Mentored training approaches help build capacity for research through mentoring networks and skill building activities. Capacity for dissemination and implementation (D&I) research in cancer is needed and mentored training programs have been developed. Evaluation of mentored training programs through quantitative approaches often provides us with information on “what” improved for participants. Qualitative approaches provide a deeper understanding of “how” programs work best.Qualitative interviews were conducted with 21 fellows of the National Cancer Institute-funded Mentored Training for Dissemination and Implementation in Cancer to gain understanding of their experiences with mentoring received during the program. Fellows were selected from all 55 trained participants based upon their gain in D&I research skills (highest and lowest) and number of collaborative connections in the program network (highest and lowest) reported in previous quantitative surveys. Phone interviews were recorded with permission, transcribed verbatim, and de-identified for analysis. Codes were developed a priori to reflect interview guide concepts followed by further development and iterative coding of three common themes that emerged: 1) program and mentoring structure, 2) importance of mentor attributes, and 3) enhanced capacity: credentials, confidence, credibility and connections.Interviews provided valuable information about program components that worked best and impacts attributed to participation in the program. Fellows reported that regular monthly check-in calls with mentors helped to keep their research moving forward and that group mentoring structures aided in their learning of basic D&I research concepts and their application. Accessible, responsive, and knowledgeable mentors were commonly mentioned by fellows as a key to their success in the program. Fellows mentioned various forms of impact that they attributed to their participation in the program including gaining credibility in the field, a network of peers and experts, and career developments .These findings suggest that mentored training works best when mentoring is structured and coupled with applied learning and when respected and dedicated mentors are on board. Increased scientific collaborations and credibility within a recognized network are important trainee experiences that should be considered when designing, implementing, and sustaining mentored training programs. Years (and lives) are lost between development of evidence-based practice and regular implementation for cancer prevention and control . DissemiMentored training approaches are used frequently in pre- and post-doctoral training initiatives and have the potential to increase capacity and networking in scientific fields –17. PrevThe National Cancer Institute’s R25 Mentored Training in Dissemination and Implementation Research for Cancer (MT-DIRC) began in 2014 with the goal of building capacity for D&I research by providing training and longitudinal evidence-informed mentoring to cancer researchers . The goaOur D&I training program was based on educational and social learning theories , along wMT-DIRC fellows were selected through a competitive application process. Doctorate-level cancer researchers interested in building their capacity for D&I research were encouraged to apply and submit a research project to work on during the program. Core faculty each reviewed and scored a selection of candidates (three reviewers per application). Allotted fellowship slots (12–14 per year) in the two-year mentored training program were offered to applicants with the highest scores. Figure Mentor-mentee matches were assigned by aligning research topic areas. Mentors were each assigned 1 to 4 mentees. This number varied from year to year given matriculation of graduating fellows and introduction of incoming fellows. Mentors were senior faculty experienced in D&I research and were identified through previous collaborations, professional networks, and rosters of mentors and faculty from similar D&I training programs , 7. We wIn addition to the in-person mentoring included in the Summer Institute, fellows also received at a minimum, monthly one-hour mentoring calls either one-on-one or with the other fellows assigned to each mentor. Since each year accepted a new cohort, mentoring groups contained at least one fellow in their second year of the program and one in the first. This was intentional so that newer cohorts could learn from experiences of earlier cohorts.https://sites.wustl.edu/mtdirc/).The program featured several components designed specifically to encourage networking. At the Summer Institute, we formed small groups with first year and second year fellows to discuss various aspects of D&I research. Generally, small groups were selected based on area of research focus specified in each fellow’s concept papers, though some years were more diverse than others. In course evaluations of the first two institutes, fellows mentioned that it was helpful to have a second-year fellow give advice on how best to take advantage of the training program. To address this, three alumni fellows were invited to present a special “lessons learned” session at the final Summer Institute to advise fellows on how best to approach the MT-DIRC program to accelerate their work in D&I research. Alumni fellows were also available for one-on-one meetings with fellows and joined small group discussions. We offered two networking dinners at each Summer Institute, one on the first night and one on the night before the last training day to close out the week. Monthly mentoring inherently included networking as groups of fellows and mentors connected on a regular basis for 2 years. A networking dinner for all fellows and alumni fellows was hosted at the Annual Conference on the Science of Dissemination and Implementation in Health, held each year in Washington, DC. We encouraged social media networking with the program’s Twitter account (@mtdirc). Through Twitter, fellows’ accomplishments  and other program announcements were shared with fellows (and their networks) in addition to the broader implementation science community (#ImpSci). We also shared accomplishments, job announcements, and program announcements by email to all fellows and mentors and posted to the training program’s website (Fellows completed a baseline (pre-institute) quantitative survey before attending their first Summer Institute. The survey assessed fellows’ perceived competency in 43 D&I research skills and was repeated at 6 months and 18 months in the program. For example, participants self-rated their skill  in “Describing a range of D&I strategies, models and frameworks,” “Defining what is and what is not D&I research,” and “Identifying common D&I measures & analytic strategies for research.” Satisfaction with mentoring and perceived mentoring competency of each fellows’ assigned mentor was also assessed in the quantitative survey at 6 and 18 months. Mentors were asked to rate their own mentoring competency each December. Additional quantitative survey measures are detailed elsewhere . All felThis study used a qualitative descriptive design which allows for a pragmatic approach to examining the experiences of a group of people, sampled purposefully and analyzed with modifiable coding systems –31. For Skill gain and research collaborations within the program’s network were main outcomes from this study. We hypothesized that those who did not gain as much from the program (skills and research collaborations) may have experienced the program differently from those fellows with the best outcomes. Therefore, we used purposive sampling to include extreme cases in skills and collaborations . Our strRev.com). Human Subjects approval was granted by the Washington University in St. Louis Institutional Review Board (#201903161).Drawing from the program’s overall conceptual model Fig. , we deveEach transcript was de-identified and uploaded into NVivo . Two of “the ability to have the kind of structured time in person was really critical to being able to really develop skills and develop kind of relationships. So just having in person time. I think the way that the in person time was structured was really well done to have kind of a mixture of the didactic kind of training with more of an in the fishbowl kind of session where you’re bouncing ideas and kind of developing ideas with feedback from your mentor and group. Having the time to be able to actually meet and with the other faculty at MT-DIRC.”In comparison to their other mentoring experiences, fellows remarked on the value of MT-DIRC’s deliberate and concentrated mentoring approach. Fellows reported mentoring was more focused and targeted around the D&I research they were working on compared to previous mentoring experiences. Fellows also remarked about the value of having structured in-person time for mentoring and devoting time specifically for their D&I research needs and skill building.“the mentoring helped me to gain the skills. The mentoring provided me with role modeling. That includes from [assigned mentor] and the other mentees, so being able to see what other people were doing and learn from their experiences, it also provided me with feedback as I applied the information that we learned from the training and also by providing me with new information as well, so suggestions and specific directions I could follow.”Fellows mentioned the two-year commitment from mentors or longitudinal mentorship as valuable to build and maintain relationships. In addition, fellows saw the value in attending more than one Summer Institute as they had the added opportunity to discuss lecture material and program readings both with other fellows at the institute and those fellows and mentors in their mentoring group. The opportunity to work one on one with the mentors in person on a specific project was seen as critical to the training. This allowed for feedback in practical application of skills versus “just doing a general training.”“setting the expectations at the beginning was really helpful, because, [assigned mentor] was like an unknown person to me. We were unknown to her. We were just kind of put in her group, and we were assigned to her … having explicit conversations about expectations makes a lot of sense almost all the time, but especially in a situation like this.”The quote above highlights the structure of the multi-layered mentoring network that MT-DIRC designed . Fellows mentioned explicit conversations with their mentors regarding the scope of mentorship and expectations for both mentors and mentees. Mentors and fellows were strongly encouraged to create mentoring plans or contracts. This was generally perceived as useful for fellows, especially initially, to understand what to expect in the next 2 years of the program following the first Summer Institute. For some, expectations were carefully articulated and goals for what the fellow and or group wanted to be accomplish helped in giving structure to what each was working on and how they were going to move forward.“It held me accountable to have something to share with the group on a regular basis. It kept me moving. I always had to have a product.”Regularly scheduled mentoring meetings and “homework” given by mentors helped to keep fellows on task with research projects. Setting deadlines, defining deliverables, the “expectation to send progress along” and feelings of being accountable to their assigned mentor was seen as helpful in accelerating work. Having regular meetings on the calendar were instrumental for one fellow in just reminding them of their overall research goals and overall career goals. Some fellows created their own agenda or update document where their progress and updates were shared regularly with the group.“When someone was really trying to identify what was innovative about their project, in terms of implementation science, I felt that it also applied to me, that I could learn about that, about how to sell my project to an implementation science audience”.Structure of regular meetings to include other peers was also seen as valuable. Fellows learned from other fellows who were in different phases of research or in different academic environments.“I feel like the team approach was helpful because I was learning a lot from the other two mentees. Well, both mentees had significant funding before. One of them had had a previous R01. And so it was really helpful to hear their processes as well. So I learned a lot, not only from [assigned mentor], but also the other mentees as well.”Fellows also remarked on insights gained from other fellows’ processes in finding funding success in terms of K-awards, R01s and other larger grants.“I think the faculty are key … .having excellent faculty who are incredibly knowledgeable is key but then faculty who really care about the fellows and really care about the program. I think that’s basically, that’s probably the secret sauce.”In addition to structure, fellows commonly noted the contribution of their assigned mentor a key to an overall positive program experience.