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Variations in histopathological evaluation of non-neoplastic colonic mucosal abnormalities; assessment and clinical significance.

The variation between three pathologists examining histological features seen in non-neoplastic colonic mucosa from 40 biopsies was analysed. Several procedures to express observer variation were used and compared, with emphasis on kappa statistics. Only five features, the presence of ulceration, villous surface, epithelioid granulomas, severe mucus depletion and crypt abscesses were sufficiently reproducible by the three pairs of pathologists. These findings suggest that other criteria used for the classification of inflammatory bowel disease are potentially unsatisfactory. When results from different studies on biopsies are being compared, influence of observer variation should be identified. Comparison of statistical techniques showed overall variation to be less useful than other statistical procedures. There was little difference between results from kappa statistics and other measures of agreement (overall agreement excluded).

Biopsy↗

Deconvolving sequence variation in mixed DNA populations.

We present an original approach to identifying sequence variants in a mixed DNA population from sequence trace data. The heart of the method is based on parsimony: given a wildtype DNA sequence, a set of observed variations at each position collected from sequencing data, and a complete catalog of all possible mutations, determine the smallest set of mutations from the catalog that could fully explain the observed variations. The algorithmic complexity of the problem is analyzed for several classes of mutations, including block substitutions, single-range deletions, and single-range insertions. The reconstruction problem is shown to be NP-complete for single-range insertions and deletions, while for block substitutions, single character insertion, and single character deletion mutations, polynomial time algorithms are provided. Once a minimum set of mutations compatible with the observed sequence is found, the relative frequency of those mutations is recovered by solving a system of linear equations. Simulation results show the algorithm successfully deconvolving mutations in p53 known to cause cancer. An extension of the algorithm is proposed as a new method of high throughput screening for single nucleotide polymorphisms by multiplexing DNA.

Algorithms↗

[Radiculo-medullary arteries of vertebral origin. Various anatomic aspects from 30 injections-dissections].

Among medullary arteries we have only examined those directly arising from the vertebral artery at the cervical level. This study is about thirty anatomical samples of cervical spine removed during necropsies; there are treated by injection-dissection method. The observed variations do not allow isolation of any artery for the cervical bulge, as possible most frequently at the lumbar bulge level. We observed variations as sometimes alternate pedicles right or left, as sometimes a symmetrical aspect finishing at the same medullar level. By injecting differently colored liquids, in the right and in the left, a side prevalence has sometimes been noted but real conclusions cannot be draw without isobar and simultaneous injections.

Adult↗

Sources of measurement variation in blood pressure in large-scale epidemiological surveys with follow-up.

The Copenhagen City Heart Study (CCHS) is a longitudinal epidemiological study of 19698 subjects followed up since 1976. Variation in blood pressure (BP) measurement in the first three CCHS surveys is evaluated by assessing two components, systematic variation and random variation [daytime and seasonally variation, observer bias, non-response bias, variation with explanatory variables, such as diabetes, hypertension, body mass index (BMI), height, plasma cholesterol and smoking] for the purpose of identifying relevant errors in population surveys. BP was measured in the seated position after a 5 min rest, with the cuff around the non-dominating arm, in accordance with recommended guidelines. The participation rate fell from 74% in survey 1 to 63% in survey 3. Significant non-response bias with respect to BP values was not found. No daytime variability was noted either in systolic (SBP) or diastolic (DBP) BPs. A trend towards a lower BP was seen during the summertime. Random variation, expressed as the standard deviation of the measured values, increased with increasing BP values (SBP: 11.9-13.4 to 21.2-25.1 mmHg; DBP: 10.6-11.2 to 11.9-13.4 mmHg). SBP was positively correlated to BMI and plasma cholesterol. SBP was 5-10 mmHg higher in diabetics (p = 0.000-0.04) than in age- and sex-matched non-diabetics. DBP did not differ between the two groups. Smokers from the age of 50 years had a 2-4 mmHg lower SBP (p = 0.000-0.01) and 1-3 mmHg lower DBP (p = 0.000-0.005) than had non-smokers. In addition, significantly fewer smokers took antihypertensive medication than did non-smokers (p = 0.000). In conclusion, judging from the degree of association with BP and/or differences between the three surveys, the most important factors to consider were seasonal variation, BMI, the use of antihypertensive drug therapy, plasma cholesterol, smoking status and diabetes. An inter-survey comparison of BP in population cohorts requires controlling for these factors.

