The primary aim of the study was to translate and evaluate the impact of a Physical Activity (PA) program on the physical function of older Aboriginal Elders on Noongar Boodjar (Country).A longitudinal design framed within an Indigenous methodology. Two groups, one metropolitan and one regional, of Aboriginal Elders, aged ≥45 years, participated in the Ironbark PA program. This comprised weekly strength and balance exercises followed by yarning circles. Physical function (primary outcome) and functional ability, cardiovascular risk factors , falls efficacy and health-related quality of life were measured at baseline 6, 12 and 24 months. Data were analyzed using generalized linear mixed effects modeling.n = 23 (44.2%) Elders participated regularly for 24 months. There was a 6-month gap in program delivery due to the COVID-19 pandemic. Participants made significant improvement in physical function at 12 months compared to baseline: . Some sustained improvement compared to baseline was still evident at 24 months after the 6-month gap in attendance . Cardiovascular risk factors showed a non-significant improvement at 12 and 24 months compared to baseline. All participants reported that they enjoyed the program, found it culturally appropriate and would recommend it to others.Fifty-two Elders initially enrolled and of those, Older Aboriginal people showed sustained improvements in physical function after engaging in a culturally appropriate PA program. Culturally appropriate PA programs provide safety, security and choice for older Aboriginal people to engage in evidence-based PA. Indigenous peoples worldwide have suffered through invasion and the impacts of colonization , 2. It hPhysical activity (PA) guidelines recommend that older adults should be participating in at least 150 min of moderate-intensity physical activity per week . HoweverHowever, there have been few studies worldwide that have evaluated PA programs for older Indigenous peoples –14. WhilTaking a decolonizing approach is to “unpack” or “undo” the privilege and power that “whiteness” has always dominated with over other cultures that are different to theirs . It is aThe objective of the study was to evaluate the impact of a PA program (the Ironbark program) on physical function of Aboriginal Elders on Noongar Country in WA. Secondary aims were to evaluate the impact of the program on functional mobility, cardiovascular risk factors , falls self-efficacy and health related quality of life. Participants' feedback about the program was also sought to understand whether Aboriginal Elders enjoyed the program and felt it could be translated widely among older Aboriginal peoples in WA. This study was part of a larger project that sought to understand how the Ironbark program could be translated into WA.The study used a longitudinal design framed within an Indigenous methodology. This study formed part of a larger project which aimed to understand how to translate the Ironbark program into WA. Some findings of this larger project have been published previously , 26. TheAboriginal Elders living on Noongar Boodjar (Country) have their own cultural practices and dialect although they engage in similar ways it is easy to make the mistake that they will work the same way, but this “one size fits all” approach does not work. One Group accepted male participants, the other did not. One group included a welcome to Country, the other did not. The PA program ran according to the needs and expectations of the Elders who would at times correct the Aboriginal and non-Aboriginal staff on how they needed to meet and work together, while the lead Researcher (MJRG) maintained a neutral position, that allowed for the voices and direction from the Elders collaborating with the Aboriginal health workers to develop their own terms (rules) for working successfully together. We were always mindful of not overstepping our boundaries as visiting researchers. This method of working with the Aboriginal Elders on Noongar Boodjar was in accordance with their “ways of working,” where could reinforce how they wanted the PA groups to operate. These relationships form part of Indigenous methodology that is essential to successfully deliver programs when working with Aboriginal and Torres Strait Islander peoples . The resAfter 12 months of operation there was a gap in program delivery of 6 months in 2020 due to the COVID-19 pandemic restrictions. The program resumed at 18 months and continued for another 6 months.Ethics approvals for the study were obtained from WA Aboriginal Health Ethics Committee (HE 842) and Curtin University (HE number 2018-0425). All participants provided written, informed consent prior to participating in the study.Aboriginal Elders who resided on Noongar Boodjar in the South West of WA were invited to participate. Inclusion criteria were being aged 45 years or older, able to attend the group and participate in exercises. Participants were Noongar Elders and Elders who lived on Noongar Country but came from other Boodjars (Countries) in WA and other regions in Australia. Groups operated at local community centers. Participants were asked to obtain a medical clearance to attend the program. Two groups of Elders were recruited, one from a regional area and one from a metropolitan area. The metropolitan group collaborated with a government department and the regional group was conducted by the local Aboriginal Controlled Community Health Service (ACCHS). The government department had an Aboriginal program director and provided an Aboriginal project officer to support the metropolitan group. Both groups were supported by Aboriginal health workers and non-Aboriginal health workers  as an operational team. Non-Aboriginal health workers who had undertaken previous work with the Aboriginal Elders were recruited to the team. These workers were guided by their own cultural competency training and worked closely with the Aboriginal team members, so they were mindful of awareness of ways of working with Aboriginal Elders.The program was operated in local community centers which were culturally safe spaces. These centers were used by other local Aboriginal people for their cultural activities and multi-cultural activities that the local Aboriginal Community participated in, so they felt comfortable in using these venues. Both venues were open and welcoming of the program, and offered use of suitable rooms. There was a regular traffic of Aboriginal faces coming in and out of both community centers. The project officer at the metropolitan group and the ACCHO in the regional setting, both in consultation with the Elders, discussed the venue and Elders provided confirmation that the venue was suitable after attending for several weeks.Ironbark means standing tall and strong like the Ironbark tree . The IroHealth outcomes evaluated were:(i) Physical function - measured using the Short Physical Performance Battery (SPPB) . This is(ii) Functional mobility - measured using the timed up and go (TUG) test that measures the time it takes in seconds for a person to stand from a chair and walk three meters, turn around, return to the chair, and sit down .(iii) Cardiovascular health–measured by waist circumference (cm) which is an easy anthropometric measure that predicts cardiovascular disease . Weight (iv) Falls self-efficacy–measured participants' concern about falling using the Short Falls Efficacy Scale International (Short FES-1) , where a(v) Health related quality of life (HRQoL)–measured using the Assessment of Quality of Life (AQoL-4) instrument  . This inParticipants' feedback about the program was undertaken using a questionnaire and “yarning” to capture the cultural appropriateness of the PA program and how it could be improved. These types of feedback had previously been used by researchers to evaluate the pilot trial that was conducted in NSW . The queDemographic data gathered at baseline included age gender, language, education, number of health conditions, history of falls (defined as “an event which results in a person coming to rest inadvertently on the ground or floor or other lower level”) , exercisAspects of the procedure have been described previously . BrieflyHealth outcomes were measured at baseline, six, and 12 months and a final assessment was completed at 24 months at the conclusion of the program. Outcome measurement days were led by the Aboriginal student researcher, who was experienced at leading data collection in communities, with the physical outcome assessments being supervised by the lead physiotherapist researcher. Participants were administered the feedback questionnaire at the 12 months timepoint, or if they were not available at the 12-month timepoint they were asked to answer the questionnaire at the 24-month timepoint. Data collection was supported by the Aboriginal health workers, the Aboriginal project officer and Aboriginal research assistants. Training for health workers and research team assistants to assist with the data collection was provided prior to program commencement and at intervals throughout the program. The Ironbark research team from NSW and WA completed training together prior to the PA program commencement in the South West of WA. This combined team was made up of an Aboriginal researcher (JC) who was the former advisor of the original Ironbark training, the WA Aboriginal lead researcher (MJRG) and the WA Aboriginal project officer and Aboriginal project officers and health workers who would be present at both Elders' groups during the 2-year PA program.Analyses were completed using STATA version 17.1 . All data from both regional and metropolitan groups were combined for analysis. All health outcomes data were summarized using descriptive statistics and presented using frequency distributions for categorical data and means and standard deviations or medians and interquartile ranges (IQR) for continuous data. Linear mixed models and mixed effects negative binomial models, with random subject effects, were used to examine longitudinal continuous and count outcomes over four timepoints . Model results were summarized using marginal mean estimates and 95% confidence intervals. As mixed effects models use maximum likelihood estimation to estimate parameters based on assumed probability distributions, all available data points, regardless of missing timepoints, were included in analysis. Data obtained from the feedback questionnaire were summarized using descriptive statistics. Data from open-ended questions were coded and summarized using frequency and percentages.n = 12 has 90% power to detect an effect size f = 0.41. Feedback from the community partners suggested that it would be reasonable to expect each group to consist of between 7 and 10 regular participants.For a within group repeated measures ANOVA over four timepoints a sample of There were 46 sessions delivered in year one of the program and 25 sessions in year two at the metropolitan site . Sessions were timed to fit into school terms with some gaps in school holidays and around public holidays. The reduction in sessions in year two was due to the COVID pandemic lockdown.The flow of participants through the study is presented in Predicted