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Biomedical subjects

C Bartlett

Publications and source records attributed to C Bartlett.

At least 19 recordsLinked to original sources
PubMed2005

The causes and effects of socio-demographic exclusions from clinical trials.

OBJECTIVES: To investigate the exclusion from trials of women, older people and minority ethnic groups, focusing on two drug exemplars, statins and non-steroidal anti-inflammatory drugs (NSAIDs). DATA SOURCES: Medical and ethical databases. Workshops with stakeholders. REVIEW METHODS: Literature was reviewed on exclusions in healthcare research and three workshops were held with stakeholders. Twenty-seven randomised controlled trials (RCTs) of statins use for secondary prevention of coronary heart disease (CHD) and 25 NSAIDs trials for pain in osteoarthritis (OA) were analysed. Using a Scottish cohort with record-linkage, profiling was carried out for 3188 people needing secondary prevention for CHD (1993-1996), ascertaining the independent effects of statins, and 131,410 people dispensed NSAIDs (1989-1996), examining adverse effects. Routine data sources were accessed to profile the need for secondary prevention of CHD in England and usage was estimated by consulting published surveys. The Somerset and Avon Survey of Health (SASH) 1996-97 and published data were accessed for information on potential need and usage of NSAIDs in OA. For both drugs, the socio-demographic profiles of trial samples, the population in potential need and those on treatment were compared. An evidence synthesis was produced to clarify the effects of statins on women and older people and the relationship of absolute effectiveness outcomes with underlying risk levels of disease events was modelled, examining the likely effects of trial exclusions. RESULTS: The average age of statins trial participants was 58.5 years; only 16.3% were women. Statins reduced cardiovascular disease (CVD) incidence by about 25% in both men and women. Older people up to 75 years of age also benefited. Meta-analysis and two landmark trials confirmed these results. The average age of NSAIDs trial participants was 61.9 years and women were well represented (68.5%). Gastrointestinal (GI) adverse events were commonly reported, but renal side-effects were not. Outcomes were seldom reported according to socio-demographic group. For both drugs, USA trials were more inclusive than UK/European trials. Ethnicity was not well reported for either drug. Some 23% of the cohort were treated with statins. Users were younger than non-statins users (but no more likely to be male) and had superior outcomes. High current exposure to NSAIDs elevated the risk of GI side-effects by about 50% versus no current exposure and renal impairment risk by nearly 140%. Side-effect risk increased with age; being female diminished risk. Approximately 537,000 incident cases of CVD would qualify for statins use in England each year. Women constitute 45% of this population with need, two-thirds of whom are aged 65 years or over. Need varies by ethnic group. No sex bias in prescribing statins was detected, but use was commoner in younger people. For NSAIDs, 6.3% of adults aged 35+ years reported hip and/or knee pain associated with OA; 3.9% of adults used prescribed analgesics for this and they were more likely to be women and to be >65 years old. For statins, women formed almost half of the 'with need' and 'on treatment' populations, but were markedly under-represented in trials. Those aged 65+ years formed nearly two-thirds of the 'with need' population, but only one-fifth of trial samples, and were less likely to be treated than younger subjects. For NSAIDs, women formed similar proportions. Associations of side-effects with socio-demographic factors was revealed in cohort data but not in trials. CONCLUSIONS: The issue of exclusion from trials of women, older people and ethnic minorities has been relatively neglected in the UK research community, and there is confusion about diversity issues. Under-representation occurs, but in drug trials at least this may not always affect the external validity of relative effect estimates. However, measures of absolute effectiveness, absolute harm and cost-effectiveness are associated with underlying risk levels in different socio-demographic groups. Under-representation will therefore bias absolute effect estimates. The following areas are suggested for future research: multi-disciplinary assessment of realistic options for trialists to address the issue of exclusions; clarification of the use of ethnic categories in health research and of the implications of the different dimensions of ageing and sex/gender; identification of barriers and facilitators to the involvement of different population groups in research, further investigation of the susceptibility of older men to NSAID adverse events, and the development of a 'register of registries and databases' and exploration of how linked health information systems in the UK could be improved.

