Incidence rates and trends of hip/femur fractures in five European countries: comparison using e-healthcare records databases.

Hip fractures represent a major public health challenge worldwide. Multinational studies using a common methodology are scarce. We aimed to estimate the incidence rates (IRs) and trends of hip/femur fractures over the period 2003-2009 in five European countries. The study was performed using seven electronic health-care records databases (DBs) from Denmark, The Netherlands, Germany, Spain, and the United Kingdom, based on the same protocol. Yearly IRs of hip/femur fractures were calculated for the general population and for those aged ≥50 years. Trends over time were evaluated using linear regression analysis for both crude and standardized IRs. Sex- and age-standardized IRs for the UK, Netherlands, and Spanish DBs varied from 9 to 11 per 10,000 person-years for the general population and from 22 to 26 for those ≥50 years old; the German DB showed slightly higher IRs (about 13 and 30, respectively), whereas the Danish DB yielded IRs twofold higher (19 and 52, respectively). IRs increased exponentially with age in both sexes. The ratio of females to males was ≥2 for patients aged ≥70-79 years in most DBs. Statistically significant trends over time were only shown for the UK DB (CPRD) (+0.7% per year, P < 0.01) and the Danish DB (-1.4% per year, P < 0.01). IRs of hip/femur fractures varied greatly across European countries. With the exception of Denmark, no decreasing trend was observed over the study period.

Ascertainment of acute liver injury in two European primary care databases.

PURPOSE: The purpose of this study was to ascertain acute liver injury (ALI) in primary care databases using different computer algorithms. The aim of this investigation was to study and compare the incidence of ALI in different primary care databases and using different definitions of ALI. METHODS: The Clinical Practice Research Datalink (CPRD) in UK and the Spanish "Base de datos para la Investigación Farmacoepidemiológica en Atención Primaria" (BIFAP) were used. Both are primary care databases from which we selected individuals of all ages registered between January 2004 and December 2009. We developed two case definitions of idiopathic ALI using computer algorithms: (i) restrictive definition (definite cases) and (ii) broad definition (definite and probable cases). Patients presenting prior liver conditions were excluded. Manual review of potential cases was performed to confirm diagnosis, in a sample in CPRD (21%) and all potential cases in BIFAP. Incidence rates of ALI by age, sex and calendar year were calculated. RESULTS: In BIFAP, all cases considered definite after manual review had been detected with the computer algorithm as potential cases, and none came from the non-cases group. The restrictive definition of ALI had a low sensitivity but a very high specificity (95% in BIFAP) and showed higher rates of agreement between computer search and manual review compared to the broad definition. Higher incidence rates of definite ALI in 2008 were observed in BIFAP (3.01 (95% confidence interval (CI) 2.13-4.25) per 100,000 person-years than CPRD (1.35 (95% CI 1.03-1.78)). CONCLUSIONS: This study shows that it is feasible to identify ALI cases if restrictive selection criteria are used and the possibility to review additional information to rule out differential diagnoses. Our results confirm that idiopathic ALI is a very rare disease in the general population. Finally, the construction of a standard definition with predefined criteria facilitates the timely comparison across databases.

Quantitative signal detection using spontaneous ADR reporting.

Quantitative methods are increasingly used to analyse spontaneous reports. We describe the core concepts behind the most common methods, the proportional reporting ratio (PRR), reporting odds ratio (ROR), information component (IC) and empirical Bayes geometric mean (EBGM). We discuss the role of Bayesian shrinkage in screening spontaneous reports, the importance of changes over time in screening the properties of the measures. Additionally we discuss three major areas of controversy and ongoing research: stratification, method evaluation and implementation. Finally we give some suggestions as to where emerging research is likely to lead.

Relative importance of physiological precursors for ketogenesis in the nutritional homeostasis of the development of the embryonic chick.

