Double-blinded, randomized controlled trial comparing real versus placebo acupuncture to improve tolerance of diagnostic esophagogastroduodenoscopy without sedation: a study protocol

Background Sedation prior to performance of diagnostic esophagogastroduodenoscopy (EGDE) is widespread and increases patient comfort. But 98% of all serious adverse events during EGDEs are ascribed to sedation. The S3 guideline for sedation procedures in gastrointestinal endoscopy published in 2008 in Germany increases patient safety by standardization. These new regulations increase costs because of the need for more personnel and a prolonged discharge procedure after examinations with sedation. Many patients have difficulties to meet the discharge criteria regulated by the S3 guideline, e.g. the call for a second person to escort them home, to resign from driving and working for the rest of the day, resulting in a refusal of sedation. Therefore, we would like to examine if an acupuncture during elective, diagnostic EGDEs could increase the comfort of patients refusing systemic sedation. Methods/Design A single-center, double blinded, placebo controlled superiority trial to compare the success rates of elective, diagnostic EGDEs with real and placebo acupuncture. All patients aged 18 years or older scheduled for elective, diagnostic EGDE who refuse a systemic sedation are eligible. 354 patients will be randomized. The primary endpoint is the rate of successful EGDEs with the randomized technique. Intervention: Real or placebo acupuncture before and during EGDE. Duration of study: Approximately 24 months. Discussion Organisation/Responsibility The ACUPEND - Trial will be conducted in accordance with the protocol and in compliance with the moral, ethical, and scientific principles governing clinical research as set out in the Declaration of Helsinki (1989) and Good Clinical Practice (GCP). The Interdisciplinary Endoscopy Center (IEZ) of the University Hospital Heidelberg is responsible for design and conduct of the trial, including randomization and documentation of patients' data. Data management and statistical analysis will be performed by the independent Institute for Medical Biometry and Informatics (IMBI) and the Center of Clinical Trials (KSC) at the Department of General, Visceral and Transplantation Surgery, University of Heidelberg.

Comparison among gold standard techniques used for the validation of methods for occlusal caries detection

The aim of this in vitro study was to assess the agreement among four techniques used as gold standard for the validation of methods for occlusal caries detection. Sixty-five human permanent molars were selected and one site in each occlusal surface was chosen as the test site. The teeth were cut and prepared according to each technique: stereomicroscopy without coloring (1), dye enhancement with rhodamine B (2) and fuchsine/acetic light green (3), and semi-quantitative microradiography (4). Digital photographs from each prepared tooth were assessed by three examiners for caries extension. Weighted kappa, as well as Friedman's test with multiple comparisons, was performed to compare all techniques and verify statistical significant differences. Results: kappa values varied from 0.62 to 0.78, the latter being found by both dye enhancement methods. Friedman's test showed statistical significant difference (P < 0.001) and multiple comparison identified these differences among all techniques, except between both dye enhancement methods (rhodamine B and fuchsine/acetic light green). Cross-tabulation showed that the stereomicroscopy overscored the lesions. Both dye enhancement methods showed a good agreement, while stereomicroscopy overscored the lesions. Furthermore, the outcome of caries diagnostic tests may be influenced by the validation method applied. Dye enhancement methods seem to be reliable as gold standard methods.

Diagnostic value of animal-side antibody assays for rapid detection of Mycobacterium bovis or Mycobacterium microti infection in South American camelids

Tuberculosis (TB) in South American camelids (SAC) is caused by Mycobacterium bovis or Mycobacterium microti. Two serological methods, rapid testing (RT) and the dual-path platform (DPP) assay, were evaluated using naturally infected SAC. The study population included 156 alpacas and 175 llamas in Great Britain, Switzerland, and the United States. TB due to M. bovis (n = 44) or M. microti (n = 8) in 35 alpacas and 17 llamas was diagnosed by gross pathology examination and culture. Control animals were from herds with no TB history. The RT and the DPP assay showed sensitivities of 71% and 74%, respectively, for alpacas, while the sensitivity for llamas was 77% for both assays. The specificity of the DPP assay (98%) was higher than that of RT (94%) for llamas; the specificities of the two assays were identical (98%) for alpacas. When the two antibody tests were combined, the parallel-testing interpretation (applied when either assay produced a positive result) enhanced the sensitivities of antibody detection to 89% for alpacas and 88% for llamas but at the cost of lower specificities (97% and 93%, respectively), whereas the serial-testing interpretation (applied when both assays produced a positive result) maximized the specificity to 100% for both SAC species, although the sensitivities were 57% for alpacas and 65% for llamas. Over 95% of the animals with evidence of TB failed to produce skin test reactions, thus confirming concerns about the validity of this method for testing SAC. The findings suggest that serological assays may offer a more accurate and practical alternative for antemortem detection of camelid TB.

