In order to examine the group difference between suspended indictment and supervised probation groups, Welch–Aspin t-test was conducted due to unequal variance of the group. Results showed there was a significant group difference in self-concept (p = 0.006) and resilience (p = 0.022). The study further examined participant’s experience of music and perceived benefits. Twenty participants had in-depth interviews about their music therapy experience which were recorded, transcribed and analyzed. Of the 109 statements derived from a qualitative content analysis of the interview transcripts, music making and song writing was repeatedly reported as helpful in gaining “new perspectives,” “courage to challenge and pursuit,” “perseverance,” and “self-acknowledgment.” The positive result of the study showed that the collaborative networking of regional and social resource to support for adolescents at-risk was successful. The results of this project are promising and suggest that other arts-based rehabilitation services and programs should be developed and implemented in juvenile justice system. For this, strategies for program sustainability for long-term facilitation are needed.This study introduces a music therapy project for young offenders through community collaboration and its efficacy through a mixed method. The project called Young & Great Music is carried out via collaboration among three parties, which are the educational institution, the district prosecutor’s office, and corporate sponsor, forming a tripartite networking system. In this paper, we present an efficacy evaluation of the project’s implementation with 178 adolescents involved with the juvenile justice system: 115 youth was on suspension of indictment and 63 youth was under supervised probation. Quantitative and qualitative measures were collected and analyzed to examine the efficacy of the project. The music therapy program was developed for 15 sessions based on the use of music to prompt positive resources through music making and song writing. The efficacy was examined using three scales; self-concept, resilience, and stress coping skills. The paired  Adolescents who are involved in the juvenile justice system are commonly referred to as at-risk youth, defined as individuals who live with risk factors, such as personality traits, environmental characteristics, or family conditions, that have been shown to increase their likelihood of engaging in delinquency and other problem behaviors . DevelopAmong at-risk youth, many are the likely to be involved in criminal behaviors and depending on the type and frequency of the delinquent behavior, the juvenile justice system responds differently. Juvenile crime in South Korea is becoming a social issue, and rates of juvenile crime have risen in recent years. Although the number of juvenile offenders have reduced to 75,150 in 2018 from 84,026 in 2017 (10%), the offenders are becoming younger, more violent, and more likely to recommit crimes. In fact, one out of two offenders are convicted of different type of crimes, and the latency period is becoming shorter . The staIn South Korea, when adolescents are charged with committing a crime for the first time, they are commonly given a 6-month conditional suspension of indictment, unless the nature of the crime is so severe as to warrant a harsher punishment. During this 6-month period, youth are required to complete a minimum number of hours of labor and community service. If they commit any type of crime during this period, they are likely to be prosecuted. Those who commit more severe crimes receive higher disposition, including supervised probation at a regional facility, where their daily schedule and whereabouts are continuously monitored and controlled. In other words, suspension of indictment is the lowest level response by the juvenile justice system and is often given to first-time offenders, while supervised probation is a higher response associated with more severe crimes and repeated offenses .Research shows that the arts have a positive impact on youth’s emotional and behavioral health . EspeciaMusic as an art form has long been used as a therapeutic medium for youth involved in the juvenile justice system. Music has been used as a powerful catalyst promoting positive personal transformation through goal-oriented experience. For example, Genuine Voice was a short-term music learning program offered in a secure treatment facility . The proGood Vibration was another successful project for young offenders that provided opportunities to engage in creative music activities, such as composition, improvisation, and performance . It was Music can be used to address various emotional and psychological issues for youth involved in delinquency . VariousAmong many therapeutic approaches for adolescents, positive psychology provides an appropriate rationale which emphasizes one’s resource rather than the problem itself. Based on the concept of positive psychology, resource-oriented therapy approach is formulated maximizing vital, creative and intrinsic motivation toward self-actualization using inner strength. Resource-oriented therapeutic interventions facilitate personal growth, expressive skills and ability to relate to others . It is bResource-oriented music therapy emphasizes the development and stimulation of a participant’s strengths and resources rather than the reduction of symptoms or cure of pathology. The focus is on the participant’s self-healing forces  via posiThe core features of resource-oriented music therapy involve four concepts . FirstlyCollaboration is becoming a practical and essential concept in the fields of music therapy setting . CollaboThe purpose of this study was to examine the efficacy of music therapy program provided through tri-partite collaboration on adolescents involved with the juvenile justice system and how the music therapy program helped the youths with their self-concept, resilience, and stress coping strategies. We also looked at whether differences existed between the participants with suspension of indictments and those under supervised probation. Lastly, we qualitatively examined the interview responses from a subgroup of participants to better understand the impact of the music therapy program on youth associated with the juvenile justice system.The Young & Great Music Project was initially developed in 2014 to bring three key stakeholders together for the common purpose of nurturing at-risk adolescents in the community. The three parties, which are the university, the district prosecutor’s office, and local corporations, came together to form a tripartite collaboration for implementation of music therapy services. These parties are invested in supporting community interests and caring for community members, including youth. It is important that current program utilized regional networking of core figures to ensure program sustainability.Each party had distinctive role in the collaboration for the project facilitation . FirstlyThe music project is formulated with music therapy interventions which utilizes music activities to achieve non-musical skills. In other words, music activities are formulated for personal and interpersonal goals using therapeutic music interventions. This is what differentiates music therapy from music learning or education. Music therapy sets the primary goal in achieving psychological and emotional well-being using music’s healing and therapeutic essence. Therefore, learning music comes only as a part of the process.Young & Great Music Project is a 15-session program that is delivered in four stages: developing relationship with music and others and increasing self-awareness through the music experience (Sessions 1 through 3), identifying one’s resources and strengths (Sessions 4 through 8), identifying challenges and learning to use strategic resources (Sessions 9 through 12), and empowering one’s own inner strength through self-actualization experiences in music (Session 13 through 15). The session objective, content and music activities per stage are shown in The participants were recruited from the project implemented in 2017–2018. From 215 adolescents, 178 who have successfully attended all 15 sessions and completed both pre and posttests participated. The participants were from two types of groups. One group had received conditional suspension of indictments (SI) and the other group was under supervised probation (SP) in an independent facility in the district. From SI group, 115 adolescents participated, and from SP group, 63 adolescents participated. Among 178, 163 were male and 15 were female. The average age was 17.5 years . The totFor the SP group, their participation was voluntary. Because the music therapy sessions were held in the facility in which they resided, they could make the decision whether to take part or stay in their room. Once they agreed to participate, however, they were encouraged to attend all 15 music therapy sessions for group consistency.Before the implementation of the program, orientation day was held to introduce about the music therapy program and its content. Adolescents, guardians, facility staff, mentors under the district prosecutor’s office were all invited to the orientation. Participant consent was received on the program orientation. The details of the program were communicated to the participants and their legal guardians before signing the informed consent on the participation and video/audio recordings of the session. Due to the nature of the study and the vulnerability of the participants, the entire program implementation and data collection procedures were strictly examined and reviewed by the district attorneys and university research team.The implementation procedure was as follows: The district attorney in charge of juvenile youth contacted the music therapy team at the university when an adolescent with suspended indictment opted to take part in the music therapy program instead of community service hours. Once the number of referred adolescents reached four or five, a music therapy group was formed.For adolescents at the supervised probation facility, music therapy sessions were provided in the equipped music room, which housed the music instruments funded by the corporate sponsor. For the suspended indictment group, local mentors from the district attorney escorted the participants from the suspended indictment group and recorded their attendance which was required as part of the youths’ conditional conviction. The music therapy sessions were offered at the university facility fully equipped with instruments and recording devices.As the final step, following the 15-week session program, the university facilitated a small concert at the regional art or concert hall where the participants sang their original songs and showed the music competency they had built during the program. This concert was funded by the corporate sponsor and was open to the public when the participants agreed .Data were collected using two different types of measures: quantitative and qualitative measures. In terms of the quantitative data, three scales were used to assess the efficacy of the music therapy program: participant’s self-concept, resilience, and stress coping strategies before and after the program. In the beginning of the program, the scales were distributed for pretest. After administering 15-week program, posttests were distributed to those who successfully completed 15-week program.For qualitative data, following the completion of the program, additional interviews took place in order to examine participant experience regarding the perceived benefits of music. The interviews were carried out individually by the researchers for about an hour. Their interviews were recorded with consent. The procedures of participant recruitment, data collection, and interview process were reviewed and approved by the Institutional Review Board at the Ewha Womans University (IRB No. 125-14).Self-concept: Self-concept was measured by the Self-concept Scale developed by Resilience Scale of Korean Adolescents: Resilience was measured by the Resilience Scale of Korean Adolescents by Stress coping strategies: The Korean version of the Stress Coping Strategies , originat-test was used. To examine the group difference between SI and SP groups, Welch–Aspin t-test was conducted due to the unequal variance between the groups.To compare changes in measures of three scales from before the program with those taken after the program, paired Twenty participants volunteered to participate in interviews after the completion of their 15-week music therapy program. Their individual interviews were arranged separately after the completion of other tools. The participants were asked to openly express any thoughts and feelings about the program and freely describe how music helped them if it was deemed helpful. The semi-structured questions allowed the participants to freely articulate whatever came to mind about their experience. The researchers who did not provide music therapy sessions carried out the interviews in order to hold neutral stance in the evaluation of the program implemented.Qualitative data were analyzed using the qualitative content analysis method. Content analysis is a method of inductive analysis in which researchers continuously compare data to systematically derive meaningful units and categories. Qualitative content analysis is a method for organizing descriptive responses into the meaning segment of qualitative data. This is done by assigning successive parts of the material to the categories of a coding frame , 2014. Tt-test to examine the pre to post changes after the program. Results showed that there were significant differences in all three measures: self-concept (p < 0.000), resilience (p < 0.000) and stress coping strategies (p < 0.000)  and resilience (p = 0.022), and no difference in stress coping strategies (p = 0.061). The study further examined the effect size. According to the Cohen’s guidelines (d = −0.59) and moderate in resilience (d = −0.49). In other words, the participants in SP group showed significantly greater changes in two scales than SI group (The study conducted paired < 0.000) . Furtheridelines , the difSI group .The interview responses of 20 participants regarding their experiences in the music therapy program were recorded and transcribed. Using the content analysis method, researchers examined what were the types of resources and benefits that participants experienced in the music therapy program. After repeatedly