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PubMed2001

Patients' perceived problems with hypertension and attitudes towards medical treatment.

OBJECTIVE: To study perceived problems and attitudes in hypertension treatment in primary health care. STUDY POPULATION AND METHODS: A cross-sectional survey of 2219 hypertensive patients, identified by general practitioners, in 26 health centres was carried out during 1 week in 1996. A total of 1782 patients (80%) returned two questionnaires and participated in a health examination. The final study population consisted of 1561 patients currently being medically treated for hypertension and 220 patients not currently on medical treatment. The questionnaires contained 82 questions on different aspects of hypertension care and treatment, which were further elaborated using factor analysis. On the basis of reliability and internal validity analyses, 14 problem indices related to medical treatment of hypertension were formed. RESULTS: The most common perceived problem was related to lack of motivation for follow-up of hypertension (72%). Many patients had difficulties to accept being hypertensive (66%). A careless attitude towards hypertension was also common (63%). Lack of information was experienced by 56% of the patients. About 33% felt hopeless about their hypertension, reported adverse effects of hypertension treatment on sexual functions and lack of support by health care personnel. The least frequent problems were reimbursement problems and modification of dosage instructions. The number of problems identified per person varied between zero and 14 with a mean of 4.9 +/- 2.6 (s.d.). CONCLUSION: Perceived problems concerning hypertension, negative attitudes and experiences are very common among hypertensive patients in primary health care.

Age Factors↗

PubMed2005

Characterization of vinblastine-induced Bcl-xL and Bcl-2 phosphorylation: evidence for a novel protein kinase and a coordinated phosphorylation/dephosphorylation cycle associated with apoptosis induction.

Bcl-xL and Bcl-2 are phosphorylated in response to microtubule inhibitors, but the kinase(s) responsible and the functional significance have remained unclear. In this study, we investigated the characteristics of Bcl-xL and Bcl-2 phosphorylation in KB-3 carcinoma cells treated with vinblastine. In both asynchronous and synchronous cell cultures, Bcl-xL and Bcl-2 underwent a well-defined and coordinated cycle of phosphorylation and dephosphorylation, with a lengthy period of phosphorylation preceding apoptosis induction, and with dephosphorylation closely correlated with initiation of apoptosis. Internally, validated inhibitors of JNK, ERK, p38(MAPK), or CDK1 failed to inhibit vinblastine-induced phosphorylation of Bcl-xL or Bcl-2. In vitro, Bcl-xL and Bcl-2 were poor substrates relative to c-Jun and ATF2 for active recombinant JNK1. Both Bcl-xL and Bcl-2 were localized primarily to the mitochondrial fraction in both control and vinblastine-treated cells, indicating that phosphorylation did not promote subcellular redistribution. Bcl-xL kinase activity was demonstrated in mitochondrial extracts from vinblastine-treated, but not control, cells. These findings suggest that phosphorylation of these key antiapoptotic proteins may be catalysed by a novel or unsuspected kinase that is activated or induced in response to microtubule damage. Furthermore, the same kinase and phosphatase system may be operating in tandem on both proteins, and phosphorylation appears to maintain their antiapoptotic function, whereas dephosphorylation may trigger apoptosis. These results provide evidence for a novel signaling pathway connecting microtubule damage to apoptosis induction, and help to clarify some of the controversy concerning the role of Bcl-2 phosphorylation in microtubule inhibitor-induced apoptosis.

Antineoplastic Agents, Phytogenic↗

PubMed2001

Measurement of near zero concentration: recording and reporting results that fall close to or below the detection limit.

Issues relating to the recording and reporting of analytical data obtained where the concentration of analyte is around or below the detection limit are discussed. The following recommendations are proposed. Analytical results should be recorded by the analyst exactly as they occur, including any negative results, and such records retained for an appropriate length of time. For the purposes of quality assurance in the laboratory (including method validation, internal quality control, and proficiency testing), negative results should be used as they stand. Analytical results reported to a customer should be accompanied by a statement of uncertainty including, in the present context, uncertainty at low concentrations of analyte. The method of editing of reported results must be a contractual matter between the analyst and the customer, but a statement of the procedure used should accompany the results and should be explicit. Normally such editing should be restricted to setting negative results to zero. The customer should be encouraged to pass on the statement to all end users. Data intended for the public domain should be accompanied by a statement detailing the uncertainty, the method of editing, and the location of the unedited data. Most types of statistical processing of datasets containing low concentrations of analyte should be undertaken on the unedited data.

