Citizens of somewhere: Examining the geography of foreign and native-born academics' engagement with external actors.

This paper explores the geography of academic engagement patterns of native and foreign-born academics, contrasting how patterns of intranational and international engagement with non-academic actors differ between these two groups. We suggest that foreign-born academics will engage more internationally than their native-born colleagues, whereas native-born academics will have greater levels of intranational engagement. Drawing upon a large multi-source dataset, including a major new survey of all academics working in the UK, we find support for the idea that where people are born influences how they engage with non-academic actors. We also find that these differences are attenuated by an individual's intranational and international experience, ethnicity and language skills. We explore the implications of these findings for policy to support intranational and international academic engagement.

Donepezil and memantine for moderate-to-severe Alzheimer's disease.

BACKGROUND: Clinical trials have shown the benefits of cholinesterase inhibitors for the treatment of mild-to-moderate Alzheimer's disease. It is not known whether treatment benefits continue after the progression to moderate-to-severe disease. METHODS: We assigned 295 community-dwelling patients who had been treated with donepezil for at least 3 months and who had moderate or severe Alzheimer's disease (a score of 5 to 13 on the Standardized Mini-Mental State Examination [SMMSE, on which scores range from 0 to 30, with higher scores indicating better cognitive function]) to continue donepezil, discontinue donepezil, discontinue donepezil and start memantine, or continue donepezil and start memantine. Patients received the study treatment for 52 weeks. The coprimary outcomes were scores on the SMMSE and on the Bristol Activities of Daily Living Scale (BADLS, on which scores range from 0 to 60, with higher scores indicating greater impairment). The minimum clinically important differences were 1.4 points on the SMMSE and 3.5 points on the BADLS. RESULTS: Patients assigned to continue donepezil, as compared with those assigned to discontinue donepezil, had a score on the SMMSE that was higher by an average of 1.9 points (95% confidence interval [CI], 1.3 to 2.5) and a score on the BADLS that was lower (indicating less impairment) by 3.0 points (95% CI, 1.8 to 4.3) (P<0.001 for both comparisons). Patients assigned to receive memantine, as compared with those assigned to receive memantine placebo, had a score on the SMMSE that was an average of 1.2 points higher (95% CI, 0.6 to 1.8; P<0.001) and a score on the BADLS that was 1.5 points lower (95% CI, 0.3 to 2.8; P=0.02). The efficacy of donepezil and of memantine did not differ significantly in the presence or absence of the other. There were no significant benefits of the combination of donepezil and memantine over donepezil alone. CONCLUSIONS: In patients with moderate or severe Alzheimer's disease, continued treatment with donepezil was associated with cognitive benefits that exceeded the minimum clinically important difference and with significant functional benefits over the course of 12 months. (Funded by the U.K. Medical Research Council and the U.K. Alzheimer's Society; Current Controlled Trials number, ISRCTN49545035.).

Rate of telomere shortening and cardiovascular damage: a longitudinal study in the 1946 British Birth Cohort.

AIM: Cross-sectional studies reported associations between short leucocyte telomere length (LTL) and measures of vascular and cardiac damage. However, the contribution of LTL dynamics to the age-related process of cardiovascular (CV) remodelling remains unknown. In this study, we explored whether the rate of LTL shortening can predict CV phenotypes over 10-year follow-up and the influence of established CV risk factors on this relationship. METHODS AND RESULTS: All the participants from the MRC National Survey of Health and Development (NSHD) with measures of LTL and traditional CV risk factors at 53 and 60-64 years and common carotid intima-media thickness (cIMT), cardiac mass and left ventricular function at 60-64 years were included. LTL was measured by real-time polymerase chain reaction and available at both time points in 1033 individuals. While LTL at 53 years was not linked with any CV phenotype at 60-64 years, a negative association was found between LTL and cIMT at 60-64 years (ß = -0.017, P = 0.015). However, the strongest association was found between rate of telomere shortening between 53 and 60-64 years and values of cIMT at 60-64 years (ß = -0.020, P = 0.006). This association was not affected by adjustment for traditional CV risk factors. Cardiac measurements were not associated with cross-sectional or longitudinal measures of LTL. CONCLUSION: These findings suggest that the rate of progression of cellular ageing in late midlife (reflected by the rate of LTL attrition) relates to vascular damage, independently from contribution of CV risk factor exposure.