Diagnostic reproducibility of tumour budding in colorectal cancer: a multicentre, multinational study using virtual microscopy

Puppa G, Senore C, Sheahan K, Vieth M, Lugli A, Zlobec I, Pecori S, Wang L M, Langner C, Mitomi H, Nakamura T, Watanabe M, Ueno H, Chasle J, Conley S A, Herlin P, Lauwers G Y & Risio M (2012) Histopathology Diagnostic reproducibility of tumour budding in colorectal cancer: a multicentre, multinational study using virtual microscopy Aims:  Despite the established prognostic relevance of tumour budding in colorectal cancer, the reproducibility of the methods reported for its assessment has not yet been determined, limiting its use and reporting in routine pathology practice. Methods and results:  A morphometric system within telepathology was devised to evaluate the reproducibility of the various methods published for the assessment of tumour budding in colorectal cancer. Five methods were selected to evaluate the diagnostic reproducibility among 10 investigators, using haematoxylin and eosin (H&E) and AE1-3 cytokeratin-immunostained, whole-slide digital scans from 50 pT1-pT4 colorectal cancers. The overall interobserver agreement was fair for all methods, and increased to moderate for pT1 cancers. The intraobserver agreement was also fair for all methods and moderate for pT1 cancers. Agreement was dependent on the participants' experience with tumour budding reporting and performance time. Cytokeratin immunohistochemistry detected a higher percentage of tumour budding-positive cases with all methods compared to H&E-stained slides, but did not influence agreement levels. Conclusions:  An overall fair level of diagnostic agreement for tumour budding in colorectal cancer was demonstrated, which was significantly higher in early cancer and among experienced gastrointestinal pathologists. Cytokeratin immunostaining facilitated detection of budding cancer cells, but did not result in improved interobserver agreement.

Diagnostic performance of line-immunoassay based algorithms for incident HIV-1 infection

Background Serologic testing algorithms for recent HIV seroconversion (STARHS) provide important information for HIV surveillance. We have previously demonstrated that a patient's antibody reaction pattern in a confirmatory line immunoassay (INNO-LIA™ HIV I/II Score) provides information on the duration of infection, which is unaffected by clinical, immunological and viral variables. In this report we have set out to determine the diagnostic performance of Inno-Lia algorithms for identifying incident infections in patients with known duration of infection and evaluated the algorithms in annual cohorts of HIV notifications. Methods Diagnostic sensitivity was determined in 527 treatment-naive patients infected for up to 12 months. Specificity was determined in 740 patients infected for longer than 12 months. Plasma was tested by Inno-Lia and classified as either incident (< = 12 m) or older infection by 26 different algorithms. Incident infection rates (IIR) were calculated based on diagnostic sensitivity and specificity of each algorithm and the rule that the total of incident results is the sum of true-incident and false-incident results, which can be calculated by means of the pre-determined sensitivity and specificity. Results The 10 best algorithms had a mean raw sensitivity of 59.4% and a mean specificity of 95.1%. Adjustment for overrepresentation of patients in the first quarter year of infection further reduced the sensitivity. In the preferred model, the mean adjusted sensitivity was 37.4%. Application of the 10 best algorithms to four annual cohorts of HIV-1 notifications totalling 2'595 patients yielded a mean IIR of 0.35 in 2005/6 (baseline) and of 0.45, 0.42 and 0.35 in 2008, 2009 and 2010, respectively. The increase between baseline and 2008 and the ensuing decreases were highly significant. Other adjustment models yielded different absolute IIR, although the relative changes between the cohorts were identical for all models. Conclusions The method can be used for comparing IIR in annual cohorts of HIV notifications. The use of several different algorithms in combination, each with its own sensitivity and specificity to detect incident infection, is advisable as this reduces the impact of individual imperfections stemming primarily from relatively low sensitivities and sampling bias.

