CACNA1S mutation-associated dental anomalies: A calcium channelopathy.

OBJECTIVES: To identify the molecular etiology of distinct dental anomalies found in eight Thai patients and explore the mutational effects on cellular functions. MATERIALS AND METHODS: Clinical and radiographic examinations were performed for eight patients. Whole exome sequencing, mutant protein modelling, qPCR, western blot analysis, scratch assays, immunofluorescence, confocal analysis, in situ hybridization, and scanning electron micrography of teeth were done. RESULTS: All patients had molars with multiple supernumerary cusps, single-cusped premolars, and a reduction in root number. Mutation analysis highlighted a heterozygous c.865A>G; p.Ile289Val mutation in CACNA1S in the patients. CACNA1S is a component of the slowly inactivating L-type voltage-dependent calcium channel. Mutant protein modeling suggested that the mutation might allow leakage of Ca2+ or other cations, or a tightening, to restrict calcium flow. Immunohistochemistry analysis showed expression of Cacna1s in the developing murine tooth epithelium during stages of crown and root morphogenesis. In cell culture, the mutation resulted in abnormal cell migration of transfected CHO cells compared to wildtype CACNA1S, with changes to the cytoskeleton and markers of focal adhesion. CONCLUSIONS: The malformations observed in our patients suggest a role for calcium signaling in organization of both cusps and roots, affecting cell dynamics within the dental epithelium.

A scoping review of risk-stratified bowel screening: current evidence, future directions.

PURPOSE: In this scoping review, we examined the international literature on risk-stratified bowel screening to develop recommendations for future research, practice and policy. METHODS: Six electronic databases were searched from inception to 18 October 2021: Medline, Embase, PsycINFO, CINAHL, Cochrane Database of Systematic Reviews and Cochrane Central Register of Controlled Trials. Forward and backwards citation searches were also undertaken. All relevant literature were included. RESULTS: After de-deduplication, 3,629 records remained. 3,416 were excluded at the title/abstract screening stage. A further 111 were excluded at full-text screening stage. In total, 102 unique studies were included. Results showed that risk-stratified bowel screening programmes can potentially improve diagnostic performance, but there is a lack of information on longer-term outcomes. Risk models do appear to show promise in refining existing risk stratification guidelines but most were not externally validated and less than half achieved good discriminatory power. Risk assessment tools in primary care have the potential for high levels of acceptability and uptake, and therefore, could form an important component of future risk-stratified bowel screening programmes, but sometimes the screening recommendations were not adhered to by the patient or healthcare provider. The review identified important knowledge gaps, most notably in the area of organisation of screening services due to few pilots, and what risk stratification might mean for inequalities. CONCLUSION: We recommend that future research focuses on what organisational challenges risk-stratified bowel screening may face and a consideration of inequalities in any changes to organised bowel screening programmes.

Cost-effectiveness of alternative changes to a national blood collection service.

OBJECTIVES: To evaluate the cost-effectiveness of changing opening times, introducing a donor health report and reducing the minimum inter-donation interval for donors attending static centres. BACKGROUND: Evidence is required about the effect of changes to the blood collection service on costs and the frequency of donation. METHODS/MATERIALS: This study estimated the effect of changes to the blood collection service in England on the annual number of whole-blood donations by current donors. We used donors' responses to a stated preference survey, donor registry data on donation frequency and deferral rates from the INTERVAL trial. Costs measured were those anticipated to differ between strategies. We reported the cost per additional unit of blood collected for each strategy versus current practice. Strategies with a cost per additional unit of whole blood less than £30 (an estimate of the current cost of collection) were judged likely to be cost-effective. RESULTS: In static donor centres, extending opening times to evenings and weekends provided an additional unit of whole blood at a cost of £23 and £29, respectively. Introducing a health report cost £130 per additional unit of blood collected. Although the strategy of reducing the minimum inter-donation interval had the lowest cost per additional unit of blood collected (£10), this increased the rate of deferrals due to low haemoglobin (Hb). CONCLUSION: The introduction of a donor health report is unlikely to provide a sufficient increase in donation frequency to justify the additional costs. A more cost-effective change is to extend opening hours for blood collection at static centres.