reviewing the interview transcripts to delineate common themes regarding the participants’ music experience, five themes were identified. The themes are operationally defined as categories based on the operational definitions accordingly .Based on the operational definitions of the initial categories derived from the data, participants’ statements were sorted accordingly. All participants provided multiple statements regarding the benefit of their music experience. Total statements drawn were 109, and these were categorized by the nature of the inner resource . Among tStatements regarding the meaning of accomplishments rated second (21 statements). These participants expressed joy about making their song lyrics and melodies. They were content not only with the quality of the music they mastered, but with the fact that they did not give up.Participants also expressed gaining courage to challenge themselves and pursue their life goals (18 statements). Because the music experience provided in the program was new for most of the participants, singing and recording their own song to share with others required courage and effort. There were also statements that revealed perseverance and self-acknolwedgement. They willingly endured to master their musical work (14 statements). At the same time, some participants used the music making moments comming in contact with new thoughts, feelings, emotions and wishes (7 statements).The purpose of this study was to examine the efficacy of a music therapy program called Young & Great Music Project for youth involved with the juvenile justice system provided through tri-partite collaboration in the community. The study showed that the participants in the music therapy program have gained positive self-concept, resilience and stress coping strategies during the 15-weekly sessions. The outcome of the study support the existing literature that music offered the opportunities to come in contact with their inner potentials and strength . The outThere are a few important implications from this study. Firstly, music provide vicarious experience for self-value through music making and playing. Musical tasks in the program reinforced a sense of control, the ability to make good choices, ownership of the music repertoire, and self-actualization through music making. This kind of self-ownership and self-authorship are two important components that can replace unresolved needs and fulfillment of a distorted identity, which otherwise were dealt with by aggressive means . It was In the same line, the interviewed statement showed that song writing prompted the participants to seek new perspectives and challenges. Among the various music interventions, lyric writing was described as the most successful way for the participants to access their unexpressed thoughts and desires, which led to making life decisions . These eSecondly, both the quantitative and qualitative data showed that this program serves to be a pivoting moment for the participants, especially those with conditional suspension of indictment (SI group). The program was deemed as a ‘condition’ to waive the indictment, however, ironically this serves as an opportunity to heal themselves and go through major changes in their attitudes and thinking. In other words music therapy was given as a conditional obligation to fulfill the conditional suspension, however, most participants became to enjoy the music experience. Upon the termination of the program, some of them inquired about joining the program again.Third, despite the fact that both groups showed significant improvement in self-concept, resilience and stress coping strategies, the supervised probation group showed greater changes. This may imply that the self-choice may have offered sincere and genuine personal work. Unlike the SI group, they volunteered to take part without any conditional obligation. Residing in the supervised facility may be rather limiting to explore something new and creative. Music may have offered them opportunities to meet these needs. Such effort is an indication of music prompting intrinsic motivation for better self, bringing a renewed attitude toward new experiences and openness . These nFourth, the results of these study suggest important implications on how practical and utilizing aspect of music’s benefit should be facilitated via community collaboration. The spirit of this music project was that it was provided through the collaborative work of regional agents among university faculty, corporate sponsors, attorneys and staff from the district prosecutor’s office. The corporate involvement as a sponsor is crucial for sustainability of the project. The university’s commitment to share its knowledge with the larger community is similarly essential. Most importantly, district attorney subscribing to the mindset of providing help and healing to youth rather than punishment is also necessary, as they are the first party to encounter youth caught up in the juvenile justice system. The therapy opportunity the adolescents received despite of their offending conduct, brought a turnaround moment in their life. The shared goals and perspective of the tripartite enabled the project to continue on for the past 7 years in South Korea. Without this common purpose, the project would have been one-and-done effort with no lasting impact.There are a few caveats of this research. As this project and research was carried out in a real world setting through community networking and collaboration involving those in the juvenile justice system, it was not controlled for optimal clinical trial condition. This means that one should keep in mind that the efficacy outcome derived from this study is based on within group pre-posttest design. For more in-depth findings of music’s therapeutic effect, random control trial design may be sought in the future studies.Secondly, another caveat of this study is that therapist-related variable may have affected the result. Since there were more than one music therapist leading the session groups, therapists’ individual traits may have affected the outcome of the overall project efficacy. For youth involved in delinquency, interpersonal interactions are sensitive issue therefore, therapist quality and style can be an important factor that affect their motivation and level of participation. In this project, regular supervisions were provided to the therapists and the project outcomes are positive, however, therapist-related factor should be always considered in further studies as well.Lastly, it would be essential to examine how music’s benefit continued in their lives after the completion of the program. A follow-up study to examine the maintenance effect of the music therapy program after certain period would strengthen music’ effect and further support the tri-partite networking and collaboration. Through examining the long-term impact of the collaboration, the networking can be systemized among the three parties as a model.As a conclusion, there is an old proverb that states, “It takes a village to raise a child.” This applies to societies as well. When it comes to at-risk youth exhibiting delinquent behavior, it is for the community partners to come together and collaborate . It is iThe datasets used to generate the results for this study can be obtained from the authors when deemed necessary.The studies involving human participants were reviewed and approved by Ewha Womans University Institutional Review Board. Written informed consent to participate in this study was provided by the participants’ legal guardian/next of kin.HC, as the PI of the proejct, designed the study. HC and JY developed the therapeutic program. JY implemented the program and collected data. Both authors contributed in the process of drafting the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Background: “Cuida tu Ánimo” (CTA [Take Care of Your Mood]) is an internet-based program for prevention and early intervention of adolescent depression implemented in Chile and Colombia. In the pilot application of the program, participants interacted with the program through a website that provided psychoeducational information, chat, and telephone appointments as well as monitoring and feedback messages. To date, most similar programs were not developed taking design features into consideration. The persuasive systems design (PSD) model is a comprehensive framework developed to aid in the design and evaluation of systems capable of influencing users' attitudes or behaviors. The purpose of this study was to evaluate the persuasiveness of CTA pilot program using the PSD model.Methods: The methodology used was expert evaluation, where specialists evaluate the program against a list of design principles.Results: Although the PSD model was not used to design the program, system features proposed by PSD were present, mainly “Dialogue support” features. Persuasion context analysis was not carried out by the developers. No aspects of the program could be related to “Primary task support” features because the developers did not define a primary task.Discussion: Key aspects of the PSD model could be incorporated in the CTA program to enhance system persuasiveness and improve adherence. The study was approved by the Human Research Ethics Committee of the Faculty of Medicine, Universidad de Chile, Chile, and Institutional Committee on Human Research Ethics Universidad CES, Colombia. Adolescents from four schools were invited to the study. They interacted with the program via monitoring and feedback messages, which were delivered every 2 weeks, and a website that allowed them to access psychoeducational content. In addition, a section of the website provided emergency information and allowed users to contact a specialist via online chat appointments. Adolescents with severe depressive symptoms or suicidal risk were invited to participate in an online chat appointment, a phone session, or a face-to-face assessment with a mental health professional, as required by each case. To promote use, several visits were made to schools that participated in the study, in which staff members distributed bracelets and handouts with information about the program along with other merchandising products.“Cuida tu ánimo” (CTA [Take Care of Your Mood]) is an internet-based program for the prevention and early intervention of adolescent depression implemented in Chile and Colombia  is a holistic framework for devising persuasive technology.This model classifies the features of persuasive technology in four main categories.Primary task support: Design principles that support the carrying out of a primary task by the user.Dialogue support: Principles related to the implementation of human-computer dialogue in a way that helps users move toward their goal or target behavior.System credibility support: Principles that describe how to design a credible system, which will be more likely to persuade its users.Social support: Principles that describe how to design a system so that it motivates its users by leveraging social influence.A brief description of the above-mentioned design principles can be found in 10 Thus, applying this model to internet-based interventions could be helpful to see how system design features are used and how they influence adherence. The objective of this study was to evaluate the persuasiveness of the CTA program by applying the PSD model as an evaluation framework,12 with the aim to produce insights and suggestions on how to improve the program's design features to promote adherence.Persuasive technology elements along with intervention characteristics could account for a substantial amount of variance in adherence rates to eMH interventions.11 The program was evaluated in terms of its system design features.12Expert evaluation was conducted by the authors, F.P. and V.M., to compare and cross-check design features included in the CTA program with those proposed by the original PSD article.Several design principles were found in the CTA program, such as Rewards, Reminders, Suggestions, Similarity, Liking, Trustworthiness, Expertise, Real-World Feel, and Third Party Endorsements, all of which are included in the “Dialogue support” and “System credibility support” categories. Nevertheless, only two design principles, Self-Monitoring and Social Learning, of the “Primary task” and “Social support” categories were identified. This indicates that CTA provided a pleasant visual environment for the adolescents to receive the intervention, as well as means to complete assessments and interact with the website content, but was more ineffective at proposing specific easy-to-accomplish tasks for its users and did not allow participants to interact with each other in any way. PSD principles were not taken into account when CTA was designed. Nevertheless, several features of the PSD model were found, which indicated that CTA provided adequate feedback to its users and contained information from reliable and professional sources, which could have made it more likely to persuade its users by supporting its credibility. In addition, CTA was designed in a colorful and appealing manner, rewarded its users for participating in the program and provided reminders and suggestions for them to navigate the site adequately.However, other important features were missing. The program was not effective in proposing a task for the users to perform, and it did not promote interaction between users since it was mostly informative, providing fewer opportunities to deploy social skills such as competition or cooperation.Suggestions derived from these results could be the inclusion of more personalized content, in order for users to interact with a more familiar interface; adding concrete tasks for users to perform during their interaction with the program , providing a supervised platform for group chat, where adolescents do not only interact with therapists exclusively but also with each other, providing a sense of familiarity and closeness to the program; and rewarding users for the completion of tasks with virtual or real-life prizes . These examples of Primary task and Social Support features could help improve the CTA program in terms of its persuasiveness with little structural changes in the website, making users more likely to adhere to the program and perform the tasks proposed by the developers.PSD could be useful for the evaluation of internet-based interventions, providing structured and concise information on system features and how to improve interventions in terms of their persuasiveness.


