Arrb1 gene (AAV-Arrb1) into the RVLM of SHRs significantly increased NO production and NO synthase (NOS) activity. Microinjection of the non-selective NOS inhibitor N-nitro-L-arginine methyl ester  into the RVLM prevented the β-arrestin1-induced cardiovascular inhibitory effect. Furthermore, β-arrestin1 overexpression in the RVLM significantly upregulated the expression of phosphorylated neuronal NOS (nNOS) by 3.8-fold and extracellular regulated kinase 1/2 (ERK1/2) by 5.6-fold in SHRs. The β-arrestin1-induced decrease in BP and RSNA was significantly abolished by treatment with ERK1/2 small interfering RNA (ERK1/2 siRNA). Moreover, ERK1/2 siRNA attenuated the β-arrestin1-induced NO production, NOS activity, and nNOS phosphorylation in the RVLM. Taken together, these data demonstrate that the antihypertensive effect of β-arrestin1 in the RVLM is mediated by nNOS-derived NO release, which is associated with ERK1/2 activation.β-Arrestin1 is a multifunctional scaffold protein with the ability to interact with diverse signaling molecules independent of G protein-coupled receptors. We previously reported that overexpression of β-arrestin1 in the rostral ventrolateral medulla (RVLM) decreased blood pressure (BP) and renal sympathetic nerve activity (RSNA) in spontaneously hypertensive rats (SHRs). Nitric oxide (NO) is widely reported to be involved in central cardiovascular regulation. The goal of this study was to investigate whether NO signaling contributes to the β-arrestin1-mediated antihypertensive effect in the RVLM. It was found that bilateral injection of adeno-associated virus containing  It is well known that β-arrestin1 is an important modulator of G protein-coupled receptor (GPCR) desensitization and internalization . IncreasNitric oxide (NO), synthesized by NO synthases (NOS) family, underlies the vasodilation of blood vessels and central functions as an important neurotransmitter in the brain . One typNeuronal NOS phosphorylation is reported to be regulated by extracellular regulated kinase 1/2 (ERK1/2) activation in the carotid artery . AccumulThus, the present study mainly focused on β-arrestin1’s effects on NO release in the RVLM, and the following two points were examined: (1) if NO in the RVLM mediates the β-arrestin1-induced cardiovascular effects and (2) if ERK1/2 signaling pathway contributes to linking to β-arrestin1’s effects on NO production.All the experimental SHRs and Wistar-Kyoto (WKY) rats were 16 weeks old and purchased from Sino-British SIPPR/BK Laboratory Animal Ltd. . The procedures were approved by the Institutional Animal Care and Use Committee of Naval Medical University and were carried out under the guidelines of the National Institutes of Health Guide for the Care and Use of Laboratory Animals. All steps were taken to minimize the animals’ pain and suffering.NM_012910). The vector that was labeled by green fluorescent protein and contained all sequence elements except the Arrb1 gene was used as the control (AAV-GFP).As previously described , the serArrb1 gene fragment were slowly bilaterally injected into the RVLM  with a 32-gauge Hamilton syringe (5 μl) in 5 min, and the bilateral injection volume was 250 nl. After the incision was well cleaned and sutured, rats were administrated with 1,000 units of penicillin by muscle injection to prevent infection.The experimental rats were anesthetized with continuous inhalation of isoflurane (3%) and placed in a stereotaxic frame , as previously described . BrieflySmall interfering RNAs (siRNAs) were purchased from Gema Biotechnology Company . Nine days after overexpression of β-arrestin1 in the RVLM, SHRs were anesthetized and received bilateral RVLM microinjections of either pooled ERK1/2 siRNA (0.3 μg in 0.7 μl 10 mM JetSITM) . This dose was tested to be effective through reducing the total ERK1/2 and p-ERK1/2 expression in the RVLM of WKY, based on a previous study , and a sIn conscious rats, BP and heart rate (HR) were continually measured by non-invasive tail-cuff system  7 days after AAV-Arrb1 was injected into the RVLM according to our previous study . In anesN-nitro-L-arginine methyl ester  into the RVLM  was performed with a multiple-barrel micropipette. The RVLM was functionally identified by a pressor response to L-glutamate (2 nmol) injection. Changes in BP, HR, and RSNA were continuously recorded by the PowerLab system.According to our previous study , the ratMeasurement of the total NO production in the RVLM was based on our previous study . BrieflyNO synthase activity detection was conducted according to a previous study . RVLM tiAs previously described , rats weAccording to our previous description , the flut-test. Differences in ERK1/2 siRNA silence efficacy and BP change in conscious rats were analyzed by one-way ANOVA with Dunnett’s multiple comparisons and repeated measurements with Turkey’s multiple comparisons tests. All the other differences in mean values were analyzed by two-way ANOVA with Turkey’s multiple comparisons tests. All the data were analyzed by GraphPad Prism . P values of < 0.05 were considered statistically significant.All data were examined as mean ± SE. Differences in β-arrestin1 expression between WKY and SHRs were analyzed by unpaired P < 0.05) decrease in BP and baseline RSNA. As shown in As shown in L-NAME (10 nmol) into the RVLM of SHRs pretreated with β-arrestin1 overexpression caused a significant increase in BP  and RSNA  compared with SHRs without β-arrestin1 overexpression.We further assessed whether the β-arrestin1-induced decrease in BP and RSNA of SHRs was mediated by NO release in the RVLM. As shown in P < 0.05) in the RVLM of SHRs compared with the SHR + AAV-GFP group. Similarly, the phosphorylated level of ERK1/2 in the RVLM of SHRs was significantly decreased compared with that of WKY (P < 0.05). Similar to the change of nNOS, the phosphorylation level of ERK1/2 (P < 0.05) by β-arrestin1 overexpression in SHRs. Immunofluorescence staining also demonstrated that treatment with β-arrestin1 overexpression increased ERK1/2 phosphorylation in the RVLM of SHRs  was observed by ERK1/2 siRNA at day 12 after β-arrestin1 overexpression compared with that treated with the CON siRNA (P < 0.05) and baseline RSNA  under the anesthetized state. These data indicated a critical role of ERK1/2 in the RVLM in the effect of β-arrestin1 on sympathetic hyperactivity and high BP.After identification of the efficacy of ERK1/2 siRNA in the RVLM, the β-arrestin1-ERK1/2 signaling pathway was verified by injection of siRNA into the RVLM of SHRs 9 days after AAV transfection. As a result, a significant increase in BP  decreased NO level and NOS activity. The phosphorylation of nNOS expression was also decreased by ERK1/2 siRNA pretreatment. These data suggested that ERK1/2 was involved in interaction between β-arrestin1 and nNOS/NO signaling in the RVLM of SHRs.As shown in This study mainly focused on the relationship between NO signaling and β-arrestin1 in the RVLM. The major findings were that (1) overexpression of β-arrestin1 in the RVLM significantly enhanced NO production and nNOS phosphorylation in SHRs; (2) β-arrestin1 overexpression in the RVLM increased ERK1/2 phosphorylation in SHRs; and (3) administration of ERK1/2 siRNA into the RVLM blocked the β-arrestin1-induced decrease in BP and increase in NO release as well as nNOS phosphorylation in SHRs. The current results suggest that NO signaling plays an important role in mediating the inhibitory effect on sympathetic tone and BP evoked by β-arrestin1 in the RVLM, which is associated with activation of ERK1/2 signaling pathway.We have previously demonstrated a significant reduction in BP of SHRs 14 days after administration of AAV-Arrb1 into the RVLM . In thisNitric oxide is well characterized for its vasodilatory role in cardiovascular regulation; and a number of studies have linked NO to cardiovascular activity in the RVLM . HoweverNitric oxide production is regulated by NOS catalysis; and the three isoforms, nNOS, eNOS, and iNOS, are located in the RVLM . Althoug2A adrenergic agonist  an enhancement in NO release is an important cause of β-arrestin1-induced protective response in the RVLM of hypertension, and (2) this effect is underpinned, at least partly, by ERK1/2-mediated nNOS activation. The present study highlights central β-arrestin1 as an important manager for cardiovascular regulation, impelling us to further explore other potential roles of neuromodulators for cardiovascular protection in hypertension.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The animal study was reviewed and approved by the Institutional Animal Care and Use Committee of Naval Medical University.J-CS, XT, and L-JG have contributed equally to conduct the experiments, collect and analyze the data of the study. J-CS drafted the initial version of the manuscript. M-JX and W-ZW provided revisions on the manuscript. All authors have read and approved the final version of the manuscript for publication, agreed to be accountable for all aspects of the work, and ensuring that questions related to the accuracy or integrity of any part are appropriately investigated and resolved. All persons designated as authors qualify for authorship, and all those who qualify for authorship are listed.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.


