AT-rich interactive domain 1A (ARID1A) functions as a tumor suppressor and several therapeutic targets in ARID1A-mutated cancers are under development. Here, we investigated the prognostic value of ARID1A for gastric cancer and its association with expression of PD-L1 and p53. ARID1A expression was examined by immunohistochemistry and negative expression of ARID1A was detected in 39 (19.5%) of 200 cases in a test cohort and in 40 (18.2%) of 220 cases in a validation cohort. Negative expression of ARID1A was associated with worse overall survival in undifferentiated cases, particularly early-stage cases. Negative expression of ARID1A was detected in 11 (50%) of 22 PD-L1-positive cases and in 68 (17.1%) of 398 PD-L1-negative cases in a combined cohort. Negative expression of ARID1A was detected in 45 (22%) of 205 p53-positive cases and in 34 (15.8%) of 215 p53-negative cases in a combined cohort. In addition, expression of EZH2, a potential synthetic lethal target in ARID1A-mutated tumors, was detected in 79 ARID1A-negative cases. An ARID1A-knockdown gastric cancer cell line was subjected to microarray analysis, but no actionable targets or pathways were identified. The present results indicate that ARID1A may serve as an early-stage prognostic biomarker for undifferentiated gastric cancer. AT-rich interactive domain 1A (ARID1A), located on chromosome 1p36.11, is a subunit of the Switch/Sucrose Non-fermentable (SWI/SNF) chromatin remodeling complex. ARID1A has a tumor suppressor function, and inactivating ARID1A mutations occur in various types of cancer1. In gastric cancer, ARID1A is frequently mutated in Epstein-Barr virus (EBV)-positive and microsatellite instability (MSI) subtypes/DNA mismatch repair (MMR) protein deficiency characterized by frequent overexpression of PD-L1/L2, CDKN2A methylation, PIK3CA mutations, and rare TP53 mutations5. Because ARID1A recruits MSH2 (an MMR protein) during DNA replication, inactivation of ARID1A leads to functional impairment of MMR and accumulation of gene mutations6. Therefore, evaluation of ARID1A expression in gastric cancer will increase our understanding of impaired MMR and tumor phenotypes, and may lead to development of novel immune checkpoint blockade therapies. Since most ARID1A mutations in gastric cancer are truncating mutations that result in lack of ARID1A protein expression, immunohistochemical (IHC) staining can be used as a surrogate marker for ARID1A mutations5.7. Several therapeutic targets in ARID1A-mutated cancers are currently under development, including enhancer of zeste homolog 2 (EZH2)8. EZH2, a histone methyltransferase subunit of a Polycomb repressor complex, is a potential target in ARID1A-mutated tumors in a synthetic lethal manner9. Several phase 1 or 2 clinical trials of EZH2 inhibitors for advanced solid tumors are ongoing, and the therapeutic use of EZH2 inhibitors has shown promise in ARID1A-mutated gastric cancer8.A meta-analysis including 15 gastric cancer cohorts revealed that low ARID1A expression is associated significantly with worse patient survival and adverse clinicopathological factors, such as lymphatic invasion and lymph node metastasisARID1A-related genes and pathways.In the present study, we performed IHC staining for ARID1A in two independent cohorts of patients with surgically resected gastric cancer. To clarify the molecular features of gastric cancer with negative ARID1A expression, we investigated the prognostic value of ARID1A and the relationship between ARID1A and cancer-related molecules, such as p53, MMR status (deficient MMR (dMMR) or proficient MMR (pMMR)), and PD-L1. In addition, we performed microarray analysis to find ARID1A expression was evaluated using IHC staining in two independent cohorts of gastric cancer patients Fig. . In the The prognostic value of ARID1A expression in gastric cancer was investigated next. Overall survival was used as an endpoint for both cohorts. Negative expression of ARID1A was associated with shorter overall survival in the test cohort (P = 0.049) Fig. . To explNext, we investigated whether ARID1A expression has prognostic value in early-stage gastric cancer. In the combined cohorts, ARID1A had no prognostic value in stage 1, stage 2, or stage 1&2 gastric cancer Fig. . HoweverARID1A mutations and rare TP53 mutations4. Therefore, we performed IHC staining for PD-L1 and p53 in the combined cohorts and investigated the correlation with ARID1A expression. Positive staining for PD-L1 at the apical cell surface, cytoplasm, or circumference of malignant cells was observed in gastric cancer cases  showed that PD-L1 mRNA expression was higher in gastric cancer cell lines with ARID1A truncating mutation (n = 6) than in wild-type ARID1A lines (n = 28)   gastric cancer dataset, which showed that PD-L1 mRNA expression was higher in patients with ARID1A truncating mutation (n = 83) than in other patients (n = 286) (P < 0.0001)  Fig. 12. This 01) Fig. 4.Figure TP53 mutation was less frequent in gastric cancer with ARID1A truncating mutations (n = 289)  Fig. .ARID1A-mutated ovarian cancer cells9. Because the response to EZH2 inhibitors often correlates with EZH2 overexpression, we investigated EZH2 expression by IHC staining in gastric cancer . ARID1A showed the greatest downregulation, confirming the validity of the experimental system.To identify genes regulated by ARID1A in gastric cancer, microarray profiling was performed using RNA isolated from N87 gastric cancer cells treated with two siRNAs against ARID1A Fig. . The resin vitro experiment suggested that INF-α and INF-β were induced by ARID1A knockdown in gastric cancer cells.The groups of genes showing >2-fold upregulation or downregulation were subjected to Database for Annotation, Visualization and Integrated Discovery (DAVID) gene annotation enrichment analysis to determine significantly enriched gene ontology (GO) terms Fig.  and S3. ARID1A mutations are inactivating mutations leading to decreased ARID1A expression, negative ARID1A expression can be used as a surrogate marker for ARID1A mutations 14. ARID1A plays an important role in development of this inflammation-related type of carcinogenesis in that the NF-κB/miR-223-3p/ARID1A axis promotes cell proliferation and migration, leading development of H. pylori-induced gastric cancer15. Furthermore, ARID1A mutations are highly prevalent in EBV-positive gastric cancer, which is characterized by frequent overexpression of PD-L1/L2 and rare TP53 mutations4. A recent report demonstrates that ARID1A deficiency contributes to impaired MMR, thereby increasing the tumor mutation burden6. Consistent with previous reports, we showed that PD-L1 is overexpressed in gastric cancer lacking ARID1A expression4. Therefore, we confirmed that the cohorts used in the present study were suitable for analysis, and that gastric cancer lacking ARID1A expression may be sensitive to PD-1-PD-L1 immune checkpoint therapies6.Gastric cancer is a heterogeneous disease associated with complex aberrations of oncogenic pathwaysARID1A mutations could provide significant therapeutic benefits in cancer because ARID1A is one of the most frequently mutated genes in various types of cancer16. Most ARID1A mutations are inactivating mutations, indicating that ARID1A itself is a poor therapeutic target4. Novel synthetic lethal approaches to the treatment of ARID1A-mutated tumors were recently proposed using EZH2 inhibitors, PARP inhibitors, or ATR inhibitors18. For example, EZH2 inhibitors are selective against ARID1A inactivation, and the response to EZH2 inhibitors often correlates with gain-of-function mutations in EZH29. In fact, a previous report demonstrated that EZH2 was overexpressed in many solid cancers, suggesting the positive therapeutic efficacy of EZH2 inhibitors for cancers, including gastric cancer19.In addition to immunotherapy, targeted therapies against ARID1A-mutated cancer. Gene enrichment analysis based on microarray results revealed that genes upregulated by ARID1A knockdown were significantly enriched in type 1 interferon signaling and virus-related pathways. INF-α and INF-β are induced by EBV infection, contributing to the cellular resistance against virus infection22. ARID1A is highly mutated in EBV-positive gastric cancer, indicating that INF-α and INF-β may be induced by EBV infection as well as by ARID1A inactivation itself in ARID1A-mutated gastric cancer.In the present study, comprehensive gene analysis was performed to identify potential candidate targets or pathways underlying ARID1A deficiency. Despite the identification of several genes induced or suppressed by ARID1A silencing, a direct actionable target was not determined. These results suggest that synthetic lethal targeted therapy is a valid approach to the treatment of 25. Fourth, our experimental analysis was performed using only the N87 gastric cancer cell line in which carcinogenesis is driven by overexpression of HER2. Therefore, the results may apply only to HER2-positive gastric cancers.The study has several limitations. First, our study included small number of patients to perform stratified analysis of stage and histological differentiation. Second, we evaluated MMR and EBV status only in the test cohort and found small number of dMMR cases. Third, we evaluated PD-L1 expression in tumor cells rather than in the tumor tissue as a whole and in immune cells. Also, we did not use a combined positive score scoring method that is reproducible, such as that used in the KEYNOTE-059 and KEYNOTE-061 trialsIn conclusion, the current study shows that ARID1A expression serves as a prognostic biomarker for gastric cancer. The present results warrant further study of the value of ARID1A in gastric cancer.The study included 420 surgical specimens collected from gastric cancer patients who underwent surgical resection at Fukushima Medical University Hospital between January 1991 and December 2014. The test cohort consisted of 200 patients recruited between 2002 and 2014, and the validation cohort consisted of 220 patients recruited between 1991 and 2001. Data regarding age, sex, TNM stage (the 7th classification), and pathological diagnosis, including lymphatic and venous invasion, were retrospectively collected. The carcinomas at the time of primary tumor resection were staged according to the Union for International Cancer Control classification.The study was approved by the ethics committee of Fukushima Medical University. All patients provided written informed consent. All experiments were carried out in accordance with the approved study plan and relevant guidelines.26. Positive expression of PD-L1 protein was defined as positive staining in gastric cancer cells.IHC staining was performed using paraffin-embedded