http://www.dspace.cam.ac.uk:80/handle/1810/751 Cambridge University central library Thu, 23 May 2013 10:32:46 GMT 2013-05-23T10:32:46Z http://www.dspace.cam.ac.uk:80/handle/1810/244606 Title: Lignin biosynthesis perturbations affect secondary cell wall composition and saccharification yield in Arabidopsis thaliana Authors: Van Acker, Rebecca; Vanholme, Ruben; Storme, Véronique; Mortimer, Jennifer C; Dupree, Paul; Boerjan, Wout Abstract: Abstract Background Second-generation biofuels are generally produced from the polysaccharides in the lignocellulosic plant biomass, mainly cellulose. However, because cellulose is embedded in a matrix of other polysaccharides and lignin, its hydrolysis into the fermentable glucose is hampered. The senesced inflorescence stems of a set of 20 Arabidopsis thaliana mutants in 10 different genes of the lignin biosynthetic pathway were analyzed for cell wall composition and saccharification yield. Saccharification models were built to elucidate which cell wall parameters played a role in cell wall recalcitrance. Results Although lignin is a key polymer providing the strength necessary for the plant’s ability to grow upward, a reduction in lignin content down to 64% of the wild-type level in Arabidopsis was tolerated without any obvious growth penalty. In contrast to common perception, we found that a reduction in lignin was not compensated for by an increase in cellulose, but rather by an increase in matrix polysaccharides. In most lignin mutants, the saccharification yield was improved by up to 88% cellulose conversion for the cinnamoyl-coenzyme A reductase1 mutants under pretreatment conditions, whereas the wild-type cellulose conversion only reached 18%. The saccharification models and Pearson correlation matrix revealed that the lignin content was the main factor determining the saccharification yield. However, also lignin composition, matrix polysaccharide content and composition, and, especially, the xylose, galactose, and arabinose contents influenced the saccharification yield. Strikingly, cellulose content did not significantly affect saccharification yield. Conclusions Although the lignin content had the main effect on saccharification, also other cell wall factors could be engineered to potentially increase the cell wall processability, such as the galactose content. Our results contribute to a better understanding of the effect of lignin perturbations on plant cell wall composition and its influence on saccharification yield, and provide new potential targets for genetic improvement. Thu, 25 Apr 2013 23:00:00 GMT http://www.dspace.cam.ac.uk:80/handle/1810/244606 2013-04-25T23:00:00Z http://www.dspace.cam.ac.uk:80/handle/1810/244603 Title: The histone deacetylase inhibitor sodium valproate causes limited transcriptional change in mouse embryonic stem cells but selectively overrides Polycomb-mediated Hoxb silencing Authors: Boudadi, Elsa; Stower, Hannah; Halsall, John A; Rutledge, Charlotte E; Leeb, Martin; Wutz, Anton; O’Neill, Laura P; Nightingale, Karl P; Turner, Bryan M Abstract: Abstract Background Histone deacetylase inhibitors (HDACi) cause histone hyperacetylation and H3K4 hypermethylation in various cell types. They find clinical application as anti-epileptics and chemotherapeutic agents, but the pathways through which they operate remain unclear. Surprisingly, changes in gene expression caused by HDACi are often limited in extent and can be positive or negative. Here we have explored the ability of the clinically important HDACi valproic acid (VPA) to alter histone modification and gene expression, both globally and at specific genes, in mouse embryonic stem (ES) cells. Results Microarray expression analysis of ES cells exposed to VPA (1 mM, 8 h), showed that only 2.4% of genes showed a significant, >1.5-fold transcriptional change. Of these, 33% were down-regulated. There was no correlation between gene expression and VPA-induced changes in histone acetylation or H3K4 methylation at gene promoters, which were usually minimal. In contrast, all Hoxb genes showed increased levels of H3K9ac after exposure to VPA, but much less change in other modifications showing bulk increases. VPA-induced changes were lost within 24 h of inhibitor removal. VPA significantly increased the low transcription of Hoxb4 and Hoxb7, but not other Hoxb genes. Expression of Hoxb genes increased in ES cells lacking functional Polycomb silencing complexes PRC1 and PRC2. Surprisingly, VPA caused no further increase in Hoxb transcription in these cells, except for Hoxb1, whose expression increased several fold. Retinoic acid (RA) increased transcription of all Hoxb genes in differentiating ES cells within 24 h, but thereafter transcription remained the same, increased progressively or fell progressively in a locus-specific manner. Conclusions Hoxb genes in ES cells are unusual in being sensitive to VPA, with effects on both cluster-wide and locus-specific processes. VPA increases H3K9ac at all Hoxb loci but significantly overrides PRC-mediated silencing only at Hoxb4 and Hoxb7. Hoxb1 is the only Hoxb gene that is further up-regulated by VPA in PRC-deficient cells. Our results demonstrate that VPA can exert both cluster-wide and locus-specific effects on Hoxb regulation. Tue, 30 Apr 2013 23:00:00 GMT