… having a mentor who is really just there to support me and kind of take my lead on where I need development and they don’t have as much riding on my success, it’s just that they want to see me do well, I think that distinction is a little bit different then what I’m used to.”“Fellows had positive experiences with mentors who were accessible, confident and open to alternatives, open to listening and providing feedback, vested in the fellow as an implementation scientist, and focused on career trajectory and the bigger picture and not just day-to-day activities. In addition, fellows appreciated when mentors came with a wide range of career experience. Fellows mentioned having someone outside their institution as a benefit to keep mentoring more focused on D&I research in general  and also to get an external perspective or neutral angle.“I also appreciated the diversity of faculty. People were from different disciplines, different geographic areas. They had different levels of focus in terms of public health research and cancer research specifically … that was really helpful … I’ve been able to look at ideas from other areas and get inspired by those.”Diversity of the mentors’ disciplines and academic background was also mentioned by fellows as helpful in learning.“They really respected the fellows. They treated our ideas with respect and were really generous with their time. So the presentations were really good. The mentoring itself was really good, and then the atmosphere, the culture was very collegial and welcoming and respectful.”Having a mentor that reviewed materials in a timely manner was also important to fellows. Having mentors who “have the time and are able to set aside some time to do it” was mentioned by one fellow as the key for a program like MT-DIRC. One fellow specifically mentioned a time when they needed feedback within a short timeframe, and were surprised that their assigned mentor prioritized this need, further demonstrating the mentor’s commitment to the fellow. Fellows expressed gratitude for mentors who made an effort to review information fellows sent ahead of meetings and were “prepared” with “appropriately critical” feedback for fellows. Having experts in the field that were “available” when needed and accessible also aided in receiving help along the process. Fellows noted the “welcoming” environment that the mentors of the program helped to create where it was safe to have questions and challenges.Fellows expressed the mentored training experience as essential for a variety of self-defined successes, or enhancing their capacity or D&I research. Fellows reported participating in the program helped to give them credibility in the field of D&I for cancer research, and demonstrated their expertise gained. With a newer field like D&I research, one fellow stated the benefit of participating was to provide “credentials,” something with which to introduce oneself. Another fellow stated that “there’s no way I would’ve even felt like I could speak up at this conference last week without that behind me.” According to one fellow, the training was the “antidote to imposter syndrome” that they experienced in certain settings. One fellow made the point that senior people in D&I did not have this opportunity or structured learning in D&I, and so, being able to tell others of their membership in a formal training program was a “huge way” to open doors.“I was able to use this education when I gave back to my institution and I joined our internal pilot grants that we have here. Some are in implementation science, so I was invited to join the review panel for those grants. That helped give me some additional recognition within my institution.”Another piece of this credibility was the fellows’ own perceptions of their competence in D&I research skills or as one fellow put it, “starting to see myself as an implementation scientist and feeling confident to have enough of a sense of the field and what I do.” Some fellows mentioned becoming the “go-to” D&I research expert at their institution, reviewing and giving advice on other’s D&I grants.“Well, honestly, I would say that I don’t know that I would be where I am in terms of working on an R01 application focused on dissemination and implementation science if it wasn’t for the mentoring program because I was able to gain knowledge that I need to work on this proposal. But then I also got feedback and mentoring. And I have a sense of confidence that I’m going in the right direction.”Fellows mentioned the program being instrumental in grant writing, especially for D&I research audiences, and obtaining subsequent funding. One fellow stated that they were “inspired to write a grant in a way that [they] probably otherwise wouldn’t have written it.” Another fellow stated the time to work on and the resources available through the program around their project in the program contributed to their project ultimately being funded.Fellows reported the program helped to define research goals and overall transformed or shaped fellows’ careers, writing grants and manuscripts that focused more on implementation science topics for the first time.One fellow’s success was the establishment of a new D&I research class at their institution which they co-teach with another fellow. The fellow attributed the course to their participation in the MT-DIRC program. Another fellow mentioned that being able to teach others what they had learned was the “best outcome” from participating in the program. In particular, this fellow began a one-day workshop in D&I research prior to a society conference and described it as a “really nice opportunity for us to spread horizons” since the group in attendance included various countries. For one fellow, having a symposium proposal accepted for presentation at the biennial Society for Implementation Research Collaboration meeting was a success attributed to participation in the fellowship. Two fellows collaborated on a session accepted for the Annual Science of D&I conference in DC, which was seen as beneficial from the small group mentoring structure.“It gave me a personal connection with people from all over the country and all over the world in many cases. And we are still in communication on a somewhat regular basis. Once you find these nodes, these MT-DIRC fellows, they have their own network that they can then refer me to.”The program’s network of fellows and mentors, and the collaboration within it, was commonly mentioned by fellows as resulting in considerable professional impact. This collaborative energy was cited as impetus for writing papers together and for four fellows, recently submitting a pilot grant together. Another fellow reported having their assigned mentor connect them with another MT-DIRC mentor with an implementation-ready intervention, ultimately leading to awarded grant funding. Fellows also reported the program’s network increased their professional reach.This reach provided a group of people with whom fellows could always “touch base.” Especially at the annual meeting, fellows looked forward to seeing other cohorts of fellows and other mentors. One fellow mentioned networking at conferences was particularly important because of the earlier stage of their career.“I can see it being more of a help in the future to be able to cold email somebody and say, ‘Hey, we were in the MT-DIRC program together.’ Or ‘You were [part of my MT-DIRC cohort] faculty. Do you mind, I would love your advice on this.’ Or ‘Here’s a potential thought I had for a collaboration.’”Another fellow saw networking as a benefit from the program that will last beyond the 2 years in the fellowship.Fellows mentioned challenges during their participation in the MT-DIRC program. In general, challenges were often the reverse of or counter to the major themes detailed previously.“I would have been very happy to have monthly meetings as a group hear what people are working on learn about D&I concepts. That just wasn’t what [the mentoring relationship] was … I think that [1st assigned mentor] did very little for me … anything would have been more … the face-to-face sessions for the MT-DIRC program, where we were there for a week in St. Louis were amazing and I took away so much from that, and I met a ton of really important people who likely I’ll reach out to and collaborate with. And so my experience for MT-DIRC was absolutely transformative, but the mentoring part I think was not what I had hoped for. I would say I still got an amazing amount of stuff out of the MT-DIRC program, but the mentoring part I did not.”A fellow spoke about the challenge of switching assigned mentors a year into the program . Even so, the fellow described the in-person session as the additional layer to the program which made up for the sub-par mentoring received in the first year of the program.“I talked to a different person who wasn’t my assigned mentor, but one of the faculty, and I brought him an idea I had for a paper. It kind of got off the ground, but then I was never really able to get on his radar screen again, once [the Summer Institute] was over. So that one kind of petered out, and I wish it hadn’t.”In addition, fellows’ expectations for engagement beyond their assigned mentor (or the mentoring network) were not always met.“It’s a bit of a tough time of the year to be able to go away for a week. That was always a challenge. We have young kids and I think a lot of the fellows also do. It’s just hard to tear away during graduation and recital season.”Finding time to devote to the weeklong training in St. Louis was likely a challenge for many fellows and was mentioned specifically by one fellow with young children.“the hard part for me was that [assigned mentor] and I are in very different areas, and I’m kind of in different areas from a lot of the other folks. So I kind of got generic mentoring, not specific to some of my work typically. But given that, it was still useful.”For a few fellows, the differences in research area for their mentor was seen as a barrier in the mentoring process in their particular research focus.Similarly, fellows mentioned having been matched with mentors who operated in different funding systems was challenging in terms of understanding the various requirements of each system.“I’m in a very odd kind of situation here at [institution C]. I am the only faculty member in my particular context … I’m not part of an academic department … I am the only faculty member where I am. I don’t have colleagues who are partnering with me on a regular basis.”A few external challenges were mentioned in terms of making progress on research during the program. One fellow mentioned their institute had a fairly well-founded D&I research capacity core, and the challenge was more in terms of getting in with an already formed infrastructure. Conversely, not having formal institutional capacity for conducting and building capacity for D&I research was a barrier for one fellow in terms of developing partnerships.In a different example, one fellow remarked about the unique challenge of providing D&I research consult to others in newer field because “not everybody knows what it is,” which was clear to the fellow because “a lot of the consult requests would not actually be implementation science.”These interviews provided valuable information about the components of MT-DIRC that were most beneficial to fellows and the role that mentoring played in the fellow’s overall experience of the program. In answering our research questions and evaluating findings against our program’s conceptual model, we confirmed the importance of mentor characteristics and program structure and format in designing and implementing mentored training programs.Fellows were not specifically asked about what makes for an effective mentor. Instead, fellows commonly responded with features of an effective mentor to several interview guide questions, reiterating the importance of the personality and characteristics of the mentor- a key concept in mentoring literature , 39 and Fellows reported the mentoring relationships coupled with the structure of the training program were beneficial for progressing in D&I research. Designing mentored training programs that introduce regular contact with both mentors and other peers may be beneficial for keeping research on track, learning from both mentors and peers, and overall connecting didactic material with application to research. These concepts were emphasized by fellows in all skill gain and social connectivity categories. Regardless of fellows’ skills gained during the program or the amount of their network growth, the mentorship component was seen as important – in its structure, the role of the mentors and the impact. In other words, mentoring may level the playing field across diverse backgrounds and factors.Scientific productivity in terms of manuscripts and grant funding is often a common measure of “success” in academic training programs. While our fellows reported scientific productivity , perhaps as important was the mention of credibility in the field of D&I. New found confidence as leaders in a relatively newer research field such as D&I research suggests the value of bidirectional relationships with membership in a recognized mentoring network, thus building skills and scientific self-efficacy. The qualitative inquiry provided