WNT10B mutations associated with isolated dental anomalies.

Isolated hypodontia is the most common human malformation. It is caused by heterozygous variants in various genes, with heterozygous WNT10A variants being the most common cause. WNT10A and WNT10B are paralogs that likely evolved from a common ancestral gene after its duplication. Recently, an association of WNT10B variants with oligodontia (severe tooth agenesis) has been reported. We performed mutational analysis in our cohort of 256 unrelated Thai families with various kinds of isolated dental anomalies. In 7 families afflicted with dental anomalies we detected 4 heterozygous missense variants in WNT10B. We performed whole exome sequencing in the patients who had WNT10B mutations and found no mutations in other known hypodontia-associated genes, including WNT10A, MSX1, PAX9, EDA, AXIN2, EDAR, EDARADD, LPR6, TFAP2B, LPR6, NEMO, KRT17, and GREM2. Our findings indicate that the variants c.475G>C [p.(Ala159Pro)], found in 4 families, and c.1052G>A [p.(Arg351His)], found in 1 family, are most probably causative. They also show that WNT10B variants are associated not only with oligodontia and isolated tooth agenesis, but also with microdontia, short tooth roots, dental pulp stones, and taurodontism.

Computational discovery of transcription factors associated with drug response.

This study integrates gene expression, genotype and drug response data in lymphoblastoid cell lines with transcription factor (TF)-binding sites from ENCODE (Encyclopedia of Genomic Elements) in a novel methodology that elucidates regulatory contexts associated with cytotoxicity. The method, GENMi (Gene Expression iN the Middle), postulates that single-nucleotide polymorphisms within TF-binding sites putatively modulate its regulatory activity, and the resulting variation in gene expression leads to variation in drug response. Analysis of 161 TFs and 24 treatments revealed 334 significantly associated TF-treatment pairs. Investigation of 20 selected pairs yielded literature support for 13 of these associations, often from studies where perturbation of the TF expression changes drug response. Experimental validation of significant GENMi associations in taxanes and anthracyclines across two triple-negative breast cancer cell lines corroborates our findings. The method is shown to be more sensitive than an alternative, genome-wide association study-based approach that does not use gene expression. These results demonstrate the utility of GENMi in identifying TFs that influence drug response and provide a number of candidates for further testing.

CHILDSPLA: a collaboration between children and researchers to design and animate health states.

AIM: The children's health state preferences learnt from animation (CHILDSPLA) project developed an interactive application presented on a touch screen device using an animated character to collect information from children about their health. BACKGROUND: The underlying hypothesis was that health information could be directly collected from children as young as 4 years old by the use of animated characters. This paper describes in detail how children were involved in the development of the application, and recounts both the challenges and benefits of that process. A child psychologist and an animation filmmaker worked closely with children to design a character and to animate it to represent different health states. Children were recruited from a local primary school (n = 38) and a paediatric specialist hospital (n = 36). Diverse interactive activities were organized to help children give feedback and guide the design process. The activities for each session were adjusted to the children's needs, based on the experience of previous sessions. RESULTS: The character and the animations were modified according to the feedback provided by the children. CONCLUSIONS: Developing the CHILDSPLA app in collaboration with children was a worthwhile and enriching experience, despite the required iteration and extension of the design process, as it enabled us to adjust the tool to the children's needs.

A systematic review of the effectiveness of individual, community and societal-level interventions at reducing socio-economic inequalities in obesity among adults.

