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Background The Anticoagulation Therapy in Selected Cancer Patients at Risk of Recurrence of Venous Thromboembolism (SELECT‐D) trial demonstrated reduction in recurrent venous thromboembolism (VTE) but increased bleeding with rivaroxaban compared with dalteparin for treatment of acute VTE in cancer patients, at 6 months. Uncertainty remains around optimal duration of anticoagulation. Objectives To assess VTE recurrence and bleeding, with anticoagulation or not, beyond 6 months. Patients/Methods In SELECT‐D, after 6 months of trial treatment for VTE, patients with active cancer and residual deep vein thrombosis (RDVT) or index pulmonary embolism (PE) were eligible for randomization to a further 6 months of rivaroxaban or placebo. Patients with no RDVT stopped anticoagulation. Primary outcome was VTE recurrence at 12 months. The second randomization closed prematurely because of low recruitment when 92 of the planned 300 patients were recruited. Results Ninety‐two of 136 eligible patients were randomized to rivaroxaban or placebo. The cumulative VTE recurrence after 6 months from the second randomization was 14% with placebo and 4% with rivaroxaban (hazard ratio, 0.32; 95% confidence interval [CI], 0.06‐1.58). The major and clinically relevant non‐major bleeding rates were 0% and 0% with placebo; and 5% (95% CI, 1‐18) and 4% (95% CI, 1‐17) with rivaroxaban. In an exploratory analysis, 7 (15%) of 46 placebo patients with RDVT or an index PE experienced recurrent VTE compared to none in the 35 patients in the RDVT‐negative cohort (P = .03). Conclusion The SELECT‐D trial was underpowered to detect a statistically significant reduction in recurrent VTE with extended anticoagulation. The absence of RDVT and/or index PE, defined a population at low risk of recurrence.

Purpose: To assess the impact of referral refinement criteria on the number of patients referred to, and first-visit discharges from, the Hospital Eye Service (HES) in relation to the National Institute for Health & Clinical Excellence (NICE) Glaucoma Guidelines, Joint College Group Guidance (JCG) and the NICE commissioning guidance. Methods: All low-risk (one risk factor: suspicious optic disc, abnormal visual field (VF), raised intra-ocular pressure (IOP) (22–28 mmHg) or IOP asymmetry (>5 mmHg) and high-risk (more than one risk factor, shallow anterior chamber or IOP >28 mmHg) referrals to the HES from 2006 to 2011 were analysed. Low-risk referrals were seen by Optometrists with a specialist interest in glaucoma and high-risk referrals were referred directly to the HES. Results: Two thousand nine hundred and twelve patient records were analysed. The highest Consultant first-visit discharge rates were for referrals based on IOP alone (45% for IOP 22–28 mmHg) and IOP asymmetry (53%), VF defect alone (46%) and for abnormal IOP and VF (54%). The lowest first-visit discharge rates were for referrals for suspicious optic disc (19%) and IOP >28 mmHg (22%). 73% of patients aged 65–80 and 60% of patients aged >80 who were referred by the OSI due to an IOP between 22–28 mmHg would have satisfied the JCG criteria for non-referral. For patients referred with an IOP >28 mmHg and an otherwise normal examination, adherence to the NICE commissioning guidance would have resulted in 6% fewer referrals. In 2010 this scheme reduced the number of patients attending the HES by 15%, which resulted in a saving of £16 258 (13%). Conclusion: The results support that referrals for a raised IOP alone or in combination with an abnormal VF be classified as low-risk and undergo referral refinement. Adherence to the JCG and the NICE commissioning guidance as onward referral criteria for specialist optometrists in this referral refinement scheme would result in fewer referrals.

