Preparing a successful research proposal is one of the most complex skills required of professional scientists, yet this skill is rarely if ever, taught. A major goal of the National Research Mentoring Network (NRMN) in the United States (U.S.) is to support the professional advancement of postdoctoral fellows and junior faculty from diverse populations by offering intensive coaching in the development of grant proposals early in their careers. This article highlights the National Institutes of Health’s (NIH) NRMN initiative to prepare diverse constituencies of early-stage biomedicine scientists for research careers by implementation of an evidence-based nationwide program of comprehensive grant writing and professional development.NRMN delivers four unique but complementary coaching models: the Proposal Preparation Program from the University of Minnesota (UMN); Grantwriters Coaching Groups from Northwestern University (NU); Grantwriting Uncovered: Maximizing Strategies, Help, Opportunities, Experiences from the University of Colorado Anschutz Medical Campus (UC) and Washington State University (WSU); and Steps Towards Academic Research from the University of North Texas Health Science Center (UNTHSC). Because these programs cater to scientists at different career stages, rather than employ a single approach, each is uniquely tailored to test its efficacy at the national level. The first two models prioritize scientists with reasonably well-developed research projects who are ready to write proposals for specific NIH research competitions. The other two models target postdoctoral fellows and early-career faculty who need more extensive guidance in proposal development plans. To achieve scalability, all programs also recruit faculty as Coaches-in-Training to learn approaches and acquire particular group facilitation skills required by each model.These efforts exemplify NRMN’s potential to enhance the career development of diverse trainees on a national scale, building research skills, competitiveness for obtaining faculty positions and capacities that will result in high quality research proposals from a diverse pool of applicants, thereby advancing innovations in science and diversifying the U.S. biomedical workforce. Specific demographic groups defined by NIH are underrepresented in biomedical science careers in the U.S. , 2. ThesCareer advancement for most research faculty is measured by their ability to obtain external funding support. This situation is particularly critical for tenure-track faculty, for whom the acquisition of NIH-level funding is often a requirement for promotion and tenure. One might argue therefore, that underrepresentation at the faculty level is likely further exacerbated by the discrepancy in rates of NIH funded research awards. In 2011, Ginther and colleagues confirmed a long-suspected disparity between racial minority groups and their White counterparts in terms of receipt of NIH research funding . In 2016One component of NRMN is the professional development of mentees and coaches. To this end, NRMN delivers four complementary coaching models: The Proposal Preparation Program (NRMN-P3) at the University of Minnesota (UMN), Grantwriters Coaching Groups at Northwestern University (NU), Grantwriting Uncovered: Maximizing Strategies, Help, Opportunities, Experiences (GUMSHOE) at the University of Colorado Anschutz Medical Campus (UC) and Washington State University (WSU), and Steps Towards Academic Research (NRMN-STAR) at the University of North Texas Health Science Center (UNTHSC). The following sections detail the creation and national dissemination of these intensive grant writing and coaching programs. Each is designed to provide diverse postdoctoral researchers and early-career faculty investigators with substantive innovative training and specialized mentorship to support the development of high-quality research proposals.Crafting successful research proposals is among the most daunting and complicated skills to master, one that most investigators struggle to acquire and hone during the initial years of their academic appointments. Mentors can be valuable resources in modeling grant writing practices. However, many junior faculty do not have access to mentors with enough time to work with them to develop this essential competency; moreover, the degree to which mentors can or do teach grant writing skills is extremely variable.In the past, NIH has tried to address this problem by providing grant writing workshops and other short-term professional development opportunities to early-career investigators. Many grant writing programs offer seminars; and some provide structured curricula spanning one or 2 days. However, the design and preparation of competitive research proposals require months of effort and iterative feedback from funded scientists, and grant writing skills often vary by career stage. This is particularly relevant for URM scientists who often have greater need for such development due to limited access where they are trained as well as poor resources to which they can connect –9. Thus,Achieving a diversified biomedical research workforce requires grant writing and professional development activities with proven success on a national scale. A key innovation of the four NRMN programs is their integration of a “Coaches-in-Training” approach to expand their reach. There are very few studies of intensive interventions like career coaching in grant writing and professional development –12. ThisEach of the four programs grew out of proven success in training early-stage investigators in grant writing and professional development at its home institution from which NRMN adopted a core of shared elements and unique practices from each in the creation of an inclusive approach to grant training. NIH supports a wide variety of designated research-related programs specified by project type, investigator initiated, budget allowed, length of research program and other additional criteria . Two pro(P3) are derived from traditional models of peer writing and review. A small cohort of 10–14 participants follows a prescribed schedule to write and revise drafts of major sections of their own proposals, and then convenes at regular intervals to receive feedback on their work-in-progress from three to five skilled coaches  and from one another. Over the program’s lifetime, 20 cohorts have been trained, comprising more than 200 UMN investigators. Funding rates for these participants have ranged from approximately 20% to 40% per cohort – laudable outcomes in the context of significant budget reductions over the past decade at federal agencies and foundations. Given its success and popularity, the program has become a training requirement for all UMN faculty who receive significant funding for research career development from the university’s Clinical and Translational Science Institute KL2 Program and from the Building Interdisciplinary Research Careers in Women’s Health K12 Program [NRMN-P3 was adapted from a program at the UMN Medical School developed in 2007 by Dr. Richard King and Dr. Anne Marie Weber-Main. It originated as a 10-session in-person faculty development program in the Department of Medicine, and has since expanded to a thrice-yearly program, timed to coincide with standard NIH application deadlines. Enrollment is open to faculty investigators in the six schools and colleges within the university’s Academic Health Center. The structure and format of the Proposal Preparation Program  Program , 16.For the NRMN adaption of the UMN-P3, which was designed for researchers preparing their first major NIH research proposal, participants are expected to enter the program at the “ready to write” stage – that is, with reasonably well-developed scientific ideas, sufficient preliminary data, and the first draft of a Specific Aims page . This expectation helps to temper the false starts observed among participants who have not fully developed their planned approach or are still waiting for preliminary data to inform key aspects of their proposals. Participants are also asked to identify a local content mentor at or near their home institution (or a mentor from a previous training experience) who can offer discipline-specific input during proposal development.The program begins with an intensive two-day, in-person workshop. To prepare for the workshop, participants are asked to critically read and comment on a draft of a Specific Aims page and a biosketch  submitted by another participant. On arrival, they immediately engage in the group review process. Program coaches and Coaches-in-Training facilitate group review and offer their own feedback. Afterward, participants attend individual coaching meetings to discuss their drafts in more detail. The workshop agenda is rounded out with didactic sessions  and two interactive panel discussions. The first features recently funded early-stage investigators, who share their stories of persistence and lessons learned on the road to funding; the second features well-funded senior investigators, who offer their perspectives on how to interpret and respond to reviewer critiques in NIH Summary Statements.NRMN-P3 training continues over the next four to 5 months in the form of seven virtual group review sessions conducted by videoconference. Participants deliver an oral critique of one of their peers’ drafts, drawing from guidance provided in writing rubrics and templates for Summary Statements. This process gives participants experience as reviewers while providing writing examples to emulate. It also fosters deeper connections within the cohort, creating the potential for future interdisciplinary and cross-institutional collaborations. Coaches provide oral critiques at each meeting, attending to each project’s scope, methodological rigor, and anticipated impact, as well as to its prose and presentation. Their explicit focus is helping trainees understand how to meet reviewers’ expectations for detail and clarity. Participants and coaches are encouraged to share more detailed written critiques or suggestions for revision by email. Peer review assignments are rotated within the group so that, over time, each participant can hear the perspectives of a range of reviewers. Participants’ local content mentors are also asked to attend two of these videoconferences so they can discern how the proposals might be perceived by researchers in disparate fields and assist participants with revisions between meetings. This schedule is ambitious, as it is designed to keep participants writing and revising well ahead of their submission deadlines. The program culminates in a formal review of completed drafts in the manner of an NIH study section. Reviewers for this event are solicited through recommendations by the participants and their local content mentors, or by inviting senior investigators who have applied to serve in this role through NRMN.Coach training in NRMN-P3 occurs largely through real-time engagement with a cohort of mentees in collaboration with current coaches. The lead coaches strive to model desirable coaching behaviors. These include 1) bringing attention to common proposal criticisms that reviewers articulate during study section meetings; 2) prompting participants to include the specific details expected in the Approach and Training Plan sections of specific grant mechanisms or study designs, as these are often neglected by less experienced applicants; 3) identifying gaps in logic within the proposal narrative; 4) balancing honest criticism with appreciation for participants’ scientific ideas and writing progress; and 5) tailoring feedback to match participants’ skill level.The conceptual and practical aspects of the NU Grant Writers Coaching Groups have been in development since the late 1990s. At that time, Dr. Richard McGee began looking for better ways to assist young investigators with grantwriting at the Mayo Clinic College of Medicine, which traditionally offered only day-long seminars. The core design elements of the Grant Writers Coaching Groups have been refined gradually since then, and in 2008 became the linchpin of research-related faculty development in the Feinberg School of Medicine at NU. Since 2008, more than approximately 300 junior faculty and postdoctoral fellows have engaged in some way with this novel group process. Writing