Journal Article↗

PubMed2003

Determination of total sulfur in diesel fuel employing NIR spectroscopy and multivariate calibration.

A method for sulfur determination in diesel fuel employing near infrared spectroscopy, variable selection and multivariate calibration is described. The performances of principal component regression (PCR) and partial least square (PLS) chemometric methods were compared with those shown by multiple linear regression (MLR), performed after variable selection based on the genetic algorithm (GA) or the successive projection algorithm (SPA). Ninety seven diesel samples were divided into three sets (41 for calibration, 30 for internal validation and 26 for external validation), each of them covering the full range of sulfur concentrations (from 0.07 to 0.33% w/w). Transflectance measurements were performed from 850 to 1800 nm. Although principal component analysis identified the presence of three groups, PLS, PCR and MLR provided models whose predicting capabilities were independent of the diesel type. Calibration with PLS and PCR employing all the 454 wavelengths provided root mean square errors of prediction (RMSEP) of 0.036% and 0.043% for the validation set, respectively. The use of GA and SPA for variable selection provided calibration models based on 19 and 9 wavelengths, with a RMSEP of 0.031% (PLS-GA), 0.022% (MLR-SPA) and 0.034% (MLR-GA). As the ASTM 4294 method allows a reproducibility of 0.05%, it can be concluded that a method based on NIR spectroscopy and multivariate calibration can be employed for the determination of sulfur in diesel fuels. Furthermore, the selection of variables can provide more robust calibration models and SPA provided more parsimonious models than GA.

Journal Article↗

PubMed2004

Assessment of the relative in vivo potency of the hydroxylated metabolite of darifenacin in its ability to decrease salivary flow using pooled population pharmacokinetic-pharmacodynamic data.

AIMS: To describe the population pharmacokinetic-pharmacodynamic relationship between darifenacin (UK-88,525) and its hydroxylated metabolite (UK-148,993), and the reduction in salivary flow (SF, a M3-mediated response). This enabled an estimation of the in vivo potency of the metabolite to decrease SF relative to that of the parent drug. METHODS: A total of 262 individuals were pooled from 11 Phase 1 studies and one Phase 2 study. A comparison was made between a series of pharmacodynamic models (direct-effect, indirect-effect, link and binding model) using NONMEM. RESULTS: The binding model yielded the best description of the decrease in SF by fully accounting for the time course of the pharmacodynamic effect. An internal validation exercise demonstrated the robustness of this model. Covariate analysis identified a circadian rhythm in SF. This model, with confidence intervals (CI) determined by likelihood profiling, indicated that the relative potency of the metabolite to darifenacin to reduce SF was 11.1% (95% CI 3.8, 19.6). This implied that the metabolite was ninefold less potent than darifenacin in vivo. Accounting for the unbound fraction of darifenacin (2%) and its metabolite (13%), the in vivo protein binding-corrected relative potency was estimated to be 2.1%, indicating that the metabolite was 50-fold less potent than the parent drug. The model supported the assumption that no other metabolites contributing to the impairment of the SF were formed during first-pass, and that the development of sensitization or tolerance was not evident over time. The validation process indicated that the i.v.-oral crossover study was necessary for the estimation of the relative potency. CONCLUSIONS: Population modelling of darifenacin and its hydroxylated metabolite yielded individual pharmacokinetic predictions that could be used to assess the in vivo potency of the metabolite to decrease SF relative to that of the parent drug. The metabolite had a negligible effect on SF.

Adolescent↗

PubMed1994

Teaching behaviours of clinical instructors: an audit instrument.