histological sections (4 μm thick) using a polymer peroxidase method. Briefly, after deparaffinization and rehydration, the sections were treated with 0.3% hydrogen peroxide in methanol for 30 min to block endogenous peroxidase activity. After rinsing in PBS, the sections were incubated with anti-ARID1A antibody , anti-EZH2 antibody , anti-PD-L1 antibody , and anti-p53 antibody  at 4 °C overnight. An additional wash in PBS was followed by treatment with a peroxidase-labeled polymer conjugated to goat anti-rabbit immunoglobulins  as the secondary antibody for 30 min at room temperature. The staining was visualized with diaminobenzidine, followed by counterstaining with hematoxylin. Protein expression was considered positive when the nucleus of the cancerous tissue and the total field of view were observed at 400× magnification. Loss of ARID1A protein was defined as the absence of nuclear staining in tumor cells in the presence of positive nuclear staining in stroma cells. The case with weak or partial positive staining for ARID1A did not define as positive staining case. Specimen staining was evaluated by investigators blinded to the origin of samples and clinical outcomes. Stained cancer cells were counted per 1000 cancer cells in the maximum field of cancer tissue by two investigators. Staining rates were classified as follows: 0%, 0; 1–10%, 1; and 11–100%, 2. The staining intensity was scored as 0 (negative), 1 (weak), and 2 (strong). The results were expressed as a product of the positivity score and staining intensity score. Positive staining was defined by a score of 2, whereas negative staining was scored at 0 or 1. Evaluation of PD-L1 expression was performed as previously described27 using primary antibodies specific for MLH1 , MSH2 , MSH6 , and PMS2 . Loss of a MMR protein was defined as absence of nuclear staining in tumor cells in the presence of positive nuclear staining in normal epithelial cells and lymphocytes. Tumors showing loss of at least one MMR protein were collectively designated as dMMR, and tumors with intact MMR protein expression were designated as pMMR.IHC staining for MMR proteins was performed for all the cases in the test cohort, as previously describedin situ hybridization (ISH) for the case with increased lymphocyte infiltration (n = 37) in the test cohort, as previously described28. EBV-encoded small RNA (EBER)-ISH was performed using the INFORM EBER probe  and the Discovery XT autostainer (Ventana), according to the manufacturer’s protocol.Integration of EBV was assessed by 2 and observed regularly under a light microscope ; cells were subcultured when they reached 80–90% confluency. During the exponential growth phase, cells were transiently transfected with siRNA at a final concentration of 5 nM using Lipofectamine RNAiMAX (Thermo Fisher Scientific) according to the manufacturer’s protocol. After 48 h of incubation, cells were used for each experiment.Knockdown experiments were performed using small interfering RNA (siRNA) oligos for ARID1A  and included two target-specific siRNAs and a control siRNA  according to the manufacturer’s protocol. The gastric cancer cell line NCI-N87 (N87) used in the present study was originally obtained from the American Type Culture Collection . Cells were cultured in RPMI-1640 medium . The monolayer cells were maintained in a 37 °C incubator with 5% CO29. N87 cells were washed twice in ice-cold PBS, pelleted by centrifugation (1500 rpm for 5 min) and stored at −80 °C. The pellet was resuspended in radioimmunoprecipitation assay buffer (Thermo Fisher Scientific) with a Halt Protease Inhibitor Single-Use Cocktail , and centrifuged at 4 °C and 15,000 rpm for 20 min. Total protein concentration was measured using the Bradford method  and a Smart Spec 3000 spectrometer (Bio-Rad Laboratories). Tris-Glycine SDS sample buffer (Thermo Fisher Scientific) and 3-Mercapto-1,2-propandiol  were added to the total protein samples and heated at 100 °C for 3 min. The 4–20% Tris-Glycine gels (Thermo Fisher Scientific) were loaded with 20 µg of protein samples and electrophoresed at 125 V for 50 min using Tris-Glycine SDS Running buffer in an Invitrogen™ XCell SureLock™ electrophoresis system (Thermo Fisher Scientific). Then, proteins were transferred onto PVDF membranes using the X Cell II™ Blot Module (Thermo Fisher Scientific) at 50 V overnight. The PVDF membranes were then blocked with 5% non-fat skimmed milk. The protein blots were incubated with anti-ARID1A antibody  and anti-EZH2 antibody  for 1 h at room temperature and incubated with goat anti-rabbit HRP secondary antibody (Santa Cruz Biotechnology) for 1 h at room temperature. The protein levels were quantified using primary mouse anti-β-actin antibody  as the internal loading control for 1 h at room temperature. Bound antibodies were detected by SuperSignal West Pico Chemiluminescent Substrate (Thermo Fisher Scientific) and visualized by autoradiography .Western blot analysis was performed as previously describedhttp://www.cbioportal.org/). The expression data of PD-L1 and mutation data of ARID1A were extracted from CCLE and TCGA provisional data.Publicly accessible datasets of gene expression and mutations were downloaded from the cBioPortal for Cancer Genomics database  according to the manufacturer’s protocol. Microarray analysis was performed using the Agilent platform (SuperPrint G3 Human GE Ver 3.0 [Design ID: 72363]) to investigate gene alterations. Data were normalized and analyzed using GeneSpring software (Agilent). The fold change in expression was defined as the ratio of expression in ARID1A knockdown cells to that in control (scrambled siRNA) cells. The raw microarray data are deposited in the Gene Expression Omnibus at the National Center for Biotechnology Information (GSE118273).https://david.ncifcrf.gov/) as previously described30.Functional enrichment analysis of genes upregulated or downregulated in ARID1A knockdown cells relative to control cells was performed using DAVID .Kaplan-Meier analysis was performed using publicly available data and the Kaplan-Meier plotter database . Survival rate curves were generated using the Kaplan-Meier method and compared by the log-rank test. Logistic regression analysis was performed by JMP software . A P value of <0.05 was considered statistically significant.Supplementary Information


Few early intervention programs aimed at maternal and child health have been developed to be integrated in the existing Child Health Service in a country where the service is free, voluntary and used by the majority of the eligible population. This study presents the process and the critical steps in developing the “New Mothers” program.Formative research uses a mixed method, allowing us to obtain data from multiple sources. A scoping review provided information on early intervention programs and studies, clarifying key elements when framing a new program. Key informant and focus group interviews offered insight of existing challenges, perceptions, identified power structures and offered reflections germane to the identified framework, securing user involvement at all stages. Monthly meetings with the project group enabled feedback loops for the data, securing program advancement.The “New Mothers” program was formed based on a salutogenic theory, emphasizing resistance and strengths. Public health nurses in the existing Child Health Service were to offer universally all first-time mothers and children home visits from gestational week 28 until the child reached 2 years, with motivational interviewing and empathic communication as methods to mentor the mothers, help them identify their strengths and resources, and provide support and information.Using formative research as mixed method ensures incorporation of detailed information from multiple resources when an early intervention program is developed. This method secured program appropriateness, both culturally and at system level, when integrating new elements in the existing service. Historically, Norway was a homogenous society. However, over the last decade, significant migration has created a complex society with immigrants from over 200 countries , and conThe Stovner District, one of Oslo’s 15 districts, experienced particularly alarming statistics in 2016. Stovner, where 55% of the inhabitants were immigrants or had parents of non-western background , compareFour years ago, the administrators of the Stovner district invited their leaders in health-related positions and researchers to a series of meetings to provide ideas and advice on how to accommodate both incremental social service demands and the new national policy guidelines. The first meeting called for identifying innovative solutions for the reduction of downstream and long-term expensive secondary measures such as CWS. The desire was to anchor new initiatives in the Child Health Service (CHS). The CHS is established by law as a key organizational component of the PHC in Norway. Its primary goal is to secure an accessible, low threshold, and free health care service for pregnant women, children and adolescents under the age of 20, focused on health promotion and risk prevention. The service is run by specialized Public Health Nurses (PHNs), midwives, and family medicine doctors, and is used nationally by 98% of the eligible population . During A new program had to be acceptable to the users of the CHS, endorsed by the PHNs, and integrated within the current Norwegian CHS structure, context and system. New political guidelines required user involvement, so the process needed to assure participation of both users of the CHS and the PHNs. Users are often involved in evaluations, but uncommonly in the process of development of new services . The shoA feasibility study clarified the acceptance and interest of a home visiting program in the district. Rather than imposing a pre-determined approach, a formative research design was chosen where data obtained from multiple sources allowed analysis, identification and clarification of applicable and critical key elements and perspectives as they emerged. This design also allowed identification of relevant aspects associated with equality and equity within the CHS. The major role of formative research is to assure program appropriateness, both culturally and demographically . It has The process is a spiral continuing to grow, never ending up at its initial base, but constant developing. It is inspired by Gadamer’s theory of a hermeneutic circle, describing the process of understanding and interpreting observations and texts . This thScoping reviews of home based early intervention, and the use of participatory research in CHS intervention development, identified existing knowledge, strategies