Design, conduct, and analyses of Breast International Group (BIG) 1-98: a randomized, double-blind, phase-III study comparing letrozole and tamoxifen as adjuvant endocrine therapy for postmenopausal women with receptor-positive, early breast cancer.

BACKGROUND: Aromatase inhibitors provide superior disease control when compared with tamoxifen as adjuvant therapy for postmenopausal women with endocrine-responsive early breast cancer. PURPOSE: To present the design, history, and analytic challenges of the Breast International Group (BIG) 1-98 trial: an international, multicenter, randomized, double-blind, phase-III study comparing the aromatase inhibitor letrozole with tamoxifen in this clinical setting. METHODS: From 1998-2003, BIG 1-98 enrolled 8028 women to receive monotherapy with either tamoxifen or letrozole for 5 years, or sequential therapy of 2 years of one agent followed by 3 years of the other. Randomization to one of four treatment groups permitted two complementary analyses to be conducted several years apart. The first, reported in 2005, provided a head-to-head comparison of letrozole versus tamoxifen. Statistical power was increased by an enriched design, which included patients who were assigned sequential treatments until the time of the treatment switch. The second, reported in late 2008, used a conditional landmark approach to test the hypothesis that switching endocrine agents at approximately 2 years from randomization for patients who are disease-free is superior to continuing with the original agent. RESULTS: The 2005 analysis showed the superiority of letrozole compared with tamoxifen. The patients who were assigned tamoxifen alone were unblinded and offered the opportunity to switch to letrozole. Results from other trials increased the clinical relevance about whether or not to start treatment with letrozole or tamoxifen, and analysis plans were expanded to evaluate sequential versus single-agent strategies from randomization. LIMITATIONS: Due to the unblinding of patients assigned tamoxifen alone, analysis of updated data will require ascertainment of the influence of selective crossover from tamoxifen to letrozole. CONCLUSIONS: BIG 1-98 is an example of an enriched design, involving complementary analyses addressing different questions several years apart, and subject to evolving analytic plans influenced by new data that emerge over time.

Thin Maintenance Surfaces - Phase I, TR-435, 1999

The first phase of a two-phase research project was conducted to develop guidelines for Iowa transportation officials on the use of thin maintenance surfaces (TMS) for asphaltic concrete and bituminous roads. Thin maintenance surfaces are seal coats (chip seals), slurry seals, and micro-surfacing. Interim guidelines were developed to provide guidance on which roads are good candidates for TMS, when TMS should be placed, and what type of thin maintenance surface should be selected. The guidelines were developed specifically for Iowa aggregates, weather, traffic conditions, road user expectations, and transportation official expectations. In addition to interim guidelines, this report presents recommendations for phase-two research. It is recommended that test section monitoring continue and that further investigations be conducted regarding thin maintenance surface aggregate, additional test sections, placed, and a design method adopted for seal coats.

Thin Maintenance Surfaces - Phase II, TR-435, 2003

In recent years there has been renewed interest in using preventive maintenance techniques to extend pavement life and to ensure low life cycle costs for our road infrastructure network. Thin maintenance surfaces can be an important part of a preventive maintenance program for asphalt cement concrete roads. The Iowa Highway Research Board has sponsored Phase Two of this research project to demonstrate the use of thin maintenance surfaces in Iowa and to develop guidelines for thin maintenance surface uses that are specific to Iowa. This report documents the results of test section construction and monitoring started in Phase One and continued in Phase Two. The report provides a recommended seal coat design process based on the McLeod method and guidance on seal coat aggregates and binders. An update on the use of local aggregates for micro-surfacing in Iowa is included. Winter maintenance guidelines for thin maintenance surfaces are reported herein. Finally, Phase One's interim, qualitative thin maintenance surface guidelines are supplemented with Phase two's revised, quantitative guidelines. When thin maintenance surfaces are properly selected and applied, they can improve the pavement surface condition index and the skid resistance of pavements. For success to occur, several requirements must be met, including proper material selection, design, application rate, workmanship, and material compatibility, as well as favorable weather during application and curing. Specific guidance and recommendations for many types of thin maintenance surfaces and conditions are included in the report.

Coocurrencia entre ansiedad y autismo: Las hipótesis del error social y de la carga alostática

Introducción. El concepto de comorbilidad en trastornos del neurodesarrollo como el autismo resulta, en ocasiones, ambiguo. La coocurrencia entre ansiedad y autismo es clínicamente signifi cativa; sin embargo, no siempre es fácil diferenciar si se trata de una comorbilidad"real", donde las dos condiciones comórbidas son fenotípica y etiológicamente idénticas a lo que supondría dicha ansiedad en personas con un desarrollo neurotípico; si se trata de una ansiedad fenotípicamente alterada por los procesos patogénicos de los trastornos del espectro autista, resultando en una variante específica de éstos, o si partimos de una comorbilidad falsa derivada de diagnósticos diferenciales poco exactos. Desarrollo. El artículo plantea dos hipótesis explicativas de dicha coocurrencia, que se retroalimentan entre sí y que no dejan de ser una refl exión en voz alta partiendo de las evidencias científi cas con las que contamos. La primera es la hipótesis del"error social", y considera que el desajuste en el comportamiento social de las personas con autismofruto de alteraciones en los procesos de cognición social contribuye a exacerbar la ansiedad en el autismo. La segunda hipótesis, la de la carga alostática, defi ende que la ansiedad es la respuesta a un estrés crónico, al desgaste o agotamiento que produce la hiperactivación de ciertas estructuras del sistema límbico. Conclusiones. Las manifestaciones prototípicas de la ansiedad presentes en la persona con autismo no siempre se relacionan con las mismas variables biopsicosociales evidenciadas en personas sin autismo. Las evidencias apuntan a respuestas hiperreactivas de huida o lucha (hipervigilancia) cuando la persona se encuentra fuera de su zona de confort, y apoyan la hipótesis del"error social" y de la descompensación del mecanismo de alostasis que permite afrontar el estrés.

