Maternal biomarkers in predicting neonatal sepsis after preterm premature rupture of membranes in preterm infants.

AIM: This retrospective cohort study aimed to assess the utility of maternal C-reactive protein (CRP) and leukocyte levels in predicting neonatal sepsis after preterm premature rupture of membranes (pPROM). METHODS: We conducted a retrospective cohort study (2009-2021), encompassing preterm infants born ≤29 + 6 weeks of gestation following pPROM. The primary outcome was early-onset neonatal sepsis within the initial 72 h of life. RESULTS: We analysed data from 706 patients with a median gestational age at pPROM of 25.1 weeks and a median gestational age at birth of 26.4 weeks. Overall survival rate was 86.1%, with 65.7% survival without severe morbidities. These rates were significantly worse in preterm infants with sepsis. Maternal CRP and leukocyte levels correlated significantly with neonatal infection markers and sepsis. However, their predictive values, correlation coefficients, and area under the curve values were generally low. Using maternal CRP ≥2 mg/dL to predict neonatal sepsis yielded a positive predictive value of 18.5%, negative predictive value of 91.5%, AUC of 0.589, 45.5% sensitivity, and 74.5% specificity. CONCLUSION: Maternal CRP and leukocyte levels were ineffective as a tool for predicting early-onset neonatal sepsis following early pPROM. Consequently, these biomarkers lack the reliability required for clinical decision-making in this context.

Vaginal Microbial Colonization after Antibiotic Treatment in Women with Preterm Premature Rupture of Membranes: An Observational Cohort Study.

Preterm premature rupture of membranes (pPROM) stands as a primary contributor to preterm deliveries worldwide, closely linked to consequential infectious peripartum complications, including chorioamnionitis and early-onset neonatal sepsis. As a prophylactic measure, individuals following pPROM routinely undergo antibiotic treatment. The aim of this study was to evaluate changes in the vaginal microbial colonization after antibiotic treatment following pPROM. Therefore, we retrospectively assessed the impact of antibiotic treatment on the maternal vaginal microbial colonization in 438 post-pPROM patients delivering before 29 gestational weeks. Vaginal samples were collected for microbiological analysis before and after antibiotic administration and analysed for seventeen pre-defined microbial groups. We observed eradication in eleven microbial groups, including beta-hemolytic streptococci group B and Gardnerella vaginalis. No significant reduction was found for the remaining groups, including Escherichia (E.) coli. Moreover, we found a notable increase in resistant bacteria after antibiotic treatment. In conclusion, broad-spectrum antimicrobial treatment exhibited substantial efficacy in eradicating the majority of pathogens in our cohort. However, certain pathogens, notably E. coli, showed resilience. Given E. coli's prominent role in infectious peripartum complications, our findings underline the challenges in antibiotic management post-pPROM and the need to establish international guidelines, particularly regarding emerging concerns about antibiotic resistances.

Clinical Early-Onset Sepsis Is Equally Valid to Culture-Proven Sepsis in Predicting Outcome in Infants after Preterm Rupture of Membranes.

BACKGROUND: Culture-proven sepsis is the gold standard in early-onset neonatal sepsis diagnosis. Infants born ≤29 weeks gestation after preterm rupture of membranes in the years 2009-2015 were included in a retrospective cohort study performed at a level III fetal-maternal unit. The study aimed to compare culture-proven sepsis, clinical sepsis and positive laboratory biomarkers ≤72 h as predictors of mortality before discharge and the combined outcome of mortality or severe short-term morbidity (severe cerebral morbidity, bronchopulmonary dysplasia and retinopathy). RESULTS: Of the 354 patients included, culture-proven sepsis, clinical sepsis and laboratory biomarkers were positive in 2.3%, 8.5% and 9.6%, respectively. The mortality rate was 37.5% for patients with culture-proven sepsis (3/8), 33.3% for patients with clinical sepsis (10/30) and 8.8% for patients with positive laboratory biomarkers (3/34), respectively. Mortality or severe morbidity occurred in 75.0% of patients with culture-proven sepsis (6/8), 80.0% of patients with clinical sepsis (24/30) and 44.1% of patients with positive laboratory biomarkers (15/34), respectively. CONCLUSION: In preterm infants after preterm rupture of membranes, clinical sepsis was almost four times more common and at least equally valuable in predicting mortality and mortality or severe morbidity compared to culture-proven sepsis.