marginal means for physical function , functional mobility (TUG test), cardiovascular health , falls self-efficacy (Short FES-1) and HRQoL (AQOL-4D) at time points of six, 12 and 24 months compared to baseline are presented in Physical function measures are summarized in Cardiovascular risk factors are summarized in p = 0.03], with participants' scores returning to less than baseline levels. HRQoL was significantly declined at 12 months compared to baseline, but not at 24 months.Falls self-efficacy and HRQoL are summarized in n = 14, (82.6%)] were willing to pay a fee to continue engaging in the program, while four participants were not. Most participants suggested they would be willing to pay a fee of $5, with four participants suggesting one dollar and one participant suggesting $10. Almost all participants suggested at least one improvement that could be enacted in the program. Improvements that were suggested were more outdoor activity , more exercises (n = 6), a different venue (n = 5) and a larger group (n = 4). Participants who reported improvements in their health ] reported improved balance, confidence and a renewed desire to walk more, particularly in public places. Some participants (n = 7) responded that they found it difficult to complete their home program. Reasons for not completing home program were: not liking to walk alone, not liking walking at all, lack of motivation or doing other exercises outside of home and family commitments.Participant feedback regarding the program is presented in Aboriginal Elders on Noongar Boodjar (Country) who participated in a 2-year PA program made significant improvements in physical function. Participants showed significant improvement in gait speed, lower limb strength and functional mobility at 12 months. These changes were reflected in the improvement in the SPPB  with scores increasing from 8.8 at baseline to 10.28 at 12 months. Since a score lower than 10 is predictive of all-cause mortality, these changes demonstrate how the program was of positive benefit to participants' health . Mean gaCardiovascular risk factors (both waist circumference and weight) improved throughout the trial, even after the gap in program delivery in the second year, although not significantly. In the NSW Ironbark program participants showed a significant improvement in BMI. The WA program ran over 2 years and there were some sessions on nutrition, similar to the NSW program . Our proElders' feedback regarding the program was highly positive. Participants stated the program was excellent and culturally appropriate and they reported feelings of confidence that developed from the program. This was important as Aboriginal and Torres Strait Islander people are not likely to attend health services that are not provided in a culturally appropriate manner , 56. PreThe success of the translation of the Ironbark program was that it was developed with the fundamentals of Aboriginal research methodology , 30. ThiStrengths of the program were the culturally appropriate design which led to Elders attending regularly, with feedback showing that 22 of the 23 Elders thought it was culturally appropriate and wanted to keep attending the program. The physical outcomes were measured at regular timepoints by trained Aboriginal health workers assisted by health professionals, using validated and reliable measures of physical function . Hence eA major strength of the Ironbark PA program in the South West of WA was that the majority of the program team were Aboriginal people who partnered with non-Aboriginal team members to implement and facilitate the exercise and yarning circles. The program was a unique opportunity that enabled older Aboriginal people to take part in PA, because it was culturally acceptable. We delivered the program using an Indigenous “ways of working” approach, that was relevant to the two communities. Maintaining strong relationships throughout the research was fundamental to its success. The research was only undertaken after an extensive 2-year community consultation that enabled Aboriginal and non-Aboriginal researchers to work closely together in a manner that privileged Aboriginal people's worldviews . ExtensiThere was a major disruption to program delivery due to the COVID 19 pandemic in 2020. The main social restrictions period of over 4 months prevented program delivery, with subsequent delay in recommencement due to new program requirements that needed to be operationalized. The research team provided support by telephone and text messages, with the aim of providing mental health support and encouraging Elders to continue their home exercises and managing their health. Elders provided Facebook support to each other through these difficult times, which was felt to contribute to participants resuming regular attendance when the program recommenced. A limitation of the research was that we did not collect data that measured the amount of home exercise that participants completed. Another limitation was that we did not re-assess participants when they returned to the program at 18 months after a 6 month pause in the program. Requirements related to COVID restrictions were perceived as causing significant increased procedural burden to both staff and participants and it was felt important to recommence the program with as few barriers as possible. To avoid participants and staff burden in future programs, it could be useful to undertake a single, simple weekly assessment that rates improvement, rather than multiple assessments. Elders who enrolled were always not able to attend weekly due to medical appointments, family commitments or community relationships. More flexibility in the program delivery might assist with these barriers. Our study was limited to providing one class per week. Additionally, not all Elders attended the program and it could be because they were not favorably disposed to the program. Also, not all Elders chose to enroll in the study or provide feedback about the Ironbark program even though they intermittently attended and participated. It would be valuable for future translation of the program, to gain these Elders' perspectives about how the program could be improved or tailored to increase regular attendance.The research did not use an experimental design. Since the benefits of exercise for older adults are well-established . The IroFew PA programs are designed specifically for older Aboriginal and Torres Strait Islander peoples. Westernized health care delivery has not addressed and acknowledged the impacts of colonization which has created exclusion, and exposure to inequalities of health service delivery –4. TransAcknowledgment of Boodjar (Country): Authors acknowledge that this research was conducted on Noongar Country. We respectfully acknowledge the Noongar peoples as the Traditional Owners of Country in the South West of Western Australia (WA), where this research has been conducted. We recognize Indigenous peoples of all Nations' continuing connection to lands, waters, and communities. We pay our respects to all Indigenous Elders past and present. Authors respectfully acknowledge all the Aboriginal and Torres Strait Islander communities and Nations who contributed knowledge to this research.Terms used by the authors: When describing the setting and interviews authors have chosen the words Noongar, acknowledging that there are many different Boodjars of Noongar people in the South West of WA. The term Aboriginal Elders is used when discussing all participants, as the groups included Aboriginal Elders from more than one Boodjars in WA, as well as Nations in other States of Australia. Elders is used as a term for all participants, respecting their knowledge and age in the community. When discussing studies from other countries the authors have respectfully used the authors' descriptions of the participants and their Nations. When discussing Australian studies in general from around Australia, the term Aboriginal and Torres Strait Islanders is used. When discussing research methodology in general and Indigenous peoples worldwide, the term Indigenous is used.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.Ethics approvals for the study were obtained from WA Aboriginal Health Ethics Committee (HE 842) and Curtin University (HE number 2018-0425). All participants provided written, informed consent prior to participating in the study.MJRG led the original drafting of the manuscript. A-MH led the study conception and design with MK, RI, JC, KH, MJRG, NB, VP, and AJ. MJRG led study procedures including ethics procedures, program delivery and data collection and management, with assistance from A-MH, TW, MK, VP, and NB. MJRG and A-MH completed statistical analyses with oversight and assistance from AJ. Revisions to the manuscript were addressed by A-MH and MJRG and approved by all authors for the final revised version of the manuscript.This study was funded by a Healthway Grant (Grant Number 31960). MJRG is a Noongar Wadjuk Ph.D. student supported by a stipend from the grant. A-MH was supported by a National Health and Medical Research Council of Australia Investigator (EL2) award.NB was employed by South West Aboriginal Medical Service Aboriginal Corporation. The remaining 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.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.


Diabetes has emerged as one of the most serious and common chronic diseases of our times, causing life-threatening, disabling and costly complications, and reducing life expectancy. Studies have shown that cardiovascular morbidity is 1–3 times higher in diabetic patients than in normal people. There are many clinical and experimental data that prove that most of the complications of diabetes are related to atherosclerosis, which suggests that chronic hyperglycemia may induce an imbalance in the proliferation of vascular endothelial cells.  This study aims to explore the relationship between QKI-7 and vascular endothelial cell dysfunction and lay a foundation for further clarifying the molecular mechanism of endothelial cell damage in the process of diabetes with atherosclerosis.  We chose blood samples and pluripotent stem cells and vascular endothelial cells of hospitalized patients with diabetes and diabetes atherosclerosis as research subjects. The expression levels of endothelial cell proliferation and genes related to endothelial cell proliferation were analyzed by RT-qPCR and Western blot, to study the influence of QKi-7 on the physiological state of endothelial cells. Through gene knockdown experiment, the effects of QKi-7 knockdown on functional genes and physiological functions of endothelial cells were analyzed. Finally, RNA immunoprecipitation was used to test the mutual effect among QKI-7 and the transcription level of functional genes, and the mRNA attenuation experiment proved that QKI-7 participated in the degradation process of functional genes. α, IL-1β, and IFN-γ, leading to excessive proliferation of endothelial cells. After QKI-7 gene knockdown, the expression levels of CD144, NLGN1, and TSG6, inflammatory factors TNF-α, IL-1β, and IFN-γ, and the cell proliferation rate all returned to normal levels. RNA immunoprecipitation showed that QKi-7 interacted with CD144, NLGN1, and TSG6 mRNAs and was involved in the transcriptional degradation of functional genes through their interactions.  