bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cost-effectiveness in clinical trials: using multiple imputation to deal with incomplete cost data
Authors: Burton Andrea , Billingham Lucinda Jane , Bryan Stirling 
Published: April 2007

Background Cost-effectiveness has become an important outcome in many clinical trials and has resulted in the collection of resource use data and the calculation of costs for individual patients. A specific example is a Cancer Research UK phase III trial comparing chemotherapy (CT) against standard palliative care in patients with advanced non-small cell lung cancer. Resource usage from trial entry until death were collected and costs obtained on a subset of 115 trial patients. For some patients, however, the unavailability of medical notes resulted in some cost components, and hence total cost, being missing. The 82 patients with complete data were not representative of all trial patients in terms of effectiveness and thus it was necessary to address the missing data problem. Methods Multiple imputation (MI) was used to impute values for the unobserved individual cost components, allowing total cost to be calculated and cost-effectiveness carried out for all patients in the cost sub-study. The results are compared with those from a complete case analysis. Results After MI, the results indicated that CT had a high probability of being cost-effective for a societal willingness to pay over £20 000 per life-year gained. This was in stark contrast with the complete case analysis, which suggested that CT was not a cost-effective use of resources at any reasonable level of willingness to pay for a life-year. Limitations Our findings are based on a relatively small retrospective study with all events observed. Conclusion In conclusion, cost-effectiveness analysis of the complete cases only may give biased results, and therefore, in situations where there are missing costs, MI is recommended. Clinical Trials 2007; 4: 154—161. http://ctj.sagepub.com
A decision rule for sequential monitoring of clinical trials with a primary and supportive outcome
Authors: Zhao Yanli , Grambsch Patricia M. , Neaton James D. 
Published: April 2007

Background Many clinical trials have multiple outcomes. Formal interim monitoring guidelines that take account of multiple outcomes can be useful to Data Monitoring Committees (DMC). Previous research has focused on marginal criteria that control the overall type I error for bivariate endpoints corresponding to efficacy and safety. Usually, an `or' decision rule is used, that is, the trial is stopped when either the safety or the efficacy endpoint crosses a boundary. Purpose In many trials there is not a clear difference between what is considered a safety and an efficacy endpoint. Likewise, in some studies there is interest in more than one disease outcome and while there may be a primary efficacy endpoint, interim monitoring might also involve a measure of overall health. For these situations, an `and' decision rule might be more appropriate; that is, the trial is stopped only when both endpoints cross a boundary. Formulation of this new decision rule at the design stage would encourage more discussion among trial investigators of monitoring guidelines and would result in improved guidelines for DMCs. Methods In this paper, we propose stopping guidelines for such trials with two major outcomes that control the overall type I error and stop early only if both endpoints indicate superiority for the same treatment. Trials with two treatments are considered and we develop sets of paired two-sided boundaries, permitting one endpoint to be primary and the other supportive, with or without pre-specifying which one is primary. Results The results show that the boundaries depend on the correlation between the two outcomes. The critical values increase as the correlation increases in most cases. For low to moderate correlation and before the last stage, critical values based on the O'Brien Fleming (or Pocock) error spending function that consider the correlation are lower than those which do not. Limitations Investigators might not want to stop a trial early with the small size of the critical values that result from this decision rule for some situations. For a trial in which the treatment effect for one outcome is large, while for the other it is small, the proposed decision rule has low power to accept this treatment for its superiority on both outcomes. Also, we do not provide a separate P-value for each outcome since type I error is not controlled for individual null hypotheses. Conclusions For trials involving two major health outcomes these stopping guidelines may be appropriate for DMCs when the trial investigators and sponsor recommend that early termination not be considered unless the findings are consistent for both outcomes. Clinical Trials 2007; 4: 140—153. http://ctj.sagepub.com
Statistical design of THRio: a phased implementation clinic-randomized study of a tuberculosis preventive therapy intervention
Authors: Moulton Lawrence H. , Golub Jonathan E. , Durovni Betina , Cavalcante Solange C. , Pacheco Antonio G. , Saraceni Valeria , King Bonnie , Chaisson Richard E. 
Published: April 2007