unique insights which enhance our previous quantitative findings , 33, 34 Understanding how membership in a network of other program trainees can build capacity within a field is a key finding from our work. In designing mentored training programs, unique ways to network within the program design can be built and perhaps can be branded for national and international recognition. For example, our program’s Twitter handle was used mainly to promote applications to the program and to share accomplishments of the fellows and mentors. In addition, the handle was often included in posts from the National Cancer Institute’s Implementation Science handle (@NCI_ImplSci) for promotion of D&I trainings, webinars and workshops. Twitter usage among academics (#AcademicTwitter) is gaining momentum as a prominent tool for career advancement , and hasThe findings also point to the importance of designing programs which deliberately involve peer mentoring. Decastro et al. previously highlighted the unique abilities of mentoring networks to address possible diverse mentoring needs of a mentee and the importance of “horizontal mentoring” . Our resContrary to our hypothesis that drove our purposive sampling, we did not find a clear pattern in differences between mentions of benefits and challenges in the main themes across the fellows’ levels of skill gain and network connections. For example, challenges of competing interests and time were mentioned by fellows with high and low skill gain and with a large and small number of network connections. This finding may highlight latent items unmeasured within the conceptual framework such as intrapersonal receptivity to programs, support from local mentors, or some other key variables in the fellow characteristics domain or other domains. It may also mean that many of the underlying reasons for how mentoring is beneficial are consistent across a diverse set of mentees.N = 6) international fellows, though none were represented in these interviews. Future evaluations of mentored training programs should include perspectives from multiple countries, especially when mentors are not in the same country as the fellow and the local context may differ. Some of the challenges to date with outcomes from mentored training programs like ours are small sample sizes and limited years of funding which further limit the ability to combine samples over time. Validated evaluation measures across similar training programs would make cross-project research more feasible when examining quantitative relationships within a conceptual framework.The lessons learned from these qualitative evaluation findings will be integrated into the recently funded R25 Institute for Implementation Science Scholars (IS-2)  which foResults from these qualitative interviews reveal the “secret sauce” of the mentored training program which contributed to the fellows’ success. Key ingredients include mentoring that is structured and coupled with applied learning and respected and dedicated mentors. These can be built into programs more explicitly . Increased scientific collaborations and credibility within a recognized network were important trainee experiences. This enhanced capacity may require additional contextual understanding to deliberately build into mentored training programs.Additional file 1. Final interview guide. This file provides the final interview guide used with fellows of the MT-DIRC program to complete the qualitative interviews described in this study.


At a time in education when it is important for programs at colleges and universities to be productive in teaching, student recruitment, and income generation, the AGHE Program of Merit review process can aid in advancing gerontology and health professions programs. The AGHE Program of Merit has expanded its review. Now Colleges of Osteopathic Medicine and all Health Professions program may apply for Program of Merit status.. The POM designation provides gerontology programs and those health professions program that include geriatrics/gerontology content in the curriculum with an AGHE “stamp of approval” which can be used to verify program quality to administrators, to lobby for additional resources, to maintain a quality program, to market the program, and to recruit prospective students into the program. This session will begin with the “Why,” “What” and “How” of applying for Program of Merit and then provide time for small group consultation regarding the Program of Merit application. Preparation of the self-study document will be detailed by the experienced faculty members followed by the review process and timelines associated with application process. Free consultation available!


The rise in pediatric obesity and its accompanying condition, type 2 diabetes (T2D), is a serious public health concern. T2D in adolescents is associated with poor health outcomes and decreased life expectancy. Effective diabetes prevention strategies for high-risk adolescents and their families are urgently needed.The aim of this study was to co-design a diabetes prevention program for adolescents by using human-centered design methodologies.We partnered with at-risk adolescents, parents, and professionals with expertise in diabetes prevention or those working with adolescents to conduct a series of human-centered design research sessions to co-design a diabetes prevention intervention for youth and their families. In order to do so, we needed to (1) better understand environmental factors that inhibit/promote recommended lifestyle changes to decrease T2D risk, (2) elucidate desired program characteristics, and (3) explore improved activation in diabetes prevention programs.Financial resources, limited access to healthy foods, safe places for physical activity, and competing priorities pose barriers to adopting lifestyle changes. Adolescents and their parents desire interactive, hands-on learning experiences that incorporate a sense of fun, play, and community in diabetes prevention programs.The findings of this study highlight important insights of 3 specific stakeholder groups regarding diabetes prevention and lifestyle changes. The findings of this study demonstrate that, with appropriate methods and facilitation, adolescents, parents, and professionals can be empowered to co-design diabetes prevention programs. Excess weight and obesity in youth continue to be a serious public health concern  and put Diabetes prevention strategies for adults have seen significant progress -17, but HCD is a qualitative problem-solving approach that engages stakeholders in the process of exploration, development, and implementation of solutions . HCD is For these reasons, we engaged at-risk adolescents, their parents, and professionals in a series of HCD sessions to answer the following questions: (1) what environmental factors inhibit/promote lifestyle changes in adolescents and their families? (2) what are the ideal characteristics of a diabetes prevention program for this population? and (3) what are the effective strategies to engage adolescents and their families in a diabetes prevention program? This paper describes the first phase of a study to co-design a diabetes prevention program for adolescents and their parents by using HCD.This formative study consisted of 4 HCD sessions: 1 professional session, 2 adolescent and parent sessions, and 1 adolescent-only session. We collaborated with Research Jam, which is part of the Indiana Clinical and Translational Sciences Institute’s Patient Engagement Core . ResearcWe recruited a group of individuals with expertise in diabetes prevention or adolescents  to participate in 1 HCD session. Initially, the primary investigator reached out to colleagues who were involved in diabetes prevention or experts working with adolescents. Examples include physicians, diabetes educators, and community youth organizations. Additional professionals were recruited through a snowball sampling technique as initial participants invited colleagues who met the aforementioned criteria. Professionals were invited to participate in one 90-minute session and were compensated with US $50 per hour for their time.Adolescents and parents were recruited in 4 ways. First, the professional group members recruited adolescents and parents in connection with their organizations by distributing flyers and word of mouth. Second, adolescents and parents were recruited from a youth diabetes prevention clinic. Third, adolescents and parents were recruited from an existing local family-focused nutrition and physical activity program. Finally, a school-based adolescent group was recruited by a school nurse from a local high school.The inclusion criteria for adolescents were (1) between the ages of 10 years and 17 years, (2) overweight , (3) with 2 additional risk factors for T2D , (4) English speaking, and (5) a parent willing to participate in the family session (with the exception of the high school group).Two adolescent and parent research sessions were offered simultaneously in the same building but in separate rooms. The school-based adolescent group took part in 1 session at a high school. Participants were compensated with US $20 per hour of their time. These sessions lasted 3 hours. The Indiana University Institutional Review Board approved this study and participants provided written informed consent prior to engaging in any research activities. In order to address ethical considerations, adolescents younger than 14 years underwent the assenting process, documents were written at a sixth-grade reading level, and compensation was set at a level that covers participants’ time and effort without being coercive.Research Jam facilitated the HCD sessions. All sessions were audio recorded with participant permission. Research Jam recorded field notes during activities and discussions. Each session consisted of activities that aligned with the study objectives to (1) better understand environmental factors that inhibit/promote lifestyle changes, (2) elucidate desired program characteristics, and (3) explore improved activation in diabetes prevention programs . The purThe Research Jam project lead conducted collaborative analysis meetings with 4 members of Research Jam who helped facilitate the sessions. The team physically separated individual pieces of explicit data onto slips of paper. Data that required interpretation such as drawings were analyzed by capturing components included in the drawings onto slips of paper. For example, a picture of people sitting still in chairs was coded as physically inactive. This work was reviewed by Research Jam team members to ensure all data were captured. The team then used affinity mapping to physically organize the data pieces by similarity . Team meFourteen individuals participated in the professional group session. This session took place at a community church that had space to accommodate this group size. The group consisted of physicians, researchers, diabetes educators, school personnel, Young Men’s Christian Association staff members, a nurse manager at a community health center, a church pastor, a youth mentor, and a youth counselor.The first adolescent and parent session consisted of 18 people with 5 parents and 13 adolescents and took place at a community church. The second adolescent and parent session consisted of 14 people with 6 parents and 8 adolescents and took place at a community center. The school-based adolescent group session consisted of 12 adolescents and took place at a high school.The session findings are presented based upon the objectives of the session. No other evaluation of participation was conducted.Both adolescents and professionals stated that creating an environment where healthy choices are acceptable and appealing was important. One professional stated, “What they would actually want to do, not what they feel like they’re supposed to do or have to do, but that the healthy choice is like the awesome choice.”Both adolescents and professionals stated that it was important that a diabetes prevention program was affirming and not judgmental.Parents and adolescents reported they wanted a program that avoided focusing on what not to do. This was best illustrated with cupcakes on the table with a sign reading “do not eat” .Adolescents and parents felt that trying new foods and activities was an important part of adopting healthy behaviors that fit their lifestyle. Adolescents were interested in trying activities that were out of the ordinary or taking ordinary things and experiencing them in novel ways. For instance, adolescents created a drinkable swimming pool as a component of the diabetes prevention party . This idAdolescents, parents, and professionals reported barriers such as lack of access to reliable transportation, access to healthy foods, and safe places for physical activity.Adolescents reported that food choices are often limited by the options offered by parents, schools, and vending machines. As one adolescent described, “If you go to the vending machine, everything has some sort of sugar or fat in it. There aren’t really options for healthy stuff.”All groups discussed the costs of healthy versus processed foods as a significant barrier. In addition, participants viewed wasted