groups begin every 4 months, and participants are encouraged to start even if they are unsure of their readiness to write. Over the years, about 40% of those who start in a group continue through proposal submission, and of those, about half are successful either with first or subsequent revised applications. Additional evidence of the effectiveness of this approach appears in the high rate of repeat participants and in word-of-mouth advertising from past participants to promote new enrollment. This model has also been successfully replicated and expanded in collaboration with the Association of American Medical Colleges through their annual Minority Faculty Career Development Seminar.The NU model emphasizes sustained coaching over a three- to four-month period, offering trainees substantial practice in using the terminology and rhetorical patterns typically found in NIH-style proposals to convey key messages. A significant strength of this model is the ongoing work of the writing group, which engages in an intense and iterative process in real time, offering immediate, constructive feedback on successive drafts of each trainee’s proposal. The program begins with a one- to two-day session that provides an overview of the peer-review processes used by NIH, followed by an introduction to a series of online tools developed to guide grantwriters through each part of their proposals. The rest of the inaugural session is devoted to reviewing a draft Specific Aims page from each participant. Central to this model is oral feedback, led by the coach, which is not a critique but a review of the thought process triggered in the coach by each word, sentence, and paragraph in the draft. The dialogue and feedback that result are far richer than those typically achieved when a reviewer provides written comments. In addition, the group model enables participants other than the author of the draft under review to benefit from the process. They quickly begin to provide their own input as they practice the behavior modeled for them. The entire conversation is audio-recorded and sent to the author to use during revisions. After the initial in-person session, the writing group meets every one to 2 weeks by videoconference, employing the same process used in the in-person session. In most groups, at least three videoconferences are devoted to the Specific Aims page, a foundational component of proposals that must create a logical and scientific roadmap for the rest of the proposal. This focus enables simultaneous consideration of issues in prose construction, logical argumentation, and research design. A similar process continues for the Significance, Innovation, and Training components of other grant applications. Writing groups usually bring less attention to the Approach section unless they have the detailed scientific knowledge to give appropriate feedback. Over a three- to four-month period, this model allows for rich, ongoing discussions of the major sections of each trainee’s proposal. As needed, the group process can be further enriched by one-on-one sessions involving the coach and each trainee. In addition to facilitating the learning needed to master grantwriting, the group model encourages camaraderie among its members, potentially mitigating the feelings of isolation and insurmountable barriers that are often experienced by early-stage scientists.As Coaches-in-Training, faculty with extensive experience writing and reviewing proposals rapidly develop the abilities needed to lead a group and employ oral and written feedback in an iterative process. Training in these skills is provided before any groups meet, so that new coaches can observe the approach modeled in an actual writing group during its initial in-person session. After the short experience of observing, new coaches are ready to adopt the model and take over their own groups right away. Additional guidance, as needed, is available to them from the model’s designer. In this way new coaches gain the knowledge and experience necessary to lead future cohorts. Among the most important facilitation skills that they acquire is how to balance peer-to-peer advice on a trainee’s proposal with expert critique. To date, more than 55 coaches have been trained in this model. They have led more than 50 groups comprising 190 postdoctoral researchers and junior faculty. By the end of 2016, 10–15 additional groups will be initiated with approximately 60 new participants and 12–15 new Coaches-in-Training.Originating at the University of Colorado Anschutz Medical Campus (Dr. Spero M. Manson) and Washington State University , and initially offered in 2015, GUMSHOE springs from innovative best practices developed in the Native Investigators Development Program. The latter effort has been funded by NIH for the past 20 years, and has achieved remarkable success in increasing the number of American Indian and Alaska Native PhDs and MDs who obtain NIH research funding –19. SincGUMSHOE is offered twice per year. Each program cycle lasts 6 months, and each program cohort is limited to 25 participants who are supported by 8–10 coaches. To optimize participant/coach interactions and coordinate workshop emphases, each program cycle focuses on conducting NIH-sponsored research with a specific health disparities population or populations. These include 1) American Indians, Alaska Natives, Native Hawaiians, and other Pacific Islanders; 2) African Americans; 3) Hispanics/Latinos; 4) rural residents; and 5) other NIH-specified populations, as resources permit [After they are selected for the program, through a multi-step process involving an application, letters of reference, a writing sample, and an interview, GUMSHOE participants are required to complete an online writing class. The curriculum involves completing exercises on writing the Specific Aims page of an NIH proposal; drafting and submitting their own Specific Aims page; and watching videos on the NIH process for proposal review. Mentees receive at least one round of extensive feedback regarding the Specific Aims submitted at the time of application, and must revise said aims accordingly prior to the initial meeting. Each participant is also assigned to a GUMSHOE coach by the two program directors .After completing the online class, participants attend a three-day, in-person workshop that formally launches the program. The workshop introduces participants to one another and to their coaches, and includes didactic, experiential, and small-group work. Didactic elements focus on research support mechanisms, funding trends, key elements of application format and content, criteria for the multi-stage NIH review process, and common errors in preparation. Experiential components help participants select research questions that are amenable to investigation and that reflect the interests of potential sponsors as well as individual GUMSHOE participants. Once an appropriate question is chosen, workshop emphasis shifts to the process of crafting a well-articulated, persuasively written, logically consistent Specific Aims page as the cornerstone of the proposal. Small-group work involves frequent discussions that constructively critique each iteration of each participants’ Specific Aims in terms of clarity, logic, organization, and feasibility. Numerous examples of Specific Aims pages from previously funded applications are offered as models to emulate. Each participant then collaborates with his or her coach on establishing an individualized work schedule to draft, revise, and complete a full proposal over the remaining 6 months of the program cycle. Schedules typically include at least two 30-min telephone conferences per month.Four key features of GUMSHOE distinguish this approach from other, similar offerings. First, during the three-day workshop, several senior methodologists circulate among participants and coaches to consult on features of participants’ study designs that are essential to addressing the research question proposed in the Specific Aims. Such features include the overall approach, sampling methods, and analytic plans. This early direction is especially effective in moving participants toward feasible, scientifically rigorous approaches and making proposal preparation more efficient. Second, the GUMSHOE workshop includes a 1.5 h interactive webinar that features a panel of three NIH Grant Program Officials (GPOs) who describe their respective journeys to service at NIH, review the nature and extent of their duties and responsibilities, and offer concrete strategies for when and how applicants should communicate with Program Officers. Their richly illustrated presentations are followed by wide-ranging question-and-answer sessions during which participants can introduce themselves and explore topics specific to their circumstances. Third, after each participant’s Specific Aims page is carefully vetted by the coaches, the program directors forward these pages – along with brief descriptions of participants’ interests, institutional affiliations, potential NIH Institutes or Centers, and preferred funding mechanisms – for review by a small, committed contingent of NIH grant program officers (GPOs). Their review attempts to ensure optimal alignment of the proposed work with the funding emphases of appropriate NIH units, and identifies responsible GPOs within those units. The GPOs, in turn, review and critique each Specific Aims page and offer a review of each proposal as it nears readiness for submission. Fourth, by focusing on specific populations of interest during each offering, GUMSHOE builds learning communities that transcend the program itself. Mentees -- faced with similar challenges in terms of science, institutional experience, and social expectations – bond in ways beyond disciplinary affiliation and commitment to research careers. They enjoy an opportunity to share a sense of mission with others that reinforces their original commitments and offers membership in a reference group that is personally as well as professionally meaningful.The peer-to-peer learning process engendered during the GUMSHOE workshop is sustained over the ensuing 6 months through a web-based system that allows participants to post their completed application components  for review and comment by their counterparts in the same cohort. In this way, learning moves beyond the coach/trainee dyad to include insights shared among participants. This process speeds the discovery of revised rules and emerging funding emphases. The web-based system also provides access to an array of resources relevant to the preparation of competitive applications, including examples of biosketches, proposals funded by various mechanisms, NIH Summary Statements, and follow-up responses.To date, 30 coaches representing 19 different disciplines have mentored 89 NRMN mentees in the GUMSHOE program. All coaches are experienced NIH-funded investigators. Their training is accomplished through direct participation in the three-day workshop. It emphasizes modeling and frequent debriefing, combined with analysis of participant progress and barriers to success.In 2005, UNTHSC established the Texas Center for Health Disparities (TCHD) to foster the relationships needed for effective health disparities research and to promote education and training for academic institutions. To achieve these ends, the TCHD Research Training and Education Core created the Steps Toward Academic Research (STAR) fellowship, which assembles a diverse group of early-stage faculty for training in professional skills and career advancement [The NRMN-STAR coaching model plays an integral role in facilitating grant writing and professional development. Coaches are established faculty from across the U.S. with extensive grant writing experience and interest in training early-stage researchers. Each coach is typically matched with two trainees based on research interest to form a coaching team. NRMN-STAR also utilizes “content coaches” to augment the grant writing process. Content coaches offer discipline-specific content expertise to trainees. They begin their training by attending a two-day kickoff meeting where they learn about the program curriculum and the principles of NRMN-STAR. Next, they engage in real time with the NRMN-STAR curriculum, as facilitated by the program directors. In addition to intensive