and impact. The reviews identified relevant programs, but with elements not suitable for the Stovner District due to cultural or organizational differences, differences in intended outcome, target groups or framing premises. The reviews focused on existing and evaluated programs, program theory, approach, outcomes and methods. Seeking to answer the who, why and how within the traditions of existing programs, we narrowed the search to interventions carried out during early childhood using home visits directed at advancing maternal and child health. We also searched for additional literature describing development of new services within existing service. In this paper we only present the data the project group identified as relevant for the development of the new program. In addition, a host of documents, including Norwegian white papers, regulatory, and policy documents were reviewed to understand and clarify obligations and regulations affecting the CHS service.Using “Early intervention (mesh term) AND nurs* AND maternal and child (mesh term) AND home visit* (mesh term)”, we carried out a search through the Pubmed, Cochrane, and EMBASE databases. Figure The scoping review identified 26 early intervention studies in total, from USA –29, AustThe project group consisted of senior administrative staff from the CHS, the Chief District medical Officer and Assisting District Director, a professor and an advisor from the University of Oslo, and the Program Coordinator. Three PHNs from the district CHS were actively involved through regular meetings and worked closely with the project group. In addition, 18 randomly chosen mothers who used the districts CHS participated in focus group interviews.The project group had monthly meetings, which clarified members’ knowledge, experience, viewpoints, and identified knowledge gaps using the process steps Fig. . AssumptAs an essential part of formative research, focus groups and key informant interviews assure user involvement at all stages of the process and assist in defining attributes and context of the target groups of interest in the particular setting , 45. ThiKey informant interviews were conducted with members of the project group, and focus group interviews with the three PHNs. The interviews lasted for an hour and clarified cultural and social norms, experiences and identified contingencies valuable for program development . Five foInterviews and focus groups were audio-recorded, transcribed, and analyzed. Together with minutes and protocols, were all available texts analyzed using Systematic text condensation, a descriptive and explorative analysis strategy , followiThe project group wanted the intervention to be universal to avoid stigmatization and to capture the needs of the mothers individually without an initial high-risk identification. In addition the intervention was to be implemented in the existing CHS. The objective was to offer all first-time mothers additional services by PHNs and establish a trusting and supporting relationship. It was presumed that if the mothers received additional help and support when they had their first child, good strategies, knowledge and habits potentially would persist when they had their next child. The suggestion was to use home visits as the delivery method. It was hypothesized that the balance of power in the relationship between the mother and the PHN would shift positively, when the PHN was a guest in the mothers’ home. In the Norwegian statutory program, the PHNs visit parents once within the first 2 weeks after birth, so they were familiar with conducting home visits. The first key component discussed was which program theory would capture the intention of the Norwegian CHS best, upholding a universal approach. The project group wanted to focus the attention during the home visits on strengths and opportunities within the family and its environment. And hence, a theory had to support such a strategy.The scoping review identified important key elements of early intervention programs, and highlighted the need of a theoretical foundation. The project group thought that the theory reflecting the desired focus for the new program model was salutogenesis, a theory by Antonovsky claiming that the way people viewed their life influenced their health . People “Sometimes we have to wrap it up and rather say: “let it go”. Then we have to think: okay, let’s focus at the things that the mother herself thinks she can do.” (PHN).Next was to determine if the theory was in accordance with how the PHNs regarded their work. Salutogenesis was not new to the PHNs; one described how their practice reflected a salutogenic theory:“The individual, that’s what’s important. That’s the real dilemma at the CHS. We sit there knowing what’s general, we have to adapt to the individual.” (PHN).The PHNs acknowledged the importance of supporting the mothers. They described how manageability was important to the parents they met, and they (the PHNs) tried to detect, support and focus on parental strengths.A negative power structure can be created if the CHS treat all users the same, without adapting to the individual. By using home visits as intervention method, the PHNs would meet the families at home, providing a different perspective on family strengths and resistance, through the individual setting reflected in their home.Mothers’ perspective“You are here to learn from your own mistakes...well this is what I know of myself. I know that I increase my trust in myself when I manage to… yeah, learn by myself” (Focus group mother).A mother in the focus group told how she liked to figure it out by her own describing a more heuristic method, strengthening her self-confidence:The mothers shared their experiences on how PHNs at times overwhelmed them with advice on how to improve their parenting skill. At times this felt intrusive, but their respect of the PHNs authority and power prohibited any response. Such an approach would contradict the universality and intended low threshold service at the Norwegian CHS, and the salutogentic theory stressing the importance of how people view their life affects their health.The PHNs regarded themselves as professionals who could provide guidance and support; the mothers wanted to be able to set the agenda but at the same time have the opportunity to get help when needed. This was in accordance with the salutogenic theory. In addition, the PHNs had experienced how seemingly well-functioning parents also at times needed additional support, in contrast to a program only aiming at high-risk families. A program based on high-risk identification would therefore be a pathogenic program. As “New Mothers” was to be universal, the salutogenic theory would better describe the intention, focus and vision of the intervention program.Some of the scoping review studies described their intervention approaches or intervention models as: “Plan to do act” , “StagesAs an early intervention program, it was important to define the best recruitment point, and period of program duration in order to achieve results.During the first years of the child’s life the most rapid and developmentally significant changes occur , 56. At “If you are not there at the beginning, when patterns are developing, you can only try to patch and repair. Most of them learn as they go on by themselves, then there are those who are more or less occasional witnesses to their own lives, how will they master this role? If you could have a knowledge based and a follow-up, I think we could create a foundation, which people could bring with them, also when they get the next child.” (PHN).The PHNs at the Norwegian CHS focus on families through a universal perspective and approach. But the required tasks are time consuming and the PHNs acknowledge a need to intervene early:“I didn’t think I would become … I have always considered myself a strong person who knows how to handle things. Then the breastfeeding came along, the feeling of being weak as a mother, or something. The first time she had the growth spurt. I knew this was something to expect. But that feeling then, that I wasn’t able to feed my child; I’m a terrible mother.” (Focus group mother).But it is not sufficient that this is acknowledged by the PHNs. The users of the CHS, the families, have to recognize a need for assistance.“I didn’t know there would be all these feelings, these weird, new experiences. You want to cry, you want to talk to someone.” (Focus group mother).The mothers also discussed how having their first child were accompanied with insecurity and a feeling of not knowing oneself anymore, and needing of someone to talk to, to make you feel better.Based on the scoping review, the project group decided to focus on the first 2 years of the child’s life. Identified programs reported reduced days of infant hospitalization , reducedTo provide support beyond the CHS’s scheduled clinic visits , the PHN“I was more open to the PHN, when talking with her at home, than going to the CHS feeling that ‘I have decided today what to do, and what to talk about.’ It is just what you want today in a way, and it is not natural communication, or a natural conversation I’d say. I don’t feel it is relaxed, as I only answer her questions. (…) But if I had a home visit, it is like the conversation is automatically more fluid.” (Focus group mother).The home visits provided the visitor with a better understanding of the families through the environments in which they lived, creating an understanding of the families’ need , 37, 39.“You arrive at the home and the visit takes place in a small room, where the mother lives with rolled down curtains in a double bed. I’ve been at home visits like this many times. And then … there’s no living room, this is her little world. Then you understand more … what … why.” (PHN).The PHNs described how conducting home visits changed their perception of the mothers as they gained insight in her world.