This study reports on integrating community perspectives to adapt a family-focused, culturally appropriate behavioural intervention program to prevent diabetes among Aboriginal children (6–11 years) in Central Australia. A participatory action research approach was used to engage a range of service providers, cultural advisors, and family groups. Appropriateness, acceptability, content, and delivery of a prevention program within the Central Australian context were discussed through a series of workshops with twenty-five service providers and seven family groups separately. The data obtained were deductively coded for thematic analysis. Main findings included: (i) the strong need for a diabetes prevention program that is community owned, (ii) a flexible and culturally appropriate program delivered by upskilling community members as program facilitators, and (iii) consideration of social and environmental factors when implementing the program. It is recommended that a trial of the adapted prevention program for effectiveness and implementation is led by an Aboriginal community-controlled health service. T2DM and obesity in children and adolescents are escalating global concerns . ObesityPrevention is critical to breaking the intergenerational cycle of metabolic risk and early intervention is crucial for effective outcomes . The LanInternational evidence suggests that youth obesity rates track from 6–7 years of age into adulthood ,20,21. TClearly, there is a need for relevant and culturally appropriate prevention programs in Australia. The Tribal Turning Point (TTP), a behavioural intervention program, incorporated those strength-based characteristics and had been successfully implemented as a pilot program with American First Nations youth aged 7–10 years with overweight/obesity. It was adapted from the national Diabetes Prevention Program in the United States ,29. Key In 2018, the Diabetes across the Lifecourse Northern Australia Partnership’s (Partnership) Aboriginal and Torres Strait Islander Advisory Group set the importance of community-based initiatives to prevent youth-onset obesity and diabetes as a priority . This prAuthors A.R. , S.M. (Certificate II in community-based research) and R.K.  conducted interviews and focus groups with a range of service providers and family groups in an urban setting in Central Australia. S.M. is a local Aboriginal woman, with experience in community consultation and Aboriginal social and emotional wellbeing. Being a local community member, S.M. was passionate about the proposed diabetes prevention program and her involvement was instrumental in providing a safe space for families and other community members to share their views and stories. R.K. is a non-Aboriginal social scientist with ten years’ experience in applying qualitative research methods in Aboriginal and Torres Strait Islander health research. A.R. is a non-Aboriginal researcher who managed this project under the supervision of R.K. A.R. was raised with an Indian cultural background, has expertise in conducting interviews in remote community settings and has five years’ experience in managing research projects.Central Australia covers 65% of the total Northern Territory (NT) of Australia. The estimated resident population in Central Australia as of 2019 was 38,728, and 35% of the population was Aboriginal and Torres Strait Islander peoples ,33. AlmoA qualitative participatory action research methodology  was emplKey stakeholders were identified through the Partnership and included: health partners in Central Australia, including the Central Australian Aboriginal Congress (Congress), an Aboriginal Community Controlled Health Service, non-health Aboriginal community-controlled organizations, non-government and government organizations. Aboriginal families with children aged 6–11 years living in Alice Springs were identified through Congress in Central Australia and a local community health researcher (S.M.). S.M. and R.K. conducted preliminary consultations with family groups and service providers who participated in the study.Ethics approval was obtained by the Central Australian Human Research Ethics Committee (CA-19-3343). Other approvals from Congress, Central Australian Health Services, other Primary Health Care services and the Northern Territory Department of Education were obtained prior to commencing the project. Participants were approached by S.M. or A.R. either by email, telephone, or face-to-face contact. Interviews or workshops with stakeholder participants occurred at participants’ workplaces and focus groups with Aboriginal families and Elders occurred in an open public space . All participants were provided with a participant information sheet and a verbal explanation regarding the project. With verbal and written consent from each participant, all interviews or workshops were audio recorded.Data collection occurred in three stages. Stage one involved engaging service partners and families to assess the suitability of the intervention including program content and structure. Six two-hour workshops and two one-hour workshops were conducted among service providers and families, respectively. Stage two established working groups that involved representatives from the community, service providers and researchers. A technical reference group was formed to oversee the community consultations, revision of the program content and provide governance for implementation and monitoring of the revised and adapted TTP program. A dietitian working group was formed for nutrition- and diabetes-related content expertise. A cultural reference group was formed to oversee the cultural aspects and language used in the program. Terms of Reference for the technical reference group, dietitians working group and cultural reference group were developed where regular meeting times and duration were agreed by all members. Stage three focused on the practical supports, such as staff training, required to trial the intervention. Five workshops were undertaken with service providers and families separately to explore revised content, delivery mode, training modules for health coaches and realistic time frames. All researchers undertook data analysis and interpretation using an Aboriginal cultural lens to ensure that Aboriginal voices were prioritised . Audio rn = 38) across three stages of consultation. Characteristics of study participants are included in Eleven workshops with twenty-five service providers and three workshops with seven family groups were conducted , “The sports equipment’s a good one.”Engaging the whole family was noted as a major strength of the program by family participants. An Aboriginal parent participant recommended that “the program needs to be flexible and dynamic” to enable any carer of the family to attend the program along with the child. Practical recommendations “about having something there [in the program] to assist the carers, parents, nannas” were highlighted by another Aboriginal parent participant. A common recommendation was to provide transport for families to and from the program location and was highlighted by an Aboriginal Elder participant that “this [transport] is the best way to support them [carers]”.https://www.supportingcarers.snaicc.org.au/connecting-to-culture/sorry-business/ (accessed on 21 May 2021)…we have all these things to go to, like ceremonial leaves and we have women’s lore meeting and men’s business.” Another important consideration for the program is being flexible, as families have commitments and competing priorities that may impede their ability to attend the program regularly. This was well reflected by the Aboriginal Cultural advisor participant, “… we have a lot of interactions, we have sorry business , which can be as painful as the loss of a loved one. https://www.clc.org.au/articles/info/aboriginal-kinship (accessed on 21 May 2021) structures influence attendance at programs, and as such, should be a consideration when planning and facilitating the program. It was suggested that small groups of participants (2–3 families) might be appropriate to promote program participation and that the best approach for recruitment is to leave it to the comfort and choice of the families. As iterated by an Aboriginal Health Promotion Officer, “We’ve got to be wary of the kinship, it is very strong in Central Australia. It is better to work individually with the families or … get all the families as different groups of families together”. Other strategies to enhance youth engagement included setting up youth groups and fun activities outside the program sessions for children attending the program. Participants also suggested breaking down program sessions and/or prioritizing content and delivering as a smaller program. It was also suggested the program be aligned with respective community sports weekends or other youth activities.Several suggestions were raised by the participants to address long term attendance and continuous commitment of families to the whole program. Kinship )). In line with this, a non-Aboriginal participant (Dietician) iterated that:There was consensus among participants that weekly program sessions are important to encourage momentum and interest in the program. Several participants suggested primary schools to be an appropriate place for program delivery. Others questioned the inclusiveness or appropriateness of this environment, with concerns that it may not be a place where all parents feel comfortable enough to participate. A few participants suggested that as health clinics work closely with the family, they should deliver the program along with other services. The majority of families and a few health service providers recommended the program be delivered in a place that encourages family participation  to extensively use visual tools to engage families and children, (ii) to have direct focus on families’ priorities, and (iii) to use localized information of the specific community while preparing program resources.It was also suggested that the program delivery needs to be more hands on rather than continuous lecturing  and that talking about various