The findings of the RT-qPCR and Western blot tests revealed that QKI-7 was highly expressed in blood samples of diabetic patients and atherosclerosis as well as in endothelial cells induced by human pluripotent stem cells and human vascular endothelial cells after high-glucose treatment. Overexpression and high glucose of QKI-7 resulted in inhibiting expressed function genes CD144, NLGN1, and TSG6 and upregulation of inflammatory factors TNF- This research initially revealed the relevant molecular mechanism of QKI-7 leading to the excessive proliferation of endothelial cells in diabetic and atherosclerotic patients. In view of the role of QKI-7 in diabetic vascular complications, we provided a potential target for clinical diabetes treatment strategies in the future. Diabete C (PKC) .Endothelial cells can produce a variety of molecules related to vascular regulation and angiogenesis, and these molecules play important physiological regulatory roles at local or in distances . VasculaAccording to relevant reports, the human genome encodes approximately 424 RNA-binding proteins (RBPs), and most RBPs are dysfunctional in the development of diabetes. The RNA-binding domains of RBPs are important regions for protein-recognizing RNA molecules. RBPs can combine precursor RNA5′ and 3′ UTR, intron and exon of the precursor RNA, and are entirely involved in the maturation, RNA localization, stability, and translation of precursor RNA . PreviouThere is a heterogeneous nucleic acid ribonucleoprotein k homology domain in QKI proteins, which is a part of Nova-1, Sam68, and a member of the FMRP family of KH RNA-binding proteins . Based oPreviously, researchers found that three major QKI family transcriptional isomers, QKi-5, QKi-6, and QKi-7, were all expressed in vascular endothelial cells, of which QKi-5 has the highest expression abundance. On the basis of available experiment data, human QKi-5 gene knockout leads to death in the embryo. Further investigations showed that QKI-5 knockout resulted in a remarkable reduction in the expression of pecam-1 and tie-2. Similarly, the knockout of QKI-5 also caused serious disturbances in the process of angiogenesis . The latThe findings show that the expression pattern of QKi-7 in diabetic patients with atherosclerosis was preliminarily investigated. The regulation function of QKi-7 on endothelial cell proliferation was elucidated. This research detected the high expression of QKi-7 in the blood samples of patients with diabetes mellitus complicated with atherosclerosis, and the same results were also obtained from HIPSC and VEC stimulated with a high concentration of glucose in vitro. Therefore, this study hopes to further explore what role QKI-7 plays in endothelial cells. We evaluated the changes in endothelial cell proliferation-related genes CD144, NLGN1, and TSG6 in hiPSCs with high-glucose treatment. Our research is to offer new theoretical profound understanding pathogenesis of diabetic atherosclerosis and provide a potential scheme for the clinical treatment of diabetic vascular complications. We selected blood samples and pluripotent stem cells and vascular endothelial cells of hospitalized patients with diabetes and diabetes atherosclerosis as research subjects. We used RNA immunoprecipitation to test the mutual effect among QKI-7 and the transcription level of functional genes, and the mRNA attenuation experiment proved that QKI-7 participated in the degradation process of functional genes.μm needle filter, and stored separately at −20°C. RNA extraction reagent TRIzol was purchased from Thermo Fisher Company, No.: 15596018. The reverse transcription kit was obtained from Takara Biological Co., Ltd., No.: RR037B. Fluorescence quantitative PCR reagents were purchased from Roche Company, No.: 4913850001. Both RIPA protein lysate and BCA protein concentration determination kit were obtained from Bibiyuntian Biological Co., Ltd., China, No.: P0013B. CD144-specific antibody was obtained from St. John's Laboratory, No.: STJ96234; NLGN1-specific antibody was purchased from Abcam, No.: ab153821. Anti-human-TNF-α was purchased from Cell Signaling Technology, Inc., No.:11948. IL-1β-specific antibody was purchased from CST, No.: 12703. IFN-γ-specific antibody was purchased from CST, No.: 8455. HRP-labeled goat anti-rabbit and goat anti-mouse secondary antibodies were purchased from Quanshijin Biotech Co., Ltd., Beijing, No.: HS101-01, HS201-01. PGI2 ELISA Kit was obtained from Elabscience Biological Co., Ltd., No.: E-EL-0022. Both L-glucose and D-glucose were purchased from SIGMA, No.: G5500, G7021. ECL protein chromogenic solution was purchased from Bio-Rad, No.: 1705060S. Human pluripotent stem cells were purchased from SIMGA, No.: IPSC0028. Human vascular endothelial cells were purchased from ATCC, No.: PCS-100-020. The kits of E-selection, ICAM-1, and VCAM-1 ELISA were purchased from R&D Biological Co., Ltd., No.: DSLE00, DCD540, DVC00. The remaining inorganic reagents were obtained from Xilong Science Co., Ltd. The full-wavelength microplate reader was obtained from Bio-Rad, USA, model: 450. The small desktop low-temperature refrigerated centrifuge was obtained from Thermo Fisher Company in the United States, model: 75002456. Western Blot electrophoresis and transfer instrument was obtained from Bio-Rad, USA, model: 1645050. A fluorescent quantitative PCR instrument was obtained from Bio-Rad, model: T100. The fluorescence quantitative PCR instrument was obtained from Thermo Fisher, model: QuantStudio 6. The chemiluminescence colorimeter was obtained from Bio-Rad, model: 1708265.PBS buffer was obtained from Biyuntian Biological Co., Ltd., China, Art. No.: C0221A. Streptozotocin was purchased from SIGMA Company, No.: S0130. Streptomycin was dissolved in PBS, prepared into 100 mg/mL of storage solution, filtered with a 0.22 This study had been approved by the Fourth affiliated Hospital of Harbin Medical University ethics committee. All participants obtained the information orally or in writing and formally signed the informed consent. This study selects 120 type 2 diabetic patients in the Department of endocrinology from June 2018 to July 2020, and the inclusion and exclusion criteria were as follows. ①They should comply with the diagnostic criteria for T2DM in the 2017 edition of “Guidelines for the Prevention and Treatment of Type 2 Diabetes in China” . The diaFasting venous blood was collected from each study subject. On the day of the blood sampling, the patient's detailed history was recorded and blood pressure was measured.μg/ml hydrocortisone hemisuccinate, 50 μg/ml ascorbic acid, and 2% FBS Vascular Cell Basal Medium.Human vascular endothelial cells were cultured with 5 ng/ml rhVEGF, 5 ng/ml rhEGF, 5 ng/ml rhFGF basic, 15 ng/ml rhIGF-1, 10 mM L-glutamine, 0.75 U/ml HS, 1 μM CHIR99021, and 25 ng/ml BMP4 were added to the basic medium; after 3 days, the medium was replaced with StemPro 34 medium containing 200 ng/ml hVEGF and 2 μM forskolin for 2 days; on the 6th day, CD144 positive cells were separated by magnetic bead separation and cultured in EGM-2 medium [Differentiation of human pluripotent stem cells was carried out as follows: human pluripotent stem cells were cultured in DMEM/F12 mixed medium, and N2, B27, 8 2 medium .Endothelial cells were plated at a density of 1105 cells/ml into 6-well cell culture plates, and D-glucose  or L-glucose  was added to the cell culture medium and incubated for 6 days. And the fresh cell culture medium supplemented with glucose was changed every 2 days.μl CCK-8 solution was added to each well, and the cell-free well but with a cell culture medium was used as a negative control. The cells were cultured for 2 hours in a cell culture chamber, and the absorbance value at 450 nm was measured by spectrophotometer.The proliferation efficiency of endothelial cells in different treatment groups was measured at 0 h, 6 h, 24 h, 48 h, and 72 h, respectively. The instructions were strictly followed to perform the operation procedures. In a 24-well cell culture plate, 50 The QKI-7 sequence was cloned into the lentiviral vector pLVX-Puro to construct the pLVX-QKI-7-Puro expression plasmid, and pLVX-QKI-7-Puro was cotransfected with pspAX2 and pMD2.G into HEK-293T cells to obtain lentiviral culture medium expressing QKi-7.Cells overexpressing the QKi-7 gene could be obtained by infecting the harvested lentivirus with endothelial cells.α, IL-1β, and IFN-γ. The primer sequence of the internal reference gene GAPDH is shown in Total cell RNA was extracted using the Trizol, and PrimeScript™ RT reagent Kit   was used to reverse the transcription of RNA into cDNA. PCR instrument  was used for cDNA synthesis, and the reaction conditions are 37°C for 15 min and 85°C for 5 s. According to TB Green® Fast qPCR Mix  instructions, a qPCR reaction solution was prepared to test CD144, NLGN1, TSG6, TNF-7 cells were mixed with 0.2 mL RIPA lysate with 2 μl 100 μM PMSF, After fully homogenizing, the slurry was placed on ice and cracked for 30 min, during which the cells were mixed with eddy oscillation once every 10 min. The supernatant was collected after centrifugation at 4°C for 12,000 g × 10 min, and the protein concentration was determined by the BCA method. The extracted total tissue protein was added with 5× loading buffer（v：v = 4 : 1） and then was bathed in boiling water for 5 min, followed by a Western blot test. After the transfer of the membrane, it was blocked in 5% BSA blocking solution at room temperature for 1 hour, and specific antibodies were used to detect CD144, NLGN1, TSG6, TNF-α, IL-1β, and IFN-γ, respectively, and were incubated overnight at 4°C . After washing three times with TBST, the goat anti-mouse secondary antibody (working concentration: 1 : 5000) was used for incubation at room temperature for 1 h. Then, the ECL chemiluminescence kit was used for color development, and the images were taken by the Bio-Rad gel imaging system. The images were processed by Image Lab software, and GAPDH was used as an internal reference protein for quantitative analysis.1 × 10The secretory expression level of E-selection, ICAM-1, VACM-1 in blood samples, and PGI2 in QKI-7 overexpressing cells were detected by a specific ELISA kit. The OD450 nm value was measured by a full-wavelength enzyme plate analyzer, and all operations were carried out in strict accordance with the actual instructions.6 endothelial cells were suspended into the Nucleofector buffer, and 5 μM of QKi-7-specific siRNA was added to the suspension and then transferred to a 37°C biochemical incubator to continue incubating for 48 hours. The QKI-7 siRNA sequence is GUGAGAGAUUGGUAUUAGUU.A total of 1 × 10α, IL-1β, IFN-γ, and PGI2 were detected according to the above methods.The mRNA and protein levels of CD144, NLGN1, TSG6, TNF-The RNA-binding protein immunoprecipitation test kit was purchased from Millipore (Art. No.: 17–700), and all the experimental steps were performed in accordance with the instructions . The celThe endothelial cells of overexpressing QKI-7 and the transcription inhibitor