Full-field electroretinogram response to increment and decrement stimuli.

PURPOSE: The d-wave is typically elicited after the termination of an increment flash, but a decrement flash provides an alternative, and perhaps more appropriate, stimulus to elicit the d-wave. Here, we investigated the affects of stimulus polarity on the electroretinogram (ERG) response. METHODS: ERG responses elicited to increment and decrement flashes of varying intensity and duration from different background levels were measured from human participants to assess the b-wave and d-wave responses as a function of adaptation level and flash polarity. Response amplitudes were measured using standard metrics for waveform analysis. RESULTS: The amplitude of the b-wave is larger than the d-wave regardless of flash polarity when using different background levels which maximized the dynamic range of the two waveforms. However, when response amplitudes are measured from a common background, the d-wave elicited with decrement flash was larger than the b-wave elicited by an increment flash. This trend was evident across a range of background levels. The b-wave and d-wave become separate entities when flash duration reaches approximately 50 ms. Rapid-on and rapid-off sawtooth stimuli were also tested against increment and decrement step stimuli that were matched in mean luminance. These two stimulus types produced different amplitude b-wave and d-wave responses, suggesting asymmetric effects of the two stimulus types on the retinal response. CONCLUSIONS: We conclude that the response properties of the b-wave and d-wave are influenced by the duration, polarity and waveform of the stimulus, as well as the background from which the stimuli arise.

Composite testing for ante-mortem diagnosis of Johne's disease in farmed New Zealand deer: correlations between bacteriological culture, histopathology, serological reactivity and faecal shedding as determined by quantitative PCR.

BACKGROUND: In the absence of overt clinical signs of Johne's Disease (JD), laboratory based tests have largely been limited to organism detection via faecal culture or PCR and serological tests for antibody reactivity. In this study we describe the application of quantitative faecal PCR for the detection of Mycobacterium avium subsp. paratuberculosis (MAP) in New Zealand farmed deer to quantify the bacterial load in cervine faecal samples as an adjunct to an existing serodiagnostic test (Paralisa™) tailored for JD diagnosis in deer. As ELISA has potential as a cheap, high throughput screening test for JD, an attempt was made to assess the sensitivity, specificity and positive/negative predictive (PPV/NPV) values of Paralisa™ for estimating levels of faecal shedding of MAP as a basis for JD management in deer. RESULTS: Correlations were made between diagnostic tests (ELISA, qPCR, culture and histopathology) to establish the precision and predictive values of individual tests. The findings from this study suggest there is strong correlation between bacterial shedding, as determined by faecal qPCR, with both culture (r = 0.9325) and histopathological lesion severity scoring (r = 0.7345). Correlation between faecal shedding and ELISA reactivity in deer was weaker with values of r = 0.4325 and r = 0.4006 for Johnin and Protoplasmic antigens, respectively. At an ELISA Unit (EU) cutoff of >50 (Johnin antigen) the PPV of Paralisa™ for significant faecal shedding in deer (>104 organisms/g) was moderate (0.55) while the NPV was higher (0.89). At an EU cutoff of ≥ 150, the PPV for shedding >105 organisms/g rose to 0.88, with a corresponding NPV of 0.85. CONCLUSIONS: The evidence available from this study suggests that Paralisa™ used at a cutoff of 50EU could be used to screen deer herds for MAP infection with sequential qPCR testing used to cull all Paralisa™ positive animals that exhibit significant MAP faecal shedding.

Determining the minimum clinically important differences for outcomes in the DOMINO trial.