This article describes the development and initial psychometric testing of an instrument that permits the observation and recording of teaching behaviours exhibited by clinical instructors while supervising nursing students. Observations of Nursing Teachers in Clinical Settings (ONTICS) consists of 44 items grouped into nine categories of desirable and undesirable teaching behaviours: questioning method; responding style; method of giving feedback; teaching skill; method of demonstration; interaction with patient/family; interactions with health team; undesirable teaching behaviours; undesirable questioning/responding method. The instrument was refined on several occasions based on input from expert judges. Construction validity, internal consistency reliability and test-retest reliability were found to be acceptable. ONTICS appears to capture an aspect of clinical teaching not readily identified by other, more subjective, instruments.

Clinical Competence↗

PubMed1999

A new learning environment: combining clinical research with quality improvement.

The emphasis provided by quality improvement strategies on performance measurement and evaluation often results in our understanding of processes of care and, perhaps, better outcomes. There are different references for process evaluation: external peers, regional profiles of performance or a trending of one's own performance patterns. This paper proposes a methodology that enables learning from the daily practice of medicine by comparing alternative care processes and outcomes. Since it is estimated that 15-20% of medical practices are based on rigorous scientific data establishing their effectiveness, we have much to learn. We propose to learn from our daily practice by combining clinical research methods with quality improvement tools. The products comprise modified clinical trial and case-control studies. In a modified clinical trial, we would use a practice guideline as a control group and modify the guideline to create an experimental group. This method would maintain the internal validity of efficacy research while maintaining the external validity of effectiveness research. In the case-control method, it is possible to quantitate risk for a given outcome and focus improvement effort on factors associated with that outcome. We believe physicians will accept this learning approach because it is a more valid learning method than traditional quality improvement and, unlike randomized clinical trials, learning will occur in the daily practice of medicine.

Case-Control Studies↗

PubMed2001

An illustrated guide to the methods of meta-analysis.

Meta-analysis is now accepted as a necessary tool for the evaluation of health care. Such analyses have been carried out in virtually every area of medicine to evaluate a wide spectrum of health care interventions and policies. This paper has three broad aims: (1) to describe the basic principles of meta-analysis, using a meta-analysis of interventions intended to reduce hospital re-admission rates for illustration; (2) to consider threats to the internal validity of meta-analysis, and the measures which can be taken to minimize their impact; and (3) to present an overview of more specialist and developing methods for synthesizing data, with the intention of outlining the directions meta-analysis may take in the future. The methods used to synthesize studies, which take 'weighted averages' of effect sizes have been refined to a high degree, while the methods for dealing with threats to the validity of meta-analyses such as publication bias, and variations in quality of the primary studies, are at a less advanced stage. However, many consider this standard 'weighted average' approach to meta-analysis not to be 'state of the art' in at least some situations, where the use of more sophisticated methods, generally to explain variation in estimates from different studies and synthesize a broader base of evidence, would be advantageous. Currently, approaches which attempt to do this are mainly still in the experimental stage and, unfortunately, ideas which sound natural and appealing are often difficult to implement in practice. Clearly, it will be some time before they are used routinely, but significant steps have been made.

Bayes Theorem↗

PubMed2002

Children with intellectual disability in rural South Africa: prevalence and associated disability.

The objective of the present study was to determine the prevalence of intellectual disability (ID) and its associated disabilities in rural South African children aged 2-9 years. It was undertaken in eight villages in the district of Bushbuckridge, Northern Province, South Africa. A two-phase design was utilized. The first phase involved screening children on a house-to-house basis by interviewing mothers or caregivers using an internationally validated questionnaire for detecting childhood disability in developing countries. The second phase consisted of a paediatric/neurodevelopmental assessment of the children who screened positive. A total of 6692 children were screened; 722 (10.8%) had a paediatric evaluation and 238 children were diagnosed with ID, giving a minimum observed prevalence of 35.6 per 1000 children in this population. The prevalence of severe and mild ID was 0.64 per 1000 and 29.1 per 1000 children, respectively. The male:female ratio of children with ID was 3:2. In the affected children, a congenital aetiology for the ID was determined in 49 subjects (20.6%), an acquired aetiology in 15 (6.3%) and the aetiology was undetermined in 174 children (73.1%). Epilepsy (15.5%) and cerebral palsy (8.4%) were the commonest associated disabilities. The present study represents the first data on the prevalence of ID and associated disabilities in rural South African children. The prevalence of ID was comparable with results from a study performed in one other African country (Zambia) as well as those from other developing countries. The data provide an initial factual insight into ID and its associated disabilities for healthcare, social service and educational policy planners. This study provides a basis for the initiation and development of appropriate and integrated services for the best possible care of individuals affected with these disabilities, and for their possible prevention.

