Fracture rate and back pain during and after discontinuation of teriparatide: 36-month data from the European Forsteo Observational Study (EFOS).

UNLABELLED: In this observational study in postmenopausal women with severe osteoporosis, the incidence of fractures was decreased during 18 months of teriparatide treatment with no evidence of further change in the subsequent 18-month post-teriparatide period when most patients took other osteoporosis medications. Fracture reduction was accompanied by reductions in back pain. INTRODUCTION: To describe fracture outcomes and back pain in postmenopausal women with severe osteoporosis during 18 months of teriparatide treatment and 18 months post-teriparatide in normal clinical practice. METHODS: The European Forsteo Observational Study (EFOS) was a prospective, multinational, observational study. Data on incident clinical fractures and back pain (100 mm Visual Analogue Scale [VAS] and questionnaire) were collected. Fracture data were summarised in 6-month intervals and analysed using logistic regression with repeated measures. Changes from baseline in back pain VAS were analysed using a repeated measures model. RESULTS: A total of 208 (13.2%) of 1,576 patients sustained 258 fractures during 36 months of follow-up: 34% were clinical vertebral fractures and 66% non-vertebral fractures. The adjusted odds of fracture were reduced during teriparatide treatment and there was no evidence of further change in the 18-month post-teriparatide period, during which 63.3% patients took bisphosphonates. A 74% decrease in the adjusted odds of fracture in the 30- to <36-month period compared with the first 6-month period was observed (p < 0.001). Back pain decreased during teriparatide treatment and this decrease was sustained after teriparatide discontinuation. Adjusted mean back pain VAS decreased by 26.3 mm after 36 months (p < 0.001) from baseline mean of 57.8 mm. CONCLUSIONS: In a real-life clinical setting, the risk of fracture decreased during teriparatide treatment, with no evidence of further change after teriparatide was discontinued. The changes in back pain seen during treatment were maintained for at least 18 months after teriparatide discontinuation. These results should be interpreted in the context of the design of an observational study.

Adjunctive anakinra in patients with active rheumatoid arthritis despite methotrexate, or leflunomide, or cyclosporin-A monotherapy: a 48-week, comparative, prospective study.

OBJECTIVE: To assess the efficacy and safety of anakinra (ANK) as an add-on therapy in RA patients with inadequate response to monotherapy with non-biological DMARDs. METHODS: A 48-week comparative, prospective study of patients with active RA [mean 28-joint disease activity score (DAS28): 6.81], despite MTX (n = 48), or LEF (n = 42), or CSA (n = 38) treatment, in whom ANK (100 mg/daily SC) was given with corticosteroid cream topical application. RESULTS: At 24 and 48 weeks the patient percentages meeting the ACR20 response criteria were 57 and 73%, respectively, 33 and 41% met ACR50, while 15 and 23% met ACR70. Significant improvements in number of swollen and tender joints, HAQ, pain, global disease assessment, CRP and haemoglobin from baseline to 24 and 48 weeks were evident. DAS28 decreased at 24 weeks (- 1.68; 95% CI - 1.46, - 1.90; P < 0.0001), as well as at study end (- 2.24; 95% CI - 2.01, - 2.47; P < 0.0001). Subgroup analysis revealed a significantly weaker response in terms of pain and DAS28 in patients treated with concomitant CSA. The most common ANK-related adverse event was injection-site reaction (29%), being less frequent in male patients, as well as in patients treated with CSA. There were 17 withdrawals, 6 of them due to inefficacy. No opportunistic infections or new safety signals were observed. CONCLUSION: Considering the limitations of an open-label study, addition of ANK appears to be an effective and well-tolerated treatment option for many RA patients with inadequate responses to non-biologic DMARDs in clinical practice.

Evidence-based recommendations for the management of ankylosing spondylitis: results of the Hellenic working group of the 3E Initiative in Rheumatology.