BACKGROUND: Although less likely to be reported in clinical trials than expressions of the statistical significance of differences in outcomes, whether or not a treatment has delivered a specified minimum clinically important difference (MCID) is also relevant to patients and their caregivers and doctors. Many dementia treatment randomised controlled trials (RCTs) have not reported MCIDs and, where they have been done, observed differences have not reached these. METHODS: As part of the development of the Statistical Analysis Plan for the DOMINO trial, investigators met to consider expert opinion- and distribution-based values for the MCID and triangulated these to provide appropriate values for three outcome measures, the Standardised Mini-mental State Examination (sMMSE), Bristol Activities of Daily Living Scale (BADLS) and Neuropsychiatric Inventory (NPI). Only standard deviations (SD) were presented to investigators who remained blind to treatment allocation. RESULTS: Adoption of values for MCIDs based upon 0.4 of the SD of the change in score from baseline on the sMMSE, BADLS and NPI in the first 127 participants to complete DOMINO yielded MCIDs of 1.4 points for sMMSE, 3.5 for BADLS and 8.0 for NPI. CONCLUSIONS: Reference to MCIDs is important for the full interpretation of the results of dementia trials and those conducting such trials should be open about the way in which they have determined and chosen their values for the MCIDs.

Disruption of Metallostasis in the Anaerobic Human Pathogen Fusobacterium nucleatum by the Zinc Ionophore PBT2.

The Gram-negative anaerobe Fusobacterium nucleatum is an opportunistic human pathogen, most frequently associated with periodontal disease through dental biofilm formation and, increasingly, with colorectal cancer development and progression. F. nucleatum infections are routinely treated by broad-spectrum ß-lactam antibiotics and metronidazole. However, these antibiotics can negatively impact the normal microflora. Therefore, the development of novel narrow-spectrum antimicrobials active against anaerobic pathogens is of great interest. Here, we examined the antimicrobial Zn ionophore PBT2, an 8-hydroxyquinoline analogue with metal chelating properties, against a single type isolate F. nucleatum ATCC 25586. PBT2-Zn was a potent inhibitor of growth and exhibited synergistic bactericidal (>3-log10 killing) activity at 5× MIC in planktonic cells, and at the MIC in biofilms grown in vitro. Physiological and transcriptional analyses uncovered a strong cellular response relating to Zn and Fe homeostasis in PBT2-Zn treated cells across subinhibitory and inhibitory concentrations. At 1× MIC, PBT2 alone induced a 3.75-fold increase in intracellular Zn, whereas PBT2-Zn challenge induced a 19-fold accumulation of intracellular Zn after 2 h. A corresponding 2.1-fold loss of Fe was observed at 1× MIC. Transcriptional analyses after subinhibitory PBT2-Zn challenge (0.125 µg/mL and 200 µM ZnSO4) revealed significant differential expression of 15 genes at 0.5 h, and 12 genes at 1 h. Upregulated genes included those with roles in Zn homeostasis (e.g., a Zn-transporting ATPase and the Zn-sensing transcriptional regulator, smtB) and hemin transport (hmuTUV) to re-establish Fe homeostasis. A concentration-dependent protective effect was observed for cells pretreated with hemin (50 µg/mL) prior to PBT2-Zn challenge. The data presented here supports our proposal that targeting the disruption of metallostasis by Zn-translocating ionophores is a strategy worth investigating further for the treatment of Gram-negative anaerobic pathogens.

Using compositional principal component analysis to describe children's gut microbiota in relation to diet and body composition.