The fetal fibronectin test is superior to cervical length measurement in predicting preterm birth in twin pregnancies: a retrospective observational study.

OBJECTIVES: Twin pregnancies have a higher likelihood to experience spontaneous preterm birth (PTB). Those with imminent PTB need to be determined in order to undergo fetal lung maturation with glucocorticoids and therewith improve neonatal outcomes. The aim of this study was to assess the predictive value of the fetal fibronectin (fFN) test and the measurement of cervical length in twin pregnancies with symptoms of imminent PTB. STUDY DESIGN: We performed an observational study on all twin pregnancies at the Medical University Vienna. Women were admitted to the hospital either due to symptoms of imminent PTB or due to a shortening of the cervical length before completed 34 weeks of gestational age. Logistic regression analysis was performed to assess the predictive value of the fFN test and cervical length on imminent preterm birth. RESULTS: The data of 82 women with twin pregnancies were eligible, of which 10 (12 %) had a positive, 45 (55 %) a negative, 21 (26 %) an unclear fFN result, and 6 (7 %) showed missing data. Cervical length ≤20 mm did not show any statistical significant prediction of PTB in our study cohort. After 7 days, 4/10 (40 %) pregnant women with positive fFN test gave birth, while 4/45 (9 %) women with a negative fFN test gave birth. Within 14 days after hospitalization, 6/10 (60 %) women with a positive fFN test gave birth, compared to 4/45 (9 %) with a negative fFN test. The positive fFN test was a statistically significant predictor of PTB within 7 days (p = 0.02) and 14 days (p = 0.004), respectively. CONCLUSION: The fFN test has the potential to detect women with twin pregnancies, who are at risk of giving birth within the following days. Hence, the practice of hospitalizing women solely due to the shortening of the cervical length cannot be supported.

Separating Business Logic from Medical Knowledge in Digital Clinical Workflows Using Business Process Model and Notation and Arden Syntax.

BACKGROUND: Evidence-based clinical guidelines have a major positive effect on the physician's decision-making process. Computer-executable clinical guidelines allow for automated guideline marshalling during a clinical diagnostic process, thus improving the decision-making process. OBJECTIVES: Implementation of a digital clinical guideline for the prevention of mother-to-child transmission of hepatitis B as a computerized workflow, thereby separating business logic from medical knowledge and decision-making. METHODS: We used the Business Process Model and Notation language system Activiti for business logic and workflow modeling. Medical decision-making was performed by an Arden-Syntax-based medical rule engine, which is part of the ARDENSUITE software. RESULTS: We succeeded in creating an electronic clinical workflow for the prevention of mother-to-child transmission of hepatitis B, where institution-specific medical decision-making processes could be adapted without modifying the workflow business logic. CONCLUSION: Separation of business logic and medical decision-making results in more easily reusable electronic clinical workflows.

Executable medical guidelines with Arden Syntax-Applications in dermatology and obstetrics.

