Object-Oriented Legacy System Trace-based Logic Testing

When reengineering legacy systems, it is crucial to assess if the legacy behavior has been preserved or how it changed due to the reengineering effort. Ideally if a legacy system is covered by tests, running the tests on the new version can identify potential differences or discrepancies. However, writing tests for an unknown and large system is difficult due to the lack of internal knowledge. It is especially difficult to bring the system to an appropriate state. Our solution is based on the acknowledgment that one of the few trustable piece of information available when approaching a legacy system is the running system itself. Our approach reifies the execution traces and uses logic programming to express tests on them. Thereby it eliminates the need to programatically bring the system in a particular state, and handles the test-writer a high-level abstraction mechanism to query the trace. The resulting system, called TESTLOG, was used on several real-world case studies to validate our claims.

Variability of anti-PF4/heparin antibody results obtained by the rapid testing system ID-H/PF4-PaGIA

BACKGROUND: Recent studies have shown that a low clinical pretest probability may be adequate for excluding heparin-induced thrombocytopenia. However, for patients with intermediate or high pretest probability, laboratory testing is essential for confirming or refuting the diagnosis. Rapid assessment of anti-PF4/heparin-antibodies may assist clinical decision-making. OBJECTIVES: To evaluate the performance of rapid ID-H/PF4-PaGIA. In particular, we verified reproducibility of results between plasma and serum specimens, between fresh and frozen samples, and between different ID-H/PF4-polymer lots (polystyrene beads coated with heparin/PF4-complexes). PATIENTS/METHODS: The samples studied were 1376 plasma and 914 corresponding serum samples from patients investigated for suspected heparin-induced thrombocytopenia between January 2000 and October 2008. Anti-PF4/heparin-antibodies were assessed by ID-H/PF4-PaGIA, commercially available ELISAs and heparin-induced platelet aggregation test. RESULTS: Among 914 paired plasma/serum samples we noted discordant results (negative vs. low-titre positive) in nine instances (1%; 95%CI, 0.4-1.6%). Overall, agreement between titres assessed in plasma vs. serum was highly significant (Spearman correlation coefficient, 0.975; P < 0.0001). Forty-seven samples tested both fresh and after freezing/thawing showed a good agreement, with one discordant positive/negative result (Spearman correlation coefficient, 0.970; P < 0.0001). Among 1376 plasma samples we noted a strikingly variable incidence of false negative results (none - 82%; 95%CI, 66-98%), depending on the employed ID-H/PF4-polymer lot. Faulty lots can be recognized by titrating commercial positive controls and stored samples of HIT-patients. CONCLUSION: Laboratories performing the assay should implement stringent internal quality controls in order to recognize potentially faulty ID-H/PF4-polymer lots, thus avoiding false negative results.

Detection and identification of 700 drugs by multi-target screening with a 3200 Q TRAP LC-MS/MS system and library searching

The multi-target screening method described in this work allows the simultaneous detection and identification of 700 drugs and metabolites in biological fluids using a hybrid triple-quadrupole linear ion trap mass spectrometer in a single analytical run. After standardization of the method, the retention times of 700 compounds were determined and transitions for each compound were selected by a "scheduled" survey MRM scan, followed by an information-dependent acquisition using the sensitive enhanced product ion scan of a Q TRAP hybrid instrument. The identification of the compounds in the samples analyzed was accomplished by searching the tandem mass spectrometry (MS/MS) spectra against the library we developed, which contains electrospray ionization-MS/MS spectra of over 1,250 compounds. The multi-target screening method together with the library was included in a software program for routine screening and quantitation to achieve automated acquisition and library searching. With the help of this software application, the time for evaluation and interpretation of the results could be drastically reduced. This new multi-target screening method has been successfully applied for the analysis of postmortem and traffic offense samples as well as proficiency testing, and complements screening with immunoassays, gas chromatography-mass spectrometry, and liquid chromatography-diode-array detection. Other possible applications are analysis in clinical toxicology (for intoxication cases), in psychiatry (antidepressants and other psychoactive drugs), and in forensic toxicology (drugs and driving, workplace drug testing, oral fluid analysis, drug-facilitated sexual assault).