BACKGROUND: Gut microbiota data obtained by DNA sequencing are complex and compositional because of large numbers of detectable taxa, and because microbiota characteristics are described in relative terms. Nutrition researchers use principal component analysis (PCA) to derive dietary patterns from food data. Although compositional PCA methods are not commonly used to describe patterns from complex microbiota data, this approach would be useful for identifying gut microbiota patterns associated with diet and body composition. OBJECTIVES: To use compositional PCA to describe the principal components (PCs) of gut microbiota in 5-y-old children and explore associations between microbiota components, diet, and BMI z-score. METHODS: A fecal sample was provided by 319 children aged 5 y. Their primary caregiver completed a validated 123-item quantitative FFQ. Body composition was determined using DXA, and a BMI z-score was calculated. Compositional PCA identified characterizing taxa and weightings for calculation of gut microbiota PC scores at the genus level, and was examined in relation to diet and body size. RESULTS: Three gut microbiota PCs were found. PC1 (negative loadings on uncultured Christensenellaceae and Ruminococcaceae) was related to lower BMI z-scores and longer duration of breastfeeding (per month) (ß = -0.14; 95% CI: -0.26, -0.02; and ß = 0.02; 95% CI: 0.003, 0.34, respectively). PC2 (positive loadings on Fusicatenibacter and Bifidobacterium; negative loadings on Bacteroides) was associated with a lower intake of nuts, seeds, and legumes (ß = -0.05 per gram; 95% CI: -0.09, -0.01). When adjusted for fiber intake, PC2 was also associated with higher BMI z-scores (ß = 0.12; 95% CI: 0.01, 0.24). PC3 (positive loadings on Faecalibacterium, Eubacterium, and Roseburia) was associated with higher intakes of fiber (ß = 0.02 per gram; 95% CI: 0.003, 0.04) and total nonstarch polysaccharides (ß = 0.02 per gram; 95% CI: 0.003, 0.04). CONCLUSIONS: Our results suggest that specific gut microbiota components determined using compositional PCA are associated with diet and BMI z-score.This trial was registered at clinicaltrials.gov as NCT00892983.

SunGold Kiwifruit Supplementation of Individuals with Prediabetes Alters Gut Microbiota and Improves Vitamin C Status, Anthropometric and Clinical Markers.

Kiwifruit are a nutrient dense food and an excellent source of vitamin C. Supplementation of the diet with kiwifruit enhances plasma vitamin C status and epidemiological studies have shown an association between vitamin C status and reduced insulin resistance and improved blood glucose control. In vitro experiments suggest that eating kiwifruit might induce changes to microbiota composition and function; however, human studies to confirm these findings are lacking. The aim of this study was to investigate the effect of consuming two SunGold kiwifruit per day over 12 weeks on vitamin C status, clinical and anthropometric measures and faecal microbiota composition in people with prediabetes. This pilot intervention trial compared baseline measurements with those following the intervention. Participants completed a physical activity questionnaire and a three-day estimated food diary at baseline and on completion of the trial. Venous blood samples were collected at each study visit (baseline, 6, 12 weeks) for determination of glycaemic indices, plasma vitamin C concentrations, hormones, lipid profiles and high-sensitivity C-reactive protein. Participants provided a faecal sample at each study visit. DNA was extracted from the faecal samples and a region of the 16S ribosomal RNA gene was amplified and sequenced to determine faecal microbiota composition. When week 12 measures were compared to baseline, results showed a significant increase in plasma vitamin C (14 µmol/L, p < 0.001). There was a significant reduction in both diastolic (4 mmHg, p = 0.029) and systolic (6 mmHg, p = 0.003) blood pressure and a significant reduction in waist circumference (3.1 cm, p = 0.001) and waist-to-hip ratio (0.01, p = 0.032). Results also showed a decrease in HbA1c (1 mmol/mol, p = 0.005) and an increase in fasting glucose (0.1 mmol/L, p = 0.046), however, these changes were small and were not clinically significant. Analysis of faecal microbiota composition showed an increase in the relative abundance of as yet uncultivated and therefore uncharacterised members of the bacterial family Coriobacteriaceae. Novel bacteriological investigations of Coriobacteriaceae are required to explain their functional relationship to kiwifruit polysaccharides and polyphenols.

Differentiation of Bifidobacterium longum subspecies longum and infantis by quantitative PCR using functional gene targets.

