Predicting smoking cessation and its relapse in HIV-infected patients: the Swiss HIV Cohort Study.

OBJECTIVES: The aim of the study was to assess whether prospective follow-up data within the Swiss HIV Cohort Study can be used to predict patients who stop smoking; or among smokers who stop, those who start smoking again. METHODS: We built prediction models first using clinical reasoning ('clinical models') and then by selecting from numerous candidate predictors using advanced statistical methods ('statistical models'). Our clinical models were based on literature that suggests that motivation drives smoking cessation, while dependence drives relapse in those attempting to stop. Our statistical models were based on automatic variable selection using additive logistic regression with component-wise gradient boosting. RESULTS: Of 4833 smokers, 26% stopped smoking, at least temporarily; because among those who stopped, 48% started smoking again. The predictive performance of our clinical and statistical models was modest. A basic clinical model for cessation, with patients classified into three motivational groups, was nearly as discriminatory as a constrained statistical model with just the most important predictors (the ratio of nonsmoking visits to total visits, alcohol or drug dependence, psychiatric comorbidities, recent hospitalization and age). A basic clinical model for relapse, based on the maximum number of cigarettes per day prior to stopping, was not as discriminatory as a constrained statistical model with just the ratio of nonsmoking visits to total visits. CONCLUSIONS: Predicting smoking cessation and relapse is difficult, so that simple models are nearly as discriminatory as complex ones. Patients with a history of attempting to stop and those known to have stopped recently are the best candidates for an intervention.

Action Research : the first steps to start up a pilot experiment in heritage education

