Although transition programs have been evaluated for adolescents with chronic conditions, these have rarely involved process evaluations. Indeed, outcomes of complex interventions are dependent on how the intervention is implemented in practice and evaluations of implementation process are therefore pivotal. The aim of this study was to evaluate the extent to which a transition program for adolescents with congenital heart disease was delivered as intended. Research questions were 1) to what level of fidelity was the program delivered? and 2) what potential moderating factors affected the delivery of the program and overall fidelity?A mixed methods design was used, where a process evaluation was embedded in the STEPSTONES randomized controlled trial in Sweden. The implementation fidelity framework by Carrol (2007) and Hasson (2010) was used to design, collect and analyze data. Quantitative data consisted of intervention records on adherence and were analyzed with descriptive statistics. Qualitative data on moderators affecting fidelity were collected through interviews, log-books and focus group interviews with healthcare professionals implementing the intervention and participatory observations of the implementation process. Data were analyzed with deductive content analysis. Triangulation was used to integrate quantitative and qualitative data within the fidelity framework.Six out of eight components of the transition program were delivered to an extent that adhered to the program theory or achieved a high level of fidelity. However, components involving peer support had a low attendance by the participating sample (32.2%), and the joint transfer meeting was challenging to implement, despite achieving high adherence. Moderators affecting the implementation process were the adolescent’s and healthcare professional’s engagement in the intervention, contextual factors and a lack of standard operating procedures for all components in the program.Barriers and facilitators for a future implementation of transition programs have been illuminated in this study. The use of an implementation fidelity framework in the process evaluation proved successful in providing a comprehensive evaluation of factors affecting the implementation process. However, implementation fidelity must be considered in relation to adaptations to the local and personal prerequisites in order to create interventions that can achieve fit.The online version contains supplementary material available at 10.1186/s12913-022-07549-7. To facilitate the transition to adulthood and transfer to adult care for adolescents with chronic conditions (CC) transition programs have been developed and evaluated through randomized controlled trials (RCT) . TransitWithin process evaluations, implementation fidelity is investigated –7. This This study is part of the STEPSTONES  project which aims to design, evaluate and implement a transition program for adolescents with congenital heart disease (CHD) in Sweden , 10. TheA mixed methods design was used in this process evaluation study in order to provide a comprehensive evaluation of factors affecting implementation fidelity. The embedded design was chosen, as qualitative and quantitative data on implementation were embedded in the STEPSTONES RCT . A protoThe transition program was developed through intervention mapping to ensure an evidence-based and theoretically rigorous intervention in line with the stakeholders’ needs , 13. TheThe transition program consisted of eight components delivered through five implementation steps Fig. . HoweverThe implementation fidelity framework by Carrol et al. (2007), further developed by Hasson (2010), , 6 was uadherence, which is defined as whether ‘a program service or intervention is being delivered as it was designed or written’ [The evaluation of implementation fidelity is focused on the concept of written’ . Adherenwritten’ , 21. TabQuality of delivery is the manner in which the HCPs deliver the program in relation to the theoretical ideal and program content [Participant responsiveness relates to how participants respond to or are engaged by an intervention. It refers to both the individuals receiving the intervention (i.e. adolescents and parents) and those delivering it (i.e. HCPs). Facilitation strategies are approaches used to enable implementation and can be the use of manuals, guidelines, and training, along with monitoring and feedback for those delivering the intervention [Recruitment focuses on procedures to approach and retain participants to the study, and finally, context refers to if and how the intervention was adapted to the local prerequisites. Context takes into account the social, organizational, and cultural events in the assessment of implementation [Fidelity is also proposed to be moderated by six factors , 6, five content . Particirvention . In the n = 67) were sampled and inclusion criteria followed those of the RCT [Adolescents randomized to the transition program at the two intervention centers  working at each intervention center were interviewed together four times throughout the intervention study. Semi-structured interviews  and information day for adolescents and parents (n = 3) were carried out longitudinally. In addition, informal interviews were carried out with the TCs if needed to verify or discuss the observation. In the observations of the outpatient meetings, sampling strived for variation [To explore how the transition program was implemented in practice, participatory observations of the outpatient visits with TCs (ariation  in termsariation .n = 4) working at the ACHD clinics at both intervention centers. The focus group was semi-structured  v.24 and presented in absolute numbers and proportions. To estimate the level of fidelity, we created four categories based on each quartile of the percentages from 0 to 100 .Qualitative data on potential moderating factors to implementation fidelity were analyzed using deductive content analysis according to Kyngäs and Kaakinen (2020), using the five domains of implementation fidelity moderators as a coding matrix . The anaQualitative and quantitative data were collected and analyzed separately. However, to increase the understanding of implementation fidelity and moderating factors, method triangulation was used to integrate the findings , 28. TriThe characteristics of the participating sample in the intervention group  and participants in the RCT is described in Table Table Quality of delivery investigated the manner in which the intervention components were delivered and is presented according to the eight components of the transition program.There was high attendance by the adolescents to the three outpatient visits with the TC Table . Accordin = 17), the adolescent along with the TC formulated goals. However, the TC sometimes needed to guide the adolescent in goal setting by using the adolescent’s personal narrative as a facilitator. The TCs expressed that goal setting was difficult for adolescents who were perceived as disengaged or who had few symptoms of their CHD. Throughout the course of the trial, the TCs found it easier to support adolescents in goal setting as they found strategies to deal with this  but a low proportion of parents sought extra support from the TC (6.8%). The observations showed that parents were present during the first 10–15 min of the outpatient visits. During this time, the TC opened up for discussion on the transition program, addressing the shift in responsibility from the parent to the adolescent.During the information day, information on the transfer to adult care and the opportunity to meet others in the same situation was delivered to the participating adolescents and parents by HCPs from adult care , the TC, and two young adults from the patient organization of CHD. Three information days were held throughout the course of the trial, two in center 1 and one in center 2, where a total of 32.2% of the adolescents in the transition program participated.A high proportion of adolescents participated in the transfer meeting and were satisfied with the arrangements made for the transfer. However, medical referral was sent to a low extent prior to this meeting Table . The quaFour factors were identified from the qualitative data that moderated the adolescents’ responsiveness to the transition program. The first factor was their level of maturity. The TCs struggled to engage adolescents who were perceived as immature when implementing components such as discussing health behaviors, goal setting and initiating conversations about the transfer and transition. In addition, recruitment in the later stages of the RCT involved patients that were 15 years old at recruitment. The TCs experienced that these patients were harder to engage in relation to their age. The second factor was mental health issues along with neuropsychiatric variations. As the intervention involved discussions on aspects related to everyday life, these issues were considered a barrier towards engagement Table . The thiThree factors were identified. First, it was essential for the TC to become accustomed to the new role. Early in the implementation of the transition program, the TCs were still finding their professional role in terms of boundaries, responsibilities and managing challenging patient situations. However, by building experience and sharing these with each other, the TCs gained coping strategies. Second, lack of knowledge sometimes gave a feeling of inadequacy. This was related to meeting patients with mental health issues and neuropsychiatric variations, for whom the TCs felt their training and role was sometimes insufficient in meeting the patients’ needs Table . The thiThe ACHD nurses perceived the transition program as an important intervention. They valued being able to participate during the information day for adolescents and parents, as it gave them the opportunity to bring up important issues in adult care and adult life before the transfer. The transition program also gave the nurses assurance that the adolescents were prepared and informed. Nevertheless, there were challenges when it came to changing the current way of working and a need to safeguard the pre-existing transfer protocol. Center 2 had a transfer meeting between the physicians from pediatric and adult care which the ACHD nurses felt conflicted with the transfer meeting in the transition program, even though they felt the content of the two meetings differed. In addition, several shortcomings were identified in the joint transfer meeting between the TCs and nurses. Generally, the nurses felt unprepared for the meeting, lacking a structure, purpose and role. The observations showed that the nurses often expected the TC to