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.

Design and establishment of a biobank in a multicenter prospective cohort study of elderly patients with venous thromboembolism (SWITCO65+).

In the field of thrombosis and haemostasis, many preanalytical variables influence the results of coagulation assays and measures to limit potential results variations should be taken. To our knowledge, no paper describing the development and maintenance of a haemostasis biobank has been previously published. Our description of the biobank of the Swiss cohort of elderly patients with venous thromboembolism (SWITCO65+) is intended to facilitate the set-up of other biobanks in the field of thrombosis and haemostasis. SWITCO65+ is a multicentre cohort that prospectively enrolled consecutive patients aged ≥65 years with venous thromboembolism at nine Swiss hospitals from 09/2009 to 03/2012. Patients will be followed up until December 2013. The cohort includes a biobank with biological material from each participant taken at baseline and after 12 months of follow-up. Whole blood from all participants is assayed with a standard haematology panel, for which fresh samples are required. Two buffy coat vials, one PAXgene Blood RNA System tube and one EDTA-whole blood sample are also collected at baseline for RNA/DNA extraction. Blood samples are processed and vialed within 1 h of collection and transported in batches to a central laboratory where they are stored in ultra-low temperature archives. All analyses of the same type are performed in the same laboratory in batches. Using multiple core laboratories increased the speed of sample analyses and reduced storage time. After recruiting, processing and analyzing the blood of more than 1,000 patients, we determined that the adopted methods and technologies were fit-for-purpose and robust.

Efficacy of an adjunctive brief psychodynamic psychotherapy to usual inpatient treatment of depression: rationale and design of a randomized controlled trial.

BACKGROUND: A few recent studies have found indications of the effectiveness of inpatient psychotherapy for depression, usually of an extended duration. However, there is a lack of controlled studies in this area and to date no study of adequate quality on brief psychodynamic psychotherapy for depression during short inpatient stay exists. The present article describes the protocol of a study that will examine the relative efficacy, the cost-effectiveness and the cost-utility of adding an Inpatient Brief Psychodynamic Psychotherapy to pharmacotherapy and treatment-as-usual for inpatients with unipolar depression. METHODS/DESIGN: The study is a one-month randomized controlled trial with a two parallel group design and a 12-month naturalistic follow-up. A sample of 130 consecutive adult inpatients with unipolar depression and Montgomery-Asberg Depression Rating Scale score over 18 will be recruited. The study is carried out in the university hospital section for mood disorders in Lausanne, Switzerland. Patients are assessed upon admission, and at 1-, 3- and 12- month follow-ups. Inpatient therapy is a manualized brief intervention, combining the virtues of inpatient setting and of time-limited dynamic therapies (focal orientation, fixed duration, resource-oriented interventions). Treatment-as-usual represents the best level of practice for a minimal treatment condition usually proposed to inpatients. Final analyses will follow an intention-to-treat strategy. Depressive symptomatology is the primary outcome and secondary outcome includes measures of psychiatric symptomatology, psychosocial role functioning, and psychodynamic-emotional functioning. The mediating role of the therapeutic alliance is also examined. Allocation to treatment groups uses a stratified block randomization method with permuted block. To guarantee allocation concealment, randomization is done by an independent researcher. DISCUSSION: Despite the large number of studies on treatment of depression, there is a clear lack of controlled research in inpatient psychotherapy during the acute phase of a major depressive episode. Research on brief therapy is important to take into account current short lengths of stay in psychiatry. The current study has the potential to scientifically inform appropriate inpatient treatment. This study is the first to address the issue of the economic evaluation of inpatient psychotherapy. TRIAL REGISTRATION: Australian New Zealand Clinical Trial Registry (ACTRN12612000909820).

Local Public-Services Provision under Public-Private Partnerships : Contractual Design and Contracting Parties Incentives

When deciding to resort to a PPP contract for the provision of a local public service, local governments have to consider the demand risk allocation between the contracting parties. In this article, I investigate the effects of demand risk allocation on the accountability of procuring authorities regarding consumers changing demand, as well as on the cost-reducing effort incentives of the private public-service provider. I show that contracts in which the private provider bears demand risk motivate more the public authority from responding to customer needs. This is due to the fact that consumers are empowered when the private provider bears demand risk, that is, they have the possibility to oust the private provider in case of non-satisfaction with the service provision, which provides procuring authorities with more credibility in side-trading and then more incentives to be responsive. As a consequence, I show that there is a lower matching with consumers' preferences over time when demand risk is on the public authority rather than on the private provider, and this is corroborated in the light of two famous case studies. However, contracts in which the private provider does not bear demand risk motivate more the private provider from investing in cost-reducing efforts. I highlight then a tradeoff in the allocation of demand risk between productive and allocative efficiency. The striking policy implication of this article for local governments would be that the current trend towards a greater resort to contracts where private providers bear little or no demand risk may not be optimal. Local governments should impose demand risk on private providers within PPP contracts when they expect that consumers' preferences over the service provision will change over time.