Peer-reviewed

Impactia: automating the study of the scientific production

Introduction The Andalusian Public Health System Virtual Library (Biblioteca Virtual del Sistema Sanitario Público de Andalucía, BV-SSPA) was set up in June 2006. It consists of a regional government action with the aim of democratizing the health professional access to quality scientific information, regardless of the professional workplace. Andalusia is a region with more than 8 million inhabitants, with 100,000 health professionals for 41 hospitals, 1,500 primary healthcare centres, and 28 centres for non-medical attention purposes (research, management, and educational centres). Objectives The Department of Development, Research and Investigation (R+D+i) of the Andalusian Regional Government has, among its duties, the task of evaluating the hospitals and centres of the Andalusian Public Health System (SSPA) in order to distribute its funding. Among the criteria used is the evaluation of the scientific output, which is measured using bibliometry. It is well-known that the bibliometry has a series of limitations and problems that should be taken into account, especially when it is used for non-information sciences, such us career, funding, etc. A few years ago, the bibliometric reports were done separately in each centre, but without using preset and well-defined criteria, elements which are basic when we need to compare the results of the reports. It was possible to find some hospitals which were including Meeting Abstracts in their figures, while others do not, and the same was happening with Erratum and many other differences. Therefore, the main problem that the Department of R+D+i had to deal with, when they were evaluating the health system, was that bibliometric data was not accurate and reports were not comparable. With the aim of having an unified criteria for the whole system, the Department of R+D+i ordered the BV-SSPA to do the year analysis of the scientific output of the system, using some well defined criteria and indicators, among whichstands out the Impact Factor. Materials and Methods As the Impact Factor is the bibliometric indicator that the virtual library is asked to consider, it is necessary to use the database Web of Science (WoS), since it is its owner and editor. The WoS includes the databases Science Citation Index (SCI), Social Sciences Citation Index (SSCI) and Arts & Humanities Citation Index. To gather all the documents, SCI and SSCI are used; to obtain the Impact Factor and quartils, it is used the Journal Citation Reports, JCR. Unlike other bibliographic databases, such us MEDLINE, the bibliometric database WoS includes the address of all the authors. In order to retrieve all the scientific output of the SSPA, we have done general searches, which are afterwards processed by a tool developed by our library. We have done nine different searches using the field ‘address’; eight of them including ‘Spain’ and each one of the eight Andalusian Regions, and the other one combining ‘Spain’ with all those cities where there are health centres, since we have detected that there are some authors that do not use the region in their signatures. These are some of the search strategies: AD=Malaga and AD=Spain AD=Sevill* and AD=Spain AD=SPAIN AND (AD=GUADIX OR AD=BAZA OR AD=MOTRIL) Further more, the field ‘year’ is used to determine the period. To exploit the data, the BV-SSPA has developed a tool called Impactia. It is a web application which uses a database to store the information of the documents generated by the SSPA. Impactia allows the user to automatically process the retrieved documents, assigning them to their correspondent centres. In order to do the classification of documents automaticaly, it was necessary to detect the huge variability of names of the centres that the authors use in their signatures. Therefore, Impactia knows that if an author signs as “Hospital Universitario Virgen Macarena”, “HVM” or “Hosp. Virgin Macarena”, he belongs to the same centre. The figure attached shows the variability found for the Empresa Publica Hospital de Poniente. Besides the documents from WoS, Impactia includes the documents indexed in Scopus and in other databases, where we do bibliographic searches using similar strategies to the later ones. Aware that in the health centres and hospitals there is a lot of grey literature that is not gathered in databases, Impactia allows the centres to feed the application with these documents, so that all the SSPA scientific output is gathered and organised in a centralized place. The ones responsible of localizing this gray literature are the librarians of each one of the centres. They can also do statements to the documents and indicators that are collected and calculated by Impactia. The bulk upload of documents from WoS and Scopus into Impactia is monthly done. One of the main issues that we found during the development of Impactia was the need of dealing with duplicated documents obtained from different sources. Taking into account that sometimes titles might be written differently, with slashes, comas, and so on, Impactia detects the duplicates using the field ‘DOI’ if it is available or comparing the fields: page start, page end and ISSN. Therefore it is possible to guarantee the absence of duplicates. Results The data gathered in Impactia becomes available to the administrative teams and hospitals managers, through an easy web page that allows them to know at any moment, and with just one click, the detailed information of the scientific output of their hospitals, including useful graphs such as percentage of document types, journals where their scientists usually publish, annual comparatives, bibliometric indicators and so on. They can also compare the different centres of the SSPA. Impactia allows the user to download the data from the application, so that he can work with this information or include them in their centres’ reports. This application saves the health system many working hours. It was previously done manually by forty one librarians, while now it is done by only one person in the BV-SSPA during two days a month. To sum up, the benefits of Impactia are: It has shown its effectiveness in the automatic classification, treatment and analysis of the data. It has become an essential tool for all managers to evaluate quickly and easily the scientific production of their centers. It optimizes the human resources of the SSPA, saving time and money. It is the reference point for the Department of R+D+i to do the scientific health staff evaluation.

Are some hypertensive patients overtreated? A prospective study of ambulatory blood pressure recording.

Ambulatory blood pressure (BP) was recorded in hypertensive patients whose physicians had been asked to reduce diastolic pressure measured in the office to 90 mm Hg or less. 34 hypertensive patients with a diastolic pressure measured by their physician of 95 mm Hg or more despite antihypertensive therapy had their treatment changed with the aim of achieving this pre-set goal within 3 months. At the beginning and the end of the study, ambulatory BP was monitored during the daytime with a portable non-invasive recorder. The results of the ambulatory recordings were not made available to the physicians until completion of the study. In half the patients the ambulatory diastolic pressure was already 90 mm Hg or less at the start. In these patients, treatment adjustment did not further decrease ambulatory BP. In contrast, patients who initially had an ambulatory diastolic pressure above 90 mm Hg had a significantly decreased ambulatory BP at the end of the study. Intensifying the therapy of hypertensive patients who have a normal ambulatory BP may result in overtreatment without any real gain in BP control.

Anal mucosectomy for haemorrhoids: should we start to speak Chinese?

