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Biomedical subjects

R Henderson

Publications and source records attributed to R Henderson.

At least 19 recordsLinked to original sources
PubMed2006

Electron imaging with Medipix2 hybrid pixel detector.

The electron imaging performance of Medipix2 is described. Medipix2 is a hybrid pixel detector composed of two layers. It has a sensor layer and a layer of readout electronics, in which each 55 microm x 55 microm pixel has upper and lower energy discrimination and MHz rate counting. The sensor layer consists of a 300 microm slab of pixellated monolithic silicon and this is bonded to the readout chip. Experimental measurement of the detective quantum efficiency, DQE(0) at 120 keV shows that it can reach approximately 85% independent of electron exposure, since the detector has zero noise, and the DQE(Nyquist) can reach approximately 35% of that expected for a perfect detector (4/pi(2)). Experimental measurement of the modulation transfer function (MTF) at Nyquist resolution for 120 keV electrons using a 60 keV lower energy threshold, yields a value that is 50% of that expected for a perfect detector (2/pi). Finally, Monte Carlo simulations of electron tracks and energy deposited in adjacent pixels have been performed and used to calculate expected values for the MTF and DQE as a function of the threshold energy. The good agreement between theory and experiment allows suggestions for further improvements to be made with confidence. The present detector is already very useful for experiments that require a high DQE at very low doses.

Computer Simulation↗
PubMed2006

Digitisation of electron microscope films: six useful tests applied to three film scanners.

A series of simple tests have been used to measure the performance of flat-bed film scanners suitable for digitisation of electron micrographs. Two of the film scanners evaluated are commercially available and one has been constructed in the laboratory paying special attention to the needs of the electron microscopist. The tests may be useful for others.

Image Processing, Computer-Assisted↗
PubMed2006

A note on testing for intervention effects on binary responses.

OBJECTIVES: In some circumstances controlled trials are not feasible and treatments can only be evaluated using clinical databases. Here we consider the situation where treatment is introduced at a particular calendar time and can only be evaluated by comparison with historical controls. In these circumstances Heuer and Abel recommended using change-point methods to search for change in characteristics over the whole study period rather than simply comparing treated and untreated patients. Their recommendation is to only conclude that the intervention had an effect if a change-point could be demonstrated close in time to the introduction of the new treatment. This reduces the risk of false positives caused by confounding changes in population characteristics or changes in patient management. For binary data we develop a method that follows their philosophy and apply it to an observational study in the treatment of pin sites after orthopaedic surgery. METHODS: Tests for change in binomial probabilities based on Brownian bridge and Hansen's approximation for maximally selected chi(2) statistics are compared to an exact test by Worsley. The approximate method is generalized to logistic regression models allowing for covariates. RESULTS: The agreement of the exact and approximate method is good for sample sizes of 100 or more. The actual test size of the Hansen approximate test allowing for covariates is close to the nominal level, whereas the Brownian bridge approximation is slightly conservative. The change in pin site treatment significantly reduces the risk of infection for both adults and children. CONCLUSIONS: We consider the Hansen approximation to provide a very good and very simple method for obtaining the p-value when testing for a change in binary data event probabilities, with or without covariates.

Adult↗
PubMed2005

Individual survival time prediction using statistical models.

Doctors' survival predictions for terminally ill patients have been shown to be inaccurate and there has been an argument for less guesswork and more use of carefully constructed statistical indices. As statisticians, the authors are less confident in the predictive value of statistical models and indices for individual survival times. This paper discusses and illustrates a variety of measures which can be used to summarise predictive information available from a statistical model. The authors argue that models and statistical indices can be useful at the group or population level, but that human survival is so uncertain that even the best statistical analysis cannot provide single-number predictions of real use for individual patients.

Carcinoma, Non-Small-Cell Lung↗
PubMed2004

Clinical effectiveness and cost-effectiveness of clopidogrel and modified-release dipyridamole in the secondary prevention of occlusive vascular events: a systematic review and economic evaluation.