BACKGROUND: Members of the genus Bifidobacterium are abundant in the feces of babies during the exclusively-milk-diet period of life. Bifidobacterium longum is reported to be a common member of the infant fecal microbiota. However, B. longum is composed of three subspecies, two of which are represented in the bowel microbiota (B. longum subsp. longum; B. longum subsp. infantis). B. longum subspecies are not differentiated in many studies, so that their prevalence and relative abundances are not accurately known. This may largely be due to difficulty in assigning subspecies identity using DNA sequences of 16S rRNA or tuf genes that are commonly used in bacterial taxonomy. METHODS: We developed a qPCR method targeting the sialidase gene (subsp. infantis) and sugar kinase gene (subsp. longum) to differentiate the subspecies using specific primers and probes. Specificity of the primers/probes was tested by in silico, pangenomic search, and using DNA from standard cultures of bifidobacterial species. The utility of the method was further examined using DNA from feces that had been collected from infants inhabiting various geographical regions. RESULTS: A pangenomic search of the NCBI genomic database showed that the PCR primers/probes targeted only the respective genes of the two subspecies. The primers/probes showed total specificity when tested against DNA extracted from the gold standard strains (type cultures) of bifidobacterial species detected in infant feces. Use of the qPCR method with DNA extracted from the feces of infants of different ages, delivery method and nutrition, showed that subsp. infantis was detectable (0-32.4% prevalence) in the feces of Australian (n = 90), South-East Asian (n = 24), and Chinese babies (n = 91), but in all cases at low abundance (<0.01-4.6%) compared to subsp. longum (0.1-33.7% abundance; 21.4-100% prevalence). DISCUSSION: Our qPCR method differentiates B. longum subspecies longum and infantis using characteristic functional genes. It can be used as an identification aid for isolates of bifidobacteria, as well as in determining prevalence and abundance of the subspecies in feces. The method should thus be useful in ecological studies of the infant gut microbiota during early life where an understanding of the ecology of bifidobacterial species may be important in developing interventions to promote infant health.

Introduction.

Alzheimer's disease (AD) is the commonest form of dementia in developed countries, accounting for approx. 50-60% of the overall cases of dementia among persons over 65 years of age. Furthermore, because of the world's ageing population, and without an effective prevention or treatment, a sharp rise in the prevalence of dementia with age is predicted. AD itself is a progressive and irreversible neurodegenerative disorder associated with three main clinical features in the domains of declines in cognitive function (neuropsychologic) and activities of daily living, together with neuropsychiatric symptoms (including behavioural disturbances). These expressions of the pathology of AD impact tremendously not only in terms of the patient, but also the carer and society in general. Considering the high frequency of AD in the aged population, the rapid growth of the elderly population, and the heavy impact in terms of disability, AD has become a major problem for healthcare systems, public health planning and society as a whole. The scale of this problem presents a huge economic burden, in terms of both direct (healthcare system resources) and indirect (unpaid carer services) costs. Thus, the last two decades have witnessed an enormous research effort directed towards discovering the cause of AD with the ultimate hope of developing safe and effective pharmacological treatments.

A collaboratively-derived science-policy research agenda.

The need for policy makers to understand science and for scientists to understand policy processes is widely recognised. However, the science-policy relationship is sometimes difficult and occasionally dysfunctional; it is also increasingly visible, because it must deal with contentious issues, or itself becomes a matter of public controversy, or both. We suggest that identifying key unanswered questions on the relationship between science and policy will catalyse and focus research in this field. To identify these questions, a collaborative procedure was employed with 52 participants selected to cover a wide range of experience in both science and policy, including people from government, non-governmental organisations, academia and industry. These participants consulted with colleagues and submitted 239 questions. An initial round of voting was followed by a workshop in which 40 of the most important questions were identified by further discussion and voting. The resulting list includes questions about the effectiveness of science-based decision-making structures; the nature and legitimacy of expertise; the consequences of changes such as increasing transparency; choices among different sources of evidence; the implications of new means of characterising and representing uncertainties; and ways in which policy and political processes affect what counts as authoritative evidence. We expect this exercise to identify important theoretical questions and to help improve the mutual understanding and effectiveness of those working at the interface of science and policy.

Ovine immune parameters following immunisation against Mycobacterium avium ssp. paratuberculosis using a lipid-based live-cell vaccine.