Adult↗

Variation in cadaveric organ donor rates in the UK.

BACKGROUND: Considerable variation exists in the organ donation rate between kidney retrieval areas (KRAs) within the UK. The causes for this are unknown. This study examines whether or not observed variations are correlated with various possible explanatory factors. METHODS: A geographical study involving Poisson regression analysis was carried out of all 21 KRAs in the UK in 1999 and 2000, with donor rate as dependent variable, and the following independent variables: road traffic accident, intracerebral haemorrhage and other trauma death rates; intensive care unit (ICU) bed numbers; co-location of transplant and neurosurgical units; population ethnicity; proportion of the population on the organ donor register; transplant coordinator numbers; and transplant unit numbers. Main outcome measures were: donor rate in each KRA; strength of association between independent and dependent variables; and magnitude of changes in the donor rate associated with changes in independent variables. RESULTS: The donor rate varied between eight and 27.4 donors per million population per year. There was an association between donor rate and general ICU bed numbers (more beds associated with a higher donor rate), but this was of borderline statistical significance (P = 0.065). However, the donor rate was negatively associated (P = 0.02) with neurosurgical ICU bed numbers (more beds, fewer donors) and the proportion of the population from minority ethnic communities. There was no statistically significant association with the other independent variables. CONCLUSIONS: There is significant variation in the organ donor rate between different parts of the UK. More research is needed to explore the counter-intuitive association between neurosurgical ICU beds and donations, and to determine the remaining causes of the observed variation.

Adolescent↗

Role of uptake in gamma-aminobutyric acid (GABA)-mediated responses in guinea pig hippocampal neurons.

Intracellular recordings were obtained from hippocampal pyramidal neurons maintained in vitro. Measurements were made of the conductance change induced by iontophoretically applied gamma-aminobutyric acid (GABA) and, using voltage-clamp techniques, of inhibitory postsynaptic currents resulting from activation of inhibitory pathways. Analysis of GABA iontophoretic charge-response curves indicated that there was considerable variation among neurons with respect to the slope of this relation. The placement of the GABA-containing pipette did not appear to be responsible for the observed variation, since vertical repositioning of the pipette did not alter the slope of the charge-response relationship. Steady iontophoresis of GABA from one barrel of a double-barreled pipette markedly affected the charge-response relation obtained when short pulses were applied to the other barrel. The curve was shifted to the left, and the slope was decreased. Concomitantly, the enhanced GABA-induced responses were prolonged. Similar alterations in GABA responsiveness were observed when the uptake blocker, nipecotic acid, was iontophoretically applied. Furthermore, bath application of saline containing a reduced sodium concentration (25% of control) also produced a prolongation of GABA-mediated responses. Under voltage clamp, inhibitory postsynaptic currents were observed to have biphasic decays. The initial, fast decay was prolonged by an average of 18% by nipecotic acid, whereas the later, slow phase was prolonged by 23%. The results of these studies support the hypothesis that a saturable GABA uptake system is responsible for the observed variation in the charge-response curves and, in turn, underlies the apparent sensitizing effect of excess GABA application. The results also suggest that a reduction of transmitter uptake affects the time course of inhibitory postsynaptic currents in the hippocampus.

Animals↗

Precision of dual photon absorptiometry measurements: comparison of three different methods of selection of the region of interest.

To determine the short-term reproducibility of bone mass calculations with dual photon absorptiometry of the lumbar spine (L2-L4), duplicate measurements in healthy subjects were used. Three different methods for selection of region of interest were compared: a rectangular region with variable height and width, an irregular region to be drawn freely by the operator and the standard calculation software supplied with the bone densitometer. Contributions of changes in size and location of the region of interest on calculated bone mineral mass were also investigated. An increase in height of the region by 2 scan lines caused an increase in bone mineral content (BMC) of 8.4% +/- 1.8%. Enlargement in width by 2 pixels in each scan line caused an increase in BMC of 2.5% +/- 1.3%. The difference between these region of interest changes was significant (P less than 0.0005). The use of a rectangular region, optimized to enclose L2-L4 in each person but of the same size in both measurements, resulted in a reproducibility of 1.4% and 0.7% respectively for 2 observers, with an inter observer variation of 1.2%. The reproducibility of the duplicate measurements was worse for the other methods of region of interest selection. A further series of duplicate DPA measurements in normal subjects, but with a standard meal between the measurements, showed a larger variation in the results. Again the reproducibility of the calculations using the rectangular region was better than with the other methods, with much less inter observer variation.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

The hit and miss of ISS and TRISS. Yorkshire Trauma Audit Group.