AIM: Circular stapled mucosectomy is the standard therapy for the treatment of symptomatic third-degree haemorrhoids and mucosal prolapse. Recently, new staplers made in China have entered the market offering an alternative to the PPH stapling devices. The aim of this prospective randomized study was to compare the safety and efficacy of these new devices. METHODS: Fifty patients with symptomatic third-degree haemorrhoids were randomized to mucosectomy either by using stapler A (CPH32; Frankenman International Ltd, Hong Kong, China; n = 25) or stapler B (PPH03; Ethicon Endo-Surgery, Spreitenbach, Switzerland; n = 25). All procedures were performed by two experienced surgeons. After the stapler was fired by one surgeon, the other surgeon, who was blinded for stapler type, evaluated the stapler line. Postoperative outcome including pain, complications and patient satisfaction were analysed. RESULTS: Demographic and clinical features were no different between the groups. There was no significant difference regarding venous bleeding (P = 0.55), but arterial bleeding was significantly more frequent when stapler B was used (P < 0.001). This led to significantly more suture ligations (P = 0.002). However, no differences regarding operation time (P = 0.99), weight of the resected mucosa (P = 0.81) and height of the stapler line (anterior, P = 0.18; posterior, P = 0.65) were detected. Postoperative pain scores (visual analogue scale) and patient satisfaction were no different either (P = 0.91 and P = 0.78, respectively). No recurrence or incontinence occurred during follow-up. CONCLUSIONS: CPH32 required significantly fewer sutures for bleeding control along the stapler line after circular mucosectomy. However, operation time, rate of postoperative complications and patient satisfaction were similar in both groups.

Obesity trends and body mass index changes after starting antiretroviral treatment : the Swiss HIV Cohort Study

BACKGROUND: The factors that contribute to increasing obesity rates in human immunodeficiency virus (HIV)-positive persons and to body mass index (BMI) increase that typically occurs after starting antiretroviral therapy (ART) are incompletely characterized. METHODS: We describe BMI trends in the entire Swiss HIV Cohort Study (SHCS) population and investigate the effects of demographics, HIV-related factors, and ART on BMI change in participants with data available before and 4 years after first starting ART. RESULTS: In the SHCS, overweight/obesity prevalence increased from 13% in 1990 (n = 1641) to 38% in 2012 (n = 8150). In the participants starting ART (n = 1601), mean BMI increase was 0.92 kg/m(2) per year (95% confidence interval, .83-1.0) during year 0-1 and 0.31 kg/m(2) per year (0.29-0.34) during years 1-4. In multivariable analyses, annualized BMI change during year 0-1 was associated with older age (0.15 [0.06-0.24] kg/m(2)) and CD4 nadir <199 cells/µL compared to nadir >350 (P < .001). Annualized BMI change during years 1-4 was associated with CD4 nadir <100 cells/µL compared to nadir >350 (P = .001) and black compared to white ethnicity (0.28 [0.16-0.37] kg/m(2)). Individual ART combinations differed little in their contribution to BMI change. CONCLUSIONS: Increasing obesity rates in the SHCS over time occurred at the same time as aging of the SHCS population, demographic changes, earlier ART start, and increasingly widespread ART coverage. Body mass index increase after ART start was typically biphasic, the BMI increase in year 0-1 being as large as the increase in years 1-4 combined. The effect of ART regimen on BMI change was limited.

Long-term outcome of patients after a single interruption of antiretroviral therapy: a cohort study.

BACKGROUND To describe the long term outcome of patients who interrupted highly active antiretroviral therapy (HAART) once, identify the variables associated with earlier need to re-start HAART, and the response when therapy was resumed. A retrospective observational cohort of 66 adult patients with HIV-1 infection who interrupted HAART with a CD4+cell count ≥ 350 cells/μL and undetectable viral load (VL) was performed. The pre-established CD4+ cell count for restarting therapy was 300cells/μL. Cox regression was used to analyse the variables associated with earlier HAART reinitiation. RESULTS The median follow-up was 209 weeks (range, 64-395). Rates of HIV-related or possible HIV-related events were 0.37 (one case of acute retroviral syndrome) and 1.49 per 100 patient-years, respectively. Two patients died after re-starting therapy and having reached undetectable VL. Three patients suffered a sexually transmitted disease while off therapy. Fifty patients (76%) resumed therapy after a median of 97 weeks (range, 17-267). Age, a nadir of CD4+ <250 cells/μL, and a mean VL during interruption of >10,000 copies/ml were independent predictors for earlier re-start. The intention-to-treat success rate of the first HAART resumed regimen was 85.4%. There were no differences by regimen used, nor between regimens that were the same as or different from the one that had been interrupted. CONCLUSIONS Our data suggest highly active antiretroviral therapy may be interrupted in selected patients because in these patients, when the HAART is restarted, the viral and clinical response may be achieved.