OBJECTIVES: To examine the clinical effectiveness and cost-effectiveness of two alternative antiplatelet agents, clopidogrel and modified-release (MR)-dipyridamole, relative to prophylactic doses of aspirin for the secondary prevention of occlusive vascular events. DATA SOURCES: Electronic databases. REVIEW METHODS: A total of 2906 titles and abstracts were rigorously screened and 441 studies were assessed in detail. Two RCTs were identified. For the assessment of cost-effectiveness, eight reviews were identified. The results were presented in structured tables and as a narrative summary. No additional clinical effectiveness data were presented in either of two company submissions. All economic evaluations (including accompanying models) included in the company submissions were assessed. Following this analysis, if the existing models (company or published) were not sufficient, a de novo model or modified versions of the models were developed. RESULTS: In the CAPRIE trial the point estimate for the primary outcome, i.e. ischaemic stroke, myocardial infarction (MI) or vascular death, favoured clopidogrel over aspirin, but the boundaries of the confidence intervals raise the possibility that clopidogrel is not more beneficial than aspirin. In terms of the secondary outcomes reported, there was a non-significant trend in favour of clopidogrel over aspirin but the boundaries of the confidence intervals on the relative risks all crossed unity. There was no difference in the number of patients ever reporting any bleeding disorder in the clopidogrel group compared with the aspirin group. The incidences of rash and diarrhoea were statistically significantly higher in the clopidogrel group than the aspirin group. Patients in the aspirin group had a higher incidence of indigestion/nausea/vomiting than patients in the clopidogrel group. Haematological adverse events were rare in both the clopidogrel and aspirin groups. No cases of thrombotic thrombocytopenic purpura were reported in either group. Treatment with MR-dipyridamole alone did not significantly reduce the risk of any of the primary outcomes reported in ESPS-2 compared with treatment with aspirin. ASA-MR-dipyridamole was significantly more effective than aspirin alone in patients with stroke or transient ischaemic attacks (TIAs) at reducing the outcome of stroke and marginally more effective at reducing stroke and/or death. Treatment with ASA-MR-dipyridamole did not statistically significantly reduce the risk of death compared to treatment with aspirin. The number of strokes was statistically significantly reduced in the ASA-MR-dipyridamole group compared with the MR-dipyridamole group. In terms of the other primary outcomes, stroke and/or death and death, the results favoured treatment with ASA-MR-dipyridamole but the findings were not statistically significant. There was no difference in the number of bleeding complications between the ASA-MR-dipyridamole and aspirin groups. The incidence of bleeding complications was significantly lower in the MR-dipyridamole treatment group. More patients in the MR-dipyridamole treatment groups experienced headaches compared to patients receiving treatment with aspirin alone. The York model assessed the cost-effectiveness of differing combinations of treatment strategies in four patient subgroups, under a number of different scenarios. The results of the model were sensitive to the assumptions made in the alternative scenarios, in particular the impact of therapy on non-vascular deaths. CONCLUSIONS: Clopidogrel was marginally more effective than aspirin at reducing the risk of ischaemic stroke, MI or vascular death in patients with atherosclerotic vascular disease, however, it did not statistically significantly reduce the risk of vascular death or death from any cause compared with aspirin. There was no statistically significant difference in the number of bleeding complications experienced in the clopidogrel and aspirin groups. MR-dipyridamole in combination with aspirin was superior to aspirin alone at reducing the risk of stroke and marginally more effective at reducing the risk of stroke and/or death. Compared with treatment with MR-dipyridamole alone, MR-dipyridamole in combination with aspirin significantly reduced the risk of stroke. Treatment with MR-dipyridamole in combination with aspirin did not statistically significantly reduce the risk of death compared with aspirin. Compared with treatment with MR-dipyridamole alone, bleeding complications were statistically significantly higher in patients treated with aspirin and MR-dipyridamole in combination with aspirin. Due to the assumptions that have to be made, no conclusions could be drawn about the relative effectiveness of MR-dipyridamole, alone or in combination with aspirin, and clopidogrel from the adjusted indirect comparison. The following would apply for a cost of up to GBP20,000-40,000 per additional quality-adjusted life-year. For the stroke and TIA subgroups, ASA-MR-dipyridamole would be the most cost-effective therapy given a 2-year treatment duration as long as all patients were not left disabled by their initial (qualifying) stroke. For a lifetime treatment duration, ASA-MR-dipyridamole would be considered more cost-effective than aspirin as long as treatment effects on non-vascular deaths are not considered and all patients were not left disabled by their initial stroke. In patients left disabled by their initial stroke, aspirin is the most cost-effective therapy. Clopidogrel and MR-dipyridamole alone would not be considered cost-effective under any scenario. For the MI and peripheral arterial disease subgroups, clopidogrel would be considered cost-effective for a treatment duration of 2 years. For a lifetime treatment duration, clopidogrel would be considered more cost-effective than aspirin as long as treatment effects on non-vascular deaths are not considered. It is suggested that the combination of clopidogrel and aspirin should be evaluated for the secondary prevention of occlusive vascular events. Also randomised, direct comparisons of clopidogrel and MR-dipyridamole in combination with aspirin are required to inform the treatment of patients with a history of stroke and TIA, plus trials that compare treatment with clopidogrel and MR-dipyridamole for the secondary prevention of vascular events in patients who demonstrate a genuine intolerance to aspirin.