OBJECTIVE: To measure interobserver variation in recording injury from case notes and its effect on calculating injury severity scores (ISS) from identical data and predicting probabilities of survival by using the combined trauma and injury severity score (TRISS). DESIGN: Observer variation study using injury severity scoring and subsequent calculation of probability of survival based on combined trauma and injury severity scores. SUBJECTS: 16 patients with a range of injury severity scores, and 15 observers. RESULTS: There was a wide variation in recorded injury severity scores, the probability of two observers agreeing on the score being 0.28 (28%). The probability of any two observers agreeing over which severity band the patient should be in was 0.5 (50%). Observer variation was independent of the training and type of observer. Survival probability (calculated by combined trauma and injury severity scoring methodology from individual observers' scores) varied by over 0.2 in six of the 16 patients and by over 0.5 in three. CONCLUSIONS: There is wide observer variation in injury severity scoring, which highlights a potential fallibility in its use for trauma audit. The use of combined trauma and injury severity scoring for individual prediction of survival is potentially inaccurate except at the extremes of probabilities. The use of the 0.5 survival line on a combined trauma and injury severity score "pre-chart" is statistically and clinically inappropriate.

Emergency Service, Hospital↗

The appearance of retinopathy and progression to proliferative retinopathy: the WHO Multinational Study of Vascular Disease in Diabetes.

AIMS/HYPOTHESIS: We aimed to estimate incidences of any retinopathy and proliferative diabetic retinopathy (PDR) by direct ophthalmoscopy and relate them to baseline risk factors in re-examined diabetic survivors from 10 centres of the WHO Multinational Study of Vascular Disease in Diabetes. METHODS: After a mean follow-up of 8.4years (11.7 years in Oklahoma), 2877 (71.6%) survivors were resubmitted to standardised direct ophthalmoscopy as at baseline. The presence of any retinopathy and PDR were recorded at each centre and their incidence estimated in those without retinopathy and PDR at baseline. The independent associations of these incidences with baseline risk factors are expressed as odds ratios derived from multiple logistic regression analyses, within individual centres (which included fasting plasma glucose in 8 and triglyceride in 5) and in pooled data. RESULTS: Of the 4662 original patients, 465 (10.4%) of those without and 77 (43.0%) of those with baseline PDR had died (p < 0.001). Any retinopathy was newly reported at follow-up in 47.7 % and PDR in 9.7 % of those free of them at baseline, with reported incidences varying substantially among centres. Incident retinopathy appeared earlier in the known course of diabetes but incidence rates rose more slowly with duration in patients with Type II (non-insulin-dependent) diabetes mellitus than in those with Type I (insulin-dependent) diabetes mellitus. In pooled data and in some individual centres, any retinopathy incidence gave significantly positive odds ratios with age, diabetes duration, systolic pressure, plasma cholesterol, BMI, insulin treatment and proteinuria, and with fasting plasma glucose in the centres where it was measured. Positive odds ratios for PDR were similarly obtained for age, duration, insulin treatment, cholesterol, proteinuria and fasting glycaemia. Smoking status odds ratios were negative for both outcomes. CONCLUSION/INTERPRETATION: Incidence of ophthalmoscopically ascertained any retinopathy varied about twofold and of PDR about threefold among centres. Although, in part attributable to differences between observers, variation in incidence in all centres and in some cases within centres was associated with a number of baseline risk factors. Such associations are not likely due to observer variation or selection biases and emerged despite the imprecision of clinical ophthalmoscopy. Improved detection and control of these risk factors should reduce the impact of diabetic retinopathy and its consequences.

Age Factors↗

Prognostic factors in whiplash-associated disorders.

