Structured education programmes are now established as an essential component to assist effective self-management of diabetes. In the case of Type 1 diabetes, the Dose Adjustment For Normal Eating (DAFNE) programme improves both glycaemic control and quality of life. Traditionally delivered over five consecutive days, this format has been cited as a barrier to participation by some patients, such as those who work full-time. Some centres in the UK have organised structured education programmes to be delivered one day a week over several consecutive weeks. This type of format may add benefit by allowing more time in which to practice skills between sessions, but may suffer as a result of weaker peer support being generated compared to that formed over five consecutive days.1c, weight, self-reported rates of severe hypoglycaemia, psychosocial measures of quality of life, and cost-effectiveness. Generalisability was optimised by recruiting patients from DAFNE waiting lists at each centre, and by mailing eligible patients from hospital clinic lists. The inclusion and exclusion criteria were identical to those used to recruit to a standard DAFNE course . Qualitative interviews were undertaken with a sub-sample of n=30 patients and their course educators (n=11) to help understand and interpret differences and similarities in outcomes between the two arms, and to identify logistical problems and unanticipated issues arising from the adaptation and delivery of a 5 week course.We aim to compare DAFNE delivered over five consecutive days (1 week course) with DAFNE delivered one day a week over five weeks (5 week course) in a randomised controlled trial. A total of 213 patients were randomised to attend either a 1 week or a 5 week course delivered in seven participating centres. Study outcomes  include HbAThis trial has been designed to test the hypothesis that the benefits of delivering a structured education programme over 5 weeks are comparable to those observed after a 1 week course. The results of the trial and the qualitative sub-study will both inform the design and delivery of future DAFNE courses, and the development of structured education programmes in other fields of medicine.Clinicaltrials.gov NCT01069393 The DAFNE  course is a 1 week structured education course teaching skills in insulin use and dietary freedom to individuals with Type 1 diabetes, which was originally adapted from a German inpatient programme . DAFNE iThe development of structured education programmes, such as DAFNE has had a major impact on the treatment of Type 1 diabetes in the UK. The Department of Health  now requSome non-DAFNE centres have reported outcomes during routine care in self-selected individuals which are comparable to those reported in the original DAFNE trial . Yet, siThere are theoretical reasons why the two approaches might lead to different outcomes. A 1 week model might lead to stronger peer support developing over the week that could help to improve incorporation of self-management skills. Alternatively, a course delivered over 5 weeks might allow patients to gain more practice in self-management skills during the weeks between education sessions, thus facilitating integration of its principles into everyday life, and hence enhance sustainability. However, the potentially weaker peer support on a 5 week course may lead to a higher drop-out rate, with less participants completing the full 5 days of skills training.Establishing whether DAFNE delivered at weekly intervals is as effective as delivering it over 5 consecutive days will help guide and inform decisions about future course delivery. Potentially it could also allow more individuals with Type 1 diabetes to receive structured education and increase patient choice. As qualitative work can provide important insights into trial outcomes , a qualiThe DAFNE 5x1 day RCT is a multi-centre randomised trial comparing 2 different methods of delivering the DAFNE programme in the UK.The objectives:1) To explore whether the outcomes of a structured education programme with identical contact time are comparable whether delivered over 1 or 5 weeks.2) To examine the cost effectiveness of a DAFNE course delivered either over 1 or 5 weeks.3) To calculate how many patients choose to receive structured education programmes over 1 or 5 weeks, by conducting a preference survey.4) The aims of the qualitative sub-study werea) Help understand and interpret any differences and similarities in biomedical and psychological outcomes between patients attending DAFNE courses delivered over 1 or 5 weeks.b) Identify any logistical problems and unanticipated issues arising from the adaptation and delivery of DAFNE as a course spread over 5 weeks.5) Provide recommendations for the timing, content and delivery of future DAFNE courses.Ethical approval was obtained from the Derbyshire Research Ethics Committee (09/H0401/91). Written informed consent was obtained from all trial participants, after they had had sufficient time to consider the Patient Information Sheet and had any questions pertaining to the trial answered. Additional written informed consent was obtained from participants in the qualitative sub-study. The study is registered with the local Research and Development department of each study centre and Sheffield Teaching Hospitals NHS Foundation Trust is acting as the sponsor.Funding was secured as part of a NIHR programme grant for applied research – Improving management of Type 1 diabetes in the UK: the DAFNE programme as a research test-bed (application number RP-PG-0606-1184).Secondary care centres with experience in delivering high quality structured education using DAFNE participated in the trial. When invited in 2009, seven out of a possible 74 DAFNE centres volunteered to take part. All eligible participants on the DAFNE waiting list received a written invitation to join the study from their local diabetes team. After indicating initial interest they were contacted by a member of the local research team or educator who provided further information, which, in some centres, included an invitation to an information evening, prior to obtaining informed consent. Participants were informed of a pair of course dates (a one week and a 5 week course) for which they would need to be available. After obtaining consent, the participants were randomised to either attend one or other format of course, i.e., either a 1 week or 5 week course. Recruitment took place between May 2010 and April 2011. When consent was obtained, patients were also asked to indicate whether their contact details could be made available to the qualitative research team in order that they might be approached to take part in the qualitative sub-study. Those who were approached were given further written information about the qualitative study and asked to opt-in using a separate consent form.inclusion criteria were as follows: Adults with Type 1 diabetes for at least 6 months, aged 18 – 80 y, HbA1c <12%, willing to undertake intensive insulin therapy, with multiple self-monitoring of blood glucose (SMBG), carbohydrate counting, insulin self-adjustment and no strong views on attending a 1 week course or a 5 week course. Participants needed to agree to randomisation regardless of preference, having not yet completed DAFNE training or equivalent.The exclusion criteria were as follows: severe diabetic complications , inability to communicate in English, strong preference for either a 1 week or a 5 week course, severe needle phobia, unenthusiastic about undertaking SMBG and insulin self-adjustment, or inability to give informed consent.The 1c of 0.5%, a standard deviation of 1.5 and groups of 7–8 participants per randomisation group, for 80% power at one-sided 5% significance 150 participants were required to complete the study procedures. Allowing for a 10% drop-out from randomisation to completion of the trial, it was anticipated that we would require 166 subjects to be randomised in the study. Thus we aimed to run 24 courses (12 courses per arm). Each centre was required to recruit 32 patients to enable 4 courses (two standard DAFNE and two 5 week) to be run with 8 participants on each. However, during the recruitment phase of the trial it became apparent that the drop-out rate between randomisation and course participation was higher than had been anticipated, at over 11%, hence one centre ran an extra pair of courses.Using a non-inferiority design, and based on clinically relevant difference of HbAThe flow of patients through the trial is shown in Figure After consent and completion of baseline data collection, the participants were individually randomised using a random block size, stratified by centre and a web-based remote randomisation system into either a 1 week course or a 5 week course. The allocation sequence was generated by MJC using a computer program called RANDOLOG (University of Southampton). The centres sent a list of participant study numbers to CE, the project manager, who performed the blinded randomisation and informed the centres of the results.Patients were randomised to either:• 1 week - The standard DAFNE 1 week course, or• 5 weeks - The DAFNE course delivered on one day a week over 5 consecutive weeksAlthough pragmatic in design, in order to try to reduce bias, each Centre’s 1 week and 5 week courses were delivered by the same two DAFNE educators, so that the skills, enthusiasm or teaching style of an educator did not favour one arm over the other. As defined for standard DAFNE courses, a participant was deemed to have completed the course if they attended for at least 4 full days of the 5 day course. Where a participant missed a day, attempts were made by the educators to cover missed material on an individual basis also as per normal DAFNE procedures. If a course could not be filled with trial participants, individuals undergoing DAFNE training but not consented to the trial (‘fillers)’ were included so as to maintain the normal dynamics of DAFNE group education.Each course took place over five consecutive days and was delivered to groups of 5–8 adults. The curriculum uses a progressive modular based structure to improve