Impact of the availability of an influenza virus rapid antigen test on diagnostic decision making in a pediatric emergency department

OBJECTIVES: Fever is one of the most commonly seen symptoms in the pediatric emergency department. The objective of this study was to observe how the rapid testing for influenza virus impacts on the management of children with fever. METHODS: We performed a review of our pediatric emergency department records during the 2008/2009 annual influenza season. The BinaxNow Influenza A+B test was performed on patients with the following criteria: age 1.0 to 16.0 years, fever greater than 38.5 °C, fever of less than 96 hours' duration after the onset of clinical illness, clinical signs compatible with acute influenza, and nontoxic appearance. Additional laboratory tests were performed at the treating physician's discretion. RESULTS: The influenza rapid antigen test was performed in 192 children. One hundred nine (57%) were influenza positive, with the largest fraction (101 patients) positive for influenza A. The age distribution did not differ between children with negative and positive test results (mean, 5.3 vs. 5.1 years, not statistically significant). A larger number of diagnostic tests were performed in the group of influenza-negative patients. Twice as many complete blood counts, C-reactive protein determinations, lumbar punctures, and urinalyses were ordered in the latter group. CONCLUSIONS: Rapid diagnosis of influenza in the pediatric emergency department affects the management of febrile children as the confirmation of influenza virus infection decreases additional diagnostic tests ordered.

Evaluation of colonoscopic allergen provocation as a diagnostic tool in dogs with proven food hypersensitivity reactions

OBJECTIVE: To evaluate the colonoscopic allergen provocation (COLAP) test as a new tool for the diagnosis of IgE-mediated food allergy. METHODS: Oral food challenges as well as COLAP testing were performed in a colony of nine research dogs with proven immediate-type food allergic reactions. In addition, COLAP was performed in five healthy dogs. RESULTS: When compared with the oral challenge test, COLAP accurately determined 18 of 23 (73 per cent) positive oral challenge reactions (73 per cent) in dogs with food allergies and was negative in the healthy dogs. CLINICAL SIGNIFICANCE: The accuracy of this new test may be higher than that for gastric sensitivity testing. Therefore, COLAP holds promise as a new test to confirm the diagnosis of suspect IgE-mediated food allergy in dogs.

The diagnostic yield of vitrectomy specimen analysis in chronic idiopathic endogenous uveitis

PURPOSE: The low diagnostic yield of vitrectomy specimen analysis in chronic idiopathic uveitis (CIU) has been related to the complex nature of the underlying disease and to methodologic and tissue immanent factors in older studies. In an attempt to evaluate the impact of recently acquired analytic methods, the authors assessed the current diagnostic yield in CIU. METHODS: Retrospective analysis of consecutive vitrectomy specimens from patients with chronic endogenous uveitis (n = 56) in whom extensive systemic workup had not revealed a specific diagnosis (idiopathic) and medical treatment had not resulted in a satisfying clinical situation. Patients with acute postoperative endophthalmitis served a basis for methodologic comparison (Group 2; n = 21). RESULTS: In CIU, a specific diagnosis provided in 17.9% and a specific diagnosis excluded in 21.4%. In 60.7% the laboratory investigations were inconclusive. In postoperative endophthalmitis, microbiological culture established the infectious agent in 47.6%. In six of eight randomly selected cases, eubacterial PCR identified bacterial DNA confirming the culture results in three, remaining negative in two with a positive culture and being positive in three no growth specimens. A double negative result never occurred, suggesting a very high detection rate, when both tests were applied. CONCLUSIONS: The diagnostic yield of vitrectomy specimen analysis has not been improved by currently routinely applied methods in recent years in contrast to the significantly improved sensitivity of combined standardized culture and PCR analysis in endophthalmitis. Consequently, the low diagnostic yield in CIU has to be attributed to insufficient understanding of the underlying pathophysiologic mechanisms.

Leydig-cell tumour in children: variable clinical presentation, diagnostic features, follow-up and genetic analysis of four cases

BACKGROUND: Testicular tumours are relatively uncommon in infants and children, accounting for only 1-2% of all paediatric solid tumours. Of these approximately 1.5% are Leydig-cell tumours. Further, activating mutations of the luteinizing hormone receptor gene (LHR), as well as of the G protein genes, such as Gsalpha (gsp) and Gialpha (gip2) subunits, and cyclin-dependent kinase gene 4(CDK4) have been associated with the development of several endocrine neoplasms. AIMS/METHODS: In this report, the clinical variability of Leydig-cell tumours in four children is described. The LHR-, gsp-, gip2- and CDK4 genes were investigated to establish the possible molecular pathogenesis of the variable phenotype of the Leydig-cell tumours. RESULTS: No activating mutations in these genes were found in the four Leydig-cell tumours studied. Therefore, the absence of activating mutations in LHR, as well as in both the 'hot spot' regions for activating mutations within the G-alpha subunits and in the regulatory 'hot spot' on the CDK4 genes in these tumours indicates molecular heterogeneity among Leydig-cell tumours. CONCLUSION: Four children with a variable phenotype caused by Leydig-cell tumours are described. A molecular analysis of all the 'activating' genes and mutational regions known so far was performed, but no abnormalities were found. The lessons learnt from these clinically variable cases are: perform ultrasound early and most importantly, consider discrepancies between testicular swelling, tumour size and androgen production.

