Simple Study Design Research Articles

The Role of Smoking History in the Development of Postoperative Nausea and Vomiting

We thank Drs. Neustein, Groudine, and Awad for their interest in our work on the effect of transcutaneous electrical stimulation of the P6 acupuncture point while neuromuscular blockade monitoring,1and would like to respond to their major comments about neuromuscular reversal and the use of stimulation modes as well as the potential confounder of nonsmoking as a trigger for postoperative nausea and vomiting (PONV).Dr. Neustein notices a relatively high incidence of PONV in our study. We did a study in women using volatile anesthetics, which are well known PONV triggers.2We strongly agree that the reduction in nausea by the P6 stimulation plays an important role in a prophylactic multimodal antiemetic approach as proposed by Scuderi et al. 3,4All patients were reversed and extubated based on clinical signs of full recovery as is daily clinical practice at the hospital. No problems were found in any of the studied patients after extubation. The intention of the study was to reduce PONV by continuous monitoring of neuromuscular blockade over the P6 acupuncture point using single-twitch response during surgery. We thank Dr. Groudine for the comment that accelerography stimulated over the median nerve has not been extensively studied, and for noting that double-burst and train-of-four stimulation are more reliable in detecting residual blockade. For patient safety reasons, we also recommend changing from the single-twitch mode to one of the modes mentioned above, which is easy to do without harming the patient during recovery from neuromuscular blockade.Conversion to open procedure occurred in five patients of the control group and in seven patients of the P6-stimulation group (P = 0.77, chi-square). We had only two problems with the accelerograph, and both were in the control group (ulnar nerve stimulation). The battery had to be replaced in both cases to continue the electrical stimulation.Because we were concerned about trigger factors for PONV, we recorded risk factors that were evenly distributed between both groups; only smoking showed a higher difference of 11%. Dr. Awad is right that stratification would have omitted that, but stratifying for all of the major risk factors (PONV history, motion sickness, and smoking) would have complicated a rather simple study design. We assumed that our relatively large sample size would distribute all confounders equally in both groups. To assure that smoking was not a potential confounder affecting the outcome, we performed a multiple logistic regression analysis (including PONV history, motion sickness, postoperative opioid therapy, and smoking),5which revealed only the different stimulation side as a significant factor (P =0.028). Because no significant difference was found for the demographic and PONV-related data, we did not include that analysis in the original manuscript.In summary, we would like to see further studies in this area using a multimodal prophylactic approach including acupuncture to reduce PONV. At the emergence from anesthesia, meticulous attention should be applied to avoid residuals of neuromuscular blockade using our approach. Smoking was evenly distributed between the ulnar nerve stimulation group and the P6-acupuncture stimulation group.*University Hospital Bern, Bern, Switzerland, and Donauspital/SMZO, Vienna, Austria. robert.greif@insel.ch

A method to distinguish between the de novo induction of thymidine kinase mutants and the selection of pre-existing thymidine kinase mutants in the mouse lymphoma assay

The mouse lymphoma assay (MLA) is the most widely used in vitro mammalian gene mutation assay. It detects various mutation events involving the thymidine kinase ( Tk) gene in L5178Y/ Tk +/− −3.7.2C mouse lymphoma cells. Mutants are detected using a thymidine analogue that arrests the growth of cells containing a functional Tk gene. However, there are a number of potential test chemicals that are thymidine analogues, and there is a problem when using the MLA to evaluate the mutagenicity of these chemicals. Thymidine analogues are activated by Tk before eliciting their toxicity. Therefore, any pre-existing Tk −/− mutants may avoid the toxicity of the test chemical and obtain a growth advantage over the Tk +/− cells, increasing the Tk mutant frequency (MF) in the culture via a selection mechanism. This potential mutant selection effect needs to be distinguished from de novo mutant induction in order to properly evaluate the mutagenicity of these chemicals. Here we describe a simple MLA study design that can differentiate between the selection of pre-existing mutants and de novo mutant induction. Trifluorothymidine (TFT), a thymidine analogue and the selection agent normally used in the MLA, and 4-nitroquinoline-1-oxide (4-NQO), a potent mutagen, were used to treat cells from two different Tk +/− mouse lymphoma cell cultures with different background MFs (approximately 112 and 305 × 10 −6). Both agents significantly increased the Tk MFs in both the normal and high background cultures ( p < 0.01). In 4-NQO-treated cultures, the induced MFs (MF of treated culture − MF of control) for the cultures with different background MFs were about the same ( p > 0.1), while in TFT-treated cultures, they were significantly different ( p < 0.01). In TFT-treated cultures, the fold-increases of MF (MF of treated culture/MF of control) for the cultures with different background MFs were about the same ( p > 0.1), while in 4-NQO-treated cultures, they were significantly different ( p < 0.01). This study confirms that, when de novo mutations are induced, the induced MF is the same for cultures with normal and artificially high background MFs. In situations where the increase in MF is due solely to selection of pre-existing mutants, the “induced” MF will be a multiple of the background MF and the magnitude of the increase of the induced MF will depend upon the magnitude of the background MF. Our results demonstrate that it is possible, using this experimental design, to distinguish between chemicals acting primarily via the selection of pre-existing Tk mutants and those inducing de novo mutants in the MLA.

