Matching Michigan, a patient safety program aimed at decreasing central line infections in over 200 intensive care units (ICUs) in England, may be an example of both. We aimed to explain why these apparent effects may have occurred.Quality and safety improvement initiatives in healthcare often display two disconcerting effects. The first is a failure to outperform the secular trend. The second is the decline effect, where an initially promising intervention appears not to deliver equally successful results when attempts are made to replicate it in new settings. Matching Michigan. We undertook further telephone interviews with 29 staff who attended program training events and we analyzed relevant documents.We conducted interviews with 98 staff and non-participant observation on 19 ICUs; 17 of these units were participating in Matching Michigan unit transformed its practices and culture in response to the program; five boosted existing efforts, and 11 made little change. Matching Michigan’s impact may have been limited by features of program design and execution; it was not an exact replica of the original project. Outer and inner contexts strongly modified the program’s effects. The outer context included previous efforts to tackle central line infections superimposed on national infection control policies that were perceived by some as top-down and punitive. This undermined engagement in the program and made it difficult to persuade participants that the program was necessary. Individual ICUs’ histories and local context were also highly consequential: their past experience of quality improvement, the extent to which they were able to develop high quality data collection and feedback systems, and the success of local leaders in developing consensus and coalition all influenced the program’s impact on local practices.One Improved implementation of procedural good practice may occur through many different routes, of which program participation is only one. The ‘phenotype’ of compliance may therefore arise through different ‘genotypes.’ When designing and delivering interventions to improve quality and safety, risks of decline effects and difficulties in demonstrating added value over the secular trend might be averted by improved understanding of program mechanisms and contexts of implementation. Health systems worldwide face the frustration of a mass of evidence repeatedly showing problems in the quality and safety of patient care, but much less compelling evidence on how such problems can be tackled effectively -3. The MKeystone’s success is sometimes attributed simply to the introduction of a checklist summarizing five evidence-based practices linked to infection control for CVCs :• Appropriate hand hygiene• Use chlorhexidine for skin preparation• Use full-barrier precautions during central venous catheter insertion• Subclavian vein placement as the preferred site• Review and remove unnecessary CVCsOther analyses propose that a more complex set of mechanisms is more likely to explain the results, however . These apost hoc theorization proposed six mechanisms that might explain the effects seen in Keystone: generating isomorphic pressures (the desire to conform to group norms) among participants; creating a densely networked community, with strong links between units, encouraged by regular meetings and communication, that reinforced these norms and enabled sharing of information; taking on many of the characteristics of a social movement and reframing CVC-BSIs as a social problem capable of being solved through grassroots activism; using multiple interventions that functioned in different ways to shape of culture of commitment to doing better; harnessing data on infection rates, collected systematically, as a disciplinary force; and deploying mainly soft tactics, such as persuasion, but also making some limited use of harder tactics such as threatening sanctions against laggards  has done it, and is signed up to it, that has huge impact.’ The training events did, however, encounter some challenges. Some ICUs sent large, eager teams to the training events; others sent one or two individuals, who had sometimes been unwillingly volunteered. Participants understood that they were being asked to collect data and ensure the CVC care bundles were fully implemented, but some appeared to have difficulty in understanding what they were required to do for the non-technical elements of the program. The sessions were inclined to become bogged down in distracting criticisms of the definitions or anxieties about the effort required to collect the data:‘[The first training session] featured a lot of sniping between consultant microbiologists about how the [program] actually defines associated and [related] CVC-BSIs.’ Matching Michigan did not have the experience of being part of a collaborative community working together towards shared goals theorized to have occurred in Keystone.Participants from different ICUs did not meet again after the training sessions, and efforts to engage them in teleconferences and webinars suffered from low participation rates. This meant that the ICUs involved in Matching Michigan training events, lack of clarity about how well or how consistently the recommended practices were being implemented was presented as a rationale for the program. It was suggested to participants that the program would, through its interventions, promote adherence to the procedures specified in the Department of Health bundles and have a more general impact on patient safety. Matching Michigan was promoted by the organizers as a clinically led, cooperative program, and participants were assured that their infection data would be used only for learning. However, the national context into which Matching Michigan was introduced meant that the program faced some scepticism. In contrast to Keystone, a centrally-led emphasis on infection control had been a feature of the English NHS since the mid-2000s Matching Michigan simply as another externally mandated program had little inclination towards genuine engagement. A multi-disciplinary team was appointed to lead the program, including a senior ICU physician who had previously been president of the European Society of Intensive Care Medicine , and a senior clinical intensive care nurse who had been head of the UK Critical Care Nurses’ Association. Despite this, the location of the program in a government agency rather than a professional organization or research collaboration appeared to contribute to an alienating sense of ‘distance’ on the part of some front-line clinicians: contrary to what was theorized to have occurred in Keystone, Matching Michigan was often seen as imposed from outside and lacking in professional ownership. Some participants remained suspicious about the potential for the data to be used for performance management or public shaming purposes:Those who saw ‘Because the NPSA is a Department of Health arm’s length body, there is certainly a view by a lot of clinical staff that oh, if it’s coming down from there then, you know what that is all about. So I think there is certainly a limitation attached to that.’ What was needed was] a consultation so that it feels like what we are implementing is coming from within, first of all…If we had taken what Matching Michigan had done, not called it Matching Michigan but taken the same things and then applied it as something that came through for example the Intensive Care Society or [another professional society]… it was dumped on top of us from above and we had no option in it.’ ‘ said, ‘we just have to be vigilant about thinking about how long the lines have been in.… He is careful to check patients’ [central lines]. It wasn’t something I necessarily saw with the other consultants. I didn’t see that they were very explicitly vigilant about how long the central lines were in,’ (Fieldnotes)Matching Michigan, although staff on some of the Boosted and Transformed units described using the program strategically to implement the changes. Telephone interviews suggested similar behaviors:Innovations such as bio-patches, specially coated catheters, and new techniques for aseptic practice were introduced by many units during the period of our observations. On the whole, staff did not attribute these new developments to ‘What I am doing is focusing on our own needs though the project. Matching Michigan was merely a hook because it enabled us to do all the things that we wanted to do.’ Matching Michigan’s non-technical interventions  struggled to involve executives.Participants’ understanding of s Figure , intendeMatching Michigan, nor was formalised or standardised practice in relation to daily goal-setting newly implemented. Only three ICUs publicly displayed CVC-BSI data so that staff were aware of their own unit’s rate. Strongly hierarchical and sometimes negative safety cultures persisted on some ICUs:Safety Surveys—one of the non-technical interventions intended to provoke local discussion and reflection—were distributed in only three of the 17 ICUs. In very few ICUs was there evidence that ‘learning from one defect a month’ was introduced as a result of ‘Working with different consultants is that I would say probably without exception as registrars [residents] we do what the consultant tells us to do, certainly where they’ve got very strong personalities, so I’ve put central lines in with just a pair of gloves with the individual who does it like that …because that’s how he does it, he won't let you do any other way and as registrars you're under pressure to do things as the consultant wants you to do them …[or] you know makes the rest of your day miserable.’ Matching Michigan could be explained by variability in infection rates and measurement, local histories, and local leadership.Our analysis suggested that much of the units’ variability in response to Program organizers emphasized at training events that the impact of previous efforts to control CVC-BSIs was unknown, given the absence of a national infection data collection system. They also emphasized that unless ICUs knew their own rates they could not be sure that they were providing safe care. It was anticipated that discovery of high rates of infection would stimulate change:‘What we did not have in this country was a measure of the outcome.... Key stakeholders in the country [were saying to us], ‘well we are fine in England, we are already matching Michigan. We have had the technical interventions. We have got it all sorted in England. So go away.’ And I actually did say to them, ‘Well, could you tell me what your rates of infection are?’ And they said ‘Oh I don’t know.” (Matching Michigan program team member)Matching Michigan reported an initial mean rate of 3.7 BSI per 1000 catheter days. Though this was less than half the initial rate in Keystone, it did suggest room for improvement. However, each of the three successive clusters joined the program on the trend line, with an initial infection rate similar to the post-intervention level of the preceding cluster. This indicated that substantial improvement occurred outside the program throughout the period it was running. In any given month, almost two-thirds of units across the program were reporting no infections.The starting rate for the program turned out to be quite different from Keystone, where the initial mean rate was 7.7 BSIs per 1000 catheter days. The first of the four clusters of adult ICUs in In the Transformed and the Boosted ICUs, collecting infection rate data had a generally positive impact on practice. These units established relatively robust data collection systems  and the ‘If I’m honest right before we started, we didn’t think we were that bad.