actinomycin D were coincubated for 0, 2, 4, 6, 8, and 12 hours, respectively, and the mRNA expression levels of CD144, NLGN1, and TSG6 in nonoverexpression cells and overexpression cells were used to evaluate the degradation function of QKI-7 for this gene .t-test to analyze the statistical significance . When p < 0.05, it indicated a statistically significant difference.All statistical data were expressed as mean ± standard error (Mean ± SE). The differences between the experimental groups were analyzed by multiple comparison corrected analysis of variance or QKI-5, QKI-6, and QKI-7 were all expressed in vascular endothelial cells, and both QKI-5 and QKI-6 were important factors in regulating angiogenesis. To explore the function of QKI-7 in the process of diabetes and atherosclerosis, we first tested the expression of QKI-7 in the blood samples of patients with diabetes and atherosclerosis. The findings proved that the expression of QKI-7 in the patients' blood of diabetes and atherosclerosis was significantly higher than its expression level in diabetic and normal samples . It provTo simulate the physiological state of endothelial cells in patients with diabetes and atherosclerosis in vitro, we took endothelial cells induced by anthropogenic pluripotent stem cells (hiPSCs) and commercial human vascular endothelial cells (VECs) as a model and treated both kinds of cells with different concentrations of glucose. It could be seen that Qki-7 was upregulated in a dose-dependent manner in high-glucose-treated human endothelial cells by RT-qPCR and WB . After hIn order to detect whether the key genes of endothelial cells had changed after high-glucose treatment, we used RT-qPCR and western blot to detect the expression levels of transcription and translation of related genes of QKI-7 in hiPSCs after high-glucose treatment. The findings proved that the expression of CD144, NLGN1, and TSG6 in endothelial cells in the untreated group was significantly higher than that after high-glucose treatment Figures . Then, wIn order to verify the low expression of CD144, NLGN1, and TSG6 genes caused by the increased expression of QKI-7, we overexpressed the cells with QKI-7. Under the normal culture conditions, we detected the transcription level of key genes in the cells by RT-qPCR. The results showed that in the control group  the mRNAα, IL-1β, and IFN-γ in hiPSC overexpression of QKI-7. The results showed that QKI-7 overexpression significantly increased the expression levels of TNF-α, IL-1β, and IFN-γ in endothelial cells (Figures To verify if the promotion of endothelial cell proliferation by QKI-7 is also related to the abnormal expression of intracellular inflammatory factors, we detected the expression of TNF- Figures . The sec Figures .The above tests proved that the expression of CD144, NLGN1, and TSG6 was inhibited in endothelial cells after high-glucose treatment and QKI-7 overexpression. In order to further verify whether this phenomenon is directly caused by the high expression of QKI-7, we knocked down the expression level of QKI-7 in hiPSC with high glucose by siRNA and detected the expression levels of CD144, NLGN1, and TSG6 in endothelial cells after a knockdown by RT-qPCR and western blot. As shown in the figure, after high-glucose treatment or with the QKI-7 gene knocked down , the expα, IL-1β, and IFN-γ were expressed highly; the cell proliferation efficiency was significantly reduced after QKI-7 knockdown. In view of the relationship between inflammatory factors and cell proliferation, we speculated that TNF-α, IL-1β, and IFN-γ would also have corresponding changes in hiPSC after QKI-7 knockdown. In order to verify this conjecture, we used the specialty of siRNA to knock down the degree of QKi-7 gene expression in HIPSCs. The findings proved that the expression of inflammatory factors TNF-α, IL-1β, and IFN-γ was significantly reduced after QKi-7 knockdown (Figures The results of previous studies showed that the proliferation efficiency of QKI-7 overexpressed endothelial cells increased; the inflammatory factors TNF- Figures . The sec Figures , indicat∗p < 0.05, taking the negative control IgG group as the control.This study found that there was a negative regulatory relationship between QKI-7 and key endothelial cell genes CD144, NLGN1, and TSG6, and QKI-7 was an RNA-binding protein. We speculated that the negative regulation of QKI-7 on CD144, NLGN1, and TSG6 was achieved through the interplay of QKI-7 with its mRNA. Therefore, we carried out RNA immunoprecipitation experiments, and the results showed that QKI-7 protein had significant specific binding with CD144, NLGN1, and TSG6 mRNA , compareThe above experimental findings proved that there was a close relationship between QKI-7 and the key genes of endothelial cells CD144, NLGN1, and TSG6 mRNAs, and QKI-7 had a negative regulatory effect on these 3 genes. Therefore, we speculated that the combination of the two promoted the degradation of key genes, which downregulated the transcription level in turn. To verify this conjecture, we treated endothelial cells of overexpressed QKI-7 with the transcription-suppressing compound actinomycin D. The results showed the degree of degradation of CD144, NLGN1, and TSG6 mRNAs in endothelial cells treated with actinomycin D was much lower than untreated group . The finDiabetes has emerged as one of the most serious and common chronic diseases of our times, causing life-threatening, disabling and costly complications, and reducing life expectancy . The gloIt has been reported that the main transcription products of QKI include QKi-5, QKi-6, and QKi-7, which have relatively conservative sequences, and the different sequences mainly exist in the C-terminal. These three QKI allosteric proteins all existed in vascular endothelial cells, and QKI-5 has the highest expression abundance . Both QKAmong the genes related to the proliferation of endothelial cells, CD144 is an important marker of endothelial cells, which is extremely important for the integrity of blood vessel walls and angiogenesis . NLGN1 iα in the plasma of patients with proliferative retinopathy is remarkably increased. The cooperation of IL-1β and TNF-α can jointly promote angiogenesis, and the two can not only promote the synthesis of collagen but also stimulate the activity of glial cells and fibroblasts and promote cell proliferation [α/IL-1 inducible secreted protein with a hyaluronic acid-binding domain, which significantly alters the formation of ECM by disrupting the link between TSG6 and hyaluronic acid by specific antibodies. In a human model of diabetes, subconjunctival injection of recombinant TSG6 protein can promote the repair of corneal epithelial cells by activating primary progenitor cells and accelerating the polarization of M2 macrophages [In studies about the complications of type 1 diabetes, the expression of TNF-feration . Researcferation . TSG6 isrophages . It is urophages . In prevα, IL-1β, and IFN-γ in the overexpression of QKI-7 in hiPSCs were remarkably higher than those in normal endothelial cells, and the secretion level of endothelial cell proliferation-related molecules PGI2 in the overexpression of QKI-7 in hiPSCs was significantly increased. It further suggested the rapid proliferation state of endothelial cells when QKI-7 was highly expressed, and the results of CCK-8 finally showed that the overexpression of QKI-7 led to a significant increase in cell proliferation efficiency. It showed that QKI-7 overexpression had a remarkable stimulating effect on endothelial cell development, which was also consistent with the endothelial cell proliferation observed in patients with diabetes and atherosclerosis in the clinic [α, IL-1β, IFN-γ, and PGI2 also decreased; the proliferation efficiency of endothelial cells was significantly reduced. Based on the above results, we can speculate that QKI-7 has a significant impact on the proliferation of endothelial cells.Both QKI-5 and QKI-6 have a positive effect on angiogenesis; however, they differ in how they act and in what cell types they function. Through sequence alignment analysis, we found that their C-terminal sequence was less conservative, which could be inferred that its unique C-terminal structure had a great influence on its unique functional characteristics. QKi-7, QKi-5, and QKi-6 all belong to the QKI family, and the C-terminal sequence of QKi-7 is also significantly different from the other two. However, the effect of QKi-7 on vascular endothelial cell function proliferation in diabetic patients with arteriosclerosis remained unclear. This research detected the high expression of QKi-7 in the blood samples of patients with diabetes mellitus complicated with atherosclerosis, and the same results were also obtained from HIPSC and VEC stimulated with a high concentration of glucose in vitro. Therefore, this study hopes to further explore what role QKI-7 plays in endothelial cells. We evaluated the changes in endothelial cell proliferation-related genes CD144, NLGN1, and TSG6 in hiPSCs with high-glucose treatment. The findings revealed that the expressions of CD144, NLGN1, and TSG6 in the group with high-glucose treatment were remarkably significantly lower than those of the control group, while the CCK-8 experimental results showed that the proliferation efficiency of hiPSC was abnormally increased after high-glucose treatment. In order to determine that the above phenomenon was directly caused by the changes in the expression of QKI-7, we tested the expression changes of the key factors of human endothelial cell CD144, NLGN1, and TSG6 in the overexpression of QKI-7 in hiPSCs. The findings revealed that the expressions of the three key factors in the overexpression of QKI-7 in hiPSCs were significantly reduced. In order to further clarify whether the proliferation ability of endothelial cells was damaged, we tested the expression level of cytokines related to endothelial cell proliferation, and the findings revealed that the levels of TNF-e clinic . In furtThere are many clinical and experimental data that prove that most of the complications of diabetes are related to atherosclerosis, which suggests that chronic hyperglycemia may induce an imbalance in the proliferation of vascular endothelial cells. To clarify the molecular mechanism of QKI-7 leading to the excessive proliferation of endothelial cells in diabetes and atherosclerosis, We analyzed the function of QKI-7 under physiological conditions. Relevant literature indicated that QKI-7, one of the RNA-binding protein families, might bind specific mRNA and recruit decapping enzyme and adenylyltransferase to target mRNA, leading to the destruction of its 5′cap structure and ultimately destroying the stability of the target mRNA, which would cause its degradation . In viewIn summary, this study initially revealed the relevant molecular mechanism of QKI-7 leading to the excessive proliferation of endothelial cells in diabetic and atherosclerotic patients. In view of the role of QKI-7 in diabetic vascular complications, we provided a potential target for clinical diabetes treatment strategies in the future. Our future research direction is to combine QKI-7 with the clinical treatment of diabetes.


