Type 1 diabetes (T1D) is increasing in young people worldwide and more children in resource limited settings are living into adulthood. There is a need for rigorous testing and reporting of evidence-based and stakeholder-informed strategies that transition individuals with T1D from pediatric to adult care. We present the development of and design of the first structured transition program in Delhi, India, to inform similar efforts in India and resource limited settings.The intervention development team included clinicians and researchers with expertise in T1D and the implementation context. To select intervention outcomes, establish intervention targets, and design session modules, we drew upon formative research conducted at prospective intervention implementation sites, consensus guidelines, and previous care transition and behavior change research conducted in developed settings. We used the Template for Intervention Description and Replication and GUIDance for the rEporting of intervention Development checklists to report the intervention and development process.The 15-month program (“PATHWAY”) includes five quarterly ~30 minute sessions delivered predominantly by diabetes educators at pediatric and adult clinics, which coincide with routine care visits. Primary program components include educational and behavioral sessions that address psychosocial drivers of clinic attendance and self-management, diabetes educators as transition coordinators and counselors, and a one-year “overlap period” of alternating visits between pediatric and adult providers.We followed a systematic and transparent process to develop PATHWAY, which facilitated rich description of intervention context, guiding principles, targets, and components. Dependence on previously published program examples to design PATHWAY may have introduced challenges for program feasibility and effectiveness, underscoring the importance of input gathering from prospective intervention actors at multiple points in the development process. This detailed report in combination with future evaluations of PATHWAY support efforts to increase rigorous development and testing of strategies to improve outcomes among emerging adults with T1D. One of the most common chronic illnesses diagnosed in childhood, type 1 diabetes (T1D) is not only increasing in incidence worldwide, but also in prevalence as treatment advances enable more children to live into adulthood . Since tThe transition between childhood and adulthood is a physiologically and behaviorally challenging stage during which individuals with T1D all around the world are least likely to meet target glycemic levels, despite being a crucial period for adopting healthy lifelong habits to prevent later adverse health outcomes –10. AlthTo improve care engagement and glycemic management during emerging adulthood, consensus guidelines promote beginning an intentional transition process from early adolescence that includes gradual practical and psychological preparation to assume self-management tasks independently and navigate the adult clinical care setting and treatment encounters ,16–20. IOur formative qualitative work among providers, patients, and parents across a sample of private and public clinics in Delhi, India indicated differences in system, clinic, and patient-level factors relevant to the transition process and post-transfer outcomes as compared to the higher resource settings that dominate the existing evidence base on emerging adults with T1D ,25. InfoHealth facilities in India also vary widely within and across public and private settings as regards provider training, treatment and prescribing practices, patient to provider ratios, patient socioeconomic status and out-of-pocket costs. Whereas a visit with an endocrinologist at a public facility could be as low as 0–10 Indian rupees and include a supply of basic insulin , the cost of a consultation at a private facility could reach up to 2000 Indian rupees, exclusive of insulin. As such, because most health care costs are borne by the patient in India, patients of public facilities are more likely to be low or middle income, uninsured, have low literacy, and be unable to afford insulin, blood glucose test strips, or advanced diabetes self-management technology; in contrast, patients of private facilities are more likely to be insured or have a level of income that affords private clinic consultation fees, analog insulin, and routine use of continuous glucose monitoring systems and insulin pumps. Because pediatric endocrinology is not a widely prevalent specialty, adult physicians may treat children from T1D diagnosis and pediatric physicians may treat children from T1D diagnosis into adulthood. Gaps in knowledge therefore persist regarding how to adapt and implement care strategies in lower resource contexts such as India that were developed and evaluated in developed settings, as well as the effectiveness of such strategies in these contexts.Additionally, detailed reports about the development processes that underpin interventions are extremely limited, which poses obstacles for intervention replication and improvement efforts ,26. MoreThe objective of this article is to report the process and outcomes of developing a formal program to improve frequency of routine clinical care attendance and self-management among emerging adults with T1D in Delhi, India after transfer from pediatric to adult care. A systematically developed, theoretically and empirically sound program is foundational to our subsequent aims to rigorously test the program via a randomized controlled trial (CTRI/2020/10/028379), modify the program for additional and larger scale evaluations, and ultimately, inform clinical practice guidelines for managing T1D care transitions in India. Through standardized, detailed reporting of the intervention development process and resulting program, we also contribute to efforts to increase rapid development, testing, and sharing of theory, evidence, and stakeholder-informed transition of care interventions for emerging adults with T1D in India and other resource limited settings.The central intervention development team was mainly comprised of endocrinologists, diabetes educators, and researchers with training in epidemiology and behavior change who had context-specific expertise in pediatric and adult T1D and who were employed by a public research hospital in Delhi, India that was also an intervention implementation site. We followed the GUIDance for the rEporting of intervention Development framework to report each step of the intervention development process  26]. Th. Th26]. A guiding principle of the intervention development process was to promote likelihood that the program could be integrated into existing clinical care practice and widely disseminated across more clinical settings in India if proven effective. As such, a priority was for intervention sessions to coincide with quarterly clinic visits–the minimum recommended frequency of clinical care visits according to consensus guidelines ,7. A relPediatric to Adult Transition Care for the Health and Wellness of Adolescents with Young Diabetes in India program (PATHWAY), we used a “combination” approach by integrating three formal approaches to intervention development [In developing the elopment . Startinelopment –23,29. Selopment .In December 2019, via a 3 hour in-person workshop with 40 providers from prospective public and private intervention sites, the central research team presented and elicited feedback on the idea of a formal transition program as well as potential intervention and program design options identified through literature review and preliminary findings from the formative research.A series of bi-weekly one hour working sessions with the central research team were subsequently held over a one-year period to integrate evidence from the formative research, published literature, and clinician feedback, in order to first draft the structure of the intervention at a high level , and then to draft session content and material in detail.To prioritize and select the constructs that the intervention would target at provider and patient level , we combined context-specific insights from the formative research together with evidence gathered through our literature review, as well as the expanded Social-Ecological Model of Adolescents and Young Adult Readiness for