Aspirin↗
PubMed2004

Clopidogrel used in combination with aspirin compared with aspirin alone in the treatment of non-ST-segment-elevation acute coronary syndromes: a systematic review and economic evaluation.

OBJECTIVES: To review systematically the clinical effectiveness and the cost-effectiveness of clopidogrel used in combination with standard therapy including aspirin, compared with standard therapy alone for the treatment of non-ST-segment elevation acute coronary syndromes (ACS). DATA SOURCES: Electronic databases. Manufacturers' submissions. REVIEW METHODS: Studies were selected using rigorous criteria. The quality of randomised controlled trials (RCTs) was assessed according to criteria based on NHS CRD Report No. 4, and the quality of systematic reviews was assessed according to the guidelines for the Database of Reviews of Effect (DARE) criteria. The quality of economic evaluations was assessed according to a specifically tailored checklist. The clinical effectiveness and cost-effectiveness of clopidogrel in combination with standard therapy compared with standard therapy alone were synthesised through a narrative review with full tabulation of the results of the included studies. In the economic evaluations, a cost-effectiveness model was constructed using the best available evidence to determine cost-effectiveness in a UK setting. RESULTS: One RCT (the CURE trial) was a randomised, double-blind, placebo-controlled trial of high quality and showed that clopidogrel in addition to aspirin was significantly more effective than placebo plus aspirin in patients with non-ST-segment elevation ACS for the composite outcome of death from cardiovascular causes, non-fatal myocardial infarction or stroke over the 9-month treatment period. However, clopidogrel was associated with a significantly higher number of episodes of both major and minor bleeding. The results from the five systematic reviews that assessed the adverse events associated with long-term aspirin use showed that aspirin was associated with a significantly higher incidence of haemorrhagic stroke, extracranial haemorrhage and gastrointestinal haemorrhage compared with placebo. Of the cost-effectiveness evidence reviewed, only the manufacturer's submission was considered relevant from the perspective of the NHS. The review of this evidence highlighted potential limitations within the submission in its use of data and in the model structure used. These limitations led to the development of a new model with the aim of providing a more reliable estimate of the cost-effectiveness from the perspective of the UK NHS. This model indicated that clopidogrel appears cost-effective compared with standard care alone in patients with non-ST-elevation ACS as long as the NHS is willing to pay GBP6078 per quality of life year (QALY). The results were most sensitive to the inclusion of additional strategies that assessed alternative treatment durations with clopidogrel. Although treatment with clopidogrel for 12 months remained cost-effective for the overall cohort, provisional findings indicate that the shorter treatment durations may be more cost-effective in patients at low risk. CONCLUSIONS: The results of the CURE trial indicate that clopidogrel in combination with aspirin was significantly more effective than placebo combined with aspirin in a wide range of patients with ACS. This benefit was largely related to a reduction in Q-wave myocardial infarction. There was no statistically significant benefit in relation to mortality. The trial data suggested that a substantial part of the benefit derived from clopidogrel is achieved by 3 months, with a further small benefit over the remaining 9 months of chronic treatment. The results from the base-case model suggest that treatment with clopidogrel as an adjunct to standard therapy (including aspirin) for 12 months, compared with standard therapy alone, is cost-effective in non-ST elevation ACS patients as long as the health service is willing to pay GBP6078 per additional QALY. However, although treatment with clopidogrel for 12 months remained cost-effective for the overall cohort, provisional findings indicate that the shorter treatment durations may be more cost-effective in patients at low risk. To estimate the exact length of time that clopidogrel in addition to standard therapy should be prescribed for patients with non-ST-segment ACS would require a prospective trial that randomised patients to various durations of therapy. This would accurately assess whether a 'rebound' phenomenon occurs in patients if clopidogrel were stopped after 3 months of treatment.