Sib-recruitment for studying migration and its impact on obesity and diabetes.

BackgroundUrban-rural comparisons are of limited relevance in examining the effects of urban migration in developing countries where urbanisation is due to growth of existing urban populations, expansion of urban boundaries, and rural in-migration. Cultural, genetic and life-style backgrounds of migrants and host populations further limit the value of rural-urban comparisons. Therefore we evaluated a sib-comparison design intended to overcome the limitations of urban-rural comparisons.MethodsUsing the framework of a current cardiovascular risk factor screening study conducted in Indian factories, we recruited the non-migrant rural sibs of migrant urban factory workers and the urban sibs of non-migrant factory workers. The response rate, completed interviews and examinations conducted were assessed. Adequacy of generic food frequency questionnaires and WHO quality of life questionnaire were assessed.ResultsAll the urban factory workers and spouses approached agreed to be interviewed. Of the 697 participants interviewed, 293 (42%) had at least one rural dwelling sibling. Twenty (22%) siblings lived further than 100 km from the study site. An additional 21 urban siblings of non-migrant factory workers were also investigated to test the logistics of this element of the study. Obesity (BMI >25 kg/m2) was more common in rural sibs than urban factory workers (age adjusted prevalence: 21.1% (17.1 to 25.0) vs. 16.1% (11.9, 20.3). Diabetes prevalence (fasting plasma glucose greater than 126 mg/dl) was higher than expected (age-adjusted prevalence: 12.5% (22 out of 93) in urban migrants and 4.5% (8 out of 90) in rural non-migrant sibs.ConclusionThe sib-comparison design is robust and has been adopted in the main study. It is possible that simple urban-rural study designs under-estimate the true differences in diabetes risk between migrants and non-migrants.

Reasons for Poor Accrual in Palliative Radiation Therapy Research Studies

BackgroundPatients with advanced-stage cancer commonly have multiple symptoms, poor performance status, and limited life expectancies. Despite the need for evidence-based practice and guidelines for palliative radiation therapy (RT), conducting clinical palliative research has proven to be a challenge in the past because of low accrual rates and high patient attrition. We explore the change in accrual rates, reasons for nonparticipation in palliative RT clinical research trials, and factors that contributed to the increase in accrual over a 3-year period. Patients and MethodsA record was kept for all patients seen at the Rapid Response Radiotherapy Program between 2002 and 2005, including information on patient demographics, disease characteristics, and whether patients were accrued into ≥1 palliative research study at the time of clinic visit. If a patient did not participate in a study, the reason for nonaccrual was recorded. ResultsDespite previous difficulties, changes to the methods of conducting palliative research and study design have resulted in an increase in patient accrual, from 14% to an average of approximately 60%. The implementation of a full-time clinical research assistant and a simple study design with realistic eligibility criteria contributed to the increase in patient participation. ConclusionDifficulties in conducting palliative clinical research trials were improved through changes in study design and research administration. Future clinics should use a dedicated clinical research assistant responsible for patient recruitment and study management. Studies should be designed specifically for the patient population receiving palliative care and should involve clearly defined and realistic eligibility criteria and brief assessments.

Statistical Analysis of a Clinical Trial in Orthostatic Hypotension -a Nonparametric Approach

SummarySome basic problems and considerations of analyzing clinical trials, in which a large amount of data is recorded on very few patients - mostly in the form of serial measurements -, are highlighted within the framework of a clinical trial in orthostatic hypotension. The method suggested to analyze these kinds of trials renounces the use of complex mathematical models and complicated statistical methods. It is simply based on the derivation of relevant aspects of the patient’s profiles and the use of well-known nonparametric tests and requires only a very simple study design. With this procedure, however, it is possible to satisfy at least the basic requirements of clinical trial methodology.

Estimating disease rates from a diagnostic test.

Incidence and remission rates are often estimated from studies that employ a diagnostic test to indicate the presence of disease. The apparent rates that result from a simple study design with one test given at two time points will be substantially different from the true rates, even if the error rates of the test are low. Estimation of the true rates requires extra assumptions or extended designs with more tests or more time points. The authors illustrate their points with the use of two examples, the second of which compares the estimates obtained to actual data from a study of onchocerciasis (river blindness) in Guatemala.