Sample sizes of studies on diagnostic accuracy: literature survey

OBJECTIVES: To determine sample sizes in studies on diagnostic accuracy and the proportion of studies that report calculations of sample size. DESIGN: Literature survey. DATA SOURCES: All issues of eight leading journals published in 2002. METHODS: Sample sizes, number of subgroup analyses, and how often studies reported calculations of sample size were extracted. RESULTS: 43 of 8999 articles were non-screening studies on diagnostic accuracy. The median sample size was 118 (interquartile range 71-350) and the median prevalence of the target condition was 43% (27-61%). The median number of patients with the target condition--needed to calculate a test's sensitivity--was 49 (28-91). The median number of patients without the target condition--needed to determine a test's specificity--was 76 (27-209). Two of the 43 studies (5%) reported a priori calculations of sample size. Twenty articles (47%) reported results for patient subgroups. The number of subgroups ranged from two to 19 (median four). No studies reported that sample size was calculated on the basis of preplanned analyses of subgroups. CONCLUSION: Few studies on diagnostic accuracy report considerations of sample size. The number of participants in most studies on diagnostic accuracy is probably too small to analyse variability of measures of accuracy across patient subgroups.

Limitations of the Odds Ratio in Gauging the Performance of a Diagnostic or Prognostic Marker

A marker that is strongly associated with outcome (or disease) is often assumed to be effective for classifying individuals according to their current or future outcome. However, for this to be true, the associated odds ratio must be of a magnitude rarely seen in epidemiological studies. An illustration of the relationship between odds ratios and receiver operating characteristic (ROC) curves shows, for example, that a marker with an odds ratio as high as 3 is in fact a very poor classification tool. If a marker identifies 10 percent of controls as positive (false positives) and has an odds ratio of 3, then it will only correctly identify 25 percent of cases as positive (true positives). Moreover, the authors illustrate that a single measure of association such as an odds ratio does not meaningfully describe a marker’s ability to classify subjects. Appropriate statistical methods for assessing and reporting the classification power of a marker are described. The serious pitfalls of using more traditional methods based on parameters in logistic regression models are illustrated.

Treatment of hyperactive children: increased efficiency through modifications of homeopathic diagnostic procedure

BACKGROUND: The rigorous test to which homeopathy was subject in our recent double-blind clinical trail of homeopathic treatment of attention deficit hyperactivity disorder (ADHD) necessitated optimized treatment meeting the highest standards. METHODS: Optimization was performed in three steps: (1) In successfully treated children, prescriptions leading to an insufficient response were analysed by a general questionnaire to identify unreliable symptoms. (2) Polarity analysis, a further development of Bönninghausen's concept of contraindications, was introduced in response to the frequently one-sided symptoms. This enabled us to use few but specific symptoms to identify the medicine whose genius symptoms exhibit the closest match to the patient's characteristic symptoms. (3) We investigated the influence of the primary perception symptoms on the result of the repertorization. Perception symptoms are not normally recorded during a patient interview even though they are among the most reliable facts related by the patients. At the same time we were able to improve the continuity of improvement of ADHD symptoms using liquid Q-potencies. RESULTS: Introducing the questionnaire, polarity analysis, and including perception symptoms, lead to an improvement in the success rate of the first prescription from 21% to 54%, of the fifth prescription from 68% to 84%.