Millions of American children under the age of 18 are being cared for by their grandparents and without the presence of the biological parents. The number of custodial grandfamilies has significantly increased over the last five years. Recent studies have shown that custodial grandparents (CPGs) are often facing specific challenges in life, such as lower emotional well-being, higher parenting burden and stress related to this unique situation. Despite these findings, few interventions take a strengths based approach to improve their mental health and resilience. We describe our efforts to address these issues by proposing intervention anchored in the Acceptance and Commitment Therapy (ACT), emphasizing the importance of acceptance of challenging circumstances outside of one’s control and promoting resilience among participants. The program consists of a web based ACT program with online coaching meetings, six common core sessions and six separate sessions for each age group over a time period of six months. This program is unique in the sense that it utilizes both individual and group session techniques to facilitate the learning process. Main active ingredients of this program are to promote effective coping strategies, to reduce parenting stress among grandparents and to increase life skills  among grandchildren. We are hypothesizing that participating in the ACT program will help CGPs to improve self-efficacy, emotional well-being, higher self-confidence, social competence, lower depressive symptoms, and parenting distress, thereby leading to positive outcomes such as improved mental health and higher resilience.


BRAF mutations; however, most eventually relapse due to acquired resistance. Here, we demonstrate that ABL1/2 kinase activities and/or expression are potentiated in cell lines and patient samples following resistance, and ABL1/2 drive BRAF and BRAF/MEK inhibitor resistance by inducing reactivation of MEK/ERK/MYC signaling. Silencing/inhibiting ABL1/2 blocks pathway reactivation, and resensitizes resistant cells to BRAF/MEK inhibitors, whereas expression of constitutively active ABL1/2 is sufficient to promote resistance. Significantly, nilotinib (2nd generation ABL1/2 inhibitor) reverses resistance, in vivo, causing prolonged regression of resistant tumors, and also, prevents BRAFi/MEKi resistance from developing in the first place. These data indicate that repurposing the FDA-approved leukemia drug, nilotinib, may be effective for prolonging survival for patients harboring BRAF-mutant melanomas.Metastatic melanoma remains an incurable disease for many patients due to the limited success of targeted and immunotherapies. BRAF and MEK inhibitors reduce metastatic burden for patients with melanomas harboring  Resistance to BRAF/MEK inhibitors is a major impediment to long-term survival for patients with BRAF-mutant melanomas. Here, the authors show that ABL kinases drive resistance by promoting MEK/ERK reactivation and the FDA-approved ABL kinase inhibitor nilotinib prevents and overcomes resistance. Moreover, for those with high metastatic burden, immunotherapy may not sufficiently reduce tumor burden or induce remission2. Melanomas harboring activating BRAF-V600E/K mutations (70–88%) can be treated with BRAF inhibitors 3; however, some BRAF-mutant melanomas are intrinsically resistant, and many that respond initially, develop resistance during treatment 4. Since a common BRAFi resistance mechanism involves BRAF-independent activation of MEK, combining BRAF and MEK inhibitors  delays resistance 3. However, the vast majority still succumb to the disease due to acquired resistance. Tumors circumvent the effects of BRAFi and BRAFi/MEKi via (1) reactivation of ERK due to mutations in MAP2K1 (MEK1), MAP2K2 (MEK2)5, MAP3K8 6, NRAS or KRAS5, overexpression of receptor tyrosine kinases (RTKs)5, or expression of BRAF-V600E splice variants3; (2) overexpression of the master melanocyte transcription factor, MITF5; or (3) PI3K/AKT activation by RTKs7 or as a result of PTEN or AKT mutations8. Thus, new drug combinations are needed to increase the 5-year survival rate for patients with advanced disease.Melanoma incidences continue to increase, and the disease remains incurable for many due to its metastatic nature and high rate of therapeutic resistance (Cancer.Net). Immunotherapy increases the cure rate for some advanced cases; however, 50–60% of patients do not respond and some cannot tolerate the therapyABL1 (a.k.a. c-Abl) and ABL2  non-receptor tyrosine kinases are best known for their oncogenic role in human leukemia, where they are partners in chromosomal translocations  that activate the kinases and drive disease progression9. The first-generation ABL inhibitor, imatinib, has been used for decades to treat BCR-ABL1-driven chronic myelogenous leukemia (CML), and second (e.g. nilotinib) and third (e.g. ponatinib)-generation drugs were developed to combat imatinib resistance9. Nilotinib, which is more efficacious than imatinib, is well-tolerated 10.11. ABL1 activation in cytoplasm/plasma membrane compartments has pro-survival/oncogenic roles, whereas nuclear ABL1 often induces apoptosis9. In contrast, ABL2, which promotes invasion , is only present in the cytoplasm/plasma membrane12. ABL1/2 are highly active in 40–60% of melanomas, and drive disease progression15; however, their role in therapeutic resistance has not been explored. Here, we utilize in vitro and in vivo experiments and patient samples to demonstrate that ABL1/2 drive resistance to BRAFi and BRAFi/MEKi. Although resistance mechanisms differ among the lines queried, targeting ABL kinases reverses resistance in all lines tested, indicating that the kinases are critical signaling nodes. Indeed, nilotinib, an ABL1/2 inhibitor that has been FDA-approved for more than a decade, reverses and prevents resistance, in vivo. These data have strong clinical relevance as they indicate that nilotinib may prolong patient survival in both BRAFi/MEKi-refractory and treatment-naïve settings.Accumulating evidence supports a role for ABL1/2 in solid tumors where they are activated downstream of other kinases or are mutationally activated in a small subset16, we tested whether ABL1/2 drive BRAFi or BRAFi/MEKi resistance. All cell lines utilized in subsequent experiments harbor BRAF-V600E mutations. Clonal, BRAFi-resistant (-BR) lines derived from Mel1617 and 451-Lu were developed by Herlyn and colleagues17 . We established polyclonal BRAFi-resistant M14 (M14-BR) and BRAFi/MEKi-resistant  lines (see “Methods”), since this more accurately mimics resistance, in vivo. All new resistant lines demonstrate high level resistance to PLX4720  or dabrafenib/trametinib   also is increased in resistant cells  and activate ERKlls Fig. . Cytoplaion Fig. , consist23. SFK activity (pY416) is elevated in many resistant lines, and inhibition of SFK activity using SFK inhibitor, SU6656, prevents ABL1 and ABL2 activation (kinase assays) in M14-resistant lines , which phosphorylate and activate ABL1/2nes Fig. , indicatent Fig. . We used12. Moreover, expression of nilotinib-resistant forms of ABL1/2 (T315I) rescues nilotinib-mediated inhibition of viability in the presence of PLX, indicating that nilotinib’s effects are mediated predominantly by ABL1/2 16 is sufficient to induce BRAFi resistance  were treated with vehicle, nilotinib, PLX4720 , or the combination. As expected, parental cells are highly sensitive to PLX alone , whereas resistant cells are impervious to the effects of the drug Fig. . Treatmence Fig. . Thus, A4. Thus, we examined whether ABL1/2 also drive resistance to BRAFi/MEKi. Importantly, targeting ABL1/2  in BRAFi/MEKi-resistant lines  reverses resistance to dabrafenib+trametinib  by inhibiting viability, colony formation, and inducing PARP and caspase-3 cleavage in the presence of D/T , treatment with nilotinib or GNF-5 29 alone has little effect or modestly reduces expression/phosphorylation of signaling proteins in resistant cells  and induction of the transcription factors, FRA1/FOSL1 and MYC, which are critical for melanoma development, progression, and resistancells Fig. . Phosphoion Fig. . PLX  ; however, the allele frequency is low indicating it is only present in a small subpopulation. M14-BR cells harbor an activating mutation in NRAS (Q61R), a known resistance mechanism in patients  mutation in 451-Lu-BR cells, and this result was confirmed using Sanger sequencing  analysis in 2018 confirmed its identity. Interestingly, MAP2K1-K57N was identified by WES at a very low allele frequency (1 out of 240 reads), and thus may represent a small subpopulation of the original line. Unlike M14-BR and Mel1617-BR, 451-Lu-BR did not have an obvious ERK pathway mutation. However, we did identify a mutation in the D-3 domain of MAP2K7 , a MAP2K (like MEK1/2) that binds JNK via D-domains, and cooperates with MAP2K4 (MKK4) to activate JNK34. There is accumulating evidence for crosstalk (negative and positive) between JNK and ERK pathways; thus, this mutation could potentially induce ERK reactivation  in all lines, indicating that ABL1/2 are key signaling nodes.To gain additional insight into the mechanism by which targeting ABL1/2 reverses BRAFi resistance, we performed next-generation whole-exome sequencing (WES), identifying new acquired mutations that are present in resistant lines but not in parental cells. Mel1617-BR cells have a mutation in 36. Nilotinib and ponatinib as well as ABL1/2 shRNA resensitize M14-BMR cells to D/T, reducing pMEK1/2, pERK1/2, pFRA1/FRA1, and MYC expression , leading to induction of pFRA1/FRA1 and MYC Fig. . Paradoxion Fig. . Thus, AMAP4K1  mutation (P422Q), which was previously identified in a patient with cutaneous melanoma 37. Significantly, expression of ERK2-GOF efficiently reverses nilotinib’s anti-survival effects in the presence of D/T, indicating that nilotinib reverses resistance by blocking ERK reactivation  form of ion Fig. . Since Ment Fig.  and in tent Fig. , and an ent Fig. . Thus, t36. CRAF directly phosphorylates/activates MEK, whereas MAP3K8 mRNA/protein upregulation activates MAP3K8 which directly activates MEK and ERK1/238. MAP3K1, another MAP3K, primarily activates MAP2K4/MAP2K7 (MKK4/MKK7), MAP2Ks that activate JNK; however, it can phosphorylate MEK1/2 under some