The Community and Hospital Allied Network Glaucoma Evaluation Scheme (CHANGES) used accredited community-based optometrists with a special interest (OSIs) in glaucoma to monitor ocular hypertensive (OHT) patients under virtual supervision of the Hospital Glaucoma Service (HGS). The purpose of this paper was to report the outcomes of the first completed community-based visit.Eligible patients underwent a glaucoma consultant-led clinical examination before transfer to CHANGES. Individualised intraocular pressure (IOP) and follow-up time interval targets were set for each patient. OSIs used applanation tonometry, slit-lamp biomicroscopy, automated visual field testing and digital optic disc photography. The hospital-based glaucoma team evaluated the data virtually. Patients were referred back to the HGS according to specific criteria.One hundred and sixty eight OHT patients were invited to attend their first OSI appointment. Of these, 144 attended their appointment (attendance rate 85.7%). Outcomes of 130 patients with complete data sets are reported. Sixteen patients (12.3%) were referred back to the HGS due to IOP above target, new visual field defects and/or optic nerve changes. The glaucoma consultant retained eight patients (6.1%) within the HGS on the basis of definite or probable glaucomatous conversion.CHANGES freed up capacity within a busy HGS. However, improvements need to be made regarding non-attendance rates in the community. The relatively high one-year definite or probable conversion rate emphasises the importance of the comprehensive review of OHT patients and of hospital-led virtual supervision to maintain patient safety.

To describe the design, activity, and quality of the referral refinement phase of a novel glaucoma shared-care scheme.Eight Optometrists with a Specialist Interest in glaucoma (OSI) were trained to perform a community-based comprehensive glaucoma evaluation of low-risk glaucoma hospital referrals (only one/none of the following factors noted for either eye: abnormal optic disc, abnormal visual field, abnormal intraocular pressure (IOP; 22-28 mmHg or IOP asymmetry)) using equipment standardized to that of the hospital glaucoma service.One hundred and thirty-eight (27%) of a total of 512 glaucoma-related referrals were deemed 'low risk'. Their choice of OSI discharged 40 (35%). The consultant agreed (virtually) with the decision to discharge with 28 (70%) and disagreed with 12 (30%). Comparing findings between OSI and consultant for 99 referred patients, sensitivity, specificity, and negative predictive values for a suspicious optic disc were 78, 61, and 79%, respectively. For an IOP of21 mmHg, they were 74, 85, and 90%, respectively. For an occludable anterior chamber angle (Van Herick's versus gonioscopy), they were 69, 88, and 94%, respectively.This referral refinement process can reduce numbers of false-positive referrals attending the hospital glaucoma service while retaining a relatively high level of examination quality.

The 5-HT(2C) receptor has been implicated in mood and eating disorders. In general, it is accepted that 5-HT(2C) receptor agonists increase anxiety behaviours and induce hypophagia. However, pharmacological analysis of the roles of these receptors is hampered by the lack of selective ligands and the complex regulation of receptor isoforms and expression levels. Therefore, the exact role of 5-HT(2C) receptors in mood disorders remain controversial, some suggesting agonists and others suggesting antagonists may be efficacious antidepressants, while there is general agreement that antagonists are beneficial anxiolytics. In order to test the hypothesis that increased 5-HT(2C) receptor expression, and thus increased 5-HT(2C) receptor signalling, is causative in mood disorders, we have undertaken a transgenic approach, directly altering the 5-HT(2C) receptor number in the forebrain and evaluating the consequences on behaviour. Transgenic mice overexpressing 5-HT(2C) receptors under the control of the CaMKIIalpha promoter (C2CR mice) have elevated 5-HT(2C) receptor mRNA levels in cerebral cortex and limbic areas (including the hippocampus and amygdala), but normal levels in the hypothalamus, resulting in > 100% increase in the number of 5-HT(2C) ligand binding sites in the forebrain. The C2CR mice show increased anxiety-like behaviour in the elevated plus-maze, decreased wheel-running behaviour and reduced activity in a novel environment. These behaviours were observed in the C2CR mice without stimulation by exogenous ligands. Our findings support a role for 5-HT(2C) receptor signalling in anxiety disorders. The C2CR mouse model offers a novel and effective approach for studying disorders associated with 5-HT(2C) receptors.