Background Tuberculosis (TB) is a major public health problem in Rio de Janeiro, where a high proportion of HIV-infected adults are co-infected with latent TB. Health officials in Brazil have recommended that HIV patients be tested for TB infection and given TB prophylaxis (isoniazid) if positive. In practice, although Brazil is a model for provision of antiretroviral therapy to patients with advanced HIV disease, relatively few such patients receive TB testing and prevention services. Purpose We initiated a randomized study of a health services intervention to train health personnel in implementation of the recommended routine of TB testing and isoniazid prophylaxis. The primary goal is to reduce incident TB disease in the HIV clinic population. Methods The clinic-level intervention will be phased in gradually over the study period until all clinics have received the intervention. The clinics' order of initiation of intervention was randomized and subjected to constraints based on clinic-level covariates. This phased intervention cluster-randomized trial required special attention to power/sample size calculation and randomization procedures, of which we provide the relevant details. Results Special design considerations accounted for within-clinic correlation, variation in the clinic size, time-varying ratio of intervention to control clinics and guaranteed post-randomization covariate balance. These were successfully implemented for the estimation of power and execution of the randomization strategy. Limitations Although the design features of randomization by clinic and phased implementation of the intervention meet logistic and local needs, they substantially lower the statistical power of the study. Conclusions Studies with cluster-randomized order of intervention introduction can provide useful information on intervention effects. Their design and analysis are more complicated than for individually randomized parallel design trials. The methods we describe represent practical approaches to the challenges raised in the course of designing this study. Clinical Trials 2007; 4: 190—199. http://ctj.sagepub.com
Eliciting and using expert opinions about dropout bias in randomized controlled trials
Authors: White Ian R , Carpenter James , Evans Stephen , Schroter Sara 
Published: April 2007

Background The analysis of clinical trials with dropout usually assumes the missing data are `missing at random', i.e. given an individual's past observed data, their probability of dropout does not depend on their present outcome. However, in many settings this assumption is implausible, so it is sensible to assess the robustness of conclusions to departures from missing at random. Purpose To develop a practical, accessible, approach that allows expert opinions about the degree of departure from missing at random in the analysis of a clinical trial to be meaningfully and accurately elicited and incorporated in sensitivity analysis. Methods We elicit experts' prior beliefs about the mean difference between missing and observed outcomes in each trial arm. Then we perform a Bayesian synthesis of the information in the trial data with that in the experts' prior, using (i) a full Bayesian analysis for which we give WinBUGS code, and (ii) a simple approximate formula for the estimated treatment effect and its standard error. We illustrate our approach by re-analysing a recent trial of interventions to improve the quality of peer review. Results In the peer review trial, the approximate formula agreed well with the full Bayesian analysis, and both showed substantially larger standard errors than an analysis assuming missing at random. Limitations Strictly, the method is only applicable if the outcome is normally distributed. We did not elicit the full bivariate prior distribution, and instead used a sensitivity analysis. Our approach is not designed to incorporate prior beliefs about the intervention effect itself. Conclusions Our proposed approach allows for the greater uncertainty introduced by missing data that are potentially informatively missing. It can therefore claim to be a truly conservative method, unlike methods such as `last observation carried forward'. It is practical and accessible to non-statisticians. It should be considered as part of the design and analysis of future clinical trials. Clinical Trials 2007; 4: 125—139. http:/ctj.sagepub.com
Contrasts in gem corundum characteristics, eastern Australian basaltic fields: trace elements, fluid/melt inclusions and oxygen isotopes
Authors: Zaw Khin , Sutherland F. L. , Dellapasqua F. , Ryan C. G. , Yui Tzen-Fu , Mernagh T. P. , Duncan D. 
Published: April 2007