Autofluorescence endoscopy in surveillance of Barrett's esophagus: a multicenter randomized trial on diagnostic efficacy

BACKGROUND AND STUDY AIMS: The reference surveillance method in patients with Barrett's esophagus is careful endoscopic observation, with targeted as well as random four-quadrant biopsies. Autofluorescence endoscopy (AFE) may make it easier to locate neoplasia. The aim of this study was to elucidate the diagnostic accuracy of surveillance with AFE-guided plus four-quadrant biopsies in comparison with the conventional approach. PATIENTS AND METHODS: A total of 187 of 200 consecutive Barrett's esophagus patients who were initially enrolled (73 % male, mean age 67 years, mean Barrett's segment length 4.6 cm), who underwent endoscopy for Barrett's esophagus in four study centers, were randomly assigned to undergo either AFE-targeted biopsy followed by four-quadrant biopsies or conventional endoscopic surveillance, also including four-quadrant biopsies (study phase 1). After exclusion of patients with early cancer or high-grade dysplasia, who underwent endoscopic or surgical treatment, as well as those who declined to participate in phase 2 of the study, 130 patients remained. These patients were examined again with the alternative method after a mean of 10 weeks, using the same methods described. The main study parameter was the detection of early cancer/adenocarcinoma or high-grade dysplasia (HGD), comparing both approaches in study phase 1; the secondary study aim in phase 2 was to assess the additional value of the AFE-guided approach after conventional surveillance, and vice versa. Test accuracy measures were derived from study phase 1. RESULTS: In study phase 1, the AFE and conventional approaches yielded adenocarcinoma/HGD rates of 12 % and 5.3 %, respectively, on a per-patient basis. With AFE, four previously unrecognized adenocarcinoma/HGD lesions were identified (4.3 % of the patients); with the conventional approach, one new lesion (1.1 %) was identified. Of the 19 adenocarcinoma/HGD lesions detected during AFE endoscopy in study phase 1, eight were visualized, while 11 were only detected using untargeted four-quadrant biopsies (sensitivity 42 %). Of the 766 biopsies classified at histology as being nonneoplastic, 58 appeared suspicious (specificity 92 %, positive predictive value 12 %, negative predictive value 98.5 %). In study phase 2, AFE detected two further lesions in addition to the initial alternative approach in 3.2 % of cases, in comparison with one lesion with conventional endoscopy (1.7 %). CONCLUSIONS: In this referral Barrett's esophagus population with a higher prevalence of neoplastic lesions, the AFE-guided approach improved the diagnostic yield for neoplasia in comparison with the conventional approach using four-quadrant biopsies. However, AFE alone was not suitable for replacing the standard four-quadrant biopsy protocol.

[The importance of clinical information in diagnostic imaging in the febrile patient]

From conventional radiography to cross-sectional imaging methods, modern radiology offers a wide range of diagnostic tools for investigating patients with fever. To achieve the best results and to yield a correct diagnosis, the radiologist must tailor the diagnostic protocol individually for every patient. The decision on the most suitable imaging method, and the type and timing of contrast media strongly depends on the suspected diagnosis. Based on patient history and laboratory data, some modalities may be contraindicated or the patient may need a premedication. The authors give a short overview of diagnostic strategies in evaluating the most important causes of fever and point to the need of discussion and co-operation between clinicians and radiologists.

Diagnostic accuracy of coronary in-stent restenosis using 64-slice computed tomography: comparison with invasive coronary angiography

OBJECTIVES: This study sought to evaluate the diagnostic accuracy of coronary binary in-stent restenosis (ISR) with angiography using 64-slice multislice computed tomography coronary angiography (CTCA) compared with invasive coronary angiography (ICA). BACKGROUND: A noninvasive detection of ISR would result in an easier and safer way to conduct patient follow-up. METHODS: We performed CTCA in 81 patients after stent implantation, and 125 stented lesions were scanned. Two sets of images were reconstructed with different types of convolution kernels. On CTCA, neointimal proliferation was visually evaluated according to luminal contrast attenuation inside the stent. Lesions were graded as follows: grade 1, none or slight neointimal proliferation; grade 2, neointimal proliferation with no significant stenosis (<50%); grade 3, neointimal proliferation with moderate stenosis (> or =50%); and grade 4, neointimal proliferation with severe stenosis (> or =75%). Grades 3 and 4 were considered binary ISR. The diagnostic accuracy of CTCA compared with ICA was evaluated. RESULTS: By ICA, 24 ISRs were diagnosed. Sensitivity, specificity, positive predictive value, and negative predictive value were 92%, 81%, 54%, and 98% for the overall population, whereas values were 91%, 93%, 77%, and 98% when excluding unassessable segments (15 segments, 12%). For assessable segments, CTCA correctly diagnosed 20 of the 22 ISRs detected by ICA. Six lesions without ISR were overestimated as ISR by CTCA. As the grade of neointimal proliferation by CTCA increases, the median value of percent diameter stenosis increased linearly. CONCLUSIONS: Binary ISR can be excluded with high probability by CTCA, with a moderate rate of false-positive results.