This paper investigates the relative importances of specific amino acids, and, in particular, branched chain amino acids and their keto derivatives as possible ketogenic precursors in suspensions of liver cells isolated from chick embryos. Addition of the branched chain keto acids stimulated ketogenesis. The order of potency was alpha-ketoisocaproic acid greater than alpha-ketoisovaleric acid greater than DL-alpha-keto-beta-methyl-n-valeric acid. The relative order of effectiveness for branched chain keto acids was maintained at all comparable concentrations, and in each case maximum rates were observed with concentrations of 1-2 mM. In contrast to the stimulation of ketogenesis by their keto derivatives, branched chain amino acids were ineffective as precursors for ketogenesis. Of the other amino acids (utilised at concentrations present in chick embryo plasma) only Tyr, Lys, Phe and Arg produced significant increases in ketone body formation above the endogenous rate. At these physiological concentrations, the effectiveness of the amino acids were in the order of Tyr greater than Lys = Phe greater than Arg. The interactions between three groups of ketogenic precursor (fatty acids, amino acids and keto amino acids, all at physiological concentrations), produced rates of ketogenesis that were purely additive. These results indicate that high concentrations of hydroxybutyrate and acetoacetate found in plasma of developing chick embryos may arise from hepatic metabolism of several distinct precursors. The relative importance of each category of precursor may vary with the precise developmental status of animals.

Effects of okadaic acid on expression of phosphoenolpyruvate carboxykinase in cultured rat hepatocytes.

In normal rat hepatocytes in primary culture the level of mRNA encoding the key gluconeogenic enzyme phospho enol pyruvate carboxykinase (PEPCK) is increased by the cyclic AMP analogue, chlorophenylthio cyclic AMP (cpt cAMP), and this response is reversed by insulin. The protein-phosphatase inhibitor okadaic acid diminished the stimulatory effects of cpt cAMP on PEPCK mRNA. Protein kinase A remained fully active in the presence of okadaic acid, therefore, the insulin-mimetic actions of okadaic acid were localised to a site subsequent to initial protein kinase A activation. Insulin produced a decrease in PEPCK mRNA expression which was similar to that of okadaic acid both in extent and mechanism (i.e., lack of change in protein kinase A activation). The effects of okadaic acid on PEPCK mRNA amount were not additive with those of insulin and the effects of insulin were not abolished by okadaic acid. These data suggest that okadaic acid and insulin may interact with the cAMP regulation of the PEPCK gene expression at a common site. The mechanisms by which this may be attained are discussed in relation to what is known about the control of specific protein kinases and protein phosphatases by insulin and okadaic acid and of the importance of protein phosphorylation state to regulation of gene-transcriptional processes.

Glycolipids isolated from cultured rat hepatocytes: analysis of their role in insulin signal transduction.

The precise mechanism by which insulin elicits its effects remains to be fully determined. A glycophospholipid, isolated from H35 cells, has been proposed as a possible precursor for an insulin-generated second messenger that mediates the intracellular effects of insulin. This glycolipid contains a hexosamine moiety, inositol, galactose and palmitate. We have isolated a glycolipid from cultured rat hepatocytes that exhibits chromatographic and radiolabelling characteristics similar to this proposed precursor. The glycolipid can be radiolabelled with glucosamine, galactosamine, galactose and palmitate, but not myristate or myoinositol. Incorporation of radiolabel into this glycolipid was insensitive to the presence of either insulin (10(-7) M) or phosphatidylinositol-specific phospholipase C (PI-PLC) in the culture medium. The cultured hepatocytes used exhibited normal insulin responses with respect to glycogen turnover and gene expression. Treatment of partially purified glycolipid with either PI-PLC or nitrous acid did not result in the generation of an aqueous soluble phosphooligosaccharide indicating that the glycolipid was not cleaved by either agent. This is in contrast to the reported cleavage of the glycolipids found in H35 hepatoma and lymphocytes. These results question the role of the putative phosphooligosaccharide mediator in the intracellular transduction system activated by insulin.

Structured assessment for prospective identification of safety signals in electronic medical records: evaluation in the health improvement network.