Indigenous youth worldwide continue to experience disproportional rates of poorer mental health and well-being compared to non-Indigenous youth. Mentoring has been known to establish favorable outcomes in many areas of health but is still in its early phases of research within Indigenous contexts. This paper explores the barriers and facilitators of Indigenous youth mentoring programs to improve mental health outcomes and provides evidence for governments’ response to the United Nations Declaration on the Rights of Indigenous Peoples.A systematic search for published studies was conducted on PubMed, Embase, Scopus, CINAHL, and grey literature through Trove, OpenGrey, Indigenous HealthInfoNet, and Informit Indigenous Collection. All papers included in the search were peer-reviewed and published from 2007 to 2021. The Joanna Briggs Institute approaches to critical appraisal, data extraction, data synthesis, and confidence of findings were used.A total of eight papers describing six mentoring programs were included in this review; six papers were from Canada, and two originated from Australia. Studies included mentor perspectives (n = 4) , mentee perspectives (n = 1), and both mentor and mentee perspectives (n = 3). Programs were conducted nationally (n = 3) or within specific local Indigenous communities (n = 3) with varying mentor styles and program focus. Five synthesized findings were identified from the data extraction process, each consisting of four categories. These synthesized findings were: establishing cultural relevancy, facilitating environments, building relationships, facilitating community engagement, and leadership responsibilities, which were discussed in the context of extant mentoring theoretical frameworks.Mentoring is an appropriate strategy for improving general well-being. However, more research is needed to explore program sustainability and maintaining outcomes in the long term.The online version contains supplementary material available at 10.1186/s12889-023-15253-2. Article 24 of the United Nations Declaration on the Rights of Indigenous Peoples states, “Indigenous individuals have an equal right to the enjoyment of the highest attainable standard of physical and mental health”. It mandates member-states to “take the necessary steps with a view to achieving progressively the full realization of this right”. Yet, Indigenous youth worldwide continue to experience disproportional rates of poorer mental health and well-being –8. PooreMentoring has been identified as an effective strategy for establishing protective factors that promote better lifestyle behaviors and is known to enhance positive developments in social, emotional, and physical domains of health and well-being among youth in different contexts , 27. SpeThere is a gap in the literature synthesizing crucial mentoring aspects that improve Indigenous youth’s mental health and well-being. A preliminary search did not identify any review publications in this context . It was This review was conducted in accordance with a priori protocol , followiDetails of the search strategy and keywords have been published elsewhere . SearcheThis study included papers from any geographical location, published in English, that described mentoring of Indigenous youth (defined as under 25 years old). We have respectfully referred to Indigenous people as all ethnic groups who are original inhabitants of a given region . See theScreening of eligible papers was conducted independently by two authors (JS and JM) against the inclusion criteria , discrepAuthors (JS and JM) independently extracted data in accordance with the a priori protocol . A randoCritical appraisal of included papers was conducted as per the JBI Critical Appraisal Checklist for Qualitative Research critical appraisal instrument (see Appendix 1). No papers were excluded in this review based on methodological quality. Two authors (JS and JM) completed assessments independently and audited by DL or EB. Discrepancies were discussed with other authors  until a consensus was reached. There was strong agreement between reviewers (ĸ>0.8). Cultural validity of the included papers was assessed against the Aboriginal and Torres Strait Islander Quality Appraisal Tool .Synthesis of data was completed using JBI meta-aggregative approach. Firstly, the extraction of findings was accompanied by illustrations from all included papers to establish a level of credibility to each finding based on the degree of support each illustration offered. These findings were then aggregated into categories according to their similarities in meaning. Categories were aggregated once again into a set of synthesized findings, which were used to generate recommendations for guidelines and practice. Cultural validation of the synthesis was conducted with a panel of First Nation researchers  resulting in a strong level of agreement being reached (ĸ >0.8).A ConQual approach was used to assess finding confidence , in whicFigure The AIME program provided Aboriginal and Torres Strait Islander students with opportunities for educational support through connections with university volunteer-mentors in partnership with multiple institutions across Australia. Two delivery models were involved: after-school sessions in Learning Centers with local high schools that were staffed by volunteer-mentors, Indigenous students from both primary and high school received support for education and participated in relevant activities. The second model offered opportunities within local universities through on-campus interactive and leadership programs for Indigenous students in their later years of high school while offering 60 h of additional support.Run by an Aboriginal-Controlled Community Organization, this Australian sports-based group-mentoring program was designed to engage Indigenous youth in remote communities in sports and physical activity, encouraging positive lifestyle behaviors and school engagement through active sporting activities. The program runs for one week, three times a year, within school settings by mentors consisting of athletes and people with specific capabilities. Mentors help teachers and Aboriginal Assistant teachers with classroom activities, including educating students on the importance of physical activity and health. After-school sports sessions are also run within the local communities during that time.This Canadian school-based peer-mentoring program was a strengths-based mentoring program that aimed to promote active engagement in schools and participation in formal education for elementary and secondary First Nations, Métis, and Inuit students to further education and pursue educational goals. Developing healthy relationships between Grades 7 to 9 students and students between Grades 10 to 12 who acted as mentors aimed to help facilitate help-seeking and self-advocacy skills, identity development through cultural activities, nurture positive relationships and enhance school engagement for all participants involved.Hosted by the Tłįchǫ Community Action Research Team as a direct response to address high rates of suicide in local Indigenous communities, the Kts’iìhtła: “We Light the Fire” project was a five-day creative art and music workshop held in the local community of Behchok (Canada) that was established to explore the role of creative arts on Indigenous youth resiliency. Built on existing capacity and established relationships with the local community, the program aimed to incorporate local values and beliefs through project collaborations and exploring critical issues within their communities experienced in their everyday lives.The IYMP was a Canadian peer-led mentoring program that focused on promoting healthy lifestyles, building on the strengths of youth who assumed leadership positions in their participation throughout the program. Programs were offered to elementary students through physical activity, healthy snacks, and relationship building activities. Based on culturally relevant and theoretical frameworks, the IYMP delivery incorporated multiple stages of mentoring, where mentoring was incorporated between YAHLs, high school mentors, and elementary school mentees to facilitate learning in all directions and establish community connections.Based on the Seven Grandfather Teachings of respect, love, wisdom, honesty, humility, and truth, the Outdoor Leadership Training Program was a ten-day community-led program designed specifically through close collaboration with local community members from the Wikwemikng community in Northeastern Ontario, Canada. Guided by local Indigenous facilitators who acted as mentors for the participants, the program involved an intensive wilderness canoe expedition - experiencing natural challenges through rapids, portages, navigation, and open-water crossings. Participants were assigned leadership responsibilities and experiences in solo components of the program.By exploring the perspectives of both mentors and mentees through qualitative data, five factors emerged from the data that facilitated positive improvements across multiple domains of Indigenous youth health and wellbeing. These five factors were: establishing cultural relevancy, facilitating environments, building relationships, community engagement, and leadership responsibilities. These factors were found across all programs that influenced improvements in social, behavioral, psychological, attitudinal, and academic performances of Indigenous youth, which in turn appeared to increase overall resilience in their communities.Acknowledging and understanding Indigenous cultures was a key to the success of the interventions and programs focusing on the health and well-being of Indigenous youth. Whilst there was significant evidence of the positive outcomes of mentoring within the literature, there have been many instances of mistrust and doubt towards mainstream services and initiatives that were seen as individualistic and differentiate from egalitarian-based models that incorporate Indigenous worldviews.For example, having relevant cultural frameworks embedded within the Indigenous youth mentoring program design was identified as an important factor in ensuring cultural relevancy. For instance, the Kts’iìhtła program was guided by the Elders and community representatives, integrating Tłįchǫ values and beliefs through shared community wellness goals with the Tłįchǫ Community Services Agency and Mental Health and Addictions Action Plan . LikewisThree fundamental approaches were highlighted which addressed cultural appropriateness and maintained cultural relevancy throughout the programs. Cultural competency training was important, especially for non-Indigenous mentors to understand the specific needs of local Indigenous youth, their families, and the community. Furthermore, incorporating traditional cultural teachings through partnerships with local community members allowed for the delivery of culturally safe programming and communication.Cross-cultural training was necessary to maximize learning opportunities for volunteer-mentors in the AIME program;  formal tCultural learning and exposure to cultural teachings and practices during program delivery were important in facilitating cultural relevancy. Connections with Indigenous members of the community and the support they received were of particular importance. Participants had opportunities to learn and connect to their cultural teachings that were presented in ways that were meaningful to participants. For instance, many mentors saw the AIME as an opportunity to connect with Indigenous members of the local community, which facilitated the importance of recognizing Indigenous cultures in the delivery of mentoring programs .Culturally appropriate pedagogical approaches involving community circles and storytelling that incorporated cultural and traditional values that allowed participants to reflect on their culture and how they were tied to their experiences in life. For instance, participants of the IYMP described increased awareness and knowledge of Indigenous culture by participating in traditional Indigenous games and teachings from the Traditional Knowledge Keepers , 42. ThiCultural engagement established a sense of pride for mentors as they were able to incorporate components of their own culture for others to learn and understand. This was important as it allowed all participants to engage in aspects related to their identities.This review suggests