Ben Carter

Genome Scale Reconstruction of a Salmonella Metabolic Model COMPARISON OF SIMILARITY AND DIFFERENCES WITH A COMMENSAL ESCHERICHIA COLI STRAIN

Salmonella are closely related to commensal Escherichia coli but have gained virulence factors enabling them to behave as enteric pathogens. Less well studied are the similarities and differences that exist between the metabolic properties of these organisms that may contribute toward niche adaptation of Salmonella pathogens. To address this, we have constructed a genome scale Salmonella metabolic model (iMA945). The model comprises 945 open reading frames or genes, 1964 reactions, and 1036 metabolites. There was significant overlap with genes present in E. coli MG1655 model iAF1260. In silico growth predictions were simulated using the model on different carbon, nitrogen, phosphorous, and sulfur sources. These were compared with substrate utilization data gathered from high throughput phenotyping microarrays revealing good agreement. Of the compounds tested, the majority were utilizable by both Salmonella and E. coli. Nevertheless a number of differences were identified both between Salmonella and E. coli and also within the Salmonella strains included. These differences provide valuable insight into differences between a commensal and a closely related pathogen and within different pathogenic strains opening new avenues for future explorations.

Comparison of cancer diagnostic intervals before and after implementation of NICE guidelines : analysis of data from the UK General Practice Research Database.

Background:The primary aim was to use routine data to compare cancer diagnostic intervals before and after implementation of the 2005 NICE Referral Guidelines for Suspected Cancer. The secondary aim was to compare change in diagnostic intervals across different categories of presenting symptoms.Methods:Using data from the General Practice Research Database, we analysed patients with one of 15 cancers diagnosed in either 2001–2002 or 2007–2008. Putative symptom lists for each cancer were classified into whether or not they qualified for urgent referral under NICE guidelines. Diagnostic interval (duration from first presented symptom to date of diagnosis in primary care records) was compared between the two cohorts.Results:In total, 37 588 patients had a new diagnosis of cancer and of these 20 535 (54.6%) had a recorded symptom in the year prior to diagnosis and were included in the analysis. The overall mean diagnostic interval fell by 5.4 days (95% CI: 2.4–8.5; P<0.001) between 2001–2002 and 2007–2008. There was evidence of significant reductions for the following cancers: (mean, 95% confidence interval) kidney (20.4 days, −0.5 to 41.5; P=0.05), head and neck (21.2 days, 0.2–41.6; P=0.04), bladder (16.4 days, 6.6–26.5; P⩽0.001), colorectal (9.0 days, 3.2–14.8; P=0.002), oesophageal (13.1 days, 3.0–24.1; P=0.006) and pancreatic (12.6 days, 0.2–24.6; P=0.04). Patients who presented with NICE-qualifying symptoms had shorter diagnostic intervals than those who did not (all cancers in both cohorts). For the 2007–2008 cohort, the cancers with the shortest median diagnostic intervals were breast (26 days) and testicular (44 days); the highest were myeloma (156 days) and lung (112 days). The values for the 90th centiles of the distributions remain very high for some cancers. Tests of interaction provided little evidence of differences in change in mean diagnostic intervals between those who did and did not present with symptoms specifically cited in the NICE Guideline as requiring urgent referral.Conclusion:We suggest that the implementation of the 2005 NICE Guidelines may have contributed to this reduction in diagnostic intervals between 2001–2002 and 2007–2008. There remains considerable scope to achieve more timely cancer diagnosis, with the ultimate aim of improving cancer outcomes.

A mixture containing galactooligosaccharide, produced by the enzymic activity of Bifidobacterium bifidum, reduces Salmonella enterica serovar Typhimurium infection in mice

The prebiotic Bimuno is a mixture containing galactooligosaccharide, produced by the galactosyltransferase activity of Bifidobacterium bifidum NCIMB 41171 in the presence of lactose. Previous studies have implicated prebiotics in reducing infections by enteric pathogens, thus it was hypothesized that Bimuno may confer some protection in the murine host from Salmonella enterica serovar Typhimurium (S. Typhimurium) infection. In this study, infection caused by S. Typhimurium SL1344nal(r) in the presence or absence of Bimuno was assessed using tissue culture assays, a murine ligated ileal gut loop model and a murine oral challenge model. In tissue culture adherence and invasion assays with HT-29-16E cells, the presence of approximately 2 mM Bimuno significantly reduced the invasion of S. Typhimurium SL1344nal(r) (P<0.0001). In the murine ligated ileal gut loops, the presence of Bimuno prevented colonization and the associated pathology of S. Typhimurium. In the BALB/c mouse model, the oral delivery of Bimuno prior to challenge with S. Typhimurium resulted in significant reductions in colonization in the five organs sampled, with highly significant reductions being observed in the spleen at 72 and 96 h post-challenge (P=0.0002, <0.0001, respectively). Collectively, the results indicate that Bimuno significantly reduced the colonization and pathology associated with S. Typhimurium infection in a murine model system, possibly by reducing the invasion of the pathogen into host cells.