Current commercial sheep vaccines against Mycobacterium avium subspecies paratuberculosis (MAP) are based on the use of live or killed cells from avirulent MAP strains. These stimulate a mixed immune response, featuring both antibody-based and cell-mediated immunity, and can only confer partial protection against Johne's disease but do not prevent infection. This study aimed to identify immune responses in sheep following immunisation with a novel lipid-based live-cell vaccine, drawing comparisons against responses observed to a commercial killed-cell vaccine (Gudair). The live vaccine was administered either subcutaneously or intra-peritoneally, as either a single-dose vaccine or in an homologous prime-boost protocol. A single-dose of the live vaccine was found to stimulate a cellular immune response similar to that of single-dose Gudair, but with markedly lower levels of antibody; however, homologous boosting with the live vaccine, by either s.c. or i.p. routes, generated higher levels of MAP-specific antibody. All immunisation regimes tended to decrease the proportion of CD4(+) T cells but increase the proportions of gammadeltaTCR(+) T cells and CD25(+) cells in antigen-stimulated ex vivo blood samples. The CD8(+):gammadeltaTCR(+) T cell ratio, thought to represent a reduced regulatory capacity among T cells responding to MAP, was increased among animals receiving either Gudair or a single i.p. dose of the live vaccine; however, only the Gudair vaccine simultaneously increased the level of lymph node IFNgamma mRNA expression, and this treatment also caused a significant elevation in the IFNgamma:IL-10 (effector:regulatory) cytokine expression ratio. Thus, among these immunisation regimes, the responses generated by a single s.c. dose of the novel live-cell vaccine appeared to selectively target the CMI-based immune profile thought necessary for control of MAP infection; in contrast, homologous prime-boosting with the live vaccine stimulated a mixed immune response similar to that produced by immunisation with Gudair.

Identification of immune parameters to differentiate disease states among sheep infected with Mycobacterium avium subsp. paratuberculosis.

Johne's disease, a chronic enteritis of ruminants, is caused by infection with Mycobacterium avium subsp. paratuberculosis. Three distinct forms have been observed in sheep: paucibacillary disease (PB), multibacillary disease (MB), and asymptomatic infection (AS). In this study, immune parameters for animals naturally infected with M. avium subsp. paratuberculosis and identified postmortem as having PB, MB, or AS were compared to provide a further understanding of the immunological reactivity contributing to or resulting from these different disease states in sheep. PB was associated with strong ex vivo M. avium subsp. paratuberculosis antigen-stimulated gamma interferon responses, pronounced increases in CD25(+) T-cell frequencies in circulation, antibody production, and a B-cell population that expanded significantly upon ex vivo antigenic stimulation. The MB group featured the highest antibody levels and a lack of cellular immune responsiveness to the M. avium subsp. paratuberculosis antigen. The AS group expressed an immunological phenotype intermediate between that for noninfected control animals and that for the PB group. The relationship between immune responses and disease severity within the PB group was investigated more closely; significant positive correlations were observed between disease severity and both the CD8(+) population in the circulating blood and the expression of interleukin-4 mRNA in antigen-stimulated blood samples ex vivo. Together, these data point toward distinct immune profiles in sheep that correspond to different Johne's disease states, which can be determined from circulating blood and/or from localized intestinal tract tissue samples.

Efficacy of novel lipid-formulated whole bacterial cell vaccines against Mycobacterium avium subsp. paratuberculosis in sheep.