lead the conversation. Moreover, the nurses were unprepared for which patient they were going to meet because it was not part of the standard operation procedures (SOP) for the TC to report any patient information prior to the meeting. To facilitate future implementation of this component the nurses requested more information or a protocol on which topics were to be covered Table .Four moderators of the participants’ engagement during these information days were identified. First, the use of movies enhanced the group discussions. The movies dealt with experiences of transfer and transition, Q&A of common medical issues, and social, vocational and financial issues when living with a CC. The movies thus served as icebreakers and facilitated the discussion by making the adolescents comfortable in communicating with the HCPs. Second, the use of patient representatives created an informal atmosphere. The representatives candidly shared their experiences and acted as conversation starters. The third moderator was the HCPs’ level of comfort in sharing power and meeting the participants on their terms. Two examples were identified. In example one, the HCPs tailored the information to the adolescents’ needs, which facilitated the discussion. In example two, the information was medically focused with use of complex terminology. This resulted in a group of disengaged adolescents. Fourth, the use of separate group discussions facilitated a safe space. For parents, this meant they could discuss worries and fears regarding the transfer and transition with parents in the same situation. For the adolescents, they could discuss sensitive topics  without parents present.SOPs were developed to guide the TCs in their work. Part of the SOP was to perform a medical chart review and consult the physician before each visit with the adolescent in the transition program. These procedures gave the TCs important medical information that prepared them and gave an understanding of the adolescents’ and families’ history. They also ensured patient safety, as the TCs were prepared for which information they could provide the adolescent within their field of responsibility. However, there were limitations in the SOPs related to the transfer meeting where the TCs lacked structure.The HEADDS tool was appreciated by the TC in getting to know the adolescent as it covered aspects related to their everyday life rather than focusing on the illness. HEADDS was also effective in engaging adolescents who had low responsiveness by initiating topics related to their CHD and care in a natural way from the adolescents’ point-of-view.To help the adolescents communicate their needs during the outpatient visits, communication tools were used. First, a shared decision-making model was used with the adolescent and parents to discuss the shift of responsibility from the parent to the adolescent during the transition to adulthood. Second, a concept map containing topics related to the CHD, care and adolescent life was used during the visits. The TCs experienced this tool as effective for adolescents who were untalkative or had cognitive challenges. Observations identified that these tools facilitated a more equal conversation, as the adolescents could choose topics to discuss. In addition, discussion of sensitive subjects  were facilitated Table . Third, The TCs experienced that meeting the adolescents sometimes revealed mental, social and family issues that were beyond the scope of their professional role. The TCs handled this by utilizing the expertise of the surrounding team at the pediatric clinic . However, safeguarding the adolescent’s confidentiality was sometimes considered a barrier to utilizing the team as the TCs felt obliged to protect this confidentiality.The final facilitation strategy was related to tailoring the components of the intervention to achieve fit. As several components were focused on information and education through PCC, the TC used several strategies to achieve implementation of these components, such as engaging the adolescents by starting from their point-of-view, being flexible towards the adolescents’ needs and using information technology . Moreover, as the TCs grew more confident in their role, they used these strategies when meeting adolescents who were disengaged or had other difficulties in expressing their needs.The recruitment for the RCT spanned from June 2016 – December 2018. Three barriers and five strategies to recruitment and retention were identified. First, lack of engagement from the adolescents was most common according to the TCs. Second, problems with the postal services resulted in missed information to presumptive participants. Third, difficulties in reaching the participants were prevalent .Strategies were used to handle these barriers. First, offering an incentive  was perceived as encouraging the participants to be more engaged and continue study participation. Second, in some cases, using the parents as gatekeepers and contacting them first proved effective. Third, calling and texting was convenient as the adolescents were used to this form of communication and responded more promptly. Fourth, study information was adapted to each individual’s needs after reading about the adolescent in the medical file. And fifth, coordinating recruitment and outpatient visits in the intervention with the medical check-ups was an effective way for retention, as the patient was already at the clinic.Social context surrounding the adolescent was a factor that affected implementation. Here, parents were considered to be both facilitators and barriers. Both interviews with the TCs and observations confirmed that some parents had difficulties in letting their adolescent manage their own care. On the other hand, the TCs considered most parents as resources to their child in the transition program. The TCs also felt the transition program gave insight into conflicts between the adolescent and parent that had to be considered by the TC Table .As the transition program was delivered in addition to usual care, the TCs had to coordinate this. Three challenges were identified. First, the TCs had challenges in reaching the physician and finding a time for consultation before the outpatient visits. The TCs described having to be flexible and adjusting their schedule according to the physician’s needs, which was more commonly the case in center two than center one. The second challenge was related to the physical context, where center two had a designated office for the TC but center one had difficulties in finding a private space for the visits due to shortage of rooms in the outpatient pediatric cardiology clinic. The third challenge concerned attitudes from HCPs in usual care towards the intervention. Right from the start of the trial, the TCs described the HCPs as being skeptical towards them in their role. As the TCs had to safeguard the intervention’s content to avoid possible contamination of the intervention to usual care, they felt that this affected the general attitude. However, throughout the course of the trial these attitudes gradually changed towards a more positive outlook on the intervention and TCs Table .Our results show that the components of the STEPSTONES transition program were delivered to a high extent in a manner that adhered to the program theory. In addition, important moderators specific to transition programs  and complex interventions for people with CCs have been illuminated. From our findings we identified two components that the participants found particularly difficult to engage in and implement - the information day for adolescents and parents and the transfer meeting with adult care. Indeed, only a third of adolescents in the transition program participated during the information day. Potential reasons for this are that adolescents with a CC might feel uncomfortable in engaging with others in the same situation and spend excessive time thinking about their illness , 30. WitIt was difficult to achieve a high level of fidelity for the transfer meeting to adult care. Reasons identified were the lack of SOPs concerning the content of the meeting, that adult care did not work with PCC, and the difficulties integrating the transition program transfer meeting with the transfer routines in usual care. These findings highlight important barriers to overcome for future implementation of transition programs and raise the issue of how to achieve fit for complex interventions into the complex social systems which healthcare systems exemplify . AlthougAlthough implementation challenges and moderators of fidelity have been identified in this study, it is worth asking whether high fidelity and its assessment is important in process evaluations of complex interventions. When comparing interventions implemented strictly according to protocol with interventions that were tailored to the local context and patient population, the tailored interventions proved to be more effective in producing change . FurtherSome methodological caveats must be raised when interpreting these findings. First, the process evaluation of the STEPSTONES project covered several aspects of the implementation, context and potential mechanisms of impact of the transition program . ConsequThe STEPSTONES transition program was delivered in a way that adhered to the program theory. Identified moderators affecting the implementation process were both the adolescents’ and HCPs’ responsiveness, contextual factors in pediatric and adult care, and the lack of comprehensive SOPs for all the implementation steps of the program. As a result, barriers and facilitators for a future implementation of transition programs into usual care have been illuminated. The use of an implementation fidelity framework to design and perform a process evaluation study proved successful in providing a comprehensive evaluation of factors affecting the implementation process. However, implementation fidelity must be considered in balance with adaptations to the local and personal prerequisites to create interventions that can achieve fit.Additional file 1.Additional file 2.Additional file 3.Additional file 4.