Optimal priming of poxvirus vector (NYVAC)-based HIV vaccine regimens requires 3 DNA injections. Results of the EV03/ANRS Vac20 Phase I/II Trial

Background: Two or three DNA primes have been used in previous smaller clinical trials, but the number required for optimal priming of viral vectors has never been assessed in adequately powered clinical trials. The EV03/ANRS Vac20 phase I/II trial investigated this issue using the DNA prime/poxvirus NYVAC boost combination, both expressing a common HIV-1 clade C immunogen consisting of Env and Gag-Pol-Nef polypeptide. Methods: 147 healthy volunteers were randomly allocated through 8 European centres to either 3xDNA plus 1xNYVAC (weeks 0, 4, 8 plus 24; n¼74) or to 2xDNA plus 2xNYVAC (weeks 0, 4 plus 20, 24; n¼73), stratified by geographical region and sex. T cell responses were quantified using the interferon g Elispot assay and 8 peptide pools; samples from weeks 0, 26 and 28 (time points for primary immunogenicity endpoint), 48 and 72 were considered for this analysis. Results: 140 of 147 participants were evaluable at weeks 26 and/ or 28. 64/70 (91%) in the 3xDNA arm compared to 56/70 (80%) in the 2xDNA arm developed a T cell response (P¼0.053). 26 (37%) participants of the 3xDNA arm developed a broader T cell response (Env plus at least to one of the Gag, Pol, Nef peptide pools) versus 15 (22%) in the 2xDNA arm (P¼0.047). At week 26, the overall magnitude of responses was also higher in the 3xDNA than in the 2xDNA arm (similar at week 28), with a median of 545 versus 328 SFUs/106 cells at week 26 (P<0.001). Preliminary overall evaluation showed that participants still developed T-cell response at weeks 48 (78%, n¼67) and 72 (70%, n¼66). Conclusion: This large clinical trial demonstrates that optimal priming of poxvirus-based vaccine regimens requires 3 DNA regimens and further confirms that the DNA/NYVAC prime boost vaccine combination is highly immunogenic and induced durable T-cell responses.

Looking for Validity or Testing It? The Perils of Stepwise Regression, Extreme-Scores Analysis, Heteroscedasticity, and Measurement Error

When researchers introduce a new test they have to demonstrate that it is valid, using unbiased designs and suitable statistical procedures. In this article we use Monte Carlo analyses to highlight how incorrect statistical procedures (i.e., stepwise regression, extreme scores analyses) or ignoring regression assumptions (e.g., heteroscedasticity) contribute to wrong validity estimates. Beyond these demonstrations, and as an example, we re-examined the results reported by Warwick, Nettelbeck, and Ward (2010) concerning the validity of the Ability Emotional Intelligence Measure (AEIM). Warwick et al. used the wrong statistical procedures to conclude that the AEIM was incrementally valid beyond intelligence and personality traits in predicting various outcomes. In our re-analysis, we found that the reliability-corrected multiple correlation of their measures with personality and intelligence was up to .69. Using robust statistical procedures and appropriate controls, we also found that the AEIM did not predict incremental variance in GPA, stress, loneliness, or well-being, demonstrating the importance for testing validity instead of looking for it.

An EORTC Phase II study of caspofungin as first-line therapy of invasive aspergillosis in haematological patients.

OBJECTIVES: Caspofungin was evaluated as first-line monotherapy of invasive aspergillosis (IA) in patients with haematological malignancies and undergoing autologous transplants. METHODS: Adults with proven or probable IA, defined strictly according to EORTC-MSG criteria, were eligible. Those with possible IA were enrolled, but were not evaluable for efficacy unless upgraded to proven/probable disease within 7 days of registration based on investigations performed within 48 h after enrolment. Caspofungin dosage was 70 mg (day 1) followed by 50 mg/day. The primary endpoint was the proportion of patients with complete or partial response at the end of caspofungin therapy in the modified intention to treat (MITT) group; secondary endpoints were response and survival at day 84 and safety. RESULTS: In the MITT group (n = 61), 75% of patients had cancer not in remission (relapsing or refractory), 85% were neutropenic at enrolment and 49% had a Karnofsky score of < or =50. At end of treatment, 1 and 19 patients had complete and partial response, respectively [success rate 33% (20/61)], 9 (15%) achieved stabilization and 31 (51%) had disease progression. One patient was not evaluable. The 6 and 12 week survival rates were 66% (40/61) and 53% (32/60), respectively. Baseline characteristics associated with survival at day 84 were an underlying disease in remission (not relapsing or refractory) and Karnofsky score. Recovery from neutropenia at the end of treatment was also significantly associated with survival. No serious drug-related adverse events or discontinuations due to drug-related adverse events were observed. CONCLUSIONS: Caspofungin provided an observed response rate compatible with the null hypothesis of a true response rate of < or =35%. Underlying disease-related factors had a major impact on results.