Purpose To establish the safety of the CHANGES glaucoma referral refinement scheme (GRRS). Methods The CHANGES scheme risk stratifies glaucoma referrals, with low risk referrals seen by a community based specialist optometrist (OSI) while high risk referrals are referred directly to the hospital. In this study, those patients discharged by the OSI were reviewed by the consultant ophthalmologist to establish a ‘false negative’ rate (Study 1). Virtual review of optic disc photographs was carried out both by a hospital-based specialist optometrist as well as the consultant ophthalmologist (Study 2). Results None of these 34 discharged patients seen by the consultant were found to have glaucoma or started on treatment to lower the intra-ocular pressure. Five of the 34 (15%) were classified as ‘glaucoma suspect’ based on the appearance of the optic disc and offered a follow-up appointment. Virtual review by both the consultant and optometrist had a sensitivity of 80%, whilst the false positive rate for the optometrist was 3.4%, and 32% for the consultant (p

A methodological framework is introduced to assess and compare a conventional fluoroscopy protocol for peripheral angioplasty with a new magnetic resonant imaging (MRI)-guided protocol. Different scenarios were considered during interventions on a perfused arterial phantom with regard to time-based and cognitive task analysis, user experience and ergonomics. Three clinicians with different expertise performed a total of 43 simulated common iliac angioplasties (9 fluoroscopic, 34 MRI-guided) in two blocks of sessions. Six different configurations for MRI guidance were tested in the first block. Four of them were evaluated in the second block and compared to the fluoroscopy protocol. Relevant stages’ durations were collected, and interventions were audio-visually recorded from different perspectives. A cued retrospective protocol analysis (CRPA) was undertaken, including personal interviews. In addition, ergonomic constraints in the MRI suite were evaluated. Significant differences were found when comparing the performance between MRI configurations versus fluoroscopy. Two configurations [with times of 8.56 (0.64) and 9.48 (1.13) min] led to reduce procedure time for MRI guidance, comparable to fluoroscopy [8.49 (0.75) min]. The CRPA pointed out the main influential factors for clinical procedure performance. The ergonomic analysis quantified musculoskeletal risks for interventional radiologists when utilising MRI. Several alternatives were suggested to prevent potential low-back injuries. This work presents a step towards the implementation of efficient operational protocols for MRI-guided procedures based on an integral and multidisciplinary framework, applicable to the assessment of current vascular protocols. The use of first-user perspective raises the possibility of establishing new forms of clinical training and education.

We describe our work in teaching for democracy through the creation and implementation of a technology-infused assignment for use in elementary social studies methods, the “Digital Documentary: Election Portfolio.” During the 2004 presidential election season, we asked our students to participate in the process as citizens and preservice teachers, considering the role that a teacher can play in the political socialization of students. As our students created an election portfolio through the collection of artifacts, responded by journaling about these artifacts, and created a documentary using iMovie, we considered how this project affected enlightened political engagement, media literacy, and the development of students' voices and participation in the political process. This article describes our thinking about the process and what we came to understand about this project through our collaboration.

The Walters Art Gallery owns seven paintings attributed to Giovanni di Paolo, from very early to very late in the artist's career. Technical examinations of these and other paintings by Giovanni di Paolo in European and American collections were compared to investigate whether his techniques changed along with his style and possible studio participation. Information gathered from 32 paintings led to the conclusion that, with minor variations, the artist's materials and techniques remained constant and strayed little from traditions set out by Cennino Cennini.

Researchers and practitioners have suggested that the use of social networking sites in formal education may be a worthwhile endeavor. Toward this goal, emerging learning platforms have included social networking features. Nevertheless, empirical literature examining user experiences, and more specifically instructor experiences, with these tools is limited. In this qualitative study, we address this gap in the literature by reporting the experiences of five instructors who used a social networking platform in their courses. We find that instructors (a) had expectations of Elgg that stemmed from numerous sources, (b) used Elgg in heterogeneous ways and for varied purposes, (c) compartmentalized Elgg and used it in familiar ways, and (d) faced frustrations stemming from numerous sources. We note that the ways Elgg came to be used “on the ground” is contested and contrasts starkly with the narrative of how social software might contribute benefits to educational practice. In addition, we note that learning management systems may frame the ways through which other tools, such as social media and Elgg, are understood, used, and experienced.