self-management in a variety of medical and social situations. The curriculum is designed to deliver key learning topics at the appropriate time within the programme. In this way, knowledge and skills are built up throughout the week with active participant involvement and problem solving as key methods of learning. The key modules are: what is diabetes; food and diabetes; insulin management; management of hypoglycaemia; sick day rules. Learning objectives for each day and each session are clearly identified and educators have instructions on session preparation and teaching materials. Lesson plans give guidance on timing and a student activity section serves to give an idea of expected responses. Each meal and snack is used as an opportunity to practise carbohydrate estimation and insulin dose adjustment.The curriculum was adapted from the standard course described above. This process was informed by qualitative interviews performed during an earlier mixed methods study of the DAFNE programme, in which patient and educator views were solicited as to how the curriculum could be adapted for a 5 week course. Four experienced DAFNE educators met with the qualitative researchers to exchange ideas and then further refinements were communicated within the group via e-mail. The contents of the two curricula were identical in terms of educational content and skills training although we made some minor changes to accommodate the needs of those attending over 5 weeks. Thus rather than providing a workbook on each day of the course, those attending 1 week courses received an entire workbook at the outset. The hope was that this would encourage participants to attend each week to gain more information and thereby reduce the drop-out rate. Also, blood glucose diaries were modified to allow for additional space to record to events / physical activity in more detail. The adapted curriculum was tested in 3 pilot courses, at 2 different centres, prior to commencement of the main trial. As a result of the pilot courses minor modifications were made to two of the sessions.1c and blood biochemistry, and completion of psychosocial questionnaires. Interviews for the qualitative sub-study were conducted during the week after courses had concluded, with follow-up interviews six months later.Patients attending both 1 week and 5 week courses were invited to a 6 week post course group-based meeting lasting 1–2 hrs to review DAFNE principles (a standard practice for regular DAFNE course attendees). At 6 and 12 months post the last day of the course, both groups were due to attend for measurement of weight, recording of hypoglycaemic episodes, collection of blood for HbAWe measured outcomes on two occasions primarily to examine the time of maximum effect, and also because repeated measures improves the power to test the main objective.The Primary outcome was:1c from baseline at 6 and 12 months. HbA1c, a measurement of glycosylated haemoglobin, is regarded as the gold standard measure of glycaemic control reflecting overall blood glucose values over the previous 8–12 weeks. There is a strong relationship between HbA1c and the risk of developing long-term diabetic complications and it is accepted as a reasonable surrogate for long-term outcomes in individuals with diabetes. HbA1c was measured at local laboratories DCCT aligned .The Secondary Outcomes were:1c from baseline at 6 and 12 months for those with a baseline HbA1c ≥7.5%, This is because some of the participants with low HbA1cs would be aiming to reduce the number of episodes of hypoglycaemia, as opposed to further reducing their HbA1c.Change in HbABiomedical: eGFR, and lipids (including HDL cholesterol), using local labs at baseline and 12 months as part of routine clinical monitoring.Hypoglycaemia: Number of episodes of severe hypoglycaemia using a standard definition of an episode leading to cognitive impairment sufficient to cause either coma or requiring the assistance of another person to recover. Psychosocial:• Quality of life: Quality of life (QoL) is assessed using both the diabetes-specific quality of life scale (DSQOLS ), and th• Emotional Well-being: is assessed using the Hospital Anxiety and Depression Scale , the di• Self-efficacy: Diabetes-specific self-efficacy is assessed using the Confidence in Diabetes Self-Care measure  a valida• Thoughts about Diabetes [Personal Models of Diabetes ,19: This• Self-Care Behaviours: The revised Self-Care Inventory, a measure of perceived adherence to diabetes self-care recommendations .• Fear of Hypoglycaemia Questionnaire . This s• Fear of Complications Questionnaire .• Social Support Questionnaire ,25: The • A single-item measure of life satisfaction from the Personal Well-Being Index .• Diabetes Knowledge Questionnaire – Revised Michigan Diabetes Knowledge Questionnaire .• Evaluation of the DAFNE course is assessed at 6 weeks using one, 9-item sub-scale of the Health Education Impact Questionnaire .• Adherence to DAFNE principles: This is assessed at the 6 week, 6 and 12 month follow ups using a DAFNE specific Self-Management questionnaire, developed for the present NIHR Psychosocial study, (MREC 08/H0808/53).1c at 12 months with baseline HbA1c as a covariate, (which will improve the power relative to the predicted power), using generalised estimating equations (GEE) to control for clustering within courses. The intracluster correlation coefficient coefficient (ICC) will be estimated using the method of moments. Poisson regression (or a zero-inflated Poisson regression if necessary) will be used on the number of hypoglycaemic episodes over 12 months, which should also have more power than a dichotomy of having/not experiencing an episode, again using GEE to account for clustering. We will use an intention to treat analysis, but will explore the issue of participants dropping out using multiple imputations. The full analysis set (FAS) for the intention to treat analysis includes all patients for whom baseline data was collected. A per protocol analysis will also be performed.The primary analysis will be a linear model of HbAAn economic evaluation will be undertaken from the NHS perspective, using both a within trial timeframe and a modelled patient lifetime timeframe. The modelled analysis will be the primary focus of the economic sub-study. Patient costs will be calculated covering training, equipment, drugs and NHS contacts relating to the management of diabetes and its associated conditions. The cost of the training associated with the control and intervention groups will be calculated through a survey of resource use and costs at each of the seven recruiting centres. The survey will cover staff input, consumables, capital and overheads, and will be followed up with discussions with staff at each centre to ensure the quality of information provided.Patient-level data will be collected for equipment, drugs and NHS contacts. Equipment and drug use will be taken from the trial’s clinical record forms, while the NHS contacts will be taken from the DAFNE Programme’s patient database. This database records all primary care contacts relating to diabetes, specific contacts for hypoglycaemic events, and diagnosis-specific inpatient admissions.Unit costs will be taken from standard sources . Quality adjusted life years (QALYs) will be estimated using EQ-5D at baseline, 6, and 12 months, and patient mortality.Two analyses, one within the trial, and another using a lifetime analysis based on the Sheffield Type 1 Diabetes Policy Model (currently in development through the NIHR Programme Grant), will be undertaken. An incremental cost effectiveness ratio (ICER) will be calculated with uncertainty around this characterised by plots on the cost-effectiveness plane and its associated cost-effectiveness acceptability curve. The impact of different training costs as observed in the different centres will be assessed using one-way sensitivity analysis.Prior to development of the 5x1 trial, as part of the NIHR programme, a qualitative evaluation had already been undertaken of standard DAFNE courses delivered over one week to understand and explore patients’ likes and dislikes of their courses, and their reasons for following or not following a DAFNE regimen post-course and over time. This qualitative evaluation comprised observation of six DAFNE courses and in-depth interviews with patients n=30) on completion of their courses and six and 12 months later. Twelve educators were also interviewed. Findings from this work have already been published  on compl with fur1) Are there any differences in the ways in which patients interact with, and support one another, when attending a DAFNE course delivered over 1 or 5 weeks, and why?2) Are patients more or less inclined and able to make changes to their insulin doses and approach to diabetes management during and after attending a course delivered over 1 or 5 weeks, and why?3) Do any logistical and/or unanticipated issues arise from the adaptation and delivery of a DAFNE course spread over 5 weeks?4) If any patients withdraw from the 5 week course, what are their reasons for doing this?5) What do patients and educators like/dislike about attending/delivering a DAFNE course for one day a week over five weeks? What are the perceived advantages and disadvantages of a DAFNE course delivered over 5 weeks rather than over 1 week? What are patients’ preferences for the timing of DAFNE courses, and why?6) How can the findings relating to the above research questions be used to explain differences/similarities in biomedical and psychological outcomes between patients attending the two types of courses?1) Observation of five week DAFNE courses to: (a) inform issues and areas explored in interviews with patients and educators who participated in these courses;(b) ascertain, through comparison with observational data collected during the evaluation of standard courses delivered over one week, whether there are any differences between the two types of course ; and, (c) identify any unanticipated issues arising from the adaptation and delivery of DAFNE courses over five weeks.2) Post-course interviews with patients to: explore their experiences of, and