http://www.dspace.cam.ac.uk:80/handle/1810/244603 2013-04-30T23:00:00Z http://www.dspace.cam.ac.uk:80/handle/1810/244600 Title: A metadata-aware application for remote scoring and exchange of tissue microarray images Authors: Morris, Lorna; Tsui, Andrew; Crichton, Charles; Harris, Steve; Maccallum, Peter H; Howat, William J; Davies, Jim; Brenton, James D; Caldas, Carlos Abstract: Abstract Background The use of tissue microarrays (TMA) and advances in digital scanning microscopy has enabled the collection of thousands of tissue images. There is a need for software tools to annotate, query and share this data amongst researchers in different physical locations. Results We have developed an open source web-based application for remote scoring of TMA images, which exploits the value of Microsoft Silverlight Deep Zoom to provide a intuitive interface for zooming and panning around digital images. We use and extend existing XML-based standards to ensure that the data collected can be archived and that our system is interoperable with other standards-compliant systems. Conclusion The application has been used for multi-centre scoring of TMA slides composed of tissues from several Phase III breast cancer trials and ten different studies participating in the International Breast Cancer Association Consortium (BCAC). The system has enabled researchers to simultaneously score large collections of TMA and export the standardised data to integrate with pathological and clinical outcome data, thereby facilitating biomarker discovery. Tue, 30 Apr 2013 23:00:00 GMT http://www.dspace.cam.ac.uk:80/handle/1810/244600 2013-04-30T23:00:00Z http://www.dspace.cam.ac.uk:80/handle/1810/244597 Title: A combination of mutations in AKR1D1 and SKIV2L in a family with severe infantile liver disease Authors: Morgan, Neil V; Hartley, Jane L; Setchell, Kenneth DR; Simpson, Michael A; Brown, Rachel; Tee, Louise; Kirkham, Sian; Pasha, Shanaz; Trembath, Richard C; Maher, Eamonn R; Gissen, Paul; Kelly, Deirdre A Abstract: Abstract Infantile cholestatic diseases can be caused by mutations in a number of genes involved in different hepatocyte molecular pathways. Whilst some of the essential pathways have a well understood function, such as bile biosynthesis and transport, the role of the others is not known. Here we report the findings of a clinical, biochemical and molecular study of a family with three patients affected with a severe infantile cholestatic disease. A novel homozygous frameshift germline mutation (c.587delG) in the AKR1D1 gene; which encodes the enzyme Δ 4-3-oxosteroid 5β–reductase that is required for synthesis of primary bile acids and is crucial for establishment of normal bile flow, was found in all 3 patients. Although the initial bile acid analysis was inconclusive, subsequent testing confirmed the diagnosis of a bile acid biogenesis disorder. An additional novel homozygous frameshift mutation (c.3391delC) was detected in SKIV2L in one of the patients. SKIV2L encodes a homologue of a yeast ski2 protein proposed to be involved in RNA processing and mutations in SKIV2L were recently described in patients with Tricohepatoenteric syndrome (THES). A combination of autozygosity mapping and whole-exome-sequencing allowed the identification of causal mutations in this family with a complex liver phenotype. Although the initial 2 affected cousins died in the first year of life, accurate diagnosis and management of the youngest patient led to successful treatment of the liver disease and disease-free survival. Wed, 15 May 2013 23:00:00 GMT http://www.dspace.cam.ac.uk:80/handle/1810/244597 2013-05-15T23:00:00Z http://www.dspace.cam.ac.uk:80/handle/1810/244596 Title: Empirical Bayesian analysis of paired high-throughput sequencing data with a beta-binomial distribution Authors: Hardcastle, Thomas J; Kelly, Krystyna A Abstract: Abstract Background Pairing of samples arises naturally in many genomic experiments; for example, gene expression in tumour and normal tissue from the same patients. Methods for analysing high-throughput sequencing data from such experiments are required to identify differential expression, both within paired samples and between pairs under different experimental conditions. Results We develop an empirical Bayesian method based on the beta-binomial distribution to model paired data from high-throughput sequencing experiments. We examine the performance of this method on simulated and real data in a variety of scenarios. Our methods are implemented as part of the RbaySeq package (versions 1.11.6 and greater) available from Bioconductor (http://www.bioconductor.org). Conclusions We compare our approach to alternatives based on generalised linear modelling approaches and show that our method offers significant gains in performance on simulated data. In testing on real data from oral squamous cell carcinoma patients, we discover greater enrichment of previously identified head and neck squamous cell carcinoma associated gene sets than has previously been achieved through a generalised linear modelling approach, suggesting that similar gains in performance may be found in real data. Our methods thus show real and substantial improvements in analyses of high-throughput sequencing data from paired samples. Mon, 22 Apr 2013 23:00:00 