Preclinical testing of strategies for therapeutic targeting of human T-cell trafficking in vivo

Naive T cells are migratory cells that continuously recirculate between blood and lymphoid tissues. Antigen-specific stimulation of T cells within the lymph nodes reprograms the trafficking properties of T cells by inducing a specific set of adhesion molecules and chemokine receptors on their surface which allow these activated and effector T cells to effectively and specifically home to extralymphoid organs. The observations of organ-specific homing of T cells initiated the development of therapeutic strategies targeting adhesion receptors for organ-specific inhibition of chronic inflammation. As most adhesion receptors have additional immune functions besides mediating leukocyte trafficking, these drugs may have additional immunomodulatory effects. Therapeutic targeting of T-cell trafficking to the central nervous system is the underlying concept of a novel treatment of relapsing remitting multiple sclerosis with the humanized anti-alpha-4-integrin antibody natalizumab. In this chapter, we describe a possible preclinical in vivo approach to directly visualize the therapeutic efficacy of a given drug in inhibiting T-cell homing to a certain organ at the example of the potential of natalizumab to inhibit the trafficking of human T cells to the inflamed central nervous system in an animal model of multiple sclerosis.

ZeroG: overground gait and balance training system

A new overground body-weight support system called ZeroG has been developed that allows patients with severe gait impairments to practice gait and balance activities in a safe, controlled manner. The unloading system is capable of providing up to 300 lb of static support and 150 lb of dynamic (or constant force) support using a custom-series elastic actuator. The unloading system is mounted to a driven trolley, which rides along an overhead rail. We evaluated the performance of ZeroG's unloading system, as well as the trolley tracking system, using benchtop and human-subject testing. Average root-mean-square and peak errors in unloading were 2.2 and 7.2 percent, respectively, over the range of forces tested while trolley tracking errors were less than 3 degrees, indicating the system was able to maintain its position above the subject. We believe training with ZeroG will allow patients to practice activities that are critical to achieving functional independence at home and in the community.

A simple, economical, and effective portable paediatric mock circulatory system

Ventricular assist devices (VADs) and total artificial hearts have been in development for the last 50 years. Since their inception, simulators of the circulation with different degrees of complexity have been produced to test these devices in vitro. Currently, a new path has been taken with the extensive efforts to develop paediatric VADs, which require totally different design constraints. This paper presents the manufacturing details of an economical simulator of the systemic paediatric circulation. This simulator allows the insertion of a paediatric VAD, includes a pumping ventricle, and is adjustable within the paediatric range. Rather than focusing on complexity and physiological simulation, this simulator is designed to be simple and practical for rapid device testing. The simulator was instrumented with medical sensors and data were acquired under different conditions with and without the new PediaFlowTM paediatric VAD. The VAD was run at different impeller speeds while simulator settings such as vascular resistance and stroke volume were varied. The hydraulic performance of the VAD under pulsatile conditions could be characterized and the magnetic suspension could be tested via manipulations such as cannula clamping. This compact mock loop has proven to be valuable throughout the PediaFlow development process and has the advantage that it is uncomplicated and can be manufactured cheaply. It can be produced by several research groups and the results of different VADs can then be compared easily.

A realistic validation study of a new nitrogen multiple-breath washout system

Background For reliable assessment of ventilation inhomogeneity, multiple-breath washout (MBW) systems should be realistically validated. We describe a new lung model for in vitro validation under physiological conditions and the assessment of a new nitrogen (N2)MBW system. Methods The N2MBW setup indirectly measures the N2 fraction (FN2) from main-stream carbon dioxide (CO2) and side-stream oxygen (O2) signals: FN2 = 1−FO2−FCO2−FArgon. For in vitro N2MBW, a double chamber plastic lung model was filled with water, heated to 37°C, and ventilated at various lung volumes, respiratory rates, and FCO2. In vivo N2MBW was undertaken in triplets on two occasions in 30 healthy adults. Primary N2MBW outcome was functional residual capacity (FRC). We assessed in vitro error (√[difference]2) between measured and model FRC (100–4174 mL), and error between tests of in vivo FRC, lung clearance index (LCI), and normalized phase III slope indices (Sacin and Scond). Results The model generated 145 FRCs under BTPS conditions and various breathing patterns. Mean (SD) error was 2.3 (1.7)%. In 500 to 4174 mL FRCs, 121 (98%) of FRCs were within 5%. In 100 to 400 mL FRCs, the error was better than 7%. In vivo FRC error between tests was 10.1 (8.2)%. LCI was the most reproducible ventilation inhomogeneity index. Conclusion The lung model generates lung volumes under the conditions encountered during clinical MBW testing and enables realistic validation of MBW systems. The new N2MBW system reliably measures lung volumes and delivers reproducible LCI values.

