Biomedical subjects

A Toby Prevost

Publications and source records attributed to A Toby Prevost.

11 recordsLinked to original sources

PubMed2006

Psychological impact of genetic counseling for familial cancer: a systematic review and meta-analysis.

BACKGROUND: Identification of a genetic basis underlying certain types of cancer has led to an increase in demand for genetic counseling about individual risks of the disease. We conducted a systematic review of the literature to determine the quality and strength of evidence relating to psychological outcomes of genetic counseling for familial cancer. METHODS: Six electronic databases were searched to identify controlled trials and prospective studies that examined the effect of genetic counseling on risk perception, knowledge, anxiety, cancer-specific worry, depression, and cancer surveillance. Twenty-one studies from 25 papers met inclusion criteria, including five controlled trials and 16 prospective studies. Analysis of each outcome was stratified by short-term (</=1 month) and long-term (>/=3 months) follow-up. Trial evidence was assessed with standardized differences of the means at follow-up between intervention and comparison groups, and these data were pooled by use of random-effects meta-analysis. RESULTS: Meta-analysis of controlled trials showed that genetic counseling improved knowledge of cancer genetics (pooled short-term difference=0.70 U, 95% confidence interval (CI)=0.15 to 1.26 U) but did not alter the level of perceived risk (pooled short-term difference=-0.10 U, 95% CI=-0.23-0.04 U). Prospective studies reported improvements in the accuracy of perceived risk. No effect was observed in controlled trials on general anxiety (pooled long-term effect=0.05 U, 95% CI=-0.21-0.31 U) or cancer-specific worry (pooled long-term difference=-0.14 U, 95% CI=-0.35-0.06 U), although several prospective studies demonstrated short-term reductions in these outcomes. Few studies examined cancer surveillance behaviors, and no studies attempted to measure informed choice. CONCLUSIONS: Genetic counseling for familial cancer is associated with improvement in knowledge but does not have an adverse effect on affective outcomes. We urge further investigation of these findings through well-designed, well-reported, randomized controlled trials with suitable comparison groups and additional outcome measures [J Natl Cancer Inst 2004; 96:122-33].

Attitude to Health↗

PubMed2005

Repression of DNA replication licensing in quiescence is independent of geminin and may define the cell cycle state of progenitor cells.

The DNA replication (or origin) licensing machinery ensures precise duplication of the genome and contributes to the regulation of proliferative capacity in metazoa. Using an in vitro fibroblast model system coupled to a cell-free DNA replication assay, we have studied regulation of the origin licensing pathway during exit from and re-entry into the mitotic cell cycle. We show that in the quiescent state (G0) loss of proliferative capacity is achieved in part through down-regulation of the replication licensing factors Cdc6 and Mcm2-7. The origin licensing repressor geminin is absent in quiescent fibroblasts, suggesting that this powerful inhibitor of the licensing machinery is not required to suppress proliferative capacity in G0. Geminin expression is induced at a late stage in the G0-S transition post pre-RC assembly. Ectopic geminin can block re-acquisition of DNA replication competence during re-entry into the cell cycle, indicating that geminin levels must be tightly down-regulated for escape from G0. Analysis of geminin levels in thyroid shows that geminin expression is suppressed in anatomical compartments/tissues harbouring quiescent cells, confirming our in vitro data. Spatio-temporal control of geminin expression may therefore be of particular relevance for multi-potential stem cells which cycle infrequently. In support of this hypothesis, we have identified a unique population of cells in the putative stem cell niche of intestinal epithelium that are unlicensed and lack geminin expression, a prerequisite for successful re-entry into cycle. Our data argue that the prolonged cell cycle times observed for intestinal stem cells could be due to exit of progenitor cells from cycle into an unlicensed "out-of-cycle" state, a powerful mechanism by which rapidly proliferating tissues may resist genotoxic insult.

3T3 Cells↗

PubMed2004

DNA replication licensing in somatic and germ cells.