circumstances, and also can activate MEK/ERK indirectly via JNK feedback activation of ERBB RTKs39. To determine whether ABL1/2 regulate MAP3Ks, we examined whether MAP3Ks were activated/upregulated in resistant cells, and whether altering ABL1/2 activities prevents their upregulation. In BRAFi-resistant cells, CRAF  and MAP3K1  phosphorylation are induced and MAP3K8 expression is modestly increased, particularly in the presence of PLX  phosphorylation/activation, and silencing or inhibiting ABL1/2 reduces pMEK1/2 in the presence of PLX or D/T Figs. . Thus, A36. MEK1 remains inhibited as reactivated ERK1/2 feeds back and phosphorylates/inhibits MEK1 (T292); however, this residue is not conserved in MEK2, and thus, MEK2 remains activated and drives resistance36. We found that M14-BMR cells harbor a mutation in MAP4K1, an upstream activator of MAP3K1  in M14-BMR cells, particularly in the presence of D/T  in the presence of D/T, and nilotinib/GNF-5 cooperate with D/T to reduce pMAP3K1 , and this resistance mechanism has been postulated to be due to MEK phosphorylation by upstream kinases which causes reduced affinity of trametinib to the allosteric siteD/T Fig. . Silenci3K1 Fig. . Althougng Figs. .35. However, in M14-BMR cells, silencing or inhibiting ABL1/2 (in the presence of D/T) inhibits MEK activity but does not reduce pJNK1/2; thus, ABL1/2 do not activate MEK via this mechanism  during resistance (+D/T) while having no effect on pJNK  with MAP4K1, pMAP3K1, CRAF, MEK, and ERK in M14-BMR cells exposed to D/T Fig. . The ABL21, and MAP3K1 also binds 14-3-3, although the consequence of this binding is unknown42. Thus, we tested whether 14-3-3 proteins mediate binding between ABL1, MAP4K1/MAP3K1, and MEK/ERK. Importantly, treatment with the 14-3-3 interaction inhibitor, BV02, prevents binding of MAP4K1, pMAP3K1, MEK1, and ERK to ABL1  but also mediate coupling of the upstream kinase, MAP4K1, specifically to MAP3K1.ABL1 binding to 14-3-3 proteins sequesters ABL1 in the cytoplasm where it has a transforming functionBL1 Fig. , indicatBL1 Fig. . SignifiBL1 Fig. . Numerou45, and tyrosine phosphorylation of 14-3-3 is known to regulate its binding to other proteins46. Co-expression of MAP3K1 and activated ABL1 or ABL2 in a heterologous system results in tyrosine phosphorylation of MAP3K1  in SCID-beige mice, and mice bearing parental tumors were treated with vehicle or PLX4720 (to assess BRAFi-mediated regression of sensitive tumors), whereas mice bearing the resistant variant were treated with vehicle, nilotinib, PLX4720 or PLX + nilotinib. Tumor regression was efficient in parental xenografts treated with PLX  were established : 26 genes unique to both responding tumors and 16 mutations unique to both non-responding tumors , an ABL1 interacting protein and regulator of ABL1 activity/signaling48. Furthermore, the protein phosphatase N4 (PTPN4), which binds ABL1 and regulates CRK-I (ABL substrate) phosphorylation49, was mutated in responding and non-responding tumors; however, the mutation observed in the responding tumors occurred in a different functional domain from the mutation observed in the non-responding tumors, and thus, potentially, could have opposite effects  were subjected to WES. There were 84 gene mutations in common between the four tumors  were followed long term. Prolonged tumor regression was observed in the triple-combination-treated group, whereas all D/T-treated animals had to be euthanized due to large tumor size (≅1000–1500 mm3) by day 81  xenografts were established in nude mice. Mice harboring parental tumors were treated with vehicle or dabrafenib+trametinib (D/T), whereas mice harboring M14-BMR tumors were treated with vehicle, nilotinib, D/T, or D/T + nilotinib. Parental tumors grew very quickly and D/T treatment induced rapid regression Fig. . Four mi 81 Fig. . MoreoveABL1 , which renders the protein insensitive to the drugs50. To test whether the resistance we observed was likely due to ABL1 or ABL2 mutation, we replaced nilotinib with ponatinib, a third-generation ABL inhibitor that inhibits the gatekeeper mutation50. Unfortunately, due to toxicity of the ponatinib+D/T combination, we were unable to treat mice daily; we often had to withhold treatment due to anorexia; and the treatment had to be discontinued after 10 days. However, despite these difficulties, ponatinib induced tumor regression in all treated mice  never exhibited relapse even after following for 160 days , mice were treated with vehicle, nilotinib, D/T, or D/T + nilotinib. Nilotinib alone had no effect on tumor growth  within the first 70 days of treatment and only 17% (2/12) relapsing by day 100 as compared to 100% relapse for D/T-treated mice by day 69 . Thus, there is an unmet need for new drug combinations to extend survival. In this work, using loss-of-function, gain-of-function and rescue approaches, as well as cell lines, patient samples, and in vivo approaches, we demonstrate that ABL1/2 drive resistance to BRAFi and BRAFi/MEKi by activating MEK/ERK/MYC via alternative MAP3K pathways. Moreover, we show that ABL1/2 play a critical role in linking MAP4K1/MAK3K1 to MEK/ERK reactivation during BRAFi/MEKi resistance. Furthermore, targeting ABL1/2 using an FDA-approved ABL1/2 inhibitor, nilotinib, resensitizes resistant cells to BRAFi or BRAFi/MEKi, inhibiting survival and promoting apoptosis, in vitro, inducing prolonged regression of BRAFi/MEKi xenografts, in vivo, and preventing resistance from developing in the first place. Thus, these studies indicate that repurposing nilotinib, an FDA-approved drug used to treat leukemia for more than a decade, has the potential to prolong melanoma patient survival in both MAPKi-refractory and treatment-naïve settings.ABL1 mRNA is elevated in melanomas from patients that relapse on BRAFi or BRAFi/MEKi therapy. (3) ABL1 cytoplasmic/nuclear ratio and ABL1-T735 phosphorylation (14-3-3 binding site) are increased in resistant cells, consistent with findings demonstrating that cytoplasmic retention drives ABL1 oncogenic function9. (4) Constitutively active forms of ABL1/2 drive resistance in treatment-naïve melanoma cells, and induce MEK/ERK reactivation. (5) Silencing ABL1/2 (and subsequent rescue with ABL1/2 addback), use of an allosteric inhibitor that targets only ABL1/2 (GNF-5), and two different ABL1/2 TKIs  reverse BRAFi/MEKi resistance and prevent MEK/ERK reactivation. (6) Expression of nilotinib-resistant, mutant forms of ABL1/2 rescues nilotinib’s anti-survival effects. Importantly, although the genomic mechanisms of resistance are different in each line, nilotinib reverses resistance in all lines queried, indicating that ABL kinases are key signaling nodes during resistance. Additionally, MYC upregulation is a convergent point for multiple resistance pathways28, and we show that ABL1/2 drive MYC upregulation during resistance using cell lines, animal models, and patient samples. Notably, our data also are consistent with findings identifying ABL1 in a kinome-wide screen for overexpressed kinases that can predict resistance to BRAFi/MEKi51. However, despite these compelling data, due to the fact that ABL1/2-T315I introduction into M14-BR cells also increases viability in the absence of nilotinib  ABL1/2 are activated in resistant lines. (2) 5, and most cell lines we queried acquired resistance in this manner; however, the mechanisms by which ERK is reactivated are distinct. We identified activating mutations in MAP2K2/MEK2 (Mel1617-BR) and NRAS (M14-BR), which are resistance mechanisms documented in patient samples5, indicating our lines are clinically relevant. The mechanisms of ERK reactivation in M14-BMR and 451-Lu-BR were more elusive. In M14-BMR, BRAFi/MEKi activate MEK1/2 indicating that upstream kinases phosphorylate MEK1/2, which reduces trametinib binding, leading to subsequent MEK2-driven resistance36. NextGen sequencing revealed that M14-BMR harbor a MAP4K1 (P422Q) mutation that has also been identified in a melanoma patient , and the residue is adjacent to a critical serine phosphorylation site . Phosphorylation of MAP3K1, a downstream substrate of MAP4K1, is increased in these cells consistent with the MAP4K1 mutation being gain-of-function. Interestingly, we show that MAP3K1 is activated in all resistant lines driven by ERK reactivation (independent of the ERK activation mutation), particularly in the presence of BRAFi or BRAFi/MEKi, and nilotinib alone (451-Lu-BR) or nilotinib in combination with MAPK inhibitors (other 3 lines) potently inhibits MAP3K1 phosphorylation/activation. Our mechanistic data provide insight into how/why this occurs by demonstrating that MAP4K1/MAP3K1 induce MEK/ERK rather than JNK/JUN activation during resistance. Moreover, ABL1/2 activity and 14-3-3 proteins are critical for the assembly of MAP4K1/MAP3K1/MEK/ERK complexes, and ABL1/2 drive coupling of MAP4K1 to MAP3K1. Our data are consistent with data obtained in other cell contexts showing that ABL1 interacts with and/or phosphorylates MAP4K1 and MAP3K154, and with the identification of increased MAP3K phosphopeptides in imatinib-resistant BCR-ABL1-expressing CML cells (indicates they are likely substrates)55.ERK pathway reactivation is a common mechanism of MAPKi resistance17; however, nilotinib alone is highly effective at reducing viability in 451-Lu-BR, whereas nilotinib cooperates with BRAFi in Mel1617-BR. Interestingly, pCRAF is elevated in Mel1617-BR, but not in 451-Lu-BR. Moreover, Mel1617-BR has a MAP2K2/MEK2 mutation . MEK1-Q56P is weakly transforming and must coexist with other lesions that activate CRAF (e.g. IGF1-R) in order to fully activate ERK and have complete transforming activity56. In contrast, 451-Lu-BR harbors a mutation in the JNK-binding domain of MAP2K7 . Breast cancer cells harboring loss-of-function mutations in MAP2K4 (and MAP3K1) lack JNK-mediated activation of ErbB→CRAF→MEK1/2, and thus, are highly sensitive to MEKi35. Loss-of-function mutations in MAP2K7 would be predicted to act similarly since MAP2K7 and MAP2K4 cooperate to activate JNK. Indeed, 451-Lu-BR cells are highly sensitive to trametinib, in contrast to Mel1617-BR cells, which display collateral resistance to trametinib  could potentially be biomarkers for resistant tumors that are highly sensitive to nilotinib alone, and thus may