views about, the DAFNE course spread over five weeks; any changes they have made to their diabetes management/self-care practices in light of the course (and why); their hopes, expectations and (any) short- and long-term treatment goals set; and (if relevant), reasons for not completing the course.3) Follow-up interviews with patients at six months to explore whether, and why, they have been able or unable to sustain their skills training in intensive insulin therapy, and any issues which they think may help promote/support effective self-management in the future.The time-point for follow-up interviews was selected (a) to mirror the design of the qualitative evaluation of the standard courses delivered over one week and (b) because this evaluation had highlighted that, by six months, sufficient time should have elapsed to establish whether, and for what reasons, patients are able/unable to put their skills training into practice and sustain the intensive approach to disease self-management taught on their courses.To contextualise and enhance understanding of patients’ accounts, other issues were also explored in their initial and follow-up interviews including: work and family commitments and the impact and implications of these for treatment adherence, course attendance, and course preferences etc.; (changing) perceptions and understandings of their disease (e.g. perceived seriousness and controllability); and, their experiences of, views about, and need for health professional and other forms of support prior and subsequent to course attendance.4) Interviews with educators on completion of courses to reflect upon their understandings and experiences of course delivery; their perceptions and views of (any) differences; issues and/or challenges arising from delivering DAFNE over five weeks rather than over one week; and, recommendations for future course development.Observational data were recorded in the form of field notes and written up by DR at the end of each day of sitting in on the DAFNE course. Topic guides have been used to inform all interviews to ensure the discussion stays relevant to the study aims and objectives, while allowing participants to raise and discuss issues they perceive as salient to them. These were adapted from those used in the qualitative evaluation of standard DAFNE courses delivered over one week to allow for data comparisons.Baseline interviews with patients were normally undertaken face-to-face and at a time and location of their choosing . Follow-up interviews were undertaken on the phone unless a patient requested a face-to-face interview. Educator interviews were undertaken by phone.Each patient and educator interview lasted around an hour, and, subject to consent, these were audio-recorded, and transcribed in full to permit in-depth analysis.Four 5 week courses were observed in their entirety, in three trial centres. The sample size of n=30 patients was determined, based on previous experience ,37, to eUsing an ongoing and iterative process data analysis started once the observations and interviews began. The study was informed by the principles of grounded theory  and the A particular strength of this trial is that it has not occurred in isolation, but as one component of a NIHR 5 year programme grant utilising DAFNE as a research test-bed. Professionals from different disciplines have collaborated on other pieces of work within this grant, thus the development of the intervention and conduct of the trial has been informed and influenced by other facets of the research programme. One such element was a psychosocial evaluation of how, and why, in the context of Type 1 diabetes in the UK, structured group education actually works -34. By iThe trial has also highlighted some of the problems involved in conducting a non-pharmaceutical funded clinical trial within the NHS. Each centre has relied largely on the goodwill of one or two DAFNE educators, a part-time administrator, plus a consultant physician to recruit participants into the trial and to collect follow-up data. The scale of this latter process cannot be under-estimated, and has been aided in some centres by help from their local CLRN . The programme grant only included a relatively small payment to be made to each centre for running the courses and for entering data (£1250 / course). Development of the five week curriculum, and production of resources was aided by the DAFNE Collaborative.Data collection is due to be complete by Summer 2012, the results will be analysed by our statistical team, and we hope to publish findings from this randomised controlled trial shortly thereafter.The authors declare that they have no competing interest.All authors participated in the design of the trial. JE devised the trial protocol and drafted the manuscript. JL and DR devised the psychosocial intervention, DR is conducting the in-depth interviews and both DR and JL are analysing the psychosocial findings. CE helped devise the protocol and is project manager. MJC is lead statistician for the trial. SD is the lead health economist for the trial. SH is CI of the NIHR programme grant for applied research – Improving management of Type 1 diabetes in the UK: the DAFNE programme as a research test-bed. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1472-6823/12/28/prepub


Adjuvant! Online is a web-based application designed to provide 10 years survival probability of patients with breast cancer. Several predictors have not been assessed in the original Adjuvant! Online study. We provide the validation of Adjuvant! Online algorithm on two breast cancer datasets, and we determined whether the accuracy of Adjuvant! Online is improved with other well-known prognostic factors.The French data set is composed of 456 women with early breast cancer. The Dutch data set is composed of 295 women less than 52 years of age. Agreement between observation and Adjuvant! Online prediction was checked, and logistic models were performed to estimate the prognostic information added by risk factors to Adjuvant! Online prediction.HER2 positive patients. HER2 status, Mitotic Index and Ki67 added significant information to Adjuvant! Online prediction. In the Dutch data set, the overall 10-year survival was overestimated by Adjuvant! Online, particularly in patients less than 40 years old.Adjuvant! Online prediction was overall well-calibrated in the French data set but failed in some subgroups of such high grade and Adjuvant! Online needs to be updated to adjust overoptimistic results in young and high grade patients, and should consider new predictors such as Ki67, HER2 and Mitotic Index. HER2 status are routine determinants of the breast cancer prognosis. To improve the ability to accurately predict the prognosis of breast cancer patients and the likely benefit of adjuvant systemic therapy, combinations of several clinicopathological prognostic factors have been tailored for clinical decision making. Nottingham Prognosis Index (NPI) is based on the Tumour Size, Tumour Grade and Lymph Node Involvement [NPI = Grade+Node+0.2*Size] et alwww.adjuvantonline.com). This index is derived from women 35 to 59 years old at diagnosis and treated between 1988 and 1992 of the US SEER  registry which includes around 10% of all US breast cancer patients. The calculation process is based on actuarial analysis using age at diagnosis, comorbidity factors, ER, tumour size, tumour grade and lymph node status as input. The program gives the estimated prognosis, but also the expected benefit of several therapeutic options in a comprehensive format, adapted for decision making. Estimates of the efficacy of adjuvant hormonal therapy and chemotherapy are based mainly on the proportional risk reduction reported by Early Breast Cancer Trialists Collaborative Group meta-analyses Breast cancer prognosis determination relies upon pathological features able to classify breast cancer in subgroups of similar behavior. Tumour size, axillary lymph node involvement, grade as defined by Elston & Ellis, Estrogen Receptor (ER) status, Progesterone Receptor (PR) status and Although Adjuvant! Online is increasingly being used by physiciansHER2 over expression status, proliferation markers or gene expression signatures Finally, several predictors such as The aim of this study was to validate Adjuvant! Online algorithm on two breast cancer datasets collected from two large European comprehensive cancer centres, and to determine whether the accuracy of Adjuvant! Online could be improved by the use of several well-known prognostic factors not used in current calculations for the prediction of 10- year overall survival.The registration of patients of the Institut Curie in this cohort received a favorable agreement of the french National Committee on Computers and Liberties . Patients gave informed written consent prior to be registered in the cohort. The study was approved by the breast cancer study group of the Institut Curie. Dutch study was approved by the medical-ethics committee of the Netherlands Cancer Institute.HER2 over-expression status) were re-assessed for each sample by pathologists of the Institut Curie. Mitotic Index (MI) was defined by the number of mitoses observed in 10 successive high power fields using a microscope with a 40x/0.7 objectives and a 10x ocular. Mitotic Index was assessed on histological sections stained by Hematein, Eosin and Saffron. Van Diest and al's criteria HER2 overexpression status was determined according to American Society of Clinical Oncology (ASCO) guidelines The French population is an original data set composed of 456 women treated at the Institut Curie between 1995 and 1996. This data set was firstly collated to validate the Ki67 rate and other factors prognostic value in a larger cohort of early-stage breast cancer patients. Inclusion criteria were early breast cancer, without lymph node involvement, initially treated by conservative surgery and radiotherapy. None of these patients received neoadjuvant treatment . The clinical data were extracted from medical records of the Institut Curie prospective breast cancer database. Histological features ; without involvement of the