OBJECTIVE: The 3E (Evidence, Experts and Exchange) Initiative is a multi-national effort that involves a large number of experts and practicing rheumatologists addressing specific questions relevant to everyday clinical practice, concerning the management of Ankylosing Spondylitis. Within this multinational group, the Hellenic working group, addressed specific issues complementary to the international ones, and formulated evidence-based recommendations, in order to improve everyday clinical practice for patients with Ankylosing Spondylitis. METHODS: A scientific committee of rheumatologists specializing in AS formulated a set of 7 questions in three domains: diagnosis, monitoring and treatment. Literature search in MedLine for papers published up to August 2006 was conducted. The evidence to support each proposition was evaluated and scored. To avoid any conflict of interest with the sponsor issues related to the use of biologics were not discussed. After extensive discussion among 50 rheumatologists and one Delphi round of votes, the final recommendations were formulated. RESULTS: A literature search resulted in a total of 320 relevant papers of which 29 were evaluated. A total of seven recommendations were formulated: two concerning diagnosis (role of HLA-B27 and MRI) and prognosis, one concerning monitoring for extra-articular manifestations and four concerning treatment (analgesics, disease modifying agents and physical therapy) were made. The level of evidence and the strength of recommendation were reported. The compiled agreement among experts ranged from 90% up to 100%. CONCLUSION: Recommendations for the management of AS were developed using an evidence-based approach followed by physicians' consensus with high level of agreement. These are complementary to existing ones, and address specific domains of everyday clinical practice.

Efficient information theoretic strategies for classifier combination, feature extraction and performance evaluation in improving false positives and false negatives for spam e-mail filtering.

Spam emails are considered as a serious privacy-related violation, besides being a costly, unsolicited communication. Various spam filtering techniques have been so far proposed, mainly based on Naïve Bayesian algorithms. Other Machine Learning algorithms like Boosting trees, or Support Vector Machines (SVM) have already been used with success. However, the number of False Positives (FP) and False Negatives (FN) resulting through applying various spam e-mail filters still remains too high and the problem of spam e-mail categorization cannot be solved completely from a practical viewpoint. In this paper, we propose a novel approach for spam e-mail filtering based on efficient information theoretic techniques for integrating classifiers, for extracting improved features and for properly evaluating categorization accuracy in terms of FP and FN. The goal of the presented methodology is to empirically but explicitly minimize these FP and FN numbers by combining high-performance FP filters with high-performance FN filters emerging from a previous work of the authors [Zorkadis, V., Panayotou, M., & Karras, D. A. (2005). Improved spam e-mail filtering based on committee machines and information theoretic feature extraction. Proceedings of the International Joint Conference on Neural Networks, July 31-August 4, 2005, Montreal, Canada]. To this end, Random Committee-based filters along with ADTree-based ones are efficiently combined through information theory, respectively. The experiments conducted are of the most extensive ones so far in the literature, exploiting widely accepted benchmarking e-mail data sets and comparing the proposed methodology with the Naive Bayes spam filter as well as with the Boosting tree methodology, the classification via regression and other machine learning models. It is illustrated by means of novel information theoretic measures of FP & FN filtering performance that the proposed approach is very favorably compared to the other rival methods. Finally, it is found that the proposed information theoretic Boolean features present a remarkably high spam categorization performance.

Improved statistical classification methods in computerized psychiatric diagnosis.

BACKGROUND: Mainstream psychiatric diagnosis involves mainly sequential, expert-system-derived, logical decision rules. Among the few statistical classification methods that have been sporadically evaluated are Bayes, k-nearest neighbor, and discriminant analysis classifiers. METHODS: A statistical classification method based on artificial neural networks (ANN) with task-specific constrained architectures was applied to a sample of 796 clinical interviews, where the symptom evaluation and the diagnostic judgments were made using the Psychiatric State Examination (PSE) system. The proposed constrained ANN (CANN) method was compared with other statistical classification methods. RESULTS: CANN was found to be superior to all other considered methods, having an overall "correct" classification rate of 80% when applied to test data. Similarly, the concordance coefficients of agreement with the PSE diagnostic categories were all very high. Among the other used methods, discriminant analysis had slightly inferior performance but better generalization capability. CONCLUSIONS: The proposed CANN method has a definite utility in psychiatric diagnosis and requires further evaluation, perhaps alongside other standard classification systems and/or with larger samples.

Statistical methodology: II. Reliability and variability assessment in study design, Part A.