coaching interactions within their teams, trainees and coaches benefit from activities in which the entire cohort forms a working group. This peer-to-peer experience builds a community of learners and fosters a broader exchange of best practices in grant writing and professional development. To date, NRMN-STAR has trained 11 coaches and 32 postdoctoral fellows and junior faculty.The skills required for grant writing at the postdoctoral and junior faculty levels are highly variable. Equally variable is the provision of institutional resources to support proposal development by early-stage investigators from underrepresented groups in biomedical, behavioral and social sciences. Therefore, professional development programs that extend beyond institutional borders are critically needed. NRMN’s significant contribution is the implementation of four intensive, complementary curricula in grantwriting and professional development that enables individualized, iterative feedback from successful senior researchers with demonstrated skills in working with minority investigators at different stages of their careers. The four curricula also help to develop a critical mass of grantwriting coaches with the requisite skills for this work. The Coaches-in-Training model implemented by NRMN prepares faculty to be effective grantwriting mentors, thereby providing a sustainable mechanism to deliver transformative professional development experiences to large numbers of underserved postdoctoral fellows and junior faculty.A key outcome of NRMN’s approach to grant-training is to increase a sustainable architecture that will support and facilitate harnessing the collective expertise of successful scientists in the interest of accelerating the research career development of a diverse constituency of faculty. Considering that proposals are a key element of academic job applications, NRMN programs targeting postdoctoral fellows is one its impactful innovations. Although outcomes are premature, it is expected that such programs will also help URM scientists to be more successful in obtaining faculty positions. As an outcome, we expect to see an increase in the number and proportion of URMs progressing in their faculty career in part by receiving NIH research grant awards. Collectively, a diverse representation of URMs have participated as trainees across all programs including postdoctoral fellows and a growing diverse cadre of faculty Coaches-in-Training. Recruitment encompasses participation from partner minority-serving institutions, attendance at the Annual Biomedical Research Conference for Minority Students, Society for Advancing Chicanos/Hispanics and Native Americans in Science and fostering collaboration with scientific National professional societies. To date, African Americans (Blacks) and Hispanic/Latino populations comprised most of the participants followed by White and Asians. Collectively, Native-American and Hawaiian Pacific Islanders comprised made up 6% of the cohorts Fig. . The NRM


There are increasing concerns about the health and well-being of individuals facing financial troubles. For instance, in the United Kingdom, the relationship between debt and mental health difficulties is becoming more evident due to the economic downturn and welfare reform. Access to debt counseling services is limited and individuals may be reluctant to access services due to stigma. In addition, most of these services may not be appropriately resourced to address the psychological impact of debt. This study describes outcomes from an Internet-based cognitive behavioral therapy (ICBT) program, Ostrich Community (OC), which was developed to provide support to those struggling with debt and associated psychological distress.The aim of this feasibility study was to assess the suitability and acceptability of the OC program in a nonclinical sample and examine mental health and well-being outcomes from using the program.A total of 15 participants  were assisted in working through the 8-week ICBT program. Participants rated usability and satisfaction with the program, and after completion 7 participants took part in a semistructured interview to provide further feedback. Before the first session and after the final session all participants completed questionnaires to measure well-being and levels of depression, stress, and anxiety and pre- and postscores were compared.Satisfaction was high and themes emerging from the interviews indicate that the program has the potential to promote effective financial behaviors and improve financial and global psychosocial well-being. When postcompletion scores were compared with those taken before the program, significant improvements were identified on psychometric measures of well-being, stress, and anxiety.The OC program is the first ICBT program that targets poor mental health associated with financial difficulty. This feasibility study indicates that OC may be an effective intervention for increasing financial resilience, supporting individuals to become financially independent, and promoting positive financial and global well-being. Further work with individuals suffering from debt and associated emotional difficulties will help to examine clinical effectiveness more closely. Cognitive behavioral therapy (CBT) ,2 is an In the midst of a recession and with the continuing move by the UK government to implement austerity measures, vulnerable members of society are suffering the consequences of an economic contraction . One of A further negative consequence of the imposed austerity measures is the continuing erosion of access to mental health services ,25. FinaIn light of the detrimental effects that debt may have on well-being, and the lack of evidence-based services that offer both financial and emotional advice, government and financial institutions now recognize that considerable work needs to be done to address this gap in services ,28. HoweTherefore, this study was conducted to assess the usability and acceptability of a novel ICBT treatment program, Ostrich Community (OC), which is designed to help individuals with their financial difficulties while supporting them to overcome any associated mental health problems. The program aims to promote development of positive behaviors, increase financial knowledge, and improve self-efficacy with regards to financial management. The study adopted a mixed-methods approach as recommended by the Medical Research Council (MRC) guidance around the development and evaluation of complex, multicomponent psychosocial interventions ,33. ThisIn line with the MRC guidance, it was important to conduct a feasibility study to explore acceptability and usability in a group of participants experiencing only moderate financial difficulties, before examining effectiveness in the target population, that is, service users accessing support for financial and mental health difficulties. This approach is important to gain insights into improvements that could be made to the program before evaluating it more formally with a group who may have more complex needs . Small-sThis was a mixed-methods feasibility study, incorporating semistructured qualitative interviews and quantitative satisfaction measures, alongside psychometric measures of stress and well-being. These measures were taken to explore acceptability and usability of the OC program.The OC ICBT program provides practical advice about management of finances and psychological well-being and clinically validated evidence-based psychosocial intervention strategies that are grounded in the theoretical underpinnings of the CBT model . Each moThe program comprises a 2-min introductory video, followed by 8 Web-based sessions at weekly intervals. Each session lasts approximately 30 min, with approximately 30 additional min per week spent practicing away from the computer  in order to encourage the user to practice the skills taught throughout the program. The program contains information delivered by video and audio to enhance engagement and accessibility. See The OC program is best suited to users who are experiencing mild to moderate stress or depression and anxiety symptoms, and who need information and guidance about money management. Participants with more serious mental health symptoms and debt issues are introduced to content on the home page and there is a toolbox that provides information on more intensive mental health and debt advice services that are more appropriate to their needs.The sample consisted of 17 students from the University of Salford, who were not in significant financial distress, but were coping with the demands of a further education course of study, alongside the low income and financial difficulties many students experience. This group was selected as it was considered important to explore acceptability and usability of the program in a group without significant financial and emotional difficulties, before testing individuals with more complex needs that are facing real financial and emotional difficulties. All participants were studying full-time and some were also working to supplement their income. Participants who consented to take part subscribed to the program by activating a Web-based account, providing an email address, and creating a password. They received a welcome message together with login details via email. Of the 17 consenting participants, 15 activated an account.Participants worked through the modules sequentially, with a new module released each week for 8 weeks together with an email reminder. Following completion of all modules, participants were invited to take part in a semistructured interview exploring acceptability and usability of the program (7 took part). Before module 1 and after module 8, participants completed two standardized psychometric assessments, measuring stress and well-being . The flowchart depicted in Three separate methods were used to examine (1) acceptability and usability of the program, (2) participant satisfaction, and (3) stress and well-being outcomes.On completion of the program, participants were offered the opportunity to take part in an interview. Interviews were conducted on a one-to-one basis with the lead author (DS) and explored participants’ views of the OC program. Open-ended questions allowed participants to elaborate on their answers. Interviews lasted approximately 30 min and were recorded using a digital Dictaphone.The interviews were transcribed and entered into NVivo qualitative data analysis software version 10 , and thematic analysis (TA) was used to analyze the transcripts. Published guidelines around the process of TA in psychological research were followed , with trThis stage of the study measured satisfaction with the program using the 8-item Client Satisfaction Questionnaire (CSQ-8) . The CSQParticipants completed the Warwick and Edinburgh Mental Well-Being Scale (WEMWBS)  and the In order to determine stress and well-being outcomes, pre- and postintervention scores on the DASS  and WEMWAs three methods were used to address three independent aims, findings from each of these are reported separately.Three themes were identified relating to (1) enhancing engagement with the OC program, (2) acceptability of program content, and (3) the programs’ potential to benefit the target population.Participants reported a number of features of the program that enhanced engagement, including presentation of modules in a sequential and progressive manner with each one building on knowledge gained from the previous session:it was organized in a way that you can do it, in a step-by-step process.Participant 1Participants also liked that the program content was delivered via interactive Web-based multimedia including video and audio, although one participant did suggest that a purely Web-based program may not be suitable for everyone:I think...the way the website was very visual, and you did a blend of different ways (to) suit people’s needs in terms of their learning style (but) I think it needs to be maybe classroom based...there’s a tutor or someone taking them through it bit by bit then taking them back to apply it.Participant 6In general, participants were positive about the content of the program, and while there was acknowledgment from participants that the content was informed by academic theory, this did not make it difficult to access or