BACKGROUND: Socioeconomic inequalities in obesity are well established in high-income countries. There is a lack of evidence of the types of intervention that are effective in reducing these inequalities among adults. OBJECTIVES: To systematically review studies of the effectiveness of individual, community and societal interventions in reducing socio-economic inequalities in obesity among adults. METHODS: Nine electronic databases were searched from start date to October 2012 along with website and grey literature searches. The review examined the best available international evidence (both experimental and observational) of interventions at an individual, community and societal level that might reduce inequalities in obesity among adults (aged 18 years or over) in any setting and country. Studies were included if they reported a body fatness-related outcome and if they included a measure of socio-economic status. Data extraction and quality appraisal were conducted using established mechanisms and narrative synthesis was conducted. RESULTS: The 'best available' international evidence was provided by 20 studies. At the individual level, there was evidence of the effectiveness of primary care delivered tailored weight loss programmes among deprived groups. Community based behavioural weight loss interventions and community diet clubs (including workplace ones) also had some evidence of effectiveness-at least in the short term. Societal level evaluations were few, low quality and inconclusive. Further, there was little evidence of long term effectiveness, and few studies of men or outside the USA. However, there was no evidence to suggest that interventions increase inequalities. CONCLUSIONS: The best available international evidence suggests that some individual and community-based interventions may be effective in reducing socio-economic inequalities in obesity among adults in the short term. Further research is required particularly of more complex, multi-faceted and societal-level interventions.

Genome-enabled prediction of genetic values using radial basis function neural networks.

The availability of high density panels of molecular markers has prompted the adoption of genomic selection (GS) methods in animal and plant breeding. In GS, parametric, semi-parametric and non-parametric regressions models are used for predicting quantitative traits. This article shows how to use neural networks with radial basis functions (RBFs) for prediction with dense molecular markers. We illustrate the use of the linear Bayesian LASSO regression model and of two non-linear regression models, reproducing kernel Hilbert spaces (RKHS) regression and radial basis function neural networks (RBFNN) on simulated data and real maize lines genotyped with 55,000 markers and evaluated for several trait-environment combinations. The empirical results of this study indicated that the three models showed similar overall prediction accuracy, with a slight and consistent superiority of RKHS and RBFNN over the additive Bayesian LASSO model. Results from the simulated data indicate that RKHS and RBFNN models captured epistatic effects; however, adding non-signal (redundant) predictors (interaction between markers) can adversely affect the predictive accuracy of the non-linear regression models.

BASH: a tool for managing BeadArray spatial artefacts.

SUMMARY: With their many replicates and their random layouts, Illumina BeadArrays provide greater scope fordetecting spatial artefacts than do other microarray technologies. They are also robust to artefact exclusion, yet there is a lack of tools that can perform these tasks for Illumina. We present BASH, a tool for this purpose. BASH adopts the concepts of Harshlight, but implements them in a manner that utilizes the unique characteristics of the Illumina technology. Using bead-level data, spatial artefacts of various kinds can thus be identified and excluded from further analyses. AVAILABILITY: The beadarray Bioconductor package (version 1.10 onwards), www.bioconductor.org

RT-SHIV, an infectious CCR5-tropic chimeric virus suitable for evaluating HIV reverse transcriptase inhibitors in macaque models.

BACKGROUND: Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are an important category of drugs for both chemotherapy and prevention of human immunodeficiency virus type 1 (HIV-1) infection. However, current non-human primate (NHP) models utilizing simian immunodeficiency virus (SIV) or commonly used chimeric SHIV (SIV expressing HIV-1 envelope) are inadequate due to the insensitivity to NNRTIs. To develop a NHP model for evaluation of NNRTI compounds, we characterized a RT-SHIV virus that was assembled by replacing the SIV mac239 reverse transcriptase (RT) with that of HIV-1HXB2. Since RT-SHIV exhibited in vitro characteristics of high infectivity, CCR5-usage, and sensitivity to HIV-1 specific NNRTIs, this virus was thought to be suitable for mucosal transmission and then was used to carry out a vaginal transmission study in pigtail macaques (Macaca nemestrina). RESULTS: RT-SHIV exhibited in vitro characteristics of an infectious CCR5-tropic chimeric virus. This virus was not only highly sensitive to HIV-1 RT specific NNRTIs; its replication was also inhibited by a variety of NRTIs and protease inhibitors. For in vivo vaginal transmission studies, macaques were either pretreated with a single dose of DMPA (depot medroxyprogesterone acetate) or left untreated before intravaginal inoculation with 500 or 1,000 TCID50 of RT-SHIV. All macaques became systemically infected by 2 or 3 weeks post-inoculation exhibiting persistent high viremia, marked CD4+T cell depletion, and antiviral antibody response. DMPA-pretreated macaques showed a higher mean plasma viral load after the acute infection stage, highly variable antiviral antibody response, and a higher incidence of AIDS-like disease as compared with macaques without DMPA pretreatment. CONCLUSION: This chimeric RT-SHIV has exhibited productive replication in both macaque and human PBMCs, predominantly CCR5-coreceptor usage for viral entry, and sensitivity to NNRTIs as well as other anti-HIV compounds. This study demonstrates rapid systemic infection in macaques following intravaginal exposure to RT-SHIV. This RT-SHIV/macaque model could be useful for evaluation of NNRTI-based therapies, microbicides, or other preventive strategies.