Assessment of test reliability and validity is often complex. Although tests of correlation are frequently used to measure interest agreement, such indexes measure only the strength of the linear relationship between variables and may not provide an accurate assessment of the correspondence between test results. Inspection of interest differences, either visually or using the r1, may provide a better indicator of the correspondence between test results and accounts for measurement biases. Strength of association between categorical variables can be measured using related tests such as the kappa statistic. Test reliability may be assessed by retesting, but this is not practical in many cases when subject memory or learning may confound the results of repeated examinations. Several methods exist for determining reliability from a single test administration and for assessing the correspondence between answers to homogeneous test questions. In the continuation article (Part B) on this subject, the concept and assessment of validity will be examined in more detail, and techniques for maximizing the reliability and validity of questionnaires will be discussed.

Statistical methodology: II. Reliability and validity assessment in study design, Part B.

Validity measures the correspondence between a test and other purported measures of the same or similar qualities. When a reference standard exists, a criterion-based validity coefficient can be calculated. If no such standard is available, the concepts of content and construct validity may be used, but quantitative analysis may not be possible. The Pearson and Spearman tests of correlation are often used to assess the correspondence between tests, but do not account for measurement biases and may yield misleading results. Techniques that measure interest differences may be more meaningful in validity assessment, and the kappa statistic is useful for analyzing categorical variables. Questionnaires often can be designed to allow quantitative assessment of reliability and validity, although this may be difficult. Inclusion of homogeneous questions is necessary to assess reliability. Analysis is enhanced by using Likert scales or similar techniques that yield ordinal data. Validity assessment of questionnaires requires careful definition of the scope of the test and comparison with previously validated tools.

Clinically meaningful changes in quantitative measures of asthma severity.

OBJECTIVE: To determine minimum clinically meaningful improvements in peak expiratory flow rate (PEFR) and dyspnea visual analog score (VAS) in patients with acute asthma exacerbation. METHODS: Patients presenting to the emergency department (ED) with acute asthma exacerbation were eligible. The PEFR and VAS were assessed at presentation and after initial asthma therapy. During reassessment, subjects were asked to describe their asthma symptoms as "much better," "a little better," "no change," "a little worse," or "much worse." Correspondence between self-reported improvement and changes in PEFR and VAS was assessed. The "minimum clinically significant change" in either index was defined as the difference between pre- and posttreatment measures in subjects reporting their symptoms "a little better." RESULTS: One hundred fifty-six subjects were included. Asthma symptoms were "much better" in 99 (64%), "a little better" in 41 (26%), and "unimproved" (composed of patients describing symptoms as "no change," "a little worse," or "much worse") in 16 (10%). The mean VAS change among the "a little better" subjects was 2.2 cm (95% CI = 1.1 to 3.4), significantly greater than the -0.4 cm (95% CI = -2.1 to 1.4) change in the "unimproved" subjects. The mean change in percent predicted PEFR among the "a little better" subjects was 11.9 (95% CI = 7.3 to 16.1), not statistically different from the change of 6.1 (95% CI = 1.1 to 11.3) in the "no change" subjects. The "much better" group showed significantly greater changes in both measures than either of the other groups. A VAS change of > or =0.5 cm reliably discriminated between subjects with and without symptom improvement. CONCLUSIONS: Improvements in VAS of 2.2 cm and in predicted PEFR of about 12 percentage points are minimal clinically significant improvements during ED asthma therapy. The dyspnea VAS is valid in assessing symptomatic changes and may detect small subjective improvements better than the PEFR.

Pimozide and amphetamine have opposing effects on the reward summation function.

The reward summation function is the plot of self-stimulation performance as a function of the number of pulses in a train of fixed duration. It has previously been shown that drugs that impair performance compress this curve but do not shift it laterally; whereas when the reinforcing efficacy is reduced by reducing current intensity, the curve shifts laterally. The amount of the shift is a measure of the magnitude of a drug's effect upon reinforcing efficacy. We report here that pimozide shifts the curve to the right in a dose-dependent manner, indicating an impairment of reinforcing efficacy, while amphetamine shifts it to the left, indicating an enhancement of reinforcing efficacy. When the two drugs are given together their effects on the reward summation function cancel out. These results are consistent with the hypothesis that pimozide and amphetamine exert their effects on reinforcing efficacy via one and the same set of dopaminergic synapses.

Reliability of crevicular fluid measurements taken in the presence of supragingival plaque.