Mycobacterium avium subsp. paratuberculosis [MAP], the causative agent of enteric Johne's disease, incurs significant economic losses to the livestock industry. Prophylactic vaccination can be employed as a control means, however mineral oil-based vaccines currently in practice have limited efficacy, produce strong antibody responses that confound serological diagnostic testing, and cause severe injection site reactions. In the present study, the safety and efficacy of a commercial mineral oil-adjuvanted vaccine (Gudair) was compared with novel parenteral-route vaccines in sheep; these comprised live or heat-killed (HK) whole cell preparations of MAP strain 316F, formulated into a food-grade lipid vaccine delivery matrix. Subcutaneous administration of lipid-formulated live or HK 316F-induced significantly fewer adverse injection site reactions than Gudair; adverse injection site reactions were eliminated altogether by intraperitoneal (i.p.) injection of lipid-formulated live 316F. Injections of lipid-formulated 316F-induced significant peripheral blood cell-mediated immune (CMI) responses in the absence of antibody, while Gudair-induced strong antibody and CMI reactivity. Vaccinated and non-vaccinated control sheep were challenged via oral inoculation of a virulent MAP isolate, and disease progress was monitored for 16 months, followed by necropsy. All vaccine regimes reduced the overall pathological grading of biopsied intestinal tract (IT) tissues; among these, only Gudair promoted a significant reduction in the incidence of histopathological IT lesions, while only i.p. injection of lipid-formulated live 316F significantly reduced the incidence of gross IT lesions. All lipid-formulated vaccines (but not Gudair) significantly reduced the incidence of bacteriological culture-confirmed MAP infection. This study identifies a new vaccination strategy against Johne's disease in sheep using conventional MAP vaccine strains formulated in a metabolisable lipid delivery matrix.

DOMINO-AD protocol: donepezil and memantine in moderate to severe Alzheimer's disease - a multicentre RCT.

BACKGROUND: Alzheimer's disease (AD) is the commonest cause of dementia. Cholinesterase inhibitors, such as donepezil, are the drug class with the best evidence of efficacy, licensed for mild to moderate AD, while the glutamate antagonist memantine has been widely prescribed, often in the later stages of AD. Memantine is licensed for moderate to severe dementia in AD but is not recommended by the England and Wales National Institute for Health and Clinical Excellence. However, there is little evidence to guide clinicians as to what to prescribe as AD advances; in particular, what to do as the condition progresses from moderate to severe. Options include continuing cholinesterase inhibitors irrespective of decline, adding memantine to cholinesterase inhibitors, or prescribing memantine instead of cholinesterase inhibitors. The aim of this trial is to establish the most effective drug option for people with AD who are progressing from moderate to severe dementia despite treatment with donepezil. METHOD: DOMINO-AD is a pragmatic, 15 centre, double-blind, randomized, placebo controlled trial. Patients with AD, currently living at home, receiving donepezil 10 mg daily, and with Standardized Mini-Mental State Examination (SMMSE) scores between 5 and 13 are being recruited. Each is randomized to one of four treatment options: continuation of donepezil with memantine placebo added; switch to memantine with donepezil placebo added; donepezil and memantine together; or donepezil placebo with memantine placebo. 800 participants are being recruited and treatment continues for one year. Primary outcome measures are cognition (SMMSE) and activities of daily living (Bristol Activities of Daily Living Scale). Secondary outcomes are non-cognitive dementia symptoms (Neuropsychiatric Inventory), health related quality of life (EQ-5D and DEMQOL-proxy), carer burden (General Health Questionnaire-12), cost effectiveness (using Client Service Receipt Inventory) and institutionalization. These outcomes are assessed at baseline, 6, 18, 30 and 52 weeks. All participants will be subsequently followed for 3 years by telephone interview to record institutionalization. DISCUSSION: There is considerable debate about the clinical and cost effectiveness of anti-dementia drugs. DOMINO-AD seeks to provide clear evidence on the best treatment strategies for those managing patients at a particularly important clinical transition point. TRIAL REGISTRATION: Current controlled trials ISRCTN49545035.

Time course of adaptation to stimuli presented along cardinal lines in color space.