food as wasted money and viewed free food as free money such as buffets and free refills.Parents felt that the time required to cook healthy meals and engage in exercise was a luxury not afforded to them. As one parent explained, “When they don’t get home and mom doesn’t get home until late, then it’s like, okay throw a pizza in.”All participant groups identified competing priorities as a barrier. The demands of work, school, financial strain, and unsafe neighborhoods made healthy lifestyle change a lower priority than imminent needs. Adolescents felt that a long sedentary school day coupled with required evening homework time impeded efforts to increase physical activity. Parents’ comments regarding the workday and challenges incorporating physical activity mirrored the adolescents’ sentiments on this topic. Additionally, parents verbalized safety concerns around independent outdoor play for youth. One parent described how different her childhood was from that of her children, “Even though I tried, my kids’ life is so much different from the way I was raised. Some of it was because I was afraid to send them out to play—but I was out and my mom didn’t know where I was most of the day…I would ride my bike 2 or 3 miles from home. That’s just not my kids’ existence. They’ve never had that.”Adolescents and parents described foods and beverages high in sugar or salt as having an addictive quality. As one parent stated, “I’m trying desperately to find things that taste good and are healthy.” They also felt that situations where others continued to eat those foods in their presence hindered their efforts. Adolescents specifically called out celebrations, which so often center around unhealthy foods, as problematic for maintaining healthy eating habits.All groups reported that having fun should be the primary focus of a diabetes prevention program.Adolescents, parents, and professionals identified “play” as an important factor in an ideal program. Adolescents expressed play as participation in sports and free movement activities . Parents identified play as hands-on learning activities such as cooking classes, recipe sharing, and exercises not available at home.All participant groups were averse to didactic lecture-style sessions. For instance, the worst program ever drawings included an instructor in front of a class saying “blah, blah, blah” and a participant saying, “May I speak now?” . AdditioAdolescents wanted a facilitator who incorporates fun. Parents desired a facilitator that adolescents can look up to. All participants wanted program staff who were fun, engaging, and respectful.Adolescents, parents, and professionals saw value in rewarding success. Adolescents verbalized money or access to an experience as motivating rewards. For instance, in one of the diabetes prevention party drawings, adolescents envisioned a reward where trying healthy behaviors gained them access to “the real party” . ParentsA central focus for all participants was the inclusion of delicious healthy foods to try.Adolescents, parents, and professionals saw value in friendships and personal relationships as part of the program. All participants identified personal relationships as vital to the success of their program or party drawings. One adolescent explained, “I think you get to know the people that you’re going to be doing the class with and it’s a lot easier. So, if you do some sort of like fun game or activity at the beginning and people get to know each other pretty well, it’s much easier to have a good time.” The ability to collaborate was also important in their drawings.All participants agreed that messaging can be vital to getting adolescents to the program. Parents suggested using an acronym that sounded fun and social, such as “FIT: Fight it Together.” Adolescents suggested using messaging that sounded better than the actual program in order to get adolescents to the door. One adolescent answered the question about how to get adolescents to attend a diabetes prevention program by saying, “Probably make it sound better than it is because once they are there, they probably won’t leave.”All groups thought it was important to use rewards that promote healthy behaviors and celebrate success.Adolescents felt that “diabetes prevention” and “health” were not motivating messages to lead with because they were associated with uninteresting didactic learning experiences such as health class. Components of the program that adolescents and parents found most important  should be highlighted in visual and written messaging and marketing of the program.There is a need for efficacious diabetes prevention interventions for adolescents and their parents. We used HCD methods to better understand barriers, improve diabetes prevention program design, and optimize participant engagement. We found that lack of financial resources, limited access to healthy foods and safe places for physical activity, and competing priorities were significant barriers to adopting lifestyle changes. This is consistent with the findings that adolescents of low socioeconomic status have lower quality diets and lower levels of physical activity than their counterparts of high socioeconomic status .We found that participants want interactive, novel, hands-on learning sessions that incorporate a sense of fun and play. Adolescents and their parents desire opportunities to try new behaviors in a supportive group environment and to work toward healthy incentives and rewards. It is important to make healthy choices intrinsically motivating because they are fun, they align with important values, or they are part of someone’s identity. If healthy choices are seen as obligatory, boring/uncool, or unenjoyable, they are less likely to be adopted. Stakeholders are averse to “one-size-fits-all” lecture-style sessions that focus on “what not to do,” recommending that the focus be kept on their interests.Other types of formative research have been used in diabetes prevention program design. Vangeepuram and colleagues  conducteThis study has the following limitations. Recruitment strategies may have attracted participants who were more keen on making lifestyle changes. Participant perspectives may not be representative of the general population as the sample was small and from 1 urban community. Demographics of the research participants were not collected. The HCD sessions focused on desired program content rather than the delivery platform. We plan to further translate these findings into a curriculum and test its effectiveness in a larger sample size. Future research should investigate participant engagement by using different delivery modalities.The findings of this study highlight important insights regarding diabetes prevention and lifestyle change from 3 specific stakeholder groups and demonstrate that, with appropriate methods and facilitation, adolescents, parents, and professionals can be empowered to co-design diabetes prevention programs.


Digital health interventions (DHIs) are increasingly becoming integrated into diabetes self-management to improve behavior. Despite DHIs becoming available to people with chronic conditions, the development strategies and processes undertaken are often not well described. With theoretical frameworks available in current literature, it is vital that DHIs follow a shared language and communicate a robust development process in a comprehensive way. This paper aims to bring a unique perspective to digital development, as it describes the systematic process of developing a digital self-management program for people with type 2 diabetes, MyDESMOND. We provide a step-by-step guide, based on the intervention mapping (IM) framework to illustrate the process of adapting an existing face-to-face self-management program  and translating it to a digital platform (MyDESMOND). Overall, this paper describes the 4 IM steps that were followed to develop MyDESMOND—step 1 to establish a planning group and a patient and public involvement group to describe the context of the intervention and program goals, step 2 to identify objectives and determinants at early design stages to maintain a focus on the strategies adopted, step 3 to generate the program components underpinned by appropriate psychological theories and models, and step 4 to develop the program content and describe the iterative process of refining the content and format of the digital program for implementation. This paper concludes with a number of key learnings collated throughout our development process, which we hope other researchers may find useful when developing DHIs for chronic conditions. Type 2 diabetes (T2D) is a progressive lifelong condition affecting over 422 million people worldwide  and is aSelf-management education can be delivered in several forms; one of these forms is via structured education programs. Structured education programs are nationally and internationally recommended for all people with T2D and meet nationally agreed criteria, including following an evidence-based curriculum that is theory-driven, evidence-based, and resource-effective, carrying out quality assurance of teaching standards and delivering regular audits . ExampleIn 2008, the National Institute of Health and Clinical Excellence published guidelines to recommend the availability of group-based structured education programs as a key priority for diabetes management . EvidencAlthough referrals to structured education have increased over the last 3 years, attendance at such programs have decreased, and attendance rates are as low as they were in 2009 . This isDigital health interventions   have becDHIs in other chronic conditions have been shown to be cost-effective, with a recent cost-effectiveness study depicting the benefits and cost-effectiveness of digital-based psychological interventions for reducing behavioral stress management and anxiety ,22. InfoAppropriate steps are essential when developing evidence- and theory-based digital programs to ensure they are implemented effectively in the real world . DespiteIM, a 6-step framework, is often applied to guide behavior change interventions and health education development. This evidence-based approach, although presented as a series of 6 steps, follows a more iterative process that bridges the gap between theory and practice. With this in mind, we aimed to develop our digital program based on a systematic and robust process such as IM, to ensure that our evidence-based program can be implemented in real-world settings. The development process for MyDESMOND was guided by the first 4 steps of IM, as illustrated in This paper describes the systematic developmental process that we undertook to adapt the content and evidence of an existing face-to-face structured self-management education program (DESMOND) for T2D and translate it into a digital self-management program (MyDESMOND). This process is presented based on the IM framework .A multidisciplinary team  was brought together to provide expertise in the psychosocial and clinical aspects of T2D, digital health, and behavior change research. Throughout the design process, our planning team worked alongside a Web-designer to ensure that the logistics and digital platform would be appropriate for a UK-based program.Patient and public involvement was essential for our development process . ThroughWe conducted a preliminary scoping search, and together with the findings of our existing research studies, we aimed to collate key learning points to explore and identify the key program goal and key behavioral determinants of MyDESMOND.Self-management involves 3 key tasks  and consists of core self-management skills, including problem-solving, decision making, resource utilization, and action planning . DigitalIn addition to knowledge and improved coping skills, social support has also been linked as a major predictor of, and positive influence on diabetes self-management. A systematic review, which explored the role of social support on biomedical and psychosocial outcomes, as well as behavior change, reported a positive impact on the aforementioned outcomes . In addiA qualitative evaluation of patient and health care professional (HCP) views on barriers to self-management and multimorbidity (including diabetes) identified 3 main factors that influence self-management: (1) capacity , (2) responsibility (the degree to which patients and HCPs agree about self-management), and (3) motivation (willingness to take-up types of self-management practices) .We conducted focused synthesis of work in 2 areas: (1) a systematic review and meta-analysis to critically appraise and quantify the evidence on the effect of digital interventions that aim to improve well-being in people with T2D , and (2)information provision and monitoring.The systematic review and meta-analysis  identifiP=.15) or distress (P=.43). Nevertheless, the review did take into consideration that the number of studies included in the meta-analysis was low, and thus, conclusions on the meta-analysis were considered with caution.The aim of this review was to examine if digital-based interventions improve well-being outcomes such as depression and diabetes-related distress; however, no significant improvements were found following