INTRODUCTION: Clinical decision support systems (CDSSs) are being developed to assist physicians in processing extensive data and new knowledge based on recent scientific advances. Structured medical knowledge in the form of clinical alerts or reminder rules, decision trees or tables, clinical protocols or practice guidelines, score algorithms, and others, constitute the core of CDSSs. Several medical knowledge representation and guideline languages have been developed for the formal computerized definition of such knowledge. One of these languages is Arden Syntax for Medical Logic Systems, an International Health Level Seven (HL7) standard whose development started in 1989. Its latest version is 2.10, which was presented in 2014. In the present report we discuss Arden Syntax as a modern medical knowledge representation and processing language, and show that this language is not only well suited to define clinical alerts, reminders, and recommendations, but can also be used to implement and process computerized medical practice guidelines. METHODS: This section describes how contemporary software such as Java, server software, web-services, XML, is used to implement CDSSs based on Arden Syntax. Special emphasis is given to clinical decision support (CDS) that employs practice guidelines as its clinical knowledge base. RESULTS: Two guideline-based applications using Arden Syntax for medical knowledge representation and processing were developed. The first is a software platform for implementing practice guidelines from dermatology. This application employs fuzzy set theory and logic to represent linguistic and propositional uncertainty in medical data, knowledge, and conclusions. The second application implements a reminder system based on clinically published standard operating procedures in obstetrics to prevent deviations from state-of-the-art care. A to-do list with necessary actions specifically tailored to the gestational week/labor/delivery is generated. DISCUSSION: Today, with the latest versions of Arden Syntax and the application of contemporary software development methods, Arden Syntax has become a powerful and versatile medical knowledge representation and processing language, well suited to implement a large range of CDSSs, including clinical-practice-guideline-based CDSSs. Moreover, such CDS is provided and can be shared as a service by different medical institutions, redefining the sharing of medical knowledge. Arden Syntax is also highly flexible and provides developers the freedom to use up-to-date software design and programming patterns for external patient data access.

Clinical Workflow Modeling in Obstetrics: Hepatitis B in Pregnancy.

Evidence-based clinical guidelines positively effect physician decision-making. Actionable clinical guidelines that actively trigger alerts, reminders, and instructive texts will increase effectiveness. We applied Activiti, a Business Process Model and Notation language system to model a clinical guideline for the prevention of mother-to-child transmission of hepatitis B as a computerized clinical workflow. Furthermore, we implemented an interconnected Arden-Syntax-based medical rule engine, which is part of the ARDENSUITE software.

The early prediction of neonatal morbidity and mortality in singleton small for gestational age infants with a birthweight < 1,500 g.

OBJECTIVE: Identify factors for discrimination of "high" and "low risk" small for gestational age infants. STUDY DESIGN: Singleton infants born small for gestational age with a birthweight  <1,500 g between 1999 and 2007 were included. Maternal, placental, and infant related factors were analyzed with regard to mortality and morbidity. Patients who died or suffered from complications were defined "high risk" as opposed to "low risk". Parameters associated with "high risk" were identified and an equation established to predict the minimal expected probability to die or suffer from neonatal morbidity. RESULTS: Around 231 patients showed a mortality rate of 12.6 %, respiratory distress syndrome in 35.5 %, necrotizing enterocolitis in 8.2 % and neurological morbidities in 6.5 %. Of these, 58.9 % survived without complications. The factors for discrimination of "high" and "low risk" were Z-score of birth weight, gestational age, and pH. CONCLUSION: We facilitate prognostication by classifying small for gestational age preterms into "low" and "high risk".

Randomized controlled trials in pregnancy: scientific and ethical aspects. Exposure to different opioid medications during pregnancy in an intra-individual comparison.

BACKGROUND: Chronic medical conditions such as opioid dependence require evidence-based treatment recommendations. However, pregnant women are under-represented in clinical trials. We describe the first within-subject comparison of maternal and neonatal outcomes for methadone- versus buprenorphine-exposed pregnancies. Although methadone is the established treatment of pregnant opioid-dependent women, recent investigations have shown a trend for a milder neonatal abstinence syndrome (NAS) under buprenorphine. However, it is not only the choice of maintenance medication that determines the occurrence of NAS; other factors such as maternal metabolism, illicit substance abuse and nicotine consumption also influence its severity and duration and represent confounding factors in the assessment of randomized clinical trials. CASE SERIES DESCRIPTION: Three women who were part of the European cohort of a randomized, double-blind multi-center trial with a contingency management tool [the Maternal Opioid Treatment: Human Experimental Research (MOTHER) study], each had two consecutive pregnancies and were maintained on either methadone or buprenorphine for their first and then the respective opposite, still-blinded medication for their second pregnancy. Birth measurements, the total neonatal abstinence score, the total amounts of medication used to treat NAS and the days of NAS treatment duration were assessed. RESULTS: Both medications were effective and safe in reducing illicit opioid relapse and avoiding preterm labor. Methadone maintenance yielded to a significantly higher neonatal birth weight. Data patterns suggest that buprenorphine exposure was associated with lower neonatal abstinence syndrome (NAS) scores. Findings from this unique case series are consistent with earlier reports using between-group analyses. CONCLUSIONS: Buprenorphine has the potential to become an established treatment alternative to methadone for pregnant opioid-dependent women. Under special consideration of ethical boundaries, psychopharmacological treatment during pregnancy must be addressed as an integral part of clinical research projects in order to optimize treatment for women and neonates.