Adult↗
PubMed2004

Advice to reduce dietary salt for prevention of cardiovascular disease.

BACKGROUND: Restricting sodium intake in elevated blood pressure over short periods of time reduces blood pressure. Long term effects (on mortality, morbidity or blood pressure) of advice to reduce salt in patients with elevated or normal blood pressure are unclear. OBJECTIVES: To assess in adults the long term effects (mortality, cardiovascular events, blood pressure, quality of life, weight, urinary sodium excretion, other nutrients and use of anti-hypertensive medications) of advice to restrict dietary sodium using all relevant randomised controlled trials. SEARCH STRATEGY: The Cochrane Library, MEDLINE, EMBASE, bibliographies of included studies and related systematic reviews were searched for unconfounded randomised trials in healthy adults aiming to reduce sodium intake over at least 6 months. Attempts were made to trace unpublished or missed studies and authors of all included trials were contacted. There were no language restrictions. SELECTION CRITERIA: Inclusion decisions were independently duplicated and based on the following criteria: 1) randomisation was adequate; 2) there was a usual or control diet group; 3) the intervention aimed to reduce sodium intake; 4) the intervention was not multifactorial; 5) the participants were not children, acutely ill, pregnant or institutionalised; 6) follow-up was at least 26 weeks; 7) data on any of the outcomes of interest were available. DATA COLLECTION AND ANALYSIS: Decisions on validity and data extraction were made independently by two reviewers, disagreements were resolved by discussion or if necessary by a third reviewer. Random effects meta-analysis, sub-grouping, sensitivity analysis and meta-regression were performed. MAIN RESULTS: Three trials in normotensives (n=2326), five in untreated hypertensives (n=387) and three in treated hypertensives (n=801) were included, with follow up from six months to seven years. The large, high quality (and therefore most informative) studies used intensive behavioural interventions. Deaths and cardiovascular events were inconsistently defined and reported; only 17 deaths equally distributed between intervention and control groups occurred. Systolic and diastolic blood pressures were reduced at 13 to 60 months in those given low sodium advice as compared with controls (systolic by 1.1 mm Hg, 95% CI 1.8 to 0.4, diastolic by 0.6 mm hg, 95% CI 1.5 to -0.3), as was urinary 24 hour sodium excretion (by 35.5 mmol/ 24 hours, 95% CI 47.2 to 23.9). Degree of reduction in sodium intake and change in blood pressure were not related. People on anti-hypertensive medications were able to stop their medication more often on a reduced sodium diet as compared with controls, while maintaining similar blood pressure control. REVIEWER'S CONCLUSIONS: Intensive interventions, unsuited to primary care or population prevention programmes, provide only minimal reductions in blood pressure during long-term trials. Further evaluations to assess effects on morbidity and mortality outcomes are needed for populations as a whole and for patients with elevated blood pressure. Evidence from a large and small trial showed that a low sodium diet helps in maintenance of lower blood pressure following withdrawal of antihypertensives. If this is confirmed, with no increase in cardiovascular events, then targeting of comprehensive dietary and behavioural programmes in patients with elevated blood pressure requiring drug treatment would be justified.

Antihypertensive Agents↗
PubMed2003

Reduced dietary salt for prevention of cardiovascular disease.