Transition (SMART), an empirically developed, stakeholder and social-ecological theory informed model of the social , interpersonal , and individual-level  factors that shape transition readiness and related health outcomes –22,30–34Once the high-level design of the intervention was established, the development of specific session activities and materials began with aggregating strategies and content from published health care transition and behavior change studies in emerging adults with T1D, or recommended by T1D or health care transition consensus guidelines to address the priority constructs ,22. ThesReinforcing findings from our qualitative formative interviews, clinician participants in the stakeholder workshop held in December 2019 expressed unanimous endorsement of a formal transition program . Due to At the follow-up workshops held in October 2020, participants were particularly concerned about successfully convincing patients to switch providers and thus emphasized the importance of incorporating repeated efforts from multiple transition program actors to persuade the patient about the rationale for transfer and manage any misunderstandings that might discourage them from seeking care. This feedback resulted in developing consistent messaging about the rationale for transfer and designing sessions so that this messaging was repeated by adult and pediatric physicians and diabetes educators throughout the program. Workshop participants also suggested that the control group be provided with slightly more support than just receiving notice of the deadline for transfer to adult care in order to motivate their participation and so that the control condition approximately mimicked the most supportive way transfer is currently managed in the existing clinical landscape. This feedback influenced the decision for the control group, and thus the PATHWAY transition program comparator condition, to represent a type of ‘bare bones’ or ‘minimalist’ one-session transition program.As previously described, a comprehensive report of the results from the qualitative formative interviews has been published elsewhere . The wayThe PATHWAY transition program that will be tested in a future randomized controlled trial is described below. The logic model in A growing evidence base suggests post-transfer clinical care engagement and glycemic management are improved through structured transition interventions that include both a “transition clinic” to build rapport with the adult diabetes providers  and “transition coordinators” who counsel emerging adults on practical and psychosocial factors that impact clinical visit attendance and self-management adherence in adulthood ,23. Our Our formative research also highlighted several context-specific reasons to position diabetes educators at the center of the structured transition program as transition coordinator and counselor. One of the facilitators of care engagement and diabetes self-management most commonly cited in our formative research included trust that the adult provider not only understands the emerging adults’ diabetes treatment regimen, but also empathizes with and helps address the psychosocial factors that shape an emerging adult’s self-management difficulties . Given tOur review of published studies and expert consensus guidelines about care transitions and behavior change among adolescents and young adults with type 1 diabetes also underscored the importance of proactively managing transition-related psychosocial factors in order to improve care engagement and health outcomes after transfer: attachment to and reluctance to leave pediatric provider, lack of awareness of transition timeline, unfamiliarity with differences in adult provider approaches, expectations of patients, and visit procedures ,23. AddiAlthough our formative work reinforced the importance of all these factors to varying degrees, when designing the intervention sessions and their comprising educational and behavioral activities, we targeted the factors that were especially salient according to our context-specific investigations . The matWe decided upon several main changes in transition program content and structure during our bi-weekly intervention development team meetings. First, findings from our formative research and first stakeholder engagement workshop led us to revise our plans to completely rely on the clinic employed diabetes educators to coordinate and deliver the program. Four diabetes educators were employed by the intervention development team to support session delivery during the randomized controlled trial so as to prevent against over-extending existing resources at participating sites, which could dilute fidelity in intervention delivery, lower the rigor with which the strategy was tested through the randomized controlled trial, and reduce provider buy-in for the program. Although this design decision will challenge immediate translation of the program into existing clinical practice if trial results indicate program effectiveness, information gathered from the planned RE-AIM evaluation  of the randomized controlled trial will generate insights about the staff time and monetary resources that may be required by practices to implement the strategy as well as generating suggestions about the components of the program that may be particularly important for driving target outcomes. These insights could inform a strategy to pare-down the program design to increase feasibility and uptake into existing settings, which could then be assessed for effectiveness through a future evaluation. Second, after the second stakeholder engagement workshop, we made adjustments to deliver a session , which we plan to rigorously test in a randomized controlled trial in future steps. Strengths include integrating the evidence base from high resource settings together with context-specific stakeholder perspectives from our formative work in order to identify the intervention targets and strategies that define the program. Such an approach may increase the potential that the program promotes intended outcomes among emerging adults with T1D in Delhi, India. Further, our use of GUIDED and TiDIER reporting frameworks  to transLimitations and persisting uncertainties include that the care transition evidence base and our formative research that informed the PATHWAY program were undertaken before COVID-19, which introduce the possibility that unexplored intervention targets and strategies could be relevant to our target population and setting, but are not incorporated into program design. Although we will not systematically collect information to address this point of uncertainty before the program is tested through a clinical trial, a planned mixed methods Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) evaluation of the trial will help to identify these factors and enable future refinement of the program. We purposively designed the program to rely on the diabetes educators employed by adult and pediatric clinics to deliver as much of the intervention as possible in order to minimize program expense and maximize potential that the program would be more widely adopted and tested if proven effective through our initial randomized controlled trial evaluation. However, this choice also introduces risk of low and variable fidelity across implementation sites. To promote fidelity and prevent drift, we designed scripted counseling materials to facilitate consistent implementation across sites and we will also monitor a random subset of intervention sessions throughout implementation as part of the trial. The aforementioned RE-AIM evaluation will enable us to understand differences in fidelity across sites and time, identify factors that potentially underly these differences, as well as explore the influence of these factors on the trial outcomes observed.Detailed reporting of interventions and their underlying processes are limited, especially in the context of resource limited settings and T1D care transitions. Our systematic development and reporting of the PATHWAY program is an important foundational step towards identifying strategies that may benefit the self-management of emerging adults with T1D in India and similarly resourced settings.S1 Appendix(DOCX)Click here for additional data file.S2 Appendix(DOCX)Click here for additional data file.S3 Appendix(PDF)Click here for additional data file.