Acute Disease↗
PubMed2004

General practitioners' concerns about childhood immunisation and suggestions for improving professional support and vaccine uptake.

In recent years childhood vaccination has been vigorously debated. Professional and parental confidence in the measles, mumps and rubella (MMR) vaccine in particular has been shaken, as reflected by its decreased uptake. A semi-structured postal questionnaire survey of general practitioners (GPs) working in the Highland region of Scotland was undertaken to assess their views on vaccination issues. A 73% response rate was achieved. Of respondents 28% expressed concerns about the possible side effects of MMR. Of GPs 98% thought it was 'likely' that the benefits of the DTP-Hib, polio and men C vaccines outweighed the possible risks. For the first and second doses of MMR 92% and 86%, respectively, believed this to be true. Approximately three quarters of GPs described themselves 'very confident' in discussing the DTP-Hib vaccine with parents, compared with 57% for MMR. Some respondents were misinformed regarding the adverse events associated with the MMR vaccine. There is professional concern about MMR. Initiatives to support GPs in promoting vaccination in order to improve immunisation rates are discussed.

Attitude of Health Personnel↗
PubMed2003

Evaluation of a hybrid pixel detector for electron microscopy.

We describe the application of a silicon hybrid pixel detector, containing 64 by 64 pixels, each 170 microm(2), in electron microscopy. The device offers improved resolution compared to CCDs along with faster and noiseless readout. Evaluation of the detector, carried out on a 120 kV electron microscope, demonstrates the potential of the device.

Electrons↗
PubMed2002

Proton translocation by bacteriorhodopsin in the absence of substantial conformational changes.

Unlike wild-type bacteriorhodopsin (BR), the BR triple mutant D96G/F171C/F219L has been shown to undergo only minor structural rearrangements during its photocycle. Nonetheless, the mutant is capable of transporting protons at a rate of 125(+/-40) H+/BR per minute under light-saturating conditions. Light adaptation of the triple mutant's retinal proceeds in a pH-dependent manner up to a maximum of 63% all-trans. These two findings imply that the transport activity of the triple mutant comprises 66% of the wild-type activity. Time-resolved spectroscopy reveals that the identity and sequence of intermediates in the photocycle of the triple mutant in the all-trans configuration correspond to that of wild-type BR. The only differences relate to a slower rise and decay of the M and O intermediates, and a significant spectral contribution from a 13-cis component. No indication for accumulation of the N intermediate is found under a variety of conditions that normally favor the formation of this species in wild-type BR. The Fourier transform infrared (FTIR) spectrum of the M intermediate in the triple mutant resembles that of wild type. Minor changes in the amide I region during the photocycle suggest that only small movements of the protein backbone occur. Electron microscopy reveals large differences in conformation between the unilluminated state of the mutant protein and wild-type but no light-induced changes in time-resolved measurements. Evidently, proton transport by the triple mutant does not require the major conformational rearrangements that occur on the same time-scale with wild-type. Thus, we conclude that large conformational changes observed in the photocycle of the wild-type and many BR mutants are not a prerequisite for the change in accessibility of the Schiff base nitrogen atom that must occur during vectorial catalysis to allow proton transport.

Archaea↗
PubMed2002

Coronary angioplasty versus medical therapy for angina. Health service costs based on the second Randomized Intervention Treatment of Angina (RITA-2) trial.