study topics in small groups is preferred to large groups. As suggested by the Aboriginal Cultural advisor participant, “Have that good communication …. They’ll sit down and listen, but you might just listen to them first.” Another Aboriginal Community Engagement Officer participant suggested the program delivery to be “culturally appropriate for the communities... something very simple, simple terms, nothing complex. Be flexible, it must be flexible if you’re working with a family.” It was recommended the Aboriginal Health Promotion officers incorporate strategies for culturally appropriate program delivery that may include “hands-on stuff rather than sitting down and talking” and “having visual videos of young families or, you know, like Indigenous family videos… like this is what we’re aiming to do, and show that, this is what this family is done etc.”All participants agreed that the frequency (one session per week) and duration (2 h) of the original TTP program would be appropriate in the urban Central Australian context. Inviting Aboriginal people who had experienced chronic conditions, “like those ladies in renal, you know, the elders there, they can talk about their life experience around having that chronic condition” was suggested by the Aboriginal Cultural advisor participant and a few other participants.Service providers and community members suggested individual family sessions as platforms for individual ‘yarning sessions’ and focused conversations for that particular family situation. This approach would assist in building trust and rapport between family members and program facilitators that is required for meaningful engagement. Booster sessions included in the TTP program were considered a good way of following up program participants however it was recommended that in Central Australia, the content included in booster sessions be more targeted according to the families’ needs.All participants agreed that it is important to set simple and short-term goals for children and family members attending the program. For example, an Aboriginal parent recommended that “the participants can come up with their own goals to the program and ask [for] advice on how to achieve those goals”. Several suggestions to follow-up ‘family goals’ were suggested including using phone applications or closed social media groups or using simple surveys with tick boxes or smiley characters. Participants including health service providers, family groups and cultural advisors suggested that depending on the family circumstances, the process of ‘following-up’ could be time-consuming as iterated by an Aboriginal parent, it is important to “be more frequent in touch basing from facilitator’s side, phone calls on how things are going, etc. [with families].”Participants highlighted the importance of acknowledging existing social determinants of health in the community to promote successful implementation and meaningful outcomes of the adapted program. Affordability and easy access of healthy food and drinks was a key concern in the community. It was suggested by an Elder that “all shops need to be involved”. As iterated by a non-Aboriginal Dietitian participant, it is crucial to be “working with the settings—with the stores, with the hostels, the food supply” to enhance uptake of behaviours promoted by the adapted program.This consultation project informed the adaptation of the TTP program for Aboriginal children and their families in Central Australia. Our consultations indicated a strong need for such a program that is owned and led by the community. Other major findings included the need for trained local facilitators, culturally appropriate program delivery and acknowledgment of social determinants of health within the community while implementing the program.The principle finding of our study was that for successful implementation, a diabetes prevention program should be community-owned. There was evidence of already existing readiness by the community to receive and facilitate the program. This aligns with previous reports that highlight the benefits of community-owned programs in remote Aboriginal settings ,38,39. COur second finding highlighted the need for training and upskilling local facilitators from the community for program facilitation. This is closely related to the ownership facet of the program. Identifying community ‘brokers’ who understand the value of the proposed program and assigning facilitation to them is key in utilising the existing strength and capacity within the community . CommuniAnother important finding from the study was the significance of culturally appropriate program delivery. Cultural appropriateness draws from when the worldviews of the community are prioritised in program design and delivery ,48. PrevOur findings also emphasize the importance of acknowledging the environmental and social context of the community while implementing the adapted TTP program. The complex interplay of wider social determinants, while instigating behaviour changes through lifestyle intervention programs (such as TTP), has been highlighted in the literature ,53. WhilA major strength of this study was that it was designed in response to a community need. The study design and the delivery were led by Aboriginal researchers  in partnership with Congress. Other strengths include in-depth consultation with a range of sectors of the community and prioritising Aboriginal perspectives. The active involvement of the local Aboriginal research officer (S.M.) to ensure local Aboriginal interpretation of data was key. However, the study is limited to perceptions and opinions of the study participants in one Central Australian urban setting as well as from a limited number of family groups. Hence, the findings may not represent all family groups or cannot be generalizable to other communities in or beyond Central Australia.Through actively engaging families, Elders and service providers, the current study provides recommendations for adapting a youth diabetes prevention program appropriate for the Central Australian context. This work highlights the identified need for such a program and recommends it is community owned and led. The approach taken to engage key stakeholder groups in the adaptation process in this study was important to meaningfully incorporate community perceptions. It is recommended that the proposed program is piloted in remote and urban community settings in Central Australia, led by a community-controlled health service.


The constitutively active BCR-ABL1 tyrosine kinase, found in t chromosomal translocation-derived leukemia, initiates an extremely complex signaling transduction cascade that induces a strong state of resistance to chemotherapy. Targeted therapies based on tyrosine kinase inhibitors (TKIs), such as imatinib, dasatinib, nilotinib, bosutinib, and ponatinib, have revolutionized the treatment of BCR-ABL1-driven leukemia, particularly chronic myeloid leukemia (CML). However, TKIs do not cure CML patients, as some develop TKI resistance and the majority relapse upon withdrawal from treatment. Importantly, although BCR-ABL1 tyrosine kinase is necessary to initiate and establish the malignant phenotype of Ph-related leukemia, in the later advanced phase of the disease, BCR-ABL1-independent mechanisms are also in place. Here, we present an overview of the signaling pathways initiated by BCR-ABL1 and discuss the major challenges regarding immunologic/pharmacologic combined therapies. BCR (break point cluster) gene, three major isoforms of BCR-ABL1 can be produced: the 185kDa, 210kDa, and 230kDa proteins found in acute lymphocytic leukemia (ALL), chronic myeloid leukemia (CML), and chronic neutrophilic leukemia (CNL), respectively [c-ABL—the cellular homolog of Abelson murine leukemia virus (A-MuLV)—on chromosome 9 is replaced by one of the BCR sequences q34;q11)—characteristic of Philadelphia chromosome(Ph1)-positive leukemia [4;q11—chaequences .The BCR part of the protein contributes to several domains responsible for regulating the enzymatic activity of BCR-ABL1 or its interactions with different binding partners ,6. At thc-ABL is a tyrosine kinase located preferentially in the nucleus , althougThe indication that this enzymatic activity was essential to induce the transformation of BCR-ABL1-positive cells led to the development of a rationally designed tyrosine kinase inhibitor (TKI)—imatinib mesylate, also known as STI571 or Gleevec . ImatiniDue to its complex structural nature, multiple proteins have been shown to directly associate with BCR-ABL1. Co-immunoprecipitation of BCR-ABL1 from the K562 CML cell line followed by mass spectrometry revealed the potential core components of the BCR-ABL1-interactome, including the adapter proteins GRB2, SHC adaptor protein 1 (SHC1), CT10 regulator of kinase 1 (CRK1), the E3 ubiquitin-protein ligase casitas B-lineage lymphoma (c-CBL), the p85α and β subunits of the phosphoinositide 3-kinase (PI3K), the suppressor of T-cell receptor signaling 1 (STS1), and the SH2 domain-containing inositol 5-phosphatase 2 (SHIP-2) . These pThe activation of the rat sarcoma virus (RAS)/rapidly accelerated fibrosarcoma (RAF)/mitogen-activated protein kinase (MAPK) pathway by BCR-ABL1 is initiated by GRB2 binding to phosphotyrosine Y177 in the BCR region, followed by the recruitment of GRB2-associated-binding protein 2 (GAB-2) and son of sevenless (SOS). The BCR–ABL1–GRB2–SOS complex drives RAS activation and the consequent activation of RAF1, MAPK/ERK Kinase (MEK), extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38MAPK. Together, these signaling pathways regulate cell proliferation, differentiation, and survival ,16,17,18BCR-ABL1 activates the PI3K/AKT/mTOR pathway both directly and indirectly through the induction of autocrine cytokines . The intAKT also induces the downstream activation of mammalian target of rapamycin (mTOR), which works as a catalytic subunit of the mTORC1 and mTORC2 protein complexes . mTORC1 Importantly, resistance to TKIs, such as imatinib, dasatinib, and nilotinib, is associated with the hyperactivation of the mTORC2/AKT signaling pathway ,37, possJanus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling is involved in growth factor independence and resistance to apoptosis in CML ,45,46,47A disturbance in the canonical WNT/β-catenin signaling pathway is associated with the pathogenesis of leukemia ,54. In tPP2A is a tumor suppressor serine-threonine phosphatase that negatively regulates the mitogenic and survival signals emanating from PI3K/AKT, RAS/MAPK, and MYC pathways . InteresUnquestionably, the BCR-ABL1 tyrosine kinase-dependent signaling events summarized above are required for the transformation of Ph1 chromosome-positive leukemia. However, the resistance to TKIs observed in some CML patients suggests that signals emanating from the BCR-ABL1 protein independently of its tyrosine kinase activity may take over, allowing the survival of leukemic cells and relapse of the disease. Indeed, it was recently shown that inhibition of the catalytic activity does not completely dismantle the BCR-ABL1 molecular complex . SignaliEqually important is the fact that LSCs homing to bone marrow niches is arguably the most important event related to TKI resistance, since it results in a high genetic, epigenetic, and transcriptional alteration leading to an increased self-renewal capacity of the LSCs themselves . AcquireAs discussed above, BCR-ABL1 activates multiple signaling pathways to induce leukemogenesis, which results in growth factor-independency and regulation of adhesion and invasion ,72,73. OThe enforced expression of BCR-ABL1 in hematopoietic cell lineages revealed its potential to prevent apoptosis induced by a variety of stimuli, including growth factor withdrawal, γ-irradiation, death receptor agonists, and multiple chemotherapeutic drugs ,77,78,79BCR-ABL1 has been shown to inhibit apoptosis at the mitochondrial level by preventing the release of cytochrome c to the cytosol and the consequent activation of effector caspases . It is iBIM that produces BIM isoforms lacking the pro-apoptotic BH3 domain has been associated with resistance to TKIs in CML [The regulation of particular pro-apoptotic BH3-only members of the BCL-2 family were also shown to contribute to the resistance to apoptosis observed in BCR-ABL1-positive cells. As previously mentioned, BCR-ABL uses the PI3K pathway to phosphorylate and inactivate BAD; however, as mentioned previously, BAD inactivation does not account for the resistance to apoptosis observed in BCR-ABL1-positive cells . Interess in CML . ApparenBCR-ABL1 has also been shown to inhibit apoptosis initiated by death receptor signaling ,88,89,90The discovery that constitutive BCR-ABL1 tyrosine kinase activity was crucial for the development of CML  warranteImatinib was developed by Novartis Pharmaceuticals and was the first TKI to successfully show an impact on the proliferation and survival of BCR-ABL1-expressing cells in vitro and in vivo ,97. In 2The TKI nilotinib was FDA approved in 2007 for the treatment of CML-AP and -CP patients who were resistant or intolerant to imatinib treatment . In vitrDasatinib is a potent second-generation inhibitor targeting several kinases, including BCR-ABL1, SRC kinases, c-KIT, and platelet-derived growth factor receptor beta (PDGFR-β) ,110. In Bosutinib is a second-generation TKI with dual inhibitory activity against SRC and ABL kinases. Different than dasatinib, this inhibitor has minimal inhibitory effects against c-KIT and PDGFR-β kinases ,115. In The third-generation TKI ponatinib is a BCR-ABL1 inhibitor with strong activity against common ABL kinase domain mutations, including the T315I mutation . In vitrAsciminib (ABL001/Sclembix) is the newest tyrosine kinase inhibitor that targets both native and mutated BCR-ABL1, including the gatekeeper T3151 mutant. Different to other TKIs, asciminib does not bind to the ATP-binding site of the kinase portion of BCR-ABL, but rather works as an allosteric inhibitor of kinase activity. Asciminib binds to the myristoyl site of the kinase domain, normally occupied by a motif that serves as an allosteric negative regulatory element. Through binding of this site, asciminib locks BCR-ABL into an inactive conformation inhibiting downstream signaling events ,126. In Although TKIs have offered a significantly improved survival and quality of life for patients with CML, the ability of this agent to eradicate quiescent CML stem cells remains a challenge. New therapies that inhibit leukemia stem cells and consequently reduce the chances of relapse are currently under investigation.The major purpose of CML therapy with TKIs is to achieve a deep molecular response. To identify those who have not achieved desired response and may be suffering from resistance to TKIs, it is necessary to apply the European LeukemiaNet criteria for treatment response ,127. It Resistance to TKIs can be classified as primary (no hematologic or cytogenetic response from the beginning of therapy) or secondary . Currently, two mechanisms of resistance are known: BCR-ABL1-dependent and BCR-ABL1-independent pathways . It is iThe first report of TKI resistance was published in 2001 when a group of patients lost response during imatinib treatment . The seqSeveral mutations were described, some more frequent than others, for example, T315I, H396P, E255K, Y253F , and mosAmplification or overexpression of the ABL1 kinase domain triggered by genetic instability can also impair TKI binding and consequently reactivation of the phosphorylation cascade . AlthougResistance to TKI therapy can occur independently of BCR-ABL1 and may involve genomic instability, epigenetic modification, the overexpression of multidrug resistance (MDR) proteins involved in the efflux of anti-cancer drugs, the activation of survival pathways , and interactions with the LSC microenvironment .The genomic instability of LSCs contributes to the emergence of genetic abnormalities. Mutations in the coding sequences of genes involved in chromatin remodeling, differentiation, proliferation, and survival of blood cells, including ASLX1, RUNX1, and NRAS, may contribute to progression and drug resistance in CML ,143. In The ATP-binding cassette (ABC) transporter family of proteins actively exports structurally unrelated substrates out of cells, presumably to protect them from possible toxicities. Overexpression of some members of this family, including P-glycoprotein (MDR1) and breast cancer resistance protein (ABCG2), have been implicated in leukemia stem cell drug resistance ,148,149.As discussed above, BCR-ABL1 induces the activation of multiple signaling pathways, such as JAK-STAT, RAS-MAPK, and PI3K-AKT, that are responsible for cell proliferation and anti-apoptotic signaling . AlthougSeveral recent studies have shown that the bone marrow microenvironment plays an important role on the response of leukemic cells to anti-cancer drugs. CML stromal cells have an abnormal gene expression pattern, despite a deep molecular response, that may contribute to disease relapse and secondary resistance . These cFinally, an important element to be considered is the pharmacokinetics of TKIs. A study showed that imatinib concentrations may vary due to the levels of cytochrome p450 isoenzyme 4A, which is responsible for neutralizing it, directly impairing the response to treatment .Despite the extensive knowledge about molecular resistance to TKIs, the biology involved in BCR-ABL1-independent mechanisms needs better elucidation. Specific molecules are under investigation as possible and potential therapeutic targets. As described previously, the activation of signaling pathways, such as PI3K-AKT, can lead to TKI resistance. The phosphorylation of FOXO transcription factors that occurs through the AKT pathway can also take place across BCR-ABL1, leading to changes in cell cycle regulation related to proliferation, differentiation, and cell death . In vitrAnother pathway that should be better analyzed is WNT-β-catenin signaling. This pathway is associated with a variety of proliferative diseases, including CML . WNT-β-cAn alternative option for a therapy target is AXL, a tyrosine kinase receptor found to be overexpressed in imatinib- and nilotinib-resistant CML cell lines and patients, as well as associated with AKT survival signaling ,166. DowAnother field that should be explored is oxidative stress. Some studies demonstrate that BCR-ABL1 increases the number of reactive oxygen species (ROS) in the cell, promoting mutations through oxidative damage to DNA. Antioxidant therapies that lead to ROS inhibition decrease mutagenesis and, consequently, TKI resistance .Vascular endothelial growth factor receptor (VEGFR) also plays a role in CML, and the use of VEGFR inhibitors has been shown to lead to a decrease in resistance to TKIs . An examBH3 mimetics, small molecule inhibitors of the prosurvival members of the Bcl-2 family, have been developed for the treatment of cancer and, particularly, hematological malignancies ,173,174.Finally, in a different avenue, strategies aiming to degrade the BCR-ABL1 protein using proteolysis-targeting chimera (PROTAC) technology have been tested. PROTACs are small molecules with a heterobifunctional structure—part of the molecule consists of a specific ligand to the protein of interest (POI) linked to an E3 ligase-recruiting domain ,181,182.It can be emphasized that within malignant hematological diseases, an exceptional result in the overall survival of patients with CML was achieved through the development of TKIs. There are obstacles related to treatment management, including the appearance of mutations and a loss of response after discontinuing TKIs. Despite these problems, the results show increased treatment effectiveness and manageable side effects compared to those obtained in other chronic leukemias with a high risk of progression to an acute form. Researchers are on the right path to improve the knowledge already consolidated and seek to understand alternative therapies that can either function synergistically with existing treatments or are superior to current therapies. Notwithstanding, efforts are still in place to find better BCR-ABL1 kinase inhibitors that can overcome multiple TKI-resistant mutants ,187,188.