“I’m thinking about power, the shift of power. Many of the PHNs aren’t aware of the power they have, sitting behind their desk with their door closed (..). I believe that at someone’s home, this balance shifts automatically. You get into another role. This also does something with the balance.” (PHN).One of the PHNs depicted home visits with “a picture tells more than a thousand words” analogy, allowing them to talk to the mothers on her terms, and this affected the power structure between them.The project group stated that user involvement of the participating families and staff at the CHS should be an ongoing process, allowing to cross-check the program progress with reality and assure program appropriateness, both at the cultural and organizational level. This leads up to the final key element: Monitoring and evaluating the development process. Both are important tools to help ensure that the activities are implemented as planned and to assess whether desired results are achieved . It was The result was “New Mothers,” an early intervention program aimed at all first-time mothers in Stovner District. If an intervention program recruited based on risk factors only, the probability of mothers feeling stigmatized could increase . “New MoUsing formative research and a participatory approach an early intervention program serving a multiethnic population was successfully developed for integration in the current Norwegian CHS. The formative research cycle resembles the hermeneutic circle. Each step of the formative research cycle provided new information and gave the project group insight into relevant and different perspectives. This is in line with how the hermeneutic circle provides a deeper understanding of different parts always in reference to the whole. Development of the key elements of the program benefitted from incorporating the formative research cycle as the study design.By using several data and information sources and user involvement at multiple levels prior to decision making, one might argue that the impact of the developers are limited. But to assume that this program was developed free of interpretation and not affected by personal values, experience or projections is not possible, and in line with the hermeneutic circle where values, experiences and projections are described as drivers to gain new knowledge .The scoping review identified studies from countries lacking an existing free and low threshold CHS and all focused on targeting high risk, first time mothers. When aiming for a new program integrated in an existing universal service in a country where 98% of the eligible population attended, this would contradict the principle of universal and equal access . The proEarly on, prior to the scoping review, the project group considered implementing a licensed early intervention program. If a program qualified for the Norwegian conditions already existed, there was no need to develop a new one. However, an existing program framework had to adapt to the universal thrust, be culturally translated and cost- effective. Some high-risk programs implemented in countries comparable to the Norwegian setting reported small intervention effects , and in The application of a salutogenic theory provided a refocus from current paradigmatic norms of measurements of pathology and surveillance, to identification of what generates and maintains health , 67. TheRelationship and trust are core elements in early intervention programs , 34, andIn Norway the PHC physicians and midwives are currently the only professionals from the CHS who have contact with the pregnant women until birth. Their responsibilities were not altered because of the New Mothers program, but the PHNs had concerns about how the mothers would interpret meeting the PHN during pregnancy. If they were to meet the mothers prenatally, it was important for PHNs to be clear about the intention of the home visits, and not overstep their professional responsibility related to routine medical and prenatal care.Another important premise was to use the home as the delivery setting. A wide range of health and social problems can be addressed by nurses visiting mothers pre- and postnatally at home , 40, 70,“The CHS is to consider home visits as a supplementary offer directed at families with additional needs. The home visit can improve contact and trust, additional to observation of skills and interaction between child, siblings and parents in their environment.” p.90.A new and revised guideline for the Norwegian CHS, from 2017, supports an increase in home visits as setting for contact, trust and observation :“The CHTo meet the escalating demand for service and the rapid demographical changes it is necessary to meet the users of the CHS at their terms, define their needs, strengths and help them individually. This means tailoring the service, and for the PHNs to work close and in collaboration with the mothers. The statutory visits at the CHS will continue, but for first time mothers the connection to their PHN will start prenatal and they will receive a closer follow up.Throughout this development period the project group has learned the necessity of user participation and systematic collection of information. The group has also built and tailored a new program to the Norwegian context.The focus groups with the mothers and the PHNs provided insight and strengthened the user involvement of the program development. A limit is that the members might not have expressed their honest thoughts, especially if their thoughts opposed the views of another member. However, focus group can generate more in depth information and rich narratives. We did not experience any language challenges, although not all mothers spoke fluent Norwegian; language differences might have limited the level of participation and engagement. The moderator tried to avoid impacting the outcome of the interviews, by focusing on that the intention of user involvement was to give a voice to the users in order to develop a program that better fitted the needs of the families and mothers in the district.To the best of our knowledge we did not identify any other published studies describing the development of an early intervention program aimed at maternal and child health employing user participation. This process seems to go unaddressed within the literature. Decision making, program theory and why programs use certain key elements and strategies, are rarely described, and we hereby provide our contribution to this knowledge gap.Formative research as study design provided information and gave directions on how to frame a CHS program. It allowed us to explore data collected from different sources, identified facilitators and barriers of key program elements, utilized user participation, and identified power structures. Interviews and focus groups provided insight on challenges, reflections and contributed with germane information for the proposed framework and secured user involvement. The scoping review provided directions on key program elements, experiences and research results. Monthly meetings with the project group enabled feedback loops’ on data and information collected that secured immersion and continued the framework development.It is, however, essential to stress the importance that this program is still developing. The next step of the process is piloting the program in Stovner. User participation will keep evolving in this phase and changes will be made to ensure culturally adaptation and user involvement, and all will be documented. There is a need to both evaluate the program qualitatively and quantitatively. The “New Mothers” program will be evaluated qualitatively, focusing at parents’ self-efficacy and program satisfaction, but also whether the program or not added a new, and hopefully positive, dimension to the CHS and the PHNs professional role.


Background: Metabolic syndrome and co-morbid physical health conditions are highly prevalent in people with a mental illness. Modifiable lifestyle factors have been targeted to improve health outcomes. Healthy Body Healthy Mind (HBHM) program was developed to provide an integrated evidence-based program incorporating practical diet and exercise instruction; alongside meditation and mindfulness strategies, and comprehensive psychoeducation, to improve the physical and mental health of those with a mental illness.Methods: We report on two data points: (1) Qualitative data derived from the first HBHM program (version 1) exploring its utility and acceptance according to patient feedback; (2) Biometric and mental health data collected on the modified and enhanced 12-week HBHM program (version 2) involving a pilot of 10 participants. Mental and physical health outcomes, weight, abdominal circumference, fasting glucose, cholesterol, and triglycerides were measured at program entry and completion.Results: Qualitative data from HBHM version 1 provided valuable feedback to redevelop and enhance the program. At the end of the HBHM (version 2) 12-week program, a significant mean weight loss of 2 kg was achieved, p = 0.023. There was also a significant reduction in abdominal circumference (mean = 2.55 cm) and a decrease in BMI of almost one point (mean = 0.96 kg/m2), p = 0.046 and p = 0.019, respectively. There were no significant changes in mental health measures or on any other biometrics.Conclusion: Pilot data from the HBHM program found significant reductions in weight and abdominal obesity. The HBHM program could benefit from further modifications, and study replication is required using a controlled design in a larger sample. A highly complex relationship exists between physical and mental health. The rates of physical morbidity and mortality in people with mental illness is substantially higher than the general population , 2. EvenThe cluster of symptoms associated with these lifestyle diseases such as, excess visceral fat, along with hypertension, glucose intolerance/insulin resistance, and/or hyperlipidaemia has been labeled Metabolic Syndrome (MetS). In mental health populations, the rate of MetS is thought to be between 41 and 67% . A largeThere is potential to modify lifestyle factors that contribute to MetS  to improve the health and well-being of people with a mental illness. There are calls for an integrated response involving early diagnosis, treatment and management of physical and mental health via lifestyle modification . SeveralTo bridge the gap and provide an evidence-based integrated health approach, we developed the “Healthy Body, Healthy Mind Program (HBHM).” The aim was to assist people with a diagnosed mental illness and metabolic syndrome to improve mental and physical well-being. We presently report on: (1) Qualitative data derived from our first version of the HBHM program in 2011, exploring its utility and acceptance according to patient and clinician feedback; (2) Biometric data and mental health data collected on the modified and enhanced 12-week, second version of HBHM program involving a pilot of 10 participants.The Melbourne Clinic in Melbourne, Australia is a private psychiatric hospital with inpatient and outpatient services. The clinic had a longstanding weight management and lifestyle program, called Healthy Body Healthy Mind (HBHM), developed and facilitated by a general practitioner (GP), exercise physiologist and dietitian. HBHM program (version 1) provided weekly nutritional support from a dietitian, psychoeducation sessions on lifestyle