Balance algorithm for cluster randomized trials

BackgroundWithin cluster randomized trials no algorithms exist to generate a full enumeration of a block randomization, balancing for covariates across treatment arms. Furthermore, often for practical reasons multiple blocks are required to fully randomize a study, which may not have been well balanced within blocks.ResultsWe present a convenient and easy to use randomization tool to undertake allocation concealed block randomization. Our algorithm highlights allocations that minimize imbalance between treatment groups across multiple baseline covariates.We demonstrate the algorithm using a cluster randomized trial in primary care (the PRE-EMPT Study) and show that the software incorporates a trade off between independent random allocations that were likely to be imbalanced, and predictable deterministic approaches that would minimise imbalance. We extend the methodology of single block randomization to allocate to multiple blocks conditioning on previous allocations.ConclusionThe algorithm is included as Additional file 1 and we advocate its use for robust randomization within cluster randomized trials.

Differences in the Recurrence and Mortality Outcomes Rates of Incidental and Nonincidental Papillary Thyroid Microcarcinoma: A Systematic Review and Meta-Analysis of 21 329 Person-Years of Follow-up

CONTEXT There is controversy as to whether papillary thyroid microcarcinoma (PTMC) represents more than one disease entity with different outcomes, requiring different treatment. OBJECTIVES To compare characteristics, outcomes, and factors associated with prognosis of incidental and nonincidental PTMC. SETTING AND DESIGN Two reviewers performed searches of online databases (1966-2012), reference lists, and conference abstract books. Longitudinal studies of subjects >16 years old receiving any treatments for papillary thyroid cancer ≤10 mm in size were included. Two reviewers independently screened abstracts and articles, extracted data, and assessed quality of studies using National Institute of Clinical Excellence and PRISMA criteria. RESULTS Of 1102 abstracts identified, 262 studies were reviewed and 17 studies included, comprising 3523 subjects, with mean follow-up of 70 months and total follow-up of 21 329 person-years. This included 854 subjects with incidental PTMC (follow-up, 4800 person-years; mean tumor size, 4.6 mm [range 3.3-6.7 mm]) and 2669 nonincidental PTMC cases (follow-up, 16 529 person-years; mean tumor size, 6.9 mm [range 5.6-8.0 mm]). The recurrence rate in the incidental group (0.5%; 95% confidence interval [CI], 0-1%, P < .001) was significantly lower than that in the nonincidental group PTMC (7.9%; 95% CI, 5-11%), with an OR of recurrence of 14.7 (95% CI, 5.6-54.8, P < .001) for nonincidental PTMC, compared with incidental PTMC. Lymph nodes were involved in 80% (126/157) of recurrences. On meta-regression, age, sex, size, tumor multifocality, lymph node involvement, and treatment modality were not significantly associated with recurrence. CONCLUSIONS Our meta-analysis strongly suggests the existence of at least two distinct entities of PTMC. Incidental PTMC has different clinical characteristics and a much lower recurrence rate than nonincidental PTMC, suggesting that management protocols should be re-considered. Additional studies with standardized data collection are required to explore potential differences between subgroups of nonincidental PTMC.

Do Mobile Phone Applications Improve Glycemic Control (HbA1c) in the Self-management of Diabetes? A Systematic Review, Meta-analysis, and GRADE of 14 Randomized Trials.