This study is meaningful in that it developed an online program to help college students improve career adaptability and identified its effectiveness. This study yielded two results. First, it successfully developed a career adaptability improvement program for undergraduate students, wherein the career development tasks, and the sub-factors of career adaptability were organically interlinked. Second, it verified the statistically significant differences in the career adaptability scores among the experimental, comparison, and control groups. The highest mean score was obtained by participants in the experimental group, followed by the comparison and the control group.This study developed an online career adaptability improvement program as part of the undergraduate curriculum to improve college students’ career adaptability and verify its effectiveness. This 13-week intervention program, developed using the Korea-Career Adaptability Scale (K-CAS), consists of three domains: (1) knowledge and recognition of the self and work environment, (2) self-directed coping related to career behavior, and (3) environmental interaction for career decisions and adaptation. Two sub-studies were conducted to achieve the research objectives: Study 1 included developing and testing a pilot program and Study 2 quantitatively analyzed the final program to test its effectiveness. In Study 1, preliminary program development and validity were verified, and in Study 2, the effectiveness of the final program was verified. As a strategy to achieve the research purpose, in Study 1, literature review and needs analysis, program design reflecting the results of the needs analysis, validity verification through Delphi survey, preliminary program implementation and evaluation, and the operation of the final program were performed. To test the effectiveness of the program in Study 2, a pre-posttest of career adaptability was conducted on experimental ( It is no longer possible to create a career plan for the next 30 years within the boundaries of one job or organization . Amidst Accordingly, in the field of career education, diverse efforts are being made to provide various career education and support programs for the successful career of college students. Previous studies on career education and group counseling program development for undergraduates have mainly proposed career exploration programs , career In accordance with this need, studies have developed programs to improve career adaptability among undergraduates, workers, and women affected by career interruptions . These pIn this regard, this study addressed three focus areas not considered in previous studies. First, it developed a program that reflects all key areas required for successful career development in Korean undergraduates. This program consists of three domains of career adaptability based on the developmental tasks of college students: (1) knowledge and recognition of the self and work environment; (2) self-directed coping related to career behavior; and (3) environmental interaction for career decisions and adaptation . This stSecond, since the provided program is an educational program linked with the career adaptability scale for Korean university students, it was designed to involve other treatments appropriate for diagnosis. Its most distinctive feature is that it can provide a learner-centered customized program based on the baseline measurement results (pretest) because it is composed of items reflecting the individual career adaptability scores in the program development stage. In this regard, there is a need to provide customized career consulting by increasing access to individual career information and designing a program tailored to individual needs, breaking away from the conventional uniform format of a special lecture course for many students . AccordiThird, due to the persistent COVID-19 pandemic, a web-based program was developed as an alternative to a conventional classroom program. A literature search for web-based career education programs indicated that most programs were developed as auxiliary tools . Studies on web-based mentoring-type career education programs are mostly for pre-college students and few online career education programs are for college students . In addiOverall, this study sought to develop and test the effectiveness of a career education program that can improve undergraduates’ career adaptability. To this end, two research questions were formulated: (1) what is the composition of a program designed to improve undergraduate students’ career adaptability? (2) What are the changes in the career adaptability level of college students who participated in the program?In the drastically changing future work environment, career development is shifted from the organization to the individual. Therefore, it seems necessary to cope adaptively with the environment and have a flexible attitude.The career adaptability concept began with career maturity  in the cStudies have conceptualized career adaptability for different subjects. Studies related to career adaptability have been conducted extensively with workers, adults, college students, high school students, out-of-school adolescents, and women with career interruptions . StudiesThis subsection examines previous studies that designed career adaptability improvement programs for college students and adults and tested their effectiveness. In Korea, studies have recently been conducted to improve career adaptability during changes in career development or other problems posed in the context of career support throughout an individual’s life cycle.Career adaptability programs have also been developed for enhancing career adaptability among various populations, such as women with interrupted careers, mature female students, and college students. These programs’ effectiveness has also been tested. The present study analyzed the main contents of the career adaptability programs developed previously, to structure the program within the scope of three domains: knowledge and recognition of the self and work environment, self-directed coping related to career behavior, and environmental interaction for career decisions and adaptation.This study aims to develop an online career adaptability improvement program for undergraduate students. Based on the program development model proposed by To investigate career adaptability needs, an open-ended questionnaire was administered to 10 career education experts. According to previous studies, the number of expert panels was suggested between 10 and 15 , which iA Delphi survey was conducted to seek opinions from experts and test the content validity of the career adaptability improvement program. Two rounds of the Delphi survey were conducted with 10 career education experts who had experience in career education and counseling programs for college students.n = 7) were undergraduate students studying in a South Korean private university, who voluntarily agreed to participate in the program after reading its content in the career design and self-development curriculum and who had previously participated in a career program. For the pilot program, participants were recruited online, and about 6–8 applicants for the program were recruited . Participants also responded to an open-ended question about their opinions and experience of the study.For the program satisfaction survey, the Client Satisfaction Questionnaire (CSQ) developed by Two rounds of expert-panel Delphi surveys were conducted to test the content validity of the program. In Round 1, expert opinions on the validity and need for revision were collected regarding the (1) definition and basic direction of the program, (2) goal and objectives of the program, (3) association between career adaptability sub-factors and positive psychological factors, and (4) educational content areas and elements. In Round 2, expert opinions for revision were collected regarding the (1) purpose and goals of the revised program, (2) content composition of the entire program, (3) program operation method, (4) contents organization of each program, and (5) program appropriateness for each session. Initially, a three-round Delphi survey was planned for content validity verification, however, Round 2 yielded a sufficiently high content validity score and degree of consensus among the experts. Considering the content validity verification results, a 13-session program was finally constructed with three career adaptability domains  and nine career adaptability sub-factors . Participants were recruited for the final program. The program was administered from September to November 2021, followed by effectiveness testing.The final program was developed following the literature review of career adaptability improvement programs and needs analysis, design and development of the pilot program, the content validity verification of the pilot program through a Delphi survey, and the implementation of the pilot program. The needs analysis was conducted using an online open-ended questionnaire survey. The survey was conducted online, and the open-ended questionnaire responses were categorized based on the theme, and the analysis was conducted in an iterative and inductive way by adding categories to new themes that did not belong to the categories and continuously comparing them with the previous ones .M) and SD of each item. Item content validity ratio (CVR) was calculated using the internal validity calculation formula developed by The expert-panel Delphi method tested the content validity of the career adaptability improvement program. The two-round expert panel survey data were analyzed by calculating the mean (χ2) statistic, and program satisfaction was measured by analyzing the response rate.For effectiveness testing of the pilot program, repeated measures ANOVA (RM ANOVA) was used. The pre-post-differences in career adaptability scores were examined using a Chi-square ,” “addition of interpersonal skills or social capital building ability as a program,” and activities that can build “self-determination ability to adapt to changing environment,” “optimism in an uncertain future,” “resilience to rechallenge after failure,” “ability to adjust goals according to circumstances,” and “ability to endure ambiguity.” Fourth, for program operation modalities, panelists found it necessary to “improve communication skills based on team-based activities,” “carry out each session with more emphasis on activities than on theories,” “encourage students to share experiences and provide feedback to one another,” “present activity outcomes in collaboration with team members,” “conduct project-based team classes,” and “check the appropriateness of the online environment and activities.” Fifth, the panelists recommended the following to improve program efficacy: contents encompassing failure, frustration, wandering, abandonment, and overcoming challenges; sharing the experiences of failure and overcoming challenges in different professions; programs to build strength to endure an uncertain environment; and development of a career adaptability program differentiating itself from conventional ones.A needs analysis for a career adaptability program was conducted with the 10 expert panelists. The interview results derived five semantic categories. First, career competencies required to improve career adaptability include the “psychological process of successfully coping with inevitable changes and unpredictable needs,” “coping ability in the face of a changing environment,” “self-regulatory strategies to adapt to the work world,” “ability to acquire and utilize knowledge and to learn and utilize cutting-edge technology,” and “ability to obtain and utilize information from social capital.” Second, regarding the need for a career adaptability program, 70.0% of panelists chose “Some student responses supporting these ideas are as follows:“It seems necessary to build the ability to obtain and utilize information through interpersonal elements or relationships to achieve career adaptability improvement. For example, it would be a valuable addition to include activities such as finding mentors and role models for career development and forming supportive relationships or finding someone with access to resources necessary for [a] career choice and requesting help.” (Panelist 1)“When constructing the entire program, I think it would be good to organize it in a top-down manner. For example, when students are preparing for [a] career choice or goal achievement, they start with a great vision for life and have the ability to set career goals and make career plans through understanding their self and information search, [and subsequently] make implementation plans . I think it [is] desirable to organize the program with these sub-factors.” (Panelist 2)Based on the results of the needs analysis, a pilot program was developed. Then for the content validity verification of the program, a Delphi survey was conducted with career education experts.SD = 0.89), slightly higher than the target value of 4.00–5.00 (SD = 0.00–1.23). The mean of the linkage between the sub-factors of career adaptability