BACKGROUND: Restricting sodium intake in elevated blood pressure over short periods of time reduces blood pressure. Long term effects (on mortality, morbidity or blood pressure) of advice to reduce salt in patients with elevated or normal blood pressure are unclear. OBJECTIVES: To assess in adults the long term effects (mortality, cardiovascular events, blood pressure, quality of life, weight, urinary sodium excretion, other nutrients and use of anti-hypertensive medications) of advice to restrict dietary sodium using all relevant randomised controlled trials. SEARCH STRATEGY: The Cochrane Library, MEDLINE, EMBASE, bibliographies of included studies and related systematic reviews were searched for unconfounded randomised trials in healthy adults aiming to reduce sodium intake over at least 6 months. Attempts were made to trace unpublished or missed studies and authors of all included trials were contacted. There were no language restrictions. SELECTION CRITERIA: Inclusion decisions were independently duplicated and based on the following criteria: 1) randomisation was adequate; 2) there was a usual or control diet group; 3) the intervention aimed to reduce sodium intake; 4) the intervention was not multifactorial; 5) the participants were not children, acutely ill, pregnant or institutionalised; 6) follow-up was at least 26 weeks; 7) data on any of the outcomes of interest were available. DATA COLLECTION AND ANALYSIS: Decisions on validity and data extraction were made independently by two reviewers, disagreements were resolved by discussion or if necessary by a third reviewer. Random effects meta-analysis, sub-grouping, sensitivity analysis and meta-regression were performed. MAIN RESULTS: Three trials in normotensives (n=2326), five in untreated hypertensives (n=387) and three in treated hypertensives (n=801) were included, with follow up from six months to seven years. The large, high quality (and therefore most informative) studies used intensive behavioural interventions. Deaths and cardiovascular events were inconsistently defined and reported; only 17 deaths equally distributed between intervention and control groups occurred. Systolic and diastolic blood pressures were reduced at 13 to 60 months in those given low sodium advice as compared with controls (systolic by 1.1 mm Hg, 95% CI 1.8 to 0.4, diastolic by 0.6 mm hg, 95% CI 1.5 to -0.3), as was urinary 24 hour sodium excretion (by 35.5 mmol/ 24 hours, 95% CI 47.2 to 23.9). Degree of reduction in sodium intake and change in blood pressure were not related. People on anti-hypertensive medications were able to stop their medication more often on a reduced sodium diet as compared with controls, while maintaining similar blood pressure control. REVIEWER'S CONCLUSIONS: Intensive interventions, unsuited to primary care or population prevention programmes, provide only minimal reductions in blood pressure during long-term trials. Further evaluations to assess effects on morbidity and mortality outcomes are needed for populations as a whole and for patients with elevated blood pressure. Evidence from a large and small trial showed that a low sodium diet helps in maintenance of lower blood pressure following withdrawal of antihypertensives. If this is confirmed, with no increase in cardiovascular events, then targeting of comprehensive dietary and behavioural programmes in patients with elevated blood pressure requiring drug treatment would be justified.

Antihypertensive Agents↗
PubMed2003

PSA-NCAM is up-regulated during optic nerve regeneration in lizard but not in goldfish.

The addition of polysialic acid (PSA) to neural cell adhesion molecule (NCAM) facilitates axon growth. Here we use Western blots and immunohistochemistry to examine expression of PSA-NCAM during optic nerve regeneration. In lizard, retinal ganglion cell axons become transiently PSA-NCAM positive. By contrast, goldfish RGC axons are PSA-NCAM negative both in normal animals and throughout regeneration with the exception of a PSA-NCAM-positive fascicle arising from newly generated RGCs. Transient sialylation of NCAM in lizard may assist regeneration in the nonpermissive reptilian visual pathway and facilitate the reestablishment of a crude topographic map; down-regulation in the long term may contribute to the breakdown in topography. The lack of sialylation in goldfish presumably reflects the permissive nature of the substrate allowing axon regeneration and the successful reestablishment of a topographic map.

Animals↗
PubMed2002

Development and use of a population based injury surveillance system: the all Wales Injury Surveillance System (AWISS).

This report details the development and use of a population based emergency room surveillance system in the UK. Despite some difficulties in accessing high quality data the system has stimulated a considerable number of research and intervention projects. While surveillance systems with high quality data collection and coding parameters remain the gold standard, imperfect systems, particularly if population based, can play a substantial part in stimulating injury prevention initiatives.