OBJECTIVE To investigate the effect of mobile phone applications (apps) on glycemic control (HbA1c) in the self-management of diabetes. RESEARCH DESIGN AND METHODS Relevant studies that were published between 1 January 1996 and 1 June 2015 were searched from five databases: Medline, CINAHL, Cochrane Library, Web of Science, and Embase. Randomized controlled trials that evaluated diabetes apps were included. We conducted a systematic review with meta-analysis and GRADE (Grading of Recommendations Assessment, Development and Evaluation) of the evidence. RESULTS Participants from 14 studies (n = 1,360) were included and quality assessed. Although there may have been clinical diversity, all type 2 diabetes studies reported a reduction in HbA1c. The mean reduction in participants using an app compared with control was 0.49% (95% Cl 0.30, 0.68; I2 = 10%), with a moderate GRADE of evidence. Subgroup analyses indicated that younger patients were more likely to benefit from the use of diabetes apps, and the effect size was enhanced with health care professional feedback. There was inadequate data to describe the effectiveness of apps for type 1 diabetes. CONCLUSIONS Apps may be an effective component to help control HbA1c and could be considered as an adjuvant intervention to the standard self-management for patients with type 2 diabetes. Given the reported clinical effect, access, and nominal cost of this technology, it is likely to be effective at the population level. The functionality and use of this technology need to be standardized, but policy and guidance are anticipated to improve diabetes self-management care.

Why do we want the right to die? A systematic review of the international literature on the views of patients, carers and the public on assisted dying

Background: Assisted dying is legal in four European countries and three American states. Elsewhere, particularly in more affluent or mainly Protestant countries, it remains controversial. Dominant headlines feature professional (medical, legal, religious) arguments versus celebrity campaigners; ordinary people are less clearly represented. Aim: To synthesise the international evidence of people’s views and attitudes towards assisted dying in order to inform current debate about this controversial issue. Design: Systematic review and mixed method synthesis of qualitative and survey data Data sources: Eleven electronic databases from inception to October 2011; bibliographies of included studies Review Methods: Two reviewers independently screened papers and appraised quality. Qualitative results were extracted verbatim; survey results were summarised in a table. Qualitative data were synthesised using framework methods and survey results integrated where they supported, contrasted or added to the themes identified. Results: Sixteen qualitative studies and 94 surveys were included; many participants considered the immediate relevance of assisted dying for them. Themes related to poor quality of life, a good quality of death, potential abuse of assisted dying and the importance of individual stance. People valued autonomy in death as much as in life. Attitudes were diverse, complex and related to definitions of unbearable suffering including physical, psycho-social and existential factors and were consistent regardless of social, economic, legal and health-care contexts. Conclusion: Our review sheds light on ordinary people’s perspectives about assisted dying, when they are ill or disabled. Unbearable suffering is a key construct, and common factors are revealed that lead people to ask for help to die. The consistency of international views indicates a mandate for legislative and medical systems worldwide to listen and understand this.

Effective and evidence-based management strategies for rosacea: summary of a Cochrane systematic review

Rosacea is a common chronic skin disease affecting the face. There are numerous treatment options, but it is unclear which are the most effective. The aim of this review was to assess the evidence for the efficacy and safety of treatments for rosacea. Searches included the Cochrane Skin Group Specialised Register, the Cochrane Central Register of Controlled Trials in The Cochrane Library, MEDLINE, EMBASE, Science Citation Index, and Ongoing Trials Registers (updated February 2011). Randomized controlled trials in people with moderate to severe rosacea were included. Fifty‐eight trials, including 27 from the original review, comprising 6633 participants were included in this updated review. Interventions included topical metronidazole, oral antibiotics, topical azelaic cream or gel, topical benzoyl peroxide and/or combined with topical antibiotics, sulphacetamide/sulphur, and others. There was some evidence that topical metronidazole and azelaic acid were more effective than placebo. Two trials indicated that doxycycline 40 mg was more effective than placebo. There was no statistically significant difference in effectiveness between doxycycline 40 mg and 100 mg but there were fewer adverse effects. One study reported that ciclosporin ophthalmic emulsion was significantly more effective than artificial tears for treating ocular rosacea. Although the majority of included studies were assessed as being at high or unclear risk of bias, there was some evidence to support the effectiveness of topical metronidazole, azelaic acid and doxycycline (40 mg) in the treatment of moderate to severe rosacea, and ciclosporin 0·05% ophthalmic emulsion for ocular rosacea. Further well‐designed, adequately powered randomized controlled trials are required.