modification and exercise practicals with an exercise physiologist. In late 2011, ethics approval was granted by The Melbourne Clinic Research Ethics Committee (HREC project number: 209) to collect qualitative data from participants to evaluate the perceived efficacy of the program's content, barriers in implementing the components, and feedback on how it could be improved. The qualitative data collected during 2011–2012 was used to redevelop and enhance the integrated lifestyle program which was pilot-tested at The Melbourne Clinic in 2016 (HREC project number: 249). This modified second program will henceforth be labeled as HBHM program (version 2).Patients attending The Melbourne Clinic outpatient services were invited to attend the program via a doctor's referral. Patients with a diagnosed mental illness  taking stable psychotropic medication (same dose for at least 4 weeks) with co-morbid diagnosed metabolic syndrome see  or obesiAt week 0, a range of medical and demographic information was collected including, age, gender, employment status, medication information, psychiatric diagnosis and medical co-morbidity. At week 0 and week 12, participants also had anthropometric measurements taken by an exercise physiologist  and completed self-report questionnaires on their mental health . In addition at week 0, participants were asked to state their goals for the program and what they hoped to achieve. They were also asked to rate their readiness to change in order to achieve their listed goals on a scale of 1–10 with 1 being “not ready” and 10 being “ready.” Participants were provided with a blood test request form to have fasting cholesterol, glucose and triglycerides measured at week 0 and week 12. The blood tests were conducted by Australian Clinical Labs.not at all to 3 = very much or most of the time). Higher scores on each scale are indicative of greater symptom severity. Scores above 11 (depression), 8 (anxiety), and 13 (stress) are considered severe, as indicated by the recommended cut-offs . All data was analyzed in SPSS 24. An alpha level of < 0.05 was used to determine significance.Qualitative data assessing the 2011 HBHM Program (version 1) was analyzed from written participant feedback forms. Comments were coded and grouped in categories by theme  and counted to obtain a frequency of mention by the 12 participants. For the quantitative data from the 2016 HBHM program (version 2), paired Written qualitative data from 12 participants  who participated in the first version of the HBHM program during 2011–2012 was thematically analyzed to aid the development of the 2016 HBHM program. n = 11; 91%). One participant commented that he/she needed “practical examples that can be implemented in day-to-day life” and less theory in order to engage with the program. However, many participants  commented that furthering their knowledge on how food effects the body and the harms of nutritionally poor food and no exercise on the body's functioning was useful as, “understanding aids motivation to change, oversimplification does not.” Poor motivation , fear of change  and difficulties engaging with the program due to low mood and anxiety  were common among participants. Additionally, many participants found cooking for one person and/or maintaining momentum on their own difficult . As one person stated, “[the] desire to try a new recipe is high at time of session but then lost when at home.” Participants requested more diagram-based notes of exercises/recipes and program content to be accessible at home due to poor recall . Injury and co-morbid physical health problems were some of the main barriers in adding exercise to their day-to-day lives . At home chair-based exercises and information on how and why to vary exercise was deemed helpful .The most beneficial/useful components of the program reported by the majority of participants were the cooking and exercise practicals  with a mean age of 51.8 years (SD = 12.9 years) . The most common primary DSM-IV psychiatric diagnosis as reported in the treating psychiatrist referral to the program was Major Depressive Disorder (MDD)  followed by Bipolar Affective Disorder , Generalized Anxiety Disorder (GAD)  and Alcohol Abuse . Psychiatric co-morbidity was common with diagnoses of Generalized Anxiety Disorder (GAD) , Binge Eating Disorder , Borderline Personality Disorder  and Major Depressive Disorder .Most of the sample was female (ars) see . Over han = 2; 25–50 mg/day), desvenlafaxine , fluvoxamine , paroxetine , venlafaxine ; escitalopram ; lamotrigine . On average participants were taking 2.4 (SD = 1.17) psychotropic medications ranging from 1 to 4 psychotropic medications. The most common psychotropic medication taken alongside a primary psychotropic medication were second generation antipsychotics  followed by mood stabilizers   see .n = 4; 40%), hypertension , arthritis , Type II Diabetes , sleep apnoea , and chronic pain/fibromyalgia . Other conditions such as, fatty liver disease , pancreatitis , ulcerative colitis , costochondritis , fructose malabsorption syndrome , endometriosis , restless leg syndrome  and hypothyroidism  wereself-reported.The most common chronic medical conditions self-reported by participants or as listed in the referral to the program were hyperlipidaemia  followed by eat healthier , reduce sugar intake  and lose weight . On average the participants rated their readiness to change as 7.75 (SD = 2.12) with ratings ranging from 3 to 10. Thus, as a whole the participants were very ready to make change.The most common goal was to increase exercise levels and fitness (t(9) = 2.75, p = 0.023. Weight change ranged from a +1.4 kg weight gain to a −6 kg weight loss. Along with weight loss, there was also a significant reduction in abdominal circumference (mean = 2.55 cm) and a drop in BMI of almost one point (mean = 0.96 kg/m2), t(9) = 2.32, p = 0.046 and t(9) = 0.96, p = 0.019. No significant changes in participant's blood levels or anthropometrics were found. Additionally, no significant changes in participant's mental health was found on the DASS when comparing week 0 to week 12 , and hence had less scope for improvement. Furthermore, when identifying goals of the program, not one participant mentioned they would like to improve their mental health. Rather the goals reported by participants were orientated toward improving their eating habits and losing weight. The incorporation of behavioral and psychological components  is deemed to benefit the delivery and engagement of the program contents and helped to adhere to recommendations in order to achieve the weight loss results.A major limitation to the current study was the small sample size and that it was uncontrolled. A larger sample with an appropriate control is required to assess the program effectiveness and allow for further feedback from participants to fine-tune the program. We also recognize that more work is needed to refine the delivery and format structure in respect to determining the best application of the program given costs and time constraints. In particular, the exercise component should aim to provide at least 90 min of moderate-to-vigorous exercise per week, as this intensity has been shown to improve psychiatric symptoms in patients with a serious mental illness . FurtherWhile the 12-week program was comprehensive, it also has its drawback in terms of time requirements, and a 6-h once per week delivery is quite intensive for people with a mental illness. A follow-up should also be employed to determine whether weight loss results are maintained, continued, or regained following the cessation of the program.There is the potential to restructure the program to have a blend of face-to-face delivery with online components, and even the use of a mobile phone app. This would provide flexibility, less demands on time, and less financial burden for the participants. Weight loss in this population is extremely challenging as many patients have co-morbid medical conditions, and limited social and economic resources. Thus, facilitating weight loss using strategies that can be implemented into everyday life is paramount to success. In addition, implementing and assessing strategies which prevent the all too frequent “weight regain” phenomena is crucial .As 60% of the sample were taking second generation antipsychotics, the results are encouraging for metabolically vulnerable patients. However, it is important to note, that the results cannot be generalized to participants with a serious mental illness as the current pilot did not include participants with schizophrenia who are at the most risk of developing MetS. It is unclear how this particular patient population would engage with this intervention. In conclusion, the pilot data of the HBHM program found significant benefits in reducing weight and abdominal obesity, with the potential to achieve substantial health benefits for patients with a mental illness and co-morbid metabolic syndrome. Study replication is required using a controlled design in a larger sample over a longer time period.This study was carried out in accordance with the recommendations of The National Statement on Ethical Conduct in Human Research 2007 and The Melbourne Clinic Ethics Committee. All subjects gave written informed consent in accordance with the Declaration of Helsinki. The projects were approved by the Melbourne Clinic Ethics Committee (Project 209 and 249).All authors contributed to the drafting and editing of the manuscript. JAM and JS is responsible for the data analysis and manuscript preparation. JM, GO, CW, RO, and AB were involved in designing the program, running the program and collecting data. CN and JS contributed to the design of the program and provided oversight of the program.JS has no direct conflict of interest, however has received either presentation honoraria, travel support, clinical trial grants, book royalties, or independent consultancy payments from: Integria Healthcare & MediHerb, Pfizer, Scius Health, Key Pharmaceuticals, Taki Mai, FIT-BioCeuticals, Blackmores, Soho-Flordis, Healthworld, HealthEd, HealthMasters, SPRIM, Kantar Consulting, Research Reviews, Elsevier, Chaminade University, International Society for Affective Disorders, Complementary Medicines Australia, Grunbiotics SPRIM, Terry White Chemists, ANS, Society for Medicinal Plant and Natural Product Research, Sanofi-Aventis, Omega-3 Centre, the National Health and Medical Research Council, CR Roper Fellowship. The funders played no role in the study design, the collection, analysis or interpretation of data, the writing of this paper or the decision to submit it for publication. 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.