Interviews were recorded and transcribed for thematic analysis using NVivo; (3) Results: Provincial funding and in-kind support from community partners were key. Initiatives were feasible to implement, and key messages were well-received by communities. Specific practices and process were commonly discussed, and strong local program leadership was crucial to implementation; (4) Conclusions: Results have implications for planning and implementing future multi-component, community-based health promotion programs that include similar partnerships. Rising rates of overweight and obesity represent a serious public health issue . OverweiResearch indicates that overweight and obesity can significantly impact the physical and psychological health of individuals, including children and youth . Being oHealth promotion involves combinations of educational, organizational, regulatory and political support for environmental and behavioural changes to support health . There iEvidence from interventions to support physical activity and healthy eating, specifically, indicates that (1) physical activity or diet-physical activity interventions delivered in schools with home or community components ,15; the Run. Jump. Play. Every Day, which promoted physical activity.Water Does Wonders, which promoted water consumption and reduced sugar-sweetened beverage consumption.Choose to Boost Veggies and Fruit, which promoted fruit and vegetable consumption.Power Off and Play! which promoted physical activity and play in place of screen time and sedentary behaviour.Drawing on the Ensemble Prévenons l’Obésité Des Enfants’  model , the forMOHLTC supported HKCC communities through funding, training, technical support, social marketing tools and other resources. Public Health Ontario (PHO) undertook a provincial evaluation of the HKCC to assess the extent to which its goal and related objectives were achieved over the three-year intervention period (2015 to 2018). While 45 communities across Ontario were selected to participate in the HKCC, this study is focused on the 39 municipally-funded communities as there is a separate community-partnered evaluation to assess the implementation and impact of the program as implemented by six Aboriginal Health Access Centres or Aboriginal Community Health Centres in Ontario.Community level factors: How the community and/or provincial context relates to HKCC program implementation .Provider characteristics: Local program providers’ perceptions of the need for and potential benefits of the program, as well as perceived self-efficacy and skill proficiency for the desired tasks.Innovation (Program) characteristics: Characteristics of HKCC programs and initiatives at the community level .Organizational capacity (Prevention delivery system): Factors related to the system delivering the HKCC. The LSC has a key role in planning and implementing initiatives in communities, and consideration of the organizational features, practices, processes and staffing of this group is relevant.Training and technical assistance (Prevention support system): training and effectively preparing local program providers to complete expected tasks related to the HKCC .Our process evaluation of the HKCC drew on Durlak and DuPre’s Ecological Framework for Understanding Effective Implementation . Durlak The objective of the process evaluation was to explore factors contributing to implementation of Ontario’s HKCC and to assess local program providers’ knowledge, attitudes and behaviours as they related to the program and its implementation. The evaluation utilized a mixed method design, including data from an online survey and in-depth semi-structured telephone interviews, both collected in 2018 near the program’s end. This manuscript integrates key findings from both data sets to explore factors contributing to implementation of the HKCC over the course of the three-year program (2015–2018).LSC survey data were collected at two time periods (Time 1 data are reported in ). This mDrawing from Durlak and DuPre’s framework, the LSC survey asked participants about their perceptions of program implementation, including the following: barriers and facilitators; roles within and attitudes towards the HKCC; health equity and reach; local program providers’ functioning and relationships among partners; training and other support.Semi-structured telephone interviews (n = 16) were undertaken with LPMs and LSC members from eight HKCC communities between August and October 2018  using Surveys@PHO, an online survey platform hosted by PHO. Based on pilot feedback, some of the original survey questions were modified prior to sending the survey broadly to the remaining communities.Interview recruitment occurred via email invitation, and LSC members were asked to communicate their interest to PHO by email or telephone. Participation in the survey and interviews was voluntary. Participants provided written informed consent to participate in this evaluation. Ethics approval for the survey and interview protocols was received from Public Health Ontario’s Ethics Research Board in August 2015.Survey analysis includes descriptive statistics, which were analyzed using Microsoft Excel. Data were grouped into three categories: agree/strongly agree, neither agree nor disagree and disagree/strongly disagree. In some instances, an “other” category was reported, which encompassed disagree, strongly disagree, prefer not to answer and don’t know.For the interview data, a theme code set was developed deductively according to the constructs of the Ecological Framework for Understanding Effective Implementation  and induInter-rater reliability was conducted by two coders using a sample of interview transcripts (10%) to determine the reliability of the theme code set and to resolve differences in interpretation. A kappa coefficient was calculated to determine the degree of agreement in coding. A Kappa score of 0.62 was calculated, which represents a substantial amount of agreement ,26. DiscFactors that contributed to the HKCC’s implementation are presented according to the five levels outlined by Durlak and DuPre’s framework : communiQuantitative survey data are presented as descriptive statistics, including open-ended data that are included to augment the survey data. Qualitative interview data are presented as verbatim quotations according to the number of times they were mentioned  and number of sources  in which they were mentioned.Overall, 124 local program providers from 26 HKCC communities completed at least a portion of the survey, with 27% identifying as an LPM  and 73% identifying as an LSC member. Most LPMs (74.2%) had been in their role for more than one year, while most LSC members had been involved in the HKCC for two or more years. LPMs were employed in a range of sectors, including public health, non-profit sector and local municipalities. Almost all LSC members who completed the survey had been involved in the HKCC for themes three and four .Sixteen local program providers from ten HKCC communities participated in an interview. Participants consisted of two LPMS and 14 LSC members, also employed in a range of sectors.Community-level factors refer to community and/or provincial contexts with the potential to affect implementation of the HKCC, including prevention theory and research, political support, funding and/or in-kind support from partnerships, policy support and community context.All 16 interview participants discussed the role of community-level factors in local HKCC implementation see . All parThe community structure for HKCC programming was discussed in relation to local geography  and local population . For example, some communities used municipal boundaries to facilitate program planning:“[W]e divided [our community] into five sections. [Our community] is a natural…like there’s a part that sticks out…so that was one section, and then [we] took the rest of the city and divided it in quarters and looked at that as local planning groups.”—ID 19Participants indicated the extent to which scientific theory and research were integrated into their planning and implementation of HKCC interventions. Both interview and survey respondents indicated that evidence supporting HKCC initiatives was strong  and that the health risks and benefits of the population had been considered in program design (91.9%). The integration of available scientific evidence into the design of local HKCC initiatives was also demonstrated:“[T]hey’d have the physical activity specialist kind of give some evidence and then the program leads, or the project leads, would have that information for when they designed their projects, which kind of try and align with what HKCC was trying to do and with what evidence for that theme was available.”—Interview ID 8Local community partner support for HKCC implementation was perceived to be high. Most (91%) survey respondents felt strong support from local community partners, while less than half (47.6%) indicated that support for the HKCC came in the form of local political commitment. Several interview participants  indicated that their mayors and local municipalities provided meaningful support to local HKCC programs. Support ranged from the endorsement of the local mayor to municipalities leveraging their resources and infrastructure for the LSC to help move HKCC programs forward. For example:“[O]ur champion was our Mayor and he bought into this program 100%. He attended almost every activity that happened.”—Interview ID 4“[H]aving our individual mayors and councils support made it [so] that we could move our initiatives forward. And, to have municipal resources at our disposal when we needed things like administration support, tech support, those types of things, we were able to access them through our individual municipalities.”—Interview ID 1Despite reports of meaningful local political support for communities, four interview participants described that it could have been stronger and more sincere. As one participant described:“[T]he municipality led the work, and the mayor was the champion. And I’m going to say that the political commitment was a little bit superficial. And just that it didn’t take full advantage of what that could have meant for being a visible leader.”—Interview ID 17Program providers indicated that program funding and in-kind support were essential components of HKCC development and implementation. Almost all interview participants  acknowledged funding as valuable, while just over half (55.9%) of survey respondents reported that a sufficient level of funding was in place from the province to support HKCC implementation. In particular, funding and in-kind support were key elements to help facilitate the engagement of community partners and development of HKCC programs. For example:“[F]rom our perspective I do think because there was some funds that came along with that we were able to do a lot more things to reach the community and engage people than we would have otherwise, because everybody has their own limited budgets with their strategies and what they already do.”