apical axillary lymph nodes; the age at diagnosis was 52 years or younger; the calendar year of diagnosis was between 1984 and 1995; and there was no previous history of cancer, except non-melanoma skin cancer. In the original study, this population was used to validate the prognostic value of a 70-gene expression profile. All patients had been treated by modified radical mastectomy or breast-conserving surgery, including dissection of the axillary lymph nodes, followed by radiotherapy if indicated. Follow-up information was extracted from the medical registry of the Netherlands Cancer Institute. Formalin-fixed, paraffin embedded tumour tissue was used to evaluate the following: tumour type, histological grade, Mitotic Index, ER status, In both data sets, Adjuvant! Online version 8.0 was used to compute 10-years survival probability.All computations were done separately on French and Dutch data sets. Analysis included two stages. First, we checked the agreement between observed and Adjuvant! Online predicted 10-years survival, and secondly, to what extent each prognostic factor adds some information to Adjuvant! Online prediction.i  and a set of corresponding probabilities pi , by fitting a simple logistic model without intercept: log(P(Yi = 1)/P(Yi = 0)) = α+β log(pi/(1−pi)), and testing the null hypothesis that intercept α is equal to 0 and β is equal to 1, corresponding to a well calibrated model.Average Adjuvant! Online predicted 10-years survival and observed 10-years survival were computed globally and for several subgroups of patients defined from major prognostic factors in breast cancer. Calibration between observed and mean predicted outcome was evaluated using the Cox method et ali taking into account AdjvuvantOnline a priori known component by including pi in the linear predictor during fitting: log(P(Yi = 1)/P(Yi = 0)) = α+βXi+log(pi/(1−pi)). Since the parameter of the offset variable is equal to 1, Adjuvant! Online prognostic value is not re-estimated in the model.If a lack of agreement between observation and prediction is detected in some specific subgroups, some variables were tested as to whether they would add prognostic information to Adjuvant! Online. Variables already used in Adjuvant! Online algorithm and variables not used in Adjuvant! Online algorithm were evaluated in two separated analyses. To perform these two analyses, we used a method derived from Bleeker Variables already used by Adjuvant! Online for 10-year survival prediction  were included together in a multivariate model with Adjuvant! Online prediction offset. In this model, a significant coefficient means that the association of a predictor with the outcome in the validation population differs from the original population Other variables not used in Adjuvant! Online algorithm  were included separately in an univariate model only with Adjuvant! Online prediction offset. In this analysis, a significant coefficient means that a predictor adds some information to Adjuvant! Online original model.R2 in linear regression. Standard errors were obtained by bootstrapping 200 resamples. Areas under the curve (AUC) were also computed.The gain in predictive inaccuracy of models including variables not used in Adjuvant! Online algorithm, as compared with model with Adjuvant! Online prediction alone, was investigated using the method of Schemper http://www.R-project.org).Significance was defined as p<0.05 (two-sided). Statistical analyses were performed using R 2.12.1 software  out of 456 patients were included in the analysis. Patients included in the analysis were compared to those not included; no statistically significant difference was observed between this two groups.Patients' clinico-pathological characteristics are shown in 10-year survival status was unknown for 48 patients. 247 out of 295 patients were included in the analysis. Patients included in the analysis were more likely to have negative ER and grade III tumors.Dutch patients were younger than the French (44±5.5 years), and tumors showed more aggressive features: 50% had T2 tumors, and 49% had grade III tumors. More than 35% of patients had undergone chemotherapy.The overall 10-year survival of the French population was very close to the Adjuvant! Online predicted survival (87% vs. 85%). HER2 over expression status, Mitotic Index and Ki67 index (data not shown). Taking into account Adjuvant! Online information as an offset in the logistic regression model, grade became non significant . Only age, Mitotic Index and 70-genes signature remained significant when analyzed with Adjuvant! Online information as offset in the logistic regression model  . Values for explained variation are higher in the Dutch data set, particularly for 70-genes signature (13.1%) and Mitotic Index (6.7%). Results were similar in term of gain of area under the curve.The gain in predictive accuracy from adding each variable not used in Adjuvant! Online algorithm is presented in HER2 positive patients). In the Dutch data set, Adjuvant! Online prediction was highly overoptimistic.Using two independent and very different data sets, this study focused on evaluation of the 10-year survival prediction performance of Adjuvant! Online. The French dataset was composed of patients with an early stage breast carcinoma with no axillary lymph node involvement. Few patients received an adjuvant systemic treatment. The Dutch Dataset was previously published as the validation study of the 70-genes molecular signatures. It was composed of patients younger than 52 years old and a significant over-representation of patients with aggressive features  was identified when compared to the French Dataset. We showed that the calibration of Adjuvant! Online was overall satisfactory in the French data set, but failed in some subgroups of patients, particularly among those with the most aggressive prognostic factors (young age, high grade and The 10-year survival estimation error in the subgroup of the youngest patients was already highlighted in three other large calibration studies Adjuvant! Online survival estimation was restricted to women in the SEER registry from 35 to 59 years of age at diagnosis et ala priori information. Thus, the global effect of grade on 10-year survival seems to be captured by Adjuvant! Online, but is underestimated in the subgroup of grade 3 tumors.In the French data set, survival of patients with grade 3 tumors seemed to be overestimated by Adjuvant! Online. Campbell HER2 status, Ki67 and Mitotic Index on the performance of Adjuvant! Online. In the French data set, Adjuvant! Online was over optimistic in HER2 positive, Mitotic Index>1 or Ki67>20 patients. All three factors brought some statistically significant prognostic information in addition to Adjuvant! Online. These results are consistent with a recent finding from Lende et alHER2+ patients do not change a lot the global accuracy of the model, but can have serious individual consequences, since these estimations may be utilized by clinicians to change their therapeutic attitude HER2To our knowledge, our study is the first to evaluate the influence of Mitotic Index and Ki-67 are both proliferative biomarkers that were correlated in early breast cancers treated with neoadjuvant therapy Despite of the fact that results from Dutch population must be interpreted with caution, it seems important to highlight that genomic information could improve prediction accuracy in breast cancer. Besides Amsterdam 70-gene prognostic signature et alHER2 status, Ki67 and Mitotic Index are well documented in many publications This study is not without limitations. First of all, Adjuvant! Online was developed in the United States. As in Campbell Another weakness of this study is the small sample size of the two validation sets, compared to other validation studies. When the sample size is large, a classical approach is to group subjects into sets with nearly constant predicted probability, and to compare observed proportion with prediction in each set. However, this method is not adapted for small sample size, since it leads to very small sets. That is why we used the Cox approach, specifically developed to test the calibration between observation and prediction with small sample size The use of a Kaplan-Meïer estimations and proportional hazard models would have been more adapted to describe survival data, like in other validation studies HER2, and Mitotic Index, known as independent risk factors in breast cancer. These recommendations are based on the analyses of two relatively small data sets, and should be validated in an independent population.In conclusion, over optimistic results of Adjuvant! Online in poor prognostic subgroups are problematic, since some therapeutic decisions are based on Adjuvant! Online results. Adjuvant! Online could therefore be updated to adjust biased predictions in young and high grade subgroups of patients, and to consider several other candidate markers, especially Ki67,