Accident Prevention↗
PubMed2001

A novel phosphotyrosine mimetic 4'-carboxymethyloxy-3'-phosphonophenylalanine (Cpp): exploitation in the design of nonpeptide inhibitors of pp60(Src) SH2 domain.

The novel phosphotyrosine (pTyr) mimetic 4'-carboxymethyloxy-3'-phosphonophenylalanine (Cpp) has been designed and incorporated into a series of nonpeptide inhibitors of the SH2 domain of pp60(c-Src) (Src) tyrosine kinase. A 2.2 A X-ray crystal structure of 1a bound to a mutant form of Lck SH2 domain provides insight regarding the structure-activity relationships and supports the design concept of this new pTyr mimetic.

Animals↗
PubMed2001

Value of flow diagrams in reports of randomized controlled trials.

CONTEXT: Diagrams of the flow of participants through a clinical trial are recommended in the Consolidated Standards for Reporting of Trials (CONSORT) statement, but it is unclear whether such flow diagrams improve the quality of trial reports. OBJECTIVE: To examine the information contributed by flow diagrams and the completeness of reporting overall in reports of randomized controlled trials (RCTs) published in 5 general and internal medicine journals. DESIGN AND SETTING: Analysis of 270 reports of RCTs published in 1998 in the Annals of Internal Medicine (AIM; n = 19), BMJ (n = 42), JAMA (n = 45), The Lancet (n = 81), and The New England Journal of Medicine (NEJM; n = 83). MAIN OUTCOME MEASURES: Proportion of reports that included a flow diagram, information provided in flow diagrams, and completeness of reporting about flow of participants overall in flow diagrams or text. RESULTS: A total of 139 reports (51.5%) of RCTs included a flow diagram, but this varied widely among journals (AIM, 21.0%; BMJ, 38.1%; JAMA, 80.0%; The Lancet, 93.8%; and NEJM, 8.4%). Diagrams generally provided useful information, but only 73 (52.5%) included the number of participants who received allocated interventions and only 32 (23.0%) included the number of participants included in the analysis. In logistic regression analysis, overall completeness of reporting about flow of study participants was associated with publication of a flow diagram. CONCLUSIONS: Flow diagrams are associated with improved quality of reporting of randomized controlled trials. However, the structure of current flow diagrams is less than ideal. We propose a revised flow diagram that includes all important counts through the stages of parallel group trials.

Algorithms↗
PubMed2001

Bone-targeted Src SH2 inhibitors block Src cellular activity and osteoclast-mediated resorption.

Src, a nonreceptor tyrosine kinase, is an important regulator of osteoclast-mediated resorption. We have investigated whether compounds that bind to the Src SH2 domain inhibit Src activity in cells and decrease osteoclast-mediated resorption. Compounds were examined for binding to the Src SH2 domain in vitro using a fluorescence polarization binding assay. Experiments were carried out with compounds demonstrating in vitro binding activity (nmol/L range) to determine if they inhibit Src SH2 binding and Src function in cells, demonstrate blockade of Src signaling, and lack cellular toxicity. Cell-based assays included: (1) a mammalian two-hybrid assay; (2) morphological reversion and growth inhibition of cSrcY527F-transformed cells; and (3) inhibition of cortactin phosphorylation in csk-/- cells. The Src SH2 binding compounds inhibit Src activity in all three of these mechanism-based assays. The compounds described were synthesized to contain nonhydrolyzable phosphotyrosine mimics that bind to bone. These compounds were further tested and found to inhibit rabbit osteoclast-mediated resorption of dentine. These results indicate that compounds that bind to the Src SH2 domain can inhibit Src activity in cells and inhibit osteoclast-mediated resorption.

Actins↗
PubMed2001

Familial aggregation in specific language impairment.