identify patients that could benefit from monotherapy; future experiments will address this exciting possibility.The IGF1 receptor is activated in 451-Lu-BR and Mel1617-BR cells59. Moreover, mice treated with the triple combination exhibited no noticeable toxicity despite use for 100–160 days. Taken together, these data indicate that the triple combination may be an effective therapy for treatment-refractory BRAF-driven melanomas. Indeed, we are currently planning a Phase I trial to test the safety and efficacy of the triple combination in the second-line setting. If positive, this may lead to critical prevention studies, where the combination has the potential to increase survival of melanoma patients from the outset.The data shown here have high clinical and translational relevance. In the in vivo resensitization assay, D/T + nilotinib significantly increased survival, and in the in vivo prevention study, 83% of mice never developed resistance to the triple combination even after 100 days of treatment. Nilotinib has been FDA-approved since 2007; its safety/toxicity profile is known; a 400 mg (b.i.d.) dose, which is used for drug-resistant CML, results in 1.95 μM plasma concentrations, well within the range of our in vitro doses; and our in vivo dose (33 mg/kg) is the same or lower than doses utilized by others in CML modelsCell lines: M14 cells were obtained from NCI (NCI-60 panel) in 2016. Mel1617, Mel1617-BR, 451-Lu, 451-Lu-BR (c5), and WM164 were obtained from Meenhard Herlyn  via an MTA in 2011. Mel1617-BR and 451-Lu-BR were described as clonal lines, established by culturing cells in increasing doses of the BRAFi, SB590885, followed by isolation of individual clones17. Resistant lines were maintained in SB590885 (1 μM). Short tandem repeat (STR) analysis was repeated on the four cell lines in 2018 . Polyclonal M14-BR, M14-BMR, and Mel1617-BMR lines were generated in our lab from M14 and Mel1617 parental cells by culturing cells in increasing concentrations of the vemurafenib analog, PLX4720  or dabrafenib+trametinib  until resistant at the indicated dosage (≅6 months), and pooling resistant clones. M14-BR was maintained in PLX (1 μM), whereas -BMR lines were maintained in D/T (100 nM/20 nM).Antibodies: See Supplementary Table 19.DNA constructs and stable expressing cell lines: pBabe-puro-HA-ERK2-GOF  deposited by Chris Counter , GST-14-3-3-ε (#13279) deposited by Michael Yaffe , and His-MAP3K1 (#12181) deposited by Gary Johnson  were obtained from Addgene . M14-BMR cells expressing HA-ERK2-GOF were obtained by transfecting either the vector or ERK2-GOF into M14-BMR cells using Lipofectamine 2000 , selecting clones with puromycin (0.5 μg/ml), picking individual clones, and screening for expression by blotting with HA antibody. Positive clones were pooled. Constitutively active ABL1 and ABL2 (PP)26 were removed from their vectors  blunted and cloned into the SwaI site of PiggyBac cumate-inducible transposable vector . Vector or ABL1/2 constructs were stably transfected into WM164 cells using Lipofectamine 2000, selected with puromycin (1.2 μg/ml), and clones were pooled . FACS analysis indicated >90% of cells were GFP positive. Expression was observed in the absence (leaky) and presence of cumate. Low-level expression can be observed via phospho-CRKL blotting, which is an indirect measurement of ABL1/2 activity. M14-BR cells expressing nilotinib-resistant ABL1/2 mutant (T315I) forms61 were established by transfecting ABL1/2-T315I, cloned into the Piggybac Transposon vector (see above), followed by puromycin selection (1.2 μg/ml) and pooling resistant clones.siRNA and shRNA-expressing cell lines: MAP3K1 (s8669) and MAP4K1 (s22080) silencer select siRNAs (or scrambled control #1) were obtained from ThermoFisher . Cells expressing IPTG-inducible shRNA targeting ABL1 and ABL2  were obtained following lentiviral infection and selection with puromycin (0.5 μg/ml). Clones were picked, expanded, and screened for knockdown by western blot. Inducible shRNA-expressing cells were treated with IPTG  prior to screening. Cells were treated with IPTG (1 mM) for 5–10 days prior to plating for CellTiter Glo, colony-forming assays, or western blots.Drugs: GNF-5 and SB590885 were purchased from Selleck , whereas ponatinib, nilotinib (for in vitro experiments and for PLX4720 + nilotinib in vivo experiments), and trametinib were purchased from MedChem Express . Nilotinib (for D/T + nilotinib in vivo experiments) and dabrafenib were kindly provided by Novartis (Switzerland) under a Materials Transfer Agreement (MTA). PLX4720 for in vitro and in vivo use was obtained under an MTA with Plexxikon Inc. . SU6656 was purchased from Calbiochem . BV02 was from MilliporeSigma.2HPO4, 4 mM NaH2PO4, 50 mM EDTA, pH 7.3 + inhibitors—see below), Triton X was added , supernatant was incubated with glutathione sepharose for 30′, beads were washed 3× in MT-PBS followed by elution buffer lacking glutathione , and eluted in elution buffer containing 15 mM reduced glutathione. Elutions were pooled, dialyzed against phosphate-buffered saline (Slide-A-Lyzer), and quantitated via SDS/PAGE comparing to a known standard (BSA).Log-phase BL21 bacteria transformed with the constructs were induced with IPTG (0.1 mM) for 5 h, pellets were lysed in MT-PBS ]. Lysates were precleared with rabbit IgG (ABL1) or normal rabbit serum (ABL2) and protein-A sepharose. ABL1 or ABL2 was immunoprecipitated from cellular lysates  using agarose-conjugated K12 antibody for ABL1 or an ABL2-specific antibody19 and protein-A sepharose for ABL2. IPs were washed twice in RIPA buffer, twice in NaCl buffer , twice in the previous buffer lacking NaCl, and twice in kinase buffer , and incubated for 40 min at room temperature in kinase buffer containing 1 μM cold ATP, 5 μCi [γ-32P]ATP  and 1 μg of GST-CRK substrate. Kinase reactions were run on SDS-PAGE gels (10%), stained with Coomassie blue , destained, dried, and exposed to film. Bands were quantitated with ImageJ64 . We previously documented the high specificity and sensitivity of this assay62.Recombinant kinase assays: His-tagged, recombinant ABL1 or ABL2  were incubated with His-tagged, full-length MAP3K1 , and/or GST-14-3-3-ε (100 ng) in the above kinase assay buffer containing 1 mM cold ATP, and no “hot” ATP, and incubated for 30′ (or 15′ where indicated) at 37 °C. Kinase assays were run on SDS/PAGE gels and blotted with phospho-tyrosine antibody.63, cells were lysed in RIPA buffer, lysate was precleared with NTA-agarose , and His-tagged MAP3K1 was pulled down with nickel agarose (Qiagen). After 3 h incubation, precipitates were washed 3× in lysis buffer containing 20 mM imidazole, resuspended in 2× SDS-sample buffer containing 400 mM imidazole, and run on SDS-PAGE gels. For coIPs, cells were lysed in TNEN buffer 64, lysate precleared with mouse or rabbit IgG and protein-A (rabbit) or protein G (mouse) sepharose (1 h), immunoprecipitated with agarose-conjugated antibodies (3 h), washed 3× in lysis buffer, and complexes run on SDS-PAGE gels and blotted.293T cells were transfected with His-tagged MAP3K1 in the absence/presence of constitutively active ABL1 or ABL2 (PP), using the calcium phosphate methodCytoplasmic/nuclear lysates were prepared with the NE-PER kit (ThermoFisher). Equal percentages of cytoplasmic and nuclear fractions were loaded for each cell line, and ABL1 cytoplasmic:nuclear ratios were then compared between cell lines following quantitation on ImageJ64 (v1.44o).CellTiter Glo (CTG): Viability was assessed by plating cells in 96-well plates, treating the next day with drugs for 72 h, followed by harvest with CellTiter Glo  according to the manufacturer’s instructions. Cells were subconfluent at harvest. Assays were performed using three-drug doses . All cell lines were taken off of drugs for 2 days prior to plating cells for experiments. MTT assays: Cells were plated in 96-well dishes, and drug-treated. After 72 h, washed cells were treated with MTT solution  were run on SDS-PAGE gels, transferred to nitrocellulose, blocked with 5% milk/TBST (0.1%), and incubated with antibodies at the concentrations and stringencies noted in Supplementary Table (1) Mel1617 reversal of BRAFi resistance xenograft assay: Mel1617 or Mel1617-BR (2 × 106) cells  were injected subcutaneously into SCID-beige mice  together with matrigel . When tumors reached a mean volume of 200 mm3, parental control mice were randomly assigned to either vehicle or PLX4720, whereas mice harboring Mel1617-BR tumors were randomly assigned to vehicle , nilotinib , PLX4720  or combination treatment groups. PLX4720 dosage was 50 mg/kg/day initially, as recommended by Plexxikon Inc., but due to anorexia, the dose was reduced to 25 mg/kg after 2 days. Mice were treated until the study endpoint .(2) M14-BMR-reversal of BRAFi/MEKi resistance xenograft assay: Parental M14 cells or BRAFi/MEKi-resistant M14-BMR cells (5 × 106 cells) were injected subcutaneously into athymic nude mice . When the mean tumor size was 200 mm3, mice harboring resistant cells were randomized to vehicle (see above), nilotinib , dabrafenib  + trametinib  or the combination, whereas mice harboring parental xenografts were treated with vehicle or D/T. Parental-vehicle-treated mice were euthanized when the largest tumor approached 1500 mm3. For mice bearing M14-BMR tumors, all vehicle- and nilotinib-treated mice and four animals from D/T and D/T+ nilotinib groups were euthanized on day 35 (some vehicle and nilotinib tumors had reached 1500 mm3), and residual tumor/matrigel dissected. The remainder of D/T− and D/T+ nilotinib-treated mice (n = 8/group) were followed long-term, and D/T mice were euthanized when each tumor reached 1500 mm3. When some D/T+ nilotinib animals eventually relapsed (≅day 95), they were treated with ponatinib . If mice showed signs of toxicity , ponatinib was withdrawn until symptoms improved.