—Interview ID 14Eighteen (66.7%) LPM and 23 (32.4%) LSC member survey respondents indicated that their HKCC community had received additional funding from their host organization  to support HKCC programming. In-kind support from host organizations was provided to 74.6% of program providers, including, for example, staff expertise and marketing support, use of facilities, office equipment, programming and administration. Provider characteristics refer to local program provider perceptions of the need for and potential benefits of the HKCC program—an important determinant of successful implementation—and their perceived self-efficacy and skill proficiency .Local program providers reported that they perceived a local need for the HKCC, and that the program was highly beneficial to their communities. For example, survey data indicated that most (90%) providers agreed or strongly agreed that the HKCC was effective in increasing knowledge of health behaviours, that the HKCC program was beneficial in supporting child health behaviours, that there was a need for HKCC initiatives in communities, that the HKCC enhanced child and parent access to programs and activities and that it contributed to a sense of community. In the same way, nearly all interview participants indicated that the HKCC program was beneficial to their community . One reported benefit included changes in the health behaviours of children and families :“I have participated in something [called] Walking to School Wednesdays at one of the local schools…I stand there and I see all these kids with their water bottles. Every single kid comes along with a water bottle. Like, that’s quite a revolution.”—Interview ID 19Among survey respondents, more than half agreed that the HKCC was effective in changing health behaviours (64.3% agreed/strongly agreed); however, there was less agreement that the HKCC was effective in reducing childhood overweight and obesity (46.8% agreed/strongly agreed). Most survey participants who were confident in their ability to engage partners (93.6%) had the belief that their community could achieve the goals of the HKCC (92.7%) and had the self-confidence and ability to implement the program in their communities (89.9%). Examples of strategies for engaging HKCC partners included targeting partners working in settings where children live, work and play , leveraging existing relationships through the themes and sharing HKCC information via social media platforms and on websites.LPM skills related to management and coordination of the HKCC were noted as vital components of successful program delivery and coordination of LSC member committees . Participants also reported an alignment between the LPM’s professional background and the knowledge and skills required to coordinate the HKCC program.Finally, the content expertise  of LSC members was observed to be beneficial in relation to planning HKCC programs in alignment with theme-based messaging. For example,“I started out in childcare and then advanced to the current position of director, so I’ve always had a very keen interest in the wellbeing of children and their families in our municipality. When our municipality [applied] to partner in this initiative with the other…communities [in our region], I right away thought that would be a great fit if I became a member of the committee.”—Interview ID 15Innovation refers to the characteristics of the HKCC program that influenced its implementation. These characteristics as reported by interview participants are outlined in All communities were encouraged to form and sustain multi-sectoral partnerships to support planning and implementation of the HKCC. Almost all program provider survey respondents reported that local community partners expanded their own programs to include HKCC initiatives (90.9%) and to spread key messages about the HKCC into the community (97.5%). Eighty-one percent of survey respondents reported having networked with diverse sectors to gain HKCC support, while new community structures and networks were developed by 73.5% of respondents.In both surveys and interviews, local community partnerships were the most commonly mentioned characteristic that affected the implementation of the HKCC in both surveys and interviews. These partnerships were largely discussed by interview participants as a success . There were a variety of partnerships with local organizations and community members that LSCs leveraged to support delivery of programming. Both private  and public  organizations partnered with HKCC communities to provide the setting for HKCC initiatives, highlighting the critical importance of partners in program planning and delivery. “I think there might have been some collaborative efforts to work a little bit together. But again, you can always do more but you’re sort of limited by time, you’re limited by resources, and then you have to get your own work done, too” (ID 6). Many interview participants reported difficulties engaging schools and school boards in their local HKCC planning and implementation :While the success of partnerships was a key theme that emerged from the interviews, many participants discussed challenges experienced in the development and maintenance of partnerships . These challenges originated from the limited time and resources of local organizations that the LSC had an interest in partnering with: “It was a little bit difficult to get the right representation from the education field…that’s just because of the nature of their beast, right. Our meetings were happening during the day, so, you know, your champion teacher wouldn’t be available…and then if you went into administration, it was hard to get us on the top of the list for a meeting to attend.”—Interview ID 4Most survey respondents indicated that coordination among partners had improved over the course of the program, and that there was a shared HKCC-related vision and goals among partners. Fewer, but still the majority of respondents, thought that their established partnerships would be sustained after the funding ended and that trust among partners had increased throughout the HKCC.Water is the way to Go!” to emphasize the fact that the healthy choice and action they were trying to influence was to choose water. In addition to the theme three “Choose to boost veggies and fruit” tagline provided by MOHLTC, another community also included the tagline “Powered by veggies and fruit” to appeal to a different age groups/audiences and tie in recreation/sports as fruits and vegetables provide the fuel and power to be active and participate in sports. Adaptations to theme 4 also emerged, as one community indicated that they used the same message for most of the program, with occasional adaptations to focus on land-based activities and the well-being that land-based activities bring to a community. The same community also adapted their messaging to highlight the importance of unstructured play for children.HKCC programs reflected the themes developed by the MOHLTC, which focused on increasing physical activity, water consumption, healthy eating and decreasing screen time. There are also examples of programs that were adapted or they changed the key messages provided by MOHLTC to promote the theme. One community modified their theme two tagline to say “There were a variety of strategies reported to promote key messages of the HKCC, including social media, local newspapers, radio stations and print advertising . For example, some communities leveraged pre-existing social media platforms run by local partners in order to reach an established social media following, e.g.,“Our Healthy Kids social media…has been linked to the [regional public health unit’s] social media platforms…sometimes it can take years to gain a following and so, we wanted to link on to… another organizations platform that has the following.”—Interview ID 11Nineteen (70.4%) LPMs indicated that they used more than one type of social media platform to share information about the HKCC. Facebook and Twitter were the most commonly used platforms, given that they can be used to share both messages and photos. Approximately half of the LPMs indicated that they leveraged another social media account of relevance in their community to help spread their message, either in addition to, or in place of, their own HKCC accounts .MOHLTC provided LPMs within HKCC communities with social marketing materials to assist in the delivery of the HKCC. Survey results indicate that most of the communities either used the materials as provided (37%) or made necessary adaptations to better fit their context (52%).Program adaptability and compatibility are recognized as important mechanisms for tailoring programs to specific stakeholders and audiences . AdaptabGiven the range of communities participating in the HKCC program and generic messaging and marketing materials provided by MOHLTC, some interventions were adapted by program providers in order to meet the needs of local communities. Almost all interview participants noted that they were able to adapt the HKCC program . There was also agreement that the HKCC was adaptable to community needs (98.2% of survey respondents), initiatives were feasible for communities to implement (91.0%) and that key messages were positively received by communities (88.3%).Interview participants discussed the HKCC’s compatibility with the priorities and practices of local organizations, specifically those that already serve children and families living in HKCC communities. The compatibility between local partners and infrastructure helped the LSC to leverage and support existing community programs. For example, “The [XXX] Child and Needs Initiative and they have a critical hours group, which is called Growing up Great and they also are looking at um, child health behaviours and um, programs and training that support that as well and they were one of our partners as well. This is one of the reasons why we reached out to them was to leverage what they were working on and see how we could work together to uh, to strengthen that.”—Interview ID 1Most survey respondents (93.7%) described a focus on reaching populations within their communities that faced structural barriers to health based on race, ethnicity, indigeneity, socioeconomic position and rurality, among other factors. Many respondents (41.8%) described challenges in reaching specific groups, citing, e.g., the time it takes to engage in the absence of pre-existing relationships and the impact of changes to organizational staff or funding among HKCC partnersKCC. Participant-level barriers to reach were reported to include cost , accessibility  and perceived lack of interest.Geography and location were identified as key challenges to reaching certain local populations, as some rural communities that participated in the program did not have centrally located hubs  where people could gather. One strategy identified for reaching children in HKCC communities was to deliver programming in settings that children already access:“[W]e kind of went to where they were…I think that was the main way [of reaching children], going to the schools, going to community events, rec centers… and sports associations…places where kids would be.”