Asymptomatic bacterial vaginosis and intermediate flora as risk factors for adverse pregnancy outcome.

We updated a previously published meta-analysis to evaluate bacterial vaginosis (BV) and intermediate vaginal flora as risk factors for adverse pregnancy outcome. Selection criteria were original, published, English-language reports of cohort studies or control groups of clinical trials including women <37 weeks' gestation with intact amniotic membranes. All women had to be screened for BV, diagnosed either by clinical criteria or by criteria based on Gram-stain findings. Outcomes were preterm delivery, late miscarriages, maternal or neonatal infections, and perinatal mortality. Fourteen new studies with results for 10,286 patients were included, so that results for 30,518 patients in 32 studies were available for this meta-analysis. BV more than doubled the risk of preterm delivery in asymptomatic patients (OR: 2.16, 95% CI: 1.56-3.00) and in patients with symptoms of preterm labor (OR: 2.38, 95% CI: 1.02-5.58). BV also significantly increased the risk of late miscarriages (OR: 6.32, 95% CI: 3.65-10.94) and maternal infection (OR: 2.53, 95% CI 1.26-5.08) in asymptomatic patients. No significant results were calculated for the outcomes of neonatal infection or perinatal mortality. Also, intermediate vaginal flora was not significantly associated with any outcome included. The results of this meta-analysis confirm that BV is a risk factor for preterm delivery and maternal infectious morbidity and a strong risk factor for late miscarriage.

The end of submacular surgery for age-related macular degeneration? A meta-analysis.

BACKGROUND: The aim of this meta-analysis was to summarize and to discuss the results of the four main submacular surgical procedures for age-related macular degeneration (AMD) as reported in the literature through 2004 and to compare them to the Submacular Surgery Trials (SST) data. METHODS: The existing data in the literature on submacular surgery for AMD from 1992 to 2004 were evaluated. The main outcomes were proportion of patients with two or more lines of improvement in visual acuity (VA) and proportion with two or more lines of deterioration in VA after surgery. RESULTS: Eighty-eight studies including 1,915 cases met the inclusion criteria. Estimates for the treatment outcome within the four groups of treatment based on a logistic regression model gave comparable results for removal of choroidal neovascularization (CNV) (improvement of VA 28%, deterioration of VA 25%), macular translocation (improvement of VA 31%, deterioration of VA 27%), and for transplantation of pigment epithelium (improvement of VA 22%, deterioration of VA 21%). Estimates for removal of subretinal hemorrhage were significantly different (improvement of VA 62%, deterioration of VA 13%). CONCLUSIONS: Selected case series showed superior results of VA compared to the SST. The question of whether this is due to selection bias that seems inevitable when dealing with medium-sized nonrandomized case series or due to better results in single centers cannot be answered. In our opinion there still seem to be indications for submacular surgery such as in patients with AMD with low preoperative VA due to large hemorrhagic or fibrotic membranes or nonresponders to photodynamic therapy (PDT).

Secondary predictors of preterm labour.