GMT http://www.dspace.cam.ac.uk:80/handle/1810/244596 2013-04-22T23:00:00Z http://www.dspace.cam.ac.uk:80/handle/1810/244595 Title: Detection of specific HPV subtypes responsible for the pathogenesis of condylomata acuminata Authors: Hawkins, Matthew G; Winder, David M; Ball, Siolian L R; Vaughan, Katie; Sonnex, Christopher; Stanley, Margaret A; Sterling, Jane C; Goon, Peter K C Abstract: Abstract Background The low-risk human papillomavirus types 6 and 11 are responsible for approximately 90% of anogenital wart cases, with approximately 190,000 new and recurrent cases reported in the UK in 2010. The UK has recently selected the quadrivalent HPV vaccine, which conveys protection against both HPV6 and HPV 11, as part of its immunisation programme for 2012 and it is expected that this will reduce disease burden in the UK. The aims of the study were to evaluate current strategies used for the monitoring of HPV infection in genital warts and to assess the suitability of laser-capture microdissection (LCM) as a technique to improve the understanding of the natural history of HPV types associated with genital wart lesions. Methods DNA and RNA were extracted from whole wart, surface swabs and LCM sections from 23 patients. HPV types present were determined using the Linear Array HPV Genotyping Test (Roche), with HPV DNA viral load and mRNA expression investigated using qPCR and qRT-PCR, respectively. Results Results indicated that swabbing the surface of warts does not accurately reflect potential causative HPV types present within a wart lesion, multiple HPV types being present on the surface of the wart that are absent in the lower layers of tissue isolated by LCM. Although it was shown that HPV DNA viral load does not directly correlate with HPV mRNA load, the presence of both DNA and mRNA from a single HPV type suggested a causative role in lesion development in 8/12 (66.6%) of patients analysed, with dual infections seen in 4/12 (33.3%) cases. HPV 6 and HPV 11 were present in more than 90% of the lesions examined. Conclusions Surface swabbing of warts does not necessarily reflect the causative HPV types. HPV type specific DNA and mRNA loads do not correlate. HPV 6 and 11 were likely to be causally involved in over 90% of the lesions. Dual infections were also found, and further studies are required to determine the biological and clinical nature of dual/multiple infections and to establish the relationship of multiple HPV types within a single lesion. Tue, 30 Apr 2013 23:00:00 GMT http://www.dspace.cam.ac.uk:80/handle/1810/244595 2013-04-30T23:00:00Z http://www.dspace.cam.ac.uk:80/handle/1810/244594 Title: Dissemination of metabolomics results: role of MetaboLights and COSMOS Authors: Salek, Reza M; Haug, Kenneth; Steinbeck, Christoph Abstract: Abstract With ever-increasing amounts of metabolomics data produced each year, there is an even greater need to disseminate data and knowledge produced in a standard and reproducible way. To assist with this a general purpose, open source metabolomics repository, MetaboLights, was launched in 2012. To promote a community standard, initially culminated as metabolomics standards initiative (MSI), COordination of Standards in MetabOlomicS (COSMOS) was introduced. COSMOS aims to link life science e-infrastructures within the worldwide metabolomics community as well as develop and maintain open source exchange formats for raw and processed data, ensuring better flow of metabolomics information. Thu, 16 May 2013 23:00:00 GMT http://www.dspace.cam.ac.uk:80/handle/1810/244594 2013-05-16T23:00:00Z http://www.dspace.cam.ac.uk:80/handle/1810/244591 Title: Understanding Hospital Admissions Close to the End of Life (ACE) Study Authors: Morris, Zoë S; Fyfe, Miranda; Momen, Natalie; Hoare, Sarah; Barclay, Stephen Abstract: Abstract Background Palliative care is a policy priority internationally. In England, policymakers are seeking to develop high quality care for all by focusing on reducing the number of patients who die in acute hospitals. It is argued that reducing ‘inappropriate’ hospital admissions will lead to an improvement in the quality of care and provide cost savings.Yet what is meant by an ‘inappropriate’ admission is unclear and is unlikely to be shared by all stakeholders. The decision process that leads to hospital admission is often challenging, particularly when patients are frail and elderly. The ACE study reopens the idea of ‘inappropriate’ hospital admissions close to the end of life. We will explore how decisions that result in inpatient admissions close to death are made and valued from the perspective of the decision-maker, and will consider the implications of these findings for current policy and practice. Design/Methods The study focuses on the admission of patients with advanced dementia, chest disease or cancer who die within 72 hours of admission to acute hospitals. The study uses mixed methods with three data collection phases. Phase one involves patient case studies of admissions with interviews with clinicians involved in the admission and next-of-kin. Phase two uses vignette-based focus groups with clinical professionals and patients living with the conditions of interest. Phase three uses questionnaires distributed to clinical stakeholders. Qualitative data will