What can be gained from comprehensive disaggregate surveillance? The Avon Surveillance System for Sexually Transmitted Infections

OBJECTIVE: To describe a new disaggregate surveillance system covering key diagnosed sexually transmitted infections in a UK locality. METHODS: The Avon System for Surveillance of Sexually Transmitted Infections (ASSIST) collects computerised person- and episode-based information about laboratory-diagnosed sexually transmitted infections from genitourinary medicine (GUM) clinics, the Avon Brook Clinic, and the Health Protection Agency and trust laboratories in primary care trusts in Avon. The features of the system are illustrated here, by describing chlamydia-testing patterns according to the source of test, age and sex, and by mapping the distribution of chlamydia across Bristol, UK. RESULTS: Between 2000 and 2004, there were 821,685 records of tests for sexually transmitted infections, with 23,542 positive results. The proportion of tests and positive results for chlamydia and gonorrhoea sent from general practice increased over time. Most chlamydia tests in both GUM and non-specialist settings were performed on women aged >25 years, but positivity rates were highest in women aged <25 years. The positivity rate remained stable between 2000 and 2004. Including data from all diagnostic settings, chlamydia rates were about twice as high as those estimated only from genitourinary clinic cases. CONCLUSIONS: The ASSIST model could be a promising new tool for planning and measuring sexual health services in England if it can become sustainable and provide more timely data using fewer resources. Collecting denominator data and including infections diagnosed in primary care are essential for meaningful surveillance.

Nanoduct(R) sweat testing for rapid diagnosis in newborns, infants and children with cystic fibrosis

Determination of chloride concentration in sweat is the current diagnostic gold standard for Cystic Fibrosis (CF). Nanoduct(R) is a new analyzing system measuring conductivity which requires only 3 microliters of sweat and gives results within 30 minutes. The aim of the study was to evaluate the applicability of this system in a clinical setting of three children's hospitals and borderline results were compared with sweat chloride concentration. Over 3 years, 1,041 subjects were tested and in 946 diagnostic results were obtained. In 95 children, Nanoduct(R) failed (9.1% failure rate), mainly due to failures in preterm babies and newborns. Assuming 59 mmol/L as an upper limit of normal conductivity, all our 46 CF patients were correctly diagnosed (sensitivity 100%, 95% CI: 93.1-100; negative predicted value 100% (95% CI: 99.6-100) and only 39 non CF's were false positive (39/900, 4.3%; specificity 95.7%, 95%CI: 94.2-96.9, positive predicted value 54.1% with a 95%CI: 43.4-65.0). Increasing the diagnostic limit to 80 mmol/L, the rate fell to 0.3% (3/900). CF patients had a median conductivity of 115 mmol/L; the non-CF a median of 37 mmol/L. In conclusion, the Nanoduct(R) test is a reliable diagnostic tool for CF diagnosis: It has a failure rate comparable to other sweat tests and can be used as a simple bedside test for fast and reliable exclusion, diagnosis or suspicion of CF. In cases with borderline conductivity (60-80 mmol/L) other additional methods (determination of chloride and genotyping) are indicated.

Sweat testing practice in Swiss hospitals

AIMS: To determine whether the current practice of sweat testing in Swiss hospitals is consistent with the current international guidelines. METHODS: A questionnaire was mailed to all children's hospitals (n = 8), regional paediatric sections of general hospitals (n = 28), and all adult pulmonology centres (n = 8) in Switzerland which care for patients with cystic fibrosis (CF). The results were compared with published "guidelines 2000" of the American National Committee for Clinical Laboratory Standards (NCCLS) and the UK guidelines of 2003. RESULTS: The response rate was 89%. All 8 children's hospitals and 18 out of 23 answering paediatric sections performed sweat tests but none of the adult pulmonology centres. In total, 1560 sweat tests (range: 5-200 tests/centre/year, median 40) per year were done. 88% (23/26) were using Wescor systems, 73% (19/26) the Macroduct system for collecting sweat and 31% (8/26) the Nanoduct system. Sweat chloride was determined by only 62% (16/26) of all centres; of these, only 63% (10/16) indicated to use the recommended diagnostic chloride-CF-reference value of >60 mmol/l. Osmolality was measured in 35%, sodium in 42% and conductivity in 62% of the hospitals. Sweat was collected for maximal 30-120 (median 55) minutes; only three centres used the maximal 30 minutes sample time recommended by the international guidelines. CONCLUSIONS: Sweat testing practice in Swiss hospitals was inconsistent and seldom followed the current international guidelines for sweat collection, analyzing method and reference values. Only 62% were used the chloride concentration as a diagnostic reference, the only accepted diagnostic measurement by the NCCLS or UK guidelines.

