Validation of an algorithm to reveal the U wave in atrial fibrillation.

Major cardiac organisations recommend U wave abnormalities should be reported during ECG interpretation. However, U waves cannot be measured in patients with atrial fibrillation (AF) due to the obscuring fibrillatory wave. The aim was to validate a U wave measurement algorithm for AF patients. Multi-beat averaging was applied to ECGs of 25 patients during paroxysms of AF and the presence of U waves compared to those from the same patients during sinus rhythm (SR). In a further database of 10 long-term AF recordings, the number of beats for effective U wave extraction by the algorithm was calculated. U waves were revealed in all AF recordings and there was no significant difference between the presence of U waves in AF and SR (p = 0.88). U wave amplitude was significantly increased in AF (mean (s.d.) amplitude 55 (39) AF vs 37 (28) µV SR, p = 0.005). The presence of U waves could easily be discerned when as few as 10 beats were used in the algorithm. The study demonstrates the validity of the algorithm to reveal U waves in AF recordings. The algorithm offers the potential to detect U wave abnormalities in patients with AF.

A study on stability analysis of atrial repolarization variability using ARX model in sinus rhythm and atrial tachycardia ECGs.

BACKGROUND: The interaction between the PTa and PP interval dynamics from the surface ECG is seldom explained. Mathematical modeling of these intervals is of interest in finding the relationship between the heart rate and repolarization variability. OBJECTIVE: The goal of this paper is to assess the bounded input bounded output (BIBO) stability in PTa interval (PTaI) dynamics using autoregressive exogenous (ARX) model and to investigate the reason for causing instability in the atrial repolarization process. METHODS: Twenty-five male subjects in normal sinus rhythm (NSR) and ten male subjects experiencing atrial tachycardia (AT) were included in this study. Five minute long, modified limb lead (MLL) ECGs were recorded with an EDAN SE-1010 PC ECG system. The number of minute ECGs with unstable segments (Nus) and the frequency of premature activation (PA) (i.e. atrial activation) were counted for each ECG recording and compared between AT and NSR subjects. RESULTS: The instability in PTaI dynamics was quantified by measuring the numbers of unstable segments in ECG data for each subject. The unstable segments in the PTaI dynamics were associated with the frequency of PA. The presence of PA is not the only factor causing the instability in PTaI dynamics in NSR subjects, and it is found that the cause of instability is mainly due to the heart rate variability (HRV). CONCLUSION: The ARX model showed better prediction of PTa interval dynamics in both groups. The frequency of PA is significantly higher in AT patients than NSR subjects. A more complex model is needed to better identify and characterize healthy heart dynamics.

Professionalism, then and now.

For centuries only three professions were recognised as such: medicine, law and theology. Now that the word 'professional' is applied to all occupations it can be difficult to understand the meaning of professionalism within dentistry and healthcare. We simply cannot treat dentistry as a commodity or business when it is a highly specialised personal service. Now more than ever, dentistry is a team game and all dental professionals must maintain the values and codes that distinguish what we do from most other vocations.

Accuracy of algorithms for detection of atrial fibrillation from short duration beat interval recordings.

Atrial fibrillation (AF) is characterised by highly variable beat intervals. The aims of the study were to assess the accuracy of AF detection algorithms from short analysis durations and to validate prospectively the accuracy on a large community-based cohort of elderly subjects. Three algorithms for AF detection were evaluated: coefficient of variation (CV), mean successive difference (Δ) and coefficient of sample entropy (COSEn), using two databases of beat interval recordings: 167 recordings of 300 s duration for a range of rhythms acquired in a hospital setting and 2130 recordings of 10s duration acquired in the community. Using the longer recordings receiver operating characteristic (ROC) analysis was used to identify optimal algorithm thresholds and to evaluate analysis durations ranging from 5s to 60s. An ROC area of 93% was obtained at recording duration of 60s but remained above 90% for durations as low as 5s. Prospective analysis on the 2130 recordings gave AF detector sensitivities from 90.5% (CV and Δ) to 95.2% (COSEn), specificities from 89.3% (Δ) to 93.4% (COSEn) and accuracy from 89.3% (Δ) to 93.4% (COSEn), not significantly different to those obtained on the initial database. AF detection algorithms are effective for short analysis durations, offering the prospect of a simple and rapid diagnostic test based on beat intervals alone.

The cost of diagnosing Type 2 diabetes mellitus by clinical opportunistic screening in general practice.