The DNA replication (or origin) licensing system ensures precise duplication of the genome in each cell cycle and is a powerful regulator of cell proliferation in metazoa. Studies in yeast, Drosophila melanogaster and Xenopus laevis have characterised the molecular machinery that constitutes the licensing system, but it remains to be determined how this important evolutionary conserved pathway is regulated in Homo sapiens. We have investigated regulation of the origin licensing factors Cdc6, Cdt1, Mcm2 and Geminin in human somatic and germ cells. Cdc6 and Cdt1 play an essential role in DNA replication initiation by loading the Mcm2-7 complex, which is required for unwinding the DNA helix, onto chromosomal origins. Geminin is a repressor of origin licensing that blocks Mcm2-7 loading onto origins. Our studies demonstrate that Cdc6, Cdt1 and Mcm2 play a central role in coordinating growth during the proliferation-differentiation switch in somatic self-renewing systems and that Cdc6 expression is rate-limiting for acquisition of replication competence in primary oocytes. In striking contrast, we show that proliferation control during male gametogenesis is not linked to Cdc6 or Mcm2, but appears to be coordinated by the negative regulator Geminin with Cdt1 becoming rate-limiting in late prophase. Our data demonstrate a striking sexual dimorphism in the mechanisms repressing origin licensing and preventing untimely DNA synthesis during meiosis I, implicating a pivotal role for Geminin in maintaining integrity of the male germline genome.

Alternative Splicing↗

PubMed2004

The ProActive trial protocol - a randomised controlled trial of the efficacy of a family-based, domiciliary intervention programme to increase physical activity among individuals at high risk of diabetes [ISRCTN61323766].

BACKGROUND: Increasing prevalence of obesity and disorders associated with sedentary living constitute a major global public health problem. While previous evaluations of interventions to increase physical activity have involved communities or individuals with established disease, less attention has been given to interventions for individuals at risk of disease. METHODS/DESIGN: ProActive aims to evaluate the efficacy of a theoretical, evidence- and family-based intervention programme to increase physical activity in a sedentary population, defined as being at-risk through having a parental family history of diabetes. Primary care diabetes or family history registers were used to recruit 365 individuals aged 30-50 years, screened for activity level. Participants were assigned by central randomisation to three intervention programmes: brief written advice (comparison group), or a psychologically based behavioural change programme, delivered either by telephone (distance group) or face-to-face in the family home over one year. The protocol-driven intervention programme is delivered by trained facilitators, and aims to support increases in physical activity through the introduction and facilitation of a range of self-regulatory skills (e.g. goal setting). The primary outcome is daytime energy expenditure and its ratio to resting energy expenditure, measured at baseline and one year using individually calibrated heart rate monitoring. Secondary measures include self-report of individual and family activity, psychological mediators of behaviour change, physiological and biochemical correlates, acceptability, and costs, measured at baseline, six months and one year. The primary intention to treat analysis will compare groups at one-year post randomisation. Estimation of the impact on diabetes incidence will be modelled using data from a parallel ten-year cohort study using similar measures. DISCUSSION: ProActive is the first efficacy trial of an intervention programme to promote physical activity in a defined high-risk group accessible through primary care. The intervention programme is based on psychological theory and evidence; it introduces and facilitates the use of self-regulatory skills to support behaviour change and maintenance. The trial addresses a range of methodological weaknesses in the field by careful specification and quality assurance of the intervention programme, precise characterisation of participants, year-long follow-up and objective measurement of physical activity. Due to report in 2005, ProActive will provide estimates of the extent to which this approach could assist at-risk groups who could benefit from changes in behaviours affecting health, and inform future pragmatic trials.

Adult↗

PubMed2004

Allowing for imprecision of the intracluster correlation coefficient in the design of cluster randomized trials.

The sample size required for a cluster randomized trial depends on the magnitude of the intracluster correlation coefficient (ICC). The usual sample size calculation makes no allowance for the fact that the ICC is not known precisely in advance. We develop methods which allow for the uncertainty in a previously observed ICC, using a variety of distributional assumptions. Distributions for the power are derived, reflecting this uncertainty. Further, the observed ICC in a future study will not equal its true value, and we consider the impact of this on power. We implement calculations within a Bayesian simulation approach, and provide one simplification that can be performed using simple simulation within spreadsheet software. In our examples, recognizing the uncertainty in a previous ICC estimate decreases expected power, especially when the power calculated naively from the ICC estimate is high. To protect against the possibility of low power, sample sizes may need to be very substantially increased. Recognizing the variability in the future observed ICC has little effect if prior uncertainty has already been taken into account. We show how our method can be extended to the case in which multiple prior ICC estimates are available. The methods presented in this paper can be used by applied researchers to protect against loss of power, or to choose a design which reduces the impact of uncertainty in the ICC.

Bayes Theorem↗

PubMed2004

Psychological impact of genetic counseling for familial cancer: a systematic review and meta-analysis.