Whiplash-associated disorders (WADs) have become an increasing problem over the years and many authors have addressed the issue. The aim of the present study is to identify predictors for perceived disability and self-registered pain from a functional perspective, as well as to study the temporal evolution of patients' complaints. Eighty-three patients suffering from pain in the neck following acute whiplash injury were included in the study and they were consecutively monitored at three weeks, three months and one year after injury. The results suggest that a linear combination of sex, self-efficacy and WAD grade significantly explains 24% of the variation observed in pain intensity at the one-year follow-up, whereas a linear combination of self-efficacy, sex and age significantly explains 36% of the variation observed in disability at the one-year follow-up. Five per cent of the patients were non-symptomatic at the first monitoring occasion and 16% at the one-year follow-up. It is concluded that WAD patients' self-efficacy at an early stage after whiplash injury significantly predicts the temporal development of pain intensity and disability. It may therefore be suggested that patients' confidence in performing daily activities should be reinforced in order to optimize treatment after whiplash injury.

Adolescent↗

Assessment of bone mineral content and bone mass by non-invasive radiologic methods.

Methods for quantitative determination of bone mineral and bone mass in normal subjects and in patients with metabolic bone disorders can be measured by the Compton scattering technique, the neutron activation analysis, by measurement of metacarpal bone mass, by single and dual photon absorptiometry, and by quantitative computed tomography. Measurement on metacarpal bone (radiogrammetry) seems to be able to distinguish between resorption and/or new bone formation at the periosteal and/or endosteal surface. The intraindividual observer variation on combined cortical thickness (D-d), cortical area (D2-d2), metacarpal bone mass (D2-d2)/D2-varies from 0.7 to 2.5 per cent and the interindividual observer variation from 1.0 to 5.8 per cent. Single photon absorptiometry measures bone mineral content in the forearm with great precision. The reproducibility using repeated measurements and automatic selection of the measuring area is about one per cent and can be used to follow changes in mineral content with time in patients with metabolic bone diseases. The dual photon absorptiometry may be used for measurements of bone mineral content in lumbar spine, in the femoral neck and measurement of total body calcium with an accuracy of less than 6 per cent and a precision below 3 per cent. Quantitative computed tomography has the ability to measure trabecular and cortical bone both centrally and peripherally. Using CT scanning, scanner related changes with time (day-to-day variation +/- 4%), patient repositioning (less than 1.5%), and fat concentration (residual uncertainty of approximately 1/6 of the biologic variation) are important factors influencing the accuracy and reproducibility of the values of the measured bone mineral content.(ABSTRACT TRUNCATED AT 250 WORDS)

Bone Diseases, Metabolic↗

The effects of blood flow and detoxification on in vivo cholinesterase inhibition by soman in rats.

The in vivo time course of cholinesterase inhibition was measured in brain, lung, spleen, hind limb skeletal muscle, diaphragm, intestine, kidney, heart, liver, and plasma of rats receiving 90 micrograms/kg soman, im. This dose of soman produced severe respiratory depression and transient hypertension, but no significant changes in the cardiac output or heart rate of anesthetized rats. The rate and maximal extent of in vivo cholinesterase inhibition by soman varied widely among the tissues. Although cardiac output was unchanged by soman administration, the blood flow in heart, brain, and lung (bronchial arterial flow and arteriovenous shunts) was increased, whereas blood flow in spleen, kidney, and skeletal muscle was decreased. The relative importance of tissue blood flow, tissue levels of cholinesterase and acetylcholinesterase, and tissue levels of soman-detoxifying enzymes (diisopropyl-fluorophosphatase and carboxylesterase) in determining the in vivo rate and maximal extent of cholinesterase inhibition was examined by multiple regression analysis. The best multiple regression model for the maximal extent of cholinesterase inhibition could explain only 63% of the observed variation. The best multiple regression model for the in vivo rate of cholinesterase inhibition contained three independent variables (blood flow, carboxylesterase, and cholinesterase) and could account for 94% of the observed variation. Of these three variables blood flow was the most important, accounting for 79% of the variation in the in vivo rate of cholinesterase inhibition. This suggests that it may be possible to use a flow-limited physiological pharmacokinetic model to describe the kinetics of in vivo cholinesterase inhibition by soman.

Acetylcholinesterase↗

Angiogenesis in breast cancer: a comparative study of the observer variability of methods for determining microvessel density.