and positive psychological factors was 4.80 (SD = 0.42) and that of the program content areas and elements was slightly high, at 4.20–4.80 (SD = 0.45–0.89). The CVR ranged from 0.40 to 0.80. Those falling short of the threshold value of 0.64 calculated by applying the minimum CVR for 10 panelists, as proposed by SD = 0.00), that of the program content areas and elements at 4.60–4.80 (SD = 0.42–0.52), and that of the appropriateness of the program operation mode at 4.8 (SD = 0.42). With 0.80, CVR was high, thus establishing the content validity of the program. Other opinions included the amount of program content, time distribution, and proposals for optional activities considering years and majors.F = 10.248, p = 0.007), coping with career-choice crisis , ability to cope with environmental stress , and overall career adaptability  revealed statistically significant differences. In the post-intervention program satisfaction survey, “program quality and satisfaction” and “support in problem-solving” resulted in generally high satisfaction with “neutral” (0%–26.67%) and “agree” (20%–86.67%). The re-participation intention was high with the yes-to-no ratio of 93.3%–6.7%.Differences in the career adaptability pretest and posttest scores were examined for pilot program participants. Of the sub-factors of career adaptability, positive career beliefs (As shown in This program has the following objectives: (1) objective understanding of one’s strengths, interests, and values to establish a clear career-related self-concept; (2) job search considering one’s greatest strengths based on the analysis of future work environment and job trends; (3) beliefs in positive results of career choice and goal achievement; (4) coping with career-choice crisis by comparing and analyzing alternatives required for problem-solving and making a comprehensive judgement; (5) planning to participate in new education, training, and various activities in preparation for job requirement changes; (6) adjusting or resetting challenging goals to achieve them in a planned way or need for readjustment in the process of pursuing career goals; (7) exploring coping strategies with positive expectations for overcoming stressful situations experienced in the course of career exploration and pioneering; (8) cooperation with others with a sense of responsibility of one’s role, respecting others’ views and adjusting differences of opinion; and (9) using social networks to achieve career goals or to solve career problems.The final program was administered to voluntary participants across 13 weekly sessions of 2 h each. Accordingly, the program is composed of 13 session topics: (1) exploring the program needs and objectives; (2) positive career beliefs; (3) self-understanding to establish identity: meaning of work and values; (4) self-understanding to establish identity: strengths; (5) understanding of work environment; (6) social responsibility; (7) and (8) resource utilization ability; (9) and (10) career choice crisis coping ability; (11) goal adjustment ability; (12) career preparation behavior; and (13) integration.Participants were recruited for the final program and the program was administered online, in real-time, from September to December 2022. Its effectiveness was subsequently tested.n = 54, 33.1%), comparison group , and the control group . The participant characteristics were 29 students (17.8%) from the College of Public Talent, 44 (27%) from the College of Science and Technology, 34 (20.9%) from the College of Health Sciences, 27 (16.6%) from the College of Life Science and Resource Science, and 8 (4.9%) from the College of Sports Science. The number of students (4.9%) was 21 students (12.9%) from foreign language colleges. Of the participants, 63 (38.7%) were male and 100 (61.3%) were female.As a result of G power verification, the required number of participants was 159 (53 in each group) when the effect size was 0.25 or higher, the two-tailed significance level was 5%, and the power level was 80%. This calculation was based on the effect sizes obtained in a previous career adaptability program study . As undeTo test the effectiveness of the final program and examine the program satisfaction, the K-CAS  and the The non-equivalent group pretest–posttest design was used to investigate the effect of the career adaptability improvement program developed in this study . Both prpost hoc test was performed.Quantitative data were analyzed using the software SPSS Statics 25.0 to examine the program’s effectiveness. Mixed ANOVA was performed to examine career adaptability pretest–posttest timing and the main and interaction effects of the experimental, comparison, and control groups to determine whether changes in participants’ career adaptability scores were statistically significant. Moreover, the effect of the career adaptability improvement program on the learner’s career adaptability was tested using covariance analysis. Baseline scores (pretest) for career adaptability were set as the covariant and post-intervention scores (posttest) of each group as the dependent variable. In addition, a Bonferroni The descriptive statistics  of the experimental, comparison, and control groups are outlined in df = 2, 145, p = 0.888; posttest score: Levene value = 0.511, df = 2, 145, p = 0.601) were used for the homogeneity test. The test results showed no statistically significant differences in the mean scores between pretest and posttest of each group, which confirmed intergroup homogeneity. Box’s test for homogeneity of covariance matrices revealed that covariance matrices were equal across the three groups, thus, satisfying the equal variances assumption . In the sphericity test, the sphericity assumption was found to be violated , and Greenhouse–Geisser ∈ was applied.Levene’s statistics  compared with the pretest . The comparison group had relatively high scores in both pretest  and posttest . The control group showed little difference .The mean and SD of the pretest and posttest scores of the experimental, comparison, and control groups are presented in F = 12.386  in the mean score of career adaptability, with the F value of 7.293  and the comparison group (M = 2.74 → 2.87). In contrast, the control group showed little difference (2.86 and 2.80). Regarding the changes in the mean pretest and posttest scores for individual sub-factors of career adaptability, an increase in posttest scores was observed in most sub-factors in the case of the experimental group: self-understanding to establish identity, search for a work environment, positive career beliefs, ability to coordinate career goals, ability to cope with environmental stress socially, and responsible behavior in the case of the comparison group. For the control group, minor changes were observed or even lower in some of the sub-factors.The mean and SD of the career adaptability scores obtained by experimental, comparison, and control groups in the pretest and posttest conducted to examine the effects of the career adaptability program on career adaptability are presented in F = 11.963, p < 0.001, post hoc test revealed that the career adaptability of the comparison group was higher than the control group and lower than the experimental group. These results suggested that the career adaptability program has a positive effect on the overall career adaptability among participants in the experimental group. Intergroup comparison of the differences in the career adaptability sub-factors revealed that there were significant differences in all sub-factors except for career preparation behavior. The posttest scores of the experimental and comparison groups were those of the control group in self-understanding to establish identity  regarding the degree of satisfaction of the program need was significantly higher in the experimental group (G1) than in the comparison group , recommendation intention , support in solving career problems , and support in career adaptability .Upon program completion, participants in the experimental and comparison groups completed a satisfaction survey regarding program quality and satisfaction, problem-solving, the degree of support in improving career adaptability, and re-participation intention. Participants in both groups responded positively to the quality of and satisfaction with the overall program. However, significant intergroup differences were revealed in the degree of satisfaction with the program need, recommendation intention, support in solving career problems, and support in career adaptability. The ratio of positive answers In the category of opinions and perceptions regarding the program and changes after the participation in the program, participants reported on “the advantage of the program linked with [a] test score,” “the pros and cons of the online career program,” “the advantage of the activities directly related to my own career,” and “better concentration due to activity-centered program operation.” Examples of participants’ responses in this regard are as follows:“At first, it felt it burdensome to do group activities online, but it was convenient to share career information. [And] It was so nice to be able to communicate with my friends in convenient online classes after missing opportunities to communicate with them.” (Student D)This study was conducted to develop and test the effectiveness of a career education program to improve undergraduate students’ career adaptability. The major results of this study lead to the following discussion points. First, the results of this study support the findings of previous studies. The career adaptability improvement program developed in this study consisted of three domains pertaining to university students’ career development tasks and nine adaptive factors to properly perform the domain objectives. Moreover, it had a positive effect on career adaptability . Most exSecond, undergraduate years fall in the late exploring phase along the life-long process of career development. The main developmental tasks in this period are career exploration and decision-making for higher studies or a job search . As therThird, the career adaptability improvement program for undergraduate students improved career adaptability. The experimental group, to which the program was administered, showed a significantly higher mean posttest score in career adaptability compared with the control group, which was exposed to no intervention. It also indicated higher career adaptability than the comparison group in some sub-factors. These results supported previous studies which reported that career adaptability programs for college students have a positive effect on their career adaptability .post hoc test. In the other sub-factors, however, such as the ability to cope with career-choice crisis, ability to coordinate career goals, ability to cope with environmental stress, and ability to utilize social resources, the experimental group scored significantly higher than the comparison group. These results suggested that the proposed program was effective in improving some career adaptation abilities that could not be improved through existing career education programs. In this respect, the proposed program made a particular contribution to the undergraduates’ unstable and confusing situation in the face of school-to-work transition after graduation by improving their abilities to cope with the career-choice crisis, coordinate career goals, cope with environmental stress, and utilize social resources essential for achieving career development tasks.Furthermore, differences in pre-post-scores for career adaptability sub-factors were observed between the experimental and comparison groups. This was similar to The significance of this study is as follows. First, at this juncture in time when the paradigm for future careers is changing, it developed a career adaptability improvement program that differentiates itself from the existing career education programs. Career education programs that improve coping ability with various career problems and solving career development tasks based on self-understanding are important for lifelong career design that considers the life cycle. Accordingly, this study is expected to contribute to meeting future career education needs. In particular, the proposed program has the advantage of being used immediately in college settings. Although many students need advice or guidance for their career problems, only a small proportion of students visit the on-campus career counseling center for assistance. Therefore, students who participate in this career adaptability improvement program have the opportunity to diagnose their career adaptability and receive a personalized program. This program can be used any time in different faculties related to careers. The career adaptability improvement program for 1st-year can screen students with low career adaptability. Those who need in-depth counseling can be linked with the relevant divisions, such as the student counseling center and the employment and career assistance office on campus.Additionally, with the increased demand for online career education programs, it can be used as a model