In our region there has been considerable success in the redesign of adult fracture clinics. The aim of this study was to define our paediatric fracture clinic load, to assess the feasibility of increasing efficiency by decreasing inappropriate attendance.Prospective case notes review of all attendees at 6 serial fracture clinics at the Royal Hospital for Sick Children (Glasgow) which has both local and tertiary referrals. Of 234 consecutive attendances across 6 fracture clinics, 34 (15%) were judged inappropriate: 13 had fractures not requiring orthopaedic follow-up , and 21 had diagnoses or situations that were not appropriate. Of the 200 attendances deemed appropriate , there were 33 new referrals from the emergency department, and a further 39 were first-time attenders at the fracture clinic after an acute admission (37 were post-operative and 2 were non-operative). Of these 200, the treatment plan was changed for 67 (34%), a cast removed or exchanged for 92 (46%), and radiographs taken for 153 (77%). The overall discharge to return ratio was 76:158 (1:2.1), and for appropriate attenders 61:139 (1:2.3).Tighter discipline can be applied to indications for fracture clinic appointments, including certain fracture types being discharged from the emergency department without unnecessary review - our particular fracture clinic numbers can be decreased by 15%. In the remaining attendances there are high radiograph and intervention rates, such that it seems unlikely that further reductions in attendance would be feasible. Fracture clinics involve the concerted action of orthopaedic surgeons, radiographers, plaster technicians and ancillary staff - in particular, secretarial and records/administration. Activity has to be co-ordinated with other services, notably theatres and the emergency department. The importance of fracture clinic organisation has long been appreciated,2. In anHowever, some fracture clinics have high return and low discharge rates, suggesting unnecessary attendance and a need for 'redesign’. For chiThe aims of this study were to define our paediatric fracture clinic load and to assess the feasibility of increasing efficiency by decreasing inappropriate attendance.Yorkhill Children’s hospital in the city of Glasgow serves the population of NHS Greater Glasgow and Clyde, having a local trauma commitment in addition to a tertiary workload from the west of Scotland. There are six orthopaedic consultants who each take call, 1 week in 6, for all days of the week. Three fracture clinics are run weekly , each under two Consultants  who undertake a 'buddy-system’ so that they are reciprocally available during annual/study leave periods. Usually both Consultants are present at the clinic. Attendance at a particular day’s clinic is governed by the patient being under one of the two particular Consultants. Fracture clinics are for patients originating in the acute system  and referred to the on-call Consultant with musculoskeletal conditions .non-concurrent plaster room clinic for new/follow-up patients for talipes and developmental hip dysplasia, elective casting, harness changes, and early post-operative review.Each consultant also has a separate Most radiographs are requested before the clinic by the registrar or fellow who is explicitly timetabled to a session for notes and radiograph review. Sometimes it is not clear if further radiographs are indicated, in which case the patient is seen first, and only then a radiograph possibly requested.All data were gathered prospectively to ensure no loss to follow-up/irretrievable notes, with real-time recording of the data prior to the release of the notes to the records department.per se.This was a descriptive study over a six-week period  in which all patients attending a Tuesday fracture clinic underwent notes review and categorisation on a predefined data sheet (not modified during study period). Referring doctors and doctors working in the clinic were not made aware of these study criteria explicitly  ie other than JSH, they were not aware of the study The data entered included:(1) named Consultant (2) diagnosis(3) new/return to orthopaedic service; if return to orthopaedic service, were they new to fracture clinic (4) appropriate attendance at fracture clinic - for reasons of clinical (including cast) review, checking fracture position or monitoring progression to union.(5) if deemed not appropriate in question four, the reason for this – an attendance was adjudged inappropriate on the basis of any of the following four pre-defined possibilities: (a) fracture not requiring orthopaedic follow-up, (b) non acute or elective musculoskeletal condition, (c) inappropriate clinical (including cast) review, (d) wrong timescale for checking fracture position or monitoring progression to union(6) whether or not the treatment plan was changed as a result of clinic attendance(7) cast removed or exchanged(8) radiograph taken at this visit(9) patient referred to another type of health professional(10) patient discharged.All information gathered in the study was recorded and analysed using the Excel software package .Approval was not required as this was a simple clinical audit with no intervention, clinical or otherwise.There were 234 attendances over the six week period. Of these, 34 15%) were judged inappropriate for fracture clinic: 13 had fractures not requiring fracture clinic attendance , and 21 were deemed inappropriate because they had non-acute or other conditions that would have been better seen in a standard elective clinic (Table 5% were jex 200) were referred on to other health practitioners, of which only 3 were for physiotherapy.The remaining 200 cases (33 new and 167 return) were judged clinically appropriate for fracture clinic, for reasons of clinical (including cast) review, checking fracture position or monitoring progression to union. Of the 200 appropriate attendances, there were 172 fractures, 11 soft-tissue injuries, 9 infections and 8 acute atraumatic limps (Table This study has been helpful in defining two groups of patients that should not be funnelled through fracture clinic: those having ongoing follow-up care for 'elective’ conditions (an unexpected finding attributable to only one of the two Consultants running the clinic) and those who could safely have been followed or discharged by the Emergency Department (ED). Once these two groups are excluded from the analysis, there was a change to treatment decision in 34%, a cast change or removal in 46%, and radiographic review in 77% ie it would appear that beyond the 'easy gains’ outlined, there is little scope for further economy, and that broadly attendances are necessary for clinical and/or radiographic review.Our figures for inappropriate attendees referred by the ED are low in contrast to those documented for the Paediatric fracture clinic in Dublin, but nevv. 25%), a similar cast change rate (44% v. 50%), a dramatically higher radiography rate (77% v. 28%), and a lower further referral rate (4% v. 10%). Morris and Bell stated that 'The use of and adherence [to] protocols to minimise clinic attendance is essential. An understanding of the natural history of fractures in children is needed to facilitate production of protocols to allow a safe reduction in clinic appointments’[In 2006, Morris and Bell[ntments’. It is dThe current study was performed as a scoping exercise for the possibility of paediatric fracture clinic redesign. Although it contains a larger and more complete (100% case capture) data-set than the study of Morris and Bell, it has A rapid review clinic of radiographs and case notes has been used elsewhere,11 to inThis study has provided the data to allow our department to institute changes to our clinical practice by: (i) tighter discipline in seeing appropriate patients within the precious resource of the fracture clinic, and (ii) direct discharge of torus, undisplaced metacarpal and clavicle fractures from the ED. Although the first measure is simple, the second involves a considerable workload with protocols/education for ED doctors, as well as parent advice sheets - these requiring editing by multiple authorities.The author declares that he has no competing interests.JSH conceived, designed, performed and wrote up the study.


Meditation has lately received considerable interest from cognitive neuroscience. Studies suggest that daily meditation leads to long lasting attentional and neuronal plasticity. We present changes related to the attentional systems before and after a 3 month intensive meditation retreat. We used three behavioral psychophysical tests - a Stroop task, an attentional blink task, and a global-local letter task-to assess the effect of Isha yoga meditation on attentional resource allocation. 82 Isha yoga practitioners were tested at the beginning and at the end of the retreat. Our results showed an increase in correct responses specific to incongruent stimuli in the Stroop task. Congruently, a positive correlation between previous meditation experience and accuracy to incongruent Stroop stimuli was also observed at baseline. We also observed a reduction of the attentional blink. Unexpectedly, a negative correlation between previous meditation experience and attentional blink performance at baseline was observed. Regarding spatial attention orientation as assessed using the global-local letter task, participants showed a bias toward local processing. Only slight differences in performance were found pre- vs. post- meditation retreat. Biasing toward the local stimuli in the global-local task and negative correlation of previous meditation experience with attentional blink performance is consistent with Isha practices being focused-attention practices. Given the relatively small effect sizes and the absence of a control group, our results do not allow clear support nor rejection of the hypothesis of meditation-driven neuronal plasticity in the attentional system for Isha yoga practice. Behavioral results show that meditation practice increases performance in attentional tasks suggesting improved allocation of attentional resources, enhanced sustained attention skills, faster re-allocation of attentional resources, improved cognitive flexibility, and decreases in automatic responding , the Stroop task (conflict monitoring/executive attention and automated responding), and a global-local task . The subjects were tested at the beginning and end of a 3-month full time Isha Yoga meditation retreat.In the attentional blink task  have a focused attention quality to them, there is also an open-monitoring aspect to the Shoonya practice that might lead to a decrease in attentional biasing.Our hypothesis was that at the end of the retreat our subjects would be able to better redirect their attention than at the beginning  and would thus show a decrease specifically in the magnitude of the local biasing effect during the global task and global biasing effect on the local task. This was hypothesized based on the fact that while some aspects of the Isha Yoga meditation practices .Shoonya meditation during an average of 4 years (± 2.8 years), 6.5 days a week (± 0.5 days). Although we do not have access to data concerning the precise time spent practicing Shoonya meditation every day, the Isha Yoga school recommends practicing it at least 15 min twice daily. Only 50 participants practiced