Unfortunately, instruction on optimal program staffing structure is lacking. Furthermore, existing data are dichotomized into large (>40 transplants/y) or small (<40 transplant/y) programs, limiting program-specific interpretation for process improvement. Moreover, there are few details on procedure volumes, inpatient census, and planning for anticipated growth. Consequently, many lung transplant programs look to data in other solid organ fields for staffing guidance.5 However, such models may not be generalizable to the lung transplant community because lung allograft recipients have greater mortality, acute rejection, and comorbidities.7 To address this knowledge gap, we performed a prospective, multicenter, survey assessment of staffing in lung transplant programs across the United States and Canada. Program leadership was surveyed about clinical volumes, staffing adequacy, anticipated growth, and accommodations for coordinator workplace flexibility. These results provide a critical overview of staffing and identify key opportunities for improving logistics.Approximately 2500 lung transplants are performed in the United States annually, yet there remains a significant shortage of suitable donor organs, resulting in lung transplant waitlist mortality of 15%.Table S1, SDC, http://links.lww.com/TP/C658) was administered via Research Electronic Data Capture to medical directors of active adult lung transplant programs in the United States and Canada identified through the Organ Procurement and Transplantation Network.8 Only 1 response was allowed per program. Weekly reminders were sent for 1 mo if there was no response.A 29-item survey .Results were stratified into thirds by program size based on transplant procedures performed in 2021 with <30, 30–65, and >65 transplants/y defining small, medium, and large programs, respectively. Results were adjusted to 2021 transplant rates or total living cohort size, to facilitate comparisons between programs. Workload was calculated by dividing the metric of interest by number of full-time equivalents for the respective role; full-time equivalent equals scheduled hours divided by number of full-time workweek hours. Kruskal-Wallis testing was used to compare continuous variables across program sizes. Pairwise comparisons were performed using Mann-Whitney Table S2, SDC, http://links.lww.com/TP/C658, summarizes the volume at each program, pretransplant metrics , and posttransplant metrics . Across all programs, 15% of referred patients were added to the transplant waitlist, whereas 40% of patients who completed evaluation were waitlisted . There was no difference in progression from referral through evaluation and waitlisting by program size. Daily inpatient census was 33% of the annual transplant volume and was significantly higher for smaller programs . The ratio of inpatient volume relative to the census of alive patients was 5% and did not vary by program size (P = 0.56). Ambulatory weekly volume was 103% of the annual transplant volume  and did not vary by program size. Weekly bronchoscopy volume was 18% of annual transplant volume, with small programs performing more bronchoscopies than large programs . Program metrics normalized to annual transplant volumes are in Figures S1, S2, SDC, http://links.lww.com/TP/C658.The survey was distributed to 63 active adult lung transplant programs, with 39 (62%) responding. Responses were received by 11 of 27 (41%), 13 of 19 (68%), and 15 of 17 (88%) of small, medium, and large programs, respectively. Medical directors (85%), other physicians (13%), or administrators (3%) provided responses. The median number of new transplants performed in 2021 was 46 (interquartile range 28–70). There was a significant difference in the number of transplants performed between small, medium, and large programs. Table S3, SDC, http://links.lww.com/TP/C658. There were significant differences in the number of surgeons, pulmonologists, inpatient advanced practice providers, coordinators, social workers, administrative assistants, and nutritionists by program size. There were no significant differences in the number of outpatient advanced practice providers, pharmacists, psychiatrists, or physical therapists by program size. There were significant differences in the number of pulmonologists and posttransplant coordinators between medium and large programs . There were significant differences in the number of pulmonologists, pretransplant coordinators, and posttransplant coordinators between small and medium programs.Professional staffing by each position is in Figure  and Table S4, SDC, http://links.lww.com/TP/C658. Across all programs, there was 1 surgeon per 16 new lung transplants and 1 pulmonologist per 13 new transplants. Each posttransplant nurse coordinator provided care for a median of 77 patients, with 15% being within the first-year posttransplant. There were significant relative workload differences for pretransplant coordinators, posttransplant coordinators, pharmacists, and social workers between medium and large programs. The only role with a difference in workload between medium and small programs was nutritionists. When referenced to total cohort size, there was a relative workload difference between medium and large programs for postcoordinators and between small and large programs for pharmacists .Relative workloads for each staff position are described in Table S5, SDC, http://links.lww.com/TP/C658). The most understaffed positions reported were pulmonologist (36%), surgeon (23%), and posttransplant coordinator (10%). There were no differences in perceived sufficiency by program size. Despite perceptions of insufficient staffing, most programs (77%) planned to increase program volume within 5 y by a median of 37% .Only 23% of programs perceived that current staffing resources were sufficient; most of these were large . Although remote work options for nurse coordinators were numerically greater in large versus small programs (60% versus 20%), this difference was not statistically significant. Nursing and medical leadership had differing perspectives as to the ideal remote work schedule, with nursing suggesting that 2 d/wk (40%) was adequate, whereas medical leadership felt that 1 d/wk (20%) was sufficient (P = 0.04).The COVID-19 pandemic provided an impetus to improve workplace flexibility for transplant staff. Regardless of program size, most programs polled (59%) instituted remote capabilities for nurse coordinators. Most programs allowed for 40% of the work week to be spent working remotely  of the week. Further assessment is necessary to determine the ideal balance between staff flexibility and patient outcomes.4 High participation was achieved because of the concise design, use of proactive weekly reminders to facilitate responses, and recognition among program leadership about the need for granular staffing data. Another strength is the breadth of representation of programs of different sizes. We also included workload assessments for a wide variety of clinical and nonclinical transplant team roles. Our study also has some limitations. Response rate of small programs was lower than large programs. In addition, we were unable to account for program-specific variation in staff role responsibilities; for example, pharmacists might have an outpatient presence in some programs, but only work with inpatient teams at others. It is also possible that staffing needs vary by patient demographics, geographic region, urban versus rural environment, patient travel distance, or involvement of medical housestaff. Notably, this work does not directly assess the influence of staffing ratios on patient outcomes, which would be an important natural extension in future studies.Our study has multiple strengths. The 62% response rate shows that our data represent most North American transplant programs and exceeds the survey response rate of 30%–40% seen in similar studies.In conclusion, our study provides a detailed description of staffing resources for lung transplant programs across North America, highlighting current staff workloads and providing critical data to provide logistical support for program optimization.