In addition to primary predictors of preterm birth which are used to estimate the baseline risk of preterm birth, secondary predictors (based on examinations done during the current pregnancy) allow a more accurate assessment of the risk of preterm birth in individual women. Screening for early signs of spontaneous preterm labour has always been an important topic in obstetric care. During the last two decades, the detection of fetal fibronectin (FFN) from cervicovaginal secretions and cervical shortening diagnosed by transvaginal ultrasonography have emerged as the major secondary predictors of preterm birth. Both markers have been extensively studied and consistently shown to be strong short term predictors of preterm birth across a wide range of gestational ages. Other secondary predictors that confirm the role of intrauterine infection in the pathogenesis of preterm birth are bacterial vaginosis (BV) and elevated levels of interleukin (IL)-6, IL-8, ferritin and granulocyte colony-stimulating factor. Apart from BV, inflammatory markers are still not routinely used. The sensitivity of single markers in predicting preterm birth is only moderate and serial examinations of markers, combinations of different markers and multiple marker tests have been studied, with limited results. Studies of interventions in order to prevent preterm birth have also yielded mixed benefits, as a consequence of which the use of these markers to screen low risk pregnancies is generally not recommended. Currently, secondary predictors of preterm birth are used mainly to design new intervention studies tailored to specific high risk populations and to avoid unnecessary interventions in the management of high risk women.

Controversies in diagnosis of preterm labour.

Despite scientific advances, efforts to prevent preterm birth can be disappointing. Obstetric care must focus on strategies to improve the outcome of preterm infants. The major goal is to delay preterm birth long enough to allow the transfer of women about to deliver preterm to a facility with a neonatal intensive care unit and to administer corticosteroids to enhance fetal lung maturation. A prerequisite for the success of this strategy is the reliable identification of women who will give birth preterm. Although symptoms of preterm labour strongly suggest preterm birth, contractions-even if combined with cervical effacement and dilation-do not reliably predict preterm birth. The diagnosis of true preterm labour that will eventually lead to preterm birth has been facilitated by the use of transvaginal cervical ultrasonography and by the detection of fetal fibronectin (FFN) in cervicovaginal secretions. The main clinical value of these tests is that preterm birth is very unlikely if the results of both tests are negative. This may help to avoid unnecessary transfer, hospitalisation and treatment of women with false preterm labour. The detection of phosphorylated insulin-like growth factor binding protein-1 in cervicovaginal secretions, or elevated levels of inflammatory markers, like interleukin-6, interleukin-8 and tumour necrosis factor-alpha (TNF-alpha), also predict preterm birth in symptomatic women. These markers, however, are not routinely used to predict preterm birth in women with symptoms of preterm labour.

Knowledge acquisition in the fuzzy knowledge representation framework of a medical consultation system.

This paper describes the fuzzy knowledge representation framework of the medical computer consultation system MedFrame/CADIAG-IV as well as the specific knowledge acquisition techniques that have been developed to support the definition of knowledge concepts and inference rules. As in its predecessor system CADIAG-II, fuzzy medical knowledge bases are used to model the uncertainty and the vagueness of medical concepts and fuzzy logic reasoning mechanisms provide the basic inference processes. The elicitation and acquisition of medical knowledge from domain experts has often been described as the most difficult and time-consuming task in knowledge-based system development in medicine. It comes as no surprise that this is even more so when unfamiliar representations like fuzzy membership functions are to be acquired. From previous projects we have learned that a user-centered approach is mandatory in complex and ill-defined knowledge domains such as internal medicine. This paper describes the knowledge acquisition framework that has been developed in order to make easier and more accessible the three main tasks of: (a) defining medical concepts; (b) providing appropriate interpretations for patient data; and (c) constructing inferential knowledge in a fuzzy knowledge representation framework. Special emphasis is laid on the motivations for some system design and data modeling decisions. The theoretical framework has been implemented in a software package, the Knowledge Base Builder Toolkit. The conception and the design of this system reflect the need for a user-centered, intuitive, and easy-to-handle tool. First results gained from pilot studies have shown that our approach can be successfully implemented in the context of a complex fuzzy theoretical framework. As a result, this critical aspect of knowledge-based system development can be accomplished more easily.

Bacterial vaginosis as a risk factor for preterm delivery: a meta-analysis.

