social policy analysis. Because of administrative failures and employer discrimination, however, ALMPs may worsen precarity without achieving the stated goal of increasing labour-market participation

A comparison between Asian and Australasia backpackers using cultural consensus analysis

This study tests the differences in the shared understanding of the backpacker cultural domain between two groups: backpackers from Australasia and backpackers from Asian countries. A total of 256 backpackers responded to a questionnaire administered in Kuala Lumpur, Bangkok and Krabi Province (Thailand). Cultural consensus analysis (CCA) guided the data analysis, to identify the shared values and the differences in the backpacker culture of the two groups. The findings revealed that while the two groups share some of the backpacker cultural values, some other values are distinctively different from one another. The study provides the first empirical evidence of the differences in backpacking culture between the two groups using CCA. Based on the study findings, we propose some marketing and managerial implications

Single-cell analysis: visualizing pharmaceutical and metabolite uptake in cells with label-free 3D mass spectrometry imaging

Detecting metabolites and parent compound within a cell type is now a priority for pharmaceutical development. In this context, three-dimensional secondary ion mass spectrometry (SIMS) imaging was used to investigate the cellular uptake of the antiarrhythmic agent amiodarone, a phospholipidosis-inducing pharmaceutical compound. The high lateral resolution and 3D imaging capabilities of SIMS combined with the multiplex capabilities of ToF mass spectrometric detection allows for the visualization of pharmaceutical compound and metabolites in single cells. The intact, unlabeled drug compound was successfully detected at therapeutic dosages in macrophages (cell line: NR8383). Chemical information from endogenous biomolecules was used to correlate drug distributions with morphological features. From this spatial analysis, amiodarone was detected throughout the cell with the majority of the compound found in the membrane and subsurface regions and absent in the nuclear regions. Similar results were obtained when the macrophages were doped with amiodarone metabolite, desethylamiodarone. The FWHM lateral resolution measured across an intracellular interface in a high lateral resolution ion images was approximately 550 nm. Overall, this approach provides the basis for studying cellular uptake of pharmaceutical compounds and their metabolites on the single cell level