Chronic medical conditions (CMCs) affect up to 35% of children and adolescents. Youth with chronic medical conditions are at an increased risk of psychological distress and reduced health-related quality of life, and report rates of mental illness up to double that of their physically healthy peers. Accessible, evidence-based interventions for young people with chronic illness are urgently required to improve their mental health and daily functioning. Self-compassion involves taking a mindful, accepting approach to difficult experiences, being aware that one is not alone in one’s suffering, and being kind and understanding with oneself during challenging times. Self-compassion shares strong associations with mental health outcomes among young people and preliminary work indicates that interventions that build self-compassion have the potential to substantially improve youth mental health. Self-compassion is also associated with better physical and mental health outcomes among individuals living with CMCs. While face-to-face self-compassion training is available, there are several barriers to access for youth with CMCs. Online self-compassion training potentially offers an accessible alternative for this high-risk group.Self-Compassion Online (SCO) is a self-compassion program that has been tested with a non-clinical adult group. For the proposed trial, a reference group of youth (16–25 years) with chronic illness reviewed the program and proposed adaptations to improve its suitability for youth with chronic illness. In alignment with the SPIRIT Checklist, this paper outlines the protocol for a CONSORT-compliant, single-blind randomised controlled trial to test the efficacy of the adapted program, relative to a waitlist control, for improving self-compassion, wellbeing, distress, emotion regulation, coping and quality of life among young Australians with CMCs. Mechanisms of action and feasibility of SCO will be analysed using quantitative data and participant interviews, respectively. Finally, cost-utility will be analysed using health-related quality of life data.The SCO program could provide a scalable solution for improving psychological outcomes and quality of life among youth with chronic illness. The proposed trial will be the first to determine its efficacy for improving these outcomes, relative to waitlist control.ACTRN12619000572167.The trial was registered on the Australian New Zealand Clinical Trials Registry on the 11th April 2019, Protocol version: Version 2, 21 December 2019. Chronic medical conditions (CMCs) are those that last longer than 6 months and are likely to require medical follow up for more than a year . IncludeYouth with CMCs are also at substantially increased risk of mental illness , with poSystematic reviews of psychological interventions for adolescents and young adults living with CMCs repeatedly highlight the need for accessible and age-appropriate interventions to address distress and promote wellbeing , 52. LowThe self-compassion intervention is based on the self-regulation model of chronic illness proposed by Lansing and Berg , which hSelf-compassion is a parsimonious construct for supporting self-regulation across cognitive, emotional and behavioural domains, particularly in the context of chronic illness , 56 and Self-compassion is associated with less psychopathology and greater quality of life across multiple chronic illness groups, including among patients with cancer , HIV 1010, epilePrevious studies of self-compassion training for adults with CMCs have demonstrated positive effects on mental and physical health outcomes. For example, a randomised controlled trial comparing self-compassion training with waitlist control for adults with diabetes found significant improvements in mental health and metabolic outcomes among the intervention group . In addiSelf-Compassion Online (SCO) is a self-guided web-based program grounded in an emotion regulation model of self-compassion . The proThe primary aim of this trial is to determine whether SCO-CMC can produce significant improvements in self-compassion, emotion regulation and coping, relative to a waitlist control, among youth with CMCs (16–25 years). In addition, we will investigate whether the intervention is associated with improvements in psychological distress, wellbeing, and quality of life and whether improvements in self-compassion, emotion regulation and coping mediate the effect of the intervention on wellbeing, distress and quality of life. A secondary aim of the study is to determine the cost-utility of the program by calculating the incremental cost-utility ratio for the intervention compared to usual care. Finally, we also aim to examine feasibility of the program, by examining enrolment and retention rates, and determine satisfaction and acceptability of the program by interviewing young people who took part.Report significant increases in self-compassion and approach coping, and significant decreases in emotion regulation difficulties and avoidant copingReport significant reductions in symptoms of psychological distressReport significant improvements in quality of life and wellbeingIt is hypothesized that relative to waitlist control, the SCO-CMC group will:It is also expected that improvements in self-compassion, emotion regulation, and coping will mediate the relationship between treatment group and reduced psychological distress, as well as improved wellbeing and QoL.The study protocol was approved by the Human Research Ethics Committee at Curtin University HRE2019–0386.The proposed study is an exploratory single-blind CONSORT-compliant randomised controlled trial, comparing online self-compassion training (SCO-CMC) with a waitlist control group (WLC). The intervention and data collection will be online, with data collected from Australian residents only.N = 96 Australian adolescents and young adults (48 per group), aged between 16 and 25 years, who self-report a current diagnosis of a CMC . Additional inclusion criteria are as follows (1) Australian resident; (2) fluent English speaker; (3) regular access to the Internet; (4) able to access online video and audio content.Participants will be Using medium effect sizes, 40 participants per group are required for power = .80 and α = .05 . To alloPsychological distress over the past 30 days will be measured using the Kessler 10-item psychological distress scale . The KSelf-compassion will be measured using the Short Form of the Self-Compassion Scale . This Emotion regulation difficulties will be measured using the Difficulties in Emotion Regulation Short Form (DERS-SF), a widely-used 18-item measure of emotion regulation problems . This seCoping will be measured using the brief COPE , a 28-itWellbeing will be measured using the World Health Organization Wellbeing Index (WHO-5), a widely-used, validated measure of subjective wellbeing designed for use in clinical trials . The WHOThe Assessment of Quality of Life – 6 Dimension (AQoL-6D) is a generic, multi-attribute utility, preference-based measure that will be used to assess health-related quality of life . It is aA health resource use questionnaire was developed for the purposes of the study, based on the core items for a standardized resource use measure highlighted by Thorn et al. . This meProgram engagement will be measured using online program metrics, including log-ins, time spent in program, and module completion, as well as self-report of engagement with practice outside of program. These variables will be treated as a measure of program feasibility and will also be explored as potential moderators of treatment effects. Program referrals and attrition data will also be gathered as a measure of program feasibility.A diagram of the study design is shown in Fig. Following completion of the pre-test, participants will be randomised to conditions using the Qualtrics randomiser function. Participants in both arms of the trial will be contacted by a research assistant shortly after completing the baseline survey, who will inform them of their condition allocation, reiterate study procedures and answer any questions: as participants are recruited on a rolling basis, those assigned to SCO-CMC will receive access to the program as soon as the research assistant has made contact with them. At four and 12 weeks after completing baseline measures, all participants will be sent an email asking them to complete the outcome measure battery again. Following completion of the third set of measures, participants in the WLC will be contacted by the research assistant, who will provide a code for program access. All participants will receive up to two reminders to complete the measure battery at each time point; participants enrolled in the intervention will also receive an email or text reminder 2 weeks post enrolment to encourage them to continue progressing through the program.At baseline, participants will be randomly selected to be invited to participate in a telephone interview to discuss their experience of participating in the SCO program: participants will be invited to participate in the interview following the third assessment point. Forty participants will be randomly selected at baseline and invitations will be issued until ten interviews are complete. Baseline selection is designed to ensure that interviewed participants include those who may have disengaged from the program. Interviews will be conducted by the research assistant and will explore the impact of the SCO-CMC program on the lived experience of young people with CMCs, identify potential mechanisms of change not assessed in quantitative measures, and gather data on potential iatrogenic effects. Interviews will also be used to gather detailed information on program satisfaction and feedback regarding potential revisions. Finally, qualitative data will also be collected by the online program . We will conduct thematic analysis of this data to identify key themes regarding program benefits, challenges, and application of program strategies to participants’ lived experience.No data monitoring committee will be engaged given that the intervention is low risk and participants are able to access care as usual while participating. Interim analyses will not be conducted. Study investigators will permit trial-related audits in line with Curtin University Human Research Ethics Committee requirements and approvals. Protocol amendments will be submitted to the Curtin University Human Research Ethics Committee, and, if approved, communicated to participants via email.A research assistant will be engaged to ensure blinding of the data analyst to group allocation, and data will be managed in line with Curtin University data management guidelines. Participant email addresses will not be stored with any of the trial data. Participants will be encouraged to liaise with the research assistant if they wish to withdraw from the trial or if they wish to be directed to additional psychological support at any point. Information about free online and telephone-assisted psychological support is also provided to participants on the participant information sheet, and within the SCO-CMC program.We will perform Intention to Treat and Per Protocol analyses, conduct a sensitivity analysis , and comMechanisms of action will be tested using multiple mediational analysis with bias-corrected bootstrap samples in MPlus, to test total and specific indirect effects. This is the most powerful test of mediation, requiring a sample of 71 participants to detect a medium effect .CUA calculates the ratio between the costs of intervention and gains – in terms of quality-adjusted life years – against the costs and gains associated with a comparator. An incremental cost-utility ratio is calculated by dividing the incremental costs by the incremental effects using the following formula:intervention − mean Costs comparator)/(mean QALYs intervention − mean QALYs comparator)., National Hospital Cost Data Collection data  and Pharmaceutical Benefits Schedule data . For the SCO-CMC group, total costs will also include the cost of the intervention. The number of QALYs per patient will be calculated by multiplying the AQoL-6D utility score by the appropriate time period. A base-case intention-to-treat analysis will be performed using all participants. To evaluate the impact of uncertainty on the cost and QALY estimates for each group, we will use bootstrapping with 5000 replications. These findings will be plotted on a cost-utility plane, which comprises four quadrants. We will also plot a cost-utility acceptability curve. This shows the probability that the intervention is SCO-CMC is cost-effective when compared with treatment as usual at different willingness-to-pay thresholds.This paper describes the protocol for a randomised controlled trial designed to assess the efficacy of an online self-compassion training program for promoting self-compassion and improving emotion regulation, coping, psychological distress, wellbeing and quality of life in young people (16–25 years) living with a CMC. The intervention approach is based on a self-regulation model of CMCs, which highlights the importance of cognitive, emotional and behavioural self-regulation for supporting self-management and optimising physical and mental wellbeing . The fouOnline self-compassion training holds promise as a highly-accessible, brief intervention to enhance mental health among this group. Self-compassion is a robust transdiagnostic predictor of a range of adaptive outcomes , 42, andhow people engage in such interventions [While there is preliminary evidence to support the efficacy of self-compassion-based interventions online , 41, thiThis study also has potential to extend our current theoretical understanding of the mechanisms of action underlying self-compassion-based interventions. Analysis of mediating mechanisms in self-compassion intervention studies is extremely limited , althougFinally, establishing efficacy of the SCO-CMC program for young people with chronic illness could provide a scalable solution for improving mental health and quality of life among this sizeable population. The proposed study will integrate cost-utility analysis to determine the incremental cost-utility of the program compared to treatment-as-usual. This will provide a preliminary understanding of whether the program provides value-for-money compared with usual care, as well as piloting methods for assessment of resource use in a heterogenous adolescent and young adult chronic conditions population.