for developing on/offline blended career education programs. In this regard, its significance lies in the empirical data accumulated by testing the effectiveness of online career education programs. An online career education program is advantageous as it can overcome physical constraints and educational environments, and can be used anytime, anywhere according to participants’ needs. However, compared to face-to-face lectures, there may be restrictions for some program content. An efficient educational environment and function may not be provided. This aspect requires further discussion.Second, the program was developed in tandem with the adaptive factors required to properly cope with domains related to college students’ career development tasks in order to improve their career adaptability. This program was composed of educational content corresponding to the overall sub-factors of career adaptability for 1st-year students. This approach is significant as it proposes a program in a practically applicable form to improve students’ career adaptability in academic career courses. Additionally, this approach improved undergraduate students’ career adaptability in various career domains centering on career development tasks that led directly lead to a student-centered intervention. This was because the program can effectively improve the adaptability needed to address student career problems.Third, this study emphasized developing the program in compliance with a systematic procedure. In the program development stage, the results of an expert panel’s career needs analysis were reflected on, and a Delphi survey was conducted to test the content validity. The results of the pilot program implementation were integrated into the program revision. Therefore, the program was developed by reflecting the opinions of an expert panel currently active in college settings and the needs of actual program participants to enhance the onsite effectiveness.Fourth, the program effectiveness was tested through quantitative analysis based on experimental design, and through a program perception and satisfaction survey with participants. This collected opinions as feedback for further program revision and improvement. This made it possible to verify the positive aspects of the program related to the career adaptability test, such as the improvement of cooperating ability and the convenience of information sharing through the online career education program administered in the contact-free class setting. However, considering that web-based teamwork may be burdensome in a contact-free setting and that it takes time to communicate smoothly, it would be required to introduce activities for building rapport among team members and checking the interim state of teamwork tasks.Regarding the study’s limitations and directions for future research, five aspects are observed. First, although this program surveyed the need for career education as perceived by career education experts for program development, it did not survey the need for a career adaptability program as perceived by college students. Future research should recruit participants considering their characteristics based on their career development status and develop a program reflecting participants’ needs. Second, the career adaptability program developed consisted of educational programs that correspond to the overall sub-factors of career adaptability for 1st-year students. This is because the program’s development process focused on an educational program best suited for the related university curricula within the limited university schedule. In the future, it would be necessary to provide a customized program composed of a common program and an optional program for learners to choose as necessary according to the result of the career adaptability diagnosis. Furthermore, there is a need for developing separate career adaptability programs for college students based on majors and education level. This is because the contents of a career program may vary depending on the major and the career development stage and tasks may vary depending on education level. Third, this study primarily used quantitative analysis to test its effectiveness. While a satisfaction survey was conducted and participants had time to share their experiences, the data collected were insufficient for qualitative analysis. Follow-up research should encourage participants to write an experience report after every session for continuous program updates so that the program contents and operation method can continuously be revised and supplemented. Fourth, program effectiveness was tested by examining the intergroup differences in pre-post-career adaptability scores. However, to monitor whether career adaptability improvement is maintained, it would be desirable to introduce follow-up tests in addition to pre-posttests. Fifth, an attempt was made in this study to develop and apply a real-time online career education program. However, it would be necessary to ensure an online learning management system that can overcome online-specific difficulties such as limited interaction between instructors and students in contact-free situations. Future research might as well develop an on/offline blended career adaptability program and prepare a platform for developing and distributing various online career education programs.This study contributes to the literature on improvement of college students’ career adaptability. Based on the results of its effectiveness verification, the following practical application strategies are proposed.First, an educational program linked with a career adaptability diagnosis tool was developed in this study to improve undergraduate students’ career adaptability. Developing an educational program linked with the sub-factors of the career adaptability scale for college student made a personalized intervention possible. In turn, this improved insufficient factors in each student’s career adaptability profile. Since this program included a wide range of career adaptability factors required to solve the career development tasks of college students, the student-centered program contents can be selectively applied in a manner that improves factors the student lacks as detected by the career adaptability diagnosis test.Second, this program considered “knowledge and recognition of self and work environment,” “self-directed coping related to career behavior,” and “environmental interaction for career decisions and adaptation” as domains to improve career adaptability. These career adaptability domains apply to university students who have to determine a career path and accomplish certain tasks, and to job-seeking students in the school-to-work transition and to employees envisaging turnover. However, the results of effectiveness verification of this program are limited to college students. Follow-up studies need to examine the effectiveness of this program when applied to population groups other than college students.Overall, the findings indicated that a career adaptability educational program was effective in improving college students’ career adaptability. The program’s content areas and activities were organically linked with college students’ career development task area and career adaptability sub-factors. Moreover, students who participated in the career adaptability improvement program, developed in this study, scored higher in overall career adaptability than those who participated in the existing career education program. Various career adaptability sub-factors required for carrying out college students’ career development tasks could be applicable in career education and counseling settings because they include a range of career problems encountered by college students.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by Dankook University. The patients/participants provided their written informed consent to participate in this study.JK conceived, designed, and awarded the grant for the study, analyzed the data, and wrote and discussed the manuscript.This work was supported by the Ministry of Education of the Republic of Korea and the National Research Foundation of Korea (NRF-2020S1A5A8042232).The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Many individuals in need of mental health services do not currently receive care. Scalable programs are needed to reduce the burden of mental illness among those without access to existing providers. Digital interventions present an avenue for increasing the reach of mental health services. These interventions often rely on paraprofessionals, or coaches, to support the treatment. Although existing programs hold immense promise, providers must ensure that treatments are delivered with high fidelity and adherence to the treatment model. In this paper, we first highlight the tension between the scalability and fidelity of mental health services. We then describe the design and implementation of a peer-to-peer coach training program to support a digital mental health intervention for undergraduate students within a university setting. We specifically note strategies for emphasizing fidelity within our scalable framework, including principles of learning theory and competency-based supervision. Finally, we discuss future applications of this work, including the potential adaptability of our model for use within other contexts. Mental illness is a pressing and growing global public health crisis with enormous societal costs . BetweenOne widely studied scalable approach, used most prominently in low-resource contexts, is for paraprofessionals to provide or support the delivery of scalable mental health services ,9. In thDigital mental health innovations via phone, computers, and other electronic devices offer another pathway for increasing access to care . Digitalscalability, to maximize intervention reach, with fidelity, to optimize quality and standards of treatment delivery. Scalability can be defined as “the capacity of an intervention to be applied in a way that reaches a large number of people” [Accordingly, mental health care models that combine paraprofessional workforces and digital mental health innovations have unique potential to expand the reach of and engagement with high-quality EBTs. One key consideration in efforts to design and implement paraprofessional-supported digital mental health interventions involves balancing  people” . Fidelit people”  to ensur people” .The purpose of this paper is to demonstrate 1 way of designing a coaching program that maintains a focus on the fidelity and delivery of high-quality EBTs, while preserving key strengths of paraprofessional models of care, including scalability. Our program was developed to support the delivery of a digital mental health intervention  on colleParaprofessional models have gained widespread attention and support as scalable models of mental health service delivery with great potential to address unmet needs for care ,24. EvidFidelity-monitoring practices have the capacity to increase therapist accountability in service of promoting treatment adherence and competence . Indeed,The financial and human resources needed to support fidelity monitoring in real-world contexts are often not available, limiting the external validity of many fidelity-monitoring strategies typically used in clinical trials . Even whDigital therapies hold significant promise for addressing problems with fidelity and bridging gaps in care access within wide-scale implementation efforts ,30. In pOne consideration in designing paraprofessional models is who should be trained to provide, or support the delivery of, mental health interventions. A prominent model focuses on training of peer-to-peer specialists, or peer coaches . Peer coYet, a major barrier to broader implementation of peer support is the mixed empirical support for these models -49. TherIn 2015, the University of California, Los Angeles (UCLA) launched a campus-wide research initiative, the Depression Grand Challenge (DGC), with the goal of cutting the burden of depression in half by 2050. The DGC comprises a number of studies that seek to uncover mechanisms underlying depression and to develop novel treatments and innovative approaches to treatment implementation. To begin tackling this problem at UCLA, the DGC launched the Screening and Treatment for Anxiety and Depression (STAND) program for UCLA students in fall 2017 . The STASTAND Digital Therapy is a modular program that combines interventions for depression, sleep, panic/agoraphobia, social anxiety, worry , and trauma (posttraumatic stress disorder), drawing upon existing evidence-based programs -66. TherFitting within this model, the initial development of our coach training program specifically targets UCLA undergraduate students as both coaches and recipients of the intervention, consistent with the peer support models described before. Enrollment as a coach trainee does not rely on any prerequisite coursework, history of service provision, or experience of personal mental health concerns or psychotherapy. Training and supervision of coaches are provided by graduate students in the clinical psychology