Samyama meditation prior to the retreat, and they practiced it for an average of 3 years (± 2 years), in average 3.2 days per week (± 2.1 day). No participant practiced Lingasanchalana meditation prior to the retreat.Prior to the retreat the participants had practiced Samyama meditation for 30-50 min and Shoonya meditation for 30 min daily. For the last 6 weeks, they practiced Lingasanchalana meditation for 2–3 h every day. Beside pure meditative practices participants also practiced yoga postures (2 h every day) as well as physical exercise (40 min every day) and chanting (1 h every day). Finally during the first 6 weeks of the retreat only they practiced breath watching (1 h a day) and specific body postures called kriyas (2 h a day).The 3 month retreat required participants to engage in daily meditative practices. For the first 6 weeks of the retreat all participants practiced At the beginning of the retreat, participants were tested on all three tasks and they were again tested on the same three tasks at the end of the retreat. Due to the relatively large number of subjects participating in the study, the pre- and post-tests could not all be done on the same day. Days of recording for pre-test started from the first day and finished up to 12 days after the retreat started. Recording for the post-tests started 16 days before and finished 3 days after the end of the retreat. We used the number of days relative to the beginning and to the end of the retreat as a statistical regressor to assess if this could have influenced our results (see Statistics).For all stimulus presentations, we used desktop computers running the Matlab Psychophysics toolbox (v3.0.8) under Windows XP operating systems. Stimuli were presented on a 17” DELL M781 mm CRT computer screen. The computer screen was set to 120 Hz and a resolution of 800 × 600. Two identical computers and screens were used to collect the data. Subjects sat 50 cm from the screen. Before performing the experiment, for training purposes, participants performed a shorter version of each of the tasks . During this training phase the participants were allowed to repeat the training tasks again if they had problems understanding them.The Stroop task consisted of showing the capitalized words “RED,” “BLUE” and “YELLOW,” or the control words “LOT” (control word for “RED”), “SHIP” (control word for “BLUE”) and “FLOWER” (control word for “YELLOW”) on a computer screen  on a computer screen. The large letters were made up of an aggregate of small letters that could be congruent  or incongruent  with respect to the large letter. The small letters were 0.8 cm high and the large letters were 8 cm high on the computer screen. A fixation cross was present at all times except when the letters were presented. Letters were shown on the computer screen until the subject responded. After each subjects response, there was a delay of 1 s before the next stimulus was presented. Before each sequence of letters, instruction were shown on a computer screen indicating to subjects whether they should respond to the presence of small  or large  letters. We instructed subjects to categorize specifically large letters or small letters and to press the letter H or T on the computer keyboard to indicate their choice. Subject performed a total of 52 trials in 4 sessions of 13 trials each. In sessions 1 and 3, subjects were instructed to focus on large letters and in session 2 and 4 they were instructed to focus on small letters Figure .Since our data did not fit the normal distribution (Kolmogorov–Smirnov test), we used non-parametric statistic Wilcoxon ranksum tests and used Bonferroni correction for multiple comparisons. For all tests, the degree of freedom was 81. For assessing the effect that meditation experience and age had on results, we used a general linear model and bootstrap statistics. We used Matlab to perform all statistical tests.p < 0.05, 86.5% correct responses at pre-test vs. 87.4% correct response at post-test)  or neutral (p = 0.7) stimuli between pre- and post-retreat tests. For each subject, we also calculated the Stroop Interference (SI) by subtracting the accuracy score to incongruent stimuli from accuracy score to congruent stimuli. We found a significant diminution of the Stroop Interference after the retreat compared to before the retreat .In the Stroop task, subjects tended to commit less errors to incongruent stimuli at the end of the retreat  Figure . We founWe did not observe any significant effects in reaction time for any of the comparisons we tested. Specifically, we did not observe a difference in RT for incongruent, congruent, or neutral stimuli when comparing pre- and post-retreat assessments. Similarly, we did not observe a significant difference in the RT Stroop Interference, computed as the difference of RT for congruent and incongruent stimuli for each subject, between pre- and post-retreat assessments.p < 0.0001). Significant increases in performance between pre- and post-tests were also found for the targets T1, and T2 long . No significant difference for detection of the absence of T2 (T2 absent) was found (mean T2 absent detection rate at pre-test 55 vs. 61% at post test). However, as shown in Figure p < 0.0002; T2 short performance increase vs. T2 long performance increase p < 0.001; T2 short performance increase vs. T2 absent performance increase p < 0.005).Attentional blink performances were improved at the end of the retreat when compared to performances at the beginning: the rate of detection of the T2 target within the window of the attentional blink  was 59% at pre-test vs. 70% at post-test .p < 0.001) see Figure p = 0.6; incongruent condition p = 0.2) or global  tasks. We computed the congruency effect interference score  but did not find significant differences between pre- and post- retreat scores on this measure either .At the beginning and at the end of the retreat, participants made significantly less errors on congruent than on incongruent trials during both the global and the local tasks . We found no significant differences between RTs before and RTs after the retreat for any of the specific trial types as a class. However, there was a significant faster mean RT in response to incongruent stimuli in the local versus global task (p = 0.04) before the retreat, and only a trend difference (p = 0.1) after the retreat.Participants were significantly faster in responding to congruent than incongruent trials during the global task both before and after the retreat  and high local interference participants had score within the last quartile . We used linear regression to assess any relationship between attentional blink performances and local interference scores and did not find any significant correlations either before or after the retreat. We did the same analysis using the global-interference measure and similarly found no significant correlations.We tested the hypothesis that performances in the global-local task would be correlated with performance in the attentional blink task. We divided participants into quartiles based on their scores on the local-interference  and global interference  measures, for both pre and post retreat assessments. Low local interference participants had scores within the first quartile , age of the participants, and performance for each of the tasks for the pre-retreat assessments. In the attentional blink task, age and previous Shoonya meditation experience of the participants both had a significant negative influence on T1 response accuracy (age: regression coefficient (reg. coef.) = −0.46, p < 0.005; previous meditation experience: reg. coef. = −0.04; p < 0.005) T2 long  and T2 short response accuracy  but not T2 absent (p < 0.1) response accuracy. In the Stroop task, the age and meditation experience of participants did not affect reaction time. However, we observed a significant positive influence of these factors on accuracy to both incongruent  and neutral stimuli . Both increased age and prior meditation experience significantly correlated with decreases of Stroop interference  Finally, there was no significant influence of either age or meditation experience on performance to congruent stimuli. In the global-local task, we did not observe any significant effect of age or meditation experience on accuracy or RT to either type of stimuli.We used a general linear model to assess the effect of participants age and prior meditation experience on task performances. For each task, we computed the correlation between years of We tested 82 meditation practitioners at the beginning and at the end of a 3 month full time meditation retreat using three attentional tasks: an attentional blink task, a Stroop task and a global-local task. Our results show a modest decrease in the magnitude of the attentional blink at the end of the retreat compared to the beginning. Unexpectedly, we also found that previous meditation experience correlated with decreased performance in accurately recognizing both the T1 and T2 stimuli of the attentional blink paradigm. Comparing the magnitude of improved performance on the attentional blink paradigm to previous studies indicated a similar magnitude of improvement in a control cohort of novices with minimal meditation experience and no significant intervention. This is thus casting doubt on the interpretation that this effect was a specific result of meditation during the retreat and more in support of this being related to improved performance secondary to simple learning mechanisms. Comparing pre- and post-retreat assessment of conflict monitoring and automated responding as assessed by the Stroop paradigm we observed decreased Stroop interference related to improved accuracy on the incongruent trials of the Stroop task. Congruent with this, previous meditation experience in our cohort also correlated with increased accuracy on incongruent trials and decreased Stroop interference at the baseline pre-retreat assessment. We found no significant main effects of the retreat on accuracy or reaction time in the incongruent trials of the global-local task although a pattern of relatively faster reaction times on the local