The measurement of gingival crevicular fluid (GCF) is commonly used in clinical studies to quantitate the severity of gingival inflammation. This study examined the influence of the presence of supragingival plaque on GCF readings. Bilateral pairs of maxillary premolars received replicate GCF measurements. One of the teeth was randomly selected to be the test tooth. Supragingival plaque was removed from the test tooth between the first and second GCF measurements. Plaque was not removed from the control tooth. The crevicular fluid was collected on filter paper strips which were placed just subgingivally. The quantity of crevicular fluid was determined with the aid of the Periotron 6000. The mean difference between the first and second GCF measurement for the control teeth was -1.5 +/- 5.7 (+/- SD). This change was not significant (P = 0.21). The mean difference between the first and second GCF measurements for the experimental teeth (-21.3 +/- 16.5) was significant (P less than or equal to .001). The mean difference between the control and the experimental GCF differences were found to be highly significant (P less than or equal to .001). The data indicate that the presence of supragingival plaque can significantly elevate the GCF measurements when determined with the Periotron 6000.

On neural network techniques in the secure management of communication systems through improving and quality assessing pseudorandom stream generators.

Random components play an especially important role in the management of secure communication systems, with emphasis on the key management of cryptographic protocols. For this reason, the existence of strong pseudo random number generators is highly required. This paper presents novel techniques, which rely on Artificial Neural Network (ANN) architectures, to strengthen traditional generators such as IDEA and ANSI X.9 based on 3DES and IDEA. Additionally, this paper proposes a non-linear test method for the quality assessment of the required non-predictability property, which relies on feedforward neural networks. This non-predictability test method along with commonly used empirical tests based on statistics is proposed as a methodology for quality assessing strong pseudorandom stream generators. By means of this methodology, traditional and Neural Network based pseudorandom stream generators are evaluated. The results show that the proposed generators behave significantly better than the traditional ones, in particular, in terms of non-predictability.

An efficient constrained training algorithm for feedforward networks.

A novel algorithm is presented which supplements the training phase in feedforward networks with various forms of information about desired learning properties. This information is represented by conditions which must be satisfied in addition to the demand for minimization of the usual mean square error cost function. The purpose of these conditions is to improve convergence, learning speed, and generalization properties through prompt activation of the hidden units, optimal alignment of successive weight vector offsets, elimination of excessive hidden nodes, and regulation of the magnitude of search steps in the weight space. The algorithm is applied to several small- and large-scale binary benchmark training tasks, to test its convergence ability and learning speed, as well as to a large-scale OCR problem, to test its generalization capability. Its performance in terms of percentage of local minima, learning speed, and generalization ability is evaluated and found superior to the performance of the backpropagation algorithm and variants thereof taking especially into account the statistical significance of the results.

Serum markers in the emergency department diagnosis of acute myocardial infarction.