Across Europe, Canada, Australia, and the United States, the prevalence of home mechanical ventilation (HMV) prevalence is 6.6-12.9 per 100,000. At-home ventilator-assisted individuals (VAIs) are often vulnerable and highly comorbid, requiring complex care. In Canada, most VAI care is provided by family, leading to poor health-related quality of life and increased caregiver burden. No supportive interventions or peer support programs are tailored to VAI caregivers. Owing to the financial, geographic, and time limitations, Web-based support delivery may especially meet VAI family caregiver needs. We have developed a peer mentor training and Web-based peer support program for VAI caregivers including information-sharing, peer-to-peer communication, and peer mentorship.Study Stage 1 aims to (1) evaluate the face and content validity of the peer mentor training program and (2) investigate participant satisfaction. Study Stage 2 aims to evaluate (1) the feasibility of participant recruitment and Web-based program delivery; (2) acceptability, usability, and satisfactoriness; (3) experiences of caregivers and peer mentors with the Web-based peer support program; and (4) effect of the Web-based peer support program on caregiver health outcomes.Study Stage 1: We will train 7 caregivers to act as peer mentors for the Web-based peer support program trial; they will complete questionnaires rating the utility of individual training sessions and the training program overall. Study Stage 2: We will recruit 30 caregiver peers for a pilot randomized controlled trial of the 12-week Web-based peer support program using a waitlist control; the program includes private chat, a public discussion forum, and weekly moderated chats. Caregiver peers will be randomized to the intervention or waitlist control group using a 1:1 ratio using Randomize.net. Both groups will complete pre- and postintervention health outcome questionnaires . Caregiver peers in the intervention arm will only complete a program evaluation and will be invited to participate in an interview to provide insight into their experience. Peer mentors will be invited to participate in a Web-based focus group to provide insight into their experience as mentors. We will judge the feasibility per the number of recruitment and program delivery goals met, use analysis of covariance to compare health outcomes between intervention and control groups, and analyze qualitative data thematically.Peer mentor training was completed with 5 caregivers in July 2018. To date, 2 caregivers have beta-tested the website, and the Web-based peer support program trial will commence in September 2018. Results are expected by early 2019.This study will result in the production and initial evaluation of a rigorously developed, evidence- and stakeholder-informed Web-based peer training and peer support program for caregivers of VAIs residing at home.PRR1-10.2196/11827 Prevalence rates for ventilator-assisted individuals (VAIs) living at home are increasing globally. The 2005 Eurovent Study estimated the prevalence of home mechanical ventilation (HMV) at 6.6 per 100,000 population across 16 European countries ,4. GivenPeer support comprises (1) emotional support ; (2) informational support ; and (3) affirmational support  . Peers—iWithin the broader family caregiver population, geographic limitations, time constraints and a lack of respite have been cited as reasons that caregivers do not utilize in-person support groups . In addiRising numbers of VAIs living at home , the burThis study aims to develop a comprehensive Web-based peer support program for VAI caregivers, including peer-mentoring, and explore the feasibility of the program.The primary objective is to evaluate the utility of the peer mentor training program.The secondary objective is to investigate participant satisfaction with the peer mentor training program.training program developed by St. Jude’s Research Hospital  for parents caring for a child with cancer ; (3) relationship to care-recipient ; and (4) sex .Prior to training, we will ask peer mentors to complete a demographic questionnaire and rate their general health status . Before and after the training program participation, we will ask peer mentors to complete the Mentoring Skills Inventory ; this quWe will report descriptive statistics from individual training session questionnaires and the end-of-training questionnaires, including counts and proportions for categorical data and means and SDs (or medians and interquartile ranges), depending on the distribution of continuous data.a-priori definitions described below and including user ratings of acceptability, usability, and satisfaction.The primary objective is to evaluate the feasibility of trial recruitment and program delivery according to The secondary objectives are to explore (1) caregiver health outcomes  before and after participation in the Web-based peer support program and (2) the experiences with the program from the perspective of caregiver peers and peer mentors.We will conduct a pilot randomized controlled trial (RCT) of the 12-week Web-based peer support program with waitlist control. Research Ethics Board approval was received from the University of Toronto in May 2017, where the research is being conducted.While the online peer support intervention is Web based, the study is being hosted at the University of Toronto. Recruitment is limited to Canadian caregivers of VAIs.currently providing care to a VAI living at home.The inclusion and exclusion criteria for the peer mentor training also apply to participants for the Web-based peer support program feasibility RCT except needing to be The end goal for this development project was to create a “social-network” style website (akin to Facebook). This website would also need to digitally capture and record all interactions between participants. To provide all the functionality needed for this study (including interaction data capture), we found that nonproprietary “off-the-shelf” software programs or templates were insufficient. Therefore, we used a hybrid of “existing-base-software” coupled with code or programming designed and integrated into this base software, making the functionality of this website unique.The content and design of the Web-based peer support program were informed by a scoping review led by the first author , a localOur primary outcome is the feasibility of trial recruitment and program delivery. The feasibility will be assessed on the basis of compliance with the protocol represented by the following criteria:The proportion of peer mentors participating weekly in any program element  for, at least, 8 out of the 12 program weeks: ≥60% of peer mentorsThe proportion of caregiver peers participating weekly in any program element  for, at least, 8 out of the 12 program weeks: ≥60% of peer mentorsDiscussion forum usage: ≥50% participants (peer mentors and caregiver peers) posting each weekLive weekly chat usage: ≥50% participants (peer mentors and caregiver peers) joining each weekThe frequency of weekly mentor contacts: ≥25% of mentors receive, at least, 1 message each weekThe proportion of peer mentors contacted: ≥50% of mentors contacted, at least, once during the 12-week programThe proportion of caregiver peer participants who contacted a mentor: ≥50% of caregiver peer participants during the 12-week programAttrition rates: ≤30% caregiver peer participants withdrawing from the study before completion of postintervention questionnairesWe have selected the following decisions to determine the feasibility ,29:0-2/8 criteria met—Stop; study design not feasible.3-5/8 criteria met—Continue with modifications; feasible study design with modifications.6-7/8 criteria met—Continue without modifications but monitor closely; feasible study design with close monitoring.8/8 criteria met—Continue without modifications; feasible study design as is.We will instruct participants to participate in the discussion forum, at least, twice a week and in each weekly chat. In addition, we will instruct participants to access peer mentors selected per their own preference, at least, once every week. Participants can choose to access only one or several peer mentors, again at their own preference. Caregiver peer participants will be instructed to respond to messages directed at them from either mentors or other peers through the Web-based peer support site within 48 hours.We will instruct peer mentors to participate in the discussion forums, at least, 2 times a week and in each weekly chat. In addition, we will instruct peer mentors to contact the research team if they are concerned about the well-being of participants. The research team will then contact those participants to assess the situation and recommend visiting their family doctor to access supports if required. We will instruct peer mentors to respond to messages directed at them through the Web-based peer support site within 48 hours.There has been no prior assessment of a peer support intervention for VAI caregivers on which to base our sample size calculations. Using feasibility criteria of 15% dropout and 70% participation in weekly chats, a sample size of 30 would allow us to be 90% confident that estimates are accurate within 22% and 28% percentage points, respectively [Recruitment procedures for the Web-based peer support program feasibility RCT are the same as those for the peer mentor training. We will aim to recruit 30 participants. We will recruit caregivers until we achieve the following minimum numbers: (1) ventilator subgroup ; (2) diagnostic category ; (3) relationship to care-recipient ; and (4) gender .We will randomize consenting participants to the peer support intervention or waitlist control using a 1:1 ratio using Randomize.net. No stratification will be applied, and allocation will be concealed using opaque sealed envelopes. Those randomized to the waitlist control will be given access to the peer support program following the 12-week intervention phase. A waitlist control group was chosen as it is believed to be a cost-effective and ethical alternative to no-treatment control groups when primarily studying psychological and behavioral interventions such as the one in this study . Those rA blinded assessor will collect the demographic and health information from participants in both the intervention group and control group and administer the exploratory caregiver- reported measures (listed in We will ask participants (intervention arm only) to complete a program evaluation . The program evaluation will assess the acceptability through a series of questions . The evaluation will assess satisfaction by asking participants the extent to which they agree with a series of questions about the program content, delivery, and outcomes  . FinallyWe will report descriptive statistics for demographic or health data, feasibility, and exploratory caregiver outcomes. To compare caregiver-reported outcomes between intervention and control groups, we will use the analysis of covariance with pretest scores as the covariate and group allocation, time, and the interaction between time and group allocation as independent variables. For nonnormally distributed scores, we will use a nonparametric alternative. All quantitative data will be analyzed in Statistical Analysis Software V9.4 (SAS Institute) using an intent-to-treat approach.We will use the thematic content analysis to analyze interview and focus group transcripts following the framework outlined by Braun and Clark, which entails a line-by-line coding of transcripts, constant comparison, and generation of recurring themes . We willWe recruited 5 caregivers to be trained as mentors. The mentor training was completed in July 2018. We have recruited 4 caregivers to participate in the Web-based peer support program. We anticipate initiating the support program September 2018. Results are expected by early 2019.Two caregivers have beta-tested the peer support website and issues identified have been addressed. Below are screenshots of the initial log-in page , home paThis study will result in the production and initial evaluation of a rigorously developed, evidence- and stakeholder-informed peer training and peer support program for caregivers of VAIs residing at home. Burdened and stressed caregivers may experience significant negative physical and emotional consequences to their own health, which may then impact their ability to care for VAIs who themselves are exceptionally vulnerable. Despite a growing body of evidence supporting the effectiveness of peer support interventions , there aThe Web-based peer support program aims to empower community-residing VAIs and their caregivers to manage diseases necessitating mechanical ventilation. We anticipate that if caregivers have better health and quality of life, they will be better able to care for their loved ones who use ventilators. This can help VAIs remain in their homes and, thereby, mitigate the declines in health and quality of life associated with residential care placement .Perceived strengths of this study include the intervention’s social networking-style interface that is likely to be familiar to participants, thereby enhancing the potential for greater usage and better usability of the peer support program. In addition, we anticipate that having multiple features on the website  will increase the likelihood that participants will engage with and benefit from this peer support hub. Finally, the mixed-method nature of this research will not only provide insight into usage patterns and changes in health outcome scores but will also allow for an in-depth exploration of participants’ experiences with the websites and perceptions of how it has influenced their health and caregiving experience. As this is a feasibility study, it is not our objective to test significance. However, we are aware that this limits our ability to comment on the findings’ relevance and have identified it as a goal for future evaluations of the peer support program. While the inclusion of multiple Web-based features has the potential to increase engagement, there is still a possibility that the study will be limited by attrition.