be explored using framework analysis whilst the questionnaire data will be examined using descriptive statistical analysis. Findings will be used to evaluate current policy and literature. Discussion Significant ethical and validity issues arise due to the retrospective nature of phase one of the study. We are not able to gain consent from patients who have died, and the views of the deceased patients cannot be included directly, which risks privileging professional views. This phase also relies on the memories of the participants which may be unreliable. Later phases of the study attempt to compensate for the “absent voices” of the deceased patients by including next-of-kin and patient focus groups. Mon, 11 Mar 2013 00:00:00 GMT http://www.dspace.cam.ac.uk:80/handle/1810/244591 2013-03-11T00:00:00Z http://www.dspace.cam.ac.uk:80/handle/1810/244589 Title: Sex-biased gene expression in the developing brain: implications for autism spectrum disorders Authors: Ziats, Mark N; Rennert, Owen M Abstract: Abstract Autism spectrum disorders affect significantly more males than females. Understanding sex differences in normal human brain development may provide insight into the mechanism(s) underlying this disparity; however, studies of sex differences in brain development at the genomic level are lacking. Here, we report a re-analysis of sex-specific gene expression from a recent large transcriptomic study of normal human brain development, to determine whether sex-biased genes relate to specific mechanistic processes. We discovered that male-biased genes are enriched for the processes of extracellular matrix formation/glycoproteins, immune response, chromatin, and cell cytoskeleton. We highlight that these pathways have been repeatedly implicated in autism and demonstrate that autism candidate genes are also enriched for these pathways. We propose that the overlap of these male-specific brain transcriptional modules with the same pathways in autism spectrum disorders may partially explain the increased incidence of autism in males. Mon, 06 May 2013 23:00:00 GMT http://www.dspace.cam.ac.uk:80/handle/1810/244589 2013-05-06T23:00:00Z http://www.dspace.cam.ac.uk:80/handle/1810/244588 Title: Deletions within COL11A1 in Type 2 stickler syndrome detected by multiplex ligation-dependent probe amplification (MLPA) Authors: Vijzelaar, Raymon; Waller, Sarah; Errami, Abdellatif; Donaldson, Alan; Lourenco, Teresa; Rodrigues, Marcia; McConnell, Vivienne; Fincham, Gregory; Snead, Martin; Richards, Allan Abstract: Abstract Background COL11A1 is a large complex gene around 250 kb in length and consisting of 68 exons. Pathogenic mutations in the gene can result in Stickler syndrome, Marshall syndrome or Fibrochondrogenesis. Many of the mutations resulting in either Stickler or Marshall syndrome alter splice sites and result in exon skipping, which because of the exon structure of collagen genes usually leaves the message in-frame. The mutant protein then exerts a dominant negative effect as it co-assembles with other collagen gene products. To date only one large deletion of 40 kb in the COL11A1, which was detected by RT-PCR, has been characterized. However, commonly used screening protocols, utilizing genomic amplification and exon sequencing, are unlikely to detect such large deletions. Consequently the frequency of this type of mutation is unknown. Case presentations We have used Multiplex Ligation-Dependent Probe Amplification (MLPA) in conjunction with exon amplification and sequencing, to analyze patients with clinical features of Stickler syndrome, and have detected six novel deletions that were not found by exon sequencing alone. Conclusion Exon deletions appear to represent a significant proportion of type 2 Stickler syndrome. This observation was previously unknown and so diagnostic screening of COL11A1 should include assays capable of detecting both large and small deletions, in addition to exon sequencing. Thu, 25 Apr 2013 23:00:00 GMT http://www.dspace.cam.ac.uk:80/handle/1810/244588 2013-04-25T23:00:00Z http://www.dspace.cam.ac.uk:80/handle/1810/244587 Title: Long term study on the effect of mollusciciding with niclosamide in stream habitats on the transmission of schistosomiasis mansoni after community-based chemotherapy in Makueni District, Kenya Authors: Kariuki, Henry C; Madsen, Henry; Ouma, John H; Butterworth, Anthony E; Dunne, David W; Booth, Mark; Kimani, Gachuhi; Mwatha, Joseph K; Muchiri, Eric; Vennervald, Birgitte J Abstract: Abstract Background Schistosoma mansoni infection is a persistent public health problem in many Kenyan communities. Although praziquantel is available, re-infection after chemotherapy treatment is inevitable, especially among children. Chemotherapy followed by intermittent mollusciciding of habitats of Biomphalaria pfeifferi, the intermediate host snail, may have longer term benefits, especially if timed to coincide with natural fluctuations in snail populations. Methods In this cohort study, the Kambu River (Intervention area) was molluscicided intermittently for 4 years, after mass chemotherapy with praziquantel in the adjacent community of Darajani in January 1997. The nearby Thange River was selected as a control (Non-intervention area), and its adjacent community of Ulilinzi was treated with