Sepsis: time to reconsider the concept.

OBJECTIVE: To discuss the difficulty in using the concept of sepsis for clinical trials and propose new ways for designing future trials for severe infections. DESIGN: Short position statement. METHODS AND MAIN RESEARCH: Using a thorough evaluation of the recent literature in the field of severe sepsis and septic shock, the authors challenge the concept of sepsis as used in the past two decades and propose new ideas for designing future trials in this setting. The two main proposals are first to use a systematic assessment of the targeted inflammatory mediators when the study intends to counteract or replace those mediators (e.g., anti-tumor necrosis factor-alpha, activated protein C) and, second, to select more homogeneous populations, coming back to "precise infectious diseases," such as severe community-acquired pneumonia, severe peritonitis, or meningitis. CONCLUSIONS: The concept of sepsis has been useful to help clinicians to suspect and detect severe infections. Due to a considerable heterogeneity in the patients and type of infections included in the trials performed in the last two decades, it has not been useful in demonstrating the efficacy of new compounds. The authors propose a dramatic change in the design of future trials dealing with severe infections.

Trends over time of virological and immunological characteristics in the Swiss HIV Cohort Study.

BACKGROUND: The long-term outcome of antiretroviral therapy (ART) is not assessed in controlled trials. We aimed to analyse trends in the population effectiveness of ART in the Swiss HIV Cohort Study over the last decade. METHODS: We analysed the odds of stably suppressed viral load (ssVL: three consecutive values <50 HIV-1 RNA copies/mL) and of CD4 cell count exceeding 500 cells/μL for each year between 2000 and 2008 in three scenarios: an open cohort; a closed cohort ignoring the influx of new participants after 2000; and a worst-case closed cohort retaining lost or dead patients as virological failures in subsequent years. We used generalized estimating equations with sex, age, risk, non-White ethnicity and era of starting combination ART (cART) as fixed co-factors. Time-updated co-factors included type of ART regimen, number of new drugs and adherence to therapy. RESULTS: The open cohort included 9802 individuals (median age 38 years; 31% female). From 2000 to 2008, the proportion of participants with ssVL increased from 37 to 64% [adjusted odds ratio (OR) per year 1.16 (95% CI 1.15-1.17)] and the proportion with CD4 count >500 cells/μL increased from 40 to >50% [OR 1.07 (95% CI 1.06-1.07)]. Similar trends were seen in the two closed cohorts. Adjustment did not substantially affect time trends. CONCLUSIONS: There was no relevant dilution effect through new participants entering the open clinical cohort, and the increase in virological/immunological success over time was not an artefact of the study design of open cohorts. This can partly be explained by new treatment options and other improvements in medical care.

Cerebral oxygenation during the Richalet hypoxia sensitivity test and cycling time-trial performance in severe hypoxia.

BACKGROUND: The Richalet hypoxia sensitivity test (RT), which quantifies the cardiorespiratory response to acute hypoxia during exercise at an intensity corresponding to a heart rate of ~130 bpm in normoxia, can predict susceptibility of altitude sickness. Its ability to predict exercise performance in hypoxia is unknown. OBJECTIVES: Investigate: (1) whether cerebral blood flow (CBF) and cerebral tissue oxygenation (O2Hb; oxygenated hemoglobin, HHb; deoxygenated hemoglobin) responses during RT predict time-trial cycling (TT) performance in severe hypoxia; (2) if subjects with blunted cardiorespiratory responses during RT show greater impairment of TT performance in severe hypoxia. STUDY DESIGN: Thirteen men [27 ± 7 years (mean ± SD), Wmax: 385 ± 30 W] were evaluated with RT and the results related to two 15 km TT, in normoxia and severe hypoxia (FIO2 = 0.11). RESULTS: During RT, mean middle cerebral artery blood velocity (MCAv: index of CBF) was unaltered with hypoxia at rest (p > 0.05), while it was increased during normoxic (+22 ± 12 %, p < 0.05) and hypoxic exercise (+33 ± 17 %, p < 0.05). Resting hypoxia lowered cerebral O2Hb by 2.2 ± 1.2 μmol (p < 0.05 vs. resting normoxia); hypoxic exercise further lowered it to -7.6 ± 3.1 μmol below baseline (p < 0.05). Cerebral HHb, increased by 3.5 ± 1.8 μmol in resting hypoxia (p < 0.05), and further to 8.5 ± 2.9 μmol in hypoxic exercise (p < 0.05). Changes in CBF and cerebral tissue oxygenation during RT did not correlate with TT performance loss (R = 0.4, p > 0.05 and R = 0.5, p > 0.05, respectively), while tissue oxygenation and SaO2 changes during TT did (R = -0.76, p < 0.05). Significant correlations were observed between SaO2, MCAv and HHb during RT (R = -0.77, -0.76 and 0.84 respectively, p < 0.05 in all cases). CONCLUSIONS: CBF and cerebral tissue oxygenation changes during RT do not predict performance impairment in hypoxia. Since the changes in SaO2 and brain HHb during the TT correlated with performance impairment, the hypothesis that brain oxygenation plays a limiting role for global exercise in conditions of severe hypoxia remains to be tested further.

