Controlled clinical trials in cystic fibrosis--are we doing better?

We have previously reported the time trends, design and interventions in randomised controlled trials (RCTs) in cystic fibrosis (CF) from 1961 through 1997 [Cheng K, Smyth RL, Motley J, O'Hea U, Ashby D, Randomised controlled trials in cystic fibrosis (1966-1997) categorized by time, design, and intervention. Pediatr Pulmonol 2000, 29:1-7.]. We maintain an ongoing register of all RCTs and controlled clinical trials (CCTs) in CF and have noted that in the five years since 1997 there has been a 48% increase in published trials. We aimed to assess whether this increase has been associated with an improvement in design quality. All RCTs and CCTs from 1961-2002 were assessed. Two epochs were then compared, 1961-1997 and 1998-2002. For each trial we recorded the design, participant numbers and the intervention studied. 261 trials in 1998-2002 were compared with 544 trials in 1961-1997. Comparing the two epochs a similar proportion of trials were parallel, double-blind and placebo controlled; also the median number of participants was similar. In the later epoch 25% of trials were multicentre, compared with 11% previously. Whilst this recent increase in clinical trials in CF is welcome, this has not been associated with improvements in quality. The trend for an increasing proportion of trials to be multicentre is encouraging. There are however, still deficiencies in the design of clinical trials in CF.     

Cognitive impairment in heart failure.

Heart failure is reaching epidemic proportions in the United States, causing a constellation of disabling symptoms. Cognitive impairment in people with heart failure may be more common than previously known with multiple etiologies from both the disease process and the treatment. Exemplars from a research study are used to illustrate the perspective of heart failure patients. Given the critical importance of memory deficits on patient education, potential nursing interventions to address the issue of cognitive impairment are described.     

Diagnostic value of lung uptake of indium-111 oxine-labeled white blood cells

One hundred sixty-two white-blood-cell scans were retrospectively reviewed to determine the sensitivity and specificity of the test for pulmonary and pleural infection. All scans were performed 18-24 hr after injection of indium-111 oxine-labeled autologous or donor cells. Pulmonary activity was graded on a scale of 0-4: 0 = equal to soft tissue; 1 = greater than soft tissue but less than rib; 2 = equal or greater than rib but less than liver; 3 = equal or greater than liver but less than spleen; 4 = equal to spleen. Activity was also characterized as being focal or diffuse. The white-blood-cell scan findings were correlated with the clinical diagnosis on the basis of physical examination, laboratory results, chest radiographs, clinical course, and pathologic studies when available. As pulmonary activity increased from grade 1 to 4, sensitivity declined from 93% to 14% and specificity increased from 64% to 100%. The sensitivity and specificity of focal uptake were 31% and 89% vs 62% and 74% for diffuse pulmonary activity. Making a distinction between focal and diffuse activity did not improve the specificity of low grades of pulmonary activity. The white-blood-cell scan can be very sensitive or very specific for pulmonary or pleural infection, depending on the criteria selected for a positive scan.     

Retroperitoneal Laparoscopic Nephrectomy in Children

Retroperitoneal pediatric laparoscopic nephrectomy is described in 3 patients requiring 3 to 5 hours with an estimated blood loss of 10 to 60 cc. The children returned to school within 7 days postoperatively. Advantages of this procedure include the avoidance of intraoperative repositioning of the patient and easy conversion to an open lumbodorsal approach, if necessary; early laparoscopic visualization of the renal artery; applicability in cases of previous abdominal surgery, and avoidance of intraperitoneal adhesion.     