The Supporting and Enhancing NICU Sensory Experiences (SENSE) program promotes consistent, age-appropriate, responsive, and evidence-based positive sensory exposures for preterm infants each day of NICU hospitalization to optimize infant and parent outcomes. The initial development included an integrative review, stakeholder input , and feasibility focus groups. To keep the program updated and evidence-based, a review of the recent evidence and engagement with an advisory team will occur every 5 years to inform changes to the SENSE program. Prior to the launch of the 2nd edition of the SENSE program in 2022, information from a new integrative review of 57 articles, clinician feedback, and a survey identifying the barriers and facilitators to the SENSE program’s implementation in a real-world context were combined to inform initial changes. Subsequently, 27 stakeholders  carefully considered the suggested changes, and refinements were made until near consensus was achieved. While the 2nd edition is largely the same as the original SENSE program, the refinements include the following: more inclusive language, clarification on recommended minimum doses, adaptations to allow for variability in how hospitals achieve different levels of light, the addition of visual tracking in the visual domain, and the addition of position changes in the kinesthetic domain. The Supporting and Enhancing NICU Sensory Experiences (SENSE) program was developed following research that identified alterations in the brain structure and function in hospitalized infants in low-stimulation NICU environments . The SENThe SENSE program was developed using a stepwise, rigorous, and scientific process, which included a review of the published literature from the previous 20 years to identify appropriate, evidence-based multisensory interventions for preterm infants in the NICU, along with the timing of when those interventions took place within each study . Expert The SENSE program was also designed to encourage parents to be the providers of positive sensory exposures to their infants. Parents often struggle with role alteration when their young infants are hospitalized in the NICU , and manSince the launch of the initial SENSE program, research has been conducted to understand the impact of the program on infant and parent outcomes. A pilot study identified that, among families who received the SENSE program, mothers demonstrated improved confidence and infants demonstrated improved neurobehavior at the term-equivalent age . SubsequResearch on the implementation of the program has identified that the SENSE program has good reach (was received by the targeted population), is effective and acceptable with minimal costs, and has good fidelity . AnotherThere has been a large demand for the SENSE program among NICU clinicians worldwide since the program materials were made available to other hospitals in 2018. The cost of the program supports only the cost of its distribution, with no direct financial benefit to any person or entity.Due to continuously emerging research on sensory exposures related to improved outcomes, we have committed to a new review of the evidence and engagement with an advisory team to inform changes to the SENSE program every 5 years. The purpose of this manuscript is to define the process for informing revisions, outline the decision-making process as to which changes should be made, and identify the refinements made to the SENSE program in 2022.The original process of the SENSE program’s development has been previously described . A compaAn updated integrative review was conducted through a systematic search for studies published from October 2015 to October 2020 using databases including MEDLINE (via PubMed), CINAHL , the Cochrane Library, and Google Scholar. Studies were included if they imposed a quantifiable environmental sensory exposure during the NICU stay, prior to 36 weeks PMA. The relevant outcomes included infant behavioral outcomes, neurobehavioral outcomes, parent well-being, and other parental outcomes. Studies with outcomes related solely to pain or feeding were excluded. Samples of healthy infants and studies with a sample size of <30 and without an a priori calculation of power were excluded. Two reviewers set the search engine and screened articles for inclusion. One reviewer performed data extraction that was checked for accuracy by a second reviewer. An assessment of study quality was independently performed by two reviewers using the United Kingdom’s National Institute for Health and Care Excellence (NICE). Study findings were summarized qualitatively, with evidence related to each type of sensory intervention defined across PMA. Fifty-seven new articles on sensory-based interventions  were identified that were used to improve outcomes for preterm infants and their parents in the NICU .Clinician input across the previous 5-year period  was compiled. With the increased focus on small baby programs, much of the clinician guidance focused on an interest in further differentiating how to safely tailor SENSE interventions to the small baby.The SENSE Program Implementation Survey was sent out to 211 hospitals who had obtained the SENSE program prior to 11 March 2020, to probe perceptions of the program and better understand implementation, costs, and adaptations made across sites. Among 114 respondents (54% response rate), important insights about acceptability, adoptability, barriers, and facilitators were identified, which informed changes to the parent education materials and administration and implementation manual. Information that guided modifications included that 33% of respondents indicated that they made adaptations to the SENSE program to facilitate implementation, and 64% of them were planned/proactive, while 36% were reactive. Most (64%) of these adaptations were determined by the therapist and had to do with adapting to the NICU context (58%). Some respondents indicated interventions in the SENSE program that their NICU did not endorse, including music (19%), massage (15%), talking to the infant during sleep (4%), use of vestibular stimulation (4%), and any interventions for infants < 26 weeks PMA (4%). There were 88% of respondents who indicated that they use the SENSE parent education materials, with most of them (80%) using the printed materials. There were 80% of respondents who indicated that they assess the tolerance of the infant, with 57% of them using the materials in the SENSE program to do so.Once the new evidence, clinician guidance, and survey had been completed and results carefully considered, a SENSE advisory team  was assembled. All healthcare professionals had a minimum of 5 years of clinical experience working in a NICU. The SENSE advisory team had the goal of ensuring that the SENSE program was evidence-based, incorporated the most current published literature, remained appropriate for different types of families, and was applicable to a variety of NICU settings. A call for members of the SENSE advisory team was made through email and social media groups for those interested in neonatal therapy research and those who were familiar with the original SENSE program. Each member was asked to commit 10 h for a period of up to one year to engage in online meetings, discussions, and individual review of materials. The larger 27-member group was broken into work groups of 2–7 individuals to weigh in on specific components of the program . The work groups reviewed the new evidence and the changes suggested to the program. An iterative and interactive process occurred with the research team until near consensus was achieved on the suggested refinements to each section.All of the findings from the previous systematic and scientific process undertaken to develop the SENSE program, the new integrative review, clinician guidance, the implementation survey, and advisory team feedback were used to refine the SENSE program, which included improvements to the parent