understand:I liked that there was a good balance between the theory, the information provided, and activities...it was nothing too strenuous.Participant 7Positive reinforcement within the program was also perceived as helpful and played an important part in supporting users to achieve the goals they set:I like the positive quotes and encouraging words that were throughout the program, I liked how rewarding it was...which made you feel like you’ve done some progress.Participant 4On the whole, participants reported that they understood the concept of the program, even though a Web-based financial capability program was a new idea:it was a new concept that I haven’t explored in other programs. It’s a financial capability program so its specialized and it’s good that its specialized to help people with financial difficulties in that sense.Participant 1The opinion among participants was that the program offered practical advice and solutions to financial difficulties and would support individuals to develop the tools necessary to overcome their financial difficulties:it was practical, there was so many things you provided in the tool box, which is a good thing because the program didn’t just talk about stuff it actually provided the tools to help people.Participant 3All 13 participants completed the usability questionnaire after each module and the CSQ-8  at the eFrom the CSQ-8 data , 92% (12Z (13)=−2.006, P<.05 There was also a significant difference in stress scores before and after (median scores of 32 and 26 respectively) with participants reporting lower levels of stress at the end of the program, Z (13)=−2.814, P<.01. There was no difference between levels of depression at the end of the program (median 22) compared with the beginning (median 26), Z (13)=−0.393, P=.69.Participants reported higher levels of anxiety before the program (median 24) than at the end (median 16) and this difference was significant, Z (13)=−2.275, P<.05.Scores on the WEMWBS were lower at the beginning of the program (median 45.00) compared with the end (median 51). Participants reported a significant increase in well-being from pre- to postprogram, The continuing government austerity measures, coupled with a bleaker outlook on jobs, have resulted in more people experiencing debt . This ofThe OC program is an innovative ICBT program that aims to support individuals who are having financial difficulties that are affecting their emotional well-being. The focus of the program is to relieve psychological stress, anxiety, and depression while teaching positive financial behaviors and resilience. This initial feasibility study was conducted to explore acceptability and usability of the program.Many participants said that they appreciated taking part in the study because it helped them to learn how to budget effectively and how to be prepared in terms of dealing with sudden financial changes. One of the benefits of this program is therefore that individuals can use it as a preventative tool regardless of their financial circumstances and in the absence of significant levels of debt ,46. IndeParticipants found the program to be helpful and easy to use and there was high satisfaction with the financial information and emotional help provided. These findings support the high satisfaction with ICBT when addressing gambling , insomniCAT integrates therapeutic content delivered by an ICBT program with a human practitioner who may provide screening, supervision, and other support to the user , whereasA “blended” approach to facilitation of ICBT programs has been demonstrated to be helpful for those individuals experiencing mental health difficulties . TherefoThis study intended to explore initial feasibility and acceptability of the OC program with a small cohort of participants experiencing some financial difficulties. This was to gain insights into improvements that could be made to the program before evaluating it with a population of service users with more complex needs. Multiple digital health studies take this approach, including studies of mental health intervention programs  and alcoThe aims of this feasibility study were to assess the acceptability and usability of a novel ICBT program for people experiencing poor mental health due to financial difficulties. A total of 15 participants worked through the program over a period of 8 weeks, and they reported satisfaction with the program and noted that it was easy to use. They also suggested that it made them consider their financial situation and gave them skills they could use beyond the immediate focus of finances. There was also a significant improvement in well-being, anxiety, and stress on completion of the program.Some participants reported that it was difficult to work through the modules individually and so future work will explore the addition of support from a practitioner and potentially a moderated peer support forum. These implementation approaches may help to increase impact , increas


Most graduates (88%) agreed or strongly agreed that the knowledge and skills acquired during their education were useful in their current job. The graduates stated that they would have wanted more applied pharmacy practice and self-care counselling, and fewer social pharmacy and histology courses. Further, 82% stated that they would start the same degree program if they were to choose again today, and 92% agreed or strongly agreed that they would recommend the program to a prospective student. Graduates were more likely to recommend the program after the re-regulation (p = 0.007). In conclusion, pharmacy graduates were very satisfied with their education, and no negative effects of the re-regulation could be observed on program satisfaction.In response to the shortage of pharmacists in Northern Sweden, a web-based Bachelor of Science in Pharmacy program was established at Umeå University in 2003. In 2009, the Swedish pharmacy market was re-regulated from a state monopoly to an open market, but it is unknown what impact this has had on education satisfaction. The objectives of this study were to examine the level of satisfaction among graduates from a web-based pharmacy program and to describe what subjects and skills students would have liked more or less of in their education. A secondary objective was to compare the level of satisfaction before and after the Swedish pharmacy market was re-regulated. A cross-sectional survey was conducted in 2015 with all alumni who had graduated from the pharmacy program between 2006 and 2014 ( Education satisfaction has been suggested to be an important influence on students’ successful learning . After cIn 2003, a web-based three-year Bachelor of Science in Pharmacy program was introduced at Umeå University. The program was initiated in response to the expressed request of Apoteket AB (the state-owned pharmacy monopoly at the time) because of their difficulties in recruiting pharmacists in the inland parts of Northern Sweden. The pharmacy program at Umeå University is web-based, and the education is mostly conducted through a virtual learning environment with regular online meetings between students and teachers and some mandatory meetings on campus in Umeå. During the on-campus meetings, the students engage in activities such as laboratory work, oral presentations, and role-play. The virtual learning environment contains recorded lectures, assignments, animations, and references to the literature. During the online meetings, the students and teachers discuss different topics concerning the specific course. The structure and content of the program has generally been the same over the years, besides regular revisions to keep the course material up to date. The courses constituting the program can be divided into three main areas—pharmaceutical chemistry, biomedical sciences, and pharmacy. After completing the bachelor’s degree program, the students are eligible to apply to the Master of Pharmaceutical Science program in order to obtain a master’s degree. This master’s program was introduced at Umeå University in 2010.In Sweden, the main place of work for graduates from the Bachelor of Science in Pharmacy program is at community pharmacies . In 2009Little is known about education satisfaction among pharmacy programs in Sweden. Hence, the main aim of this study was to examine the level of education satisfaction among pharmacy graduates at Umeå University and to describe what subjects and skills students would have liked more or less of in their education. A secondary objective was to compare the level of satisfaction before and after the re-regulation of the Swedish pharmacy market.The study questionnaire was developed using information from the literature  as well In n = 437). The paper copy also had a link to an online version. To protect graduates’ privacy, address labels were printed by the administrative department, and a research assistant was in charge of posting the envelopes. Those with no Swedish registered address (n = 74) were sent an email invitation asking if they wanted to participate or opt out from further communication regarding the survey. The contents of the paper version and the online version were identical. The link to the online version was active for two months (May and June 2015).A paper copy of the questionnaire was posted in May 2015 to people who graduated from the Bachelor of Science in Pharmacy program (a three-year web-based program) and/or the Master of Pharmaceutical Science program (a two-year web-based program) between 2006 and 2014 and who had a Swedish address in the university’s administrative system  and “agree” (Likert responses 4 and 5). Job satisfaction was measured with the question “All things considered, how often are you satisfied with your job?” and the answers were dichotomized into “not satisfied” (those who responded “never or rarely” and “sometimes satisfied”) and “satisfied” .Those who graduated before (2006–2009) and after (2010–2014) the re-regulation and those who were satisfied and not satisfied with their education were compared using the Pearson chi-square test and Student’s The answers to the questions regarding educational satisfaction among those who graduated before the re-regulation (2006–2009) and after the re-regulation (2010–2014) were compared, and a multivariate logistic regression model was constructed. The model had educational satisfaction as the dependent variable and included age and year of graduation (2006–2009 or 2010–2014) as independent variables. In the multivariate model, the variables were dichotomized into “disagree” (Likert responses 1–3) and “agree” (Likert responses 4 and 5) and into “no” (Likert responses 1–4) and “yes” (Likert response 5). In the analysis comparing year of graduation, 192 persons were included in the final analysis because data for eight respondents were missing. p-value of <0.05 was considered statistically significant. Open-ended responses were analyzed using a modified thematic analysis, which involved an open coding technique.Responses were collected and analyzed using SPSS version 23. A No ethical committee approval was sought prior to beginning this research because it is not obligatory under Swedish law for this type of study. All data were anonymized before analysis. The participants in this study were informed about de-identification of the material and about the aim of the study, and they consented to the data being used for research purposes.n = 21) were excluded because this paper focuses on the education satisfaction among graduates from the bachelor program. This also includes graduates with both a bachelor and master’s degree (n = 9). One respondent did not state the degree they received and was also excluded from further analysis. The characteristics of the respondents are shown in Of 511 graduates, 222 graduates completed the survey for a response rate of 43%. In this study, only graduates from the Bachelor of Pharmaceutical Science program were analyzed, leaving a final sample of 200 graduates. Respondents graduating from the Master of Pharmaceutical Science program (The majority of graduates (88%) agreed or strongly agreed that the knowledge and skills acquired during the education were useful in their current job. The majority of the graduates (92%) agreed or strongly agreed that they would recommend the program to a prospective student . Furtherp < 0.001).There were no differences among graduates who were satisfied with their education and graduates who were not satisfied regarding age and gender . SignifiGraduates reported that during their education they would have liked more of subjects such as applied pharmacy practice and self-care counselling and more training in skills such as communication. Other subjects mentioned included business administration, economics, sales, and leadership. Further, they wanted less of subjects such as social pharmacy and histology .The majority of the participants (75%) thought that their duties at work reflected their education. Graduates who answered “no” to this question were asked to provide further comments. From the analysis of these open-ended responses, two broad themes were identified: (1) I learned about this but have not had any use of this knowledge, and (2) This was not included in the program, but I need it at work.Theme 1: I learned about this but have not had any use of this knowledge.The program gives much deeper and more detailed knowledge than what is needed in order to handle prescriptions at a pharmacy”.