No currently used cardiac-specific serum marker meets all the criteria for an "ideal" marker of AMI. No test is both highly sensitive and highly specific for acute infarction within 6 hours following the onset of chest pain, the timeframe of interest to most emergency physicians in making diagnostic and therapeutic decisions. Patients presenting to the ED with chest pain or other symptoms suggestive of acute cardiac ischemia therefore cannot make a diagnosis of AMI excluded on the basis of a single cardiac marker value obtained within a few hours after symptom onset. The total CK level is far too insensitive and nonspecific a test to be used to diagnose AMI. It retains its value, however, as a screening test, and serum of patients with abnormal total CK values should undergo a CK-MBmass assay. Elevation in CK-MB is a vital component of ultimate diagnosis of AMI, but levels of this marker are normal in one fourth to one half of patients with AMI at the time of ED presentation. The test is highly specific, however, and an abnormal value (particularly when it exceeds 5% of the total CK value) at any time in a patient with chest pain is highly suggestive of an AMI. There have been several improvements of CK-MB assay timing and subform quantification that appear highly useful for emergency physicians. Rapid serial CK-MB assessment greatly increases the diagnostic value of the assay in a timeframe suitable for ED purposes but unfortunately still misses about 10% of patients ultimately diagnosed with acute MI. Assays of CK-MB subforms have very high sensitivity, and, although unreliable within 4 hours of symptom onset, have excellent diagnostic value at 6 or more hours after chest pain begins. Automated test assays recently have become available and could prove applicable to ED settings. The cardiac troponins are highly useful as markers of acute coronary syndromes, rather than specifically of AMI, and abnormal values at any time following chest pain onset are highly predictive of an adverse cardiac event. The ED applicability of the troponins is severely limited, however, because values remain normal in most patients with acute cardiac events as long as 6 hours following symptom onset. Myoglobin appeared promising as a marker of early cardiac ischemia but appears to be only marginally more sensitive than CK-MB assays early after symptom onset and less sensitive than CK-MB at 8 hours or more after chest pain starts. Rapid serial myoglobin assessment, however, appears highly useful as an early marker of AMI. The marker has a very narrow diagnostic window. The clinician is left with several tests that are highly effective in correctly identifying patients with AMI (or at high risk for AMI), but none that can dependably exclude patients with acute coronary syndromes soon after chest pain onset. A prudent strategy when assessing ED patients with chest pain and nondiagnostic ECGs is to order CK-MB and troponin values on presentation in the hope of making an early diagnosis of AMI or unstable coronary syndrome. Although it is recognized that normal values obtained within 6 hours of symptom onset do not exclude an acute coronary syndrome, patients at low clinical risk and having normal cardiac marker tests could be provisionally admitted to low-acuity hospital settings or ED observation. After 6 to 8 hours of symptom duration has elapsed, the cardiac-specific markers are highly effective in diagnosing AMI, and such values obtained can be used more appropriately to make final disposition decisions. At no time should results of serum marker tests outweigh ECG findings or clinical assessment of the patient's risk and stability.

CoLD: a versatile detection system for colorectal lesions in endoscopy video-frames.

In this paper, we present CoLD (colorectal lesions detector) an innovative detection system to support colorectal cancer diagnosis and detection of pre-cancerous polyps, by processing endoscopy images or video frame sequences acquired during colonoscopy. It utilizes second-order statistical features that are calculated on the wavelet transformation of each image to discriminate amongst regions of normal or abnormal tissue. An artificial neural network performs the classification of the features. CoLD integrates the feature extraction and classification algorithms under a graphical user interface, which allows both novice and expert users to utilize effectively all system's functions. It has been developed in close cooperation with gastroenterology specialists and has been tested on various colonoscopy videos. The detection accuracy of the proposed system has been estimated to be more than 95%. As it has been resulted, it can be used as a supplementary diagnostic tool for colorectal lesions.

Competency to stand trial among adolescents.

Both adolescents and adults were administered a standardized measure of competency to stand trial. Results suggested that competency to stand trial does increase through the adolescent years, but that even older adolescents, aged 15 to 17, received lower scores than did adults. These results have implications for the continuing policy changes that have made the juvenile court increasingly adversarial.

Solving the linear interval tolerance problem for weight initialization of neural networks.

Determining good initial conditions for an algorithm used to train a neural network is considered a parameter estimation problem dealing with uncertainty about the initial weights. Interval analysis approaches model uncertainty in parameter estimation problems using intervals and formulating tolerance problems. Solving a tolerance problem is defining lower and upper bounds of the intervals so that the system functionality is guaranteed within predefined limits. The aim of this paper is to show how the problem of determining the initial weight intervals of a neural network can be defined in terms of solving a linear interval tolerance problem. The proposed linear interval tolerance approach copes with uncertainty about the initial weights without any previous knowledge or specific assumptions on the input data as required by approaches such as fuzzy sets or rough sets. The proposed method is tested on a number of well known benchmarks for neural networks trained with the back-propagation family of algorithms. Its efficiency is evaluated with regards to standard performance measures and the results obtained are compared against results of a number of well known and established initialization methods. These results provide credible evidence that the proposed method outperforms classical weight initialization methods.

Absence of radiographic progression of hip arthritis during infliximab treatment for ankylosing spondylitis.