doctoral program at UCLA for all stages of coach training. Graduate supervisors attend group supervision-of-supervision with a licensed clinical psychologist (author EGG).In our program, coach training occurs in weekly sessions, wherein trainees review digital CBT content, engage in didactic instruction of coaching materials, and complete role-play exercises focusing on basic interpersonal process skills. Coaches move through 4 primary phases of training: (1) beginner, (2) intermediate, (3) advanced, and (4) certified. Weekly training consists of a 2-hour training session as well as 2 hours of assignments completed between training sessions. Each level of training is completed over 1 academic quarter (10 weeks), at which point trainees are advanced to the subsequent level of training based on supervisor evaluations.The goals of the beginner phase of training are to (1) introduce coaches to digital CBT content and increase knowledge of the intervention and (2) provide early practice with interpersonal process skills to initiate the process of translating declarative knowledge during coaching delivery. In service of these aims, beginner-level trainees enroll as users of the digital CBT and advance through the digital CBT content themselves, completing homework exercises associated with the program and reading foundational material on cornerstone CBT topics between didactic training sessions. In addition, beginner-level trainees are introduced to 6 core interpersonal process skills that are routinely assessed to monitor coaching effectiveness throughout the coach training program: (1) authenticity, (2) nonverbal skills, (3) open-ended questioning, (4) reflecting emotions, (5) content summaries, and (6) collaborative inquiry -69. ThesBeginner-level trainees participate in (1) didactics regarding digital CBT content and interpersonal process skills, (2) discussions regarding other cornerstone topics , and (3) role-play exercises to begin practicing application of the 6 core interpersonal process skills. Beginner trainees also attend sessions with advanced trainees, in which they serve as mock or practice participants for advanced trainees who are coaching full mock sessions (described in detail in the Advanced-Level Training section). Role-play exercises are recorded or observed live by supervisors, who provide oral and written feedback, as well as numerical ratings on each interpersonal process skill  translating knowledge into coaching delivery and (2) applying interpersonal process skills to support engagement with digital CBT content. During these sessions, trainees participate in (1) brief digital CBT module content review, (2) intensive role-play exercises applying core process skills, and (3) introduction to protocols for managing advanced clinical issues .To continue supporting trainee development of interpersonal process skills and digital CBT content knowledge, trainees are continually rated on their process skills throughout intensive role-plays. Each week, supervisors review trainees’ intensive role-play segments and provide trainees with written feedback and numerical ratings on core interpersonal process skills. In addition, group supervision sessions incorporate oral feedback from supervisors and peer coaches, including in vivo corrective feedback during role-play exercises.Once trainees reach the advanced stage, the main goal is for trainees to achieve certification to serve as coaches for participants. This is accomplished by demonstrating (1) competency across all 6 core interpersonal process skills and (2) continued knowledge of digital CBT content. Advanced trainees conduct practice coaching sessions  with beginner trainees as mock participants. In addition to these practice sessions, advanced trainees attend a weekly supervision group consisting of intensive role-play exercises, with role-play targets focused on digital CBT content, interpersonal process skills, and management of advanced clinical issues .To support advanced coaches in progressing toward certification, advanced-level trainees receive written and numerical ratings on their full 30-minute practice coaching sessions. These ratings are used to certify trainees on competency across all process skills. Next, trainees achieve certification on digital CBT content by passing quizzes, which ensures knowledge of the intervention and promotes continued fidelity to the treatment model.Following successful advancement through the prior 3 stages of the program, trainees are certified to support the digital CBT with continued supervision. Certified trainees who are engaged in coaching continue to attend weekly supervision groups in which they discuss coaching sessions with their supervisor and peers. To ensure continued fidelity to coaching standards, supervisors review video recordings of each coaching session and rate the coaches’ application of process skills according to the behavioral rating scale described before. Video review further enables supervisors to use didactics and role-play exercises in response to common challenges or to address drift from the coaching protocol. Certified trainees additionally provide feedback to the supervision team to inform potential future iterations of the coaching program.Increased attention to trainee learning processes within mental health provider training and supervision procedures has potential to increase fidelity to EBTs . One wayvariability of learning contexts is applied through (1) independent trainee review of digital CBT content (outside of sessions), (2) didactic training (during sessions), (3) role-play exercises , and (4) participation in mock sessions (observed by the entire supervision group). Likewise, applying the principle of spaced instruction, digital CBT content and interpersonal process skills are introduced and revisited at multiple timepoints within and across training levels. Interleaved instruction is similarly used to promote initial learning of digital CBT content and process skills simultaneously . Furthermore, retrieval practices assess digital CBT knowledge throughout all stages of trainee development to support long-term retention of learning .From the outset of coach training, we have applied core principles of learning theory to guide the instruction of digital CBT content and process skills. For example, Following certification, ongoing fidelity-monitoring practices include (1) completion of a self-evaluation coaching checklist following all coaching sessions, (2) discussion of coach adherence to the digital CBT module during supervision, and (3) continued completion of mock coaching sessions during supervision with peer-to-peer and supervisor feedback.Following the acquisition of new knowledge and skills, competency-based supervision techniques can provide trainees with a pathway for transforming declarative knowledge into procedural knowledge -81. PrioIn this paper, we outlined 1 example of a scalable peer-to-peer mental health paraprofessional training and supervision program. Although many models of paraprofessional support have been described and tested previously, high demand and minimal resources have often corresponded with a reduced focus on fidelity monitoring and quality assurance . Lack ofWe believe this model has several notable strengths. Of note, our program focuses explicitly on fidelity, while also attending to the need for scalable care. As illustrated, the focus on fidelity is integrated into the program in 2 primary ways: digital technology as the primary agent for CBT content delivery  and contcore components, defined within the Consolidated Framework for Implementation Research (CFIR) as the “essential and indispensable elements” of the program, and the adaptable periphery, defined as the aspects of the program that can be modified and varied from site to site [Another strength is that our program is designed to be malleable and can be adapted in various ways based on implementation context factors. Along with fidelity, program flexibility is well established as a key ingredient to successful implementation of interventions in numerous settings ,85. Impl to site ,87. Incl to site . AlthougIn our program, we have identified several components of the adaptable periphery that have been tailored for various implementation contexts, with community partnership. For instance, although this paper describes implementation at 1 university, we are currently piloting coach training and supervision for the launch of STAND digital CBT in numerous other types of community settings, including local community colleges and health care systems. In partnership with community stakeholders, 1 example of a component in the adaptable periphery that we have modified to meet the needs of a new implementation site is the length of training time, which has been shortened to accommodate local resources. This has been accomplished by combining components of beginner and intermediate levels of training and including additional review and feedback of recorded role-plays outside of sessions to accelerate learning and growth. In another example of adaptation, we have worked with various sites to situate and design our coaching risk protocols  within the contexts of existing resources, infrastructure, and referrals. Another example of adaptation has been to integrate specific training on trauma-informed care strategies to support implementation of this program in communities with higher trauma prevalence rates. Cultural considerations are also essential, particularly in planning implementation of coach training programs in diverse settings such as ours. Working in partnership with community stakeholders to co-design cultural adaptations can lead to improved program acceptability and community engagement. Although we have made and discussed modifications within the adaptable periphery based on the unique implementation and contextual factors within various environments, the same guiding principles described in this paper serve as the foundational core components across settings.A final strength of our program is that it is intended not only to train students to serve as coaches to their peers but also to provide critical CBT skills to trainees themselves. Many coaches in our program anecdotally report that their experience throughout training has taught them invaluable interpersonal and cognitive-behavioral skills. In the broader literature, paraprofessionals describe feeling that their training experiences were associated with personal development and growth and increases in knowledge, self-confidence, and skill use . In the Several key limitations of our program should also be noted. First, because this program is situated within the scope of a large research initiative, ongoing funding has been available to sustain coach training and supervision. Beyond the realm of research, efforts to provide continuous funding for paraprofessional support programs in routine care settings are critical. In the initial iteration of our program, coaches have served as volunteers, engaged in all program elements as an additional responsibility outside of their other obligations. Data suggest that among volunteer staff supporting digital interventions, administrative issues, such as time constraints, may contribute to barriers to training completion and attrition . AdditioSecond, although we maintain a focus on fidelity in our program, the primary objective of our peer-to-peer program is to serve as a scalable model of care in real practice settings. Thus, given the resource constraints of real-world implementation contexts, we have designed our fidelity-monitoring procedures to minimize supervisor and trainee burden. However, in doing so, we recognize limitations in our capacity to optimally monitor fidelity, and acknowledge that fidelity is not monitored to the same degree in our program compared to standard clinical trials .Third, to maximize scalability of the program, coaching is provided virtually using videoconferencing. Prior research has raised the possibility that compared with self-administered or fully automatized options, digital mental health interventions may be most effective for adolescents and young adults when incorporating in-person elements . HoweverLast, our program was initially designed for use in a specific setting . Additional efforts and reliance on existing implementation science and human-centered design frameworks, such as the CFIR, are needed to determine how this program and similar ones may be adapted and augmented for use in other types of settings and with new populations. A number of conceptual frameworks to adapt interventions in new contexts have been proposed, and these can be used to guide adaptation of paraprofessional support programs for new settings .Finally, we consider future directions for this work, falling within the scope of the paraprofessional field at large. First, to meet rising rates of mental illness worldwide, expansion of paraprofessional mental health programs into new settings is critically needed. Second, funding for these programs must also encompass sufficient resources to support quality assurance in training, supervision, and treatment delivery , as has