The purpose of this study was to evaluate the reliability of different methods for estimating neovascularization in breast cancer and to compare them in terms of observer variability. The microvessel endothelium was stained immunohistochemically by antibodies against CD34. The investigated methods included Chalkley counting, estimation of intratumoral microvessel density (MVD) by one hot-spot, MVD by the mean value of three hot-spots, and the highest value of MVD in three hot-spots. In addition, we applied stereology in the quantification of angiogenesis in the whole tumor section by random and systematically distributed sampling fields. Each of forty tumors was measured with all methods, twice by the same observer and once by another observer. Observer variation was analyzed by orthogonal regression, estimating the slope and intercepts with 95% confidence intervals (CI), and by analysis of agreement using difference plots. Intraobservationally, the methods had variations of the same magnitude (coefficient of variation [CV] approximately 20%). Interobservationally, the stereologic estimate of vessel profiles, Q(A), from the whole tumor section and the Chalkley counting method had the lowest variation (CV approximately 21%), with a small contribution by observers alone (CV 8% to 9%). Interobservationally, the MVD methods had considerable variation with a large contribution by observers alone (CV approximately 30%), which was lowest using the mean of three hot-spots. Correlation slope and 95% CI of Chalkley were 1.18 (0.95, 1.48), CV 20%; slope of MVD (mean) was 1.14 (0.91, 1.43), CV 31%; and slope of MVD (max) was 1.15 (0.92, 1.45), CV 36%. The slope of MVD on one hot-spot was 1.33 (1.08, 1.63); CV 38%. Additional measurements performed using a conference microscope, eliminating subjectivity in hot-spot selection and field sampling, optimized the reproducibility: slope was 1.02 (0.99, 1.04); CV of differences, 3.5%. On the other hand, reproducibility was not necessarily optimized by choosing the same hot-spot area, because variation in selecting a microscopic field could yield different counting numbers. The stereologic estimation of QA based on the whole tumor section had a high reproducibility, with low variation due to observers. The Chalkley and MVD methods had moderate reproducibility, and the Chalkley method had low variation due to observers alone. For all methods, the biologic variation among patients was the major contributor to the total variation. The Chalkley and MVD methods have been published to provide significant prognostic estimates in breast cancer, but the Chalkley method has less observer variation and may be superior from a methodologic point of view.

Antigens, CD↗

Variation in GP referral rates: what can we learn from the literature?

BACKGROUND: Variations in referral rates exist, at GP and practice level. Although the National Institute for Clinical Excellence is to produce referral guidelines, it is unclear if this variation requires regulation. A critical review of the literature on variation in referral rates was undertaken to see if existing evidence could inform the debate. OBJECTIVES: The aim of this study was to describe the variation in referral rates; to identify likely explanatory variables; and to describe the effect of GPs' decision making on the referral process. METHODS: Six bibliographic databases, the Cochrane Library, the NHS Centre for Reviews and Dissemination, and the National Research Register were searched. RESULTS: Patient characteristics explain <40% of the observed variation; practice and GP characteristics <10%. The availability of specialist care does affect referral rates, but its influence on the observed variation of referral rates is not known. Intrinsic psychological variables are important. GPs who are less tolerant of uncertainty or who perceive serious disease to be a more frequent event may refer more patients. There is a lack of consensus about what constitutes an appropriate referral, and the use of guidelines has had only limited success in altering referral behaviour. CONCLUSIONS: Variation in referral rates remains largely unexplained. Targeting high or low referrers through clinical guidelines may not be the issue. Rather, activity should concentrate on increasing the number of appropriate referrals, regardless of the referral rate. Pressure on GPs to review their referral behaviour through the use of guidelines may reduce their willingness to tolerate uncertainty and manage problems in primary care, resulting in an increase in referrals to secondary care. The use of referral rates to stimulate dialogue and joint working between primary and secondary care may be more appropriate.

Decision Making↗

[Genetic demographic study of Zulia State, Venezuela, by isonymy].