AbstractCorundum xenocrysts from alkaline basalt fields differ in characteristics and hence lithospheric origins. Trace element, fluid/melt inclusion and oxygen isotope studies on two eastern Australian corundum deposits are compared to consider their origins. Sapphires from Weldborough, NE Tasmania, are magmatic (high-Ga, av. 200 ppm) and dominated by Fe (av. 3300 ppm) and variable Ti (av. 400 ppm) as chromophores. They contain Cl, Fe, Ga, Ti and CO2-rich fluid inclusions and give δ18O values (5.1–6.2‰) of mantle range. Geochronology on companion zircons suggests several sources (from 290 Ma to 47 Ma) were disrupted by basaltic melts (47 ± 0.6 Ma). Gem corundums from Barrington, New South Wales, also include magmatic sapphires (Ga av. 170 ppm; δ18O (4.6–5.8‰), but with more Fe (av. 9000 ppm) and less Ti (av. 300 ppm) as chromophores. Zircon dating suggests that gem formation preceded and was overlapped by Cenozoic basaltic melt generation (59–4 Ma). In contrast, a metamorphic sapphire-ruby suite (low-Ga, av. 30 ppm) here incorporates greater Cr into the chromophores (up to 2250 ppm). Fluid inclusions are CO2-poor, but melt inclusions suggest some alkaline melt interaction. The δ18O values (5.1–6.2‰) overlap magmatic sapphire values. Interactions at contact zones (T= 780–940°C) between earlier Permian ultramafic bodies and later alkaline fluid activity may explain the formation of rubies.
JAK2 617V>F–positive polycythemia rubra vera maintained by approximately 18 stochastic stem-cell divisions per year, explaining age of onset by a single rate-limiting mutation
Authors: Vickers Mark A. 
Published: April 2007

AbstractAs the rates of most cancers are proportional to the fourth to fifth power of age (“log-log” behavior), it is widely believed that 5 to 6 independent mutations are necessary for malignant transformation. Conversely, the peak incidences of most cancers are similar to stem-cell mutation rates at single loci, implying only one rate-limiting mutation. Here, flow cytometrically measured red blood cells mutated at a selectively neutral locus, glycophorin A, allow observation of individual stem-cell differentiation events in a log-log malignancy, polycythemia rubra vera. Contrary to predictions from multistep models, the clone is driven by infrequent (< annual) and rare (∼ 18 per year) differentiation events. These parameters imply that malignant stem cells have a modest selective advantage. Correspondingly minor, typically less than 20%, increases in stochastic self-renewal ratios are modeled to show that single mutations can result in the observed fourth power relationship with age. The conundrum between log-log behavior and mutation rate is thereby reconcilable, with the age of onset arising not from the requirement for multiple, independent mutations but from infrequent, stochastic stem-cell division rates and single mutations causing initially minor effects, but initiating a clone whose expected number increases successively with age—an “exponential phenotype.”
TREM-1 ligand expression on platelets enhances neutrophil activation
Authors: Haselmayer Philipp , Grosse-Hovest Ludger , von Landenberg Philipp , Schild Hansjörg , Radsak Markus P. 
Published: April 2007

Abstract
The triggering receptor expressed on myeloid cells 1 (TREM-1) plays an important role in the innate immune response related to severe infections and sepsis. Modulation of TREM-1–associated activation improves the outcome in rodent models for pneumonia and sepsis. However, the identity and occurrence of the natural TREM-1 ligands are so far unknown, impairing the further understanding of the biology of this receptor. Here, we report the presence of a ligand for TREM-1 on human platelets. Using a recombinant TREM-1 fusion protein, we demonstrate specific binding of TREM-1 to platelets. TREM-1–specific signals are required for the platelet-induced augmentation of polymorphonuclear leukocyte (PMN) effector functions (provoked by LPS). However, TREM-1 interaction with its ligand is not required for platelet/PMN complex formation, which is dependent on integrins and selectins. Taken together, the results indicate that the TREM-1 ligand is expressed by platelets, and the TREM-1/ligand interaction contributes to the amplification of LPS-induced PMN activation. Our results shed new light on our understanding of TREM-1 and its role in the innate inflammatory response in infections and might contribute to the development of future concepts to treat sepsis.
High-dose immunosuppressive therapy and autologous hematopoietic cell transplantation for severe systemic sclerosis: long-term follow-up of the US multicenter pilot study
Authors: Nash Richard A. , McSweeney Peter A. , Crofford Leslie J. , Abidi Muneer , Chen Chien-Shing , Godwin J. David , Gooley Theodore A. , Holmberg Leona , Henstorf Gretchen , LeMaistre C. Fred , Mayes Maureen D. , McDonagh Kevin T. , McLaughlin Bernadette , Molitor Jerry A. , Nelson J. Lee , Shulman Howard , Storb Rainer , Viganego Federico , Wener Mark H. , Seibold James R. , Sullivan Keith M. , Furst Daniel E. 
Published: April 2007