BACKGROUND: Pharmacovigilance signal detection largely relies on individual case reports, but longitudinal health data are being explored as complementary information sources. Research to date has focused on the ability of epidemiological methods to distinguish established adverse drug reactions (ADRs) from unrelated adverse events. OBJECTIVE: The aim of this study was to evaluate a process for structured clinical and epidemiological assessment of temporally associated drugs and medical events in electronic medical records. METHODS: Pairs of drugs and medical events were selected for review on the basis of their temporal association according to a calibrated self-controlled cohort analysis in The Health Improvement Network. Six assessors trained in pharmacovigilance and/or epidemiology evaluated seven drugs each, with up to 20 medical events per drug. A pre-specified questionnaire considered aspects related to the nature of the temporal pattern, demographic features of the cohort, concomitant medicines, earlier signs and symptoms, and possible confounding by underlying disease. This informed a classification of drug-event pairs as known ADRs, meriting further evaluation, or dismissed. RESULTS: The number of temporally associated medical events per drug ranged from 11 to 307 (median 50) for the 42 selected drugs. Out of the 509 relevant drug-event combinations subjected to the assessment, 127 (25 %) were classified as known ADRs. Ninety-one (24 %) of the remaining pairs were classified as potential signals meriting further evaluation and 291 (76 %) were dismissed. Suggestive temporal patterns and lack of clear alternative explanations were the most common reasons that drug-event pairs were classified as meriting further evaluation. Earlier signs and symptoms and confounding by the underlying disease were the most common reasons that drug-event pairs were dismissed. CONCLUSIONS: Exploratory analysis of electronic medical records can detect important potential safety signals. However, effective signal detection requires that statistical signal detection be combined with clinical and epidemiological review to achieve an acceptable false positive rate.

Growth of rat seminal vesicle epithelial cells in culture: neurotransmitters are required for androgen-regulated synthesis of tissue-specific secretory proteins.

Epithelial cells from enzymically dispersed seminal vesicle tissue of castrated adult rats were grown on collagen-coated surfaces in serum-containing medium for up to 6 weeks. Androgens were neither required for growth nor were they mitogenic. They also failed to induce the synthesis of tissue-specific secretory proteins that serve as markers of androgen action in vivo. A variety of potential growth factors and culture procedures (such as feeder layers, extracellular matrices, collagen gels, and growth from tissue explants) were examined for their ability to support androgen action. Testosterone and 5 alpha-dihydrotestosterone were only able to induce seminal vesicle secretory protein synthesis in the presence of neurotransmitters (acetylcholine, noradrenaline, or serotonin). The mechanism of this permissive effect of neurotransmitters on androgenic induction has been examined. It is not related to their mitogenic activity since other mitogens (epidermal growth factor and corticosterone) did not facilitate androgen action. Agents that raise intracellular cAMP were also ineffective so cAMP is probably not involved, but the phosphatidyl inositol pathway may be important.

Lack of association between DQ A and DX A polymorphisms with rheumatoid arthritis and Felty's syndrome.

DQ A and DX A RFLPs were studied in DR4-positive rheumatoid arthritis, Felty's syndrome, and in DR4-positive control subjects, and in the light of the previously documented association between Felty's syndrome and the DQ B 3.1 allele (3b RFLP). In these DR4-positive subjects there were no preferential associations between DQ A or DX A polymorphisms and rheumatoid arthritis or Felty's syndrome and no evidence for unusual DQ A-B haplotypic associations in Felty's or rheumatoid subjects.

DNA variants of alpha-1-antitrypsin in rheumatoid arthritis with and without pulmonary complications.

Restriction fragment length polymorphisms (RFLPs) of alpha-1-antitrypsin were studied in 99 subjects with rheumatoid arthritis alone, 21 subjects with rheumatoid arthritis and pulmonary fibrosis, 26 subjects with rheumatoid arthritis and bronchiectasis, and 86 controls. No associations with either rheumatoid arthritis itself or with the associated pulmonary disorders were noted in this U.K. Caucasoid population.

Capillary growth in relation to blood flow and performance in overloaded rat skeletal muscle.