“Some of the graduates explained that they have more knowledge than they need in their current job, which is exemplified by this comment:Everything you learn about, for example, pharmacodynamics, pharmacokinetics and general chemistry, you unfortunately never use at a community pharmacy… This knowledge, that you knew really well, is forgotten… Very sad”.“Another graduate mentioned:The boring thing is that when you work at a community pharmacy there are few people who ask for our competence. Neither employers nor customers are especially interested in what we know”.“These comments highlight how some of the knowledge that the graduates gained might not be used and/or applied in their current jobs. In addition, some respondents mentioned that they would like to use their knowledge more, and they also felt that the knowledge they have is not requested, as exemplified by this quote:Now it is only about selling products (outpatient care products) and earning money. You rarely get to use the knowledge you have. For example, giving advice and informing/discussing medicines with the customers. There is no time for that”.“Theme 2: This was not included in the program, but I need it at work.A common reason for the mismatch between their education and their current job was that some graduates perceived that the current focus of community pharmacies is on selling products. One of the graduates noted:I think the program focused too much and in too much detail on chemistry at the expense of, for example, outpatient care and animal medicines, which we had on only one occasion”.“More practice, more about medicines and how they work in the body. More depth and a longer course”.“Some of the graduates mentioned that some subjects within the pharmacy degree were missing. For example, they would have liked more practical knowledge in areas such as patient counselling and therapeutics, but less focus on chemistry and basic science, as exemplified by these quotes:There is a lot of focus on sales at pharmacies, but we never heard anything about that in the program”.“Some respondents also mentioned competences outside the field of pharmacy, and particularly emphasized the lack of education regarding sales during the program; however, they did not say if they wanted more emphasis on knowledge of “how to sell”.During my studies I did not learn to sell cosmetics and body lotion, which is something I am expected to do at work”.“Another graduate mentioned:Graduates were also asked if they work in a sector that is completely outside of pharmacy, and nine (4.5%) answered yes to this question. These graduates were asked why they chose to change careers after obtaining their pharmacy degree. Most of the explanations provided were about job satisfaction. One of the graduates commented: “It’s just stress. There are no opportunities for continuing professional development, and it is difficult to get a good working schedule.” Another mentioned: “Working at a pharmacy did not live up to my expectations. I thought it was like working in any other store”.I worked at a pharmacy for six months, had children, and then got a better job in my hometown in my previous profession”.“Two of the graduates mentioned that they could not get a permanent job in their hometown.p = 0.007)  . No otheThe main findings from this study are that pharmacy graduates were very satisfied with their education. Also, graduates stated that during their education they would have wanted more subjects such as applied pharmacy practice and self-care counselling, and fewer social pharmacy and histology courses. Further, people graduating after the re-regulation were more likely to recommend the program to a prospective student. That the vast majority of respondents were female and the mean age was 40 years is similar to what has been reported for the Swedish pharmacy workforce ,13.This study provided an opportunity for graduates to look back at their education and to consider if it provided the necessary skills and knowledge to perform their job. Most of the respondents stated that if they were to choose today, they would start the same degree program. Comparisons with other studies are somewhat difficult because different designs and questions are used; however, compared to one study from Australia, the results in the present study indicate a higher education satisfaction . FurtherBecause community pharmacy is the major workplace for the graduates, it was important to understand whether the graduates’ education had responded to changes in the labor market. Graduates were positive about the knowledge and skills acquired and were willing to recommend the program to a prospective student. It is interesting to note how this is even higher after the re-regulation. Despite the changes in the pharmacy market, graduates would be willing to study pharmacy again. This might indicate that although the pharmacy market and the role of the pharmacist have changed, the education still succeeds in preparing the students for relevant job assignments. Another possible explanation is the increased number of community pharmacies with different owners , which hGraduates in the present study wanted more pharmacy practice, self-care counselling, and communication training. This is probably a reflection of their duties at a community pharmacy. Usual work tasks at a community pharmacy are to serve at the counter or in the OTC self-selection department, advising customers . A pharmAlthough the majority of the graduates work at community pharmacies, graduates from the Bachelor of Science in Pharmacy program can also work in other places such as the pharmaceutical industry and government agencies. Offering broad knowledge as well as expertise that addresses the labor market changes is a balancing act. There is a coexistence of different perspectives that needs to be considered when developing and changing higher education, and perhaps one way is to allow more dialogs in an external context.The results of this study show that the re-regulation did not have a great impact on graduates’ education satisfaction. Perhaps the education is broad enough to address the new labor market. It seems that Umeå University pharmacy graduates are satisfied with their education, but not with some of the tasks at their workplace.One of the limitations of this study was that all graduates completing the survey are now working in a liberalized pharmacy market, and graduates’ opinions about their education might be reflected by their current workplace, i.e., in the re-regulated pharmacy market. Further, some of the graduates might have experience with the former market, but the extent of this is not known. Also, years of work experience have not been corrected for, which might be a confounder. It would have been interesting to ask the graduates more detailed questions about how they have experienced the re-regulation in order to be able to compare the situation before and after, but this was beyond the scope of the study. There is also a risk of selection bias, and it cannot be excluded that students who are more positive about their education were more likely to complete the survey, which might influence the results.This study provided an opportunity to investigate education satisfaction among graduates between 2006 and 2014. Pharmacy graduates were very satisfied with their education, and no negative effects of the re-regulation could be observed on program satisfaction. The subjects and skills the students would have liked more or less of in their education probably reflected their current duties at the community pharmacy.


Among monoclonal gammopathies of undetermined significance (MGUSs), the immunoglobulin M (IgM) MGUS subtype stands as a unique entity and plays a pivotal role as a pre-malignant condition for multiple B-cell non-Hodgkin lymphomas, most notably Waldenström macroglobulinemia (WM). A relationship between IgM MGUS and WM has been proposed for decades. However, insight regarding the pathobiology of these two conditions improved significantly in recent years, strengthening the hypothesis that WM and IgM MGUS are different stages of the same disease. Therefore, the understanding of IgM MGUS and that of WM are interconnected and advances in one will likely impact the other. Furthermore, IgM MGUS has been more commonly recognized as the underlying etiology of IgM-related disorders. In this review, we explore recent advances in the understanding of the pathobiology of IgM MGUS and WM and the treatment of common IgM-related disorders. CLL arises from a pre- or post-germinal center CD5+ B cell2. WM arises from a post-germinal center B cell that has undergone somatic hypermutation but not heavy-chain class switch3. The cell of origin in MM is a B cell that has fully differentiated into a plasma cell4.Even though multiple myeloma (MM), chronic lymphocytic leukemia (CLL), and Waldenström macroglobulinemia (WM) are unique diseases with distinct presentations, prognoses, and treatment strategies, they all originate from B cells in the late stages of differentiation6. Although immunoglobulin M (IgM) MGUS is the probable precursor condition for WM, the relationship between these two entities is not as well stablished as in CLL and MM. Moreover, IgM MGUS has been shown to be a distinct entity from non-IgM or light-chain MGUS7.Along with the closely related cells of origin, these diseases also seem to be preceded by pre-malignant conditions. CLL and MM are always preceded by monoclonal B-cell lymphocytosis (MBL) and monoclonal gammopathy of undetermined significance (MGUS), respectivelyThis review explores recent advances in the understanding of IgM MGUS and its relationship with WM and focuses on the pathobiology and management of IgM MGUS.8. In contrast, the Second International Workshop on WM consensus defined IgM MGUS as a serum IgM monoclonal protein of any size without bone marrow involvement by an LPL9. A monoclonal IgM paraprotein can be detected in a number of diseases, and a differential diagnosis of IgM monoclonal gammopathies is shown inThe definition of IgM MGUS is not universally agreed upon. The Mayo Clinic criteria characterize IgM MGUS as a serum IgM monoclonal protein of less than 3 g/dL, bone marrow lymphoplasmacytic lymphoma (LPL) involvement of less than 10%, and no evidence of signs or symptoms secondary to the lymphoplasmacytic infiltrative process11. Whereas the prevalence of MGUS seems higher in African-Americans (3.7%) and African blacks (5.8%) compared with Caucasians (2.3%), the prevalence of the IgM subtype is fivefold higher in Caucasians compared with African-Americans12. This racial disparity is consistent with the reported higher incidence of WM in Caucasians13.The prevalence of MGUS, based on large population studies, is estimated at 2 to 3% in adults over the age of 50 years, and the median age at diagnosis is about 70 years. The incidence of MGUS increases with age and is more common in males than females. IgM MGUS represents only 15 to 17% of all MGUS cases8. The initial concentration of M-protein at IgM MGUS diagnosis is a strong predictor for progression. Patients with an M-protein of more than 2.5 g/dL had a 3.1-fold greater risk for progression than those with an