a meta-analysis in depression  to include both direct and indirect communication, in the form of a chat forum or messages.On the basis of the findings above, we considered the following elements in our development work: (1) to have a professional-led, rather than peer-led program, (2) to include some form of This systematic review of the reviews  exploredOur face-to-face self-management program  was deveIn 2017, we developed our first digital-based self-management program on a responsive digital platform to promote physical activity in women with a history of gestational diabetes (BabySteps) . This diask the expert function, (4) use short videos to provide information, (5) include quizzes as a form of interactive learning, and (6) consider a frequently asked question page to enhance engagement.It was important to consider that BabySteps was a prevention program with a focus on physical activity . We therefore supplemented our needs assessment step with further work conducted by our lead author  to develOverall, the outcomes of the needs assessment provided the evidence for our program goals and defined the purpose of our digital program, which was to provide a digital self-management program to people with T2D to improve medical, behavioral, and emotional self-management. This was developed with the aim to improve and maintain self-management behaviors, improve knowledge, promote self-care skills, increase self-efficacy, and improve well-being.On the basis of our scoping literature and mixed methods studies (as part of step 1), we produced a logic model of the problem, illustrating the link between behavioral determinants and the behavioral and environmental factors, which lead to the targeted health problems .This step involved developing the specific change objectives and identifying specific behaviors that determine behavior change for this target population. Informed by the findings from our needs assessment, our planning group identified 5 key behavioral determinants and 5 performance objectives , which we anticipated would influence the behavioral outcome . In detaIn a complex environment, dealing with influences on an individual, social, and cultural level, we aimed to adapt and develop a digital program that was theory-based to break down targeted health behaviors. Theory-based interventions are more effective than non–theory-based interventions and can provide a clear understanding of what works in terms of adapting interventions across populations, behaviors, or contexts . Thus, wA key conceptual framework of self-management was developed by Corbin and Strauss. Self-management programs  often include at least one of the three main overarching areas: cognitive , behavioral (such as lifestyle changes and managing medication effectively), and emotional  . On the We applied the COM-B model as it provides a common language for the reporting of behavior change interventions . Atkins process model, the Health Action Process Approach (HAPA) model informed the development of our digital program. Intention alone does not always change behavior [Despite the application of the behavior change taxonomy, it was still essential to adopt a model that helped explore the process of change and helped explain how individuals decide to engage in healthy behavior. Known as a behavior , thus wiemotional support, which focuses on sharing life experiences and reassurance; instrumental support, which can include practical support such as material or services that users can access directly; informational support, which involves evidence-based information or advice; and appraisal support, which includes concepts such as constructive feedback and affirmation. Lakey and Cohen’s [digital social support and individuals’ appraisals and coping skills, which can, in turn, mediate distress levels and improve overall well-being and T2D self-care.Social support plays an integral part in the management of diabetes and is often associated with health behaviors such as physical activity. Thus, it was deemed appropriate to base our digital program on a social support-focused theory. We considered all 4 types of social support : emotion Cohen’s  Social SWhat is T2D, Medication, Complications of diabetes, Food choices, Physical Activity, Sedentary behavior, Emotions, Diabetes-related distress, Setting goals, and Relapse.On the basis of key learnings from our face-to-face program (DESMOND) and our digital programs (BabySteps and myWellbeing) in combination with our theory-based approach, we had a clear idea of the program themes, material list, and aim of MyDESMOND. With the involvement of our multidisciplinary team, we designed scripts and material in line with the Corbin and Strauss self-management framework, incorporating content around medical, role, and emotional management. Once the content was adapted and developed, we liaised with our Web-designer and information technology team to map the material  onto an appropriate digital platform that was easy to access from any electronic device . MyDESMOND was developed to meet the objectives detailed in step 3. The following topics are included in MyDESMOND: have a go at MyDESMOND at various points of the development phase and provide feedback. Examples of PPI feedback and suggestions, which refined MyDESMOND included the following: (1) to provide the chat forum function as optional to the user (and not mandatory), as not all users would seek Web-based interaction with peers; (2) to include a separate section on well-being and discuss about diabetes-related distress and negative emotions in a nonjudgmental way—this suggestion from the PPI members reiterated issues around stigma and blame; (3) to provide weekly additional sessions on well-being, physical activity, and food choices—this change resulted in the development of additional mini videos to ensure that the users received regular information on important topics; and (4) to introduce mini videos of testimonials of MyDESMOND users sharing personal experience. Additional feedback received from our PPI members included (1) the navigation system of MyDESMOND was easy to use, (2) to make our logo clear to reassure that we are a reliable and trustworthy source; (3) digital ongoing support is much needed poststructured education programs; therefore, all content must be available at all times to the users.In addition to our previous work mentioned in the above sections, it was essential that we also involved patient and public feedback throughout the development of MyDESMOND. Furthermore, PPI work with early users helped inform and refine the content and format of our digital program. PPI work took place based on an iterative process, whereby 9 PPI members were provided logging details to The interface and features were designed as such to improve diabetes self-management practices. The focus was directed toward daily step count, challenges, notifications, and the release of weekly education bite-sized sessions. These short sessions consisted of animations, gamification, quizzes, and games designed to be no more than 5 min in duration. Features include interactive learning, monitor health, activity tracking, ask the expert, community , goal setting, challenges , and invite a buddy (invite family and friends to join the program). MyDESMOND is accessible on any digital device . The platform was built using progressive Web applications (PWAs), a type of mobile app delivered through the Web. It operates similar to a native app, but its responsive design allows it to work across all modern browsers and devices . External SMEs carried out a number of security tests, including penetration testing (to ensure data remains safe) and a source code review (to ensure it complied with Open Web Application Security Project level 2). The purpose of this security testing was to attempt to identify any potential or actual vulnerability to an attack launched across a computer network that could threaten the confidentiality, availability, and integrity of the information being stored and processed.In this paper, we described the application of the IM framework for the adaptation and development of a digital self-management program, MyDESMOND. This paper brings a unique perspective to digital development, as it illustrated the process from adapting and translating the evidence and content of a face-to-face education program (DESMOND) to developing a digital version of it.We described the 4 IM steps that were followed to develop MyDESMOND. In step 1 of the IM process, we established a planning group and a patient and public involvement group and described the context of the intervention and program goals. In step 2, we identified objectives and determinants at early design stages to maintain a focus on the strategies adopted. Step 3 focused on generating the program components underpinned by appropriate psychological theories and models. This led to step 4, which described the adaptation and development of the program content and the iterative process of refining the content and format of MyDESMOND.This paper has described in detail the three key perspectives of IM that informed the development of MyDESMOND: the use of evidence, the participation and engagement of stakeholders, and the use of theories and BCTs. Overall, our development work was based on a well-established and comprehensive theoretical framework, which has been used extensively in the development of behavior change programs.The development process was heavily guided by stakeholder and PPI input, to ensure that we received regular feedback throughout the development phase and to ensure that the program was designed appropriately and was relevant to the target population, culturally and contextually. This approach helped refine and structure the format and content of MyDESMOND to reflect the unmet needs of this population accordingly. It is also important to highlight that although our needs assessment and evidence synthesis were predominantly based on findings from systematic reviews, our evidence was also based on rigorous research studies evaluating face-to-face and digital programs.Some of the main limitations of IM, which we experienced during this development process, are the complexity and time-consuming aspects of this framework. Following a robust process such as IM, which included conducting systematic reviews, synthesizing evidence from existing studies, obtaining regular feedback from stakeholders, and identifying key theories and BCTs, required substantial time and resources from our team. Nevertheless, we found IM to be an extremely useful resource, which helped develop the best possible digital self-management program for our people with T2D.DHIs in diabetes self-management and other chronic conditions are increasing. It is important that future research recognizes the complexity of DHIs and continues to adopt a robust development process informed by evidence and theory. During the development of MyDESMOND, we identified key learning points that might be helpful to other researchers developing DHIs for chronic conditions.The expertise of our research, project development, and clinical team members was critical to the successful development of the content, including diabetes education, diabetes clinical expertise, and behavior change. Together with experts in Web-design and digital health, the infrastructure of the program was shaped in such a way that it is now usable on NHS systems and maintains the ethical administration of sensitive information. The collaboration between research teams and Web developers was essential so that the focus of development is not only on the content of the program but also on the user interface and functionality of MyDESMOND.We followed a target population-centered approach, based on the taxonomy of approaches to developing DHI . This apreal world [The role of theories in DHI is crucial, but yet not all programs are guided by theories . It is ial world . We ensubuddies. Literature in chronic self-management has an established series of evidence to confirm that providing a secure platform for communication , allows the end user to share personal experiences, increase their knowledge, and improve self-care [buddies) can enhance collaboration, accountability, and peer support [Step 1 of the IM process, which included the mixed methods needs assessment, allowed us to collate findings and insight not only from our own work but also from the current literature. This helped identify a number of key functions that were eventually incorporated in MyDESMOND, including information, personal stories, interactions with other app users, and elf-care -57. In a support .The evaluation and implementation of MyDESMOND is currently ongoing in the United Kingdom and Australia, and results on its effectiveness will follow . A folloIM framework was an effective approach to bring together research evidence and theoretical concepts to guide the adaptation and development of MyDESMOND. Our evidence- and theory-based digital program provides ongoing support and guidance to people with T2D. We hope that our paper can be used as an example for other researchers and HCPs who are developing similar digital self-management programs across chronic diseases.