Reframing video gaming and internet use addiction : empirical cross-national comparison of heavy use over time and addiction scales among young users

BACKGROUND AND AIMS: Evidence-based and reliable measures of addictive disorders are needed in general population-based assessments. One study suggested that heavy use over time (UOT) should be used instead of self-reported addiction scales (AS). This study compared UOT and AS regarding video gaming and internet use empirically, using associations with comorbid factors. DESIGN: Cross-sectional data from the 2011 French Survey on Health and Consumption on Call-up and Preparation for Defence-Day (ESCAPAD), cross-sectional data from the 2012 Swiss ado@internet.ch study and two waves of longitudinal data (2010-13) of the Swiss Longitudinal Cohort Study on Substance Use Risk Factors (C-SURF). SETTING: Three representative samples from the general population of French and Swiss adolescents and young Swiss men, aged approximately 17, 14 and 20 years, respectively. PARTICIPANTS: ESCAPAD: n =22 945 (47.4% men); ado@internet.ch: n =3049 (50% men); C-SURF: n =4813 (baseline + follow-up, 100% men). MEASUREMENTS: We assessed video gaming/internet UOT ESCAPAD and ado@internet.ch: number of hours spent online per week, C-SURF: latent score of time spent gaming/using internet] and AS (ESCAPAD: Problematic Internet Use Questionnaire, ado@internet.ch: Internet Addiction Test, C-SURF: Gaming AS). Comorbidities were assessed with health outcomes (ESCAPAD: physical health evaluation with a single item, suicidal thoughts, and appointment with a psychiatrist; ado@internet.ch: WHO-5 and somatic health problems; C-SURF: Short Form 12 (SF-12 Health Survey) and Major Depression Inventory (MDI). FINDINGS: UOT and AS were correlated moderately (ESCAPAD: r = 0.40, ado@internet.ch: r = 0.53 and C-SURF: r = 0.51). Associations of AS with comorbidity factors were higher than those of UOT in cross-sectional (AS: .005 ≤ |b| ≤ 2.500, UOT: 0.001 ≤ |b| ≤ 1.000) and longitudinal analyses (AS: 0.093 ≤ |b| ≤ 1.079, UOT: 0.020 ≤ |b| ≤ 0.329). The results were similar across gender in ESCAPAD and ado@internet.ch (men: AS: 0.006 ≤ |b| ≤ 0.211, UOT: 0.001 ≤ |b| ≤ 0.061; women: AS: 0.004 ≤ |b| ≤ 0.155, UOT: 0.001 ≤ |b| ≤ 0.094). CONCLUSIONS: The measurement of heavy use over time captures part of addictive video gaming/internet use without overlapping to a large extent with the results of measuring by self-reported addiction scales (AS). Measuring addictive video gaming/internet use via self-reported addiction scales relates more strongly to comorbidity factors than heavy use over time.

Cycling Time Trial Is More Altered in Hypobaric than Normobaric Hypoxia

PURPOSE: Slight physiological differences between acute exposure in normobaric hypoxia (NH) and hypobaric hypoxia (HH) have been reported. Taken together, these differences suggest different physiological responses to hypoxic exposure to a simulated altitude (NH) versus a terrestrial altitude (HH). For this purpose, in the present study, we aimed to directly compare the time-trial performance after acute hypoxia exposure (26 h, 3450 min) by the same subjects under three different conditions: NH, HH, and normobaric normoxia (NN). Based on all of the preceding studies examining the differences among these hypoxic conditions, we hypothesized greater performance impairment in HH than in NH. METHODS: The experimental design consisted of three sessions: NN (Sion: FiO2, 20.93), NH (Sion, hypoxic room: FiO2, 13.6%; barometric pressure, 716 mm Hg), and HH (Jungfraujoch: FiO2, 20.93; barometric pressure, 481 mm Hg). The performance was evaluated at the end of each session with a cycle time trial of 250 kJ. RESULTS: The mean time trial duration in NN was significantly shorter than under the two hypoxic conditions (P < 0.001). In addition, the mean duration in NH was significantly shorter than that in HH (P < 0.01). The mean pulse oxygen saturation during the time trial was significantly lower for HH than for NH (P < 0.05), and it was significantly higher in NN than for the two other sessions (P < 0.001). CONCLUSION: As previously suggested, HH seems to be a more stressful stimulus, and NH and HH should not be used interchangeability when endurance performance is the main objective. The principal factor in this performance difference between hypoxic conditions seemed to be the lower peripheral oxygen saturation in HH at rest, as well as during exercise.