… We thought, you know, [we] don’t really have a problem with central line infections. But I think what it was, nobody ever looked to see whether we were any good … and when we compared our infection rates, actually they were far worse than any of us ever realized.’ ‘It was hard to sit and have the error of your ways pointed out when you actually already knew [how things ought to be done]. So, I think enough of us felt like that we put the wheels in motion really.’ Matching Michigan data on infection rates could have effects that were in the opposite direction from those intended. Low-impact units varied substantially in the extent to which they established robust local data collection systems and how far the data were regarded as credible by clinicians locally. On some units, evidence of high infection rates was dismissed as poor quality data, and change was thus stymied. On some others, low infection rates were taken as evidence that no change was needed—but the data were not always collected accurately enough to justify such a conclusion. This meant that sometimes very hierarchical cultures that were not fully supportive of patient safety were reinforced, and that opportunities for improvements in practice went unrecognized.However, Local histories of efforts to control CVC-BSIs were deeply implicated in the differing responses to the program. In the Transformed unit, previous attempts to improve practice had been largely ineffectual. The program was seen by staff locally has having provided the tools and techniques they needed to make change, where nothing had seemed to work before:[Consultant says] ‘Matching Michigan has genuinely made a real difference here … We’ve seen some really quite big changes around here … you can see real actual evidence of improvement in patient outcomes.’ (Fieldnotes)Matching Michigan, that central line infections were a problem that they needed to tackle. These units had made significant gains before Matching Michigan, but recognized that there was still some room for further improvement. On these units, local leaders were keen to drive improvement, but had sometimes experienced barriers or resistance to change. These individuals explained how the program helped them consolidate their gains or make new improvements. Having a national, centrally led program was helpful because it enabled them to ask for resources, demonstrate that proposed changes were evidence based, persuade reluctant colleagues that conformity with good practice was now compulsory, and learn how their infection rates compared with other units:On the five Boosted units, the program was absorbed as part of a local narrative of cumulative improvement. Staff on these units described having already recognized, long before ‘We already had things like a lines trolley in place and I think that worked reasonably well. Perhaps wasn’t always stocked as well as it should be.... Being involved in Matching Michigan project certainly sort of tightened up vigilance.… We certainly didn’t have an insertion checklist, and this certainly wasn’t the sort of the culture whereby everybody felt that line infections were pretty much preventable. [The change was] the continuous measurement system, … actually doing the checklist and publishing the results that we were getting back.’ Matching Michigan, given that the technical practices were the same as those that had already been adopted as policy. Many saw it as addressing a problem that they believed had already been solved:In the Low-Impact units, a few staff were resentful or hostile to the program, but more commonly they expressed apathy, exasperation, and bewilderment. On these units, staff argued that they had already invested heavily in changing practices to reduce CVC-BSIs in response to previous policy initiatives, that the prevalence of CVC-BSIs had already greatly diminished, and that the program was a largely superfluous data collection exercise. ICU staff on the Low-Impact units were often unsure what was new or distinctive about ‘Compared to what we were already doing it seemed to be that wearing a hat [was the only difference] basically. We were already going over to packs anyway.’ Matching Michigan’ scribbled out and ‘Exceeding Michigan’ written in:Staff reported that they could not understand why CVC-BSIs in ICUs were being targeted by a dedicated program, when what they saw as other, more pressing problems—such as ventilator-acquired pneumonia or CVCs in non-ICU settings—were being neglected. Some saw the program as a failure to respect what had already been achieved by ICUs. Even its title caused resentment: in one unit, a file about the program was defaced, with ‘‘There is sort of an attitude that, actually, it’s come in a little too late.’ What was notable about these Low Impact units was that these views were held not only by the staff ‘on the ground,’ but often also by those on the safety team set up locally to implement the program. These local leads were not always fully convinced of the need for, or value of, Matching Michigan.Perhaps the single most important influence on program response by individual units—either in promoting or resisting change—was the extent of consensus and coalition among the senior medical and nursing staff on individual ICUs. The commitment, characteristics, and skills of local leads were pivotal. Transforming or boosting of efforts was most likely to occur when those locally charged with implementation were sincere in their beliefs about the value of the program, were able to create transdisciplinary alliances, had local credibility among peers, were prepared to tolerate debate but exercise firmness, and used multiple tactics including role modelling, persuasion, sanctioning, reminders, and constant feedback:‘Cultural change is the biggest threat, because all of a sudden it fundamentally means that what you’ve been doing so far is maybe wrong, or people don’t value what you’ve done for the last 15 years. People think ‘oh, there’s the smartarse telling us how we’re supposed to do things.’ So there were a lot of discussions and persuasion.’ [Consultant says] ‘I think it’s been successful because it’s a unifying program, it’s one of the few things that we’ve done that hasn’t been just a doctor thing, or just a nurse thing, it’s involved the doctors and the nurses together.’ (Fieldnotes)Authoritative and unwavering support from senior consultants was especially important in enabling nurses to act as a disciplinary force for junior doctors, who performed most CVC insertions:‘So the fact that the lead consultant was passionate about it helped us to bring about change. [We could] actually  ‘You will gown up! You will put a mask on!’ And that was coming from [the lead consultant] as much as it was from [the nurses].’ Matching Michigan, staff in this unit reported, was the first that came from and was owned by the ICU, rather than being imposed from the outside. Led by a young and determined entrepreneurial consultant, a team was developed that crossed intra-professional hierarchies and inter-professional work domains. This individual and his consultant colleagues went about rebuilding the unit culture according to the program’s goals. He described how he and his colleagues modelled Matching Michigan’s preferred practice for the insertion of CVCs and insisted on compliance from junior doctors. Both junior and senior medical trainees, as well as nurses were included in the data collection process. He used the introduction of the checklist and observation as ways of flattening unit hierarchies and empowering nurses and junior medics to act on any breaches of aseptic technique they observed:In the transformed unit, collecting data for the program revealed previously unrecognized high rates of CVC-BSIs. This shocked unit staff into action; a local leadership team emerged who used the program’s tools and techniques to secure change, and collecting data over time confirmed that the interventions were effective in reducing rates to zero from an initial high rate. In the very beginning we made sure that it was the charge nurse, or one of the sisters, who would take the role of the observer. So [we chose someone who would] feel more confident, and was actively encouraged to interrupt if there was something [wrong with our technique]…[We did this] so that the juniors could see. And if one of the consultants was putting the central line in we would make sure that [a nurse observed] us as well. To make sure that people see it applies for us exactly as for anybody else…it’s the same rules apply for everybody. If we put a line in or [one of the junior medics does], it doesn’t matter.’ (Consultant)Matching Michigan had less impact, senior consultants were not persuaded that all elements of the program were grounded in high quality evidence, saw it as an illegitimate policy or bureaucratic intrusion into professional work, or deemed it irrelevant to their concerns and interests. Apparently minor issues—such as the recommendation to wear hats and masks during CVC insertion—caused irritation and resistance in some settings because they were perceived to lack sound evidence. If local program leads did not successfully build consensus among senior staff that central line infections were a problem, and that Matching Michigan was the right answer to the problem, the program was inclined to stall:In the units where ‘I recall from reading that there wasn’t anything that made me change my practice. I haven’t seen any people [using hats and masks] and I certainly wouldn’t you know ask my juniors to do that.’ ‘It can be a struggle. It can even be difficult if you’ve got one [consultant] who’s a real advocate and saying, ‘Yeah this is the best thing since sliced bread!’ And then you’ve the six others who are like, ‘What a load of crap, we’re not using it.” Executive involvement that generated enthusiasm, conferred authority, and allocated resources was helpful to the implementation of the program in local settings. Where executive involvement was limited to exhorting the ICUs to produce ‘the numbers [of infections],’ it reinforced a view of the program as a mandated, performance management national audit, and risked undermining the program’s aims:‘They were getting e-mails [from the hospital executive] saying, ‘Why haven’t you submitted your data? So you go back to just tick boxing.… There’s a complete lack of interest now in line insertion.’ Matching Michigan[Matching Michigan. Compliance with procedural good practice and low infection rates could also be achieved by units in the program without implementing—or only partially implementing—the program’s non-technical interventions. The phenotype of compliance with good practice could therefore arise in different ways, of which full and authentic engagement in the program was only one. That improved compliance could occur through many different routes or ‘genotypes’ may help to explain the finding that Matching Michigan did not exceed the secular trend; most ICUs had begun incrementally improving their practices before the program began, and continued to do so thereafter, sometimes introducing innovations not part of the program. Our analysis suggests that whatever explains the declines in central line infections observed over the course of Matching Michigan, it was not the set of mechanisms that were theorized [Our qualitative study is consistent with the quantitative evaluation of  Michigan in suggeheorized  to have Matching Michigan built the social movement thought to have characterised Keystone, not least because there was so little contact between participants over the course of the program. Absence of ongoing contact also suppressed the possibility for the remaking of professional norms; participants believed that whatever they were doing locally was standard. The delivery vehicle mattered hugely. Keystone may have been able to engage emotional commitment and create a sense of a community-based enterprise by mobilizing the star qualities of its leaders, by building on the bonds people felt with their local hospital association, and by partnering with a highly prestigious out-of-state university with a track record of achievement in the area of patient safety [The program bore a strong resemblance to the original, but primarily at the level of components rather than hypothesized mechanisms . There wt safety . ICU stat safety , this wat safety .Matching Michigan was introduced. Staff’s experience of previous centrally-led programs as harsh and performance-oriented contributed to alienation among some. Collecting data on infection rates often did not always produce a norm-disrupting effect that challenged units to change their practices and cultures; instead, in some units, it reinforced the status quo. Features of ICUs’ internal context also appeared relevant to explaining how they responded to the program. In units where change—either transformative or boosting—was attributed by staff to Matching Michigan, several things needed to happen. At least one senior physician needed to exert strong leadership, and to work in coalition with senior nurses. These leaders needed to be recognized by their peers as committed, credible, and engaging, and to communicate a sincere belief in the program. They needed to do enough listening to ensure peers felt heard, but also know when to ‘push it hard.’ Data collection systems needed to be rigorous enough to command credibility. Leaders also needed to be canny enough to appropriate the centrally-led, external nature of the program to confer authority and legitimacy on their efforts and to drive through improvements that would otherwise have been difficult to achieve.The challenges of program design and delivery were intensified by the contexts into which Matching Michigan was launched was highly influential in modifying its possibilities for effecting change, and further helps in explaining the possible decline effect. The Keystone project had the benefit of newness and freshness; ICUs in England, on the other hand, had been exposed to a long series of initiatives and pressures in relation to infection control, and believed that they had already made changes in response.The broader context in which Matching Michigan was seen by some staff as a failure to respect what they had already achieved, and, given the other challenges facing hospitals, a misdirection of resources. The goals, interests and priorities of the program were therefore widely seen as misaligned with those of staff at the sharp-end. Further, it may well have been the case that in some units there genuinely was very little headroom for improvement: all the gains that could be made had already been made, and in such contexts improvement programs characteristically struggle to demonstrate further change [The possibility that staff in English ICUs would, as was theorized to have occurred in Keystone, come to recognize CVC-BSIs as a social problem capable of being solved  was under change ,22.Matching Michigan interventions  in improving compliance with evidence-based practices and reducing infection rates. Much depended on context: program interventions were able to deliver positive change where they were implemented. As the ‘transformed’ unit showed, under the right conditions and deployed appropriately, these interventions could be used to bring about substantial improvements. The disappointment of the program is that it did not achieve these effects on a larger scale; some ICUs that could have benefited from strengthening their organizational culture and consistency of good practice did not take advantage of the opportunity to do so. We propose that though the interventions ‘work,’ Matching Michigan did not fully work as program because of features of program design and delivery and contexts of implementation.Importantly, our study does not challenge the efficacy of the Matching Michigan was running. Almost two-thirds of units across the program reported no infections, meaning a median of zero—the same as seen in Keystone. A 60% decline in infection rates over the course of the program is non-trivial, even if it is difficult to pin the credit on the program.None of this is to deny that improvement in rates of CVC-BSIs did occur while Matching Michigan came into being because there was already strong policy and professional pressure—not least because of the success of Keystone—to do better in reducing rates CVC-BSIs. A recently published analysis of 20 years of data shows that CVC-BSI rates began to plummet from 1990 onward, and the increasing rarity of the infections is likely to have undermined the view that they were the price of doing business in ICUs [Matching Michigan in a context where there is an overall trend in a particular direction may be to add to the pressures and provide structures and legitimacy for change. Had the relevance of the context been more fully acknowledged, and the program more faithful to the hypothesized mechanisms of the original, more might have been achieved.Only one other study appears to have concurrently studied CVC-BSIs acquired outside the ICU, and this too identified a strong secular trend  suggesti in ICUs ,25. The  in ICUs . The maiMatching Michigan ‘worked’: the quantitative evaluation [Our study has a number of important limitations. Our ethnographic visits to units were not longitudinal, but rather snapshots in time; changes in response to the program could have occurred after our visits. We did not conduct a systematic audit of culture and practices, and thus some inaccuracies in our assessments may be present. We did not evaluate possible modifiers of effect of factors such as size of unit, number of consultants and nurses, and other environmental features. We had access to ICUs’ reported infection rates only if they provided them directly to us; for information governance reasons, these rates could not be verified. It is possible that we have offered too pessimistic an interpretation of whether aluation  may haveMatching Michigan reproduced many of the components of the original Keystone project, it did not reproduce many of the features of Keystone that were theorized to have enabled it to work. This, together with the contexts in which it was introduced, helps to explain both the decline effect and the apparent failure to outperform the secular trend. Our analysis will inform future research in this area [Our study points to the need for clear understanding of the mechanisms by which improvement programs work. Though his area  by demonA favorable opinion was obtained from Berkshire NHS Research Ethics Committee was obtained for this study.Matching Michigan project, conducted in parallel with the ‘Lining Up’ project on which this article is based. His employers were financially compensated for his time by the National Patient Safety Agency. No other authors declare financial relationships with any organizations that might have an interest in the submitted work in the previous three years or other relationships or activities that could appear to have influenced the submitted work No other authors have a conflict of interest.Julian Bion held the advisory role of senior clinical lead for the MDW, CT, and JB conceived of and designed the study, conducted the literature review, obtained the funding, and recruited participating sites. MDW and CT led on obtaining ethics and governance approvals. CT and ML undertook ethnographic observations and interviews in participating sites. MDW and CT coordinated the study. MDW, CT, and ML devised the analytic framework. ML undertook coding, which was checked by MDW. MDW and ML led on drafting of the manuscript, with extensive contributions from CT and JB. All authors read and approved the final manuscript.


BCR-ABL1 fusion is the most common. Instances of tyrosine kinase inhibitor (TKI) resistance in e19a2 BCR-ABL1 CML patients have rarely been reported. A case of e19a2 BCR-ABL1 CML is described in whom imatinib resistance, associated with a Q252H ABL1 kinase domain mutation, became apparent soon after initiation of TKI therapy. The patient rapidly transformed to myeloid blast crisis (BC) with considerable bone marrow fibrosis and no significant molecular response to a second generation TKI. The clinical course was complicated by comorbidities with the patient rapidly succumbing to advanced disease. This scenario of Q252H-associated TKI resistance with rapid BC transformation has not been previously documented in e19a2 BCR-ABL1 CML. This case highlights the considerable challenges remaining in the management of TKI-resistant BC CML, particularly in the elderly patient.A minority of chronic myeloid leukaemia (CML) patients express variant transcripts of which the e19a2  BCR-ABL1 oncogene is the molecular hallmark and causative event of CML. Most CML patients express either e13a2 or e14a2 BCR-ABL1 fusion transcripts, but approximately 5% of patients express variant transcripts that may involve fusion of alternative exons, insertions, or breakpoints within exons. Of these variant BCR-ABL1 fusions, e19a2 is the most common. CML with e19a2 BCR-ABL1, that encodes a 230 kDa protein [The  protein .BCR-ABL1 kinase domain (KD) that prohibit effective binding of imatinib [BCR-ABL1 KD mutations have been reported in e19a2 BCR-ABL1 CML [Soon after the introduction of TKI therapy for CML, it became apparent that a significant proportion of patients are either primary refractory, display suboptimal responses, or acquire resistance to imatinib . One of imatinib . Greaterimatinib . Very feABL1 CML –15 makinDespite evidence suggesting that fewer patients transform to accelerated and blast crisis (BC) phases when treated with long term imatinib , transfo9/L, haemoglobin 13.4 g/dL, and platelets of 762 × 109/L. The white cell differential was comprised of neutrophils 19.8 × 109/L, myelocytes 2.0 × 109/L, metamyelocytes 2.0 × 109/L, lymphocytes 5.0 × 109/L, monocytes 1.3 × 109/L, eosinophils 0.3 × 109/L, and basophils 2.4 × 109/L. A bone marrow aspirate was hypercellular with significant myeloid and megakaryocytic hyperplasia with reduced erythroid series and no fibrosis evident. Cytogenetic analysis revealed 45,X,-Y,t in 20/20 metaphases. A standard reverse-transcriptase polymerase chain reaction (PCR) methodology for detection of BCR-ABL1 transcripts [BCRABL1 fusion leading to a diagnosis of chronic phase CML. The patient commenced on hydroxycarbamide 1 g/day then imatinib 400 mg od one week later. He achieved haematological remission within three months, but thrombocytopenia became rapidly evident prompting an increase in imatinib to 800 mg od. Again, his blood counts normalized, but this was not sustained. Peripheral blood quantitative PCR (qPCR) was performed as previously described [BCR-ABL1 transcript levels  indicating myeloid blast crisis. A further fragmented bone marrow biopsy demonstrated hypercellularity secondary to increased blast cell numbers  of the ABL1 KD were considered to have a high degree of imatinib resistance and a particularly poor prognosis [in vitro analysis of many ABL1 KD mutations that has provided a rationale for selection of second generation TKI therapy, the Q252H mutation appears responsive to nilotinib, dasatinib, and bosutinib [The e19a2 is the most common reported –15. All rognosis . Howeverosutinib . The lacosutinib .Also of note is the manifestation of fibrosis associated with the blast crisis. Whereas progressive bone marrow fibrosis is considered an indicator of treatment failure in CML, TKI therapy can reverse fibrosis significantly but does not eliminate its unfavourable prognosis nor guarantee against further fibrotic evolution –33. The BCR-ABL1 CML and its association with TKI resistance and progression to BC. The case also serves to highlight the considerable challenges in the treatment of CML BC particularly in the elderly patient with significant comorbidities.This report describes for the first time, the presence of the Q252H mutation in e19a2