—Interview ID 10“[S]ome schools’ participation was lower than we wanted, but I don’t really think that was HKCC related, it was kind of school by school and the enthusiasm of each school and their willingness to participate” (Interview ID 8). These opposing experiences reaching community members through the school setting highlight the important role that local context can have for local partners in HKCC implementation.While schools were perceived as an appropriate place to reach children, some communities were challenged by a lack of school-level capacity for program participation. For example: While sustainability is not a construct of Durlak and DuPre’s Framework, it aligns with the purpose of the Framework, which is to focus on evaluating the capacity to identify, select, plan, implement, evaluate and sustain interventions . Asking Survey and interview results indicated that sustainability of the HKCC program was an important implementation outcome. Sustainability can be measured through program maintenance or the capacity to continue to deliver a program through a network of agencies, instead of, or in addition to, the agency that originally implemented the program . More th“Healthy Kids superhero toolkits which includes all of the resources from Themes 1–4 and it also includes, a new live theatre script that incorporates all four themes…and it was videotaped so that it can be accessed by schools and other community groups in the future.”—Interview ID 11Other participants noted that toward the end of the program, when the LSC interviews took place, they were engaging in discussions on how to sustain theme-based messaging and programming that was implemented over the course of the program:“Well, that’s about where we are at this moment is trying to solidify that by talking to our partner agencies. We’re having conversations with our local health unit. We’re having some conversations at the municipal level and then we will be having them at the school board level to find ways with the resources that we have at our disposal to keep things moving forward.”—Interview ID 15Nearly 75% of survey participants recognized that there were community champions who strongly supported the program, that community members  were feeling engaged with the program and that the HKCC was integrated into partner organizations. More than 62% of respondents indicated that their HKCC community had developed a sustainability plan for their program to extend beyond the formal funding period (2015–2018).There were also reported challenges and barriers to sustaining local HKCC programs. Participants noted that sustaining HKCC programs would be difficult without an LPM or ongoing funding:“I think anything that was, sort of special that came out of HKCC won’t happen just due to lack of funding. You know if they had $3,000 for a certain after school program, well, without that $3000 dollars it might not happen, you know?”—Interview ID 6“I hate seeing [programs] start for two years, two or three year programs and then get cut just right off, and then without some of that funding, the programs do die.”—Interview ID 15“And I guess my fear would be, without the Healthy Kids [LPM] in the future it’s going to be very difficult… as much as we’re going to try to transfer and keep it going, and what not, I think that’s going to be really hard for those partnerships, to survive when there isn’t the [LPM] there to, kind of, be that glue to hold it all together.”—Interview ID 16Organizational capacity to deliver the HKCC program refers to the functioning of the local program provider , and relationships among HKCC partners. Organizational factors were essential to the successful delivery of the program.Across the 16 interviews, specific practices and processes engaged in by LSCs  were the most commonly discussed factors that affected their organizational capacity to implement the HKCC . There wPositive organizational climate and the presence of a shared vision were two general organizational factors that supported an LSC’s ability to plan, develop and implement the HKCC program . Shared “I think pretty much what the plan was, we were able to follow through with it and I think a lot of that resulted from the fact that our committee was a collaboration of a number of municipalities and communities. We would have never been able to achieve what we did if it was a single community trying to carry the initiative forward, so the fact that it was a collaboration of many communities, that gave us the power and support that we needed to move things forward.”—Interview ID 15There was agreement that communication between and coordination of LSC members helped to facilitate successful program execution. In terms of communication, LSC members discussed the purpose and function of their LSC meetings and how they contributed to planning their local HKCC programs. Other interview respondents discussed the role that LSC meetings played in strengthening connections between LSC members and the organizations they were employed by. For example:“I think the regular meetings helped, as well because it keeps people engaged, inspired, and it keeps those connections going with those partnerships”—Interview ID 6Results from interviews and survey respondents are aligned, where more than 80% of LSC members agreed that there was strong LSC leadership, that community champions supported the HKCC and that they were satisfied with the way the LSC functioned, including good communication among LSC members see .There was general agreement that local program staffing considerations were crucial to the program’s success . Participants discussed the importance of the leadership and support of LPMs, LSC members, program champions and managers within host organizations for the HKCC’s success. Interview participants mainly discussed the leadership of their LPMs and LSC members as being vital to local HKCC implementation . For example:“I think that having [an LPM], particularly in our situation because it was multiple rural communities, having someone to tie everybody together and a little bit of the planning and promotion, and rolling things out, I think that for us, was huge.”—Interview ID 14Training refers to support that prepared providers for their new roles related to the HKCC, while technical assistance refers to support provided to communities after implementation commenced. There was agreement among LPMs who participated in the survey that the MOHLTC and other resources  were helpful throughout implementation of the HKCC.While few interview participants discussed the importance of these factors, some participants discussed the value of technical assistance provided to their community by the MOHLTC :“I think the resources that were created by the Ministry were essential to the success, that Ministry support was essential to the success.”—Interview ID 13Some interview participants noted areas where the technical assistance from the MOHLTC could have been improved. For example, a delay in receiving materials and messaging acted as a barrier to program implementation:“What was hard, though, was the fact that they delayed, at the Ministry level, the pouring out of the themes, okay. Your next theme is water and we’ll get that material to you when we do and we’re all standing by waiting for stuff and nothing happens because something stalled at the Ministry.”—Interview ID 19The objective of this study was to explore factors contributing to implementation of the HKCC—a province-wide community-based program intended to improve children’s health behaviours in Ontario. Findings from the survey and interviews of LSC members and LPMs in HKCC communities indicate that Durlak and DuPre’s  frameworBased on the EPODE model , the HKCProvider-level factors include the belief that the HKCC was both needed and beneficial and that it contributed to a sense of community and enhanced access to programming. However, among survey respondents, more than half agreed that the HKCC was effective in changing health behaviours; however, there was less agreement that the HKCC was effective in reducing childhood overweight and obesity. These findings are not surprising, given the downstream nature of these outcomes and the focus of the program on the promotion of healthy behaviours.Regarding organizational capacity, program staff members were critical to successful program implementation, including strong leadership from the LSC, and that community champions can play a key role. There was satisfaction with the LSC functioning, including a communication mechanism between members. LPMs and LSC members were confident in their ability to engage partners and achieve program goals, and LPM management and coordination was vital to program delivery and coordination of the LSC. Hiring and managing high-quality staff to run health promotion programs is noted as a key leadership function . SpecifiStakeholder relations, interpersonal skills and cultural competence can help to support partner development and targeted reach of the HKCC. Targeting settings  where children and parents live, work and play helped to improve intervention reach. However, there may be further opportunity to conceptualize and assess the context and implementation of this complex intervention more fully. For example, Pfadenhauer, Gerhardus, Mozygemba, Lysdahl, Booth, Hofmann et al.  developeWhile most communities focused on reaching populations that faced structural barriers to health, some experienced barriers in doing so, including a lack of time allotted to develop relationships with local populations, turnover of HKCC program staff, funding and challenges related to geography and transportation to access programming. Participant-level barriers included accessibility  and cost . If similar future community-based health promotion programs aim to reduce health disparities, they should use a structural approach to target upstream determinants of health and attempt to strike a balance between individual-focused and structurally focused health promotion interventions .Some notable challenges were evident with partner development. Previous research examining multisectoral partnership development in health promotion identified core elements of positive partnership processes including shared mission, diverse partners, trustworthy leadership, balance formal and informal roles, trust-building throughout, balance maintenance and production activities, consideration of the context  of the work