Orofacial quantitative sensory testing (QST) is an increasingly valuable psychophysical tool for evaluating neurosensory disorders of the orofacial region. Here, we aimed to evaluate the current evidence regarding this testing method and to discuss its future clinical potential.We conducted a literature search in Medline, Embase and Scopus for English‐language articles published between 1990 and 2019. The utilized search terms included QST, quantitative, sensory testing and neurosensory, which were combined using the AND operator with the terms facial, orofacial, trigeminal, intraoral and oral.Our findings highlighted many methods for conducting QST—including method of levels, method of limits and mapping. Potential stimuli also vary, and can include mechanical or thermal stimulation, vibration or pinprick stimuli. Orofacial QST may be helpful in revealing disease pathways and can be used for patient stratification to validate the use of neurosensory profile‐specific treatment options. QST is reportedly reliable in longitudinal studies and is thus a candidate for measuring changes over time. One disadvantage of QST is the substantial time required; however, further methodological refinements and the combination of partial aspects of the full QST battery with other tests and imaging methods should result in improvement.Overall, orofacial QST is a reliable testing method for diagnosing pathological neurosensory conditions and assessing normal neurosensory function. Despite the remaining challenges that hinder the use of QST for everyday clinical decisions and clinical trials, we expect that future improvements will allow its implementation in routine practice. Standardized blunt needles with a 0.25‐mm diameter and a weight range from 8 to 512 mN are used, and the shape, size and angulation affect the pain threshold. Modified dental probes can also be used intraorally.3.3.5Both simple and more sophisticated pressure algometers are available, and several types have been described for intraoral use . Investigations with these devices provided the first insights into thermal topographical variation. Tests were also performed using thermal rollers that are cooled or heated in a water bath . Investigation of the orofacial region requires smaller contact areas (1–4 cm2) to test the different dermatomes of the trigeminal nerve, which can be too small to test with regular probes or instruments  and have a contact surface of up to 10 cm2, Nd‐YAG and thulium‐YAG lasers) can be used intraorally, but sometimes they can only be applied in the anterior region because the rays have to pass through articulating arms. A recently launched new generation of laser stimulators, termed diode lasers, are more stable, smaller and cheaper, and are thus promising for QST  compiled a “QST battery” of seven tests, including 13 parameters: cold detection threshold (CDT), warm detection threshold (WDT), paradoxical heat sensation (PHS), thermal sensory limen (TSL), cold pain threshold (CPT), heat pain threshold (HPT), mechanical detection threshold (MDT), mechanical pain threshold (MPT), mechanical pain sensitivity (MPS), dynamic mechanical allodynia (DMA), wind‐up ratio (WUR), vibration detection threshold (VDT) and pressure pain threshold (PPT)  on QST and pain ratings in patients undergoing orthodontic treatment. It was shown that patients treated with LLLT had lower pain ratings and higher CDT, WDT, CPT, HPT thresholds indicating a treatment effect that is measurable with QST  rather than according to aetiology   of the inferior alveolar nerve, reporting that NCS showed a higher sensitivity compared to QST or QualST (Teerijoki‐Oksa et al., 4Evidence concerning orofacial QST and its diagnostic value has markedly increased over recent years, demonstrating that QST is a reliable method for assessing neurosensory function under normal and pathological conditions. Translation of QST to clinical practice remains challenging due to several factors, and additional research is needed to enable differentiation between pathological entities. Integration of the entire QST battery, or the use of some QST parameters combined with other diagnostic tools, could further increase accuracy and support QST implementation in routine practice.


Arid1a, and for Apc, the major silencer of Wnt pathway, chromatin was more accessible and histone marks turned into active ones at the Epo downstream enhancer. Activating β-catenin signaling increased binding of Tcf4/β-catenin complex and upregulated its enhancer function. The loss of Arid1a together with β-catenin signaling, resulted in cell-autonomous EPO transcription in mouse and human hepatocytes. In mice with Apc-Arid1a gene invalidations in single hepatocytes, Epo de novo synthesis led to its secretion, to splenic erythropoiesis and to dramatic erythrocytosis. Thus, we identified new hepatic EPO regulation mechanism stimulating erythropoiesis.Erythropoietin (EPO) is a key regulator of erythropoiesis. The embryonic liver is the main site of erythropoietin synthesis, after which the kidney takes over. The adult liver retains the ability to express EPO, and we discovered here new players of this transcription, distinct from the classical hypoxia-inducible factor pathway. In mice, genetically invalidated in hepatocytes for the chromatin remodeler  Chromatin dynamics strongly modulates gene expression, and the liver is a prominent tissue in which chromatin opening is a pre-pattern for cell fate programming . ARID1A,ARID1A is the chromatin modifier gene the most frequently inactivated (>13% of HCCs). These mutations are preferentially found in HCC with activating mutations of the CTNNB1 gene encoding β-catenin, accounting for one third of HCC   located in the vicinity of target genes . Chromatli (Apc)  and/or A (Arid1a  are lostApc and/or Arid1a floxed genes with a low dose of Cre-expressing Adenovirus (AdCre) known to mainly target the liver  exhibited blood-filled lacunar spaces , 18 [Arid1a]ko-focal (n = 18), or control (n = 10) mice studied. [Apc-Arid1a]ko-focal mice exhibited 50% and 100% mortality at 10 and 14 months, respectively   , associas (RBCs) . We thusApc]ko-focal mice , and spleen; these are the three major organs responsible for erythropoiesis during embryogenesis . In [Apc-Arid1a]ko-focal liver non-parenchymal cells (NPCs) relative to controls, there was no difference in TER119+/CD71+ progenitors revealing no intra-hepatic erythropoiesis (+/CD71-). This liver erythrocytosis was confirmed by immunostaining of the hemoglobin subunit beta (HBB) in liver tissue sections, showing that RBCs, but not erythroblasts, accumulated in these livers   . Epo expnditions . Mutatioell line .EPO mRNA expression was also regulated by both the chromatin remodeler ARID1A and the Wnt/β-catenin signaling pathway in primary human hepatocytes after siRNA-mediated ARID1A and APC downregulation , known to be involved in Epo transcription in the embryonic liver, as well as the known Hif- (HIF-REs) and Hnf4-containing responses elements (HREs)  . This Tcs (HREs) . We demonscribed . HoweverEpo gene .Epo transcription through the Epo-3’E. We transfected a luciferase reporter (pEpoE-luc) containing the HIF and HNF4-binding sites into primary mouse hepatocytes  signaling is the master pathway regulating cription . We invee livers . A small targets . As expeor Hif2α  resultedor Hif2α . Interesh Arid1a .Epo enhancer in a hypoxia- and HIF-independent manner.In all, the Wnt/β-catenin pathway controls erythropoietin expression in hepatocytes through the 3’ Epo-3’E HRE  in control liver nuclear extracts  was not affected by Arid1a status  in the embryonic liver or anemic/hypoxic adult liver. We demonstrated that Tcf4/β-catenin bound the Hnf4-Responsive Element (Hnf4-RE) in the Epo-3’E and that the enhancer activity is independent of HIF in this context, contrary to what is reported in colorectal cancer cell lines, in which transcriptional cooperation between HIF and β-catenin occurs in hypoxia adaptation , histone mark, β-catenin and Arid1a cistromes (ChIP-Seq) in liver chromatin from Arid1a-null and β-catenin-activated hepatocytes.We found here that the loss of Arid1a does not change the transcription of hepatic canonical Wnt/β-catenin target genes. As for Arid1a in liver carcinogenesis. In turn, confirmation of such a role would corroborate a recent study showing that hepatic Arid1a can harbor either a tumor suppressor or oncogenic role depending on the cellular context  adenovirus as described . For panlobular genetic inactivation, 8-week-old Apcflox/flox/Ttr-CreTam and Arid1aflox/flox/Ttr-CreTammale mice were given a tamoxifen diet  for 4 days. These mice are referred to as [Apc-Arid1a]ko-TOTAL, [Apc]ko-TOTAL, and [Arid1a]ko-TOTAL mice.Mice carrying two floxed alleles in the 14th exon of the boratory ) or the boratory ),were inTam mice , resultiescribed . Mice wiMice were housed under conventional conditions and all reported animal procedures were carried out according to French government regulations . The animal welfare assurance number is APAFIS#14472.After sacrifice, livers were harvested, fixed overnight in 4% formalin buffer, and embedded in paraffin. FFPE liver sections were treated as previously described for immunocytochemistry and HE stainings . AntibodRNA in situ hybridization was done on freshly cut 7 μm FFPE liver or kidney sections using the RNAScope 2.5 HD Duplex Kit, with HybEZ II hybridization system, following the manufacturer’s instructions (Advanced Cell Diagnostics). The following RNAscope probes were used: Epo , Axin2 , DapB , Polr2a .Hematological parameters were measured using a CoulterMAXM automatic analyzer (Beckman Coulter) as previously described .inferior vena cava