task relative to the global task both pre and post retreat indicated that this cohort showed an unusual local attentional biasing, possibly related to the practices in this tradition being more in the focused attention domain.Because of the large number of subjects and our limited data collection capabilities, some subjects were recorded after the beginning of the retreat and some subjects were recorded before the end of the retreat. We thus checked for correlation of pre- and post test performances with pre- and post- test date expressed as the day the test occurred relative to the beginning and the end of the retreat. Overall, we computed 18 regressions scores that did not lead to significant correlation with pre- or post-retreat test date after applying the Bonferroni correction for multiple comparisons.Our results show increased accuracy scores on incongruent Stroop stimuli at the end of the retreat compared to the beginning. In addition, previous meditation experience correlated with more accurate performance at the baseline assessment. These results are in accordance with a previous reports demonstrating less Stroop interference in experienced Buddhist meditators compared to controls  of the target T2 presented in the short interval after T1  relative to the pre-retreat test (59%). One previous study assessed the effect of meditation and the attentional blink effect.Slagter et al.  did a prOur study found an improvement in the meditation retreat participants equal to the control group participants in the Slagter study (from about 60 to 70% T2-short correct) and not as robust as the meditator group participants in that study (who showed an average of about 60 to 80% T2-short correct). As we did not have a control group to compare the meditator cohort data in this study, we cannot assume that the rather modest improvement in performance was specifically related to the intensive meditation practice during the Isha Yoga retreat. Of note, during the Isha Yoga meditation retreat considered here, participants spent about 1.5–4 h daily sitting in silent meditation whereas in Slagter et al. 's study Shoonya, Samyama, and Lingasanchalana practices done in the Isha Yoga retreat have a less explicit focus on open-monitoring and are instead favorising the focused attention spectrum of practice. Consistent with this interpretation, in contrast to the negative correlation we obtained between previous Isha Yoga meditation practice and attentional blink performance at baseline, Van Leeuwen et al. (The contrast in findings between this study of the effects of the Isha Yoga 3-month retreat and the earlier report before and after a 3-month Vipassana retreat seems to indicate that intensive open-monitoring/mindfulness training may more specifically modulate the attentional capacities underlying the performance of the attentional blink paradigm. This is possibly related to Vipassana practice engaging the attentional mechanisms on present moment awareness with a greater focus on sensitively attending to internal and external experience with concomitant purposeful cognitive non-elaboration on experience. In contrast, the n et al.  showed tAlthough our modest improvement in performance and lack of a control cohort precludes our attributing the improvements that we did observe in the attentional blink paradigm to the meditation practiced in retreat, it is also possible that some of this improvement may have been due to the “open monitoring” aspect of the diverse Isha Yoga meditation practices. Indeed, Olivers and Nieuwenhuis , 2006 deOverall we take the smaller improvement in attentional blink performance in this Isha Yoga retreat cohort relative to the previous Vipassana retreat cohort assessed by Slagter et al.  using a Both at the beginning and at the end of the retreat, participants were faster to respond in the local task than in the global task to stimuli with incongruent global and local features. Moreover, participants were faster to respond at the global level when stimuli were congruent than when stimuli were incongruent and the speed of responding was thus biased by local features. However, there was only a trend difference in reaction time between congruent and incongruent stimuli when responding to the local level at both the beginning and end of the retreat, indicating a decreased magnitude of global biasing relative to local biasing. These results suggest that overall this global-local paradigm tended to evoke in this cohort a non-standard tendency for local processing to predominate over global processing. Previous literature Navon,  has demoThe only pre-/post- differences in performance on the global-local task found was related to slight decrease in the magnitude of the faster reaction time to incongruent stimuli in the local relative to global task condition. This finding indicates a possible slight relative increase in global attentional processing after the retreat, somewhat in line with the hypothesized increase in global attentional biasing that we predicted might accompany improvements in attentional blink performance. However this metric is not as specific and robust a metric of global processing as the global-local interference effects which were not found to be affected by the retreat so reading much into this finding is unwarranted.It is of note that the one previous study assessed the global-local task as well as Stroop performance in experienced meditators vs. controls also found improvements in Stroop task performance but no effect of meditation in performance on the global-local task (Chan and Woollacott, Another explanation pertains to the type of meditation we studied. Other types of meditation involving visualization such as those practiced in Tibetan Buddhism might be expected to engage a more robust effect compared to Isha Yoga meditation which does not involve any visualization. For example, Carter et al.  have fouOur study reinforces that increased cognitive flexibility and decreases in automatic responding as indexed by the Stroop task is one likely concomitant to diverse forms of meditative practice including Isha Yoga practices which involve more focused attentional mechanisms as well as some explicit focus on self-transcending. The results point toward a negligible effect of this form of more focused meditation on the efficiency of temporal attentional resource allocation indexed by the performance on the attentional blink task in contrast to the improvements previously observed with open-monitoring practices. Lastly, there is some indication that this form of practice may predispose individuals toward greater local precedence in spatial visual attention instead of the more typical global precedence seen in the population through performance on the Local-Global task. The Stroop task result is the most robust since increases in accuracy in the task seen between pre- and post- recording is reinforced in the observed correlation between previous meditation experience and improved performance on this task. All of these effects would be much more reliably interpreted in the presence of a control group, which is the primary limitation of this study.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Electroconvulsive therapy (ECT) is the most effective treatment for a refractory major depression in the context of both unipolar and bipolar affective disorders. However, the relapse rate within the first 6 months after a successful course of ECT to treat a depressive episode can be as high 50%. Evidence-based strategies to prevent relapse have partial efficacy and are associated with problematic adverse effects limiting their use as long-term treatments. Repetitive transcranial magnetic stimulation (rTMS) has demonstrated efficacy in treatment-resistant depression with a favorable adverse effect profile. Herein, we describe six patients, four with unipolar and two with bipolar depression, where rTMS was used to maintain response after a successful course of acute and continuation ECT. rTMS was administered once or twice weekly, at 120% of the resting motor threshold. Patients received sequential bilateral rTMS . The site of stimulation was 6 cm anterior and 1 cm lateral from the site of maximum stimulation of the abductor pollicis brevis muscle. Depressive symptoms were monitored with the quick inventory of depressive symptoms-self rated. Five of the six patients were able to maintain their response status from 6 to 13 months at the time of last observation. The use of rTMS may be an important relapse prevention strategy following an acute course of ECT. Controlled studies comparing rTMS to current evidence-based relapse prevention strategies are warranted. Electroconvulsive therapy (ECT) is an established and important treatment for severe or treatment-resistant depression (TRD) . Despite24The best evidence for preventing relapse in depression after an acute course of ECT consists of continuation pharmacotherapy (C-Pharm) or continuation electroconvulsive therapy (C-ECT) , 8. A CoRepetitive transcranial magnetic stimulation (rTMS) has emerged as a new treatment for TRD . Unlike Though its efficacy may not be as robust as ECT, rTMS may have a similar mechanisms of action , 25, as Herein we describe the use of rTMS to maintain response in six patients who initially responded to an acute and continuation course of ECT and requested to discontinue the course of ECT due to poor tolerability or cognitive side effects.Imipramine-equivalent dose of the antidepressant medications during the maintenance rTMS period was 294 ± 161 mg/day in these patients  pulse width (0.3 ms) ECT with seizure threshold titration. Subsequent treatment was administered at six times the seizure threshold. This technique has been shown to be an effective treatment with a reduced cognitive side effect profile . Two patRepetitive transcranial magnetic stimulation was administered using a MagPro RX100 Repetitive Magnetic Stimulator  and a hand-held B65, figure-of-8 coil. rTMS was administered once or twice weekly, at an intensity of 120% of the resting motor threshold. The intensity was administered at as a percentage of the maximum stimulator output (MSO). For