BACKGROUND: Identification of a genetic basis underlying certain types of cancer has led to an increase in demand for genetic counseling about individual risks of the disease. We conducted a systematic review of the literature to determine the quality and strength of evidence relating to psychological outcomes of genetic counseling for familial cancer. METHODS: Six electronic databases were searched to identify controlled trials and prospective studies that examined the effect of genetic counseling on risk perception, knowledge, anxiety, cancer-specific worry, depression, and cancer surveillance. Twenty-one studies from 25 papers met inclusion criteria, including five controlled trials and 16 prospective studies. Analysis of each outcome was stratified by short-term (< or =1 month) and long-term (> or = 3 months) follow-up. Trial evidence was assessed with standardized differences of the means at follow-up between intervention and comparison groups, and these data were pooled by use of random-effects meta-analysis. RESULTS: Meta-analysis of controlled trials showed that genetic counseling improved knowledge of cancer genetics (pooled short-term difference = 0.70 U, 95% confidence interval [CI] = 0.15 to 1.26 U) but did not alter the level of perceived risk (pooled short-term difference = -0.10 U, 95% CI = -0.23 to 0.04 U). Prospective studies reported improvements in the accuracy of perceived risk. No effect was observed in controlled trials on general anxiety (pooled long-term effect = 0.05 U, 95% CI = -0.21 to 0.31 U) or cancer-specific worry (pooled long-term difference = -0.14 U, 95% CI = -0.35 to 0.06 U), although several prospective studies demonstrated short-term reductions in these outcomes. Few studies examined cancer surveillance behaviors, and no studies attempted to measure informed choice. CONCLUSIONS: Genetic counseling for familial cancer is associated with improvement in knowledge but does not have an adverse effect on affective outcomes. We urge further investigation of these findings through well-designed, well-reported, randomized controlled trials with suitable comparison groups and additional outcome measures.

Affect↗

PubMed2003

Randomised crossover trial comparing the performance of Clinical Terms Version 3 and Read Codes 5 byte set coding schemes in general practice.

OBJECTIVE: To determine whether Clinical Terms Version 3 provides greater accuracy and consistency in coding electronic patient records than the Read Codes 5 byte set. DESIGN: Randomised crossover trial. Clinicians coded patient records using both schemes after being randomised in pairs to use one scheme before the other. SETTING: 10 general practices in urban, suburban, and rural environments in Norfolk. PARTICIPANTS: 10 general practitioners. SOURCE OF DATA: Concepts were collected from records of 100 patient encounters. MAIN OUTCOME MEASURES: Percentage of coded choices ranked as being exact representations of the original terms; percentage of cases where coding choice of paired general practitioners was identical; length of time taken to find a code. RESULTS: A total of 995 unique concepts were collected. Exact matches were more common with Clinical Terms (70% (95% confidence interval 67% to 73%)) than with Read Codes (50% (47% to 53%)) (P < 0.001), and this difference was significant for each of the 10 participants individually. The pooled proportion with exact and identical matches by paired participants was greater for Clinical Terms (0.58 (0.55 to 0.61)) than Read Codes (0.36 (0.33 to 0.39)) (P < 0.001). The time taken to code with Clinical Terms (30 seconds per term) was not significantly longer than that for Read Codes. CONCLUSIONS: Clinical Terms Version 3 performed significantly better than Read Codes 5 byte set in capturing the meaning of concepts. These findings suggest that improved coding accuracy in primary care electronic patient records can be achieved with the use of such a clinical terminology.

Adult↗

PubMed2003

Derivation and identification of questions that act as predictors of abdominal pain of musculoskeletal origin.

OBJECTIVE: Although most causes of abdominal pain have a visceral origin, the musculoskeletal system must be considered when the cause is not obvious. This prospective study aimed to identify questions that would aid the diagnosis of patients with abdominal pain of musculoskeletal origin. DESIGN: Assessment of consecutive patients with abdominal pain recruited from gastroenterological outpatient clinics to develop diagnostic pointers to identify abdominal pain arising from musculoskeletal disorders. PARTICIPANTS: Subjects with benign abdominal pain, with or without a change in bowel habit, were recruited from gastroenterological clinics. Patients with inflammatory or neoplastic disease were excluded. SETTING: The study was conducted in the Physiotherapy Department, Addenbrooke's NHS Trust Hospital, Cambridge. MAIN OUTCOME MEASURES: A set of questions developed to indicate a musculoskeletal cause of a patient's abdominal symptoms. RESULTS The questions 'Does taking a deep breath aggravate your symptoms?' and 'Does twisting your back aggravate your symptoms?' had a significant positive indication of abdominal symptoms of musculoskeletal origin. The questions 'Has there been any change in bowel habit since onset of your symptoms?', 'Does eating foods aggravate your symptoms?' and 'Has there been any weight change since onset of symptoms?' had a significant negative indication for abdominal symptoms not of musculoskeletal origin. A combination of these questions gave 96% specificity and 67% sensitivity. CONCLUSION: These questions may help with the early identification of patients with abdominal pain of musculoskeletal origin and will be tested in further studies.