Annals of Global Health documents some of the most interesting advances from the MEPI program. Several of these innovations deserve to be highlighted.The Medical Education Partnership Initiative, MEPI, has been an audacious program launched by The President’s Emergency Fund for AIDS Relief (PEPFAR), NIH and HRSA to improve medical education in a dozen African countries effected by the HIV/AIDS pandemic. It was established because the tremendous deficit in Africa of health-care professionals – from physicians and nurses to the entire group of allied health-care workers. For NIH, it also has evolved a new approach to the way we have traditionally supported research training in low- and middle-income countries. PEPFAR was born when President George W. Bush became convinced that the HIV/AIDS pandemic was a threat to the stability of Africa and the security of the United States. The emergency phase of the program set out to determine whether massive U.S. funding for HIV treatment and control could slow the pandemic, allowing longer-term solutions that would turn over greater leadership to African governments. Eric Goosby, the US Ambassador for PEPFAR, and Francis Collins, the NIH Director, reasoned that if the African governments were to take ownership of the epidemic tomorrow, they needed to build their own workforce and systems to deliver preventive and curative services for their populations today. MEPI focused on ramping up the training of physicians, teachers and researchers and developing health systems to deliver treatment long term, essentially care for life. Whenever foreign “emergency” health care workers could be replaced with local physicians and nurses, the cost of these programs could be reduced and trainees could assume greater leadership for the HIV health needs of the country. This initiative would also create jobs, save lives, improve health and worker productivity, and turn around the economies of the countries affected. Awards were offered exclusively to African institutions that had obtained government engagement and that had competed successfully through an NIH peer review process. The awardees could choose their own American collaborators as partners, a practice that reversed a long tradition of giving grants to U.S. institutions, which would then subcontract to their foreign partners. The African awardees had to demonstrate a track record of responsible grants management, a tradition of excellence in research, and a history of interacting with U.S. collaborators. This supplement of the The concept of putting trust in the African investigators and their institutions to handle the $130 million-dollar program over a five-year period required careful monitoring and the ability to make in-course corrections. This task was handled by a separate grant made by HRSA to a partnership of a U.S. and an African Coordinating Center (CC). Over the period of the grant, the activities of the CC would shift from the U.S. to the African grantee, a transition that could lead to the longer-term sustainability of this effort with greater local leadership and continual improvement over time.The first meeting of the MEPI program surprised us all in a most engaging way. Thirteen major grants were awarded for capacity building and 12 awards from NIH were linked to research training at the same institutions, so we expected 13 deans to be present. However, a number of grantees had reached out to include other medical schools in their proposals, so we were surprised and pleased that deans and representatives from about 40 African medical schools arrived, about one-fourth of all the medical schools in sub-Saharan Africa! Many of the African grantees concluded that if the goal of the program was to increase the quantity and quality of physicians being trained in-country, they should share the grants and engage other medical schools as partners of their program. Only a few of the principal investigators (PIs) knew each other before the program began but comradery in this shared mission grew rapidly.The PIs have held one large annual meeting and a small PI council meeting each year to monitor progress of the program. As part of the annual evaluation, site visits were made to each school and PIs were included in the teams.By the end of the five-year program, the PIs had bonded and developed a common vision with the aspiration that the MEPI network would transform medical education in Africa and should continue regardless of whether the original grant was renewed.A PI council set up working groups to address common themes. One group engaged in strengthening the medical curriculum, introducing simulation labs to give medical students experience with manikin models before engaging with patients, training at district hospitals so students could have more direct hands-on experience with patients, and working in inter-professional teams with nurses, pharmacists and other allied health students. Many medical students participated in research projects that addressed questions that could improve the delivery of care. Medical school libraries were transformed from dusty collections of old texts and poorly archived journals to 21st Century e-Libraries connected by broadband to Hanari, NLM and other websites, allowing immediate access to the most current medical literature. An eLearning working group spearheaded the introduction of tablet PCs to all medical students in the prime grantees institution, networked through hotspots on campus.All schools established Research Support Centers to provide help with ethical review, grants administration, grant writing and information about research calls. During the five years of the program, more than 100 other grants from more than 11 NIH Institutes and Centers were awarded to the MEPI institutions, proof that the local investigators and their partners were able to compete for research grants on topics best studied in an African setting.At Fogarty, we encouraged local governments to support the MEPI initiative but we not sure how this might happen. In Zimbabwe, the Minister of Education realized that the work of MEPI fell into his portfolio so he provided an additional $400,000 to his National Medical School to support the program. In Zambia, the MEPI PI convinced the Minister of Health to open a new state-funded medical school to accelerate the training of physicians with teachers who graduated from the MEPI program. In Tanzania, the Minister of Telecommunications visited the MEPI site at Moi University in Arusha and offered free high-speed broadband access for 10 years to facilitate the spread of their innovative eLearning curriculum around the country.Most important, the PIs became so engaged with each other that they established AFREHealth, the African Forum for Research and Education in Health, as a way to sustain the advances made by the MEPI grantees and spread the positive outcomes throughout Africa schools of medicine, nursing and allied health sciences.The MEPI program has been transformative for medical education in each country at the main institutions and in networks with their partners. However, the task of strengthening medical education, increasing the supply of physicians, nurses and allied health professionals does not occur overnight. MEPI has started the process which will require further investments over the next decade to continue building on the outstanding frameworks that have been established. New initiatives will be needed to sustain this momentum in the future bringing in funds from the government, the private sector, and the broader philanthropic and donor community.What might have happened if we had not supported MEPI? Clearly, there would be an even greater delay in building the workforce needed to address the HIV pandemic. However, another value of the MEPI program has been its ability to address problems of global health security. When the Ebola outbreak began in 2014, MEPI partners stood ready. In Uganda, they were quick to stop the spread of an outbreak of another fatal viral disease caused by the Marburg virus on their own, and with no fanfare. In Ghana, grantees from a linked MEPI program training emergency health professionals screened people at border crossings from the Ebola-affected areas, providing a first line of defense against the introduction of the disease in country. In Nigeria, an NIH-funded grantee helped stop the immediate spread of Ebola from the first Ebola victim who arrived in Lagos, an intervention that prevented a major outbreak in the most populous country of Africa. And in those countries without a MEPI-style program – Sierra Leone, Guinea and Liberia – without robust lab facilities and a cadre of trained personnel, the Ebola outbreak spread wildly, requiring a multi-billion-dollar emergency response. Clearly, having skilled manpower on site with the ability to network with their peers had enormous benefits that could prevent outbreaks and save lives the next time a problem erupts. We need a MEPI-style program for these countries as well.Academic Medicine document a few of the many lessons we have all learned from the MEPI experience. The supplement was initiated by the MEPI PIs to highlight their activities and the accomplishments of the program through their own eyes. The program to us has confirmed the huge and sustained value of these south-south and south-north networks, and the creative ability of African academic leaders to work together and build a program of their own which is much greater than the sum of its parts. This network, built over the past six years, needs to mature and continue into the future. It has sprouted a major African initiative to bring together African institutions of health, medicine, nursing and allied health sciences. AFREhealth can be a commons to share ideas, a clearing house of opportunities, an organization to provide leadership and best practices for teaching and research, and a place to innovate education of health professionals throughout sub-Saharan Africa. Many of these activities we could not have envisioned at the start of the program. Today, we are proud to see how well this experiment has worked. Giving these African leaders, these PIs, their own voice to work together, share experiences, set their own priorities and choose their own partners has been a formula that has succeeded. It will take years, if not decades, to fully develop this capacity. MEPI is a flagship that we hope will gather increased visibility from governments, the private sector and international funders to help sustain a program that has already contributed so much. The future of improved health in Africa and the world’s success in ending the pandemic of HIV/AIDS will depend upon it.In summary, this supplement and the previous supplement in