example, if the resting motor threshold was 40% MSO the intensity of treatment would be delivered at 48% MSO. Choice of one or two treatments per week was based on the severity of depression and patient’s compliance to the treatment. Patients received sequential bilateral rTMS using low frequency right (LFR) for 600 pulses in one continuous train, then high frequency left (HFL) for 3000 pulses. For the HFL stimulation the number of pulses per train was 50, for 60 trains with an inter-train interval of 20 s. The site of stimulation was 6 cm anterior and 1 cm lateral from the site of maximum stimulation of the abductor pollicis brevis muscle. This location has been advocated as more accurately targeting the dorsolateral prefrontal cortex (DLPFC) , 33. TheCase 1 is a 27-year-old woman with a major depressive episode in the context of bipolar disorder (BD) type I. The depressive episode was of moderate to severe severity without psychotic symptoms. She had failed several antidepressant and mood stabilizers including lithium during the current depressive episode. She had an acute course of nine RUL-UB pulse width treatments over 1 month and eight continuation RUL-UB pulse width treatments over 3 months. During ECT treatment, she was not prescribed any psychotropic medications. She had a greater than 50% reduction in QIDS scores at the end of her ECT course (23 to 10). She wished to stop the C-ECT course due to concerns over the disruption in her daily schedule and cognitive adverse effects. She began a course of rTMS within 1 week of her last ECT treatment and had a total 40 sessions over 6 months twice per week, that consisted of 600 pulses of LFR prefrontal rTMS at 41% of the MSO and 3000 pulses of HFL prefrontal rTMS at 43% MSO. During rTMS treatment she was prescribed trazodone for sleep, PRN lorazepam for anxiety, and zopiclone PRN. When she began rTMS  her QIDS-SR score was 13 and dropped to 10 at the end of her rTMS course .Case 2 is a 47-year-old woman with a major depressive episode in the context of BD type II. The depressive episode was of moderate severity and she had failed two adequate trials of an antidepressants with augmentation. She had an acute course of 18 RUL-UB pulse width treatments over 2 months and 31 continuation and maintenance RUL-UB pulse width treatments over 9 months. During ECT treatment, she was prescribed venlafaxine, nortriptyline, olanzapine, aripiprazole, lithium, and zopiclone. The venlafaxine and olanzapine were discontinued during the acute ECT course and the nortriptyline dose was optimized. She had a greater than 50% reduction in QIDS-SR scores at the end of her ECT course (13 to 3). At the end of the acute ECT course her QIDS-SR score were in the remission range. She began to notice cognitive impairments during the maintenance ECT course and wished to discontinue the treatment. Due to her history of recurrent episodes rTMS was considered. She received a total 58 sessions on a once weekly basis over 13 months that consisted of 600 pulses of LFR rTMS at 54% MSO and 3000 pulses of HFL rTMS at 46% MSO. During rTMS treatment, nortriptyline, lithium, aripiprazole, and zopiclone were prescribed with no dose changes. When she began rTMS (after stopping her maintenance ECT course) her QIDS-SR score was 2 and was maintained at 3 at the last observation.Case 3 is a 58-year-old woman with a depressive episode in the context of a major depressive disorder (MDD). The depressive episode was of moderate severity. She had failed two antidepressant of adequate dose and duration. She had an acute course of 10 RUL-UB pulse width treatments. During ECT treatment she was prescribed fluoxetine. Despite achieving remission (QIDS-SR score of 3) with her acute course of ECT she did not like the anesthetic side effects and declined a course of C-ECT, she also declined the addition of lithium due to concern over side effects. Given her history of recurrent episodes a course of rTMS was offered. She received 66 sessions of rTMS twice weekly over 11 months. She received 600 pulses of LFR rTMS at 43% MSO and 3000 pulses of HFL rTMS at 52% MSO. During rTMS treatment, fluoxetine was continued. Her QIDS score was 2 at the last observation.Case 4 is a 51-year-old man with a major depressive episode in the context of MDD. The depressive episode was of severe severity and failed to respond to at least two antidepressants trials of adequate dose and duration. He had an acute course of six RUL-UB pulse width treatments, but due to lack of response he was then switched to bitemporal ECT for another 14 treatments. During ECT treatment, he was prescribed mirtazapine, paroxetine, clonazepam, gabapentin, and zopiclone. The gabapentin and clonazepam were discontinued during the ECT course. He had a partial response to ECT and the severity of depression was reduced to the moderate range (QIDS-SR went from 18 to 13). Due to cognitive adverse effects he was offered a course of rTMS. As the patient lived a far distance from the hospital he was only able to attend on a once weekly basis. He received 52 rTMS treatments once weekly over 7 months that consisted of 600 pulses of LFR rTMS at 57% MSO and 3000 pulses of HFL rTMS at 57% MSO. During rTMS treatment, he took mirtazapine, paroxetine, and zopiclone. When he began rTMS  his QIDS score was 13 and dropped to 12 at the last observation, during periods of his rTMS course his QIDS score was as low as 7. Subjectively, the patient reported significant improvement in his symptoms during the rTMS course.Case 5 is a 51-year-old man with a major depressive episode in the context of MDD. The depressive episode was of severe severity and he failed two antidepressants of adequate dose and duration. He received an acute course of 11 RUL-UB pulse width treatments and 15 continuation and maintenance RUL-UB pulse width treatments over 7 months. During ECT treatment, he was prescribed venlafaxine and nortriptyline. He had a partial response to the acute ECT course and the severity of the depression was reduced to the moderate range (QIDS score of 11). Due to cognitive adverse effects he was offered a course of rTMS. He received a total 65 rTMS treatments, twice per week, over 10 months that consisted of 600 pulses of LFR rTMS at 54% MSO and 3000 pulses of HFL rTMS at 57% MSO twice a week for 5 months. Due to ongoing partial response (QIDS score of 12) he was switched to 6000 pulses of HFL rTMS at 56% twice a week over the next 5 months. At periods during the 6000 pulse HFL rTMS course his QIDS score was as low as 8. At the last observation period his QIDS score remained in the moderate range at 11. The reduction of his depression scores into the moderate range was greater than the improvement he had with medication and led to the continuation of rTMS despite the partial response.Case 6 is a 56-year-old woman with a major depressive episode in the context of MDD. The depressive episode was severe with psychotic features. She had an acute course of 13 RUL-UB pulse width treatments and 10 continuation RUL-UB pulse width treatments over 2 months. At the beginning of her ECT treatment, she was prescribed mirtazapine, desvenlafaxine, risperidone, and clonazepam. The venlafaxine was switched to nortriptyline and the clonazepam was discontinued during the ECT course. She had a good response to the acute course of ECT and her QIDS-SR score were in the remission range. Despite achieving remission (QIDS-SR score of 2) with ECT she had difficulty tolerating the side effects of the anesthesia, the disruption in her daily life, and wished to discontinue the C-ECT. Due to her history of a severe episode with psychotic features and her history of recurrent episode she was offered a course of rTMS. She received a total of 44 rTMS treatments, twice per week, over 6 months that consisted of 600 pulses of LFR rTMS at 82% MSO and 3000 pulses of HFL rTMS at 72% MSO. During rTMS treatment, she was prescribed mirtazapine, nortriptyline, and risperidone. At the last observation her QIDS-SR score was a 9. Despite experiencing a mild worsening in her depressive symptoms she continued to be significantly improved from her index episode.Figure In this case series we present data for the effectiveness of rTMS to maintain response after achieving remission and/or response following a course of ECT in refractory depression. There is relatively little data that has investigated maintenance rTMS treatment to prevent relapse in TRD patients who have responded well to an acute course of ECT . This caThe maintenance of response or partial response from the end of the ECT course ranged from 6 to 13 months at the last observation period during the rTMS course. Only one patient had a partial worsening of symptoms. The maintenance of the response for the patients in this case series was clinically significant in the context of the chronicity of their illnesses.These results suggest that once ECT is effective for TRD, rTMS preferably at a frequency of twice per week can maintain the response achieved by ECT. All patients tolerated the treatment well. The rTMS delivered in this series was felt to be less invasive and more tolerable to the patients. The alternative evidence-based options to maintain response within the first 6 months after response from an acute ECT course can pose tolerability issues and patients often decline the two options. The adverse effect profile and tolerability of rTMS may be more appealing to patients. However, the twice weekly treatment schedule may be overly onerous to some.There are several limitations to this case series. First, clinician-rated measures of clinical symptom severity were not collected. There are limitations to self-report measures that are not corroborated by a clinician-rated measure , 39. SecThese limitations notwithstanding, this case series suggests that maintenance rTMS may be another potential treatment to maintain response after a successful course of ECT. Controlled studies comparing rTMS to current evidenced-based relapse prevention strategies such as C-ECT or C-Pharm are warranted. Such studies should include comprehensive measures of cognition.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.