Abstract
More effective therapeutic strategies are required for patients with poor-prognosis systemic sclerosis (SSc). A phase 2 single-arm study of high-dose immunosuppressive therapy (HDIT) and autologous CD34-selected hematopoietic cell transplantation (HCT) was conducted in 34 patients with diffuse cutaneous SSc. HDIT included total body irradiation (800 cGy) with lung shielding, cyclophosphamide (120 mg/kg), and equine antithymocyte globulin (90 mg/kg). Neutrophil and platelet counts were recovered by 9 (range, 7 to 13) and 11 (range, 7 to 25) days after HCT, respectively. Seventeen of 27 (63%) evaluable patients who survived at least 1 year after HDIT had sustained responses at a median follow-up of 4 (range, 1 to 8) years. There was a major improvement in skin (modified Rodnan skin score, −22.08; P < .001) and overall function (modified Health Assessment Questionnaire Disability Index, −1.03; P < .001) at final evaluation. Importantly, for the first time, biopsies confirmed a statistically significant decrease of dermal fibrosis compared with baseline (P < .001). Lung, heart, and kidney function, in general, remained clinically stable. There were 12 deaths during the study (transplantation-related, 8; SSc-related, 4). The estimated progression-free survival was 64% at 5 years. Sustained responses including a decrease in dermal fibrosis were observed exceeding those previously reported with other therapies. HDIT and autologous HCT for SSc should be evaluated in a randomized clinical trial.
Maturation of the mucosal immune system underlies colitis susceptibility in interleukin-10-deficient (IL-10−/−) mice
Authors: Etling Michele R , Davies Sarah , Campbell Melanie , Redline Raymond W , Fu Pingfu , Levine Alan D 
Published: April 2007

AbstractElevated mucosal IL-12/23p40 and IFN-γ accompany early inflammation in IL-10-deficient (IL-10−/−) mice and then later decline while inflammation persists. This report addresses whether this cytokine profile reflects disease progression or inherent, age-related changes in mucosal immunity. IL-10−/− and wild-type (WT) mice were maintained in an ultrabarrier facility or transferred to conventional housing at 3, 12, or 30 weeks of age. Weight, stool changes, and histologic features were followed. Lamina propria mononuclear cells were cultured for cytokine analysis by ELISA. Ultrabarrier-housed IL-10−/− mice are statistically indistinguishable from WT mice by weight, disease activity index, and histologic inflammation. IL-10−/− mice but not WT, transferred at 3 weeks, develop colitis gradually, reaching a significant, sustained maximum by 15 weeks of age. Transfer at 12 weeks induces rapid disease onset in both strains, maximal at 15 weeks of age. Inflammation persists in IL-10−/−, and WT recover. IL-10−/− and WT mice transferred at 30 weeks demonstrate transient diarrhea and weight loss but no chronic inflammation. Probiotics delay symptom onset only in the 12-week-old group. IFN-γ production from ultrabarrier-housed IL-10−/− mice is elevated at 12 weeks of age, and older animals have decreased IFN-γ and increased IL-4. IL-10 is important for suppressing inflammation after transfer at 3 weeks of age and limiting inflammation after transfer at 12 weeks but has little influence at 30 weeks of age. Colitis onset, progression, and response to probiotic therapy vary with immune system age, suggesting that a distinct, Th1-driven, age-dependent cytokine profile may contribute to increased colitis susceptibility in otherwise healthy mice.
Erlotinib Plus Gemcitabine Compared With Gemcitabine Alone in Patients With Advanced Pancreatic Cancer: A Phase III Trial of the National Cancer Institute of Canada Clinical Trials Group
Authors: Moore Malcolm J. , Goldstein David , Hamm John , Figer Arie , Hecht Joel R. , Gallinger Steven , Au Heather J. , Murawa Pawel , Walde David , Wolff Robert A. , Campos Daniel , Lim Robert , Ding Keyue , Clark Gary , Voskoglou-Nomikos Theodora , Ptasynski Mieke , Parulekar Wendy 
Published: April 2007