with a heparinized needle (Sigma Aldrich – H3393-50KU). Plasma samples were stored at −80°C. Plasma EPO protein levels were determined using a Quantikine mouse EPO enzyme-linked immunosorbent assay kit (R and D systems – MEP00B), according to the manufacturer’s instructions.At sacrifice, peripheral blood was collected from the Apc-Arid1a]ko-focal and control mice were injected with anti-erythropoietin rabbit serum, as previously described  with collagenase. The liver cell suspension was collected, and hepatocytes were separated from NPCs by centrifugation for 2 min at 48 g as previously described . The sup5 cell/cm²) and cultured in a humidified 5% CO2 atmosphere at 37°C in hepatocyte growth medium .Cryopreserved human hepatocytes were obtained from Triangle Research Laboratory (Lonza). They were seeded at confluency  directed against Arid1a (Qiagen SI00230405) or control siRNA (Dharmacon D-001210-01-05) in the presence of Lipofectamine 2000 (Thermo Fisher Scientific). The next day, cells were stimulated, or not, with 100 ng/ml recombinant mouse Wnt3a (1324-WN) and 100 ng/ml recombinant mouse R-Spondin 3 Protein (4120-RS) (R and D Systems). Molecular analyses were performed 48 hr after transfection or stimulation.Arid1a or β-catenin (QiagenSI00942039) or control siRNA. Molecular analyses were performed 72 hr after the first transfection.HEPA 1.6 cells were transfected for 24 and 48 hr with 20 nM siRNA directed against APC  or ARID1A (Qiagen 1027416) at day 1 and day 3 after seeding, using Lipofectamine RNAiMAX .Adherent primary human hepatocytes were transfected with 20 nM non-targeting siRNA or siRNAs specific for For luciferase assay, primary mouse hepatocytes were transfected using Lipofectamine 2000 (ThermoFisher Scientific) with 1 μg of a luciferase reporter driven by erythropoietin 3’ enhancer region  , and/or Healthy and peliosis-like areas were isolated from 15 to 20 paraffin sections (10 µm) using a small needle under a binocular magnifying glass. After deparaffinization, FFPE tissues were lysed for 24 hr in tissue lysis with proteinase K (Qiagen) at 60°C. Microarray transcriptomic analysis from paraffin-embedded (FFPE) tissue sections was performed on the MTA-31461 chip. Gene set enrichment analysis (GSEA) was performed using the Java tool application available at the Broad Institute . The analysis was performed using Hallmark gene data sets.Total RNA was extracted with Trizol reagent (Thermo Fisher Scientific) as previously described . Reversegene expression/mRNA expression of undeleted gene expression)) x 100.Arid1a and Apc mRNAs were analyzed by RT-qPCR. For each gene, we used two distinct Taqman assays: (1) One contained two primers both located in undeleted regions. It allowed to detect both wild type and inactivated genes, so the relative mRNA expression of ‘TOTAL’ gene; (2) In the other, one primer was located in the deleted region. Thus, this Taqman assay allowed to detect and amplify only the ‘non excised’ gene. We quantified the percentage of inactivation as follows: % of gene inactivation =  with protease inhibitors (Roche - 11697498001), and boiled in Laemmli sample buffer (Sigma Aldrich – S3401-1VL). 50 µg of protein per lane were run on 8% polyacrylamide gels. The resulting protein bands were electrotransferred onto a 0.2 µm nitrocellulose membrane (Biorad 162–0112), which was then blocked with 5% blocking reagent (Biorad 170–6404) in TBS/Tween 0.1% for 1 hr at RT, probed overnight with the primary antibody, and then incubated with IgG HRP-conjugated secondary antibody for detection with the Clarity ECL substrate (Biorad 70–5061).To analyze nuclear protein extracts, livers were lysed in Hepes 10 mM pH7.9, KCl 10 mM, EDTA 0.1 mM, EGTA 0.1 mM, DTT 1 mM, AEBSF 0.5 mM. Then, after addition of 12,5 µl of NP40 20% and centrifugation, the pellet was resuspended in Hepes 20 mM pH7.9, NaCl400 mM, EDTA 1 mM, EGTA 1 mM, DTT 1 mM, AEBSF 1 mM, PIC1X, Glycerol 5%, and the supernatants boiled in Laemmli. We next ran 70 µg of protein per lane on Bolt 4–12% Bis-TrisPlus Gels . Detection was performed by using Super Signal West Dura ECL system .Nuclear proteins preparation and LXR electromobility shift assay (EMSA) were performed as previously described . The proApc-Arid1a]ko-focal mice and their wild-type littermates and erythroid cell populations were identified and analysed using CD71/TER119 flow-cytometric assay. Staining was performed in a 96-well plate and samples (5.104 cells) were washed once in PBS, 0.4% BSA, 0.1% Sodium Azide, sample staining volume was 50 µl of mix primary-antibody solution, to a final concentration 1.0 × 106 cells/ml. Primary antibody staining mix were prepared for CD71-FITC and Ter119-PE. Unstained cells, Isotype Ig and single stained cells were used as control and to define boundaries between negative and positive cell labelling. After incubation in the primary antibody stain, two washes were performed by adding 200 µl of staining buffer to each sample.Primary mouse bone marrow, spleen cells, and NPC liver cells were harvested from eLife. Your revised article has been evaluated by Didier Stainier (Senior Editor) and a Reviewing Editor.Thank you for resubmitting your work entitled "ARID1A loss in adult hepatocytes activates β-catenin-mediated erythropoietin transcription" for further consideration by The manuscript has been improved but there are some remaining issues that need to be addressed before acceptance, as outlined below:The manuscript of Riou et al. has been substantially modified and reorganised. The authors have performed the majority of the essential revisions, in particular the RNAscope analyses of EPO expression in the wild-type and mutant livers and kidneys. The only experiment that could not be performed was the analyses of the phenotype of the female mice that is likely to take a much longer time due to the COVID crisis that restricted access and breeding in the animal facility.While the manuscript is very much improved, several issues still require attention and should be addressed before final acceptance.1) In the rebuttal letter and in the revised text, the authors describe the EPO expression seen by RNAscope experiments as “bursty” or “stochastic”. While this may be the case, it is not fully justified, nor necessary to explain the phenotype to describe EPO expression in this way. The text should be modified.Arid1a inactivation, in fact, chromatin accessibility appeared to decrease compared to Apc inactivation alone. It appears that only a single primer set was used that overlaps with the TCF binding site. From this limited analysis, it is difficult to assess exact nucleosome positioning and how it may be affected by Arid1a loss. It would have been more appropriate to test several amplicons spanning the enhancer. This would have perhaps better revealed how Arid1a loss affects nucleosome positioning and accessibility.2) The ATAC-qPCR experiments did not reveal increased chromatin accessibility upon 3) Last but not least, the quality of the English in the revised version is very poor leading to lack of precision and making the text difficult to follow. A thorough revision of the text by a native speaker is essential. Essential revisions:1) In Figure 9, the authors summarize their data and proposes a model for how Arid1A regulates TCF4-b-cat activation of the EPO gene. It would be essential to perform ATAC-seq or at least ATAC-qPCR to demonstrate changes in accessibility of the EPO regulatory element under the different conditions. The model proposes that in wild-type conditions and in APC-mutant conditions the SWI/SNF complex is bound at the regulatory element and that it is released under conditions where Arid1a is deleted. This model can be easily tested using antibodies that ChIP components of the SWI/SNF complex. The best would be Arid1a in combination with other subunits, but if there are no ChIP-grade Arid1a antibodies, the authors could at least determine whether SWI/SNF is present under these conditions and released upon Arid1a inactivation. One could also imagine other models where SWI/SNF without Arid1a is also bound when the element is activated, but with different functional outcome in the presence or absence of Ardi1a. Additional ATAC or ChIP experiments could easily discriminate these possibilities. It is essential that the authors address these issues.Epo enhancer and such binding was slightly higher in [Apc]ko-TOTAL and much higher in [Apc-Arid1a]ko-TOTAL hepatocytes than in controls . After a single β-catenin activation process, the H3K27me3 repressive mark slightly decreased and chromatin was more accessible . In contrast, the loss of Arid1a strongly decreased H3K27Me3 repressive mark without modifying chromatin access. In [Apc-Arid1a]ko-TOTAL hepatocytes, a H3K27Ac active histone mark was induced while chromatin accessibility was lower.” This is also discussed: “For Epo enhancer, the increased binding of Tcf4/β-catenin complex to the Hnf4-RE is dependent on Arid1a, whose loss decreases H3K27me3 repressive mark. That could be due to the complex existing balance between the Polycomb complex PRC2  and the SWI/SNF complex . Accordingly, the inhibition of the Polycomb EZH2 subunit is synthetically lethal in ARID1A-mutated tumors . Therefore, Arid1a and Polycomb complex could act in concert to modulate liver expression of the Epo gene”.We agreed with this essential requirement. We had tried ChIP-qPCR experiments using antibodies against Arid1a or against Brg1. But primary mouse hepatocytes are difficult to study by ChIP and this previously took us time to implement ChIP against Tcf4 and/or β-catenin . Consequently, we got no convincing data using these antibodies. We thus undertook ATAC-qPCR experiments