that youth with strong links to cultural awareness and identity resulted in an increased sense of belonging, self-confidence, autonomy, and overall functioning, suggesting protective factors against adverse mental health outcomes .An important aspect of these mentoring programs was facilitating a culturally relevant strengths-based approach, with the idea of empowering both program participants and their communities through a sense of ownership and cultural identity to influence future career aspirations. As a result, programs presented mentees and youth with a strength-based mindset rather than a deficit model that encourages expectations, assumptions and stereotypes that are problematic within modern-day society. Mentors within the AIME, especially first-year mentors who had limited contact with Indigenous communities, reflected upon the differences in pre-conceived thoughts between their expectations of Indigenous youth mentees to their actual experiences within the program. One mentor described her experience as “just normal, like I could be talking to any other kid from the local feeder High School”  p. 402. Facilitating safe and secure environments for all participants was essential in designing and delivering mentoring programs. Program participants described many opportunities in developing their social networks. Participants mentioned that programs enabled them to establish new relationships and strengthen existing relationships within their local communities. These connections between mentors and mentees created a safe and secure environment for program participants, facilitating a sense of belonging within the program. One of the youth mentors in the IYMP program stated, “Once you step inside that program your entire mood will change no matter what”  p. 5.Many participants mentioned the comforting environments that facilitated opportunities to build these supportive relationships, describing program settings as a safe and welcoming. One participant mentioned developing a mutual understanding between peer group members saying, “We get to talk with different people that we usually don’t talk with”  p. 98. FThese relationships increased social cohesion both within and outside of the program, promoting positive changes in forming new friendships and encouraging increased participation through growth in self-confidence. The development of emotional wellness was a key outcome of program participation through building relationships with one another. These relationships provided a safe and comforting environment for program participants where engagement and trust felt natural. Participation in the program revealed opportunities to relieve stress for both mentors and participants due to the calming nature of the program. Furthermore, through the development of skills in the creative arts, youth participants in the Kts’iìhtła program found the workshop environment to provide opportunities to discuss community issues and visions for change reflected within their final art projects .Mentoring programs were found to facilitate the development of relationships, including connections to people, culture, and communities. The program design was important for facilitating these connections, as mentors described naturally occurring interactions within programs. Mentoring relationships provided opportunities to discuss backgrounds, interests, personalities, and sharing of stories, all of which were important for the ongoing development of the program. When respect was reciprocal, mentees described instances of belonging to the program and the community, “The more and more I went there, the more I felt like I belonged there ‘cause it was really fun meeting all these people, playing games with them, and sharing stuff with them”  p.741. HRespect for mentors (compared to other authority figures) was unique, as participants mentioned the value of mentor relationships that teachers may not provide within school settings, “…Because with teachers, we do listen but with the mentors they make sure we know and we keep it locked down. Sometimes teachers don’t do that, so it doesn’t always click in. But they [mentors] always try to make sure we remember”  p. 98.Involvement in these connections was not only beneficial for student participants, but was bi-directional as mentors described personal growth, self-confidence, and increased self-awareness of their community and culture as a result of participating in their mentorship role. One of the Indigenous mentors mentioned this prompted self-reflection upon what it meant to be Indigenous, as well as their own connections to family and community stating, “Looking at community initiatives that were being implemented and taking that information back to my home community”  p. 43.For non-Indigenous mentors, connections with Indigenous mentees enabled a deeper understanding of educational disadvantages for non-Indigenous youth, influencing how they interacted with Indigenous communities in future engagements. Furthermore, mentors also described instances of teaching their families and those around them, mentioning the importance of teaching and providing support for those not directly involved in the program, “A lot of my family are not connected with that Aboriginal side, so it gives me the chance to explain things to them and to give them some of the knowledge that I’ve learned”  p. 540. The ability of mentoring programs to develop relationships and connections at all levels of the program also had specific influences on other positive outcomes of the program. For instance, participants of the IYMP felt that the program facilitated opportunities for learning, growth, and building a positive self-image .Connecting identity through connections with others reinforced the idea of healthy relationships with others through their experiences. Developing relationships between mentees and mentors were of significant importance in providing opportunities to share and discuss culture. Student participants felt they were understood and accepted as First Nations peoples due to a shared understanding of the cultural backgrounds of the program facilitators . This reOne of the key features of program delivery was the level of engagement with the community. Strong emphasis was placed on effective communication between schools and communities for the successful implementation of the programs, including the use of appropriate language for easier participation in the program. This included simplifying language to discuss program aims that targeted community values in improving participants’ health outcomes. Participation in programs such as the IYMP was influenced by program information sheets and consent forms that were easy to understand for the students’ parents, grandparents, and guardians , 42.We have often brought in like community members for the cultural activities…We made a Circle of Courage poster kind of thing where we would separate into groups and be like what does being independent mean and the kids [mentees] would come up with scenarios and then they would draw pictures and then we brought it all together as a big circle [g circle  p. 6.Specific connections directly with the Indigenous facilitators and mentors were essential for program delivery due to the opportunities provided to program participants. Engagement with community members, Elders, and traditional knowledge keepers through participation in cultural activities during the programs, such as fishing and drumming, and integrating traditional Indigenous teachings through knowledge sharing, were vital for program success and ensuring cultural relevancy:Programs also invited guest instructors and visitors from the community to facilitate program activities and further ties between participants and their connections to others outside the program, “I think that was really cool to bring in other people that had knowledge that we didn’t necessarily have and then we all got to do it together”  p. 743. Valuing mentor roles was seen as a factor for driving successful program implementation. Some peer mentors described the challenge in developing leadership qualities as having to step outside of their comfort zones in their ability to learn, grow, and embrace their roles in leading group activities . ProgramAn important aspect of the programs was the skills and knowledge that mentors brought into the community. Mentors were seen as role models for the program mentees, exposing them to opportunities available outside their local communities. Mentees were given a chance to explore different skills and experiences within mentorship programs, with the aim of giving youth a sense of empowerment through participation in program activities. Mentees were encouraged to engage with successful mentors and role models, “The more they’re exposed to the reality of what is possible for them, and the more they see people from their own culture being successful in that area who still had their culture … people who still are able to connect with them, that’s very empowering”  p. 39.This review examined current literature on Indigenous youth mentoring programs and found five facilitating factors in the design, delivery, and sustainability of these programs to improve general mental health and wellbeing. These factors, found across all programs, demonstrated positive influences in social, behavioral, psychological, attitudinal, and academic performances of Indigenous youth, which in turn suggested increased overall resilience in these communities. Theoretical implications of the findings are discussed below, with reference to extant literature within the context of cultural relevancy, facilitating environments, building relationships, community engagement and leadership aspects of mentoring.I don’t want to be an ignorant person… I just wanted to personally come into closer contact with it so I understood for myself what it meant, rather than just – a lot of the ways that Indigenous people are treated in Australia it’s very distant. I just don’t think that’s helpful and I just don’t want to be ignorant about it [about it  p. 400.The significance of ensuring cultural relevancy within the programs can be considered in reference to the Multicultural Feminist Mentoring theory, which suggests that in order for mentors to have multicultural competence in meeting the unique needs of diverse mentees, the skewed power structure of the dyadic relationship should be recognized and the mentee should be equipped with tools to be empowered when encountering systemic racism . MentorsIt is important to consider the mentee, the mentor and the mentoring relationship being affected by a series of social and cultural contexts, which can either empower or disenfranchise the mentee . This peWithin the concept of facilitating safe environments, the Holding Environment theory describes how mentoring relationships can be viewed as a type of anchoring relationship. The application of this theory “yields the prediction that the presence of a high-quality relationship should moderate the expected negative association between ambient racial discrimination and organizational commitment”  p. 215. Building mentoring relationships where mentors are seen as trustworthy and reliable sources of support allows for positive youth development and overall resilience , 51. HigResilience is often tied to strong family and community support networks that establish a sense of belonging and identity, and active engagement in community activities promote positive lifestyle outcomes . ResilieFinally, this review found that the leadership aspect of mentoring by facilitating engagement and leading by example provided positive impacts on mentees and maintained healthy ongoing relationships. It has been shown that mentoring others can improve individuals’ leader identity and leader self-efficacy . This reProgram designers should look to empower Indigenous communities through strong community partnerships, collaboration in design and implementation, and promoting Indigenous-led, culturally appropriate programming that facilitates community buy-in and community resilience.Learning from and effective integrating international models of mentoring programs may influence the success of Indigenous youth mentoring programs. There is a need to assess homogeneity and practicability in the local context.This paper discussed positive outcomes of mentoring programs on general youth wellbeing however more research is needed to further