AIMS: Type 2 diabetes is associated with serious complications and shortens life. Its prevalence is increasing rapidly worldwide and no cure is available. One logical response is to diagnose the condition as early as possible. Clinical opportunistic screening is one mechanism for making the diagnosis before symptoms are reported. This paper reports the cost of using this technique in UK general practice. METHODS: In one UK general practice, the electronic medical records were searched to determine the number of blood glucose and oral glucose tolerance tests undertaken for non-pregnant adults without known diabetes over three consecutive years. The laboratory, staff and administrative costs associated with these screening tests were calculated. The records of all patients newly diagnosed with Type 2 diabetes during the same period were reviewed to identify diagnoses made by clinical opportunistic screening. Total costs were divided by the number of diagnoses to determine a cost per diagnosis detected by opportunistic screening. RESULTS: During the study period, 5720 screening tests were conducted for 2763 patients. Over the 3 years, 86 patients were diagnosed with Type 2 diabetes, 54 (63%) via screening (yield 2.0%; number needed to screen 51.2). The screening costs totalled £ 20,372. The average cost per new screen-detected diagnosis was £ 377. CONCLUSIONS: Almost two-thirds of new cases of Type 2 diabetes can be detected before symptoms are reported, at reasonable cost by opportunistic screening in general practice, without the use of extra resources. As an affordable alternative to population screening, clinical opportunistic screening merits further consideration.

The prevalence, correlates and treatment of pain in the European Union.

OBJECTIVES: To report on the results of a recent large-scale, internet-based survey of the population, prevalence and attributes of pain experience in the United Kingdom (UK), France, Spain, Germany and Italy. METHODS: The results reported here are taken from the internet-based, 2008 National Health and Wellness Survey (NHWS). In addition to detailing the prevalence of pain, the survey reports on the correlates of pain - socio-demographic characteristics of respondents, health status and health related quality of life, pain associated comorbidities, satisfaction with care, employment and productivity and utilization of health care resources. In addition, the survey also captures treatment patterns, satisfaction with medications (both prescription and over the counter [OTC]) and adherence experience. RESULTS: An estimated 49.7 million persons in these five countries reported pain by both its severity and frequency in the previous month. Of these, 11.2 million reported severe pain, 29.4 million reported moderate pain and 9.0 million reported mild pain. The population prevalence of daily pain is 8.85% with 3.47% reporting severe daily pain and 4.70% moderate daily pain. The cumulative burden of pain is demonstrated in terms of HRQoL, employment status and workforce activities as well as in healthcare resource utilization. The most striking impacts are seen in the impact of severe and frequent pain on HRQoL. Of the measures employed, the impact on the physical component score (PCS) of the SF-12 and the SF-6D absolute utility scores are substantial. The presence of severe and daily pain not only reduces the PCS score against that reported for the no pain population by over 20 points (or approximately 40%) but the impact on the absolute utility score is to reduce it from a no pain average of 0.74 to a score of 0.54. As far as productivity losses to the community are concerned the impact of severe pain is equally dramatic. CONCLUSIONS: The reported prevalence of pain in these five countries represents a substantial burden to individuals, employers, healthcare systems and society in general. The fact that one in five of the adult population has experienced pain presents a major policy challenge. This would involve not only reducing the prevalence of pain - where chronic pain may be considered a disease in its own right - but to co-ordinate pain management programs across a range of disease states and socio-economic groups.

Spatial and temporal organization of the dominant frequencies in the fibrillating heart: body surface potential mapping in a rare case of sustained human ventricular fibrillation.

AIMS: The aim of this study was to assess the spatial and temporal variability of dominant fibrillation frequencies in a rare case of sustained human ventricular fibrillation (VF). METHODS AND RESULTS: Body surface potential mapping was performed in a patient with sustained VF and who was supported by a biventricular assist device. Dominant frequencies at 54 body sites were calculated from two recordings obtained 38 days apart. Variability of dominant frequencies between recordings and across body sites was quantified. Median dominant frequencies within recordings varied between 6.1 and 7.2 Hz in recording 1 and 5.6 and 6.6 Hz in recording 2, indicating a significant reduction in dominant frequencies between the recordings (P < 0.0001). Dominant frequencies differed across body sites by a mean (range) of 1.7 (0.4-2.8) Hz. CONCLUSION: In this rare case of sustained VF, there was significant spatial and temporal variability of VF dominant frequencies. These findings should be considered in future ECG studies on VF where the spatial variability of dominant frequency might not otherwise have been considered.