Study protocol for a pragmatic randomised controlled trial in general practice investigating the effectiveness of acupuncture against migraine.

BACKGROUND Migraine is a chronic neurologic disease that can severely affect the patient's quality of life. Although in recent years many randomised studies have been carried out to investigate the effectiveness of acupuncture as a treatment for migraine, it remains a controversial issue. Our aim is to determine whether acupuncture, applied under real conditions of clinical practice in the area of primary healthcare, is more effective than conventional treatment. METHODS/DESIGN The design consists of a pragmatic multi-centre, three-armed randomised controlled trial, complemented with an economic evaluation of the results achieved, comparing the effectiveness of verum acupuncture with sham acupuncture, and with a control group receiving normal care only. Patients eligible for inclusion will be those presenting in general practice with migraine and for whom their General Practitioner (GP) is considering referral for acupuncture. Sampling will be by consecutive selection, and by randomised allocation to the three branches of the study, in a centralised way following a 1:1:1 distribution (verum acupuncture; sham acupuncture; conventional treatment). Secondly, one patient in three will be randomly selected from each of the acupuncture (verum or sham) groups for a brain perfusion study (by single photon emission tomography). The treatment with verum acupuncture will consist of 8 treatment sessions, once a week, at points selected individually by the acupuncturist. The sham acupuncture group will receive 8 sessions, one per week, with treatment being applied at non-acupuncture points in the dorsal and lumbar regions, using the minimal puncture technique. The control group will be given conventional treatment, as will the other two groups. DISCUSSION This trial will contribute to available evidence on acupuncture for the treatment of migraine. The primary endpoint is the difference in the number of days with migraine among the three groups, between the baseline period (the 4 weeks prior to the start of treatment) and the period from weeks 9 to 12. As a secondary aspect, we shall record the index of laterality and the percentage of change in the mean count per pixel in each region of interest measured by the brain perfusion tomography, performed on a subsample of the patients within the real and sham acupuncture groups. TRIAL REGISTRATION Current Controlled Trials ISRCTN98703707.

Immune responses to JC virus in patients with multiple sclerosis treated with natalizumab: a cross-sectional and longitudinal study.

BACKGROUND: Natalizumab is used to prevent relapses and progression of disability in patients with multiple sclerosis but has been associated with progressive multifocal leukoencephalopathy (PML). We aimed to better understand the associations between JC virus, which causes PML, and natalizumab treatment. METHODS: We prospectively assessed patients with multiple sclerosis who started treatment with natalizumab. Blood and urine samples were tested for the presence of JC virus DNA with quantitative real-time PCR before treatment and at regular intervals after treatment onset for up to 18 months. At the same timepoints, by use of proliferation and enzyme-linked immunospot assays, the cellular immune responses against JC virus, Epstein-Barr virus, cytomegalovirus, myelin oligodendrocyte glycoprotein, and myelin oligodendrocyte basic protein (MOBP) were assessed. Humoral immune response specific to JC virus was assessed with an enzyme immunoassay. The same experiments were done on blood samples from patients with multiple sclerosis before and 10 months after the start of interferon beta treatment. FINDINGS: We assessed 24 patients with multiple sclerosis who received natalizumab and 16 who received interferon beta. In patients treated with natalizumab, JC virus DNA was not detected in the blood at any timepoint. However, JC virus DNA was present in the urine of six patients and in most of these patients the concentrations of JC virus DNA were stable over time. Compared with pretreatment values, the cellular immune response was increased to cytomegalovirus at 6 months, to JC virus at 1, 9, and 12 months, and to Epstein-Barr virus and MOBP at 12 months. Humoral responses remained stable. There were no increases in cellular immune responses specific to the viruses or myelin proteins in the 16 patients treated with interferon beta. INTERPRETATION: Natalizumab increases cellular immune responses specific to viruses and myelin proteins in the peripheral blood after 1 year, without evidence of viral reactivation. FUNDING: Swiss National Foundation, Swiss Society for Multiple Sclerosis, and Biogen Dompé.