quantify the impact that may have on mental health. Measuring the associated risk and protective factors of resilience through both quantitative and qualitative outcomes can provide meaningful analysis within this field.There was potential for publication bias in limiting recruitment of potential studies that did not meet the strict inclusion and exclusion criteria. As this review focused on qualitative papers only, the findings were limited to factors relating to mentoring program experiences, excluding quantitative findings that may provide objective indicators of improvements in mental health and overall resilience through validated tools. Furthermore, our review only included results from studies that originated in Australia and Canada. This was surprising as many papers have explored mentoring as an approach to addressing disproportionate rates of suicide and overall health in countries such as America, New Zealand, and Greenland. As this review aimed to include studies based in these regions, findings may not be relevant due to potential differences in local community needs relating to specific cultural values and traditions, structural and language/ heritage/ cultural barriers, nuanced experience with colonization, displacement, dispossession, economic exploitation, racism, and marginalization, local priorities and preferences, and local solutions that have been trialed.Furthermore, analysis in cross-cultural or cross-national differences between the programs, as well as any potential effect of Indigenous compared to non-Indigenous mentors were not conducted as a convergent model was used to synthesize similarities between programs. These reduce the sensitivity of the analysis in picking up unique nuances such as Indigenous versus non-Indigenous mentors and reduce the generalizability in applying findings to other Indigenous cultures; however, it is hoped that analyzing commonalities will increase the specificity of the findings which may apply to other First Nations countries not explicitly stated in the review since despite culture differences, Indigenous people around the world share common problems and experienced disadvantaged and vulnerability. Another limitation that was found to be problematic across most studies was issues with small sample sizes. Small samples of Indigenous youth participation in mentoring programs specifically make it difficult to generalize findings from the sample population to the community.This qualitative systematic review explores the perspectives of program facilitators, mentors, and mentees on factors that sustain Indigenous youth mentoring programs in varying contexts. Mentoring has shown to be a successful strategy that can be implemented within Indigenous contexts when culturally relevant approaches are appropriately implemented. Whilst mentoring in isolation has proven to result in positive outcomes, more research is needed on mentoring as part of broader initiatives in addressing Indigenous health and wellbeing.Mentoring programs that are culturally tailored to meet the needs of the local community is the best approach to successful mentoring regardless of program aims and objectives. Holistic approaches involving strong community partnership links that build upon the strengths of Indigenous youth have provided the best outcomes on mental health and overall resilience of Indigenous youth and their communities regardless of their surrounding environments. Whilst mentoring programs have resulted in positive social and emotional wellbeing in the short term, more research and organizational commitment is needed to sustain these programs for long-term benefits.Below is the link to the electronic supplementary material.Supplementary Material 1


Implementation integrity is known to be critical to the success of interventions. The Health At Every Size® (HAES®) approach is deemed to be a sustainable intervention on weight-related issues. However, no study in the field has yet investigated the effects of implementation on outcomes in a real-world setting.This study aims to explore to what extent does implementation integrity moderate program outcomes across multiple sites.n = 45) were assessed using a mix of qualitative and quantitative data analysis. Adaptations to the program curriculum were categorized as either acceptable or unacceptable. Multilevel linear modeling was performed with participant responsiveness and other implementation dimensions predictors. Intervention outcomes were intuitive eating and body esteem.One hundred sixty-two women nested in 21 health facilities across the province of Québec (Canada) were part of a HAES® intervention and completed questionnaires at baseline and after the intervention. Participant responsiveness (e.g. home practice completion) along with other implementation dimensions  and providers’ characteristics (sr(23) = .59, p = .003) and past experience with facilitating the intervention (r(23) = .47, p = .03). Participant responsiveness showed a significant interaction between time and home practice completion  on intuitive eating scores.Unacceptable adaptations were significantly associated with providers’ self-efficacy (Except for participant responsiveness, other implementation dimensions did not moderate outcomes. Implications for future research and practice are discussed. Health care professionals and researchers call for a need to intervene more effectively to reduce the disease burden associated with high body mass index (BMI)  quality of delivery, referring to the skills with which the intervention was provided ; (4) participant responsiveness, the degree to which a participant displays interest in the intervention; (5) program differentiation, meaning the uniqueness of the program in comparison with other interventions; (6) monitoring of the control/comparison conditions; (7) program reach, meaning the scope of the program, and finally; (8) adaptation, referring to the changes that were made to the original program while it has been delivered. Based on this theoretical frame, Berkel et al.  (What about losing weight?) is a HAES®-based intervention for women which promotes intuitive eating and self-acceptance, following the example of the fat acceptance and size diversity movement. The intervention consists of 13 weekly three-hour sessions, plus an intensive six-hour day, provided in small groups of 10–15 participants and led by a social worker or psychologist as well as a dietitian. It aims to develop healthy ways of coping with weight management such as reevaluating eating habits and food intake, enjoying physical activity and being critical towards diets. By the end of the program, it prompts participants into free and informed decision-making about losing weight. A realistic action plan of behavior changes customized to their own personal situation is then designed accordingly. As such, the success of intervention of CdM? relies on outcomes reflecting a healthier relationship with oneself such as improvement of body esteem and intuitive eating  across the province of Québec in response to the public health action plan led by the Ministère de la santé et des services sociaux  to promote healthy habits and prevent weight-related issues MSSS, . The disHSSCs from across the province of Quebec (Canada), spread over 9 different regions from Quebec , were provided with the instructions and assessment materials by the research team. They were entirely in charge of recruitment and data collection, and delivery of the intervention. Participants of CdM? were recruited starting from September 2010 to December 2011. Procedures were approved by the research ethics committee (REC) of the Health and Social Services Agency of Montreal. They were also ratified by each HSSC local ethics committee. This study was conducted following the principles of the Declaration of Helsinki.Identification of CdM? core components below). Qualitative data from the reminder and interview verbatim transcripts were imported in NVivo v.9.0 for analysis.CdM? providers gave participants a series of pen-and-paper questionnaires to complete at home at baseline (T1 = 0 month), after the intervention (T2 = 4 months) and at 1-year follow-up (T3 = 16 months). Only data from T1 to T2 were used as this study focuses only on the processes related to the implementation. Participants also had to complete a sociodemographic questionnaire at baseline, and a feedback survey about CdM? at the end of the intervention (T2). Providers completed an evaluation grid which was used as a reminder at the end of every session to report the conduct of each planned activity. These reminders were all sent back to the research team by mail at the end of the intervention. Providers had to report in their grid the extent in which the activity was performed with integrity, meaning whether the activity was: (1) performed accordingly to the manual; (2) performed with some modifications; or (3) not performed. They also had to report the length of each activity and, if required, described the modifications they made. An individual semi-structured interview was then conducted by phone at the end of the program with each provider in order to better understand the course of implementation in their respective HSSC. The interview was recorded and lasted approximately one hour. The research goals as well as the independency of sources of funding were recalled at the beginning of each interview. The interview guide had 30 questions that were derived from evidence-based factors known to influence implementation integrity  were invited to provide the research team with their subjective insight on core components of the program. Instigators had first identified primary theoretical core components of the program, namely: the non-diet, self-acceptance and empowerment approaches. They completed a grid listing each activity of the program, which were rated according to their degree of importance  and then associated with core components. They were also asked to comment on the level of flexibility they would allow adaptations on (a) the holding of the activity, (b) its content, (c) its facilitation style and (d) its length. Grids were sent back to the research team and led to the creation of a decisional algorithm allowing the classification of modifications to the program made by providers into two distinct categories: (1) acceptable adaptations and (2) unacceptable adaptations see . Five ma216 adult women from the community participated in CdM?, nested within HSSCs across the province of Quebec (Canada). The intervention was opened to any woman seeking treatment for eating or weight-related problems. Apart from being aged 18 years-old and over, no formal exclusion criteria were used for restricting entrance to the program. A mandatory information session was held prior to the program to ensure their understanding of the themes covered during the program. Participants reporting a pregnancy over the course of the study (n = 5) were excluded from the analyses for sample homogeneity reasons. 