M-protein of less than 0.5 g/dL, likely reflecting the impact of a higher tumor burden on the risk of progression14. Early studies have also suggested that IgM MGUS patients harboring the MYD88L265P mutation have an increased risk of progression to WM16. However, the pathogenic role of the MYD88L265P mutation in the transformation to WM has not been established yet. The relevance of IgM MGUS lies not only in the increased risk of progression to a hematologic malignancy but also in the risk of developing end-organ damage secondary to autoimmune properties or deposition of the IgM paraprotein9.Patients with IgM MGUS are at increased risk of progression to a hematologic malignancy. Long-term follow-up of 213 patients with IgM MGUS showed the development of non-Hodgkin lymphoma (NHL) in 17 patients, WM in six patients, CLL in three patients, and light-chain (AL) amyloidosis in three patients. The risk of developing any lymphoid neoplasm or related disorder compared with the expected incidence was 16-fold higher in patients with IgM MGUS. The risk of developing WM was 262-fold higher. The probability of progression was estimated at 1.5% per year and the risk continued to increase even 20 years after the initial diagnosis17. Presence of LPL is a requirement for the diagnosis of WM but can also be identified in patients with IgM MGUS depending on the diagnostic criteria used14. A large cohort of IgM MGUS patients with long-term follow-up seen at Mayo Clinic demonstrated less than 10% bone marrow involvement by an LPL in all assessed patients and influenced the current Mayo Clinic diagnostic criteria for IgM MGUS14. Additionally, bone marrow evaluation by MFC of patients with IgM MGUS showed less than 10% bone marrow infiltration by clonal B cells in 99% of the cases18.The understanding of the pathobiology of IgM MGUS and WM has grown significantly over the last few years as technological advances, such as multidimensional flow cytometry (MFC), gene expression profiling (GEP), and next-generation sequencing (NGS), provided valuable insight into the unique relationship between these two entities. LPL, an indolent NHL, is characterized by bone marrow infiltration with malignant cells ranging from small mature-appearing B cells to lymphoplasmocytes and plasma cells18. IgM levels correlated with the degree of plasma cell clonality but not with the proportion of bone marrow involvement. Clonal B-cell bone marrow infiltration (>10%) and degree of clonality (100%) were highly specific to exclude the diagnosis of IgM MGUS but not to identify patients with WM. The phenotype of clonal plasma cells seen in WM was unrelated to the clonal plasma cells seen in MM18.Quantification of tumor mass and clonality by MFC showed increasing bone marrow involvement by clonal B cells from IgM MGUS to smoldering WM and symptomatic WM patients. Additionally, a progressive increase in the proportion of clonal B cells with cytoplasmic expression of the patient-specific light-chain isotype was seen from IgM MGUS to smoldering and symptomatic WM patients. However, despite the progressively higher degree of patient-specific light-chain isotype clonal plasma cells in the bone marrow from IgM MGUS to symptomatic WM, the proportion of bone marrow involvement by clonal plasma cells was similar in all three stages of disease19. Fluorescentin situ hybridization directed at chromosome 6 confirmed the 6q deletion in 55% of patients with WM but in none of the patients with IgM MGUS20. A genome-wide study of copy number abnormalities (CNAs) and loss of heterozygosity (LOH) using microarray technology identified deletion 6q(23.3–25.3) and +18q(22.1) as the most common structural abnormalities . Genomic imbalances typically observed in WM  were rarely seen in patients with IgM MGUS. The frequency of patients displaying CNAs progressively increased from IgM MGUS (36%) to smoldering (73%) and symptomatic  WM but a similar frequency of LOH was noted in all three disease stages21.Among the cytogenetic findings, chromosome 6q deletion is the most common structural abnormality and is seen in about half of patients with WM, followed by trisomy of chromosome 5 and monosomy 8MYD88,CXCR4,ARID1A,KMT2D,TP53,NOTCH2,PRDM1,CD79b,TRAF3,TNFAIP3, andMYDBBP1A) in patients with IgM MGUS (n = 56) or WM (n = 63) demonstrated 151 mutations in 74% of the patients. Patients with IgM MGUS harbored a significantly lower number of mutations than patients with WM, conceivably implying that multiple genetic hits are needed for the progression from IgM MGUS to WM. Somatic mutations in MYD88, CXCR4, and KMT2D were more frequently seen in patients with WM  than in patients with IgM MGUS , possibly suggesting that mutations in these genes are an earlier event in the pathobiology of IgM MGUS and WM22. A similar proportion of MYD88L265P mutation was detected in patients with IgM MGUS (42–54%) or WM (93–97%) when allele-specific polymerase chain reaction was used in an analysis of either bone marrow or peripheral blood samples24. However, no conclusion regarding a driver mutation in those genes can be made. Clonal B cells from bone marrow of patients with IgM MGUS, smoldering WM, and symptomatic WM were evaluated using immunophenotypic protein expression profile (iPEP) and GEP techniques. Early studies demonstrated a distinct molecular signature by GEP between patients with IgM MGUS and those with WM25. However, these findings were not confirmed in later studies involving larger cohorts and a more comprehensive microarray panel26. Virtually no differences were observed in the iPEP or GEP of patients with IgM MGUS compared with patients with WM, implying that the WM clone may already be present in patients with IgM MGUS21.Targeted NGS evaluating the presence of somatic mutations in 11 selected genes , GEP showed differentially expressed genes related to the interleukin-6 (IL-6), NF-κB, JAK/STAT, PI3K/AKT, inositol tetrakisphosphate (IP4), and 3-phosphoinositide biosynthesis pathways, which are related to cell growth and survival21. The first step in the pathogenesis of MGUS and MM has been hypothesized to be an abnormal response to antigenic stimulation through Toll-like receptors with overexpression of IL 1R leading to increased levels of IL-6 and promotion of an IL-6 autocrine loop27. The next step would be acquisition of genetic abnormalities, probably in a stepwise fashion, leading to the malignant transformation and clonal expansion28. In an attempt to demonstrate common antigenic stimulation in the pathogenies of IgM MGUS and WM, Varettoniet al.29 studied the immunoglobulin heavy chain (IGH) variable gene rearrangement repertoire in patients with these conditions. Immunoglobulins, including the monotypic IgM expressed by malignant cells in IgM MGUS and WM, are assembled by somatic recombination of a large number of gene segments in the IGH region and continuously shaped by exposure to exogenous antigens. Finding stereotyped IGH rearrangements could support the hypothesis of an antigenic stimulation as the early event in the development of these diseases. A remarkably biased IGH variable gene usage repertoire was seen in patients with IgM MGUS and WM. A predilection for the IGH variable gene 3 (seen in 83% of patients) in preference to IGH variable genes 1 and 4 was noted. No intra-disease stereotyped clusters were seen. These results imply that the cell of origin of IgM MGUS and WM is a heterogeneous B cell that may have responded to a diversified antigenic stimulation during a physiologic response before its malignant transformation29.However, post-translational modifications and epigenetic changes between patients with IgM MGUS and those with WM were not assessed. The iPEP of clonal B cells harboring the MYD88Finding a clear distinction between the malignant cell in patients with IgM MGUS and those with WM has been fundamentally challenging. Although the answer to this question could lie in the fact that these two conditions are merely different stages of the same entity, one cannot overlook a limitation of the studies investigating this question: variability of quality and representativeness of samples analyzed as well as the timing of sampling and handling methods.30. The term ‘IgM-related disorders’ has been proposed to describe this group of patients which encompass not only IgM MGUS and WM but any underlying condition associated with a monoclonal IgM paraprotein9. Among 377 patients with IgM-related disorders, the most common diagnoses were MGUS (42%), WM (28%), B-cell NHL such as CLL, extranodal marginal zone lymphoma, and splenic marginal zone lymphoma (18%), primary cold agglutinin disease (4%), AL amyloidosis (4%), cryoglobulinemia (2%), and IgM MGUS-associated neuropathy (1%)31.Although patients with IgM MGUS have minimal to no bone marrow involvement by LPL and usually low levels of circulating IgM, they may still have symptoms attributable to the IgM properties. Though infrequent, organ damage may result from an IgM paraprotein with autoimmune activity or altered structure prone to tissue deposition32. Cold agglutinin disease, leading to extravascular hemolytic anemia after cold exposure caused by IgM binding to red blood cell surface antigens and subsequent complement cascade activation, has been described in patients with IgM MGUS33. Cryoglobulinemia, manifested by acrocyanosis, Raynaud phenomenon, urticaria, peripheral neuropathy, renal failure, or vasculitis resulting from IgM immune-complex precipitation in cold temperatures, has been associated with IgM MGUS as well34. Immune thrombocytopenic purpura and acquired von Willebrand disease are uncommonly seen in IgM MGUS35.The peripheral neuropathy associated with IgM MGUS usually presents as a distal, symmetric, and slowly progressive sensorimotor neuropathy with predominantly demyelinating features in the nerve conduction studies. A causal relationship between anti-myelin-associated glycoprotein (MAG) IgM antibodies, identified in half of the patients, and neuropathy has been established. IgM paraprotein directed to other antigens such as GD1b ganglioside, sulphatide, and chondroitin sulphate has also been described, although the pathologic significance is not well understood31. IgM-related AL amyloidosis less frequently presents with cardiac involvement than non-IgM AL amyloidosis but has a higher prevalence of peripheral neuropathy secondary to the amyloid deposition. Renal failure, seen in up to 68% of the patients, is the most common manifestation36. Schnitzler syndrome is a rare entity characterized by the presence of an IgM paraprotein and a chronic urticarial rash in association with other inflammatory symptoms, lymphadenopathy, hepatosplenomegaly, or bone pain37. The pathophysiology of Schnitzler syndrome is not well understood, but upregulation of the IL-1 pathway plays a pivotal role39. Renal failure can also be seen in IgM MGUS patients as the result of monoclonal protein deposition disease, which includes light-chain, heavy-chain, or light- and heavy-chain deposition disease; proliferative glomerulonephritis; cryoglobulinemic glomerulonephritis; or direct LPL infiltration41.AL amyloidosis, caused by extracellular tissue deposition of misfolded immunoglobulins, is a rare but devastating complication of IgM MGUS42. Therefore, a ‘watch and wait’ approach is the preferred choice in asymptomatic patients.Owing to the lack of evidence suggesting a survival advantage or prevention/delay of progression to a hematologic malignancy and the concern of treatment-related toxicities, treatment is not recommended for asymptomatic patients with IgM MGUSTreatment is indicated for patients presenting with IgM-related disorders. The intensity of treatment should be balanced by the severity of symptoms and potential for short- and long-term sequelae. For minimally symptomatic patients, supportive care may suffice in most cases. For more significant symptoms or risk of irreversible organ damage, treatment directed toward the malignant clone should be considered.43. Two randomized, double-blind clinical trials of IVIG versus placebo in patients with IgM-related peripheral neuropathy showed at least partial improvement of symptoms in 28 to 45% of patients. The clinical benefit with IVIG was, however, short-lived45. Rituximab monotherapy has also shown activity in the treatment of IgM-related neuropathy with sustained results. Multiple