The genetic structure of Zulia State, Venezuela, was studied through the distribution of surnames from individuals above 40 years of age, obtained from the register of electors. The sample studied consisted in 440, 190 individuals and 10,423 different surnames. For each of the 81 counties of the State, the following estimators were calculated: percentage of the population included in surnames which appear only once (estimator A), percentage of the population included in the seven most frequent surnames (estimator B), the coefficient of consanguinity due to random isonymy phi ii, and Karlin and McGregort's ni (v), an estimator of migration. The correlation between phi ii and B was 0.92, indicating that 85% of the variation observed in the coefficient of consanguinity due to random isonymy is due to the seven most frequent surnames. The correlation between A and ni was 0.93, so that 86% of the variation observed in ni, is due to surnames which appear only once. On the other hand, correlations between A and B, and between phi ii and v were non significant (-0.08 and -0.17 respectively), meaning that they are measuring different features of population structure: B and phi ii, isolation, while A and v, migration. The most isolated counties of Zulia are localized towards the northwestern portion of the State, within the Venezuelan Guajira, although relative isolation is also observed in the southern counties. Isolation by distance is estimated through the correlation between the logarithmic transformations of Euclidean and geographic distances, giving a value of 0.63. This high value might be partially due to the barrier effect of the Lake of Maracaibo. Eight surnames with a focal distribution within Zulia were identified: Almarza, Badell, Bastidas, Bohórquez, Cardozo, Carmona, Espina and Matos. Carriers of these surnames have a high probability of having their origin at the counties where they are localized.

Adult↗

[Genetic structure of the population of Guarico, Venezuela, studied through isonymy].

The genetic structure of the State of Guárico, Venezuela, was studied through the distribution of surnames from individuals above 40 years of age, obtained from the register of electors. The sample studied consisted in 109,200 individuals and 14,138 different surnames. For each of the 32 counties of the State, the following estimators were calculated: percentage of the population included in surnames which appear only once (estimator A), percentage of the population included in the seven most frequent surnames (estimator B), the coefficient of consanguinity due to random isonymy (n phi ii), and Karlin and McGregors ni nu, an estimator of migration. The correlation between n phi ii and B was 0.97, indicating that 94% of the variation observed in the coefficient of consanguinity due to random isonymy is due to the seven most frequent surnames. The correlation between A and ni was 0.93, so that 86% of the variation observed in ni, is due to surnames which appear only once. On the other hand, correlations between A and B, and between n phi ii and nu were non significant (0.25 and 0.01 respectively), meaning that they are measuring different features of population structure: B and n phi ii, and v were non significant (0.25 and 0.01 respectively), meaning that they are measuring different features of population structure: B and n phi ii, isolation, and A and nu, migration. The most isolated counties of Guárico, according to n phi ii and B, are Santa Rita, Espino, El Calvario, Ortiz and Santa María de Ipire. Microdifferentiation of the State was studied through the estimation of RST, which gave a value of 0.0008. Comparing this value with those obtained in other Venezuelan States, it is found that Guárico, with Aragua and Yaracuy, are among the least differentiated States, probably because of the absence of important geographical barriers and the nearness to the Capital City of our country.

Adult↗

Brief report: parainfluenza virus type 3 infections: findings in Sydney and some observations on variations in seasonality world-wide.

Parainfluenza virus type 3 (Para 3) is an important childhood pathogen causing a significant amount of bronchiolitis and pneumonia in infants. Virus data were analysed over a twelve-year period (1978-1989), and a peak incidence of infection was observed in spring as in Houston, USA, unlike in the United Kingdom where summer epidemics appear to be the norm. The temperature ranges were analysed in the different study areas during Para 3 epidemics and similar ranges in temperature were noted which might provide an explanation for the apparently discordant findings in seasonality reported from different parts of the world.

Australia↗

Assessment of follicular development in clomiphene induced cycles by means of ultrasound and laparoscopy: a comparative study.

Fifty clomiphene/H.C.G. stimulated patients undergoing laparoscopy as part of their infertility work up consented to participate in a study on: the reproducibility of ultrasonic measurement of follicular size as expressed by the inter and intra observer variation; the accuracy of ultrasonic assessment of location, number and size of follicles and the growth rate of the Graafian follicle during the last 12 hr prior to oocyte collection. The inter and intra observer variation was moderate to good. Correct diagnosis of the dominant follicle was made in 73%, of the number of follicles in 72% and of follicular size (difference in size between ultrasound and laparoscopy less than 2 mm) in 48% of the material studied. There was a rather wide range in follicular growth rate values during the last 10-17 hr prior to laparoscopy.

Chorionic Gonadotropin↗