Purpose Patients with advanced pancreatic cancer have a poor prognosis and there have been no improvements in survival since the introduction of gemcitabine in 1996. Pancreatic tumors often overexpress human epidermal growth factor receptor type 1 (HER1/EGFR) and this is associated with a worse prognosis. We studied the effects of adding the HER1/EGFR-targeted agent erlotinib to gemcitabine in patients with unresectable, locally advanced, or metastatic pancreatic cancer. Patients and Methods Patients were randomly assigned 1:1 to receive standard gemcitabine plus erlotinib (100 or 150 mg/d orally) or gemcitabine plus placebo in a double-blind, international phase III trial. The primary end point was overall survival. Results A total of 569 patients were randomly assigned. Overall survival based on an intent-to-treat analysis was significantly prolonged on the erlotinib/gemcitabine arm with a hazard ratio (HR) of 0.82 (95% CI, 0.69 to 0.99; P = .038, adjusted for stratification factors; median 6.24 months v 5.91 months). One-year survival was also greater with erlotinib plus gemcitabine (23% v 17%; P = .023). Progression-free survival was significantly longer with erlotinib plus gemcitabine with an estimated HR of 0.77 (95% CI, 0.64 to 0.92; P = .004). Objective response rates were not significantly different between the arms, although more patients on erlotinib had disease stabilization. There was a higher incidence of some adverse events with erlotinib plus gemcitabine, but most were grade 1 or 2. Conclusion To our knowledge, this randomized phase III trial is the first to demonstrate statistically significantly improved survival in advanced pancreatic cancer by adding any agent to gemcitabine. The recommended dose of erlotinib with gemcitabine for this indication is 100 mg/d.
A Longitudinal Study into Changing Ethical Attitudes of Newly-Qualified Dentists in South-East England
Authors: Gordon Edgar , Batchelor Paul 
Published: April 2007

Objective To report the ethical stances taken by newly-qualified dental graduates working in the south-east of England and how these changed over their first two years in practice. Methods A longitudinal self-completed questionnaire-based study using scenarios and closed questions was completed by an initial group of 135 vocational dental practitioners at the very beginning of their vocational training year, at the end of the year, and, finally, at the end of the subsequent year. Their answers were then analysed to see whether or not their views had changed during this period. Results At the commencement of the study in 2003, 133 (99%) newly-qualified dental graduates completed the questionnaire and answered the closed questions. The following year, 129 (96%) completed these documents and in 2005, at the end of the study, this figure was 97 (72%). There was considerable variation in the attitudes taken by the responding dentists. Reported attitudes changed over the study period in seven of the nine scenarios. Responses to the scenarios used could be grouped into three categories: those in which there was no change; those in which the change happened following completion of vocational training; and those in which there was a continual change. Answers to the four closed questions indicated a growing negativity to practice within the National Health Service over the study period. Conclusions Dental educators need to be aware of the findings from this study. The importance of the ethical attitudes held and the reasons underpinning them should be explored if problems with delivery of care are to be avoided in the future.