Transforming growth factor-beta 1, activin and follistatin in patients with hepatocellular carcinoma and patients with alcoholic cirrhosis.

BACKGROUND: Transforming growth factor-beta 1 (TGF-beta1) exerts an inhibitory effect on DNA synthesis in hepatocytes. Activin, through different mechanisms, also exhibits an apoptotic effect on hepatocytes. Follistatin antagonizes the actions of activin. METHODS: Patients with hepatocellular carcinoma (HCC, n = 20), patients with alcoholic cirrhosis (n = 12), patients with cirrhosis due to other causes (n = 5) and normal controls (n = 19) were studied. TGF-beta1, activin and follistatin concentrations in blood and ascites were measured by ELISA. RESULTS: All three groups of patients had significantly higher serum levels of total TGF-beta1, activin and follistatin compared to those of controls. In patients with HCC, the total TGF-beta1 level correlated negatively with tumour size (r = -0.644, P = 0.001). The activin level correlated with alkaline phosphatase (ALP) level (r = 0.374, P = 0.046). The follistatin level correlated with the ALP level (r = 0.404, P = 0.026), and the glutamyl transpeptidase level (r = 0.457, P = 0.01). In patients with alcoholic cirrhosis, serum activin correlated with the Child-Pugh score (r = 0.601, P = 0.01). The levels of the cytokines in ascites (n = 16) did not correlate with the corresponding levels in serum. CONCLUSIONS: Serum levels of total TGF-beta1, activin and follistatin were elevated in patients with hepatocellular carcinoma and in patients with alcoholic cirrhosis. Apoptosis of tumour cells may be reduced by a subsequent decrease in serum TGF-beta1 levels when the tumours expand in size. Activin and follistatin were associated with tumour activity, as both correlated with ALP and/or GGT levels. Further studies are required to define the exact relationships between these cytokines, the dynamics of tumour growth and their significance in cirrhosis.

Revising regulatory networks: from expression data to linear causal models.

Discovering the complex regulatory networks that govern mRNA expression is an important but difficult problem. Many current approaches use only expression data from microarrays to infer the likely network structure. However, this ignores much existing knowledge because for a given organism and system under study, a biologist may already have a partial model of gene regulation. We propose a method for revising and improving these initial models, which may be incomplete or partially incorrect, with expression data. We demonstrate our approach by revising a model of photosynthesis regulation proposed by a biologist for Cyanobacteria. Applied to wild type expression data, our system suggested several modifications consistent with biological knowledge. Applied to a mutant strain, our system correctly modified the disabled gene. Power experiments with synthetic data that indicate that reliable revision is feasible even with a small number of samples.

Expression of Fas antigen (CD95) in peripheral blood lymphocytes and in liver-infiltrating, cytotoxic lymphocytes in patients with hepatocellular carcinoma.

BACKGROUND: Fas-expressing cytotoxic T lymphocytes (CTLs) are important antitumor immune effector cells in patients with hepatocellular carcinoma (HCC). The role of transforming growth factor beta 1 (TGF-beta1) in modulating the expression of Fas by CTLs is not known in HCC. The objectives of this study were to characterize the expression of Fas by CTLs and natural killer (NK) cells among peripheral blood lymphocytes (PBLs) and tumor-infiltrating lymphocytes (TILs) in patients with HCC and to correlate the association, if any, with serum TGF-beta1 levels. METHODS: PBLs from 18 patients with HCC and TILs from 5 HCC liver specimens were isolated, and Fas expression was analyzed by three-color flow cytometry. The results were compared with results from normal control volunteers (n = 19 individuals). Serum TGF-beta1 levels in patients with HCC were measured by enzyme-linked immunosorbent assay. RESULTS: The median percentage of Fas expression by CD3 positive T cells was significantly higher in patients with HCC compared with normal controls (54.37% vs. 32.03%, respectively; P = 0.0036), and this was attributable solely to Fas expression by CD4 positive PBLs (54.46% vs. 34.90%, respectively; P = 0.0234). In contrast, Fas expression was significantly higher in all the subtypes of TILs (CD3 positive, CD4 positive, CD8 positive, NK cells, and natural T cells) compared with controls (all P values were < 0.001). Tumor size was inversely proportional to the TGF-beta1 levels (correlation coefficient [r] = -0.725; P < 0.0001), which were correlated inversely with Fas expression by CD4 positive PBLs (r = -0.516; P = 0.01). CONCLUSIONS: In patients with HCC, TILs exhibit significantly increased expression of Fas compared with PBLs that may enhance their susceptibility to apoptotic mechanisms. Larger tumors were associated with lower serum TGFbeta1 levels, and this was correlated with greater Fas expression by CD4 positive PBLs.