AIMS: The second Randomized Intervention Treatment of Angina (RITA-2) trial compares an initial strategy of PTCA with continued medical management in patients with arteriographically proven coronary artery disease. This paper employs resource use data collected in the trial to compare the health service costs of the two strategies over 3 years follow-up. METHODS AND RESULTS: 1018 patients were randomized, 504 to PTCA and 514 to continued medical management. Health service resource use data were collected prospectively on all patients. Hospital unit costs were estimated in collaboration with five U.K. centres. PTCA patients underwent more subsequent coronary arteriograms, but subsequent (non-randomized) PTCAs were more common in patients randomized to medical management (118 procedures in 102 patients) compared to those randomized to PTCA (73 procedures in 62 patients). The likelihood of undergoing CABG was similar in the two groups. The use of antianginal medications was higher in patients randomized to an initial strategy of medical management. There was an overall mean additional cost per patient over 3 years in patients randomized to PTCA of pound 2685 (95% CI pound 2074- pound 3322). CONCLUSIONS: In RITA-2, the cost of an initial strategy of PTCA exceeded the cost of an initial strategy of medical management by 74% over 3 years.

Angina Pectoris↗
PubMed2001

Use of surgery and electron beam irradiation, with or without chemotherapy, for treatment of vaccine-associated sarcomas in cats: 78 cases (1996-2000).

OBJECTIVE: To evaluate responses of cats with vaccine-associated sarcomas to treatment with surgery and radiotherapy, with or without adjunctive chemotherapy. DESIGN: Retrospective study. ANIMALS: 76 cats (78 tumors). PROCEDURE: Medical records were reviewed. Factors potentially associated with survival time, time to recurrence, and time to development of metastases were evaluated. RESULTS: Following excision, electron beam radiation, and, in some cases, chemotherapy, 32 (41%) cats experienced recurrence, and 9 (12%) cats developed metastases. One- and 2-year survival rates were 86 and 44%, respectively. Median survival time from onset of disease was 730 days (range, 30 to 2,014 days). Median disease-free interval was 405 days (range, 30 to 925 days). Cats that underwent only 1 surgery prior to radiotherapy had a lower recurrence rate than did cats that underwent > 1 surgery and had a significantly longer disease-free interval. Survival time and disease-free interval decreased as time between surgery and the start of radiotherapy increased. Cats that developed metastases had significantly shorter survival times and disease-free intervals than did cats that did not develop metastases. Castrated male cats had a significantly shorter survival time than did spayed female cats. Cats with larger tumors prior to the first surgery had shorter survival times. Twenty-six cats received chemotherapy in addition to surgery and radiotherapy. Whether cats received chemotherapy was not associated with recurrence rate, metastasis rate, or survival time. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggest that excision followed by electron beam irradiation may be beneficial for treatment of cats with vaccine-associated sarcomas. Extent of excision prior to radiotherapy did not seem to be associated with recurrence rate.

Animals↗
PubMed2001

Accuracy of point predictions in survival analysis.

Survival time prediction is important in many applications, particularly for patients diagnosed with terminal diseases. A measure of prediction error taken from the medical literature is advocated as a practicable method of quantifying reliability of point predictions. Optimum predictions are derived for familiar survival models and the accuracy of these predictions is investigated. We argue that poor predictive capability is inherent to standard survival models with realistic parameter values. A lung cancer example is used to illustrate difficulties in prediction in practice.

Carcinoma, Non-Small-Cell Lung↗
PubMed2001

Using DNA and hemoglobin adducts to improve the risk assessment of butadiene.

The purpose of this paper is to review what we know about various biomarkers of butadiene in animal, human and in vitro studies, and to draw inferences from these data that impact on the accurate assessment of human risks for cancer. Studies comparing the DNA and hemoglobin adducts of butadiene with exposure, metabolism and genotoxicity have provided a great deal of insight that is applicable to biologically based risk assessment. First, the DNA and hemoglobin adduct data strongly support the conclusion that 3,4-epoxy-1,2-butanediol is the major electrophile available for binding to these macromolecules. Biomarker studies have also provided insight into the possibility of a sensitive population associated with the GSTT1 null genotype. While it is clear that lymphocytes from GSTT1 null individuals are more sensitive for the induction of sister chromatid exchanges (SCE) following in vitro exposure to 1,2,3,4-diepoxybutane, there was no such increase in SCE or other biomarkers of genotoxicity in workers exposed to 1-3 p.p.m. butadiene, regardless of GST genotype. The globin adduct data also demonstrate that there is roughly a tenfold range for interindividual differences in the metabolism of butadiene. This type of analysis represents an excellent means for providing scientific data for this critical determinant. Another useful application of hemoglobin adducts in risk assessment was demonstrated by regressing data for various endpoints for genotoxicity against that individual's biologically effective dose, thereby providing an independent mechanism for evaluation that excludes any possible confounding by inappropriate controls. Finally, biomarker studies have identified critical gaps in our knowledge that are needed for the accurate assessment of butadiene. Most notable of these is the lack of diepoxide-specific biomarkers in mice, rats and humans.