Visual sensitivity is a process that allows the visual system to maintain optimal response over a wide range of ambient light levels and chromaticities. Several studies have used variants of the probe-flash paradigm to show that the time course of adaptation to abrupt changes in ambient luminance depends on both receptoral and postreceptoral mechanisms. Though a few studies have explored how these processes govern adaptation to color changes, most of this effort has targeted the L-M-cone pathway. The purpose of our work was to use the probe-flash paradigm to more fully explore light adaptation in both the L-M- and the S-cone pathways. We measured sensitivity to chromatic probes presented after the onset of a 2-s chromatic flash. Test and flash stimuli were spatially coextensive 2 degrees fields presented in Maxwellian view. Flash stimuli were presented as excursions from white and could extended in one of two directions along an equiluminant L-M-cone or S-cone line. Probes were presented as excursions from the adapting flash chromaticity and could extend either toward the spectrum locus or toward white. For both color lines, the data show a fast and slow adaptation component, although this was less evident in the S-cone data. The fast and slow components were modeled as first- and second-site adaptive processes, respectively. We find that the time course of adaptation is different for the two cardinal pathways. In addition, the time course for S-cone stimulation is polarity dependent. Our results characterize the rapid time course of adaptation in the chromatic pathways and reveal that the mechanics of adaptation within the S-cone pathway are distinct from those in the L-M-cone pathways.

The Erlanger chest pain evaluation protocol: a one-year experience with serial 12-lead ECG monitoring, two-hour delta serum marker measurements, and selective nuclear stress testing to identify and exclude acute coronary syndromes.

STUDY OBJECTIVE: We determine the overall use of a 6-step accelerated chest pain protocol to identify and exclude acute coronary syndrome (ACS) and to confirm previous findings of the use of serial 12-lead ECG monitoring (SECG) in conjunction with 2-hour delta serum marker measurements to identify and exclude acute myocardial infarction (AMI). METHODS: A prospective observational study was conducted over a 1-year period from January 1, 1999, through December 31, 1999, in 2,074 consecutive patients with chest pain who underwent our accelerated evaluation protocol, which includes 2-hour delta serum marker determinations in conjunction with automated SECG for the early identification and exclusion of AMI and selective nuclear stress testing for identification and exclusion of ACS. In patients not undergoing emergency reperfusion therapy, physician judgment was used to determine patient disposition at the completion of the 2-hour evaluation period: admit for ACS, discharge or admit for non-ACS condition, or immediate emergency department nuclear stress scan for possible ACS. A positive protocol was defined as a positive result in 1 or more of the 6 incremental steps in our chest pain evaluation protocol: (1) initial ECG diagnostic of acute injury or reciprocal injury; (2) baseline creatine kinase (CK)-MB level of 10 ng/mL or greater and index of 5% or greater or cardiac troponin I level of 2 ng/mL or greater; (3) new/evolving injury or new/evolving ischemia on SECG; (4) increase in CK-MB level of +1.5 ng/mL or greater or cardiac troponin I level of +0.2 ng/mL or greater in 2 hours; (5) clinical diagnosis of ACS despite a negative 2-hour evaluation; and (6) reversible perfusion defect on stress scan compared with on resting scan. All patients were followed up for 30-day ACS, which was defined as myocardial infarction (MI), percutaneous coronary intervention/coronary artery bypass grafting, coronary arteriography revealing stenosis of major coronary artery of 70% or greater not amenable to percutaneous coronary intervention/coronary artery bypass grafting, life-threatening complication, or cardiac death within 30 days of ED presentation. RESULTS: Discharge diagnosis in the 2,074 study patients consisted of 179 (8.6%) patients with AMI, 26 (1.3%) patients with recent AMI (decreasing curve of CK-MB), and 327 (15.8%) patients with 30-day ACS. At 2 hours, sensitivity and specificity for MI (AMI or recent AMI) of SECG plus delta serum marker measurements was 93.2% and 93.9%, respectively (positive likelihood ratio 15.3; negative likelihood ratio 0.07). At the completion of the full ED evaluation protocol (positive result in >or=1 of the 6 incremental steps), sensitivity and specificity for 30-day ACS was 99.1% and 87.4%, respectively (positive likelihood ratio 7.9; negative likelihood ratio 0.01). CONCLUSION: An accelerated chest pain evaluation strategy consisting of SECG, 2-hour delta serum marker measurements, and selective nuclear stress testing in conjunction with physician judgment identifies and excludes MI and 30-day ACS during the initial evaluation of patients with chest pain.