praziquantel in December 1996. Snail numbers were recorded monthly at 9–10 sites along each river, while rainfall data were collected monthly, and annual parasitological surveys were undertaken in each village. The mollusciciding protocol was adapted to local conditions, and simplified to improve prospects for widespread application. Results After the initial reduction in prevalence attributable to chemotherapy, there was a gradual increase in the prevalence and intensity of infection in the non-intervention area, and significantly lower levels of re-infection amongst inhabitants of the intervention area. Incidence ratio between areas adjusted for age and gender at the first follow-up survey, 5 weeks after treatment in the non-intervention area and 4 months after treatment in the intervention area was not significant (few people turned positive), while during the following 4 annual surveys these ratios were 0.58 (0.39-0.85), 0.33 (0.18-0.60), 0.14 (0.09-0.21) and 0.45 (0.26-0.75), respectively. Snail numbers were consistently low in the intervention area as a result of the mollusciciding. Following termination of the mollusciciding at the end of 2000, snail populations and infections in snails increased again in the intervention area. Conclusion The results of this study demonstrate that in the Kenyan setting a combination of chemotherapy followed by intermittent mollusciciding can have longer term benefits than chemotherapy alone. Wed, 17 Apr 2013 23:00:00 GMT http://www.dspace.cam.ac.uk:80/handle/1810/244587 2013-04-17T23:00:00Z http://www.dspace.cam.ac.uk:80/handle/1810/244586 Title: In vivo MRI-based simulation of fatigue process: a possible trigger for human carotid atherosclerotic plaque rupture Authors: Huang, Yuan; Teng, Zhongzhao; Sadat, Umar; He, Jing; Graves, Martin J; Gillard, Jonathan H Abstract: Abstract Background Atherosclerotic plaque is subjected to a repetitive deformation due to arterial pulsatility during each cardiac cycle and damage may be accumulated over a time period causing fibrous cap (FC) fatigue, which may ultimately lead to rupture. In this study, we investigate the fatigue process in human carotid plaques using in vivo carotid magnetic resonance (MR) imaging. Method Twenty seven patients with atherosclerotic carotid artery disease were included in this study. Multi-sequence, high-resolution MR imaging was performed to depict the plaque structure. Twenty patients were found with ruptured FC or ulceration and 7 without. Modified Paris law was used to govern crack propagation and the propagation direction was perpendicular to the maximum principal stress at the element node located at the vulnerable site. Results The predicted crack initiations from 20 patients with FC defect all matched with the locations of the in vivo observed FC defect. Crack length increased rapidly with numerical steps. The natural logarithm of fatigue life decreased linearly with the local FC thickness (R2 = 0.67). Plaques (n=7) without FC defect had a longer fatigue life compared with those with FC defect (p = 0.03). Conclusion Fatigue process seems to explain the development of cracks in FC, which ultimately lead to plaque rupture. Mon, 22 Apr 2013 23:00:00 GMT http://www.dspace.cam.ac.uk:80/handle/1810/244586 2013-04-22T23:00:00Z http://www.dspace.cam.ac.uk:80/handle/1810/244583 Title: A phase II randomized clinical trial on cerebral near-infrared spectroscopy plus a treatment guideline versus treatment as usual for extremely preterm infants during the first three days of life (SafeBoosC): study protocol for a randomized controlled trial Authors: Hyttel-Sorensen, Simon; Austin, Topun; van Bel, Frank; Benders, Manon; Claris, Olivier; Dempsey, Eugene; Fumagalli, Monica; Greisen, Gorm; Grevstad, Berit; Hagmann, Cornelia; Hellström-Westas, Lena; Lemmers, Petra; Lindschou, Jane; Naulaers, Gunnar; van Oeveren, Wim; Pellicer, Adelina; Pichler, Gerhard; Roll, Claudia; Skoog, Maria; Winkel, Per; Wolf, Martin; Gluud, Christian Abstract: Abstract Background Every year in Europe about 25,000 infants are born extremely preterm. These infants have a 20% mortality rate, and 25% of survivors have severe long-term cerebral impairment. Preventative measures are key to reduce mortality and morbidity in an extremely preterm population. The primary objective of the SafeBoosC phase II trial is to examine if it is possible to stabilize the cerebral oxygenation of extremely preterm infants during the first 72 hours of life through the application of cerebral near-infrared spectroscopy (NIRS) oximetry and implementation of an clinical treatment guideline based on intervention thresholds of cerebral regional tissue saturation rStO2. Methods/Design SafeBoosC is a randomized, blinded, multinational, phase II clinical trial. The inclusion criteria are: neonates born more than 12 weeks preterm; decision to conduct full life support; parental informed consent; and possibility to place the cerebral NIRS oximeter within 3 hours after birth. The infants will be randomized into one of two groups. Both groups will have a cerebral oximeter monitoring device placed within three hours of birth. In the experimental group, the cerebral oxygenation reading will supplement the standard treatment using a predefined treatment guideline. In the control