The demand for health professionals continues to increase, partially due to the aging population and the high proportion of practitioners nearing retirement. The University of British Columbia (UBC) has developed a program to address this demand, by providing support for internationally trained Physiotherapists in their preparation for taking the National Physiotherapy competency examinations.The aim was to create a program comprised of the educational tools and infrastructure to support internationally educated physiotherapists (IEPs) in their preparation for entry to practice in Canada and, to improve their pass rate on the national competency examination.The program was developed using a logic model and evaluated using program evaluation methodology. Program tools and resources included educational modules and curricular packages which were developed and refined based on feedback from clinical experts, IEPs and clinical physical therapy mentors. An examination bank was created and used to include test-enhanced education. Clinical mentors were recruited and trained to provide clinical and cultural support for participants.The IEP program has recruited 124 IEPs, with 69 now integrated into the Canadian physiotherapy workforce, and more IEPs continuing to apply to the program. International graduates who participated in the program had an improved pass rate on the national Physiotherapy Competency Examination (PCE); participation in the program resulted in them having a 28%  greater possibility of passing the written section than their counterparts who did not take the program. In 2010, 81% of all IEP candidates who completed the UBC program passed the written component, and 82% passed the clinical component.The program has proven to be successful and sustainable. This program model could be replicated to support the successful integration of other international health professionals into the workforce. Health-care education around the world varies in educational standards, curriculum, and evaluation methods. The increasing demographic presence of ‘visible minorities’ and internationally-trained professionals, demands equal access to employment opportunities that support practice in occupational roles according to their qualifications and work experience. Support for this transition is essential to maximize skilled contribution to the development of a country . Canada In order to obtain a license to practice Physiotherapy in Canada, in all provinces except Québec, Physiotherapists educated outside Canada must complete the two-part national Physiotherapy Competency Exam (PCE). In 2005 there was a notable discrepancy in pass rates between internationally trained Physiotherapists and Canadian graduates; less than 50% of internationally trained Physiotherapists exam attempts translated into passes, compared to greater than 92% of Canadian educated candidate attempts . The chaThere is some literature about internationally trained health professionals; this literature mainly reflects the process of examining the credentials, competency, demographic characteristics and distribution of international medical graduates (IMGs) -11. TherTo meet the demand for licensed Physiotherapists in Canada, and more specifically British Columbia (BC), and to provide support for internationally-trained physiotherapists who wish to continue to practice their skills and gain licensure, the “Internationally Educated Physiotherapists (IEP) Program Project” was established at the University of British Columbia.The aim of this project was to create the educational tools, curriculum, and infrastructure needed to sustain a program supporting internationally trained Physiotherapists applying for licensure in BC. The primary objective of the program was to increase the pass rate of internationally trained Physiotherapists taking the PCE. The UBC ethics board states that ethical approval is not needed for program evaluation.The project team used a conceptual framework to map the program components, clarify the nature of program goals, and guide the program development . To thisThe IEP project was developed in a partnership with key BC Physiotherapy stakeholders  which provided oversight, guidance, communication services, advertising and marketing support, identification and recruitment of mentors and content experts. A key role in the management of the program was the Program Coordinator, who was a trained and licensed Physiotherapist with over 40 years of practice experience. The Program Coordinator was responsible for all activities of the program, including recruiting, scheduling, data collection, communication and feedback sessions related to exam modules. All inputs and activities are shown in Figure The program consists of two separate streams to assist IEPs in the preparation for the PCE: one in preparing for the written component (QE), and the other to prepare for the clinical component (PNE) of the national exam. IEPs had the option to participate in both streams of the program, or to receive support for the preparation of only one component of the PCE (the written (QE) component or the clinical (PNE) component). The QE consists of 200 multiple-choice questions (MCQs) and the PNE is an objective structured clinical examination (OSCE) to evaluate candidate’s interactions in controlled scenarios with standardised clients. The primary objective of the program is to assist IEPs with their preparation for taking these exams. To achieve this objective, modules including examination writing skills, content area review, and practice exam experiences (using tested-enhanced learning theory) were developed . Many reContent experts developed initial versions of the curricular modules covering the four primary areas of Physiotherapy practice using the DACUM (Developing a Curriculum) model . All modAccess to Physiotherapy mentors was initially identified as important to provide IEPs with the acquisition and reinforcement of practical skills in a Canadian context. Mentors were recruited from the clinical community based on area of clinical expertise, and experience teaching and supervising students. Three mentor-training workshops that focussed on facilitation techniques to support the learning of entry-level physiotherapy skills were offered to interested physiotherapists across the province. IEPs were matched with mentors who specialize in the primary areas of practice. The responsibilities of the mentors were to facilitate the development of the knowledge, clinical skills and clinical reasoning in each content area as expected in Physiotherapy practice in Canada. Mentors were also responsible for supporting the IEPs to achieve the competencies, as outlined in each module.The program evolved since inception as a result of feedback from a variety of sources, including data collected from the IEPs, mentors and the IEP Advisory committee through focus groups and interviews. Feedback indicated that sample exam questions and practice exams were not perceived to accurately reflect the final PCE exam, and that there was a lack of detailed feedback after practice exams. Furthermore, IEPs suggested that modules were not specific enough and that IEPs were unfamiliar with terminology used within the Canadian Physiotherapy context. In response, study questions and a glossary of terms were added to each module, more complex vignette-based questions were developed, and based on the results of their exams IEPs are provided with guidance to further resources and study suggestions.Several new initiatives resulted from the interviews with IEPs, including: clinical skills lab reviews; written tutorial workshops; mobile mentors; small group mentorship; delivery of written exam modules to remote communities; and transitioning the written program to an on-line platform. In addition, the written exam preparation was transitioned to a fully on-line program, so all aspects of the module was accessible to IEPs throughout BC, across Canada and even internationally.The first step of the Program Evaluation was the formation of a program logic model followed by analysis of the outcomes defined in the model. Data for IEP candidates, all international Physiotherapy graduates, and Canadian graduates is shown for the PCE across time Table . The difSeven modules, based on the PCE blueprint and the core competencies of entry level physiotherapy in Canada, were developed and trialled.More than 500 MCQs and 22 OSCE questions were developed, reviewed and, stored in the exam bank with marking guides and patient model instructions where appropriate. This supported the administration of internal written tests and internal clinical tests.Initially 35 mentors were trained and paid for a maximum of 10 hours per IEP to provide one-on-one support and expertise during the exam preparation. The number of mentors trained was sufficient for the number of IEPs residing in the Lower Mainland of British Columbia, however, there were challenges pairing mentors with IEPs who resided out of the Lower Mainland, particularly those IEPs in rural areas. To address this, mobile and small group mentorship models were developed, which involved mentors from the Lower Mainland travelling to meet with IEPs in remote areas. This model proved to be cost effective and time efficient. In addition, higher IEP to mentor ratios , maximised the mentor time and provided a more “dynamic” session for the IEPs. Feedback from IEPs and mentors, indicated that few IEPs utilized the allocated time with mentors, and that IEPs found the other components of the program  of more benefit. The mentorship model therefore moved to self-regulated access; that is, IEPs were given contact details for mentors and were encouraged to make independent arrangements to meet with mentors according to need.The first cohort of