OBJECTIVE: We performed a meta-analysis to evaluate bacterial vaginosis as a risk factor for preterm delivery. STUDY DESIGN: Selection criteria were (1). the data appeared in original, published English-language reports of prospective studies or control groups of clinical trials that included women at <37 weeks of gestation with intact amniotic membranes, (2). all the women had to have been screened for bacterial vaginosis that was diagnosed by either clinical criteria or criteria that were based on Gram stain findings, and (3). the outcomes were preterm delivery, spontaneous abortion, maternal or neonatal infection, and perinatal death. RESULTS: Eighteen studies with results for 20,232 patients were included. Bacterial vaginosis increased the risk of preterm delivery >2-fold (odds ratio, 2.19; 95% CI, 1.54-3.12). Higher risks were calculated for subgroups of studies that screened for bacterial vaginosis at <16 weeks of gestation (odds ratio, 7.55; 95% CI, 1.80-31.65) or at <20 weeks of gestation (odds ratio, 4.20; 95% CI, 2.11-8.39). Bacterial vaginosis also significantly increased the risk of spontaneous abortion (odds ratio, 9.91; 95% CI, 1.99-49.34) and maternal infection (odds ratio, 2.53; 95% CI, 1.26-5.08). No significant results were calculated for the outcome of neonatal infection or perinatal death. CONCLUSION: Bacterial vaginosis, early in pregnancy, is a strong risk factor for preterm delivery and spontaneous abortion.

Fetal fibronectin--how useful is it in the prediction of preterm birth?

OBJECTIVE: To determine the value of cervicovaginal fetal fibronectin as a marker for preterm delivery, a previously published meta-analysis was updated. STUDY DESIGN: Selection criteria confined the analysis to English-language original reports of prospective studies including women at <37 weeks' gestation with intact amniotic membranes. For the outcomes of delivery <37 or <34 weeks' gestation or delivery within 7, 14, or 21 days after fibronectin sampling, we calculated sensitivity and specificity rates for each study, for subgroups of studies, and for all studies combined. RESULTS: A total of 40 studies were included. Statistical heterogeneity was seen in the majority of calculations of combined results and a random-effects model was used in these cases. For the outcomes of delivery <37 and <34 weeks' gestation, overall sensitivity rates were 52% and 53%, and overall specificity rates were 85% and 89%, respectively. For the outcomes of delivery within 7, 14, and 21 days, we calculated sensitivity rates of 71%, 67%, and 59% and specificity rates of 89%, 89%, and 92%, respectively. For the subgroup of women with symptoms of preterm labour, sensitivity rates for delivery <37 and <34 weeks' gestation or delivery within 7, 14, and 21 days of 54%, 63%, 77%, 74%, and 70% and specificity rates of 85%, 86%, 87%, 87%, and 90% were calculated. CONCLUSIONS: Cervicovaginal fetal fibronectin is an effective short-term marker of preterm delivery, especially in women with symptoms of preterm labour. Because results appear to be heterogeneous in different studies, caution should be taken when they are applied to a specific population.

Antibiotic treatment of bacterial vaginosis in pregnancy: a meta-analysis.

OBJECTIVE: The purpose of this study was to evaluate the effectiveness of antibiotic treatment of bacterial vaginosis in pregnancy to reduce preterm delivery. STUDY DESIGN: We performed a meta-analysis of published, English-language, randomized, placebo-controlled clinical trials of antibiotic treatment of bacterial vaginosis in pregnant women with intact amniotic membranes at <37 weeks of gestation. Primary outcomes included preterm delivery, perinatal or neonatal death, and neonatal morbidity. RESULTS: Ten studies with results for 3969 patients were included. In patients without preterm labor, antibiotic treatment did not significantly decrease preterm delivery at <37 weeks of gestation, in all patients combined (odds ratio, 0.83; 95% CI, 0.57-1.21) nor in high-risk patients with a previous preterm delivery (odds ratio, 0.50; 95% CI, 0.22-1.12). In both groups, significant statistical heterogeneity was observed. A significant reduction in preterm delivery and no statistical heterogeneity were observed in 338 high-risk patients who received oral regimens with treatment durations of > or =7 days (odds ratio, 0.42; 95% CI, 0.27-0.67). Nonsignificant effects and no statistical heterogeneity were observed in low-risk patients (odds ratio, 0.94; 95% CI, 0.71-1.25) and with vaginal regimens (odds ratio, 1.25; 95% CI: 0.86-1.81). In one study antibiotic treatment in patients with preterm labor led to a nonsignificant decrease in the rate of preterm deliveries (odds ratio, 0.31; 95% CI, 0.03-3.24). CONCLUSION: The screening of pregnant women who have bacterial vaginosis and who have had a previous preterm delivery and treatment with an oral regimen of longer duration can be justified on the basis of current evidence. More studies are needed to confirm the effectiveness of this strategy, both in high-risk patients without preterm labor and in patients with preterm labor.