Child↗

PubMed2000

Seroepidemiology of human plague in the Madagascar highlands.

We conducted a seroepidemiological survey of human plague in the general population using random sampling in the area of Ambositra, the main focus of plague in the central highlands of Madagascar (520 confirmed and presumptive cases notified during the past 10 years). Sera were tested using an ELISA IgG F1 assay. Considering the internal validity of the assay and the sampling method, the overall corrected prevalence of F1 antibodies was 0.6% (95% CI: 0.2%-1.8%). Being nearly 0 up to the age of 40, the corrected prevalence increased markedly after 45 years to 6.2%. Six of 20 individuals who declared to have been treated for clinical suspicion of bubonic plague in the past had F1 antibodies. The seroprevalence did not differ according to gender except in individuals > 60, where antibodies were significantly more frequent in males. This study suggests that the number of clinically suspected cases of plague provided by the surveillance network was plausible, despite some true cases being missed and a significant number of false positives. We also confirm that Yersinia pestis infections may occur without marked clinical manifestations and patients may recover without treatment, in accordance with old observations of pestis minor.

Adolescent↗

PubMed2003

Improving the evidence-base in surgery: evaluating surgical effectiveness.

This second of two articles about clinical epidemiology reviews the generation and synthesis of evidence for the effectiveness of surgical procedures. While well-designed randomized controlled trials of surgical procedures are considered the 'gold standard' of evaluation design, they may achieve high internal validity at the expense of external validity (generalizability). Improving the -evidence-base in surgery likely will require a comprehensive approach to surgical outcomes assessment, involving both improvements in the quality and quantity of randomized controlled trials as well as recognition of the complementary role of alternate study designs.

Algorithms↗

PubMed2000

Conservative treatment of urge urinary incontinence in women: a systematic review of randomized clinical trials.

OBJECTIVE: To assess the efficacy of physical therapies for first-line use in the treatment of urge urinary incontinence (UUI) in women, using a systematic review of randomized clinical trials (RCTs). MATERIALS AND METHODS: A computer-aided and manual search was carried out for RCTs published between 1980 and 1999 investigating the treatment of UUI defined by the keywords 'physical therapies', e.g. bladder (re)training (including 'behavioural' treatment), pelvic floor muscle (PFM) exercises, with or without biofeedback and/or electrical stimulation. The methodological quality of the included trials was assessed using methodological criteria, based on generally accepted principles of interventional research. RESULTS: Fifteen RCTs were identified; the methodological quality of the studies was moderate, with a median (range) score of 6 (3-8.5) (maximum possible 10). Eight RCTs were considered of sufficient quality, i.e. an internal validity score of >/= 5.5 points on a scale of 0-10, and were included in a further analysis. Based on levels-of-evidence criteria, there is weak evidence to suggest that bladder (re)training is more effective than no treatment (controls), and that bladder (re)training is better than drug therapy. Stimulation types and parameters in the studies of electrical stimulation were heterogeneous. There is insufficient evidence that electrical stimulation is more effective than sham electrical simulation. To date there are too few studies to evaluate effects of PFM exercise with or without biofeedback, and of toilet training for women with UUI. CONCLUSION: Although almost all studies included reported positive results in favour of physical therapies for the treatment of UUI, more research of high methodological quality is required to evaluate the effects of each method in the range of physical therapies.

Behavior Therapy↗

PubMedDate not supplied

Economic evaluations relating to diabetes: a descriptive review and their compliance with guidance.