trials reported at least partial improvement of symptoms in 31 to 86% of patients, and responses lasting more than 36 months were reported in a small prospective single-arm study48. The Eighth International Workshop in Waldenström Macroglobulinemia consensus panel for the diagnosis and management of IgM-associated peripheral neuropathy in patients with MGUS recommends tailoring of the initial therapy on the basis of the presence (or not) of anti-MAG antibodies. For patients with a positive anti-MAG assay, rituximab monotherapy is the preferred first line of therapy, whereas immunosuppressive or immunomodulatory therapy  is preferred for patients with a negative anti-MAG assay49. Treatment of patients presenting with IgM-related amyloidosis should follow the standard approach for patients with AL amyloidosis with combination therapy and consideration for autologous stem cell transplant50. Multidrug regimens may also be necessary for the treatment of severe or relapsed/refractory symptoms when an attempt to eradicate the malignant clone is warranted30.For patients who present with peripheral neuropathy severe and progressive enough to warrant therapy and in whom AL amyloidosis was excluded, a trial of intravenous immunoglobulin (IVIG) could be considered as the initial therapy51. Rilonacept, an IL-1 neutralizing fusion protein, and canakinumab, a monoclonal antibody against IL-1 beta, have also demonstrated activity in Schnitzler syndrome53.The treatment of Schnitzler syndrome, in contrast, is not directed toward the malignant clone but toward the upregulated cytokine state. Anakinra, an IL-1 receptor antagonist, has been shown to be a very effective therapy in Schnitzler syndrome. In a French multicenter study, all patients (n = 29) treated with anakinra attained a response lasting as long as the patients were followed (median of 36 months)The understanding of IgM MGUS, as a pre-malignant precursor condition to multiple subtypes of B-cell NHL, is pivotal to comprehend the development of related hematological malignancies, most importantly WM. Available data suggest an aberrant response to a normal antigenic stimulation as the potential initial step in the pathogenesis of IgM MGUS. Additional somatic mutations would be needed to allow the persistence of the abnormal clone, and a multi-hit hypothesis is proposed to explain the progression to WM.Despite an increased mutation burden seen in patients with WM compared with IgM MGUS, the GEP of clonal B cells is virtually indistinguishable in these two conditions and no driver mutation has been clearly identified to explain why some patients with IgM MGUS progress to WM. Perhaps the answer to this question lies in post-translational or epigenetics changes not yet identified. It is also possible that changes in the bone marrow microenvironment are responsible in part for the progression of IgM MGUS to WM. An effort to prospectively collect samples and information from patients with a variety of pre-malignant conditions, including IgM MGUS, is under way (NCT02269592) and could provide valuable data for future studies.54. One may wonder whether the same concept could be applied to IgM MGUS and WM given the suggested upregulation of the IL-6 pathway seen in these patients and the known association between IL-1 and IL-6.The role of early treatment of patients with IgM MGUS to prevent or postpone transformation to WM is still unknown. It is unlikely that large clinical trials will be carried out to investigate this question given the rarity of this disease and need for long follow-up. A unique approach using anakinra to induce a chronic disease state in patients with smoldering MM showed promising results but has never been validated in large clinical trialsMany impressive advances have occurred in recent years, shedding light on the pathobiology of IgM MGUS and WM. Our understanding of these conditions is poised to expand in the near future and is likely to favorably impact the outcome of this disease.


N = 206) were randomly assigned in classes to either an intervention or a control group and assessed at baseline and post-test. Results showed a significant (p = 0.009) and small to moderate  pre-post decrease in parent-reported anxiety symptoms for the intervention group, in conjunction with a non-significant (p = 0.708) and negligible  pre-post increase for the control group. A larger randomized controlled trial assessing longer term effects is needed. In addition the program needs to be simplified for year 1–2 students with a separate more developmentally appropriate program for year 3 students.The Aussie Optimism Program: Feelings and Friends (AOP-FF) is a 10 week, universal mental health promotion program based on social/emotional and cognitive and behavioral strategies. The aim of the current study was to evaluate the efficacy of a universal Cognitive Behavioral Therapy based program in preventing and reducing internalizing problems in 6–8 year olds . Year 1–3 students from a low SES primary school ( The two internalizing disorders, anxiety and depression, are recognized as the most common and increasingly prevalent childhood disorders  curriculum is a widely known program designed to promote social and emotional competence through cognitive skills building in Grades 1–3 children .positive support network .H1b Selected or Indicated Prevention Effects: Children in the intervention group who were initially identified as being “at risk”  will exhibit a significant decline in internalizing difficulties at post-test.H2 It is hypothesized that:Informed consent was obtained from both next of kin and the children in written form. The child consent form contains information that the child can understand and has their signature of consent on it and the case is the same for the parents. This study has been approved by the Curtin University Human Research Ethics Committee. If needed, verification of approval can be obtained either by writing to the Curtin University Human Research Ethics Committee, c/- Office of Research and Development, Curtin University of Technology, GPO Box U1987, Perth, 6845 or by telephoning 9266 2784.Participants were 206 Years 1–3 students in one large Primary school in the Perth Metropolitan area. Figure The double stream Primary School came from a very low socioeconomic (SES) status area in the Perth Metropolitan area and was placed in the 10th lowest decile of the H-Index which is used to rank SES in schools in Western Australia. The sample consisted of 85 boys and 107 girls (14 students did not give their gender), with approximately equal numbers of males and females across the conditions . Participants were aged between 6 years 5 months, and 9 years 6 months.To evaluate the pilot program for each year group, the 10 Year 1–3 classes were blocked into year groups. From within these three blocks, the classes were then randomly allocated to the intervention and usual care control conditions. The numbers of students in each year group in both intervention and control conditions are presented in Table Children's Depression Inventory .The Assessment of Children's Emotional Skills . The correlation between SCAS-P and CBCL-internalizing (r = 0.27) is significantly higher than the correlation between SCAS-P and CBCL-externalizing , providing evidence for both divergent and convergent validity.The Parent version of Strengths and Difficulties Questionnaire . High internal consistency was also noted . The SC-T was found to be significantly correlated with the prosocial scale of the SDQ-P .A 3-item scale teacher-rated Social Competence (SC-T) scale was constructed based on three pertinent domains of social competence, which were also the three aspects targeted by the program: social skills , empathy, and social problem-solving. Teachers rated each child on a 5-point Likert-type scale (significantly below average to significantly above average). Test-retest reliability for the control group was high  were used with the Year 3 children only because of the poor reliability and validity noted on self-report measures with very young children .Training was provided to the teachers who agreed to be part of the study, and included detailing the rationale for promoting mental health within the school curriculum, teaching the various components in the program via direct instruction and role-playing, as well as supervised practice with the materials. Training was provided by the researcher and two registered clinical psychologists.To ensure the integrity of the program, facilitators of the program were asked to self-monitor their implementation of the program by completing a checklist and rating of the content covered in each module. Independent integrity measures were obtained by random observation of two of the teachers administering two different modules. This allowed for the comparison of teacher and expert ratings of program implementation, which provided a measure of implementation fidelity. Social validity aspects of the Years 1–3 program were examined by asking the students to rate their enjoyment of the program and parents to rate the effectiveness and utility of the program. Small focus groups were also held with students and teachers regarding usefulness, enjoyment of the program, suggested improvements and implementation issues.The psychometric data  were analyzed with a multi-level mixed effects linear regression model , the multi-level mixed effects regression model does not rely on participants providing data at every assessment point; GLMM uses all the data present at each assessment point thereby reducing the impact of subject attrition on statistical power. Moreover, GLMM is relatively robust to unequal group sizes.There was no child attrition at post-test for either group; however, 18 intervention parents and 11 control parents dropped out at post-test yielding attrition rates of 29 and 21%, respectively. There were no differences between the intervention and control drop-outs in terms of their pre-test outcome measures. Descriptive statistics for intervention and control groups on all outcomes are reported in Table F = 3.39, p = 0.067, partial eta-squared = 0.009]. The group main effect was also non-significant . There was, however, a significant main effect of time  indicating a significant pre-post improvement in emotional skills for both groups.The Group × Time interaction was non-significant , as were the main effects of group , and time .The Group × Time interaction was non-significant , as were the main effects of group , and time .The Group × Time interaction was non-significant . LSD (least significant difference) post-hoc contrasts indicated a significant pre-post decrease in anxiety symptoms for the intervention group , but no pre-post change for the control group .The Group × Time interaction was significant , as were the main effects of group , and time .The Group × Time interaction was non-significant , as were the main effects of group , and time .The Group × Time interaction was non-significant , as were the main effects of group , and time .The Group × Time interaction was non-significant . Post-hoc LSD contrasts indicated a significant pre-post decrease in parent-reported anxiety for the intervention males (p = 0.004), in conjunction with a significant increase for the control males (p = 0.025). There was no pre-post change for the intervention females (p = 0.372) or the control females (p = 0.222). It appears that the previously reported pre-post decrease in parent-reported anxiety for the intervention group was carried by the males.The Group × Time interaction reflects the intervention effect. A significant Gender × Group × Time interaction, therefore, would indicate that gender moderates the intervention effect. The three-way interaction was significant for SCAS-P . Post-hoc LSD contrasts indicated a significant pre-post increase in teacher-reported social competence for the intervention females (p = 0.041), in conjunction with a non-significant pre-post decrease for the control females (p = 0.112). There was a non-significant pre-post decrease for the intervention males (p = 0.079) and no change for the control males (p = 0.578).The Gender × Group × Time interaction was also significant for SC-T [p > 0.05).In total, 100% of the modules were completed by two of the five intervention classes, 90% with one class, 80% with another, and 