nine IEPs was admitted into the program in July 2008. Figure Table Of the 65 IEPs taking the QE exam 65% had English as their first language, of these 63% passed the exam. Of the 35% who did not have English as their first language, 40% passed the QE. IEP candidates who have English as their first language have a non-statistically significant 58% increased risk of passing the QE, RR = 1.58 . Of the 83 IEPs taking the PNE exam, 74% had English as their first language, of these 93% passed the exam. Of the 26% who did not have English as their first language, 67% passed the PNE. For the PNE, IEP candidates who have English as their first language have a statistically significant, 40% increased risk of passing with an RR = 1.4.Of the 124 people who entered the IEP program 69 are known to have entered the Canadian physiotherapy workforce, with 34 of these known to be working in the public sector, five people are temporarily not in the Canadian workforce, due to child care or visa problems, and 20 are awaiting immigration approval for entry to Canada.The aim of the IEP Program was to create the educational tools and infrastructure needed to sustain a program supporting internationally trained Physiotherapists applying for licensure in BC. Consideration was given to developing a program that included the necessary curriculum, resources, mentorship and practice opportunities to assist IEPs in their preparation for the exams and entering the Canadian workforce. As many resources as possible were made available on-line to serve the needs of IEPs from clinical practice sites distant from Vancouver. Evaluation was built into the program to inform continuing program improvements and the development of additional program initiatives. This has resulted in the Program attracting greater numbers of IEPs than projected, and providing the flexibility to support and accommodate these greater numbers. Projections identified the capacity to support and accommodate 8 IEPs per year in the practical and 16 in the written, and over the first 4 years of the program (2008–2011), 124 IEPs have participated. The program now recovers its expenses through charging the IEPs, and although participation has declined relative to the funded program, enrolment has been sufficient to cover costs. Using a framework to build the modules, gaining regular feedback and, making the necessary changes to develop an internationally educated health professional program has proven highly successful. Only 24 health professionals (19%) who entered the program were unable to succeed in national examinations and join the Canadian physiotherapy workforce. However, these professionals may retake the examination and enter the workforce in the future. The long-term data regarding entry of IEPs into practice indicates that at least 69 IEPs, who completed the IEP Program, entered the Canadian Physiotherapy workforce, with 34 of these working in the public sector.The IEPs who participated appear to be representative of the population of Canadian immigrants; in the Canadian general populace the ratio of European to Asian immigrants is changing over time. In our population 58% of students came from the UK in 2009 and 12% in 2011, versus 10% of students from India in 2009 and 40% in 2011. The top four countries for physiotherapist immigrants practicing in Canada to have received their basic physiotherapy education, from 2007 to 2009, were UK (21%), India (15%), USA (10%) and Australia (8%) . The IEPThe primary objective of this program was to increase the pass rate of internationally trained Physiotherapists taking the PCE. The success of the program in increasing the pass rate of IEPs taking the PCE has been achieved with international graduates who took the program having a 28% greater possibility of passing the written section than their counterparts who did not take the program. The results for the clinical exam are even more impressive with the IEP program students having a 39% increase in risk of passing. A greater percentage of Canadian-educated candidates for the PCE continue to pass both elements of the PCE but the gap is closing, particularly in the clinical component. The program was developed partially due to the observation that in 2005 less than 50% of PCE attempts translated into passes in IEPs ; the stuIt may be expected that those who do not have English as their first language would have more difficulty with participating in the course and passing the exams, in particular, the written element. This appears to be false for the QE, the relative risk is 1.58 but the confidence interval is very wide, crossing 1  and is not significant. However, in the slightly larger number of people taking the PNE (n = 81), the relative risk demonstrates that those with English as their first language have a significant, 40% greater risk of passing the clinical element. The IEP success rate on the PNE indicates a slight decrease over time, when more candidates who did not have English as their first language participated.Although the IEP program targets internationally trained Physiotherapists, this model could be transferred to other health professions given the identified need to support internationally trained health professionals transitioning into the Canadian workforce , and theAs this is a relatively new program, there are not sufficient numbers of IEPs who have participated to enable sub-analyses of the data and examination of particular elements of the program. Collecting more qualitative data will allow for more in-depth analysis of the IEPs integration into Canadian practice and the impacts on acculturation and socialization.Potentially this program model could be applied to support integration of international health graduates from any background into the workforce. While this program used as a primary outcome measure improved performance on national competency examinations, many program elements also support international practitioner’s integration into the Canadian health care system and practice. Further examination of the role specific program elements may have on improving internationally educated health professional’s understanding of the cultural context of Canadian practice is needed.GP received reimbursement for her work coordinating the IEP program.AG conceived of the study and participated in its design and coordination and helped to draft the manuscript. DD carried out the analyses and drafted the manuscript. SM participated in study design and coordination. GP participated study coordination. BL oversaw study concept, design and coordination. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1472-6920/13/140/prepub


There is longstanding recognition of the striking association between ageing in humans and the incidence rates of many common types of cancer. The biological basis of this link is likely to be multi-factorial including both age-associated decline in anti-oncogenic functions, such as repair of oxidative damage to DNA, timing of etiologic exposures and/or protracted time required for accumulation of a full set of oncogenic mutations ,2.Acute leukemias have an unusual age-associated incidence with a peak at a young age (2-5 years) followed by a later increasing incidence with age in adults. In this instance, however, the biological and genetic subtypes of leukemia are distinct at different ages .BCR-ABL1 gene fusion is the result of the ‘Philadelphia’ chromosome - the first specific genetic abnormality described in cancer and which is a translocation between chromosomes 9 and 22 [BCR and generating two different sized proteins: p210 BCR-ABL1 predominantly associated with chronic myeloid leukemia and p190 BCR-ABL1 linked to B cell precursor acute lymphoblastic leukemia (ALL). Both sub-types of leukemia have increased incidence with age.9 and 22 . Two verp190 BCR-ABL1? Vicente-Dueñas et al [BCR-ABL1 expression is not activated until after the transplant.So what might be the biological basis of the age-associated incidence of B-ALL with as et al  designedBCR-ABL1. What might this be? A plausible explanation is offered in another paper recently published by Henry et al [p190 BCR-ABL1. In their case, this was performed by transfecting ‘young’ (2 months) versus ‘old’ (22-24 months) bone marrow cells with a p190 BCR-ABL retrovirus and transplanting these into recipients which were selected to provide either ‘young’ (2 months) or ‘old’ (22-24 months) competitor normal cells. They observed higher rates of leukemia (up to 200 days post-transplant) with transfer of ‘older’ cells. More rapid onset of leukemia in aged p190 BCR-ABL1 cells or more efficient leukemogenesis probably reflects more ‘target’ cells being transformed which, in turn, would increase the probability of the acquisition of secondary genetic abnormalities such as IKZF1 deletion which, at least for leukemia in patients with BCR-ABL1+ ALL, appear to be critical for malignant progression [BCR-ABL1 undergo more rapid polyclonal expansion early after transplantation.Although all mice eventually developed ALL, this result is compatible with the notion that ‘old’ B progenitors have some competitive advantage when expressing ry et al . This grry et al . In theiry et al , they algression . This ingression  that ‘olBCR-ABL1 actually has more potent selective advantage in older cells because it restores defective kinase signalling in ageing cells. They provide supportive evidence for this by showing increased expansion of young BCR-ABL1+ B cell progenitors under conditions of reduced kinase signalling via the regulatory molecule IL7 [Additionally, Henry et al  observedcule IL7 .These data are compelling but one alternative explanation might also be considered. B cell lymphopoiesis declines dramatically with age in both mice and humans and this inevitably produces substantial changes in the cellular architecture of bone marrow . TransfoWith ionizing radiation-induced ALL, children  or youngWhatever the mechanisms, or combination of mechanisms, involved, these two new papers add a new dimension to our understanding of the complexity of age-associated leukemogenesis and, perhaps, cancer in general.