Correction to: High-throughput method for ear phenotyping and kernel weight estimation in maize using ear digital imaging.

[This corrects the article DOI: 10.1186/s13007-018-0317-4.].

Molecular analysis of the iduronate-2-sulfatase gene in Thai patients with Hunter syndrome.

Molecular defects in the gene encoding the enzyme iduronate-2-sulfatase (IDS) result in Hunter disease (mucopolysaccharidosis type II, MPS II). To determine the molecular basis of MPS II in Thailand, the IDS gene was analysed in 20 Thai patients with Hunter syndrome from 18 unrelated families. A total of 19 different mutations, including 9 missense mutations, 3 nonsense mutations, 3 splice site alterations, 1 deletion, 2 indels, and 1 rearrangement were identified, 8 of which were novel (p.R101C, p.D148V, p.G224A, p.K227E, p.E254X, p.W337X, c.440_442delinsTT and c.720_731delinsTTTCAGATGTTCTCCCCAG). Evaluation of the IDS activity of two hemizygous variants identified in the same patient, p.R101C and p.R468Q, by expression of IDS with the individual mutations in COS 7 cells indicated that only the p.R468Q mutation affected IDS protein activity. Two exonic mutations, c.257C>T (p.P86L) and c.418G>A, were found to activate multiple cryptic splice sites, resulting in aberrantly spliced transcripts. Thus, MPS II in Thailand is caused by a diverse set of defects affecting both IDS protein production and activity.

Cost-effectiveness of magnetic resonance-guided focused ultrasound surgery for treatment of uterine fibroids.

OBJECTIVE: To estimate the cost-effectiveness of a treatment strategy for symptomatic uterine fibroids, which starts with Magnetic Resonance-guided Focused Ultrasound Surgery (MRgFUS) as compared with current practice comprising uterine artery embolisation, myomectomy and hysterectomy. DESIGN: Cost-utility analysis based on a Markov model. SETTING: National Health Service (NHS) Trusts in England and Wales. POPULATION: Women for whom surgical treatment for uterine fibroids is being considered. METHODS: The parameters of the Markov model of the treatment of uterine fibroids are drawn from a series of clinical studies of MRgFUS, and from the clinical effectiveness literature. Health-related quality of life is measured using the 6D. Costs are estimated from the perspective of the NHS. The impact of uncertainty is examined using deterministic and probabilistic sensitivity analysis. MAIN OUTCOME MEASURES: Incremental cost-effectiveness measured by cost per quality-adjusted life-year (QALY) gained. RESULTS: The base-case results imply a cost saving and a small QALY gain per woman as a result of an MRgFUS treatment strategy. The cost per QALY gained is sensitive to cost of MRgFUS relative to other treatments, the age of the woman and the nonperfused volume relative to the total fibroids volume. CONCLUSIONS: A treatment strategy for symptomatic uterine fibroids starting with MRgFUS is likely to be cost-effective.

High-throughput method for ear phenotyping and kernel weight estimation in maize using ear digital imaging.

BACKGROUND: Grain yield, ear and kernel attributes can assist to understand the performance of maize plant under different environmental conditions and can be used in the variety development process to address farmer's preferences. These parameters are however still laborious and expensive to measure. RESULTS: A low-cost ear digital imaging method was developed that provides estimates of ear and kernel attributes i.e., ear number and size, kernel number and size as well as kernel weight from photos of ears harvested from field trial plots. The image processing method uses a script that runs in a batch mode on ImageJ; an open source software. Kernel weight was estimated using the total kernel number derived from the number of kernels visible on the image and the average kernel size. Data showed a good agreement in terms of accuracy and precision between ground truth measurements and data generated through image processing. Broad-sense heritability of the estimated parameters was in the range or higher than that for measured grain weight. Limitation of the method for kernel weight estimation is discussed. CONCLUSION: The method developed in this work provides an opportunity to significantly reduce the cost of selection in the breeding process, especially for resource constrained crop improvement programs and can be used to learn more about the genetic bases of grain yield determinants.