From a search of the Health Economics Evaluations Database (HEED), 301 studies relating to diabetes-related interventions were identified. Of these, 223 studies contained some original data, i.e., were applied studies. Over the 1990s, the number of studies undertaken in this area appears to be increasing year on year, and more of the studies are applicable to the USA than to all other countries combined. Most studies are peer reviewed, the main type of analysis is cost-consequence, and the interventions most often assessed are pharmaceutical and care services. Both the public and the private sectors sponsor many of these studies. However, only a fraction of these studies appear to accord with guidance for good economic evaluation. For example, when the search criteria were tightened to capture only those studies that consider both outcomes and costs, 173 studies were identified. Narrowing the search criteria to capture only those studies that were based on randomized controlled trial (RCT) or modeling data-the methods recommended by the US Panel and the National Institute of Clinical Excellence (NICE)-reduced the sample to 56 studies. With specific focus on those studies that evaluated pharmaceuticals, only the modeling approach appeared to show any compliance at all with another key recommendation of the existing guidance on methods; that of using outcome measures that are applicable to a long-term time horizon. Though modeling does offer certain advantages over RCTs (for example, a larger range of comparators can be more readily incorporated, long-term outcome measures can be more easily and inexpensively estimated), modeling results have less internal validity. Also, modeling in itself relies on good RCT data. Therefore, the results of economic evaluations should be interpreted with care, irrespective of whether they are principally based on RCT or model-based methods.

Diabetes Mellitus, Type 2↗

PubMedDate not supplied

Medication compliance feedback and monitoring in a clinical trial: predictors and outcomes.

OBJECTIVE: The objective of this study was to demonstrate the utility of continuous monitoring and enhancement of medication compliance during a long-term clinical trial, predictors of compliance, and relationships to drinking outcomes. METHODS: Alcohol-dependent patients enrolled in a multicenter VA cooperative study were randomly assigned to once-daily naltrexone (NTX) for 3 or 12 months (short-term or long-term NTX) or placebo for 12 months of treatment. All medications were dispensed in bottles with medication event monitoring (MEMS, AARDEX, Union City, CA) caps with a microprocessor that recorded openings as presumptive doses. Patients were trained to develop personal cues as dosing reminders. Monthly feedback sessions included review of compliance data and cues. RESULTS: There were no significant differences among short-term NTX, long-term NTX, and placebo (209 each) groups in measures of compliance. Overall compliance rates were 71% +/- 31% of doses for the first 13 weeks and 43% +/- 33% of doses over 52 weeks. Some doses were taken during 83% +/- 27% of the first 13 weeks. Higher medication compliance predicted fewer drinks per drinking day (P = .02) throughout follow-up and a lower percentage of drinking days (P = .002 during the first 13 weeks) with no significant effect for treatment group. CONCLUSIONS: The feedback and monitoring programs were important features to demonstrate that lack of treatment effect was not a result of poor compliance. Medication compliance data supported the internal validity of the trial by demonstrating that good compliers had better outcomes, irrespective of treatment with NTX or placebo. The MEMS feedback methodology is feasible for use in multicenter trials.

Alcoholism↗

PubMed2006

New screening test to predict the potential impact of ivermectin-contaminated cattle dung on dung beetles.

According to European Union recommendations, a test method has been developed to evaluate the effects of veterinary pharmaceuticals on dung feeding insects. This test method was evaluated with the dung beetle Aphodius constans by using fecal residues of ivermectin after a pour-on administration. Dung of different age (and thus containing different concentrations of ivermectin) as well as mixtures of highly-contaminated spiked dung with untreated control dung were studied in five test runs in two laboratories. The concentration of ivermectin (active substance; a.s.) in the dung samples was verified analytically. The main test endpoint was the survival of first instar larvae. The LC50 using dung directly obtained from treated cattle ranged from 470 to 692 microg a.s. kg(-1) dung (dry weight; d.w.) and 67 to 97 microg a.s. kg(-1) dung (fresh weight; f.w.). Using mixtures, the outcome of two tests was almost identical: 770 to 781 microg a.s. kg(-1) dung (d.w.); 109 to 132 microg a.s. kg(-1) dung (f.w.). In comparison to the LC50 values obtained when ivermectin was spiked in control dung at several concentrations (LC50 880-985 microg a.s. kg(-1) dung (d.w.)), the LC50 values were again very similar. Three conclusions can be drawn from these results. The proposed test method seems to be robust and allows for the initiation of an international validation process (including ringtesting). Because of only small differences found in tests in which the test substance was spiked into control dung and those in which dung from treated cattle was applied, the use of a standard test method is proposed. The effects of ivermectin on ecologically relevant dung beetles obtained in a standardised test method reflect the results from field studies and are in the range of environmentally relevant concentrations.