Effect of lead exclusion for the manual measurement of QT dispersion.

To investigate the effect of different lead exclusion criteria for the manual measurement of QT dispersion (QTd). Simultaneous 12-lead ECGs from three groups of 25 subjects were studied; healthy normal subjects, subjects with a myocardial infarction, and subjects with arrhythmias. Leads were excluded with (1) small absolute T wave amplitudes, (2) small relative T wave amplitudes, and (3) small and/or large relative QT measurements. QTd was calculated as the QT range and assessed for its ability to differentiate between the normal and pathological groups. With exclusion of no leads or low absolute amplitude T waves (< 50 microV) significant differences were observed only between normal and myocardial infarct groups (P < 0.05). Significant differences between normal and both pathological groups were observed when excluding the lead with the smallest amplitude T wave or shortest QT (P < 0.05), or when two leads of either type were excluded (P < 0.005). There was good agreement between leads excluded by amplitude or QT (P < 0.01). Lead exclusion for QTd is important. Exclusion of the two smallest amplitude or two shortest QT leads from each subject produced the greatest differences between the normal and pathological groups.

Dispersion of QT intervals: a measure of dispersion of repolarization or simply a projection effect?

QT interval dispersion may provide little information about repolarization dispersion. Some clinical measurements demonstrate an association between high QT interval dispersion and high morbidity and mortality, but what is being measured is not clear. This study was designed to help resolve this dilemma. We compared the association between different clinical measures of QT interval dispersion and the ECG lead amplitudes derived from a heart vector model of repolarization with no repolarization dispersion whatsoever. We compared our clinical QT interval dispersion data obtained from 25 subjects without cardiac disease with similar data from published studies, and correlated these QT dispersion results with the distribution of lead amplitudes derived from the projection of the heart vector onto the body surface during repolarization. Published results were available for mean relative QT intervals and mean differences from the maximum QT interval. The leads were derived from Uijen and Dower lead vector data. Using the Uijen lead vector data, the correlation between measurements of dispersion and derived lead amplitudes ranged from 0.78 to 0.99 for limb leads, and using the Dower values ranged from 0.81 to 0.94 for the precordial leads. These results show a clear association between the measured QT interval dispersion and the variation in ECG lead amplitudes derived from a simple heart vector model of repolarization with no regional information. Therefore, measured QT dispersion is related mostly to a projection effect and is not a true measure of repolarization dispersion. Our existing interpretation of QT dispersion must be reexamined, and other measurements that provide true repolarization dispersion data investigated.

Can you measure the quality of this life? Interview by Lauren M. Walker.

The value and application of quality of life measurements in evaluating health care remain difficult to determine and controversial. Can quality of life be measured in a meaningful way? Can improved quality of life be connected to productivity improvements or other cost factors? We talked to two of the liveliest (and most opinionated) researchers in the field of quality of life outcomes assessment. Paul C. Langley, PhD, is currently employed by 3M Pharmaceuticals as U.S. and international manager of health economics. Before that, he was director of the Program in Pharmaceutical Economics and Health Systems Research at the University of Colorado. Marcia A. Testa, MPH, PhD, is a senior lecturer in biostatistics at the Harvard School of Public Health and a consultant with Phase V Technologies Inc., a firm that assists health care organizations in outcomes trials. Here are their thoughts on the state of the art.

Formulary submission guidelines for Blue Cross and Blue Shield of Colorado and Nevada. Structure, application and manufacturer responsibilities.

From 1 January 1999, all requests by pharmaceutical manufacturers and others to Blue Cross and Blue Shield (BCBS) of Colorado and Nevada for the listing of new pharmaceutical products or any proposed change to the formulary status of an existing product must be accompanied by a submission which meets the informational and analytical standards set out in the BCBS Guidelines for Formulary Submissions for Pharmaceutical Product Evaluation. These submission requirements relate both to the anticipated therapeutic impact of a new product and to claims made as to its anticipated pharmacoeconomic impact. The guidelines have been developed because BCBS is concerned that decisions to admit a drug to formulary have been based in the past on incomplete information. In order to rectify this situation (and to meet quality control objectives), it has been decided that all submissions to BCBS should meet a common information standard that describes both the characteristics of the product and its expected impact in a disease or therapeutic area. Unlike guidelines that have been introduced in countries such as Australia and the Canadian Province of Ontario, these guidelines take an explicit systems approach to the case a manufacturer must make before a product is considered for formulary listing. While the notion of systems impact requirements is not new, this is the first time that a managed healthcare system in the US has adopted this explicit perspective and notified manufacturers that traditional pharmacoeconomic evaluations may not meet the information needs of drug purchasers. The purpose of this paper is to describe the BCBS formulary guidelines and to demonstrate how manufacturers are expected to meet the information needs of a systems impact perspective in submissions to the pharmacy and therapeutics committee.