and evaluation of the partnerships for consistent improvement . These ePrevious research highlighted the need for politicians to act as advocates of programs at local and provincial levels, in addition to mobilizing their peers to modify programs and policies that support physical activity and healthy eating environments . RelatedThese evaluation results may benefit communities directly  given that data may inform future training and support, and therefore, increase local-level community capacity for delivering community-based health promotion programs, activities and services. The findings may have positive implications for the local level policy , and urban planning initiatives .Broadly, the findings support the value in monitoring intervention adaptation and compatibility to understand how the HKCC worked in real-world settings. Specifically, Durlak  identifiStrategies to successfully engage and reach populations that face structural barriers to health deserve further attention, particularly given the focus of the HKCC on reaching these groups. Future research exploring the implications of political support for population-level social marketing interventions, as well as strategies to improve the feasibility of forming successful local multi-sectoral partnerships, is needed.This research has three main strengths. First, the survey and interviews were designed around the Durlak and DuPre framework  a prioriIn addition to the strengths, the survey and interview data and analysis have some limitations that must been considered. First, the survey and interview recruitment approach—requesting that LPMs forward the survey link to their LSC members—led to uncertainty about how many people were reached as potential participants. This approach prohibited us from calculating an appropriate denominator to report a survey response rate. Second, based on the fact that survey participation was optional, there was a risk of selection bias in those that did not complete the survey. It is also possible that LPMs and LSC members, who were more engaged in the HKCC closer to the end of the program, were more likely to have completed the survey. Third, some survey respondents dropped out as the survey progressed, which could have been as a result of the survey length and the time it took to complete. Finally, these results are not necessarily representative of all LPM and LSC members, given that participation only represented two-thirds of 39 municipally-funded communities. Despite these limitations, the data provide an understanding of the functioning of the LSC and some of the successes and challenges of HKCC implementation.In the context of the interview data, qualitative research captures stories to understand people’s perspectives, understand how systems function and their consequences for people’s lives, as well as the context—what is going on around the people, groups, organizations, communities or systems of interest . Given t


IgM deficiency has been reported in patients with many autoimmune diseases treated with Rituximab (RTX). It has not been studied, in detail, in autoimmune mucocutaneous blistering diseases (AIMBD). Our objectives were: (i) Examine the dynamics of IgM levels in patients with and without RTX. (ii) Influence of reduced serum IgM levels on clinical and laboratory parameters. (iii) Explore the possible molecular and cellular basis for reduced serum IgM levels. This retrospective study that was conducted in a single-center from 2000 to 2020. Serial IgM levels were studied in 348 patients with five AIMBD  and found decreased in 55 patients treated with RTX, IVIG, and conventional immunosuppressive therapy (CIST). Hence the incidence of decreased serum IgM is low. The incidence of decreased IgM in patients treated with RTX was 19.6%, in patients treated with IVIG and CIST, it was 52.8% amongst the 55 patients. IgM levels in the post-RTX group were statistically significantly different from the IVIG group (p<0.018) and CIST group (p<0.001). There were no statistically significant differences between the groups in other clinical and laboratory measures. Decreased serum IgM did not affect depletion or repopulation of CD19+ B cells. Patients in the three groups achieved clinical and serological remission, in spite of decreased IgM levels. Decrease in IgM was isolated, since IgG and IgA were normal throughout the study period. Decreased IgM persisted at the same level, while the patients were in clinical remission, for several years. In spite of persistent decreased IgM levels, the patients did not develop infections, tumors, other autoimmune diseases, or warrant hospitalization. Studies on IgM deficiency in knockout mice provided valuable insights. There is no universally accepted mechanism that defines decreased IgM levels in AIMBD. The data is complex, multifactorial, sometimes contradictory, and not well understood. Nonetheless, data in this study provides novel information that enhances our understanding of the biology of IgM in health and disease. IgM is an important molecule for many reasons. Interestingly, it is the first immunoglobulin produced as a part of the adaptive immune system, which has evolved over 500 million years . The varIn spite of its evolutionary and current importance in the immune system, it has not been studied in detail in autoimmune diseases.A molecule of such phylogenetic importance and one which currently seems to be of significance in the immune response of humans deserves attention. Recently, we published a review of Rituximab (RTX) associated serum IgM decrease in multiple autoimmune diseases . While mIn this study, we present data on patients with pemphigus vulgaris (PV), pemphigus foliaceus (PF), bullous pemphigoid (BP), mucous membrane pemphigoid (MMP), and ocular cicatricial pemphigoid (OCP), who had decreased levels of serum IgM, during their systemic therapy.PV affects the skin and mucosal tissues in the oral cavity, nose, pharynx, larynx, esophagus, genitalia, anal canal, and nails . In PF, BP manifests as tense blisters predominantly involving only the skin, usually in an acral distribution. The blisters are subepidermal on histology, and the autoantibody binds to the basement membrane zone (BMZ) .MMP involves the mucosa predominantly, less frequently the skin. The mucosa of the nose, oral cavity, conjunctiva, pharynx, larynx, esophagus, genitalia, and anal canal. The most important feature of MMP is that, as the lesions heal, they cause scarring. The blisters are submucosal, and the autoantibody binds to the BMZ. When the disease predominantly involves the eye, causing scarring in the conjunctiva, and possible blindness, it is referred to as OCP .Rituximab is a chimeric monoclonal antibody that targets CD20+ B cells. Recently its use has been associated with decreased levels of serum IgM in several autoimmune diseases. RTX has been used in the treatment of autoimmune diseases that are mediated by autoantibodies or T cells –15.In the study, we present the data on patients with PV, PF, BP, MMP, and OCP who were treated with RTX, intravenous immunoglobulin (IVIG), and conventional immunosuppressive therapy (CIST), and in whom the levels of IgM were followed for long periods of time.The purpose of this study was to analyze the dynamics of IgM deficiency in these patients and to determine its influence on clinical course, clinical outcomes, relapse rate, and CD19+ B cell levels.The Center for Blistering Disease (CBD) is a tertiary care center for AIMBD patients. This study was approved by the New England Institutional Review Board (IRB).Hence this is a single-center retrospective study of 55 patients with low Ig M levels seen between 2000 and 2020 at the Center for Blistering Diseases in Boston, MA. The identity or personal characteristics of none of the patients were disclosed.The following inclusion criteria were used: 1) The diagnosis of diseases  was made on the basis of a combination of clinical presentation, histological features, and every patient had immunopathological confirmation of their diagnosis , 9. 2) IExclusion criteria included (1) Lack of baseline IgM level recording or at least two consecutive blood sampling tests with IgM deficiency, (2) Patients who were previously treated with Rituximab, and (3) Patients who lacked histopathology and immunopathology confirmation of diagnosis.The method by which patient records were screened and patients with low serum IgM levels were identified are present in The patients were divided into three groups. Patients in Group I were treated with RTX. Patients in Group II were treated with IVIG. Some of these patients subsequently got RTX. Patients in Group I and II had moderately severe or severe disease, with multiple sites of involvement. Patients refractory to other therapies were treated with RTX, according to the Ahmed protocol . This prThe following data were collected on every patient: sex, ethnicity, disease category, age at onset, duration of disease prior to entering the study, and systemic drugs used by patients prior to entering the study Table 1.CIST consisted of systemic corticosteroids (CS) and nonsteroidal adjuvant therapy such as dapsone or minocycline. Immuno-suppressive agent (ISA) was chosen based on severity, extent, and type of disease. The data is presented in 2, given in four consecutive infusions, once weekly for four weeks. None of the patients were treated with RTX using the rheumatoid arthritis protocol. IVIg was given at a dose of 2gm/kg/cycle. The frequency of the infusion was based on clinical response. This protocol has been used in most of AIMBD’s with significant success and clinical outcomes. It is referenced at the bottom of RTX was administered according to the lymphoma protocol at a dose of 375 mg/mAt the time of initial evaluation, serum IgG, IgM, and IgA were determined in all 348 patients. Laboratory outcomes were measured as follows: the duration and time to IgM deficiency, time to CD19+ B-cell depletion, and repopulation in patients treated with RTX. In these 55 patients, each time IgM was measured serum IgG and IgA were also measured. The rate and time to serologic remission were noted in each patient and compared among the patient groups.L and ≥6 cells µL, respectively. Levels of autoantibodies to Dsg 1 and 3 (For PV and PF), antibodies to BP 180 and 230 BPAg1  antibodies were measured prior to initiation of therapy and subsequently periodically assessed to determine serological remission. These assays were done by a commercial laboratory using kits made by MBL Ltd Nagoya Japan.The lymphocyte subset CD19+ B cell levels of depletion and repopulation were defined as <6 cells µSerious adverse events and the number of hospitalizations due to disease or as a consequence of its therapy