Mast cell tryptase stimulates the synthesis of type I collagen in human lung fibroblasts.

Mast cell activation is a characteristic feature of chronic inflammation, a condition that may lead to fibrosis as a result of increased collagen synthesis by fibroblasts. We have investigated the potential of tryptase, the major protease of human mast cells, to stimulate collagen synthesis in the human lung fibroblast cell line MRC-5. Tryptase was isolated from human lung tissue by ion-exchange and affinity chromatography. At concentrations of 18 and 36 mU/ml, tryptase stimulated both an increase in cell numbers, and a fivefold increase in DNA synthesis as determined by methyl-[3H]thymidine incorporation. Similar concentrations of tryptase resulted in a 2.5-fold increase in collagen synthesis as determined both by incorporation of [3H]proline into collagen, and by assay of hydroxyproline concentrations in the supernatants. There was also a twofold increase in collagenolytic activity in the culture medium after tryptase treatment, indicating that the increase in collagen synthesis was not a consequence of decreased collagenase production. All of these actions of tryptase were reduced in the presence of the protease inhibitors leupeptin and benzamidine hydrochloride, indicating a requirement for an active catalytic site. SDS-PAGE and autoradiographic analysis of the [3H]collagen produced by the cells revealed it to be predominantly type I collagen. Our findings suggest that the release of tryptase from activated mast cells may provide a signal for abnormal fibrosis in inflammatory disease.

TELEMAM: a cluster randomised trial to assess the use of telemedicine in multi-disciplinary breast cancer decision making.

AIM: The TELEMAM trial aimed to assess the clinical effectiveness and costs of telemedicine in conducting breast cancer multi-disciplinary meetings (MDTs). METHODS: Over 12 months 473 MDT patient discussions in two district general hospitals (DGHs) were cluster randomised (2:1) to the intervention of telemedicine linkage to breast specialists in a cancer centre or to the control group of 'in-person' meetings. Primary endpoints were clinical effectiveness and costs. Economic analysis was based on a cost-minimisation approach. RESULTS: Levels of agreement of MDT members on a scale from 1 to 5 were high and similar in both the telemedicine and standard meetings for decision sharing (4.04 versus 4.17), consensus (4.06 versus 4.20) and confidence in the decision (4.16 versus 4.07). The threshold at which the telemedicine meetings became cheaper than standard MDTs was approximately 40 meetings per year. CONCLUSION: Telemedicine delivered breast cancer multi-disciplinary meetings have similar clinical effectiveness to standard 'in-person' meetings.

A randomised controlled trial of postoperative radiotherapy following breast-conserving surgery in a minimum-risk older population. The PRIME trial.