Animals↗

PubMed2002

Race: predictor versus proxy variable? Outcomes after spinal cord injury.

OBJECTIVE: To examine the impact of race on acute, rehabilitation, and long-term outcomes after spinal cord injury (SCI). DESIGN: Two case control studies (study 1: acute and rehabilitation outcomes, study 2: long-term outcomes) in which white and nonwhite individuals were matched case for case on multiple demographic, medical, and geographic characteristics with the rationale being that a case-control methodology would increase the internal validity of the design, thereby increasing confidence in the assertion that any between-group differences observed may be specifically attributed to race. SETTING: Data drawn from the Spinal Cord Injury Model Systems. Institutional practice and general community. PARTICIPANTS: Study 1: 187 pairs of individuals, study 2: 158 pairs of matched individuals. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Outcome measures assessed included economic (eg, cost of care), treatment-related (eg, length of hospital stay), functional (eg, FIM instrument), and medical (eg, number of medical complications) variables, as well as self-reported life satisfaction, level of handicap, and mental and physical health. RESULTS: In study 1, none of the outcome measures differed significantly across racial groups. Similarly, study 2 failed to indicate significant differences in any of the outcome variables across racial groups, with the exception that nonwhites were at increased risk of greater self-reported handicap in the area of mobility. Power analyses indicated these finding were not merely the result of inadequate power. CONCLUSION: For the outcomes assessed in studies 1 and 2, race appeared to act primarily as a proxy for other variables (eg, injury severity, age, educational achievement), which in turn may be associated with poor outcome after SCI. Theoretical implications and recommendations are discussed.

Activities of Daily Living↗

PubMed2005

The application of special technologies in diagnostic anatomic pathology: is it consistent with the principles of evidence-based medicine?

Proponents of evidence-based medicine (EBM) have emphasized the need to consider the quality of different sources of medical information and have proposed various methods to integrate available "best evidence" into rules, guidelines and other diagnostic, therapeutic and prognostic models. The various factors that can affect the internal validity of studies in anatomic pathology, such as interobserver variability, use of retrospective rather than prospective data and others, are reviewed. The need for testing for the external validity of the results of anatomic pathology studies is introduced, using "test sets" of cases that have not been used to generate the classification or prognostic models. This methodology has been seldom used in anatomic pathology to validate the generalizability of various "entities," usefulness of diagnostic tests under different conditions and other information. Basic concepts of meta-analysis for research synthesis are introduced; these methods have been seldom used in anatomic pathology to integrate information from different studies using quantitative techniques rather than summary tables that merely list the results of various publications. The potential use of decision analysis and value of information analysis for the adoption of new tests is briefly discussed.

Data Interpretation, Statistical↗

PubMed2002

The before/after study design in transfusion medicine: methodologic considerations.

To ascertain the effectiveness of an intervention, a randomized controlled trial (RCT) is considered the gold standard. An obstacle to conducting an RCT only rarely discussed is the universal implementation of an intervention. Universal implementation clearly precludes the feasibility of conducting an RCT. Thus, the most attractive alternative study design in such instances becomes the before/after study. This article describes important methodologic considerations in undertaking a before/after evaluation. The methodologic considerations to be discussed are (1) threats to internal validity, (2) precision and (3) generalizability. Two before/after studies evaluating the potential effectiveness of universal leukoreduction serve as examples. Because of the universal application of many transfusion interventions, one has to consider carefully the methodologic rigor as to which of these interventions are evaluated. We have outlined the major methodologic issues one must consider when undertaking a before/after study design. When properly conceived, conducted, and analyzed, such a before/after study design can yield informative associations.

Adult↗