education materials and the implementation and administration manual.The new integrative review (2015–2020) identified many interventions that had already been defined in the previous integrative review (1995–2015). However, the new integrative review provided evidence to support some additions, as well as modifications, to the timing and wording of the information contained in the SENSE program. Below, we identify the changes and rationale for the recommendations related to each sensory system, as well as for content in the The previous integrative review identified evidence-based tactile interventions to be gentle human touch, skin-to-skin care, holding, and massage. The new integrative review expanded the evidence base for skin-to-skin holding to include its use as early as in the delivery room ,27. TherThe timing for the introduction of massage received increased attention by the SENSE advisory team following the second integrative review. There is some emerging evidence supporting massage as early as 28 weeks PMA . HoweverThe terminology for “gentle human touch” was changed to “hand hugs” in the 2nd edition of the SENSE program, as this terminology has grown in acceptance and was considered to be more parent-friendly than other terms such as facilitated tuck, containment, and gentle human touch.The previous integrative review identified evidence-based auditory interventions to be live music or singing, recorded sound , and recorded biological sounds. The new integrative review did not add additional interventions but did bring up some needed clarifications, such as the use of different decibel levels, use of headphones (versus not using headphones), type of music (such as pentatonic harp), and type of lullaby (such as Brahms lullaby). The auditory guideline remained the same in the 2nd edition of the SENSE program, with the use of quiet conversations at the bedside at the earliest PMAs, introducing reading and singing at the bedside at 28 weeks PMA, introducing music at 32 weeks if the infant tolerates it, and building up to a minimum of 3 h of intentional auditory exposure per day by term-equivalent age with a focus on an environment rich in language exposure.There were studies from the new integrative review using recorded maternal voice and music prior to 32 weeks. One study using Brahms lullaby between approximately 29 and 34 weeks PMA identified differences in oxygen saturation levels, which was not a primary outcome of interest for our integrative review . HoweverDecibel levels have also been a focus of attention. While the American Academy of Pediatrics and the World Health Organization recommendation for sound exposure is an average of 45 decibels, few NICUs meet this requirement ,39. The The previous integrative review identified maternal scent and breast milk as the only evidence-based olfactory exposures. Clarifications about the use of breast milk scent were added to the 2nd edition, as the original program largely focused on the smell of the parent. A discussion occurred regarding the addition of an assigned time recommendation for olfactory exposure, as it is one of the only senses in the program that did not have a time target. This idea of a time target also heightened discussions about the use of a constant smell and whether infants might habituate to it. In addition, there was discussion about the potential impact and associated learning if a scent was placed by an infant and then they had multiple noxious stimuli that occurred. Based on evidence supporting the use of the scent of the parent and breast milk for 3 h , this miIn the previous integrative review, interventions largely focused on the light environment, specifically on the use of cycled light, starting at 32 weeks PMA. There was also some evidence on the use of the parent’s face for visual exposure closer to term-equivalent age. The new integrative review identified positive outcomes associated with having infants fix and follow a toy or human face starting at 34 weeks PMA . TherefoThere is not strong evidence to support cycled light prior to 32 weeks ,46, whicFor cycled light, a specific time  has been replaced with “during the day” and “during the night” in the 2nd edition to allow NICU staff to find a pattern that works for them . Another important factor discussed was the benefit of gradual light transitions as in normal day/night rhythms. This is important, because sudden changes in light can impact sleep ,47,48. SAnother important discussion point was light intensity. The literature identifying the impact of cycled light has variable lux levels ranging from 75 to 500 lux during the daytime , with moThe previous integrative review included interventions described as physical therapy, but with outcomes largely focused on bone health. The new integrative review expanded the repertoire of evidence-based kinesthetic interventions to include guided movement and position changes. There is also emerging evidence to support passive range of motion (PROM), but since the positive outcomes in these studies were related only to bone health and weight gain (and not to neurobehavior), PROM was not added to the SENSE program at this time. The guideline continues to include opportunities for free movement and supporting the infant’s smooth movements when appropriate . Clarifications were added that infants at low PMA may not tolerate free movement, and that such free movement can be contained and/or occur within the confines of positioning devices or by allowing movement of one extremity at a time, especially when performed with the 23–28 week PMA population.The 2nd edition of the SENSE program also now includes recommendations that the infant experience at least two different positions each day for a minimum of 10 min each  at the earliest PMAs. By 34 weeks PMA, the recommendation is for infants to experience being in at least three different positions each day, with tummy time being one of them. These positions may occur at any time throughout the course of a 24 h period and may already be encouraged based on position change recommendations that are part of standard care. Tummy time is important throughout infancy , and encParent education materials for the 2nd edition of the SENSE program consist of an 88-page booklet written at a 5th to 8th grade reading level that includes a glossary of common NICU terms along with chapters that detail the importance of parents and why their involvement matters, development of the senses, specific guidelines for how to provide sensory experiences, guidance on when to interact based on their baby’s cues, a “how to” guide with recommendations for sensory experiences to share with their baby each day of hospitalization with “doses” to target that evolve across PMA, and detailed instructions and videos for how to share sensory experiences (such as massage or gentle rocking) with their baby. This parent booklet is now available in English, Spanish, Arabic, French, Korean, Hindi, Chinese, and Hebrew, with additional translations ongoing. In addition to a print version of the booklet, these materials are also accessible electronically via a QR code to enable easy access on smart phones and/or tablets.General changes were made to the wording in the 2nd edition of the SENSE program based on the results of the integrative review, advisory team feedback, survey responses, and informal clinician feedback. The chapters of the parent education booklet were re-organized and modified for inclusion, clarity, and promotion of parent engagement. Minor formatting changes were made to improve the aesthetics of the program and enhance the clarity of the content.In recognition of evidence regarding gender-affirming care , the lanThe weekly infant assessment of tolerance is included as an optional component of the SENSE program to allow clinicians to formally evaluate whether infants are tolerating the interventions as described. In a large level IV NICU, it was found that 95% of infants tolerated the