(3) In vivo resistance assay: To mock resistance that occurs in patients, parental, BRAFi/MEKi-sensitive M14 melanoma cells were injected into athymic nude mice, and when the mean tumor volume reached 200 mm3, mice were randomly assigned to vehicle, nilotinib, D/T, and D/T + nilotinib groups. Tumors initially regressed on D/T, but later developed resistance, similar to what is observed in patients. A cell line was obtained from a resistant tumor by excising the tumor under sterile conditions, mincing into 3–4 mm pieces, treating with collagenase B  and dispase  in HBSS for 20′ at 37 °C (5 ml volume), centrifuging for 5′ at 800g, resuspending the cells in media containing D/T, and plating in a 100 mm dish. Mice were euthanized when each tumor reached 1500 mm3. All animal experiments were performed in the University of Kentucky Biomedical Biological Sciences Research Building vivarium barrier facility with ambient air temperature of 70 °F, cage temperature of 75–76 °F, 50% humidity, and 14/10 light/dark cycle. All animal experiments were approved by the Institutional Care and Use Committee (IACUC) at the University of Kentucky (Protocol #00946M2005), and experiments were performed in accordance with University and NIH guidelines.Tumors from mouse xenograft studies were fixed in formalin (24 h), followed by incubation in 70% ethanol (at 4 °C) until sectioning. The Markey Cancer Center Biospecimen and Tissue Procurement Shared Resource performed immunohistochemistry. Slides containing 4 μm sections were stained with anti-MYC antibody  on a Ventana Discovery Ultra auto-stainer (antibody is prediluted at an estimated concentration of 24 μg/ml). Visualization was carried out with Ventana Ultramap Alkaline Phosphatase reagent (Roche # 760-4314) and Discovery Red Chromogen (Roche #760-228) according to the manufacturer’s recommendations. Slides were blindly scored by a pathologist (D. Richards), and photographs were obtained following scanning on an AperioScan Digital Scope .General: For in vitro studies, two-sample (comparisons between-treatment groups) or one-sample t-tests  using the Holm’s method for multiple comparisons adjustment was performed. For in vivo studies, ANOVA with Sidak correction for multiple comparisons was used to compare tumor volume across treatment groups. Kaplan–Meier curves and the logrank test with the Holm’s method for multiple comparisons adjustment were used to compare time-to-tumor doubling across treatment groups. For all analyses, two-tailed P values are reported.Analysis of Existing Microarray and mRNA-Seq Clinical Datasets (Pre-/Post-ERK pathway therapy): Datasets for Fig. ABL1 mRNA was elevated or downregulated following resistance. In Fig. 65. After combining the datasets, Spearman’s rank-order correlation analysis was performed to test the correlations between ABL1 and MYC before and after treatment, respectively. For Supplementary Fig. ABL1 and MYC mRNAs.Whole-exome sequencing: WES was performed by the University of Kentucky Markey Cancer Center Oncogenomics Shared Resource. DNA was sheared using the Covaris E220 sonicator. Library preparation and exome capture was performed using the Agilent SureSelectXT Clinical Research Exome v2. Paired-end sequencing was done on an Illumina HiSeq 2500 in rapid run mode (2 × 100 bp). Sequencing reads were trimmed and filtered using Trimmomatic (V0.39)66, then aligned to human reference genome b37/hg19 using BWA (V. 0.7.17)67. PCR duplicates were removed using Picard . The Genome Analysis Toolkit (GATK v4.1.2.0)68 was used for base quality score recalibration. For comparisons between resistant lines and their parental counterparts, somatic mutations present in the resistant line but not in the parental line were detected using Mutect269 (part of the GATK toolkit) tumor/normal mode with the parental line as the reference. Mutations passing the contamination filter and orientation bias filter were annotated 70.MAP2K1 in genomic DNA isolated from 451-Lu-BR cells was performed by ACGT, Inc. using the primers described in Supplementary Table Sanger sequencing of Further information on research design is available in the Supplementary InformationPeer Review FileDescription of Additional Supplementary FilesSupplementary Data 1Supplementary Data 2Supplementary Data 3Supplementary Data 4Supplementary Data 5Supplementary Data 6Supplementary Data 7Supplementary Data 8Supplementary Data 9Reporting summary


To the Editor—Animal-assisted intervention (AAI) programs, used extensively in healthcare facilities, have numerous reported benefits to patients.3 These programs have increasingly been used for healthcare workers, as a targeted intervention to reduce occupational stress and burnout symptoms.4 However, barriers, specifically infection control concerns, prevent AAI programs from being used in many hospitals and among their diverse populations. This has become more apparent during the coronavirus disease 2019 (COVID-19) pandemic, and many AAI programs have been suspended due to apprehension about coronavirus spread, despite the critical need for proven mental health support programs for patients and employees during this taxing period.This qualitative study aimed to capture opinions pertaining to benefits and concerns related to AAI from individuals directly involved in hospital programs, particularly occupational health benefits for hospital staff and infectious disease concerns. We report on these key stakeholders’ perspectives and experiences and, through these reports, present a conceptual framework to recommend measures to better implement and support these programs. Although we focused our research on infectious diseases broadly, participant responses and our research findings are reflective and applicable to concerns for AAI programs related to the COVID-19 pandemic.5As part of a larger study on hospital AAI program-related risks and exposures, we interviewed 37 healthcare workers and therapy animal handlers from multiple hospitals. We thematically coded interview transcriptions based on deductive programmatic framework analysis. The study underwent research ethics review and approval. Further details on methodology and study participants have been previously published.Participants reported that these programs did benefit hospital staff by reducing stress and bolstering morale. They felt this led to an improvement in job performance through increased employee engagement, and by providing an “additional tool in their toolbox” for improved patient care. Finally, these programs were reported to be a gateway to other therapy programs, such as mental health counseling. In spite of these cited benefits, participants identified administrative barriers to implementation, such as balancing clinical duties. They conveyed that these obstacles could be overcome with appropriate leadership, and from collaboration across the hospital and management “buy-in,” to underscore the value of staff inclusion in AAI.Infection concerns were reported as a frequent barrier to program implementation, both for patient and healthcare worker use. Participants described their concern of the dog serving as an intermediary vector of pathogen spread among patients, staff, and the hospital environment. However, many participants, both pet therapy handlers and healthcare workers, felt this risk was minimal due to effective control measures, which should target the animal, the patients, and the hospital environment, designed with practical input from multiple stakeholders. The primary facilitator to appropriately enact control measures was the designation of individuals responsible for safety, and relevant training for all individuals involved with these programs about potential infectious risks and mitigation strategies.6 and the Environmental Protection Agency’s Risk Management Framework,7 which links our major themes in the context of program implementation. Hospital objectives and needs feed into program implementation, accomplished by addressing program barriers through facilitators (blue box). Perceived barriers, both administrative and infection risk as described, can be addressed through a risk management framework (yellow box): (1) identify the hazard , (2) assess and characterize said hazard, and (3) hazard management through applying and monitoring control measures. This approach results in an adaptive protocol based on individual program needs. Critical to the design and execution of program implementation is multiple stakeholder and hospital leadership engagement (red boxes) to ensure diverse, comprehensive input on protocols. Implementing adaptive AAI programs, through targeted facilitators, results in program benefits for both patients and staff, such as those listed in the figure, since many program barriers and facilitators apply to both. This ultimately creates a reinforcing feedback loop improving program implementation by substantiating hospital needs.Based on these reports, we developed a conceptual framework Fig. , adaptedOur qualitative study provided insight into appropriate AAI program implementation, both directed towards patients and HCW, based on the unique experiences and perspectives from individuals actively involved in these programs with crucial roles in their administration. Through participant reports and developing our conceptual framework, we identified 3 major areas for program improvement. First is the need for a tailored risk assessment to understand barriers unique to individual programs, hospitals, departments, and patient populations, to develop adaptive protocols. Secondly, leadership roles, or “champions,” are essential to advocate for the programs’ worth, plus communicate and ensure adherence to policies critical to success. Lastly, collaboration across the hospital is needed to design protocols for AAI with input from multiple stakeholder groups to ensure that program guidelines are comprehensive and practical.This conceptual framework can serve as a scaffold for hospitals wishing to start or extend AAI programs, and it is noteworthy for hospital administrators, healthcare epidemiologists, and occupational health specialists. More currently, this framework can be used to design plans to restart suspended AAI programs due to COVID-19, as well as potentially other patient well-being volunteer programs. The detailed level of contextual qualitative data obtained from our participants can be utilized to develop a practical quantitative survey to collect data from a wider scope of hospitals and participant groups to increase our recommendations’ generalizability. The results of this, and future work, will have significant implications in the utilization and preservation of these valuable AAI programs.