NLRs and genes encoding NLR-like proteins suggest that plant and animal NLRs have independently arisen in evolution. Furthermore, the demonstration of interfamily transfer of plant NLR functions from their original species to phylogenetically distant species implies evolutionary conservation of the underlying immune principle across plant taxonomy. In this review we discuss plant NLR evolution and summarize recent insights into plant NLR-signaling mechanisms, which might constitute evolutionarily conserved NLR-mediated immune mechanisms.In plants and animals, nucleotide-binding domain and leucine-rich repeats (NLR)-containing proteins play pivotal roles in innate immunity. Despite their similar biological functions and protein architecture, comparative genome-wide analyses of  Plants rely entirely on innate immunity to fight pathogens , as theyThe mechanism of effector recognition by plant NLRs has been well established. Plant NLRs utilize two major modes of effector recognition: a direct and an indirect recognition mode –8. In boKnowledge on signal initiation and transduction mediated by plant NLRs is rather sparse compared to the effector detection mechanism. However, through recent progress in plant NLR biology, the mechanisms of signal initiation and signaling relay are gradually being revealed. Furthermore, the demonstration of interfamily transfer of NLR functions across plant lineages implies evolutionary conservation of the underlying immune mechanisms. On the following pages, we will discuss plant NLR evolution and summarize recent insights into plant NLR-signaling mechanisms, which might hint at yet unidentified, evolutionarily conserved NLR-mediated immune signaling mechanisms. Furthermore, comparative genome-wide analyses of genes encoding NLRs and NLR-like proteins among various plant lineages give insights into the presumed history of plant NLR evolution and consequently important clues to elucidate NLR functions in innate immunity and possibly functions beyond innate immunity.Similar to animal NLRs, plant NLRs are modular proteins that generally consist of three building blocks: a N-terminal domain, the central NB-ARC domain , and a C-terminal LRR (leucine-rich repeats) domain . The cenNLR repertoires, typically comprising ca. 20 members  and sea squirt , which possess 206 and 203 NLRs, respectively (Drosophila melanogaster) and nematode (Caenorhabditis elegans) apparently lack NLRs, suggesting that NLRs have been lost in these invertebrate species . This dataset was further enriched with the genomic and transcriptomic data available for 5,126 species of nine major early plant lineages . The results of this large-scale data mining imply that the core building blocks of NLRs, such as NB-ARC, NACHT, TIR, and LRR, already existed before eukaryotes and prokaryotes diverged, since these constitutive domains are also found in the genomes of eubacteria and archaebacteria surveyed  genes encoding members of an atypical CNL group also appear to be absent from the plant species lacking TNLs , summarized in Plant Resistance Gene Wiki , many “atypical” domain arrangements of plant NLRs have been reported. Some examples are TNTNL and TTNL in Arabidopsis , TNLT, Tuncatula , TNLT, Tuncatula , 90. Theuncatula , 91.CNLs and TNLs or from negative selection acting on the resulting chimeras. On the other hand, it might suggest that physical interaction between CNLs and TNLs is not functionally relevant. At least, the CNLs in monocots and some other particular plant species can function in the absence of TNLs . However a paradox would be the fact that some TNL functions are dependent on ADR1 family and also likely on NRG1 which both belong to the CNL type of NLRs (Tandem assemblies of the same domains are reminiscent of homotypic dimerization (oligomerization) that have been reported for several plant NLRs , 92–95.  of NLRs , 54. ThuNLRs are modular proteins and therefore the reverse implication of the “Rosetta Stone Hypothesis” would suggest that separated modules or “truncated” versions of NLR could still be functional proteins. Below we discuss the phylogenetic and functional analyses, which support this hypothesis.A. thaliana genome encodes 20 TNs and 27 TXs . According to the phylogenetic analysis of the TIR-encoding genes in Arabidopsis, some large families of TNs and TXs share a common origin with TNLs, but diversified independently from the TNL family  of those proteins are truncated forms of NLR . These tL family .Similar truncated forms were identified in numerous other plant species including gymnosperm species, wine grape, poplar, and rice , 96. PhyA particular family composed of atypical XTNXs was identified in Arabidopsis. BLAST searches revealed 35 homologs for these XTNXs in rice, grape, soybean, poplar, sorghum, physcomitrella, castor bean, maize, cassava, cucumis, papaya, and mimulus. These homologs have a high identity percentage. Therefore, this XTNX family seems to be highly conserved among land plants, including monocots, basal angiosperms, and magnoliids .CHS1 encodes a TN protein which confers cold resistance by limiting chloroplast damage and cell death at low temperature. CHS1 function is achieved by regulating a PAD4-EDS1-dependent and SA-independent resistance pathway like many other TNLs  possess a putative N-terminal transmembrane domain and a CC motif. This CC motif displays a high similarity with the CC found at the N-termini of a group of CNLs, sometimes referred to as RPW8-type CNLs , 100. RPNLR transcripts. This phenomenon has already been described for diverse NLRs like L6 and N  and a degenerate NB domain that completely lacks the P-loop motif  is pivotal for plant NLR function. It has been proposed that perception of the cognate effector induces an initial conformational change of the receptor, leading to an exchange of ADP by ATP at the NB-ARC domain. The ATP binding is expected to induce subsequent conformational changes of the NLR for signal initiation . This moop motif . Interesop motif . The ADRop motif , 54, 55.Altogether, these data suggest that a subset of NLRs might use an unconventional activation mechanism. Some of them also have an atypical function, suggesting that along the diversification process, some functional innovations might have arisen in these NLR families.The study of NLRs and NLR-like proteins in various plant species has revealed that some NLRs consist of domain combinations different from the classical TNL or CNL structures. Other additional domains and other N-terminal domains have been reported. We believe that these findings might help uncovering hidden interactions and mechanisms involved in NLR function.In the indirect recognition mode, the NLR detects effector-induced modifications of a plant protein, which is designated as “guardee,” a protein targeted by an effector, or “decoy,” a protein that mimics the target of an effector but does not have a clear biological function. It has been reported that different NLRs could monitor a guardee/decoy to detect different effector activities when effectors target the same guardee/decoy –8. In liA mutation in the WRKY domain of RRS1 impairs DNA-binding and induces constitutive defense activation . InteresA negative regulatory role was found for the C-terminal LIM domain  of CHS3/DAR4 , 111. OtSolanaceae often possess an extended N-terminus. This extended N-terminus frequently contains a homologous domain, called the solanaceae domain (SD)  . The SD ain (SD) . The SD ain (SD) .P. patens have a protein kinase (PK) domain [Ref.   . In addi-MAPKKK) . Unfortu-MAPKKK) . PK, MAPn tomato . The preNLR repertoires. Pathogens have evolved effectors either to increase virulence or to escape detection by the cognate NLR; in turn, plants further evolved NLRs to detect the novel effectors  functions in the eudicot plant thale cress  against barley powdery mildew Blumeria graminis f. sp. hordei (Bgh) (Pseudomonas Syringae 4) and RRS1  also confers resistance in cucumber (Cucurbitaceae), N. benthamiana, and tomato (Solanaceae)  . The MLAbidopsis . These rPseudomonas syringae and obligate biotrophic oomycete Hyaloperonospora arabidopsidis) physically associate with the same host (Arabidopsis) proteins positioning at intersections of the host protein interaction network . LOV1 is activated upon direct binding of its cognate toxin, called victorin, to a host thioredoxin related to immunity , an immediate downstream target of NOD2, resulting in reduced binding affinity of RICK to NOD2. As a consequence, NOD2 is able to form a complex with caspase-1 other than RICK, resulting in higher IL-1β production. This appears to increase the intestinal permeability for the bacterial invasion  to obtain a niche in the already established gut microbial community  mediates susceptibility to st cells . Similarinvasion . Consistinvasion . Similarommunity , suggestThus host immune response is sometimes beneficial for pathogens in plants and animals. Plant pathogens might also exploit host immune mechanisms to compete with host associating microorganisms. Plants and animals deploy an array of NLRs to fight against pathogens, whilst deployment of NLRs must be tightly balanced. Otherwise, these could be exploited by pathogens. Such a constraint might also contribute to shaping the current repertoires of NLRs in plants and animals.Apart from the host cell death response, NLR action is often associated with transcriptional changes. Here we review the emerging picture how NLRs actively participate in transcriptional regulation in plants.It has been shown that transcriptional differences in resistant vs. susceptible interactions are rather quantitative than qualitative in several cases. This implies that NLRs amplify or sustain defense-related gene expression mediated by pattern-recognition receptors , 143–147Pseudomonas Syringae 2) and RPM1 (Resistance to Pseudomonas Syringae pv Maculicola 1) results in transcriptional reprograming  were examined. A genetic and biochemical screen identified a group of Ca2+-dependent PKs , acting as signaling mediators between the NLRs and the transcription factors WRKY8, WRKY28, and WRKY48. Those WRKYs are proposed to regulate gene expression downstream of RPS2 and RPM1. Notably, another group of CPKs (CPK1 and 2) appears to be involved in host cell death response rather than transcriptional reprograming, suggesting the existence of a bifurcated CPK-dependent signaling pathway mediating distinctive NLR-triggered immunity outputs . However, it still remains unclear how RPS2 and RPM1 activate the set of CPKs. So far, a direct interaction between the CPKs and RPS2 or RPM1 was not detected  is compromised . Similarthamiana . Disrupteffector . Togethecis-element. The MLA10-HvMYB6 complex, in turn, greatly enhances transcription downstream of the cis-element compared to HvMYB6 alone in a transient assay. While this interaction greatly adds to our understanding of MLA function in barley, it cannot explain the conserved function of MLA1 in Arabidopsis  in thamiana . The assilencing .Close re-examination of yeast-two-hybrid data generated by Mukhtar et al.  providescis-elements and recruiting a group of transcriptional regulators  in its inactive state was resolved . The strThe LRR domain of plant NLRs is also involved in forming “security locks” by cooperating with the other domains in the absence of pathogens , 163–166NLRs in various species. Whole-transcriptome analysis at single transcript level combined with ChIP-seq analysis (chromatin immunoprecipitation followed by sequencing) allows to uncover underlying mechanisms for NLR functions in the nucleus. Furthermore, structural biology provides in-depth understanding of mechanistic insights into NLR actions. Nevertheless, a balanced combination of those technologies and “classical” genetics and biochemical studies are important to unravel the principle of NLR functions.Over the past few decades, many NLRs and NLR-like proteins were isolated from plants and animals and their functions have been extensively studied. The development of new technologies has further accelerated research on NLR biology. For example, deep sequencing technology offers more opportunities to conduct comparative genome-wide analyses of As we discussed above, a plant NLR might initiate downstream signaling by connecting to multiple signaling targets rather than through a single evolutionarily conserved target. Despite a lack of direct experimental evidence to date, putative compartment-specific activities of plant NLRs, particularly in the cytoplasm and nucleus , 167, suThe 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.