Animals↗
PubMed2001

Electron crystallographic analysis of two-dimensional crystals of sensory rhodopsin II: a 6.9 A projection structure.

Sensory rhodopsins, phototaxis receptors in Haloarchaea, were purified and reconstituted into halobacterial lipids to form photoactive two-dimensional crystals. Images of vitreous ice-embedded, flattened, tubular crystals of sensory rhodopsin II (SRII) of Natronobacterium pharaonis were recorded using a field emission gun electron cryo-microscope. Fourier components for the SRII structure were determined either from the separated image transforms from single layers that formed each side of flattened tubes, or by a deconvolution procedure when two layers were stacked in register so that they generated a single crystal lattice by superposition. Most micrographs showed significant diffraction to 6.9 A after computer processing, and the results provide the first intermediate- resolution information obtained for an archaeal sensory rhodopsin. The projection structure of SRII indicates that the helix positions match the seven-helix arrangement of the archaeal transport rhodopsins rather than that of the eukaryotic visual pigments. The structural similarity of SRII to the transport rhodopsins supports models in which the transport and signalling mechanisms of archaeal rhodopsins derive from the same retinal-driven changes in protein conformation.

Animals↗
PubMed2001

The impact of ferrous ion reduction of chlorite ion on drinking water process performance.

The use of chlorine dioxide (ClO2) as a primary disinfectant and pre-oxidant in drinking water treatment is being explored as an alternative to chlorine for reducing disinfection by-product formation and to assure compliance with United States Environmental Protection Agency's Stage 1 Disinfection/ Disinfection By-Products Rule. However, the ClO2 by-product chlorite ion (ClO2-) is also regulated by the same regulation. Ferrous iron (Fe(II)) has been shown to effectively reduce chlorite ion to chloride ion (Cl-) and this study was conducted to evaluate the impact on overall treatment process performance due to the ferric hydroxide solids that form from the reaction. Ferrous iron application was explored at three different points in a pilot-scale water treatment system: pre-rapid mix. pre-settling and pre-filter. Chlorite ion concentrations were effectively reduced from 2mg/L to less than 0.3mg/L using an Fe(II) dose of approximately 6mg/L for all trials. Fe(II) addition at the rapid mix caused no adverse effects and, in fact, allowed for reduction of the alum dose due to the newly formed ferric hydroxide acting as a supplemental coagulant. An increase of 241 and 247% of total suspended solids influent to the filter process was observed when Fe(II) was applied at the pre-settling and pre-filter locations. Pilot-scale filter runs during these trials were less than 2 h and never obtained true steady state conditions. Jar testing was performed to better understand the nature of the ferric hydroxide solids that are formed when Fe(II) was oxidized to Fe(III) and to explore the effectiveness of Fe(II) addition at intermediate stages in the flocculation process.

Chlorides↗
PubMed2001

Multicenter US study of hospital resource utilization associated with cytomegalovirus-related readmission of renal and heart transplant patients.

Incidence of cytomegalovirus (CMV)-related rehospitalization and associated resource use were captured by the Transplant Infection Cost Analysis (TICA) program, which examined patient records and hospital billing data in multiple solid organ transplant centers in the US. The experiences of two adult heart and three adult renal transplant centers were each pooled for analysis. Financial data were standardized to 1998 US dollars using the Medical Care component of the US Consumer Price Index. CMV-related readmissions among renal transplant patients averaged 10.5 days (range 1-56) with average charges of $22,598. Heart transplant patients readmitted for CMV incurred an average charge of $42,111 and average hospital stay of 10.9 days (range 2-95). CMV-related hospital resource use represented a significant portion of the average cost of the original transplant and associated length of stay.

Adult↗