162 participants completed the questionnaire at the end of the intervention and were used for the analyses.Recruited dyads of providers consisted of a registered dietitian and a psychologist or social worker who were already trained by ÉquiLibre and engaged into delivering CdM?. All HSSCs that had at their disposal a trained dyad of CdM? providers were approached for recruitment (n = 41). From these invitations, 6 refused to participate in the study and 14 HSSCs were not giving the intervention at the time of data collection, thus resulting in 21 eligible HSSCs and a total of 24 dyads . All providers agreed to participate in the study, although three of them did not complete data collection, one for medical reasons and the remaining two, due to lack of time. The final sample size of providers was n = 45  and multiplied by 100 to obtain a percentage of adherence to the curriculum. Adherence has been documented in the past as a percentage of program activities completed  was photocopied and given to participants as examples to make their own compilations at home’; or bringing together activities with similar themes: ‘Moved the [presentation on the body's resistance to weight loss] to Session 12 ’.This variable herein refers to the number of modifications performed per providers’ dyad  that were classified as unacceptable adaptations by the decisional algorithm. They could be, for instance, the addition of a new activity without consulting participants, ‘We’ll do the taboo foods exercise (which is not planned in the program) […]’; while omitting theoretical content, ‘[The physiological consequences of obesity of the energy balance presentation sheet] not completed […]’, or limiting group discussions and interventions, which was considered to obstruct empowerment.: ‘[…]we asked women to limit their interventions when giving feedback about their visualization exercise’. It is to be noted that all removal modifications were classified as unacceptable.A questionnaire developed by the research team was used to assess participants’ responsiveness to CdM?. We hereby define participant responsiveness as a multidimensional construct referring to involvement and interest to the program that includes attendance, subjective improved knowledge, home practice completion and satisfaction. We also included goal achievement as another evidence of their responsiveness to the program. Qualitative information was collected in concomitance to the quantitative assessment of their responsiveness, using written feedback on the intervention. For instance, participants were asked to provide explanations as to why they would not have met their goals, or reasons behind their assessment of their satisfaction towards each activity.Goal achievement. Participants were asked whether they have achieved their main goal over the course of the program, to which they could either answer (1) yes, (2) more or less or (3) no.Attendance. The attendance of participants to each session of CdM? was documented by providers of the program who reported it at the beginning of each session. Attendance was computed by summing up attendance to each session by the end of the program.Subjective Improved Knowledge (SIK). Participants were assessed on their improvement of knowledge on theoretical subjects thoroughly discussed during the program . Participants could answer either ‘1 = slightly’, ‘2 = moderately’ or ‘3 = a lot’. A mean score was calculated by averaging scores for the six learning components. Higher scores indicate higher improved knowledge. Internal consistency was acceptable (α =  .70).Home Practice Completion (HPC). Participants self-reported on a Likert-scale how often they put into practice the several methods and problem-solving exercises learned during the program . Ten behaviors were assessed: (1) be aware of false hunger; (2) do an enjoyable substitutive activity not related to food; (3) listen to your body; (4) taste the food you eat; (5) feel and respect satiety signals; (6) choose the desired foods; (7) relax; (8) be active; (9) express your feelings; and (10) assess difficult situations. A mean score was then computed, where higher scores reflect higher home practice completion. Internal consistency was acceptable (α =  .73).Satisfaction. Participants were asked to rate their level of satisfaction towards the several types of activities conducted during the program. They were asked: ‘Are you satisfied with the following activities?’, to which they could answer ‘1 = slightly’, ‘2 = moderately’ or ‘3 = a lot’. More specifically, nine types of activities were assessed: (1) energy balance assessment; (2) true signals of hunger exercise; (3) tasting exercise; (4) role-playing; (5) modeling dough exercise; (6) theoretical/conceptual presentation; (7) visualization exercises; (8) relaxation/mindfulness exercise; and (9) action plan design. A final score was averaged from all types of activities. Higher scores indicate higher satisfaction. The internal consistency for this variable was however lower than the other measurements of responsiveness (α = .61). This weaker reliability may be attributed to the eclectic and multidimensional nature of the program, which relies on significantly different types of activities.Providers were asked to report the number of years of experience they had in their respective professional area . A mean score was computed for each providers’ dyad.CdM? experience refers to the specific program-related experience of the providers, meaning how often they have offered CdM? in the past in their current HSSC or other establishments.Providers were assessed on three theoretical founding pillars of CdM?: (1) the non-diet approach; (2) the self-acceptance approach and (3) the empowerment approach. Providers were asked: ‘To which degree do you feel able to convey information about [e.g. the non-diet approach]?’ and had to report it on a 5-point Likert-scale . They were similarly assessed about a set of relevant skills for multipatient interventions: (1) group dynamic facilitation, (2) handling emotional participants, (3) handling quiet participants, (4) handling overwhelming participants, (5) managing auto-facilitated sessions, (6) managing dyadic facilitation, and (7) adopting a non-directive style of facilitation. A mean score averaging the up-mentioned items was computed for each provider and dyad of providers, resulting in a mean self-efficacy score. Higher scores indicate higher sense of self-efficacy. Internal consistency was good (α = .83).The Intuitive Eating Scale (IES) is a scale of 21 items displaying a total score as well as 3 subscales: (1) Eating for physical rather than emotional reasons, (2) Unconditional permission to eat when hungry and what food is desired, and (3) Reliance on internal hunger and satiety cues Tylka, . This quThe Body Esteem Scale is a validated 23-item questionnaire composed of 3 subscales, namely the (1) Appearance, (2) Weight and (3) Attribution subscales  when assumptions could not be met for parametric statistic tests  linear modeling (MLM) (time (1), and participants (2) nested in HSSC implementation sites (3)) was performed through SPSS MIXED MODELS for the examination of the effect of implementation dimensions on prediction of outcomes of the intervention over time. MLM is an appropriate statistical method when data is nested in units of a higher level of analysis by allowing the study of the relationship between a dependent variable and one or more explanatory variables without violating assumptions of independence in linear multiple regression. Assumptions regarding normality of residuals and absence of outliers using Mahalanobis distance were assessed for the set of predictors. A null model in which no covariates were added (intercepts-only model) was tested for each outcome to provide intraclass correlation among each level of the hierarchy. Models were then tested with centered predictors .Using SPSS v.25, we performed descriptive statistics and bivariate pairwise Pearson correlations between variables, while we used Spearman correlations (rM = 4.64) reported greater self-efficacy on this skill than dietitians (M = 3.68), U = 111.5, p = .001, 2 = .25.Descriptive statistics of CdM? participants are presented in sr = .37, p < .001), and home practice completion and satisfaction , both with a medium effect size. Unacceptable adaptations showed strong positive associations with providers’ dyads CdM? experience  and their overall self-efficacy , while self-efficacy correlated with CdM? experience . Dosage did not correlate significantly with any other variable. Adherence correlated positively with subjective improved knowledge , but with no other variable.Means and correlations regarding participant responsiveness and other implementation dimensions are shown in t (18.91) = 50.28, p < .001), with p < .001, p  = .03, and p = .11. Intraclass correlations (ICC) were calculated accordingly,  = .68,  = .21 and  = .10 respectively for intraindividual residual error, participant and HSSC levels. We similarly obtained a total mean score on BESAP of 1.39 (t (15.20) = 20.72, p < .001), with  = .21, p < .001, p < .001, and  = .004, p = .89. ICC were then calculated, resulting in 2  = 636.03–416.78 = 219.25, p < .001 for IES and 2  = 259.03, p < .001 for BESAP. Results of models are presented in p < .001), which significantly deviated between participants, and had an average increase in IES of .08 per month over the course of the intervention. Home practice completion was the only significant predictor interacting with time  = 2.13, p < .05), showing an additional increase in scores of IES of .07 per month for each increase of one unit of home practice completion. Other predictors did not have a significant effect on the slope. For body esteem, p < .001). Participants had a lower intercept of .46 points for each increase of one unit for subjective improved knowledge, meaning that those who reported higher scores on subjective improved knowledge had a lower body esteem at baseline. No other significant effect was found among participant responsiveness predictors.The null model tested with intercepts only resulted in a total mean score on IES of 2.93 . Meanwhile, results in terms of adherence are difficult to interpret since no benchmark was defined prior to the conduct of this study, again suggesting caution in results interpretation. We also noted that each providers’ dyad has performed acceptable and unacceptable modifications to the program. Moreover, providers reported a very high sense of self-efficacy on theoretical pillars of the HAES® movement, as well as on skills required to facilitate a program in a group setting, regardless of their occupation. An exception to this would be the handling of emotional patients, as dietitians reported feeling less confident on this matter. This could indicate the relevance of having providers with complementary fields of expertise.per se. As such, it is likely that the providers confident in their abilities felt more comfortable to perform adaptations of greater extent. This could instead reflect on a good mastery of the program. Providers could also have either overreported or underreported the adaptations made. This could provide an alternative explanation as to why unacceptable adaptations were associated with self-efficacy. Overreporting adaptations, a downside from using self-reported methods in fidelity of implementation ’, while others held onto their goal to lose weight and expressed being now ‘better equipped’ for it. When participants reported dissatisfaction from their participation to the program, they generally mentioned having felt ‘overwhelmed by the amount of homework to do’ or ‘for not having invested as much (efforts) as they would have wanted to’. Regarding their satisfaction towards each activity, most participants’ feedbacks were generally positive, except for the play dough activity, which generated polarized reactions. This high responsiveness among participants could, all in all, reflect a high-quality implementation.This study presents several strengths that are worth mentioning. First, this is, to our knowledge, the first study in the field of HAES® to examine outcomes of a disseminated and community-based intervention through the lens of implementation science. We might as well point out that we based our study on a model of implementation as it is recommended by the current guidelines in implementation science  had a positive effect on intuitive eating. More studies in the field are needed to explore which components of implementation matter the most, especially given the complexity of implementing and scaling-up interventions. The question of whether a ‘lack of adherence’ could have the same detrimental effect as the wrongdoing of unacceptable modifications to the treatment would also deserve, in our opinion, further investigation. More particularly, researchers should explore the impacts of different types of adaptations and better understand the context in which they are performed. In that regard, our study showed unexpectedly that unacceptable adaptations made to the program were associated with greater self-efficacy and experience with the program. Finally, more attention should be given to the monitoring of implementation in the field of obesity as it would step up the quality and accuracy of findings in future effectiveness studies.In conclusion, our study showed the complexity of implementing a multi-dimensional intervention in a community-based setting. Our main analysis failed to demonstrate an effect of HSSC-level implementation on outcomes. While disappointing in terms of findings, this ‘absence of results’ could be seen positively, as it is possible that participants improved their intuitive eating and body esteem independently from Many thanks to Hans Ivers, Ph.D., for his teaching of statistical analysis.Click here for additional data file.