Rat extensor digitorum longus muscles were overloaded by stretch after removal of the synergist tibialis anterior muscle to determine the relationship between capillary growth, muscle blood flow, and presence of growth factors. After 2 wk, sarcomere length increased from 2.4 to 2.9 micrometers. Capillary-to-fiber ratio, estimated from alkaline phosphatase-stained frozen sections, was increased by 33% (P < 0.0001) and 60% (P < 0.01), compared with control muscles (1.44 +/- 0.06) after 2 and 8 wk, respectively. At 2 wk, the increased capillary-to-fiber ratio was not associated with any changes in mRNA for basic fibroblast growth factor (FGF-2) or its protein distribution. FGF-2 immunoreactivity was present in nerves and large blood vessels but was negative in capillaries, whereas the activity of low-molecular endothelial-cell-stimulating angiogenic factor (ESAF) was 50% higher in stretched muscles. Muscle blood flows measured by radiolabeled microspheres during contractions were not significantly different after 2 or 8 wk (132 +/- 37 and 177 +/- 22 ml. min-1. 100 g-1, respectively) from weight-matched controls (156 +/- 12 and 150 +/- 10 ml. min-1. 100 g-1, respectively). Resistance to fatigue during 5-min isometric contractions (final/peak tension x 100) was similar in 2-wk overloaded and contralateral muscles (85 vs. 80%) and enhanced after 8 wk to 92%, compared with 77% in contralateral muscles and 67% in controls. We conclude that increased blood flow cannot be responsible for initiating expansion of the capillary bed, nor does it explain the reduced fatigue within overloaded muscles. However, stretch can present a mechanical stimulus to capillary growth, acting either directly on the capillary abluminal surface or by upregulating ESAF, but not FGF-2, in the extracellular matrix.

A retrospective evaluation of a data mining approach to aid finding new adverse drug reaction signals in the WHO international database.

BACKGROUND: The detection of new drug safety signals is of growing importance with ever more new drugs becoming available and exposure to medicines increasing. The task of evaluating information relating to safety lies with national agencies and, for international data, with the World Health Organization Programme for International Drug Monitoring. RATIONALE: An established approach for identifying new drug safety signals from the international database of more than 2 million case reports depends upon clinical experts from around the world. With a very large amount of information to evaluate, such an approach is open to human error. To aid the clinical review, we have developed a new signalling process using Bayesian logic, applied to data mining, within a confidence propagation neural network (Bayesian Confidence Propagation Neural Network; BCPNN). Ultimately, this will also allow the evaluation of complex variables. METHODS: The first part of this study tested the predictive value of the BCPNN in new signal detection as compared with reference literature sources (Martindale's Extra Pharmacopoeia in 1993 and July 2000, and the Physicians Desk Reference in July 2000). In the second part of the study, results with the BCPNN method were compared with those of the former signalling procedure. RESULTS: In the study period (the first quarter of 1993) 107 drug-adverse reaction combinations were highlighted as new positive associations by the BCPNN, and referred to new drugs. 15 drug-adverse reaction combinations on new drugs became negative BCPNN associations in the study period. The BCPNN method detected signals with a positive predictive value of 44% and the negative predictive value was 85%. 17 as yet unconfirmed positive associations could not be dismissed with certainty as false positive signals. Of the 10 drug-adverse reaction signals produced by the former signal detection system from data sent out for review during the study period, 6 were also identified by the BCPNN. These 6 associations have all had a more than 10-fold increase of reports and 4 of them have been included in the reference sources. The remaining 4 signals that were not identified by the BCPNN had a small, or no, increase in the number of reports, and are not listed in the reference sources. CONCLUSION: Our evaluation showed that the BCPNN approach had a high and promising predictive value in identifying early signals of new adverse drug reactions.

Eliciting public preferences for healthcare: a systematic review of techniques.