An implantable carotid sinus baroreflex activating system: surgical technique and short-term outcome from a multi-center feasibility trial for the treatment of resistant hypertension

OBJECTIVES: To assess perioperative outcomes and blood pressure (BP) responses to an implantable carotid sinus baroreflex activating system being investigated for the treatment of resistant hypertension. METHODS: We report on the first seventeen patients enrolled in a multicenter study. Bilateral perivascular carotid sinus electrodes (CSL) and a pulse generator (IPG) are permanently implanted. Optimal placement of the CSL is determined by intraoperative BP responses to test activations. Acute BP responses were tested postoperatively and during the first four months of follow-up. RESULTS: Prior to implant, BP was 189.6+/-27.5/110.7+/-15.3 mmHg despite stable therapy (5.2+/-1.8 antihypertensive drugs). The mean procedure time was 202+/-43 minutes. No perioperative strokes or deaths occurred. System tests performed 1 or up to 3 days postoperatively resulted in significant (all p < or = 0.0001) mean maximum reduction, with standard deviations and 95% confidence limits for systolic BP, diastolic BP and heart rate of 28+/-22 (17, 39) mmHg, 16+/-11 (10, 22) mmHg and 8+/-4 (6, 11) BPM, respectively. Repeated testing during 3 months of therapeutic electrical activation demonstrated a durable response. CONCLUSIONS: These preliminary data suggest an acceptable safety of the procedure with a low rate of adverse events and support further clinical development of baroreflex activation as a new concept to treat resistant hypertension.

Population pharmacokinetics of sevoflurane in conjunction with the AnaConDa: toward target-controlled infusion of volatiles into the breathing system

BACKGROUND: The Anesthetic Conserving Device (AnaConDa) uncouples delivery of a volatile anesthetic (VA) from fresh gas flow (FGF) using a continuous infusion of liquid volatile into a modified heat-moisture exchanger capable of adsorbing VA during expiration and releasing adsorbed VA during inspiration. It combines the simplicity and responsiveness of high FGF with low agent expenditures. We performed in vitro characterization of the device before developing a population pharmacokinetic model for sevoflurane administration with the AnaConDa, and retrospectively testing its performance (internal validation). MATERIALS AND METHODS: Eighteen females and 20 males, aged 31-87, BMI 20-38, were included. The end-tidal concentrations were varied and recorded together with the VA infusion rates into the device, ventilation and demographic data. The concentration-time course of sevoflurane was described using linear differential equations, and the most suitable structural model and typical parameter values were identified. The individual pharmacokinetic parameters were obtained and tested for covariate relationships. Prediction errors were calculated. RESULTS: In vitro studies assessed the contribution of the device to the pharmacokinetic model. In vivo, the sevoflurane concentration-time courses on the patient side of the AnaConDa were adequately described with a two-compartment model. The population median absolute prediction error was 27% (interquartile range 13-45%). CONCLUSION: The predictive performance of the two-compartment model was similar to that of models accepted for TCI administration of intravenous anesthetics, supporting open-loop administration of sevoflurane with the AnaConDa. Further studies will focus on prospective testing and external validation of the model implemented in a target-controlled infusion device.

Microbiological tined-lead examination: does prolonged sacral neuromodulation testing induce infection?

OBJECTIVE: To investigate whether prolonged sacral neuromodulation (SNM) testing induces a substantial risk of infection because of the percutaneous passage of the extension wire. PATIENTS AND METHODS: A consecutive series of 20 patients with negative prolonged SNM testing for >or=14 days who underwent tined-lead explantation were prospectively evaluated. The explanted tined leads were sent for microbiological examination. The tined lead, gluteal, and extension wire incision sites were investigated for clinical signs of infection according to the Centers for Disease Control and Prevention classification system. RESULTS: In all, 17 patients had bilateral and three unilateral implanted tined leads. The median (range) test period was 30 (21-62 days). Bacterial growth (Staphylococcus species) was detected in four of 20 (20%) patients on seven of 37 (19%) explanted tined leads. There were clinical signs of infection in one of 20 (5%) patients at none of 37 tined lead, one of 20 (5%) gluteal, and none of 20 extension wire incision sites. There were no clinical signs of infection in the remaining three of four patients with bacterial growth. CONCLUSIONS: After prolonged tined-lead testing, we found an infection rate comparable to that reported with the usual short test period. In addition, most patients with bacterial growth on tined leads showed no clinical signs of infection. Thus, prolonged tined-lead testing does not seem to induce clinically relevant infection, warranting randomized trials.