It is crucial that residents learn in environments that are psychologically safe and free of morale-harming rumors. This workshop introduced the Ladder of Inference as a means for programs to foster psychological safety, mitigate against rumors, and increase trust.Residents and faculty of two residency programs (cohorts A and B) were introduced to the Ladder of Inference. After an interactive discussion, small groups applied the concept to engaging, highly relevant hypothetical situations. Debriefing and reflection followed the group work. Finally, attendees completed an assessment of the workshop's effectiveness (10 7-point questions) and their satisfaction (one 7-point question).M = 65.9 out of 70) and satisfactory (6.3 out of 7). Twenty-eight residents and faculty from cohort B completed the workshop, and 15 completed the assessment (response rate: 54%). Cohort B participants also found the workshop favorable (M = 64.8) and satisfactory (6.8). Both cohorts felt the workshop was effective in helping them understand the concept of the Ladder of Inference (6.5 for both cohorts) and would provide value in their residency program in the future  and at other organizations .Seventeen residents from cohort A completed the workshop, and 15 completed the assessment (response rate: 88%). Participants found it favorable (This workshop is an effective method whereby participants can develop and apply an understanding of the Ladder of Inference. This shared understanding can promote trust and enhance the resilience of a program. Then, they are free to focus on collective goals, prevention, and improvement rather than on self-protection.3Psychological safety has been identified as a key factor in the success of organizations that are complex and require expertise and close collaboration.4In a residency program, learners are under pressure to acquire and develop new skills unerringly while under the intense scrutiny of faculty supervisors. In addition, high-achieving young physicians have high expectations of themselves, making them particularly vulnerable to challenges to their psychological safety. When they receive negative feedback, they may be at particular risk of perceiving threats to their self-image, compromising their ability and desire to enhance their own performance and the collective performance of their residency. It has been suggested that learners’ desire to protect their self-image is tied to a desire to avoid internal shame. In turn, low psychological safety may thus have negative effects on learning and well-being.5 Psychological safety has been shown be an important factor in resident satisfaction in the clinical learning environment. The Accreditation Council for Graduate Medical Education (ACGME) Annual Survey of Residents is an anonymous, externally administered measure assessing trainees’ satisfaction with their learning environment.6 Results from recent years (2016–2019) suggest that there is room for improvement nationally on two items that could be potential markers for psychological safety: “Satisfied with process to deal with problems and concerns” and “Residents can raise concerns without fear.” The ACGME does not provide a range of scores. However, leaders of programs scoring low on these measures may be particularly motivated to improve the psychological safety of their programs.Psychological safety can have positive effects on patient care and is predictive of residents’ intention to report adverse events.8In the clinical environments of 23 neonatal intensive care units, psychological safety has been shown to predict success for teams learning and implementing new practices, in turn demonstrating lower risk-adjusted mortality.9Aside from the stress associated with low psychological safety, an additional potential stressor for residency programs is rumors. The charged environment and long hours spent together can foster camaraderie but are also fertile for promoting rumors and gossip between and among residents and the faculty they work alongside.A residency program's faculty and program director are simultaneously teachers of residents and representatives of their mutual employer. As educators, the faculty must foster a safe and accessible educational environment in accord with ACGME guidelines. As representatives of the employer, the faculty must manage the program in a coherent, rational way in accordance with institutional requirements and legal regulations. At times, there may be tension between adhering to those requirements and fostering a healthy educational environment. For example, limitations on information sharing, such as may be necessary during a sudden departure of a member of the residency, can promote distrust among members of the program. Particularly in such times of crisis and in the context of a high-pressure residency environment, rumors can sprout freely and have a profound and negative impact on trust, morale, and perceived psychological safety within the educational community.10 Rumors are propositions of allegations without corroborative evidence, and they “scamper about organizations like some mischievous poltergeist, until skillful managers exorcise the allegations or the allegations vanish into thin air.”10 They exist to fill in information gaps as a form of speculation when not enough information is available.10 In a residency program, change inevitably occurs within a network of highly interconnected residents and faculty who share overlapping interests. When legal or other reasons mandate that information cannot be fully shared to fill in the blanks during times of change, the information famine can readily spawn such a poltergeist.Rumor theory explains that rumors tend to spring from the collective concerns of a group of interconnected individuals.11 The four steps proposed are to (1) remain indifferent to avoid empowering the rumor, (2) understand how the impact will affect various stakeholders, (3) measure the pros and cons of addressing versus ignoring the rumor, and (4) remedy and redress the rumor through the proper route, possibly with assistance from Human Resources or the Office of Graduate Medical Education. Other authors within the health care domain suggest means of stopping rumors. Ribeiro and Blakeley recommend assessing and analyzing the grapevine, identifying those individuals who are habitual spreaders of rumors, and keeping employees informed.12 Chase and Stuart suggest preventing and influencing rumors, debriefing and transforming them, and clarifying and informing.13 These approaches generally depend on a person with authority presenting facts to dispel the rumor. Yet these strategies of keeping employees informed and presenting facts to dispel the rumor are not available when an information blackout must be imposed. In fact, if a leader shares information with residents and faculty too widely, it can result in charges of defamation that can be considered a tort under state laws.14Rahmani recently expressed skepticism that program directors are equipped to manage rumors within their programs and proposed a framework for rumor management.How, then, can a program director or other organizational leader maintain an environment of trust and reduce anxiety in the context of uncomfortable, possibly unwelcome change about which little information can be shared?15 The ladder is a mental model that acknowledges the shortcuts people take in their thinking and the erroneous conclusions that can result. The lowest rung of the metaphorical ladder is observable data and experiences—things that concretely occur in the physical world. Given humans’ finite capacity to absorb and attend to such data, only a portion of what occurs in the world receives attention. What is attended to may be informed by past experiences. Receivers of the data assign meaning to that slice of reality, then fill in with their assumptions the vast amount of relevant information not observed. They make conclusions about the information, become certain of their belief, and take action based upon it. Between the time that observable data from the external world are perceived and action is ultimately taken, an enormous amount of mental processing manipulates and massages reality within the brain's black box, all in the span of milliseconds. When there is a partner or group of partners in a team interaction, the possibilities for misunderstanding are abundant as the participants all race up their own ladders of inference. Imperfect as this process may be, it is a consequence of humans’ limited capacity to process information and is thus a ubiquitous feature of workplace interactions.The Ladder of Inference, as described by Argyris, suggests a means whereby organization leaders such as program directors can treat or even inoculate against rumors that could be detrimental to harmonious program functioning.16The Ladder of Inference has been suggested among health care managers as a tool to facilitate candid conversations, to decrease errors and serious sentinel events, and to protect against staff dissatisfaction and turnover.Residents are immersed in a training environment that can pose a continuous threat to their psychological safety and harm their morale. The social milieu of a residency is fertile ground for the generation or propagation of rumors, which can also harm morale.We believe that previously proposed approaches for program directors to manage rumors are inadequate, especially when divulging information is not an option. We also believe that opportunities exist to create greater psychological safety in residency programs. For a target audience of residency program faculty and residents, our goal was to utilize the Ladder of Inference concept to facilitate trustful communication in order to mitigate against damaging rumors and enhance psychological safety in general.We introduced the concept of the Ladder of Inference as a means of coming to a shared understanding about how all members of a residency habitually and by necessity climb up this ladder. With the shared acknowledgment that team members inevitably make assumptions and draw incorrect conclusions, we were able to introduce a tool that could inoculate a program against rumors, create a resilient and trusting team, and enhance psychological safety even in challenging situations and information famines. This novel application of a model from systems theory in the medical education environment has widespread applicability throughout educational, clinical, and organizational settings.The intended audience for this activity is the residents, faculty, and director of a singular residency program. Appropriate settings include a program retreat or a dedicated residency half-day didactic or conference session.The workshop was implemented on two occasions with different participants. For cohort A, we presented the workshop as a 2-hour activity within the context of regularly scheduled Thursday morning didactics for the residents of a mid-Atlantic psychiatry residency program based within an academic medical center. The group included 15 of the program's 17 residents as well as the program director and one faculty member. Participants needed no prerequisite knowledge, although the facilitator had to have familiarity with the presented concepts and the proper operation of the activity. The facilitator was a former director of a family medicine residency at the same institution, as well as being an investigator in the study. The participants of cohort B were the 24 residents and four faculty of a mid-Atlantic family medicine residency program at a different hospital affiliated with a different academic medical center. Cohort B received a 3-hour version of the workshop with the same facilitator as cohort A.The Fifth Discipline Fieldbook17 and/or Pause for Breath.18Prior to the workshop, the facilitator had to be familiar with the Ladder of Inference concept from reading After identifying the participants, we calculated the number of small groups for the activity such that each group ideally contained three to four participants but no more than six. Each group had one clipboard and one permanent marker. We printed one large poster  of the Ladder