Abdominal Pain↗

PubMed2003

A methodology for the functional comparison of coding schemes in primary care.

There has been massive investment in the development of clinical terminologies for use in electronic patient records. However, there has been little published evidence for the added value for primary care that implementation of such a terminology would offer. This paper outlines a methodology that has been used to compare two existing coding schemes (Read codes 5 byte set and Clinical Terms Version 3-CTV3) and demonstrates their relative performance using a certainty-agreement diagram. In the study described, CTV3 offers improved accuracy and consistency with improved usability. The potential advantages of the recently released terminology, SNOMED Clinical Terms, are briefly considered in this context.

Family Practice↗

PubMed2003

Influences on the variation in prevalence of type 2 diabetes between general practices: practice, patient or socioeconomic factors?

BACKGROUND: The prevalence of type 2 diabetes is known to vary between countries, districts and general practices. The influence of early detection and screening on the variation of prevalence between general practices has not previously been investigated. AIM: To test the hypothesis that the prevalence of type 2 diabetes is associated with awareness of and screening for diabetes within general practices and to explore other factors that may explain the variation in prevalence between practices. DESIGN OF STUDY: Cross-sectional study of general practices. SETTING: Forty-two general practices in Newcastle and North Tyneside; 20% random sample of patients with type 2 diabetes (n = 1056). METHOD: Factors thought to be associated with the variation of type 2 diabetes prevalence were collected from general practices through practice managers, medical records, and patient questionnaire. Pearson's correlation coefficient was used to quantify the association, and variables significant at the 5% level were entered into a multiple linear regression model. RESULTS: There was a wide inter-practice variation in age/sex standardised type 2 diabetes prevalence (range = 0.69% to 2.73%; P < 0.001). There was no significant association between the prevalence of type 2 diabetes and the proportion of patients detected outside primary care or the proportion of patients detected through screening, accounting for only 2% and 3% of the variation in type 2 prevalence between practices, respectively. The mean Townsend deprivation score accounted for 42% of the variation in type 2 diabetes prevalence between practices, with more deprived practices having a higher prevalence. CONCLUSION: This study suggests that socieconomic deprivation, rather than detection through screening or awareness of diabetes, accounts for much of the variation in prevalence of type 2 diabetes between practices.

Adolescent↗

PubMed2002

Diagnosis of genito-urinary tract cancer by detection of minichromosome maintenance 5 protein in urine sediments.

BACKGROUND: Because cystoscopy is invasive and expensive and urine cytology has low sensitivity, alternative methods for detecting bladder cancer are sought. Minichromosome maintenance (Mcm) proteins have been used as diagnostic markers for cervical cancer. We investigated whether one Mcm protein, Mcm5, can be used to detect urothelial cancer cells in urine sediments. METHODS: We used two monoclonal antibodies against His-tagged human Mcm5 (amino acids 367-582) in an immunofluorometric assay to measure Mcm5 levels in cells in the urine of 353 patients who presented with hematuria or lower urinary tract symptoms or who were undergoing follow-up cystoscopy for urothelial neoplasia. Urine samples were also subjected to routine cytologic analysis. Patients underwent upper urinary tract imaging and cystoscopy within 12 hours of producing the urine sample. Data were analyzed by comparing areas under a nonparametric receiver operating characteristics (ROC) curve and by McNemar's test and Fisher's exact test. All statistical tests were two-sided. RESULTS: At the assay cut point where the false-negative and false-positive rates were the same, the Mcm5 test detected primary and recurrent bladder cancers with 87% (95% confidence interval [CI] = 77% to 94%) sensitivity and 87% (95% CI = 83% to 91%) specificity. At the cut point where the specificities of urine cytology and the Mcm5 test were equal (97%, 95% CI = 95% to 99%), the Mcm5 test was statistically significantly (P<.001) more sensitive than urine cytology, 73% (95% CI = 61% to 83%) versus 48% (95% CI = 35% to 60%). At the lower detection limit of the Mcm5 test, sensitivity was highest, 92% (95% CI = 83% to 97%) and specificity was 78% (95% CI = 72% to 83%). Patients with prostate cancer had higher levels of Mcm5 in their urine sediments than did men without malignancy (P<.001). CONCLUSIONS: Elevated levels of Mcm5 in urine sediments are highly predictive of bladder cancer.

Age Factors↗