BACKGROUND: Limited resources coupled with unlimited demand for healthcare mean that decisions have to be made regarding the allocation of scarce resources across competing interventions. Policy documents have advocated the importance of public views as one such criterion. In principle, the elicitation of public values represents a big step forward. However, for the exercise to be worthwhile, useful information must be obtained that is scientifically defensible, whilst decision-makers must be able and willing to use it. AIMS AND OBJECTIVES: The aim was to identify techniques that could be reasonably used to elicit public views on the provision of healthcare. Hence, the objectives were: (1) to identify research methods with the potential to take account of public views on the delivery of healthcare; (2) to identify criteria for assessing these methods; (3) to assess the methods identified according to the predefined criteria; (4) to assess the importance of public views vis-à-vis other criteria for setting priorities, as judged by a sample of decision-makers; (5) to make recommendations regarding the use of methods and future research. METHODS: A systematic literature review was carried out to identify methods for eliciting public views. Criteria currently used to evaluate such methods were identified. The methods identified were then evaluated according to predefined criteria. A questionnaire-based survey assessed the relative importance of public views vis-à-vis five other criteria for setting priorities: potential health gain; evidence of clinical effectiveness; budgetary impact; equity of access and health status inequalities; and quality of service. Two techniques were used: choice-based conjoint analysis and allocation of points technique. The questionnaire was sent to 143 participants. A subsample was followed up with a telephone interview. RESULTS: The methods identified were classified as quantitative or qualitative. RESULTS - QUANTITATIVE TECHNIQUES: Quantitative techniques, classified as ranking, rating or choice-based approaches, were evaluated according to eight criteria: validity; reproducibility; internal consistency; acceptability to respondents; cost (financial and administrative); theoretical basis; whether the technique offered a constrained choice; and whether the technique provided a strength of preference measure. Regarding ranking exercises, simple ranking exercises have proved popular, but their results are of limited use. The qualitative discriminant process has not been used to date in healthcare, but may be useful. Conjoint analysis ranking exercises did well against the above criteria. A number of rating scales were identified. The visual analogue scale has proved popular within the quality-adjusted life-year paradigm, but lacks constrained choice and may not measure strength of preference. However, conjoint analysis rating scales performed well. Methods identified for eliciting attitudes include Likert scales, the semantic differential technique, and the Guttman scale. These methods provide useful information, but do not consider strength of preference or the importance of different components within a total score. Satisfaction surveys have been frequently used to elicit public opinion. Researchers should ensure that they construct sensitive techniques, despite their limited use, or else use generic techniques where validity has already been established. Service quality (SERVQUAL) appears to be a potentially useful technique and its application should be researched. Three choice-based techniques with a limited application in healthcare are measure of value, the analytical hierarchical process and the allocation of points technique, while those more widely used, and which did well against the predefined criteria, include standard gamble, time trade-off, discrete choice conjoint analysis and willingness to pay. Little methodological work is currently available on the person trade-off. RESULTS - QUALITATIVE TECHNIQUES: Qualitative techniques were classified as either individual or group-based approaches. Individual approaches included one-to-one interviews, dyadic interviews, case study analyses, the Delphi technique and complaints procedures. Group-based methods included focus groups, concept mapping, citizens' juries, consensus panels, public meetings and nominal group techniques. Six assessment criteria were identified: validity; reliability; generalisability; objectivity; acceptability to respondents; and cost. Whilst all the methods have distinct strengths and weaknesses, there is a lot of ambiguity in the literature. Whether to use individual or group methods depends on the specific topic being discussed and the people being asked, but for both it is crucial that the interviewer/moderator remains as objective as possible. The most popular and widely used such methods were one-to-one interviews and focus groups. (ABSTRACT TRUNCATED)

Use of discrete choice experiments to elicit preferences.

This paper considers the application of discrete choice experiments for eliciting preferences in the delivery of health care. Drawing upon the results from a recently completed systematic review, the paper summarises the application of this technique in health care. It then presents a case study applying the technique to rheumatology outpatient clinics. 200 patients were questioned about the importance of six attributes: staff seen (junior doctor or specialist nurse); time in waiting area; continuity of contact with same staff; provision of a phone-in/advice service; length of consultation; and change in pain levels. The systematic review indicated that discrete choice experiments have been applied to a wide number of areas and a number of methodological issues have been addressed. Consistent with this literature, the case study found evidence of both rationality and theoretical validity of responses. The approach was used to establish the relative importance of different attributes, how individuals trade between these attributes, and overall benefit scores for different clinic configurations. The value of attributes was estimated in terms of time, and this was converted to a monetary measure using the value of waiting time for public transport. Discrete choice experiments represent a potentially useful instrument for eliciting preferences. Future methodological work should explore issues related to the experimental design of the study, methods of data collection and analysis, and satisfaction with the economic axioms of the instrument. Collaborative work with psychologists and qualitative researchers will prove useful in this research agenda.