were carefully recorded. Any serious infection that warranted systemic antimicrobial therapy or hospitalization was recorded.At the time of initial evaluation, in all 348 patients, extensive serological testing was done for a panel of autoantibodies to exclude polyautoimmunity. If all serologies were negative, patients had a CT scan of the neck, chest, abdomen, and pelvis to exclude any possible tumor or latent infection since almost all the therapies used were immunosuppressive.Statistical analysis was performed using SPSS version 27. Categorical data defined as proportions of patients were compared with Pearson’s Chi-Squared Test. Normally distributed quantitative data was identified as mean (Range). According to the homogeneity, two groups were compared with independent t-test and Mann-Whitney U test, respectively. One-way ANOVA and Kruskal-Wallis tests were performed for three group comparisons. The levels of P-value and 2-tailed P values less than 0.05 were considered statistically significant.348 patients with AIBD screened for immunoglobulin levels at CBD. Among these, 132 were treated with Rituximab or IVIG, and 216 were treated with CIST. Low serum IgM levels developed in 17 patients on CIST (Group III), 26 on RTX (Group I), and 12 on IVIG (Group II). The overall incidence of decreased serum IgM is low. In addition the number of patients in the three groups is relatively low and has the potential to negatively influence the interpretation of results.The demographics of 55 patients with low IgM levels are presented in The comparison of clinical and laboratory data on patients in Group I and II are presented in Amongst the 132 patients unresponsive to CIST, the incidence of IgM deficiency was as follows. In Group I treated with RTX, it was 19.6%, in Group II treated with IVIG, it was 9.6%, and in Group III (CIST), it was 7.8%. When the aggregate 55 patients with IgM deficiency were evaluated, 47.2% were on RTX, while 52.8% did not receive RTX.In all 55 patients, serum IgA levels were normal (Range from 49 to 298), with minor fluctuation. This evaluation was essential for all patients who were treated with IVIG, to exclude IgA deficiency.In the 348 patients with AIMBD, all were screened for IgG. In 55 patients, IgG levels were determined on multiple occasions and were normal (Range from 52 to 300). Patients who were treated with IVIG had higher than normal levels of IgG because IVIG contains only IgG.In all of the 38 patients treated with RTX, B cell depletion began within one month of the initiation of the therapy. B cells remained depleted for a mean of 18 months (Range 12-36) for Group I. IgM deficiency was recorded after three months of therapy (Range 1-24) for Group I. Reduced IgM was already present in Group II, because of earlier treatment with CIST. In Group II, B cells were depleted for a mean of 16 months (Range 9-36) Figure 2The level of IgM in the three groups was statistically significantly different Figure 3Some of the patients in Group II who had low IgM initially, when treated with RTX subsequently, the levels of IgM did not decrease further Figure 4The rate of clinical remission in Group I was 92% and 100% in Group II. This high rate of clinical remission in Group II can partially be attributed to the prior use of immunosuppressive agents (ISA). While the ISA did not produce a sustained clinical remission, their pharmacologic actions attributed to the final clinical outcome. In Group I, clinical remission began at a mean of 6 mo (Range 3-60) and was observed for a mean of 23 mo (Range 3-72). In Group II, it began at a mean of 10 mo (Range 3-24) and was observed for a mean of 26 mo (Range 3-105).The time to serologic remission rate was a mean of 18 mo (Range 3-60) for Group I, 16 mo (Range 1-60) for Group II.According to the results, one of 26 (3.8%) patients in Group I and one of 12 (8.3%) patients in Group II had pneumonia during the entire period of observation. It was diagnosed radiologically. It was resolved after oral systemic antibiotic therapy, which was administered at home by visiting nurses and ambulatory care. None of the patients were hospitalized because of their diseases or as a consequence of their treatments Table 2.The follow-up period was a mean of 54 months (Range 12-117) for Group II, and a mean of 37 months (Range 12-99) for Group I Table 2.Since the patients with low IgM levels treated with CIST had a milder disease, they were not included in the comparisons table. The mean time to IgM deficiency was a mean of 13.5 months (Range 6-21), and the mean duration of observation was 22 mo (Range 3-96). The rate of clinical remission in 16 patients was 94.2%, which occurred in a mean of 9 months (Range 1-48). The rate of serologic remission was 52.9% in 9 out of 17 patients. This occurred in a mean of 16 months (Range 3-120). The rate of SAE infection was one of 17 patients (5.9%).None of the 55 patients in our study group developed a second autoimmune disease. The detailed serologic evaluation did not show the presence of any autoantibodies associated with other autoimmune diseases. All of them were seen by a trained rheumatologist. Repeat serologies were negative. CT scans of the neck, chest, abdomen, and pelvis during remission did not reveal any tumor or infectious process.In the study, we have provided clinically relevant information on 55 patients treated at the CBD, Boston, MA, with various AIMBD, who developed IgM deficiency.There are statistically significant differences in the IgM deficiency in patients pre and post RTX therapy and between patients who received RTX compared to those on CIST. There were no significant differences in clinical outcomes, infection rate, and serological remission in all disease categories. Furthermore, IgM deficiency does not influence B cell depletion and repopulation and continues after clinical remission, off all systemic therapy, while CD20+ B cells reach normal pre-treatment levels.Since 52.8% of 55 patients had low IgM levels without RTX, it can be safely concluded that RTX alone is not responsible for low IgM levels. Low IgM levels are reported in other autoimmune diseases . The datDuring the follow-up period, some patients treated with RTX had low IgM levels up to twelve years of observation. In other autoimmune disorders such as RA, SLE initially low IgM levels are associated with long-term IgM deficiency , 19.This data demonstrates that the low IgM levels did not influence the duration of CD19+ B cells or the time for repopulation of B cells (CD19+). Interestingly, B cell repopulation to normal levels also did not influence the continued low levels of serum IgM. Only one patient with normal IgM prior to RTX therapy recovered from IgM hypogammaglobulinemia.It has been reported that the serum levels of IgM decreased with each consecutive infusion of RTX . In AIMBNone of the 55 patients with AIMBD with decreased levels of IgM needed to be hospitalized for infections, during the entire clinical course and follow-up period. This data suggest that there is no increased incidence of infection in IgM deficiency in AIMBD, as reported in other autoimmune disorders , 22.The underlying diseases can affect the prevalence and type of hypogammaglobulinemia . The IgMThe influence of drugs on serum IgM levels is multifactorial. The most important variable is the drug, the clinical indication, and when used during the clinical course. Patients with SLE who were treated with RTX and later mycophenolate mofetil developed low levels of IgM . LikewisThere are several limitations in the study. The first is that it is a retrospective study from a single tertiary care center. A control group is lacking. Most importantly, the lack of information on serum IgM levels at the time of diagnosis and before any systemic therapy was initiated, would have provided important insight into the peripheral immune system. Finally, the exact duration of IgM deficiency is not known and the ultimate or final consequence of this long term deficiency of IgM serum is not know . During In spite of these limitations, the observations in this study clearly demonstrate that in this cohort of patients with AIMBD, there is a selective decrease of serum IgM. Serum IgA and IgG levels are unaffected. While the frequency differed, all systemic therapy was associated with decreased serum IgM levels. These levels were present when the patient discontinued systemic therapy, were in clinical remission, and it lasted for considerably long durations. They did not after repopulation of CD19+ B cells, and these cells upon reaching normal and pretreatment levels and did not change serum IgM levels. The patients did not suffer from any severe infection or warrant hospitalization. Hospitalization is not very concerning to physicians in many countries for different reasons. In the US lack of hospitalization is critical because the cost of hospitalization is high and affects the overall cost of any therapy. None of the patients developed tumors or other autoimmune diseases. It is very important to note that the serum IgM levels were never undetectable. They significantly decreased but were never zero.IgM is considered to be a protector, regulator, and scavenger. Membrane-bound Ig M is dimeric, serves as the B cell receptor (BCR), and is important in B cell survival –31. SeruReduction of serum levels of IgM raises the important question of which cells produce IgM. Current data suggests that peritoneal B cells  are the main source . The bonReduction in serum IgM, which promotes survival of B cells in the peritoneum, reduces BCR signaling. Increased peritoneal B cells could provide more autoantibodies . This fuIgM deficiency predisposes to autoimmunity in humans and mice . ApoptotOne of the other mechanisms for the development of autoimmunity is the altered response to infections which can lead to chronic inflammation by an increased presence of (B1) B cells. This has been demonstrated in mouse models for SLE and diabetes , 43. NotRelevant to this study and others that use B cell depleting agents, is the observation that peritoneal B cells, seem to be fairly well protected from the B cell depletion, caused by the use of CD20 specific antibodies, such as RTX . Low serThe addition of IgM to commercially available intravenous immunoglobulin infusion (IVIg) could enhance its efficacy, protection from infection, and autoimmunity. This would help advance our knowledge on IgM and facilitate the development safe and novel therapies.In some patients with AIMBD, IgM deficiency is observed. While some readers may consider a cohort of 55 patients with AIMBD a small number, they need to realize two facts. First, these are orphan diseases. In such rare diseases, larger cohorts are not possible. Multicenter or multinational studies are not possible because pharmaceutical companies, who not infrequently fund such studies, would have no interest in reduced serum IgM. Second, these patients were studied in detail and had long term follow-up, which makes these observations meaningful and opens the road for investigators studying more common autoimmune diseases to study IgM deficiency in more detail. Could peritoneal B cells provide protection from infection and prevent autoimmunity?Factors that predispose a patient to develop IgM deficiency are currently unknown. It does not appear to affect clinical courses or outcomes and persist during remission. The study presents an interesting question. Could autoreactive B cells and/or plasma cells influence IgM synthesis, and what makes this process persist? Another key question that this study raises is whether IgM deficiency is the cause or the effect of autoimmunity and what are the predisposing factors. Investigators of the future may provide valuable insights on this conserved antibody that we know has existed for 500 million years.