Increased competition for research funding has led to growth in proposal submissions and lower funding-success rates. An agent-based model of the funding cycle, accounting for variations in program officer and reviewer behaviors, for a range of funding rates, is used to assess the efficiency of different proposal-submission strategies. Program officers who use more reviewers and require consensus can improve the chances of scientists submitting fewer proposals. Selfish or negligent reviewers reduce the effectiveness of submitting more proposals, but have less influence as available funding declines. Policies designed to decrease proposal submissions reduce reviewer workload, but can lower the quality of funded proposals. When available funding falls below 10–15% in this model, the most effective strategy for scientists to maintain funding is to submit many proposals. At the U.S. National Science Foundation (NSF), 96% of funds are awarded through a competitive merit review This increased competition for limited resources has established the scientific equivalent of the famous problem in game theory known as the Prisoner's Dilemma Under what conditions is submitting as many proposals as possible an inefficient strategy? How do selfish or negligent reviewers affect the peer-review process To explore these questions, we employ an agent-based model of peer review and funding, modified from N scientists is composed of two evenly sized groups. Group 1 (G1) produces one proposal every two time units (split randomly between those times), whereas group 2 (G2) produces a proposal every time unit. We set a time unit to six months, award length to three years, and all grants to equal value. G1 scientists who obtain funding do not submit new proposals until the final year of the grant. In contrast, G2 scientists continue to submit grant proposals regardless of their funding status. We assume that the quality of an individual scientist (Qs) follows a normal distribution with mean 100 and standard deviation 10. Each scientist produces proposals of variable quality Qp, which are drawn from a normal distribution with mean Qs and standard deviation 5. These characteristics are identical in both groups.In this system, proposal development is modeled as follows . A commuK independent reviewers, randomly chosen by the program officer of the funding agency from the N–1 available scientists . No limits are placed on the number of reviews that a scientist can conduct. The reviewers recommend to the program officer either to fund or to decline. Each reviewer is one of three types: correct, harried or selfish. The correct reviewer recommends funding only for high-quality proposals, defined as those exceeding a minimum threshold . The harried reviewer behaves like the correct reviewer, but assesses proposal quality imperfectly. This assessment is modeled as a normal distribution with mean Qp and standard deviation 5; that is, the assessments are correct in the mean but not necessarily on a case-by-case basis. Finally, selfish reviewers recommend declining a proposal that is either superior to their own work or below a minimum quality . Thus, a low-quality scientist who is a selfish reviewer might recommend rejection of nearly all proposals considered, whereas a very high-quality scientist but selfish reviewer would recommend rejection of relatively few high-quality proposals.Proposal review is then modeled . Each prNext, the funding decision is modeled . The annQp and thus can precisely rank proposals. The reputation-based program officer is a correct program officer who substitutes quality of the scientist Qs for Qp in the rankings. The model logic detailed in The decision to fund reconsidered proposals is made according to one of two program-officer types: correct or reputation-based. The correct program officer has perfect knowledge of To start, we form a perfect scenario in which all reviewers and the program officer are correct, and for which there are no external funding limits , case a.Next, we form a baseline case with a mix of reviewers  and a target funding rate of 15% , case b.The decisions by the program officer (number of reviewers and program officer type) determine the outcome of many proposals at NSF, where about 25% of funding decisions are made by the program officer contrary to the reviewer recommendations Counterintuitively, imperfections in the review process are also key. The presence of non-correct reviewers retards the effectiveness of the G2 strategy, especially when program officers use more reviewers and require unanimity . If, howThe quality of funded proposals is also sensitive to the reviewer mix for G1 and G2, as suggested in actual funding data Qp for G2) increase G2's share of the funding, whereas negative feedbacks (a 5-point drop in Qp for G2) do the opposite , whereas limiting G2 scientists to one funded grant substantially reduces G2's share of funding and success rate , case f.Funding agencies also have tried to decrease the number of proposal submissions through other means. For example, the U.K. 's Engineering and Physical Sciences Research Council (EPSRC) bars proposal submissions from scientists for 12 months if, in the preceding two years, they have had at least three proposals ranked in the bottom half of a funding prioritization list or were rejected by a panel review and have an overall success rate of less than 25% Our results emphasize the importance of the program officer's approach and funding agency's rules, which can vary substantially across divisions within the same agency and over time . This is consistent with recent research that suggests that optimal decision-making is a complex interaction of factors including the number of judges, the accuracy of those judges, and the decision rules used Highly capable research clusters may profitably and efficiently choose to submit many proposals, which may or may not be tolerable from the perspectives of science and society because of the increased proposal burden and possibly lower-quality funded research


Public education is one of the most important elements of earthquake preparedness. The present study identifies methods and appropriate strategies for public awareness and education on preparedness for earthquakes based on people's opinions in the city of Tehran.				This was a cross-sectional study and a door-to-door survey of residents from 22 municipal districts in Tehran, the capital city of Iran. It involved a total of 1 211 individuals aged 15 and above. People were asked about different methods of public information and education, as well as the type of information needed for earthquake preparedness.				"Enforcing the building contractors' compliance with the construction codes and regulations" was ranked as the first priority by 33.4% of the respondents. Over 70% of the participants (71.7%) regarded TV as the most appropriate means of media communication to prepare people for an earthquake. This was followed by "radio" which was selected by 51.6% of respondents. Slightly over 95% of the respondents believed that there would soon be an earthquake in the country, and 80% reported that they obtained this information from "the general public". Seventy percent of the study population felt that news of an earthquake should be communicated through the media. However, over fifty (58%) of the participants believed that governmental officials and agencies are best qualified to disseminate information about the risk of an imminent earthquake. Just over half (50.8%) of the respondents argued that the authorities do not usually provide enough information to people about earthquakes and the probability of their occurrence. Besides seismologists, respondents thought astronauts (32%), fortunetellers (32.3%), religious figures (34%), meteorologists (23%), and paleontologists (2%) can correctly predict the occurrence of an earthquake. Furthermore, 88.6% listed aid centers, mosques, newspapers and TV as the most important sources of information during the aftermath of an earthquake, Discussion: A participatory approach to earthquake-preparedness planning is recommended. This would ensure that program planners use methods, tools, media, and educational materials that are compatible with the culture, needs, and skills of the local communities.		         The findings of this study also reveal methods and tools that the local community considers to be most effective for earthquake-preparedness planning and management. The development of an earthquake-resistance and a safe community requires a high level of collaboration between broadcasting organizations, seismologists, experts in the disaster- preparedness field, as well as the local community. This will allow for timely planning, development, and dissemination of essential information to all stakeholders including the local communities.		 Indeed, in the past few centuries, Iran has endured quite a few large and destructive earthquakes. In a recent World Disaster Report, Iran was cited among the countries which have suffered the highest number of casualties from earthquakes.2 Although a society is an amalgamation of various stakeholders, when a natural disaster strikes, three groups of stakeholders are most impacted: the authorities, the experts, and the general public . Each of these entities can play a crucial role both during and in the aftermath of a natural disaster. Therefore, they all can benefit from disaster-preparedness planning. However, research shows that in disaster-preparedness planning, the roles and functions of the local communities are often not taken into consideration or are given lower priority.3 The extent to which disaster-preparedness programs fall short in engaging communities in pre-quake preparedness activities results in an increase in the local community’s likelihood of suffering from physical, financial, and emotional injuries, post-quake.4 Therefore, in providing effective disaster-preparedness programs, planning should be based on a periodic needs-assessment of the communities at risk. This will allow planners to consider knowledge, attitudes, behaviors, and skills of the at-risk communities in preparedness goals, designs, activities, and expected outcomes.Worldwide, evidence shows that there is an upward trend       in the number of people who are impacted physically, socially, and economically by the threats of natural disasters.5 For example, in the first hours after a natural disaster, due to the delay in transferring vital information; interruption in electronic communications; difficulties in accessing the affected areas; and organizing and mobilizing the aid forces, a considerable amount of time is wasted before the mobilized forces can reach the affected areas. At this time, commonly referred to as the “golden hours”, the survivors and the local residents are among the first who can help the injured effectively.6 During any natural disaster, the vulnerable and affected communities are the center of considerable attention.Community-based disaster-preparedness programs can play a major role in training people to facilitate mobilization of aid across the affected areas. These programs should strive to deliver training materials that are in tune with the needs of the community members and are culturally sensitive and appropriate in content and design. Also, training in preparedness activities should be sensitive to the participants’ socio-demographic characteristics as well as their religious affiliations. Hence, identification of the means by which, and the mechanisms through which, culturally sensitive and appropriate training materials and activities can be delivered to the people in the communities are important steps in designing an effective community-based disaster-preparedness program.Therefore, the specific aim of this study was to assess knowledge and attitudes of a sample of residents in Tehran in respect to what they consider to be an appropriate means and strategies for designing and delivering community-base earthquake-preparedness programs.Sample and procedureThis was a cross-sectional survey study conducted in 22 municipal districts in Tehran, the capital city of Iran. Participation in the study was voluntary and providing written consent and being 15≥ years old were the only inclusion criteria for the eligibility in the study. The study sample was interviewed over a period of four weeks. Cluster sampling was used in which the clusters were drawn systematically. A semi-structured questionnaire was developed by the members of the research team and was pilot-tested before its full implementation. Consented participants were interviewed by trained study interviewers on the door-step of their homes. The questionnaire included items related to knowledge and attitude of participants concerning issues related to earthquake-preparedness-training programs.MeasuresFor the purpose of the current study, participants’ responses to the following questions were selected and described, from the main study questionnaire.1.What measures should authorities or governmental organizations and agencies take to prevent earthquake-related causalities, assuming that eventually there will be an earthquake in Iran? Respondents were asked to prioritize their