Antipsychotic drugs and heart muscle disorder in international pharmacovigilance: data mining study.

OBJECTIVES: To examine the relation between antipsychotic drugs and myocarditis and cardiomyopathy. DESIGN: Data mining using bayesian statistics implemented in a neural network architecture. SETTING: International database on adverse drug reactions run by the World Health Organization programme for international drug monitoring. MAIN OUTCOME MEASURES: Reports mentioning antipsychotic drugs, cardiomyopathy, or myocarditis. RESULTS: A strong signal existed for an association between clozapine and cardiomyopathy and myocarditis. An association was also seen with other antipsychotics as a group. The association was based on sufficient cases with adequate documentation and apparent lack of confounding to constitute a signal. Associations between myocarditis or cardiomyopathy and lithium, chlorpromazine, fluphenazine, haloperidol, and risperidone need further investigation. CONCLUSIONS: Some antipsychotic drugs seem to be linked to cardiomyopathy and myocarditis. The study shows the potential of bayesian neural networks in analysing data on drug safety.

Decision support methods for the detection of adverse events in post-marketing data.

Spontaneous reporting is a crucial component of post-marketing drug safety surveillance despite its significant limitations. The size and complexity of some spontaneous reporting system databases represent a challenge for drug safety professionals who traditionally have relied heavily on the scientific and clinical acumen of the prepared mind. Computer algorithms that calculate statistical measures of reporting frequency for huge numbers of drug-event combinations are increasingly used to support pharamcovigilance analysts screening large spontaneous reporting system databases. After an overview of pharmacovigilance and spontaneous reporting systems, we discuss the theory and application of contemporary computer algorithms in regular use, those under development, and the practical considerations involved in the implementation of computer algorithms within a comprehensive and holistic drug safety signal detection program.

The application of knowledge discovery in databases to post-marketing drug safety: example of the WHO database.

After market launch, new information on adverse effects of medicinal products is almost exclusively first highlighted by spontaneous reporting. As data sets of spontaneous reports have become larger, and computational capability has increased, quantitative methods have been increasingly applied to such data sets. The screening of such data sets is an application of knowledge discovery in databases (KDD). Effective KDD is an iterative and interactive process made up of the following steps: developing an understanding of an application domain, creating a target data set, data cleaning and pre-processing, data reduction and projection, choosing the data mining task, choosing the data mining algorithm, data mining, interpretation of results and consolidating and using acquired knowledge. The process of KDD as it applies to the analysis of spontaneous reports can be exemplified by its routine use on the 3.5 million suspected adverse drug reaction (ADR) reports in the WHO ADR database. Examples of new adverse effects first highlighted by the KDD process on WHO data include topiramate glaucoma, infliximab vasculitis and the association of selective serotonin reuptake inhibitors (SSRIs) and neonatal convulsions. The KDD process has already improved our ability to highlight previously unsuspected ADRs for clinical review in spontaneous reporting, and we anticipate that such techniques will be increasingly used in the successful screening of other healthcare data sets such as patient records in the future.

Calculus-like deposit on the apical external root surface of teeth with post-treatment apical periodontitis: report of two cases.

AIM: To report two cases in which calculus-like material was found on external root surfaces of (i) an extracted root and (ii) an apicected part of a root, both of which were removed due to post-treatment refractory apical periodontitis. SUMMARY: In each case, there was a fistulous tract, which did not heal after conventional root canal treatment. The first case did not heal even after apical surgery, and subsequent tooth extraction revealed calculus-like material on a root surface of complex anatomy. The second case showed radiographic signs of healing after apicectomy. Histology of the apical biopsy revealed a calculus-like material on the external surface of the root apex. It is suggested that the presence of calculus on the root surfaces of teeth with periapical lesions may contribute towards the aetiology of failure. KEY LEARNING POINTS: Biofilm on the external root surface has been implicated in the failure of apical periodontitis to heal, despite adequate root canal treatment. Calculus-like material was found, in two cases, on the root surface of teeth with post-treatment apical periodontitis, where the only communication externally was a sinus tract.