20% by the fifth class. As one of the classes completed only 20% of the modules, a multiple regression, controlling for pre-test levels, was conducted to determine whether there was a dosage effect that would warrant excluding this class from analysis. There was no evidence of a dosage effect for any of the measures  on a scale of 1–5, with 1 indicating “not at all” and 5 indicating “very much.” Parents also rated a moderately high overall satisfaction of the program  Parents reported moderate ratings of the effectiveness of the program , and noticing positive changes in their children . Few parents reported noticing negative changes in their children since participating in the program . It appears though, that children did not talk to their parents about the program to a great extent . As this may have impacted on parent's evaluation of the program, secondary analyses were conducted on students who were rated as having spoken to their parents to a fair degree . Parents from this sample rated their children's enjoyment more highly  as well as overall usefulness of the program .Student enjoyment of the program was high, with 92% of children reporting that they enjoyed the program. Parents rated their children's enjoyment of the program highly  commented that the program was too difficult for their students and needed to be adapted and simplified.The aim of the present study was to evaluate the short term efficacy of a universal school based prevention program that was piloted for the prevention of anxiety and depression in Years 1–3 children in an Australian primary school.With regards to internalizing symptoms, students in the prevention group did not show a greater decrease in depressive or anxiety symptoms compared with students in the control group. As such, the hypothesis that children in the prevention group would have significantly lower depression and anxiety scores as compared to children in the control group was not supported. This finding is in contrast with the findings of researchers targeting the prevention of internalizing disorders in older children, such as Barrett and Turner's  universaWhile no significant effects were found for child self-reports, parents of children in the prevention group reported a significantly greater decrease in their children's level of anxiety compared to parents of children in the control group. The issue of congruence between parent and child report has been problematic, with numerous researchers noting poor agreement between parent and child reports . With regards to self-reported levels of anxiety or depression, the study provided no evidence that a greater proportion of children in the intervention group who score in the normal range at pre-test maintained their pre level scores.A third aim was to examine the prevention effects of the intervention on “at risk” children (Selected or Indicated prevention effects). It was predicted that a greater proportion of intervention children who exhibited symptoms of internalizing difficulties at pre-test would exhibit a decline in internalizing difficulties at post-test. There was no evidence of this found to support this hypothesis. This is not consistent with results found with the PENN program . Whether there are indirect pathways through improving emotional competence  or social competence remains to be evaluated via longer term follow-up and improved measures of social competence.Perhaps one of the most obvious explanations for the lack of significant findings is the lack of program fidelity achieved by two of five teachers in the intervention group. The fact that the program was not completed or adhered to may have reduced the full potential of effects that might have been found. The lack of effect could be due to a latency effect, whereby a period of time is required for elements of the program (such as the strategies and concepts) to be adopted and integrated for effective use  is insufficient to bring about significant and lasting acquisition of protective skills.Finally, the absence of significant effects for universal programs are not wholly unexpected, and are consistent with several research findings such as those from the meta-analysis conducted by Merry et al.  and fromUniversal prevention programs generally require large sample sizes in order to capture clinically significant population effects. Cujipers  estimateA further aim of the study was to ascertain the level of social validity and consumer satisfaction of the program so as to ensure the long-term viability of program. The vast majority of students reported that they enjoyed the program, with older students showing particularly good retention and being able to identify how the program was beneficial in their lives. Parents commented on the merits of the program, with some parents noting a number of positive changes in their children. Teacher feedback regarding the efficacy and usefulness of the program varied. Overall, the Years 2 and 3 teachers positively endorsed the program. However, the 2 Year One teachers who did not complete the program rated the program less favorably, stating the developmental inappropriateness of the program to their younger children being a major limitation. On the whole, child, parent and teacher feedback converge on the overall merits of such a prevention program, with the majority of teachers and students describing the experience as worthwhile and enjoyable.Several methodological limitations pertaining to the actual program and its implementation must be noted. One of the most important being the lack of program implementation fidelity for two of the five intervention classes. The program was run concurrently with at least one other universal program which meant that the demand on the teachers' resources was high. Thus, it is recommended that future programs be conducted in schools who are not simultaneously running other programs.Another potential limitation was that the program appeared too complex for Year 1 and 2 students, many of whom are only just beginning to learn to read and write. The complexity of the program may have reduced the likelihood of gaining the full benefit for year 1 and 2 students so it is recommended that a separate developmentally appropriate with less reading and writing be developed for this age groups and the current version of the program maintained for Year 3 students.There are several limitations pertaining to assessment issues. Firstly, self-report measures of internalizing symptoms were only available for the Year 3 children. This may have diluted the intervention effects that may have been found if self-report measures of internalizing difficulties were available for all year levels. In addition, as a result of random assignment, the reliance on only Year 3's resulted in a small control group, and the disproportionate sizes of both groups, may well have resulted in a corresponding loss of power. The decision not to use the self-report questionnaires also resulted in a reliance on parent measures of internalizing symptoms, where the response rate was not ideal. Secondly, the lack of program effects in terms of gains in social competence may in part be attributed to the validity of teacher ratings on the social competence measure.Based on feedback regarding the developmental appropriateness and length of each session, future revisions of the Feelings and Friends program should target the length of the program by using more, but briefer modules. The program also needs to be simplified for the younger age group (incorporating Years 1 and 2). In addition, in light of the importance of soliciting family support and active familial engagement in the prevention process, it would be helpful to incorporate a parent component.There was some evidence suggesting that the program was able to prevent anxiety in children. However, longer term follow up is required in further trials to investigate whether the program has longer term effects on anxiety, depression, or social and emotional competence. Although this study suffered from some implementation and assessment limitations, these results, when taken in the context of previous research, provide grounds for optimism in the field of early prevention of internalizing disorders. This study highlights the importance and usefulness of targeting emotional wellbeing in young children. It also highlighted a number of program implementation issues that can guide future researchers on how to overcome some difficulties encountered in real-world applications of programs in schools. The findings of the present study provide evidence that with further modification, the Feelings and Friends program may be of benefit to the mental health of 6–8 year old children and it is clear that a larger trial of a developmentally modified program with follow up periods needs to be carried out.EP—Conducting the study and contribution in writing the manuscript draft. RR—Principal Investigator of the Healthway grant that funded the current project, contribution to introduction and discussion of the manuscript. RK—Methodology and data analysis. MN—Chief Investigator of the current project, revising the draft and contribution to the discussion section of the manuscript. MD—Revising the drafts and conceptualization of the project. NB—Contribution to introduction and discussion sections of the manuscript. SH—Revising drafts and contribution to the discussion section of the manuscript.This study was supported by the Western Australian Health Promotion Foundation , through research grant (15148).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Cost-effectiveness of the vaccination programs was then estimated to measure the tradeoff between the past national poultry vaccination program and the alternative vaccination program. Ex ante analysis showed that the focus areas for the alternative vaccination program included 1137 communes, corresponding to 50.6% of total communes in the Delta, and located primarily in the coastal areas to the east and south of Hanoi. The cost-effectiveness analysis suggested that the alternative vaccination program would have been more successful in reducing the rate of disease occurrence and the total cost of vaccinations, as compared to the national poultry vaccination program.This study addresses the tradeoff between Vietnam’s national poultry vaccination program, which implemented an annual two-round HPAI H5N1 vaccination program for the entire geographical area of the Red River Delta during the period from 2005–2010, and an alternative vaccination program which would involve vaccination for every production cycle at the recommended poultry age in high risk areas within the Delta. The  The Highly Pathogenic Avian Influenza (HPAI) subtype H5N1 has had serious, detrimental effects on the economy and human health in Vietnam since the first reported outbreak on 27 December 2003 . Market Green Book 17] whichThe suitable areas for the vaccination campaign are shown in vs. U.S. $4.50 million), it resulted in reducing the rate of disease occurrence by 93.26% as compared to 61.66% of the national poultry vaccination program. As a result, this reduced the cost of immediate responses to the disease occurrence, including stamping out and emergency vaccination, government compensation, and farmers’ losses. This contributed to lower total costs associated with the alternative vaccination program as compared to the national poultry vaccination program (U.S. $6.92 million vs. U.S. $9.70). The results of the analysis suggested that Vietnam may face lower costs with the alternative vaccination program. The cost-effectiveness analysis indicated that the alternative vaccination program would better prevent the occurrence of the disease at lower costs associated with disease prevention than the national poultry vaccination program. Although the cost of the alternative vaccination program was estimated to be higher than that of the national poultry vaccination program  to 93.26% rate of reduction . The cost analysis indicated that the alternative vaccination program would have saved the government and farmer resources because of lower total costs associated with prevention. Total losses imposed on both the government and farmers were higher for the national poultry vaccination program (U.S. $9.70 million) than for the alternative vaccination program (U.S. $6.92 million).