responses based on the following response categories: a) they should enforce the building-contractors’ compliance with the construction codes and regulations; b) they should increase manufacturing and use of earthquake-resistant buildings supplies; c) they should increase communities’ earthquake preparedness knowledge and awareness by means of mass media communication; d) they should provide regular earthquake-preparedness training opportunities for the members of the communities to participate and practice test drills; and e) they should assist members of the community to identify safe locations at home, in the neighborhood, and at work to be used as shelters in the event of any earthquake.2.What types of media and what kinds of training and educational materials would you prefer to use to prepare yourself for an earthquake? Respondents were asked to prioritize their responses based on the following response categories: a) TV and radio; b) newspapers and magazines; c) flyers and posters; d) training workshops/classes; e) pamphlets; and f) videos, films, and /or an internet.3.During the past 12 months, have you heard any “gossip” or “news” about the possibility of an upcoming earthquake in Iran? (Yes/No).4.What was the source of this information? Response categories included: a) general public; b) TV; c) newsletters and magazines; d) radio; e) internet; f) academic institutions like universities and research institutes.5.Which means of communications do you think are the most important for receiving news about the possibility of an earthquake?6.What means of communications do you think are the most effective for receiving news/information during the aftermath of an earthquake?7.Other than seismologists, who else do you think can correctly predict the occurrence of an earthquake?8.During the aftermath of an earthquake, how can people access or obtain necessary information to properly deal with this disaster?The respondents to the questionnaire included 1211 residents of Tehran comprising of 623 women (51/4%) and 588 men (48/6%). The age group for the men ranged from 15 to 100 years old (Mean= 37.3), and for the women it ranged from 15 to 84 (Mean= 34.5). The majority of the respondents had less than high school education (38.7%), and were married (60.9%) The overwhelming majority of the respondents (95.1%) said they have heard either on the news or through some gossip that there would soon be an earthquake in the country. When respondents were asked what means of communication they consider to be the most effective to deliver news/information about the aftermath of an earthquake, 70% endorsed news media in general. However, over fifty percent (58%) of the participants believed government officials and agencies are responsible for disseminating pertinent information about the possibility of an imminent earthquake. But 50.8% believed these agencies and organizations do not fulfill their responsibilities proficiently and effectively, and therefore, people are not provided with enough information in order to prepare them for an earthquake.In addition to seismologists, respondents thought astronauts (32%), fortunetellers (32.3%), religious figures (34%), meteorologists (23%), and paleontologists (2%) could correctly predict the occurrence of any earthquake. Furthermore, 88.6% listed aid centers, mosques, newspapers and TV as the most important sources of information during the aftermath of an earthquake.Several points can be deduced from the results of this study:8 Earthquake-preparedness programs that are sensitive to the needs of the local community members can mobilize their efforts to develop their skills and capacities for dealing with any natural disasters.12First, in any disaster-preparedness planning, it is important to take into account the local community’s input. This will allow programmers to recognize local communities’ needs and capacities, thereby matching training materials and activities in ways that would address pertinent needs of the communities.14 Although modern public health models offer a different perspective, they still assume individuals are rational beings and if provided with information they will behave rationally by avoiding risk and taking preventive actions.16 The authoritative nature of this model encounters much resistance from the communities to participate wholeheartedly in the innovative programs.18As long as communities are viewed as passive consumers of pre-packaged programs, often prepared by the experts, there will be less success in any health promotion activities or interventions.20 Participatory processes are not entirely new in disaster management.21 A participatory approach to earthquake-preparedness planning allows program planners to use methods, tools, media, and educational materials that are compatible with the culture, needs, and skills of the local communities.21Participatory theories and approaches, on the other hand, strive to take into account local communities’ culture and strengths, and build on their available assets while strengthening them by building a trusting relationship and mutual commitments.Second, the findings of this study, although preliminary, nonetheless reveal methods and tools that the local community considers to be most effective in earthquake-preparedness planning and management. As noted earlier, participants in this study believe that government organizations and agencies should take a more proactive role in ensuring the building contractors’ compliance with the construction codes. Also the overwhelming majority of the participants believed that TV and radio are the most appropriate sources of media communication to prepare them for an earthquake. Nearly everybody in the study believed that an eventual earthquake is inevitable (95%). Furthermore, approximately three-quarters of this sample considered the media as the source from which news about earthquake should be disseminated to the public.Third, a community needs-assessment can inform the program planners, developers, and broadcasting organizations about where, what type of program, which day of the week, and what time of the day, earthquake-preparedness programs are most preferred to be implemented or broadcasted. Active participation of the local community in the design and production of earthquake-preparedness educational materials and programs helps the experts to customize their methods for the delivery of news, information, and educational materials in such a way that they represent the local people’s needs and situations. It will also empower the local community and help institutionalize such programs after the experts leave the community.Fourth, regarding all aspects of earthquake preparedness management, and injury prevention, television with its wide coverage can be considered as an appropriate media for disseminating pertinent information. Cartoons, regularly scheduled programs and shows, as well as brief announcements are among various types of TV programming which could be used at many levels: national, regional, and local. In addition to TV, local radio stations should be equipped with sufficient financial and support systems to disseminate earthquake-related information to the communities where access to TV and internet is more limited . This is especially important, since TV broadcasting can be interrupted during an earthquake. Adding a weekly column in the most popular newspapers regarding earthquake preparedness and management would also be useful for the public. In addition, culturally sensitive disaster-preparedness videos films and CDs can reach various groups of society.Fifth, the development of earthquake-resistance and a safe community requires a high level of collaboration between broadcasting organizations, seismologists, experts in the disaster-preparedness field, as well as the local community. This will allow for timely planning, development, and dissemination of essential information to all stakeholders including the local communities.Last but not least, proper and timely process evaluation of the earthquake-preparedness programs can inform all stakeholders in charge of such programs of how communities are struggling with the initiation and sustainment of disaster preparedness programs. Long-term evaluation of these programs can highlight changes in the community’s knowledge, attitudes, behaviors, and skills related to disaster preparedness. It also can show the long-term effectiveness of setting up and equipping the local community to be in charge of, lead, and sustain such programs.Although limited in design and analysis, we nevertheless hope that this study will inspire other researchers to further study and provide a better understanding of people’s perspectives on earthquake-preparedness planning. Such understanding is important for the development and monitoring of earthquake-preparedness programs and proper allocation of available resources.


From its inception in 1997, the ACR/EULAR exchange program (AEEP) has brought young rheumatologists together from Europe and the USA. Over 40 junior physician-scientists and their respective senior rheumatologist mentors have travelled across the Atlantic Ocean to meet with and discuss science, medicine, and clinical practice patterns with their counterparts on the opposite side of the Pond. The format for the program of attending either the ACR Annual Scientific Meeting (the European colleagues) or the EULAR meeting (the American colleagues) followed by visiting several outstanding academic institutions in the week subsequent to the meeting has remained virtually unchanged since the beginnings of the AEEP , and, pNotable spin-offs from the AEEP that have also been quite successful have been the yearly AEEP Study Group sessions held at the ACR Annual Scientific Meetings and the corresponding "Forum for Young Rheumatologists" at the EULAR meetings. Because the AEEP group as a whole has a broad spectrum of research interests and scientific approaches this has allowed for a rather varied group of rheumatology related topics in these special sessions each year. The symposia have allowed for talks from the AEEP young investigators alongside lectures from invited experts in the field of study for the particular topic of that year's AEEP Study Group and Forum for Young Rheumatologists' meeting. Previous topics and speakers in the recent past have included the following: "Synoviocyte and NK T Cell Signaling" with Drs. Gary Firestein  and Mitchell Kronenberg (La Jolla Institute for Allergy & Immunology), "Regulatory T Cells and Autoimmunity" with Drs. Ethan Shevach  and Berent Prakken , "Aging and Autoimmunity" with Drs. Bruce Richardson (University of Michigan) and Cornelia Weyand (Emory University), "Endothelium and Autoimmunity" with Drs. Ulrich von Andrian (Harvard University) and Umar Mahmood (Harvard University), and most recently, "Interleukin-1 and Related Molecules" with Drs. Hasan Yacizi (University of Istanbul) and Cem Gabay , as well as "B Cell Targets in Rheumatology" with Dr. Peter Lipsky (formerly at the NIH). Whether or not the AEEP continues on as originally intended (as an exchange program), it is likely the study group sessions will continue for the excellence of the content presented by the junior and more senior lecturers.If the ACR and EULAR decide to re-establish the exchange program portion of the AEEP, the success of the venture will continue to rely heavily on the quality and enthusiasm of the selected junior faculty physician-scientists, but will also be dependent on outstanding host faculty and institutions. Some 14 years after its implementation there have been no less than 16  of its approximately 40 AEEP "junior" faculty participants who have proceeded to rheumatology directorships at prestigious institutions in the USA and Europe. From the American side, a disproportionate number of pediatric rheumatologists  have benefited from this program, and all have gone to directorships. This degree of academic success may in part reflect the selection process for participation in the exchange program but also likely demonstrates the benefits accrued from participation. The exchange program likely would have benefited from involvement of pediatric rheumatologists from Europe, as well as pediatric rheumatologists serving as senior faculty participants. Moreover, most all the former junior faculty AEEP participants, both adult and pediatric rheumatologists, have gone on to highly successful academic careers and have taken on leadership positions in rheumatology spanning the Atlantic Ocean as the founders of the AEEP could only have hoped for when the program was first contemplated. This seems to have been a rather strong return on investment for the ACR and the EULAR.If, on the other hand, the American/European exchange portion of the AEEP comes to an end, it was the privilege of all the former participants to have been involved in this ambitious endeavor. For most all participants, junior and senior scientists alike, participation in the AEEP was a stepping stone to further and greater academic success, a camaraderie of sorts, a source of many and varied rich scientific collaborations, and, if nothing else, a conduit to long lasting friendships bridging the Atlantic Ocean.