original SENSE program as described, but 5% required temporary adaptations based on a medical status that typically lasted a few days to a few weeks before returning to the program recommendations . ExperieThe implementation and administration manual is a supplemental resource that serves as a “user manual” for clinicians to implement and support the program, with information regarding the development of the program, strategies for implementation, and adaptations that can be made to the program. Changes to the implementation and administration manual of the SENSE program were made based on the SENSE implementation survey, clinician guidance, and the advisory team’s feedback. A definition of the SENSE program was added, along with a rationale for the program and a detailed description of the process of developing the SENSE program. The ongoing commitment to evidence-based programming was emphasized, with the intention to update it every 5 years. The manual was reorganized to guide clinicians in three main subsections: components of the program, necessary personnel, and materials to assist in implementation. The added items to assist with implementation were a map of an implementation strategy, an implementation checklist, and examples of adaptations that can be made based on individual and organizational factors. It was also clarified that the process of implementation can be an iterative process of implementation, assessment of progress, and then adaptation. Specific lux levels and decibel levels to go along with the program recommendations were added to the manual for clinicians to have quantifiable targets, with suggested tools to aid clinicians in assessing light and sound in their NICUs. Additional factors surrounding the first 72 h were added to aid clinicians in evidence-based practice and determine choices of sensory exposures that align with their hospital’s policies and culture. The manual was also updated to include strategies for engaging families, provide applause for small progress toward positive sensory exposures, and outline recommendations to integrate the program into the context of daily life in the NICU.This manuscript discusses changes to the SENSE program that were made in 2022. The goal was, and will continue to be, to keep the SENSE program aligned with the latest evidence. The refinements made ensure that the program stays evidence-based and meets the needs of infants, families, and healthcare providers worldwide. The program will continue to be updated every 5 years using a similar process of an integrative review of new evidence, advisory team input, and survey feedback from hospitals that have obtained the program.While the research to date has identified associations of the SENSE program with parent confidence, as well as infant neurobehavior and outcomes ,18,21, mWhile a systematic and rigorous process was used to refine the SENSE program, there were some limitations. The integrative reviews that now encompass 25 years of research were limited based on the inclusion and exclusion criteria, and many of the studies lacked clarity of when the interventions were conducted. This led to assumptions being made with the available information. The informal feedback from clinicians that was compiled over the previous 5 years was not formally analyzed using qualitative techniques, and it could be subject to bias based on receiving responses only from individuals who reached out. The implementation survey is limited by being a survey, rather than a direct observation of the SENSE program implementation. The timing of this survey was also challenging due to the impact of the COVID-19 pandemic on medical care in the NICU. The SENSE advisory team was made up of parents and healthcare professionals who were willing to volunteer their time to aid this process and may not reflect all the views of parents and healthcare professionals. When combining all the information through these processes, choices and decisions were not always clear, and discussions had to occur until near consensus was achieved. Despite the limitations, we have confidence that the 2nd edition of the SENSE program is evidence-based, incorporates stakeholder feedback, and is best practice in terms of sensory exposures for preterm infants in the NICU.There has been a high demand for the SENSE program, especially in the United States, but also extending to other countries including Canada, Italy, Malta, Mexico, Chile, Switzerland, Spain, Taiwan, the United Arab Emirates, Qatar, Australia, South Africa, Argentina, New Zealand, Costa Rica, Turkey, the United Kingdom, Singapore, India, and Israel. More than 400 hospitals have obtained the program worldwide. Updates to the program will ensure that the thousands of infants and families who are reached by the program are receiving sensory experiences that have the power to improve hospital, family, and infant outcomes.


Structured lifestyle change education reduces the burden of cardiometabolic diseases such as diabetes. Delivery of these programs at worksites could overcome barriers to program adoption and improve program sustainability and reach; however, tailoring to the worksite setting is essential.The Integrating Diabetes Prevention in Workplaces (INDIA-WORKS) study tested the implementation and effectiveness of a multi-level program for reducing cardiometabolic disease risk factors at 11 large and diverse worksites across India. Herein, we describe and classify program adaptations reported during in-depth interviews and focus group discussions with worksite managers, program staff, and peer educators involved in program delivery, and program participants and drop-outs. We used thematic analysis to identify key themes in the data and classified reported program adaptations using the FRAME classification system.Adaptations were led by worksite managers, peer educators, and program staff members. They occurred both pre- and during program implementation and were both planned (proactive) and unplanned (proactive and reactive). The most frequently reported adaptations to the individual-level intervention were curriculum changes to tailor lessons to the local context, make the program more appealing to the workers at the site, or add a wider variety of exercise options. Other content adaptations included improvements to the screening protocol, intervention scheduling, and outreach plans to tailor participant recruitment and retention to the sites. Environment-level content adaptations included expanding or leveraging healthy food and exercise options at the worksites. Challenges to adaptation included scheduling and worksite-level challenges. Participants discussed the need to continue adapting the program in the future to continue making it relevant for worksite settings and engaging for employees.This study describes and classifies site-specific modifications to a structured lifestyle change education program with worksite-wide health improvements in India. This adds to the literature on implementation adaptation in general and worksite wellness in India, a country with a large and growing workforce with, or at risk of, serious cardiometabolic diseases. This information is key for program scale-up, dissemination, and implementation in other settings.Clinicaltrials.gov NCT02813668. Registered June 27, 2016 Contributions to the literatureThis paper describes adaptations to an evidence-based lifestyle change education program for prevention of diabetes and other cardiometabolic diseases at eleven large and diverse worksites in India. India has the second largest workforce in the world and has a large population at risk of developing conditions like type 2 diabetes and high blood pressure at younger ages.To successfully implement programs shown to be effective in research studies for population-wide impact, scientists, clinicians, and community leaders need to understand how these programs were adapted to the needs of the target population. This study provides guidance