A case-control family study design, in which the current language-related abilities of all biological, primary relatives (mother, father, siblings) of probands with specific language impairment (SLI) and matched controls were assessed, was used to investigate familial aggregation for language disorders. Current test data from each family member showed the rate of language impairment for mothers, fathers, sisters, and brothers of the SLI probands to be significantly higher than for members of control families. Impairment rates for fathers and mothers were approximately equal, whereas rates for brothers were significantly higher than for sisters. In SLI proband families, Language Impairment (LI) occurred in 13.0% of offspring (excluding proband) with neither parent affected, 40% of offspring with one parent affected, and 71.4% of offspring in families in which both parents were language impaired. Rates of impairment as determined in current testing were compared directly to impairment rates estimated from family-history questionnaires collected from the same families. Group data showed impairment rates estimated from the family-history questionnaires to be similar to the rates based on actual testing. Furthermore, both appeared in line with rates based primarily on questionnaire data as reported previously in the literature. However, case-by-case analyses showed poor intrasubject agreement on classification as language impaired on the basis of current testing as compared to history information.

Adolescent↗
PubMed2001

Optimizing erythropoietin therapy in hemodialysis patients.

The European Best Practice Guidelines for the management of anemia in patients with chronic renal failure recommend the percentage of hypochromic red blood cells (%HRCs) as the best measure of iron use by erythropoietic tissues. They suggest that "sufficient iron should be administered to attain: serum ferritin 100 ng/mL, HRCs <10%. In practice, to achieve these minimum criteria will mean aiming for optimal levels of serum ferritin 200-500 ng/mL, HRCs <2.5%." We increased prospectively the delivered dose of iron supplements to a large (n = 228) unselected hemodialysis cohort with a sustained (24-month) hemoglobin (Hb) outcome meeting the UK Renal Association minimum standard of 85%, greater than or equal to 10.0 g/dL. This was managed through a computer-aided decision support system for erythropoietin (EPO) and intravenous iron sucrose therapy. Hb outcome was maintained with medians between 11.3 and 11.8 g/dL. Median red blood cell hypochromia (%HRCs) decreased from 8% (interquartile range [IQR], 3 to 15) to 4% (IQR, 2 to 8; P < 0.001, U-Mann Whitney test). Serum ferritin level increased from a median of 188 (IQR, 115 to 256) to 480 ng/mL (IQR, 397 to 595; P < 0.001, U-Mann Whitney test). Median EPO dose decreased from 136 (IQR, 83 to 216) to 72 IU/kg/wk (IQR, 33 to 134), which strongly correlated with median %HRCs through the range less than 10% (Spearman's correlation, 0.73; P < 0.01). These data suggest that EPO responsiveness continues to improve toward the normal range for %HRCs (<2.5%) and aspiring to values much less than 10% is cost-effective. The ferritin outcome required to achieve these lower values for %HRC outcome is greater than the current recommended range, although in steady state, the mean iron treatment dose is similar to that in previous studies (ie, approximately 60 mg/wk).

Anemia↗
PubMed2001

Intravenous iron for CAPD populations: proactive or reactive strategies?

BACKGROUND: The European best practice guideline [Nephrol Dial Transplant 1999; 14 (Suppl 5)] (5A) for the management of anaemia suggests that > 85% of the CAPD population should have a haemoglobin level of > 11.0 g/dl. METHODS: We developed and implemented an outpatient-based protocol for intravenous iron sucrose (IV Fe) and erythropoietin (Epo) in CAPD patients showing iron deficiency despite oral iron therapy. We managed a total of 103 patients over 13 months of study. All CAPD patients were included, regardless of co-morbidity. Treatment developed in two phases: in phase 1 (reactive) (months 1-8), patients with markers of iron deficiency (ferritin < 100 ng/ml or ferritin 100-500 and percentage hypochromic red cells (%HRC) > or =5) were converted from oral iron to IV Fe (300 mg) and reviewed after 4-8 weeks according to haemoglobin (Hb). In phase 2 (proactive) (months 9-13), the criteria for iron therapy were extended: ferritin < 150 ng/ml or ferritin 150-500 and %HRC > or = 2. Patients then received IV Fe (200 mg) and were reviewed after 4 weeks according to Hb. RESULTS: The median haemoglobin increased from 11.0 (Inter quartile range, IQR, 10.1-12.6) g/dl to 11.7 (11.0-12.7) g/dl (P = 0.06). The proportion of patients with absolute iron deficiency (ferritin < 100 ng/ml) decreased from 24 to 2%. The percentage of hypochromic red cells (%HRC) decreased from 4 (2-7) to 1 (1-4) (P < 0.01). CONCLUSIONS: An integrated Epo and IV Fe policy increased the number of patients reaching the European guideline from 50 to 75% with no increase in the population median Epo requirements (42 (IQR, 25-95) IU/kg/week vs 45 (27-101) (P = NS)). This study demonstrates the benefit of early (proactive) intervention in achieving population compliance within current guidelines for renal anaemia.