group, the cerebral oxygenation reading will not be visible and the infant will be treated according to the local standards. The primary outcome is the multiplication of the duration and magnitude of rStO2 values outside the target ranges of 55% to 85%, that is, the ‘burden of hypoxia and hyperoxia’ expressed in ‘%hours’. To detect a 50% difference between the experimental and control group in %hours, 166 infants in total must be randomized. Secondary outcomes are mortality at term date, cerebral ultrasound score, and interburst intervals on an amplitude-integrated electroencephalogram at 64 hours of life and explorative outcomes include neurodevelopmental outcome at 2 years corrected age, magnetic resonance imaging at term, blood biomarkers at 6 and 64 hours after birth, and adverse events. Discussion Cerebral oximetry guided interventions have the potential to improve neurodevelopmental outcome in extremely preterm infants. It is a logical first step to test if it is possible to reduce the burden of hypoxia and hyperoxia. Trial registration ClinicalTrial.gov, NCT01590316 Tue, 30 Apr 2013 23:00:00 GMT http://www.dspace.cam.ac.uk:80/handle/1810/244583 2013-04-30T23:00:00Z http://www.dspace.cam.ac.uk:80/handle/1810/244580 Title: Prevalence of autism in mainland China, Hong Kong and Taiwan: a systematic review and meta-analysis Authors: Sun, Xiang; Allison, Carrie; Matthews, Fiona E; Sharp, Stephen J; Auyeung, Bonnie; Baron-Cohen, Simon; Brayne, Carol Abstract: Abstract Background The prevalence of autism spectrum conditions (ASC) is 1% in developed countries, but little data are available from mainland China, Hong Kong and Taiwan. This study synthesizes evidence relating to the prevalence of ASC in these areas and assesses the effects of research methodology on prevalence estimates. Methods Systematic literature searches were conducted in PubMed, Web of Knowledge, China Web of Knowledge and Weipu databases, as well as relevant papers published from 1987 to 2011, reporting prevalence estimates of ASC or childhood autism in mainland China, Hong Kong and Taiwan. Summary estimates of prevalence were calculated with a random effects model. The effects of research methodology on the prevalence estimates were assessed using a meta-regression model. Results There were 25 studies eligible for review, 18 of which were suitable for inclusion in a meta-analysis. Pooled prevalence of childhood autism was 11.8 per 10,000 individuals (95% confidence interval (CI): 8.2, 15.3) in mainland China. Pooled prevalence of ASC was 26.6 per 10,000 (95% CI: 18.5, 34.6) in three areas. Substantial heterogeneity was identified between studies (I 2>75%). The prevalence estimate of childhood autism was most strongly associated with the choice of screening instrument. After adjustment for age group, the odds ratio for prevalence estimates when using the Autism Behavior Checklist (ABC) as the screening instrument compared with those using the Clancy Autism Behavior Scale (CABS) was 0.29 (95% CI: 0.12, 0.69), and 1.79 (95% CI: 0.70, 4.55; P= 0.20) when using the Checklist for Autism in Toddlers (CHAT) compared to the CABS. Conclusions The available studies investigating the prevalence of ASC in China, Hong Kong and Taiwan have focused mainly on childhood autism rather than the whole spectrum. The prevalence estimates are lower than estimates from developed countries. Studies using more recently developed screening instruments reported higher prevalence than older ones. However, available studies have methodological weaknesses and therefore these results lack comparability with those from developed countries. Our findings indicate a potential under-diagnosis and under-detection of ASC in mainland China, Hong Kong and Taiwan, and a need to adopt more advanced methods for research of ASC in these areas. Mon, 08 Apr 2013 23:00:00 GMT http://www.dspace.cam.ac.uk:80/handle/1810/244580 2013-04-08T23:00:00Z http://www.dspace.cam.ac.uk:80/handle/1810/244572 Title: Germ-line DICER1 mutations do not make a major contribution to the etiology of familial testicular germ cell tumours Authors: Sabbaghian, Nelly; Bahubeshi, Amin; Shuen, Andrew Y; Kanetsky, Peter A; Tischkowitz, Marc D; Nathanson, Katherine L; Foulkes, William D Abstract: Abstract Background The RNase III enzyme DICER1 plays a central role in maturation of microRNAs. Identification of neoplasia-associated germ-line and somatic mutations in DICER1 indicates that mis-expression of miRNAs in cancer may result from defects in their processing. As part of a recent study of DICER1 RNase III domains in 96 testicular germ cell tumors, a single RNase IIIb domain mutation was identified in a seminoma. To further explore the importance of DICER1 mutations in the etiology of testicular germ cell tumors (TGCT), we studied germ-line DNA samples from 43 probands diagnosed with familial TGCT. Findings We carried out High Resolution Melting Curve Analysis of DICER1 exons 2–12, 14–19, 21 and 24–27. All questionable melt curves were subjected to confirmatory Sanger sequencing.Sanger sequencing was used for exons 13, 20, 22 and 23. Intron-exon boundaries were included in all analyses. We identified 12 previously reported single nucleotide polymorphisms and two novel single nucleotide variants. No likely deleterious variants