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.Both authors (AA and MA) contributed equally to the manuscript. MA collected the database and did the data analysis. AA generated the concept, edited the topic and revised the manuscript. All authors contributed to the article and approved the submitted version.This study was supported in part, by an unrestricted educational grant from the Dysimmune Diseases Foundation.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Chrebp overexpression causes fatty liver and lower plasma glucose levels, and ChREBP deletion prevents obesity and fatty liver. Intestinal ChREBP regulates fructose absorption and catabolism, and adipose-specific Chrebp-knockout mice show insulin resistance. ChREBP also regulates the appetite for sweets by controlling fibroblast growth factor 21, which promotes energy expenditure. Thus, ChREBP partly mimics the effects of carbohydrate, especially HFCS. The relationship between carbohydrate intake and diseases partly resembles those between ChREBP activity and diseases.Carbohydrates are macronutrients that serve as energy sources. Many studies have shown that carbohydrate intake is nonlinearly associated with mortality. Moreover, high-fructose corn syrup (HFCS) consumption is positively associated with obesity, cardiovascular disease, and type 2 diabetes mellitus (T2DM). Accordingly, products with equal amounts of glucose and fructose have the worst effects on caloric intake, body weight gain, and glucose intolerance, suggesting that carbohydrate amount, kind, and form determine mortality. Understanding the role of carbohydrate response element binding protein (ChREBP) in glucose and lipid metabolism will be beneficial for elucidating the harmful effects of high-fructose corn syrup (HFCS), as this glucose-activated transcription factor regulates glycolytic and lipogenic gene expression. Glucose and fructose coordinately supply the metabolites necessary for ChREBP activation and de novo lipogenesis.  Most foods  contain carbohydrates, which are macronutrients in the three groups monosaccharides, disaccharides, and polysaccharides . In addiResearch on the mechanism by which fructose and sucrose induce fatty liver and body weight gain has focused on the role of carbohydrate response element binding protein (ChREBP) ,8,9. ChRIn this review, I try to clarify the role of ChREBP in the relationship between carbohydrate intake and diseases. I first describe the relationship between carbohydrate intake and mortality, then the relationship between ChREBP and nutrition-related diseases, and finally unsolved problems related to ChREBP and nutrition.A recent study showed a nonlinear relationship between carbohydrate intake and mortality ,22,23. HAs the amount of mono- and disaccharides increases, mortality also increases. As sugar content increases in foods, the risk of obesity, T2DM, NAFLD, and mortality worsen in humans. The Y axis indicates the percentages of starch, glucose, fructose, sucrose, and dietary fiber to total carbohydrate contents in foods . Abbreviation: high-fructose corn syrup, HFCS.Among the several types of carbohydrates, sucrose and fructose are considered candidates that increase cardiometabolic risk ,25,26. SHowever, intestinal fructose absorption is slower than glucose absorption . ConsistSucrose and glucose/fructose feeding elicited insulin resistance and fatty liver in animal models ,35. In cHigh-fructose corn syrup (HFCS) is a sweetener made from corn starch  that is Dietary fiber is composed of a spectrum of nondigestible food ingredients, including nonstarch polysaccharides, oligosaccharides, lignin, and analogous polysaccharides . DietaryIncreased quintiles of dietary fiber intake were significantly associated with decreased mortality due to total cardiovascular disease, respiratory disease, and injury . Total fAs described in Formerly, carbohydrate response elements in the promoters of glucose response genes, such as liver-type pyruvate kinase, fatty acid synthase, and acetyl-CoA carboxylase, were identified as two E boxes separated by five nucleotide spaces (CAYGYGnnnnnCRCRTG); however, transcription factors that bind carbohydrate response elements (ChoREs) in lipogenic genes remain unidentified ,53,54. YChrebp mRNA in mice.ChREBP is a large protein Mr = 94,600 Da) composed of 864 amino acids and belongs to the MONDO family of basic helix-loop-helix- and leucine zipper-type transcription factors 00 Da com,52,57,582) activate ChREBP and thereby induce gene expression in the fructolytic pathway [Regarding the regulation of ChREBP, glucose-derived metabolites are important. Sucrose and fructose are more potent inducers of lipogenesis than starch and glucose. It is easier to metabolize fructose than glucose into acetyl-CoA, a substrate for lipogenesis ,68. A hi pathway ,12,13,14 pathway ,12,13,14 pathway ,72,73. U pathway ,72,73. U pathway . TherefoHFCS contains equal amounts of glucose and fructose and promotes intestinal fructose absorption. Much of the ingested fructose is converted into glucose metabolites in the intestine and delivered to the liver. HFCS also induces lipogenic genes and VLDL secretion. Hepatic ChREBP induces FGF21, a suppressor of sweet consumption, and adipose ChREBP regulates glucose uptake, lipogenesis, and branched chain fatty acid synthesis.The mechanism of ChREBP activity suppression has also been reported ,75,76,77Chrebp overexpression evoked fatty liver [Regarding its physiological roles, ChREBP regulates glucose and lipid metabolism in various tissues. In the liver, hepatic ty liver ,79, and ty liver ,81. Intety liver ,79,80,81ty liver ,79. Furt-/- mice. Whether dietary fiber promotes irritable bowel syndrome in ChREBP-/- mice remains unclear. As dietary fiber also promotes gut microbiota fermentation, dietary fiber intake may also cause irritable bowel syndrome in these mice. I will further investigate this phenomenon.In the intestines, ChREBP regulates both hepatic and fructose metabolism ,16,17. IChrebp caused systemic insulin resistance by reducing the levels of palmitic acid esters of hydroxy stearic acids (PAHSAs) [ChREBP is abundantly expressed in white adipose tissue ,54. ChRE(PAHSAs) . Moreove(PAHSAs) . WhetherChrebp suppression may also disrupt thermogenesis in a different manner. ChREBP may also exhibit a U-shaped regulatory effect on the function of brown adipose tissues.ChREBP is also highly expressed in brown adipose tissue ,86,87,88Chrebp-/- mice. Moreover, cholesterol is converted into cortisone in adrenal glands. Chrebp-/- mice showed normal adrenal cholesterol and cortisol content but decreased triglyceride content [ChREBP is moderately expressed in the adrenal glands . Plasma  content . Therefo content .Chrebp deletion causes improvement in proteinuria in streptozotocin-induced diabetic mice [ChREBP is highly expressed in pancreatic β cells ,91,92,93tic mice ,96. As oChREBP potentially regulates the intake of foods, especially sweets. Hepatokine FGF21 is regulated by ChREBP at the transcriptional level ,19,20. IChrebp in vitro and in vivo leads to a p53-dependent reduction in tumor growth [Finally, the relationship between ChREBP and malignant tumors has been investigated ,101,102.r growth , which ir growth .Thus, these results indicate that ChREBP has both beneficial and harmful effects on the development of chronic diseases, such as metabolic syndrome and cancers . These fChrebp suppression prevents obesity and fatty liver but promotes sucrose insufficiency and insulin resistance. Chrebp overexpression promotes lower plasma glucose but fatty liver.Studies in humans have shown that carbohydrate type is an essential determinant of food intake. Moreover, the different effects of whole fruits and sugar-sweetened soft drinks are interesting. In an animal study, the route of glucose/fructose administration was not considered. Therefore, to evaluate the effect of carbohydrates on metabolic conditions, we should consider the composition of carbohydrates  . ConsideThe order of eating (vegetable first and carbohydrate last) is also known as the method of lowering plasma glucose and body weight ,106,107.Currently, a low-carbohydrate diet is widely recommended to obese people for the purpose of lowering body weight. In elderly patients, protein intake is recommended to prevent sarcopenia . HoweverThe role of ChREBP in muscle function is also an interesting topic.MondoA-/- mice exhibit muscle fiber atrophy, a reduced proportion of type II fibers compared to type I fibers, and an increased muscle glycogen level [The relationship between ChREBP and muscle function, MondoA, a ChREBP paralog, has been studied. MondoA, a ChREBP paralog, is abundantly expressed in muscle ,114. MonChrebp-/- mice show insulin resistance [-/-MondoA mice, the muscle glycogen content in Chrebp-/- mice is similar to that in wild-type mice [Mondoa-/- mice, ChREBP might compensate to regulate glucose metabolism and improve muscle glucose uptake; however, the MondoA binding site (CACGTG) was not always the same as the ChREBP binding site (CAYGYGnnnnnCRCRTG) [-/-Chrebp x. -/-Mondoa mice will be needed.Regarding ChREBP, sistance . Unlike ype mice . Howeverype mice , ChREBP nCRCRTG) ,115,116.Recent human studies have shown that the appropriate amount of carbohydrate intake is essential for longevity. These findings are the same as the results of studies using mouse models modulating ChREBP activity. Excess carbohydrate restriction or carbohydrate  intake may be harmful through the overmodification of ChREBP activity. Clarifying the position of ChREBP in diseases and diet therapy will be important in understanding the relationship between carbohydrate intake and mortality.