for culturally adapting a structured lifestyle change education program at worksites in India and could assist in program implementation in other similar settings.Implementation research is a growing field of study; however, there are limited studies that systematically report program modifications and adaptations, a key factor in successful implementation. This paper reports on the adaptations made to the INDIA-WORKS implementation trial at 11 worksites across India and categorizes and describes them using the Framework for Reporting Adaptations and Modifications-Enhanced (FRAME).Our study adds to the limited literature using FRAME in a low- and middle-income country context. In the discussion, the study team reflects on the utility and challenges of using this tool in the context of Indian worksites.At least 101 million and 136 million people in India have diabetes or prediabetes, respectively, many of whom are working age adults –5. LifesDelivering lifestyle interventions at worksites, using the existing structure of worksite health facilities for testing and utilizing employees as peer educators, could be an effective and cost-effective approach for delivering lifestyle change education. Furthermore, it may overcome many individual-level barriers to participation in a lifestyle change program  and could be beneficial to employers  –27. To bhttps://classic.clinicaltrials.gov/ct2/show/NCT02813668) implementation study. INDIA-WORKS aimed to overcome barriers to worksite delivery of lifestyle interventions by using the peer educator model while promoting worksite-based environmental changes to support program participants. We applied the FRAME  would even come to our rooms and ask us how to present a certain thing etc. We gave individual attention to everyone”.Scheduling (and rescheduling) classes around participant schedules, travel time to and around the worksite, production deadlines, and shift work was a “Herculean task” (Worksite Manager) and was discussed more frequently than any other adaptation barrier and across interview participant type. Similarly, sites with multiple worksites or a diversity of employee roles/positions found it challenging to find convenient schedules for classes and noted that program champions and staff had to gain support from management at each site or unit.Interviewees also noted that the teaching ability, confidence to lead, and dedication of the peer educators varied greatly across sites. For example, at one site, peer educators often did not turn up for classes they were assigned to lead, leaving INDIA-WORKS staff to coach participants, while at another worksite, peer educators engaged in teaching classes and leveraged the INDIA-WORKS staff to provide assistance with more complex lessons and tailor class scripts to the health literacy and education level of workers in their classes.[INDIA-WORKS participants] were regularly doing the exercises by walking around the building. Once the privatization issue came up, people started blaming the lack of orders on this walking routine around the building. So the person in charge told me to avoid walking around the building and to walk on one side instead. This was based on the superstition that if one walks around a building, it causes a negative effect. So that caused people to lose their heart a little. INDIA-WORKS staffConcurrent with INDIA-WORKS (but starting before COVID-19-related disruptions), several worksites were affected by major organization-level challenges such as privatization and a company shut down, which made it more difficult to adapt and deliver the INDIA-WORKS program. These challenges resulted in a lack of funds for implementation of environmental-level interventions like canteen changes and difficulty prioritizing the individual-level intervention for managers and participants. In addition, workers’ reactions to these challenges affected how peer educators, INDIA-WORKS staff, and managers were able to adapt the program at their worksites. For example, at one worksite where plans to privatize the worksite were being implemented, some employees at the site blamed the walking patterns of the INDIA-WORKS participants:Interview participants suggested additional content adaptations to consider in the future to improve sustainability and scalability of the lifestyle change program. Participants felt continued adaptations would be beneficial including timing and location of classes, variety of exercise types, and widening inclusion criteria. Interviewees suggested expanding the curriculum content by including additional diet and activity advice, information on worksite specific hazards , and more audio-visual materials. Peer educators, staff, and managers suggested that the class scripts will need periodic updates to make them fresh and appealing to workers: “things keep on changing. So, you should also keep on changing”. (Worksite Manager).Participants were conflicted about optimal timing and length for the program. Several peer educators and INDIA-WORKS completers suggested that longer or more frequent class periods were needed to cover all the material, provide individual feedback to participants, and do exercise classes, which were especially well received by people in their cohorts. Other interview participants suggested a shorter program ; these interviewees felt that shorter classes would improve participants’ attention and learning: “They come. They sleep. They fiddle the phone. You know attention span is maximum fifteen twenty minutes.… And in this small session, is only a small gathering. so, everybody is interactive”. (Worksite Manager).Other suggestions mentioned by peer educators and INDIA-WORKS staff focused on creating an environment that enabled Peer Educator success. Suggestions included scheduling classes around peer educators’ time first and expanding the training program for peer educators to include more role playing, visual examples, and additional training on lecturing/teaching to help them feel better prepared to lead classes.Integrated innovation theory posits that in order for an intervention to be successful in complex situations like community settings, it must integrate scientific/technological, social, and business innovations . INDIA-WINDIA-WORKS program adaptations included changes to the curriculum, recruitment or retention plans, and creation or use of health programming and resources at the worksites. The majority of adaptations were done during implementation to respond to the needs of the participants and worksite, although adaptations like language translation and changes to worksite exercise and food environments where adapted pre-implementation. Most adaptations were planned, reflecting the large number adaptable components in INDIA-WORKS. Unplanned adaptations occurred in reaction to unanticipated challenges with study recruitment, retention, and classroom logistics due to worksite-specific barriers or challenges. Other unplanned adaptations, such as adding additional cultural adaptation to diet lessons or new types of physical activity, where made in reaction to requests and interests of program participants. Participants’ requesting additional physical activity options might reflect improvements in fitness, as increased fitness can lead individuals to engage in a wider variety of exercise types .Except in one case (where a peer educator changed the order of lessons), adaptations were fidelity-consistent. This may have occurred because the program was carefully designed and presented to study partners with clearly defined core components, those necessary to program fidelity and aligned with proven behavioral health theories or strongly associated with program success in prior studies, and adaptable components which could be changed to be responsive and appropriate to the needs of the individual worksites . This isAll key players in overseeing program implementation were empowered to adapt program components. Adaptations by peer educators involved the program