OBJECTIVES: To assess whether omission of postoperative radiotherapy in women with 'low-risk' axillary node negative breast cancer (T0-2) treated by breast-conserving surgery and endocrine therapy improves quality of life and is more cost-effective. DESIGN: A randomised controlled clinical trial, using a method of minimisation balanced by centre, grade of cancer, age, lymphatic/vascular invasion and preoperative endocrine therapy, was performed. A non-randomised cohort was also recruited, in order to complete a comprehensive cohort study. SETTING: The setting was breast cancer clinics in cancer centres in the UK. PARTICIPANTS: Patients aged 65 years or more were eligible provided that their cancers were considered to be at low risk of local recurrence, were suitable for breast-conservation surgery, were receiving endocrine therapy and were able and willing to give informed consent. INTERVENTIONS: The standard treatment of postoperative breast irradiation or the omission of radiotherapy. MAIN OUTCOME MEASURES: Quality of life was the primary outcome measure, together with anxiety and depression and cost-effectiveness. Secondary outcome measures were recurrence rates, functional status, treatment-related morbidity and cosmesis. The principal method of data collection was by questionnaire, completed at home with a research nurse at four times over 15 months. RESULTS: The hypothesised improvement in overall quality of life with the omission of radiotherapy was not seen in the EuroQol assessment or in the functionality and symptoms summary domains of the European Organisation for Research in the Treatment of Cancer (EORTC) scales. Some differences were apparent within subscales of the EORTC questionnaires, and insights into the impact of treatment were also provided by the qualitative data obtained by open-ended questions. Differences were most apparent shortly after the time of completion of radiotherapy. Radiotherapy was then associated with increased breast symptoms and with greater fatigue but with less insomnia and endocrine side-effects. Patients had significant concerns about the delivery of radiotherapy services, such as transport, accommodation and travel costs associated with receiving radiotherapy. By the end of follow-up, patients receiving radiotherapy were expressing less anxiety about recurrence than those who had not received radiotherapy. Functionality was not greatly affected by treatment. Within the randomised controlled trial, the Barthel Index demonstrated a small but significant fall in functionality with radiotherapy compared with the no radiotherapy arm of the trial. Results from the non-randomised patients did not confirm this effect, however. Cosmetic results were better in those not receiving radiotherapy but this did not appear to be an important issue to the patients. The use of home-based assessments by a research nurse proved to be an effective way of obtaining high-quality data. Costs to the NHS associated with postoperative radiotherapy were calculated to be of the order of 2000 pounds per patient. In the follow-up in this study, there were no recurrences, and the quality of life utilities from EuroQol were almost identical. CONCLUSIONS: Although there are no differences in overall quality of life scores between the patients treated with and without radiotherapy, there are several dimensions that exhibit significant advantage to the omission of irradiation. Over the first 15 months, radiotherapy for this population is not a cost-effective treatment. However, the early postoperative outcome does not give a complete answer and the eventual cost-effectiveness will only become clear after long-term follow-up. Extrapolations from these data suggest that radiotherapy may not be a cost-effective treatment unless it results in a recurrence rate that is at least 5% lower in absolute terms than those treated without radiotherapy. Further research is needed into a number of areas including the long-term aspects of quality of life, clinical outcomes, costs and consequences of omitting radiotherapy.

The clinical effectiveness and cost-effectiveness of screening for open angle glaucoma: a systematic review and economic evaluation.

OBJECTIVES: To assess whether open angle glaucoma (OAG) screening meets the UK National Screening Committee criteria, to compare screening strategies with case finding, to estimate test parameters, to model estimates of cost and cost-effectiveness, and to identify areas for future research. DATA SOURCES: Major electronic databases were searched up to December 2005. REVIEW METHODS: Screening strategies were developed by wide consultation. Markov submodels were developed to represent screening strategies. Parameter estimates were determined by systematic reviews of epidemiology, economic evaluations of screening, and effectiveness (test accuracy, screening and treatment). Tailored highly sensitive electronic searches were undertaken. RESULTS: Most potential screening tests reviewed had an estimated specificity of 85% or higher. No test was clearly most accurate, with only a few, heterogeneous studies for each test. No randomised controlled trials (RCTs) of screening were identified. Based on two treatment RCTs, early treatment reduces the risk of progression. Extrapolating from this, and assuming accelerated progression with advancing disease severity, without treatment the mean time to blindness in at least one eye was approximately 23 years, compared to 35 years with treatment. Prevalence would have to be about 3-4% in 40 year olds with a screening interval of 10 years to approach cost-effectiveness. It is predicted that screening might be cost-effective in a 50-year-old cohort at a prevalence of 4% with a 10-year screening interval. General population screening at any age, thus, appears not to be cost-effective. Selective screening of groups with higher prevalence (family history, black ethnicity) might be worthwhile, although this would only cover 6% of the population. Extension to include other at-risk cohorts (e.g. myopia and diabetes) would include 37% of the general population, but the prevalence is then too low for screening to be considered cost-effective. Screening using a test with initial automated classification followed by assessment by a specialised optometrist, for test positives, was more cost-effective than initial specialised optometric assessment. The cost-effectiveness of the screening programme was highly sensitive to the perspective on costs (NHS or societal). In the base-case model, the NHS costs of visual impairment were estimated as 669 pounds. If annual societal costs were 8800 pounds, then screening might be considered cost-effective for a 40-year-old cohort with 1% OAG prevalence assuming a willingness to pay of 30,000 pounds per quality-adjusted life-year. Of lesser importance were changes to estimates of attendance for sight tests, incidence of OAG, rate of progression and utility values for each stage of OAG severity. Cost-effectiveness was not particularly sensitive to the accuracy of screening tests within the ranges observed. However, a highly specific test is required to reduce large numbers of false-positive referrals. The findings that population screening is unlikely to be cost-effective are based on an economic model whose parameter estimates have considerable uncertainty. In particular, if rate of progression and/or costs of visual impairment are higher than estimated then screening could be cost-effective. CONCLUSIONS: While population screening is not cost-effective, the targeted screening of high-risk groups may be. Procedures for identifying those at risk, for quality assuring the programme, as well as adequate service provision for those screened positive would all be needed. Glaucoma detection can be improved by increasing attendance for eye examination, and improving the performance of current testing by either refining practice or adding in a technology-based first assessment, the latter being the more cost-effective option. This has implications for any future organisational changes in community eye-care services. Further research should aim to develop and provide quality data to populate the economic model, by conducting a feasibility study of interventions to improve detection, by obtaining further data on costs of blindness, risk of progression and health outcomes, and by conducting an RCT of interventions to improve the uptake of glaucoma testing.