This study aims to examine the impact of long-term treatment with the anti-TNF antibody infliximab on radiographic progression of hip arthritis in ankylosing spondylitis. Anteroposterior X-rays of the pelvis obtained at baseline from consecutive patients with ankylosing spondylitis and bilateral hip arthritis were compared with X-rays obtained after 6 ± 2.5 years (mean ± SD) of continuous infliximab treatment. Analysis was performed by the Bath Ankylosing Spondylitis Radiology Hip Index (BASRI-h) scoring system (min 0, max 4). Hip joint space width was also assessed by the average of measurements at three distinct sites between the acetabulum and femoral head. In 23 patients with active disease (21 men, mean age and disease duration of 45 and 16 years, respectively), the BASRI-h score at baseline was 1 in 7, 2 in 16, 3 in 16, and 4 in 7 hips (including two arthroplasties). Individual BASRI-h scores at baseline (2.50 ± 0.86, mean ± SD) remained unchanged in all patients at end of follow-up. At baseline, the average width of the whole joint space (3.56 ± 0.70 mm, n = 44) was not associated with disease activity measurements but negatively correlated with BAS functional index (Spearman r = -0.5, P = 0.007). After 2-10 years of infliximab treatment, the average width of the whole joint space in these patients (3.59 ± 0.79 mm) was not reduced. These results suggest that radiographic progression of hip arthritis in ankylosing spondylitis may be arrested during infliximab treatment.

Effects of teriparatide in postmenopausal women with osteoporosis pre-treated with bisphosphonates: 36-month results from the European Forsteo Observational Study.

OBJECTIVES: To describe fracture rates, back pain, and health-related quality of life (HRQoL) in postmenopausal women with osteoporosis and prior bisphosphonate therapy, treated with teriparatide for up to 18 months and followed up for a further 18 months. DESIGN: Prospective, multinational, and observational study. METHODS: Data on prior bisphosphonate use, clinical fractures, back pain visual analog scale (VAS), and HRQoL (EQ-5D) were collected over 36 months. Fracture data were summarized in 6-month intervals and analyzed using logistic regression with repeated measures. Changes from baseline in back pain VAS and EQ-VAS were analyzed using a repeated measures model. RESULTS: Of the 1581 enrolled patients with follow-up data, 1161 (73.4%) had a history of prior bisphosphonate use (median duration: 36 months). Of them, 169 (14.6%) sustained ≥1 fracture during 36-month follow-up. Adjusted odds of fracture were significantly decreased at each 6-month interval compared with the first 6 months of teriparatide treatment: 37% decrease in the 12 to <18 months period during teriparatide treatment (P=0.03) and a 76% decrease in the 12- to 18-month period after teriparatide was discontinued (P<0.001). Significant reductions in back pain and improvement in HRQoL were observed. CONCLUSIONS: Postmenopausal women with severe osteoporosis previously treated with bisphosphonates had a significant reduction in the incidence of fractures compared with the first 6 months of therapy, a reduction in back pain and an improvement in HRQoL during up to 18 months of teriparatide treatment. These outcomes were still evident for at least 18 months after teriparatide was discontinued. The results should be interpreted in the context of an uncontrolled, observational study in a routine clinical setting.

Fracture Incidence, Quality of Life, and Back Pain during 18-Months Treatment with Teriparatide in Greek Postmenopausal Women with Osteoporosis: Results from the European Forsteo Observational Study.

Objective. To evaluate fracture incidence, effects on health-related quality of life(QoL), back pain (BP) occurrence and treatment compliance in Greek post-menopausal osteoporotic women treated with teriparatide (TPTD) for up to 18 months, in a naturalistic setting. Methods. 301 patients provided baseline information on demographic characteristics, fracture history, osteoporosis-related medication and risk factors. During treatment, QoL and BP severity were evaluated. Results. Mean (SD) age was 69.5 (±8.5) years. Fracture history was reported by 92.5% of patients. Incidence of fractures (per 10,000 patients/years) ranged from 402 during 0-6 months of treatment, to 346 during 12-18 months. All 5 dimensions of QoL showed improvement. At baseline and 18 months, BP was reported by 93.2% and 64.2% of patients, respectively. BP and limitation of activities were quantified as moderate or severe by 89.9% and 62.3% of patients at baseline versus 32.4% and 14.8% at 18 months. Patients on treatment at 6, 12, 17, and 18 months were 92.6%, 88.3%, 79.6%, and 36.5%, respectively. Conclusions. In the Greek EFOS study cohort, patients prescribed TPTD were severely osteoporotic, with considerable health-related problems. Significant improvements in QoL and BP together with low fracture rates and high compliance have been recorded during treatment.