using OMNI-ATAC recently described technique, which works on frozen liver tissue. We clearly found that chromatin accessibility increased after β-catenin activation on GS, Axin2 and Epo enhancer. But surprisingly, this was not the case when Arid1a gene is inactivated. This goes well with the fact that Arid1a is a facultative component of BAF SWI/SNF chromatin complex, which can be replaced by Arid1b. This has been added in Figure 8F, leading to a modified model of transcription of Epo shown in Figure 9. This is described in the text: “Tcf4 bound in vivo to the 2) The data for physiologically relevant production of Epo by hepatocytes in the model must be more convincingly shown. The absence of systemic/hepatic and renal hypoxia should be more robustly demonstrated. The production of physiologically meaningful Epo by hepatocytes should be shown. It is proposed that the 2-4-fold increase in transcript/reporter observed in cell lines is responsible for the 2-3-fold increase in systemic Epo; most of which is derived from kidney physiologically. Comparing kidney as positive control at transcript level would be helpful as well as measurement at protein level in liver and kidney. The authors should quantify and compare hepatic and kidney EPO expression in the different genetic backgrounds. This could be done by both qRT-PCR and by RNA-fish/RNAscope on sections from both kidney and liver. It is essential the authors quantify relative EPO expression in both organs.Here again, the reviewers indicated some useful experiments to perform. We first assessed Epo mRNA expression by qPCR in the transgenic kidneys, and showed that there is no increase in renal Epo expression after either focal  or panlobular  Apc/Arid inactivations. In this latter case, there is rather a slight decrease of renal Epo after hepatic Apc/Arid knock-out. This clearly showed that the systemic impact of Epo is due to hepatic de novo transcription. We also performed. In this context, measuring renal hypoxia was not of interest. We focused on hepatic localization of Epo transcripts. After some attempts to perform classical in situ hybridizations, even if we are expert in mRNA ISH in the liver , they failed when assessing Epo transcripts. We thus performed highly sensitive RNAScope experiments, and as expected we showed: (1) that Epo mRNA are only detectable in rare renal interstitial cells of normal kidney; (2) that no Epo is detected in normal livers . In transgenic livers, we were able to detect Epo transcripts only in rare Axin2-expressing (and thus β-catenin-activated) hepatocytes of Apc/Arid knock-out livers. This exciting experiment clearly underlines a stochastic and bursty transcription of Epo as described previously for several hepatic mRNAs by Itzkovitz’ team using single-RNA ISH .3) The authors should address if the observed peliosis is related to sinusoidal obstruction related to the polycythaemia. If this is the case then this would be consistent with the splenomegaly – due to portal hypertension. Is there flow in the peliotic regions on ultrasound? An alternative explanation for the results in this paper would be that a combination of Arid1/APC deletion results in sinusoidal constriction/obstruction with pooling/extravasation of blood. This constriction would then lead to portal hypertension and increased Epo release by the kidney resulting in polycythaemia and peliosis. This seems a potential explanation and is not refuted by the data presented.In keeping with this hypothesis, we performed dynamic ultrasound using microbubble administration and an example is shown in Figure 1—figure supplement 2. It clearly showed that there is a decrease in hepatic vascular perfusion within echogenic areas enriched in Apc/Arid inactivated hepatocytes. However, no modification in kidney Epo expression was seen, showing that the primary defect resulting in polycythaemia and peliosis is a hepatic one.4) Peliosis and HCC have been described together in HCC but this is not referenced e.g. doi: 10.1007/s00534-008-0035-9. Furthermore, interrogation of publicly available datasets (e.g. TCGA) may add strength to the proposition that Wnt pathway mutations in combination with Arid1A give rise to Epo production within the liver tumour.ko-focal mice”) and commented in the Discussion.Thank you for the reference about peliosis and HCC, added in the Discussion paragraph eight. We have interrogated TCGA dataset as legitimately proposed. We could not find Epo overexpression in CTNNB1/ARID1A mutated HCCs. However, the frequent hypoxia found in cancers rendered this observation not so surprising. This has been added as a supplemental figure  and in the text (subsection “Emergence of peliosis-like regions in the liver of [Apc-Arid1a]5) A statement regarding the cause of death in APC/Arid1 animals should be provided to support the authors claim that this is secondary to peliosis. This is not normally itself a fatal disorder, so why do the authors propose it is in this model? Similarly, is there correlation between the ultrasound findings and endpoint liver examination at post mortem?To clarify this issue, we have added in Figure 1D a picture of a necropsy from a Apc/Arid 13-month old mouse whose entire liver was diseased with a dramatic erythrocytosis and no healthy area in its liver. This is representative of the 3 mice necropsied before dying, as they were reaching the endpoints: “At necropsy of dying mice, the whole liver was diseased, appearing dark red, filled with blood, with large necrotic areas, and no remaining healthy zones ”.6) In line with general recommendations in mouse work it would be important to show that the key findings are present in both male and female model systems.We agree with this comment. We did all the analyses in males because the initial question was to analyze liver carcinogenesis for which an important delay in females is described. We tried to generate new female mice with the different genotypes. We got no enough female mice with the 4 genotypes expected in March. Unfortunately, we could not continue the breedings due to the COVID19 crisis as the access to the animal facility has been severely restricted.7) Additional replicates are necessary to show absence of effects of HIF targets. There do appear to be differences in at least some of these and it is likely that n=4 will be insufficient to demonstrate equivalence.ko and Apc-Arid1ako livers, such as Eno2, Car9 and Rab42, confirming that β-catenin and HIF signaling share some transcriptional targets  .”We agree with this comment and have expanded this analysis to n=8 (n=7 for Arid ko livers). There are some differences in the expression of Eno2, Car9 and Rab42 mRNA expressions, which were seen in Apcko and Apc/Aridko livers . This underlines an overexpression of some HIF targets after β-catenin activation, and does not emphasize that Apc/Arid-ko livers are specifically HIF-activated. This is written in the text: “A small subset of Hif1α/Hif2α targets was slightly overexpressed in both ApcThe manuscript of Riou et al. has been substantially modified and reorganised. The authors have performed the majority of the essential revisions, in particular the RNAscope analyses of EPO expression in the wild-type and mutant livers and kidneys. The only experiment that could not be performed was the analyses of the phenotype of the female mice that is likely to take a much longer time due to the COVID crisis that restricted access and breeding in the animal facility.While the manuscript is very much improved, several issues still require attention and should be addressed before final acceptance.1) In the rebuttal letter and in the revised text, the authors describe the EPO expression seen by RNAscope experiments as “bursty” or “stochastic”. While this may be the case, it is not fully justified, nor necessary to explain the phenotype to describe EPO expression in this way. The text should be modified.in situ hybridization approach to better describe gene expression in the liver, as it was done by Itzkovitz’ lab.We agree that our interpretation of RNAscope experiments was hypothetic. We have suppressed these words, and have only discussed the interest of single-RNA 2) The ATAC-qPCR experiments did not reveal increased chromatin accessibility upon Arid1a inactivation, in fact, chromatin accessibility appeared to decrease compared to Apc inactivation alone. It appears that only a single primer set was used that overlaps with the TCF binding site. From this limited analysis, it is difficult to assess exact nucleosome positioning and how it may be affected by Arid1a loss. It would have been more appropriate to test several amplicons spanning the enhancer. This would have perhaps better revealed how Arid1a loss affects nucleosome positioning and accessibility.We limited the chromatin accessibility analysis due to the difficulty to design accurate PCR primers in the region of the enhancer. For this revision, we finally designed three additional primer pairs which work for qPCR (added in the key resources table), but we could not technically try amplicons in the flanking regions, nor get an amplicon specific for the Hnf4/Wnt responsive element . We revealed an increased chromatin accessibility when the amplicon is centered on the Hnf4/Wnt responsive element. These data are added as Figure 8—figure supplement 2 and commented in the legend.3) Last but not least, the quality of the English in the revised version is very poor leading to lack of precision and making the text difficult to follow. A thorough revision of the text by a native speaker is essential.The text of the Results and the Discussion has been thoroughly revised by a professional scientific proofreader and editor.