The coxibs and traditional nonsteroidal anti-inflammatory drugs: a current perspective on cardiovascular risks.

There is strong evidence from randomized clinical trials that the highly selective cox-2 inhibitors (coxibs), compared with placebo, cause an excess of serious cardiovascular events that are not mitigated by low-dose acetylsalicylic acid. Both Health Canada and the Food and Drug Administration have concluded that the excess cardiovascular events may be a 'class effect' of all the nonsteroidal anti-inflammatory drugs (NSAIDs), including traditional NSAIDs (tNSAIDs) and coxibs, and now require appropriate black box labelling of all these agents. Celecoxib and lumiracoxib are the only coxibs remaining on the market in Canada. The prostanoid pathways, the roles of cox-1 and cox-2, as well as the inhibitory effects of acetylsalicylic acid, traditional tNSAIDs and the coxibs, are briefly reviewed. Current recommendations for the ongoing use of coxibs and the tNSAIDs are summarized.

Cerebellar contribution to higher and lower order rule learning and cognitive flexibility in mice.

Cognitive flexibility has traditionally been considered a frontal lobe function. However, converging evidence suggests involvement of a larger brain circuit which includes the cerebellum. Reciprocal pathways connecting the cerebellum to the prefrontal cortex provide a biological substrate through which the cerebellum may modulate higher cognitive functions, and it has been observed that cognitive inflexibility and cerebellar pathology co-occur in psychiatric disorders (e.g., autism, schizophrenia, addiction). However, the degree to which the cerebellum contributes to distinct forms of cognitive flexibility and rule learning is unknown. We tested lurcher↔wildtype aggregation chimeras which lose 0-100% of cerebellar Purkinje cells during development on a touchscreen-mediated attentional set-shifting task to assess the contribution of the cerebellum to higher and lower order rule learning and cognitive flexibility. Purkinje cells, the sole output of the cerebellar cortex, ranged from 0 to 108,390 in tested mice. Reversal learning and extradimensional set-shifting were impaired in mice with⩾95% Purkinje cell loss. Cognitive deficits were unrelated to motor deficits in ataxic mice. Acquisition of a simple visual discrimination and an attentional-set were unrelated to Purkinje cells. A positive relationship was observed between Purkinje cells and errors when exemplars from a novel, non-relevant dimension were introduced. Collectively, these data suggest that the cerebellum contributes to higher order cognitive flexibility, lower order cognitive flexibility, and attention to novel stimuli, but not the acquisition of higher and lower order rules. These data indicate that the cerebellar pathology observed in psychiatric disorders may underlie deficits involving cognitive flexibility and attention to novel stimuli.