Outcomes of patients on dual-boosted PI regimens: experience of the Swiss HIV cohort study.

Dual-boosted protease inhibitors (DBPI) are an option for salvage therapy for HIV-1 resistant patients. Patients receiving a DBPI in the Swiss HIV Cohort Study between January1996 and March 2007 were studied. Outcomes of interest were viral suppression at 24 weeks. 295 patients (72.5%) were on DBPI for over 6 months. The median duration was 2.2 years. Of 287 patients who had HIV-RNA >400 copies/ml at the start of the regimen, 184 (64.1%) were ever suppressed while on DBPI and 156 (54.4%) were suppressed within 24 weeks. The median time to suppression was 101 days (95% confidence interval 90-125 days). The median number of past regimens was 6 (IQR, 3-8). The main reasons for discontinuing the regimen were patient's wish (48.3%), treatment failure (22.5%), and toxicity (15.8%). Acquisition of HIV through intravenous drug use and the use of lopinavir in combination with saquinavir or atazanavir were associated with an increased likelihood of suppression within 6 months. Patients on DBPI are heavily treatment experienced. Viral suppression within 6 months was achieved in more than half of the patients. There may be a place for DBPI regimens in settings where more expensive alternates are not available.

Multiple prisoner's dilemma games with (out) an outside option: An experimental study

Experiments in which subjects play simultaneously several finite prisoner's dilemma supergames with and without an outside optionreveal that: (i) subjects use probabilistic start and endeffect behaviour, (ii) the freedom to choose whether to play the prisoner's dilemma game enhances cooperation, (iii) if the payoff for simultaneous defection is negative, subjects' tendency to avoid losses leads them to cooperate; while this tendency makes them stick to mutual defection if its payoff is positive.

Automatic selection of tidal volume, respiratory frequency and minute ventilation in intubated ICU patients as start up procedure for closed-loop controlled ventilation.

OBJECTIVE: Before a patient can be connected to a mechanical ventilator, the controls of the apparatus need to be set up appropriately. Today, this is done by the intensive care professional. With the advent of closed loop controlled mechanical ventilation, methods will be needed to select appropriate start up settings automatically. The objective of our study was to test such a computerized method which could eventually be used as a start-up procedure (first 5-10 minutes of ventilation) for closed-loop controlled ventilation. DESIGN: Prospective Study. SETTINGS: ICU's in two adult and one children's hospital. PATIENTS: 25 critically ill adult patients (age > or = 15 y) and 17 critically ill children selected at random were studied. INTERVENTIONS: To stimulate 'initial connection', the patients were disconnected from their ventilator and transiently connected to a modified Hamilton AMADEUS ventilator for maximally one minute. During that time they were ventilated with a fixed and standardized breath pattern (Test Breaths) based on pressure controlled synchronized intermittent mandatory ventilation (PCSIMV). MEASUREMENTS AND MAIN RESULTS: Measurements of airway flow, airway pressure and instantaneous CO2 concentration using a mainstream CO2 analyzer were made at the mouth during application of the Test-Breaths. Test-Breaths were analyzed in terms of tidal volume, expiratory time constant and series dead space. Using this data an initial ventilation pattern consisting of respiratory frequency and tidal volume was calculated. This ventilation pattern was compared to the one measured prior to the onset of the study using a two-tailed paired t-test. Additionally, it was compared to a conventional method for setting up ventilators. The computer-proposed ventilation pattern did not differ significantly from the actual pattern (p > 0.05), while the conventional method did. However the scatter was large and in 6 cases deviations in the minute ventilation of more than 50% were observed. CONCLUSIONS: The analysis of standardized Test Breaths allows automatic determination of an initial ventilation pattern for intubated ICU patients. While this pattern does not seem to be superior to the one chosen by the conventional method, it is derived fully automatically and without need for manual patient data entry such as weight or height. This makes the method potentially useful as a start up procedure for closed-loop controlled ventilation.