Drug therapy of urinary urge incontinence: a systematic review.

OBJECTIVE: To review the efficacy of drug therapy for urinary urge incontinence by examining the published literature. METHODS OF STUDY SELECTION: In October 1999, we searched the medical databases MEDLINE, EMBASE, and Cochrane Controlled Trials Register to identify prospective randomized, double-blind, placebo-controlled clinical trials in the English literature evaluating drug therapy (except hormonal therapy) of urinary urge incontinence. Trials were categorized by type of drug and outcome variables. TABULATION, INTEGRATION, AND RESULTS: Forty-seven trials were identified. Twenty-four, 12, and 11 trials evaluated anticholinergic drugs, drugs with anticholinergic and calcium antagonistic properties, and alternative regimens, respectively. Data regarding treatment effects of anticholinergic drugs are consistent with a high therapeutic efficacy and characteristic side effects. Therapeutic efficacy and side effect patterns of terodiline, an agent with anticholinergic and calcium antagonistic properties, were comparable to those of anticholinergic agents. Terodiline, however, has been withdrawn from the market because of its association with cardiac arrhythmia. Of the investigated alternative drug regimens, the papaverine-like smooth muscle relaxant flavoxate was reported to be ineffective. Studies investigating the dopamine agonist bromocryptine, the alpha-adrenoceptor blocker prazosin, or the gamma-aminobutyric acid receptor agonist baclofen showed subjective and/or objective improvement of symptoms without reaching statistical significance, whereas the tricyclic antidepressant doxepin, the neurotoxin capsaicin, and the prostaglandin synthase inhibitor flurbiprofen led to statistically significant subjective and/or objective improvement of symptoms. No data for subjective and/or objective improvement of symptoms could be extracted from the studies using the anticholinergic and calcium antagonistic agent propiverine and the calcium antagonist thiphenamil. CONCLUSION: Published trials support anticholinergic drugs as efficacious therapy for urinary urge incontinence, with predictable side effects. At present, these agents represent the pharmacological treatment of choice for this condition. The potential value of selected alternative drugs is underscored by the available data.

Evaluation of two different models of semi-automatic knowledge acquisition for the medical consultant system CADIAG-II/RHEUMA.

As part of a plan to promote semi-automatic knowledge acquisition for the medical consultant system CADIAG-II/RHEUMA, this study sought to explore and cope with the variability of results that may be anticipated when performing knowledge acquisition with patient data from different patient settings. Patient data were drawn both from a published study for the classification of rheumatoid arthritis (RA) and from a large database of rheumatological patient charts developed for the CADIAG-II/RHEUMA system. An analysis of the relationships between RA and selected CADIAG-II/RHEUMA symptoms was done using two models. In one of them, we controlled for the differences in baseline frequencies of symptoms and diseases in the two study populations as an important factor influencing the results of the calculations. Other factors that were identified included inconsistent definitions of symptoms and diseases, and the different composition of study groups in the two study populations. By eliminating differences in baseline frequencies as the most important bias, the results obtained from the two different knowledge sources became more consistent. All remaining inconsistencies and uncertainties about the contribution and relative importance of the factors were formalized using fuzzy intervals.