Aim To investigate whether the publication of the National Institute for Health and Clinical Excellence (NICE) glaucoma guidelines had an effect on the agreement of examination findings between professionals involved in an established glaucoma referral refinement pathway. Methods To report inter-professional agreement for the clinical examination findings of optometrists with a special interest in glaucoma (OSI), optometrists with no specialist interest in glaucoma (non-OSI) and a glaucoma consultant. Part 1 investigated agreement between an OSI and consultant and part 2 investigated agreement of clinical findings between the non-OSI and a specialist clinician (OSI or consultant). Results Part 1: Agreement between OSI and consultant in determining an abnormal intraocular pressure (IOP) (>21 mm Hg) expressed as a percentage positive predictive value (PPPV) was no different pre-NICE (60.6%) and post-NICE (61.4%, p=0.51) guidelines. PPPV for identification of an abnormal optic disc was better pre-NICE (60.6%) than post-NICE (42.7%, p=0.02). The appropriate referral rate for patients referred by an OSI was higher pre-NICE (69.6%) than post-NICE (61.2%) (p=0.07). Part 2: The PPPV between non-OSI and specialist clinician for an abnormal IOP was better pre-NICE (62.5%) than post-NICE (50.9%, p=0.12). This was also observed for abnormal optic discs, 70.0% pre-NICE and 52.9% post-NICE (p=0.04). Conclusions The accuracy for detecting an abnormal IOP by the OSI has remained unchanged post-NICE, but there was a reduction in accuracy in detecting an abnormal optic disc as well as the appropriate referral rate. For the non-OSI, there was a decline in both IOP and optic disc assessment accuracy.

Summary. Background: Circadian rhythms control a vast array of biological processes in a broad spectrum of organisms. The contribution of circadian rhythms to the development of megakaryocytes and the regulation of platelet biology has not been defined. Objectives: This study tested the hypothesis that murine megakaryocytes exhibit hallmarks of circadian control. Methods: Mice expressing a PER2::LUCIFERASE circadian reporter protein and C57BI/6 mice were used to establish if megakaryocytes expressed circadian genes in vitro and in vivo. Mice were also subjected to 3 weeks on a restricted feeding regime to separate food-entrained from light-entrained circadian rhythms. Quantitative real time polymerase chain reaction (PCR), flow cytometry and imunohistochemistry were employed to analyse gene expression, DNA content and cell-cycle behavior in megakaryocytes collected from mice over a 24-h period. Results: Megakaryocytes exhibited rhythmic expression of the clock genes mPer2 and mBmal1 and circadian rhythms in megakaryopoiesis. mPer2 and mBmal1 expression phase advanced 8 h to coincide with the availability of food; however, food availability had a more complex effect on megakaryopoiesis, leading to a significant overall increase in megakaryocyte ploidy levels and cell-cycle activity. Conclusions: Normal megakaryopoiesis requires synchrony between food- and light-entrained circadian oscillators.