Prosthetic graft infection: limitations of indium white blood cell scanning

The lack of a rapid, noninvasive, and accurate method to confirm or rule out prosthetic graft infection continues to constitute a compelling and vexing clinical problem. A host of adjunctive diagnostic techniques has been used in the past, but early promising results subsequently have usually not yielded acceptable sensitivity (reflecting false negatives) and specificity (reflecting false positive) data. White blood cell (WBC) indium 111 scanning has recently been added to this list. The utility and accuracy of 111In WBC scans were assessed by retrospective review of WBC scan results in 70 patients undergoing evaluation for possible prosthetic graft infection over a 7-year period. Operative and autopsy data (mean follow-up, 18 months for survivors with negative scans) were used to confirm the 22 positive, 45 negative, and three equivocal WBC scans. The false positive rate (+/- 70% confidence limits) was 36% +/- 6% (n = 8) among the 22 patients with positive scans (44% +/- 6% [11 of 25] if the three equivocal scans are included as false positive), yielding a specificity of 85% +/- 5% and an overall accuracy rate of 88% +/- 4% (80% +/- 5% and 84% +/- 5%, respectively, if the three equivocal cases are considered as false positive). All three patients with equivocal scans ultimately were judged not to have prosthetic graft infection. As implied by the high accuracy rate, the sensitivity of the test was absolute (100% [14 of 14]); there were no false negative results. (ABSTRACT TRUNCATED AT 250 WORDS)     

The complex enterprise of modelling prenatal exposure to cigarettes: what is ‘enough’?

While there is a burgeoning body of research linking smoking during pregnancy to problem behaviour in offspring, a major criticism of this work has been the crude measurement of exposure in these studies (e.g. retrospective, self-reported only) that could lead to biased estimates. To address this issue, we used a pregnancy cohort with repeated prospective measures of exposure as well as biological assays to generate estimates of exposure patterns using a range of modelling techniques. In this paper we report on the analytical approaches we have developed, including patterns of exposure over time and best-estimate approaches that combine self-report and cotinine measures, and compare their predictive value in relation to different dimensions of fetal growth as a first step towards examining the utility of greater precision of exposure measurement.
Surprisingly, in this sample the more complex assessments of exposure, including biological measures, generally did not perform better than simple indicators of exposure based on repeated self-report measures, with one exception: a combined self-report cotinine 'best estimate' of third trimester exposure was uniquely associated with lower brain : body ratio. Further study is needed using more sophisticated cotinine assays and testing prediction of a range of outcomes to ascertain whether these findings represent true differences or are specific to the sample, methods and outcomes used. Such research will inform the development of guidelines for adequate exposure characterisation in developmental studies.     

Interaction of HPV-18 and nitrosomethylurea in the induction of squamous cell carcinoma

A strong correlation exists between the presence of specifictypes of human papillomavirus (HPV) and the development of anogenitalcancer, as well as significant epidemiologic evidence suggestingsmokers are at increased risk of developing cervical, vulvarand/or anal carcinomas. Primary and human papillomavirus type18 (HPV-8)-immortalized human keratinocytes were used to addressthe co-carcinogenic potential of HPV and nitrosomethylurea (NMU)in tumorigenesis. Only cells containing HPV-18 and treated withNMU and the tumor-promoting phorbol ester, TPA, were transformedto a malignant phenotype. An in vitro system is described whichinitiates studies involving the mechanisms of HPV and chemicalcarcinogen co-operation in the etiology of squamous cell carcinomas.     

Immunopotentiation of bovine herpes virus subunit vaccination by interleukin-2.

Cattle were immunized with glycoprotein IV (gIV) from bovine herpes virus-1 (BHV-1). Groups of five animals were then given either 2, 3, 4, or 5 doses of interleukin-2 (IL-2) (0.5 microgram/kg) at 12-hr intervals. Animals that received no IL-2 exhibited specific immune responses that are typical for BHV-1 infection, i.e. enhanced specific cytotoxicity, lymphocyte proliferative responses to gIV, and increased gIV-specific (ELISA) and virus-neutralizing antibodies. Treatment of animals with five doses of IL-2 significantly augmented all of these responses except serum neutralization (P less than 0.05). Furthermore, the dose of IL-2 that was selected did not induce any non-specific responses, i.e. hypergamma-globulinaemia, changes in blood chemistry, increased lymphokine-activated killer (LAK) cell activity, changes in mitogen responsiveness or alterations in the phenotypic profile of circulating lymphocytes. Nor were there any clinical changes associated with IL-2 therapy (e.g. depression, pyrexia, diarrhea). Animals that were treated with less than five doses of IL-2 also exhibited elevated immune responses, but they were not significantly different from untreated immunized controls. Interestingly, animals given five doses of IL-2 responded to minor contaminants present in the gIV preparation. This allows speculation that this dose regimen of IL-2 is not only a potent adjuvant for conventional vaccine immunizing doses, but will also allow the use of minute quantities of antigen for immunization.