Anemia, Hypochromic↗
PubMed2000

Structure-based design of an osteoclast-selective, nonpeptide src homology 2 inhibitor with in vivo antiresorptive activity.

Targeted disruption of the pp60(src) (Src) gene has implicated this tyrosine kinase in osteoclast-mediated bone resorption and as a therapeutic target for the treatment of osteoporosis and other bone-related diseases. Herein we describe the discovery of a nonpeptide inhibitor (AP22408) of Src that demonstrates in vivo antiresorptive activity. Based on a cocrystal structure of the noncatalytic Src homology 2 (SH2) domain of Src complexed with citrate [in the phosphotyrosine (pTyr) binding pocket], we designed 3',4'-diphosphonophenylalanine (Dpp) as a pTyr mimic. In addition to its design to bind Src SH2, the Dpp moiety exhibits bone-targeting properties that confer osteoclast selectivity, hence minimizing possible undesired effects on other cells that have Src-dependent activities. The chemical structure AP22408 also illustrates a bicyclic template to replace the post-pTyr sequence of cognate Src SH2 phosphopeptides such as Ac-pTyr-Glu-Glu-Ile (1). An x-ray structure of AP22408 complexed with Lck (S164C) SH2 confirmed molecular interactions of both the Dpp and bicyclic template of AP22408 as predicted from molecular modeling. Relative to the cognate phosphopeptide, AP22408 exhibits significantly increased Src SH2 binding affinity (IC(50) = 0.30 microM for AP22408 and 5.5 microM for 1). Furthermore, AP22408 inhibits rabbit osteoclast-mediated resorption of dentine in a cellular assay, exhibits bone-targeting properties based on a hydroxyapatite adsorption assay, and demonstrates in vivo antiresorptive activity in a parathyroid hormone-induced rat model.

Adsorption↗
PubMed2000

A Src SH2 selective binding compound inhibits osteoclast-mediated resorption.

BACKGROUND: The observations that Src(-/-) mice develop osteopetrosis and Src family tyrosine kinase inhibitors decrease osteoclast-mediated resorption of bone have implicated Src in the regulation of osteoclast-resorptive activity. We have designed and synthesized a compound, AP22161, that binds selectively to the Src SH2 domain and demonstrated that it inhibits Src-dependent cellular activity and inhibits osteoclast-mediated resorption. RESULTS: AP22161 was designed to bind selectively to the Src SH2 domain by targeting a cysteine residue within the highly conserved phosphotyrosine-binding pocket. AP22161 was tested in vitro for binding to SH2 domains and was found to bind selectively and with high affinity to the Src SH2 domain. AP22161 was further tested in mechanism-based cellular assays and found to block Src SH2 binding to peptide ligands, inhibit Src-dependent cellular activity and diminish osteoclast resorptive activity. CONCLUSIONS: These results indicate that a compound that selectively inhibits Src SH2 binding can be used to inhibit osteoclast resorption. Furthermore, AP22161 has the potential to be further developed for treating osteoporosis.

Amino Acid Sequence↗