of Inference  or B forThe workshop required a room large enough to accommodate all the participants seated in a circle as well as breakout space for smaller groups. Ideally, this was a large, open room with ample chairs, few tables or other obstructions, and plentiful wall space upon which posters could be affixed.In advance of the activity, we printed one unique Character Card from On the day of the activity, stations for each small group were arranged throughout the room with adequate space between them. At each station were a clipboard and permanent marker, and a copy of the Ladder of Inference poster hung on the wall or sat upon an easel.At the outset of the workshop, participants’ chairs were arranged in a circle. The facilitator proceeded with the presentation using the prominently displayed Ladder of Inference poster or a screen image.The first half of Exercise 1: Same Situation, Characters Vary proceeded as laid out in detail in With the small groups remaining at their stations, the facilitator proceeded with exercise 2: Different Situations . Rather Upon conclusion of exercise 2, the whole group reconvened at the circle of chairs. The second half of This study was approved by the Penn State College of Medicine Institutional Review Board through expedited review and was considered not to be human research.19 We modified questions to appropriately assess the educational objectives of this workshop . To index overall workshop impression, we calculated a summary score of the 10 impression questions. The satisfaction question asked about overall satisfaction with the workshop and was answered on a different 7-point Likert scale . Demographics included year in residency, age, gender, race, and ethnicity. The assessment took approximately 5 minutes. We did not compensate attendees for completion of the assessment.For both cohort A and cohort B, all attendees received a paper copy of the assessment immediately following the workshop. The 12-item assessment was a modified version of the evaluation questionnaire created by Allen and Baughman.workshop . The eva20 Similar to Allen and Baughman,19 to index overall workshop impression, we calculated a summary score of the impression questions ranging from 10 to 70, with 70 being the most favorable impression. We performed correlations to determine the relationship between summary and satisfaction scores. No formal analysis was conducted for the qualitative question, as there were few responses.We calculated descriptive statistics for all quantitative questions using SAS 9.4.SD = 9.1). On average, the respondents found the workshop to be favorable (6.3 out of 7). Similar to Allen and Baughman,19 we found a strong positive correlation between the single satisfaction question and the summary score from the impression questions (r = .8).A total of 15 residents (88% response rate) completed the assessment. Five attendees responded to the qualitative question asking for comments and suggestions regarding the workshop. They provided responses such as “This was a very interactive, engaging & creative workshop,” “need more like this,” and “interactive & thought provoking!”SD = 6.1). On average, the respondents found the workshop to be favorable (6.8 out of 7). Similar to Allen and Baughman,19 we found a strong positive correlation between the single satisfaction question and the summary score from the impression questions (r = .9).A total of 15 residents and faculty (54% response rate) completed the assessment. Four attendees responded to the qualitative question asking for comments and suggestions about the workshop. They submitted responses such as “This was the first time in a formal setting that I was able to think through the concepts of the ladder of inference” and “This was an excellent workshop. Will definitely like to work on improving my thought process.”A summary of the descriptive analysis of questions for both cohorts appears in 4 However, residency training is rife with threats to psychological safety. We created a workshop to introduce residents to the concept of the Ladder of Inference in order to enhance psychological safety and reduce feelings of shame, defensiveness, and vulnerability. We found that the activity was effective in helping residents understand how humans take mental shortcuts that result in erroneous conclusions, which can violate psychological safety.Psychological safety is critical to the growth and education of residents and is necessary for the collective good of a program.The very positive responses to assessment questions 1 and 2 suggest that the workshop achieved objective 1, introducing the concept of the Ladder of Inference in an engaging way. The positive responses to question 3 suggest that participants were able to recognize the applicability of the Ladder of Inference to themselves (objective 2). That participants could recognize the detrimental impact of assumptions on their program (objective 3) is suggested by the positive scores on questions 4 and 6. Finally, the positive responses to questions 5 and 7 indicate that objective 4 was met and that participants felt they could use their new insights to improve interpersonal communication in their professional roles.Ratings for the workshop were very similar. There was a trend for ratings of the workshop to be slightly lower for cohort A as compared to cohort B, although a comparison of the groups was not a primary goal of the study. This difference in ratings could potentially be due to subtle differences in the execution of the workshop, differences in the identity  of the participants, or other factors.The Ladder of Inference has been suggested in other clinical contexts as a means of improving communication. It appears that the concept can be successfully taught to residents and faculty in the context of this workshop.We strongly suggest that all members of the educational structure of the residency program participate in the workshop. At a minimum, this would include all residents, faculty, and the program director. Administrative staff and others who regularly interact with the residency in important ways could also be included. This could encompass clinical staff such as nurses. However, enlargement of the group by inclusion of more participants might detract from the degree of intimacy and candor of the group and should be considered in planning. Inclusion of clinical staff may so enlarge the group as to make the workshop difficult to execute and could also shift the focus of the workshop from academics to clinical considerations. This may or may not be desirable depending on the needs of the group.4We offer this workshop and the Ladder of Inference as tools for enhancing communication. Future work could measure the impact of these tools in practice. Metrics of psychological safety could be deployed before and sometime after participation in the workshop to assess effectiveness of the tool. ACGME survey results could serve as secondary markers of psychological safety. However, it must be noted that many factors intrinsic and extrinsic to a residency program can influence feelings of psychological safety, and thus, isolating the impact of the workshop may be difficult.Our study was limited by its execution within only two residency programs based in academic medical centers. Its acceptability and effectiveness could thus be a reflection of factors unique to the participants of the programs or academic medical centers, limiting generalizability. However, the similarity of responses despite the differing specialties of the residency programs suggests that the workshop could have a wider applicability. Additionally, we did not collect any data regarding the prevalence and effect of rumors in residency programs. A validated metric for assessing these aspects before and after the workshop would be very helpful in demonstrating the practical impact of the workshop.Future research could assess the effectiveness of the workshop among other specialties and within both academic and community-based sites. The participants’ opinion that the workshop would have value in other organizations suggests that it may be of use in other academic settings, such as among medical students. It could also have applicability within health care systems and organizations more broadly. In particular, the Situation and Character Cards could be adapted so that the workshop serves as an educational session dealing with issues of bias and diversity. Other applications could be developed by adapting the Situation and Character Cards to reflect local needs. For example, members of a public corporation that includes both engineering and marketing divisions could host workshops bringing together members of disparate teams. Cards could be modified to reflect the perspectives of the two divisions. Through the workshop, different teams working from disparate perspectives toward the same goal of generating revenue could come to understand one another better. Negotiations between management and union leaders could similarly benefit from an introduction to the ladder as a means of enhancing trust in pursuit of success for a business and its workers. In future deployments, the workshop itself could be modified to function via teleconference using shared screens and files rather than as an in-person event.This study demonstrates that the Ladder of Inference is a mental model that can be effectively taught and applied within residency programs. The importance of psychological safety and the apparent effectiveness of the workshop suggest that teaching the ladder can mitigate against the stresses of residency and the corrosive effect of rumors and assumptions. By extension, the workshop could improve concrete outcomes such as increased adverse event reporting, as well as trust and morale within programs. To the degree that a residency team develops a shared understanding and application of the Ladder of Inference model, it could foster resiliency, enhance collegiality, and improve educational and clinical outcomes.Ladder of Inference Poster.pptxLadder of Inference Poster.docxCharacter Cards.docxSituation Cards.docxRung Concept Cards.docxLadder of Inference Presentation.pptxExercise 1 Instructions and Talking Points.docxExercise 2 Instructions and Talking Points.docxLadder of Inference Workshop Assessment Tool.docxAll appendices are peer reviewed as integral parts of the Original Publication.


The Support at Home pilot program provided financial support for the purchase of home care services by middle-income adults with disabilities in San Francisco to support aging in place. Enrollees had income below the area median and made copayments based on household income. The mixed-methods evaluation of the program incorporated administrative records, surveys of clients and comparison group members, surveys of unpaid caregivers, surveys of paid care providers, and focus groups with clients and unpaid caregivers. Outcome measures included the Older People’s Quality of Life Questionnaire, Patient Health Questionnaire-2, an adapted Burden Scale for Family Caregivers, and self-reported falls, emergency department visits, and hospitalizations. Analyses included pre-post chi-squared and t-test comparisons between client and comparison groups and multivariate regressions. An economic analysis was conducted to learn whether changes in costs associated with reduced health care utilization were greater than the costs of the program. Results indicated statistically significant positive changes in client ratings of personal and financial stress, but not in the composite quality of life score. There were statistically significant reductions in attendance at medical appointments, falls, emergency department visits, and hospitalizations. Similar changes were not found in the comparison group. The focus group data supported the findings regarding personal and financial stress and indicated that clients and their caregivers perceived quality of life benefits. The economic analysis indicated substantial cost savings from the program due to reduced use of medical services. Due to its positive impacts, San Francisco has made Support at Home a permanent program.