were identified; notably no mutations that were predicted to truncate the protein were identified. Conclusions Taken together with previous studies, the findings reported here suggest a very limited role for either germ-line or somatic DICER1 mutations in the etiology of TGCT. Sun, 31 Mar 2013 23:00:00 GMT http://www.dspace.cam.ac.uk:80/handle/1810/244572 2013-03-31T23:00:00Z http://www.dspace.cam.ac.uk:80/handle/1810/244570 Title: Study protocol for iQuit in Practice: a randomised controlled trial to assess the feasibility, acceptability and effectiveness of tailored web- and text-based facilitation of smoking cessation in primary care Authors: Sutton, Stephen; Smith, Susan; Jamison, James; Boase, Sue; Mason, Dan; Prevost, A Toby; Brimicombe, James; Sloan, Melanie; Gilbert, Hazel; Naughton, Felix Abstract: Abstract Background Primary care is an important setting for smoking cessation interventions. There is evidence for the effectiveness of tailored interventions for smoking cessation, and text messaging interventions for smoking cessation show promise. The intervention to be evaluated in this trial consists of two components: (1) a web-based program designed to be used by a practice nurse or other smoking cessation advisor (SCA); the program generates a cessation advice report that is highly tailored to relevant characteristics of the smoker; and (2) a three-month programme of automated tailored text messages sent to the smoker’s mobile phone. The objectives of the trial are to assess the acceptability and feasibility of the intervention and to estimate the short-term effectiveness of the intervention in increasing the quit rate compared with usual care alone. Methods/design The design is a two parallel group randomised controlled trial (RCT). 600 smokers who want to quit will be recruited in up to 30 general practices in the East of England. During a consultation with an SCA, they will be individually randomised by computer program to usual care (Control) or to usual care plus the iQuit system (Intervention). At the four-week follow-up appointment, the SCA will record smoking status and measure carbon monoxide level. There will be two further follow-ups, at eight weeks and six months from randomisation date, by postal questionnaire sent from and returned to the study centre or by telephone interview conducted by a research interviewer. The primary outcome will be self-reported abstinence for at least two weeks at eight weeks. A sample size of 300 per group would give 80% power to detect an increase in quit rate from 20% to 30% (alpha = 0.05, 2-sided test). The main analyses of quit rates will be conducted on an intention-to-treat basis, making the usual assumption that participants lost to follow up are smoking. Discussion This trial will focus on acceptability, feasibility and short-term effectiveness. The findings will be used to refine the intervention and to inform the decision to proceed to a pragmatic trial to estimate longer-term effectiveness and cost-effectiveness. Trial registration ISRCTN56702353 Tue, 09 Apr 2013 23:00:00 GMT http://www.dspace.cam.ac.uk:80/handle/1810/244570 2013-04-09T23:00:00Z http://www.dspace.cam.ac.uk:80/handle/1810/244547 Title: Global health education in U.S. Medical schools Authors: Khan, Omar A; Guerrant, Richard; Sanders, James; Carpenter, Charles; Spottswood, Margaret; Jones, David S; O’Callahan, Cliff; Brewer, Timothy F; Markuns, Jeffrey F; Gillam, Stephen; O’Neill, Joseph; Nathanson, Neal; Wright, Stephen Abstract: Abstract Interest in global health (GH) among medical students worldwide is measurably increasing. There is a concomitant emphasis on emphasizing globally-relevant health professions education. Through a structured literature review, expert consensus recommendations, and contact with relevant professional organizations, we review the existing state of GH education in US medical schools for which data were available. Several recommendations from professional societies have been developed, along with a renewed emphasis on competencies in global health. The implementation of these recommendations was not observed as being uniform across medical schools, with variation noted in the presence of global health curricula. Recommendations for including GH in medical education are suggested, as well as ways to formalize GH curricula, while providing flexibility for innovation and adaptation Fri, 18 Jan 2013 00:00:00 GMT http://www.dspace.cam.ac.uk:80/handle/1810/244547 2013-01-18T00:00:00Z http://www.dspace.cam.ac.uk:80/handle/1810/244534 Title: Monsef Benkirane awarded 2013 Ming K. Jeang Foundation Retrovirology Prize: Landmark HIV-1 research honoured Authors: Berkhout, Ben; Lever, Andrew; Wainberg, Mark; Fassati, Ariberto; Borrow, Persephone; Fujii, Masahiro Abstract: AbstractDr. Monsef Benkirane, from the Laboratoire de Virologie Moleculaire in Montpellier, France, has been announced as the recipient of the 2013 Retrovirology Prize. This bi-annual prize covers all aspects of the Retrovirology field and celebrates groundbreaking research from retrovirologists aged between 45 and 60. Monsef is among the brightest young "stars" in HIV-1 biology. At 45 years of age, he is the youngest recipient of the Retrovirology prize. This year the competition was particularly fierce with 4 