Treatment patterns and health care resource utilization in a 1-year observational cohort study of outpatients with schizophrenia at risk of nonadherence treated with long-acting injectable antipsychotics

Purpose: To describe (1) the clinical profiles and the patterns of use of long-acting injectable (LAI) antipsychotics in patients with schizophrenia at risk of nonadherence with oral antipsychotics, and in those who started treatment with LAI antipsychotics, (2) health care resource utilization and associated costs. Patients and methods: A total of 597 outpatients with schizophrenia at risk of nonadherence, according to the psychiatrist's clinical judgment, were recruited at 59 centers in a noninterventional prospective observational study of 1-year follow-up when their treatment was modified. In a post hoc analysis, the profiles of patients starting LAI or continuing with oral antipsychotics were described, and descriptive analyses of treatments, health resource utilization, and direct costs were performed in those who started an LAI antipsychotic. Results: Therapy modifications involved the antipsychotic medications in 84.8% of patients, mostly because of insufficient efficacy of prior regimen. Ninety-two (15.4%) patients started an LAI antipsychotic at recruitment. Of these, only 13 (14.1%) were prescribed with first-generation antipsychotics. During 1 year, 16.3% of patients who started and 14.9% of patients who did not start an LAI antipsychotic at recruitment relapsed, contrasting with the 20.9% who had been hospitalized only within the prior 6 months. After 1 year, 74.3% of patients who started an LAI antipsychotic continued concomitant treatment with oral antipsychotics. The mean (median) total direct health care cost per patient per month during the study year among the patients starting any LAI antipsychotic at baseline was 1,407 ( 897.7). Medication costs (including oral and LAI antipsychotics and concomitant medication) represented almost 44%, whereas nonmedication costs accounted for more than 55% of the mean total direct health care costs. Conclusion: LAI antipsychotics were infrequently prescribed in spite of a psychiatrist-perceived risk of nonadherence to oral antipsychotics. Mean medication costs were lower than nonmedication costs.

Melt variability in percolated peridotite: an experimental study applied to reactive migration of tholeiitic basalt in the upper mantle

Melt-rock reaction in the upper mantle is recorded in a variety of ultramafic rocks and is an important process in modifying melt composition on its way from the source region towards the surface. This experimental study evaluates the compositional variability of tholeiitic basalts upon reaction with depleted peridotite at uppermost-mantle conditions. Infiltration-reaction processes are simulated by employing a three-layered set-up: primitive basaltic powder ('melt layer') is overlain by a 'peridotite layer' and a layer of vitreous carbon spheres ('melt trap'). Melt from the melt layer is forced to move through the peridotite layer into the melt trap. Experiments were conducted at 0.65 and 0.8 GPa in the temperature range 1,170-1,290 degrees C. In this P-T range, representing conditions encountered in the transition zone (thermal boundary layer) between the asthenosphere and the lithosphere underneath oceanic spreading centres, the melt is subjected to fractionation, and the peridotite is partially melting (T (s) similar to 1,260 degrees C). The effect of reaction between melt and peridotite on the melt composition was investigated across each experimental charge. Quenched melts in the peridotite layers display larger compositional variations than melt layer glasses. A difference between glasses in the melt and peridotite layer becomes more important at decreasing temperature through a combination of enrichment in incompatible elements in the melt layer and less efficient diffusive equilibration in the melt phase. At 1,290A degrees C, preferential dissolution of pyroxenes enriches the melt in silica and dilutes it in incompatible elements. Moreover, liquids become increasingly enriched in Cr(2)O(3) at higher temperatures due to the dissolution of spinel. Silica contents of liquids decrease at 1,260 degrees C, whereas incompatible elements start to concentrate in the melt due to increasing levels of crystallization. At the lowest temperatures investigated, increasing alkali contents cause silica to increase as a consequence of reactive fractionation. Pervasive percolation of tholeiitic basalt through an upper-mantle thermal boundary layer can thus impose a high-Si 'low-pressure' signature on MORB. This could explain opx + plag enrichment in shallow plagioclase peridotites and prolonged formation of olivine gabbros.

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.