11beta-Hydroxysteroid dehydrogenase type 2 is a glucocorticoid metabolizing enzyme that catalyzes rapid inactivation of corticosterone and cortisol to inert 11-keto derivatives. As 11beta-hydroxysteroid dehydrogenase type 2 is highly expressed in the developing brain, but not in the adult CNS, we hypothesized that it may represent a protective barrier to the deleterious actions of corticosteroids on proliferating cells. To test this hypothesis we have investigated the development and growth of the cerebellum in neonatal C57BL/6 mice and mice lacking 11beta-hydroxysteroid dehydrogenase type 2 (-/-). 11beta-Hydroxysteroid dehydrogenase type 2-/- mice had consistently lower body weight throughout the neonatal period, coupled with a smaller brain size although this was normalized when corrected for body weight. The cerebellar size was smaller in 11beta-hydroxysteroid dehydrogenase type 2-/- mice, due to decreases in size of both the molecular and internal granule layers. When exogenous corticosterone was administered to the pups between postnatal days 4 and 13, 11beta-hydroxysteroid dehydrogenase type 2(-/-) mice were more sensitive, showing further inhibition of cerebellar growth while the wildtype mice were not affected. Upon withdrawal of exogenous steroid, there was a rebound growth spurt so that at day 21 postnatally, the cerebellar size in 11beta-hydroxysteroid dehydrogenase type 2-/- mice was similar to untreated mice of the same genotype. Furthermore, 11beta-hydroxysteroid dehydrogenase type 2-/- mice had a delay in the attainment of neurodevelopmental landmarks such as negative geotaxis and eye opening. We therefore suggest that 11beta-hydroxysteroid dehydrogenase type 2 acts as to protect the developing nervous system from the deleterious consequences of glucocorticoid overexposure.

The changing of ventilator circuitry is a costly, time-consuming exercise. The current practise of changing circuits every 72 hours is not supported by research and is therefore being challenged. This literature review supports a change in practice from changing circuits every 72 hours to every 7 days or between patients, whichever occurs first. Previous research studying the time interval between circuit changes is reviewed. Contributing factors such as the contamination of tubing by various means are discussed and finally research-based proposals for future practice will be made.

A loss and recovery of polysomes coincident with the temperature-dependent interruption and resumption of pear fruit (Pyrus communis, L.) senescence establishes a close correlation between the presence of protein-synthesizing machinery and the progression of senescence and ripening.

Preterm infants are at increased risk of cardiometabolic disease in later life. Extrauterine growth restriction, catch-up growth, altered adiposity, and abnormal hypothalamic-pituitary-adrenal axis activity could be predisposing factors. Altered DNA methylation (5-methylcytosine, 5mC) might be one underlying mechanism. We hypothesised that preterm infants have altered 5mC at the linked differentially methylated region 2 (DMR2) of IGF2 and the H19 imprinting control region (H19 ICR) compared with term infants over the first year of life.We recruited 46 preterm (range 25 weeks + 2 days' gestation to 31 + 5, mean 28 + 6) and 40 term infants (38 + 3 to 42 + 2 weeks' gestation, mean 40 + 2). Anthropometric variables including body composition were measured at term age and 3 months corrected age with air displacement plethysmography and at 1-year-corrected age with skin-fold thickness. Salivary cortisol was measured at 3 months corrected age after the physical examination. Percentage methylation (%5mC) was analysed with pyrosequencing on buccal DNA. Statistical analysis used Student's t test and multivariate linear regression.Preterm infants demonstrated growth deficit early in postnatal life but had greater percentage body fat at term age (β=5·73, p0·001), but not at 3 months (β=-0·28, p=0·82). Compared with term infants, preterm infants had a blunted cortisol response to physical examination (mean difference 0·38 μg/dL, p=0·024). At birth, preterm infants had a significant decrease in %5mC at DMR2 compared with term infants at birth (β=-11·48, p0·001) and compared with preterm infants at term-corrected age (t=3·13, p=0·01). By term-corrected age, preterm infants had decreased %5mC at both DMR2 (β=-2·84, p=0·013) and the H19 ICR (β=-2·31, p=0·048) compared with term infants at birth, although this difference disappeared at 1 year. Social deprivation was independently associated with decreased %5mC at DMR2 at birth (β=-1·73, p=0·006) and term-corrected age (β=-0·86, p=0·016) but not at 1 year (β=-0·89, p=0·07).Our results show that decreased %5mC accompanies the early growth deficit in preterm infants. The marked reduction in %5mC at IGF2 DMR2 in preterm infants at birth compared with term-age supports existing evidence that imprinting at secondary regions is established after fertilisation, whereas imprinting is established during gametogenesis at primary regions (H19 ICR). Both regions might be susceptible to early life stressors such as preterm birth and social deprivation.Chief Scientist Office of the Scottish Government.