strong contenders. Thu, 04 Apr 2013 23:00:00 GMT http://www.dspace.cam.ac.uk:80/handle/1810/244534 2013-04-04T23:00:00Z http://www.dspace.cam.ac.uk:80/handle/1810/244533 Title: 'You can't just hit a button': an ethnographic study of strategies to repurpose data from advanced clinical information systems for clinical process improvement Authors: Morrison, Cecily; Jones, Matthew; Jones, Rachel; Vuylsteke, Alain Abstract: Abstract Background Current policies encourage healthcare institutions to acquire clinical information systems (CIS) so that captured data can be used for secondary purposes, including clinical process improvement. Such policies do not account for the extra work required to repurpose data for uses other than direct clinical care, making their implementation problematic. This paper aims to analyze the strategies employed by clinical units to use data effectively for both direct clinical care and clinical process improvement. Methods Ethnographic methods were employed. A total of 54 contextual interviews with health professionals spanning various disciplines and 18 hours of observation were carried out in 5 intensive care units in England using an advanced CIS. Case studies of how the extra work was achieved in each unit were derived from the data and then compared. Results We found that extra work is required to repurpose CIS data for clinical process improvement. Health professionals must enter data not required for clinical care and manipulation of this data into a machine-readable form is often necessary. Ambiguity over who should be responsible for this extra work hindered CIS data usage for clinical process improvement. We describe 11 strategies employed by units to accommodate this extra work, distributing it across roles. Seven of these motivated data entry by health professionals and four addressed the machine readability of data. Many of the strategies relied heavily on the skill and leadership of local clinical customizers. Conclusions To realize the expected clinical process improvements by the use of CIS data, clinical leaders and policy makers need to recognize and support the redistribution of the extra work that is involved in data repurposing. Adequate time, funding, and appropriate motivation are needed to enable units to acquire and deliver the necessary skills in CIS customization. Tue, 09 Apr 2013 23:00:00 GMT http://www.dspace.cam.ac.uk:80/handle/1810/244533 2013-04-09T23:00:00Z http://www.dspace.cam.ac.uk:80/handle/1810/244520 Title: Evaluating complex interventions in End of Life Care: the MORECare Statement on good practice generated by a synthesis of transparent expert consultations and systematic reviews Authors: Higginson, Irene J; Evans, Catherine J; Grande, Gunn; Preston, Nancy; Morgan, Myfanwy; McCrone, Paul; Lewis, Penney; Fayers, Peter; Harding, Richard; Hotopf, Matthew; Murray, Scott A; Benalia, Hamid; Gysels, Marjolein; Farquhar, Morag; Todd, Chris; on behalf of MORECare Abstract: Abstract Background Despite being a core business of medicine, end of life care (EoLC) is neglected. It is hampered by research that is difficult to conduct with no common standards. We aimed to develop evidence-based guidance on the best methods for the design and conduct of research on EoLC to further knowledge in the field. Methods The Methods Of Researching End of life Care (MORECare) project built on the Medical Research Council guidance on the development and evaluation of complex circumstances. We conducted systematic literature reviews, transparent expert consultations (TEC) involving consensus methods of nominal group and online voting, and stakeholder workshops to identify challenges and best practice in EoLC research, including: participation recruitment, ethics, attrition, integration of mixed methods, complex outcomes and economic evaluation. We synthesised all findings to develop a guidance statement on the best methods to research EoLC. Results We integrated data from three systematic reviews and five TECs with 133 online responses. We recommend research designs extending beyond randomised trials and encompassing mixed methods. Patients and families value participation in research, and consumer or patient collaboration in developing studies can resolve some ethical concerns. It is ethically desirable to offer patients and families the opportunity to participate in research. Outcome measures should be short, responsive to change and ideally used for both clinical practice and research. Attrition should be anticipated in studies and may affirm inclusion of the relevant population, but careful reporting is necessitated using a new classification. Eventual implementation requires consideration at all stages of the project. Conclusions The MORECare statement provides 36 best practice solutions for research evaluating services and treatments in EoLC to improve study quality and set the standard for future research. The statement may be used alongside existing statements and provides a first step in setting common, much needed standards for evaluative research in EoLC. These are relevant to those undertaking research, trainee researchers, research funders, ethical committees and editors. Tue, 23 Apr 2013 23:00:00 GMT http://www.dspace.cam.ac.uk:80/handle/1810/244520 2013-04-23T23:00:00Z