Association Between Portable Screen-Based Media Device Access or Use and Sleep Outcomes: A Systematic Review and Meta-analysis

Importance Sleep is vital to childrens biopsychosocial development. Inadequate sleep quantity and quality is a public health concern with an array of detrimental health outcomes. Portable mobile and media devices have become a ubiquitous part of childrens lives and may affect their sleep duration and quality. Objective To conduct a systematic review and meta-analysis to examine whether there is an association between portable screen-based media device (eg, cell phones and tablet devices) access or use in the sleep environment and sleep outcomes. Data Sources A search strategy consisting of gray literature and 24 Medical Subject Headings was developed in Ovid MEDLINE and adapted for other databases between January 1, 2011, and June 15, 2015. Searches of the published literature were conducted across 12 databases. No language restriction was applied. Study Selection The analysis included randomized clinical trials, cohort studies, and cross-sectional study designs. Inclusion criteria were studies of school-age children between 6 and 19 years. Exclusion criteria were studies of stationary exposures, such as televisions or desktop or personal computers, or studies investigating electromagnetic radiation. Data Extraction and Synthesis Of 467 studies identified, 20 cross-sectional studies were assessed for methodological quality. Two reviewers independently extracted data. Main Outcomes and Measures The primary outcomes were inadequate sleep quantity, poor sleep quality, and excessive daytime sleepiness, studied according to an a priori protocol. Results Twenty studies were included, and their quality was assessed. The studies involved 125 198 children (mean [SD] age, 14.5 [2.2] years; 50.1% male). There was a strong and consistent association between bedtime media device use and inadequate sleep quantity (odds ratio [OR], 2.17; 95% CI, 1.42-3.32) (P < .001, I2 = 90%), poor sleep quality (OR, 1.46; 95% CI, 1.14-1.88) (P = .003, I2 = 76%), and excessive daytime sleepiness (OR, 2.72; 95% CI, 1.32-5.61) (P = .007, I2 = 50%). In addition, children who had access to (but did not use) media devices at night were more likely to have inadequate sleep quantity (OR, 1.79; 95% CI, 1.39-2.31) (P < .001, I2 = 64%), poor sleep quality (OR, 1.53; 95% CI, 1.11-2.10) (P = .009, I2 = 74%), and excessive daytime sleepiness (OR, 2.27; 95% CI, 1.54-3.35) (P < .001, I2 = 24%). Conclusions and Relevance To date, this study is the first systematic review and meta-analysis of the association of access to and the use of media devices with sleep outcomes. Bedtime access to and use of a media device were significantly associated with the following: inadequate sleep quantity, poor sleep quality, and excessive daytime sleepiness. An integrated approach among teachers, health care professionals, and parents is required to minimize device access at bedtime, and future research is needed to evaluate the influence of the devices on sleep hygiene and outcomes.

Antiemetic treatment for acute gastroenteritis in children: an updated Cochrane systematic review with meta-analysis and mixed treatment comparison in a Bayesian framework.

Objective To assess the evidence for the safety and effectiveness of antiemetics on gastroenteritis-induced vomiting in children and adolescents. Design Systematic review. Data Sources The Cochrane Central Register of Controlled Trials, MEDLINE and EMBASE searched from 1980 to March 2012. Methods Methods included comprehensive searches, data synthesis, meta-analysis and mixed treatment comparisons (MTC). Review methods Reference lists were checked, and missing or inconsistent data were sought from trial investigators. Randomised controlled trials comparing antiemetics in participants younger than 18 years and who were vomiting due to acute gastroenteritis. Four meta-analyses and three MTC were carried out. Results 10 trials (1479 participants) and five treatments were included: dexamethasone, dimenhydrinate, granisetron, metoclopramide and ondansetron. There was clear evidence that ondansetron (oral or intravenous) compared with placebo increased the proportion of patients with cessation of vomiting (orally administered) (RR 1.44, 95% CI 1.29 to 1.61), reduced the immediate hospital admission rate (orally administered) (RR 0.40, 95% CI 0.19 to 0.83) and the need for intravenous rehydration therapy (orally administered) (RR 0.41, 95% CI 0.29 to 0.59). No significant difference was noted in the revisit rates, but ondansetron was associated with an increase in episodes of diarrhoea. There was no evidence for the use of dexamethasone or metoclopramide and limited evidence that dimenhydrinate or granisetron increased the cessation of vomiting. The MTC analysis suggested that ondansetron was the most likely treatment to stop the child vomiting. Nine studies were carried out in secondary care and one in primary care. Conclusions This systematic review used a method novel to this clinical area and found clear evidence that ondansetron was the most likely treatment to allow oral rehydration therapy to commence. Given the significance of these results, the authors urge healthcare policy makers to consider the wider use of ondansetron in secondary care. Furthermore, randomised controlled trials are needed to investigate the effectiveness of antiemetic treatment in primary care (including ambulatory care interventions).