Meeting the information needs of drug purchasers: the evolution of formulary submission guidelines.

The emergence of formulary submission guidelines in the 1990s has been seen by many as an attempt to come to grips with the issue of drug management within health systems and to provide, for the first time, a coherent and methodologically rigorous approach to formulary selection. Judging from the available evidence, however, guidelines have fallen far short of their potential. The purpose of this paper is to consider what role guidelines have played in health system management and whether they play a useful role in providing a methodologically sound basis for drug-impact assessment. Two polar cases in guideline development are examined: the Australian guidelines first published in 1992 and now undergoing a second major revision and the guidelines recently published by Blue Cross and Blue Shield of Colorado and Nevada. The former guidelines represent what can be described as the traditional, clinical paradigm of drug-impact assessment; the latter represent what can be called the system-impact paradigm. The argument put forward is that the Australian guidelines are essentially an anachronism, offering little to those whose principal concern is with the management of health systems. In their emphasis on a hierarchy of evidence and a clinical trial-focused, cost-effectiveness evaluation perspective, they represent a methodologic dead end in a number of important respects. The systems-based approach, on the other hand, with its emphasis on validation of claims and the need to consider a range of drug-impact and risk-management scenarios, offers an analytic framework that, while possibly less rigorous, is likely to contribute significantly to the management of health care systems.

Ultrastructural localization of unique neurosecretory granules in the corpora cardiaca of the stable fly, Stomoxys calcitrans, and the tsetse fly, Glossina morsitans.

Ultrastructural analysis of the corpora cardiaca of the stable fly, Stomoxys calcitrans, and the tsetse fly, Glossina morsitans, revealed the presence of elementary neurosecretory granules (ENG) unique to the intrinsic neurosecretory cells (INC) of these species. In addition to electron-dense spheres, the INC of the corpus species. In addition to electron-dense spheres, the INC of the corpus cardiacum of the stable fly contain electrondense angular granules, either square or rectangular in shape, while the INC of the tsetse fly contain electron-dense spindle-shaped ENG. The distinctive granules of these INC can be traced within nerves to their sites of storage and release, eliminating the need for labeling with artificial probes. Although the INC of the corpus cardiacum of most species have been found to be fuchsinophilic, neither the INC of the stable fly nor the tsetse fly are aldehyde-fuchsinophilic. These peptigenic cells offer neuroendocrinologists a unique opportunity to study the physiology and biochemistry of neurosecretory cells.

The cost effectiveness of patient-applied versus provider-administered intervention strategies for the treatment of external genital warts.

OBJECTIVE: External genital warts are one of the fastest growing sexually transmitted diseases in the United States today. Two forms of therapy are available: provider-administered and patient-applied. In the most widely used provider-administered ablative therapies, sustained clearance rates range from 18.5% to 40.1%. With nonablative, patient-applied therapies, which are typically more acceptable to patients, sustained clearance rates range from 19.6% with podofilox gel to 44.0% with imiquimod cream. The purpose of this study, given the range of therapies available, their cost differences, and clinical trial-reported differences in rates of sustained clearance, is to determine which therapy modalities, from the providers' perspective, are the most cost effective and which are likely to be the most acceptable to the patient population. STUDY DESIGN: We consider the cost effectiveness of the two patient-applied therapies as first-line therapy followed by provider-administered ablative treatment as second-line therapy. A decision-analytic model framework is developed, with data drawn both from clinical trials and from previously published studies. RESULTS: When considering a two-stage therapy model, with an average sustained clearance rate of 30% assumed for provider-administered ablative therapies, estimated costs per sustained cleared patient are $1265 for patients initially treated with imiquimod and $1304 for patients initially treated with podofilox gel. CONCLUSIONS: Initial treatment with imiquimod is the preferred intervention option as it yields a 39% greater sustained clearance rate than podofilox gel while being 3% less costly per successful outcome.