curriculum or participant retention, items which interfaced directly with participants, while INDIA-WORKS staff focused on adaptations necessary to the conduct of the study at each setting including tailoring of curriculum and recruitment methods to best suit the worksite environment and workers. Manager-led adaptations were often in areas requiring higher-level approvals and coordination . In Weiner, Lewis, and Linnan’s theory of the organizational determinants of effective program implementation at worksites, the authors argue that the complexity of implementing projects at worksites require active participation by both management and employees . Other sAlthough, delivering a diabetes prevention program at worksites in India at no monetary cost to the employee can overcome many of the barriers to lifestyle change , interview participants still described barriers to adapting the program to the worksites. These included unanticipated worksite changes and disruptions, the ongoing challenge of scheduling and rescheduling classes, and diversity of employees, which have been reported as barriers to worksite health programming in other studies , 46, 47.This study adds to the limited literature using the FRAME to describe program adaptations and modifications in the Indian context. Although the FRAME was able to categorize and describe most modifications with sufficient detail and clarity, there were some challenges to using the framework. Although various players were involved in suggesting program adaptations, implementation of adaptations always involved the worksite managers, with curriculum changes being the exception . India remains strongly hierarchal, and worksites reflect this top-down model . ManagerThere was also additional challenges in categorizing some of the modifications because of lack of clarity with definitions in the FRAME documentation. For example, we categorized adaptations to program recruiting and retention activities and scheduling of classes as content modifications because they related to the way the treatment  was delivered. Furthermore, these adaptations were not related to any of the categories of contextual modifications described in the FRAME . In practice, use of the FRAME to document and monitor program adaptations by worksites would be even more challenging, given lack of training and experience in implementation sciences.Finally, it was both time and resource intensive to document and categorize adaptations in detail and over time. To ensure we understood the full extent of adaptations, we conducted interviews with an array of key players involved in program implementation, and we continued interviews until data saturation was met. Each interview was then transcribed and coded, and thick descriptions were developed before categorizing the data using FRAME. This work was feasible given that this was a large, National Institutes of Health-funded study; however, less resourced study teams or community-based evaluators may not be able to commit to work of this scope to properly document program modifications and adaptations, leading to additional gaps in the literature on real-world implementation of health programs. Additional methodological development is needed to understand how to efficiently document program adaptations on an ongoing basis and how to best use this information to continuously improve interventions during implementation.This manuscript describing adaptations to the INDIA-WORKS intervention program has several notable strengths. Although there is tremendous growth in the number of community-based interventions, reporting of program adaptations is still limited and often done non-systematically , 50. AdaHowever, the FRAME did not guide data collection. Instead, the framework was applied during data analysis to capture information on modifications emerging in the data. This could result in missing data including not all modifications being identified or fully characterized. Similarly, using IDIs only to track adaptations might lead to underreporting of program changes. Future studies of this type should consider using the FRAME and mixed methods data collection systematically to describe and track adaptations in real time. Similarly, although we interviewed a variety of stakeholders involved in the program implementation, including program delivery personnel, managers, and participants, the qualitative data collection was not focused primarily on understanding adaptations, and all worksite-specific changes might not have been captured.Lastly, we did not explore how specific modifications and adaptations influenced implementation success and intervention effectiveness. The COVID-19 pandemic precluded further qualitative data collection at sites and made collection of additional information from the already-overburdened worksites practically impossible . Future studies should evaluate various adaptations for improving participation, retention, program delivery, and indicators of program effectiveness like weight loss. However, there is still great value in reporting program modifications. Very little is known about how programs are adapted in general and in low -and middle-income countries and worksites, specifically. This study goes beyond simply describing planned program methods to provide important guidance on how the program was delivered at individual worksites. This information can be used to help with program scaling and guide other researchers and program planners designing similar programs. Documenting unplanned modifications is particularly important as they can be proactively considered in the future to ensure all adaptation are fidelity consistent. Similarly, this work can be used to help with the design and planning of worksheets and other documentation for recording adaptations and provides documentation to assist in manualizing the intervention for broader dissemination .In conclusion, this manuscript describes and characterizes, using the FRAME classification system, worksite specific adaptations to the INDIA-WORKS intervention. Sites reported adaptations to the curriculum, participant recruitment and retention, and worksite health resources. This study adds to the growing literature reporting on program adaptations in implementation research in general and is one of the first to specifically describe implementation of lifestyle programs for early identification of non-communicable disease and prevention of cardiometabolic disorders at worksites in India.


Reflexive thematic analysis will be used with qualitative data. Findings from this study are expected to provide learnings to upscale conventional childhood obesity treatment services, in the hopes of curbing the rising rate of childhood obesity.E-Health childhood obesity treatment interventions may serve as favorable alternatives to conventional face-to-face programs. More studies are needed to evaluate the effectiveness of such interventions beyond immediately post-program completion, including exploring program features impacting effectiveness. This randomized controlled trial with a qualitative component and waitlisted control group will evaluate the effectiveness of a 10-week family-focused e-Health program for school-aged children with overweight/obesity and explore the experience of families completing the program. The primary outcome is the change in BMI z-score and will be assessed from baseline to 10 weeks. Secondary outcomes include (the change in) waist circumference, dietary intake, physical activity, quality of life, and experiences, and will be assessed at baseline, post-10 weeks, and/or immediately, 3-, 6-, and/or 12-months post-program completion. Independent  Obesity remains highly prevalent worldwide, with an increased prevalence of school-aged children aged 5–16 years) living with severe obesity 6 years l,4,5,6,7.The historically high global obesity rate over the past decade is attributable to the high accessibility to and the promotion of energy-dense foods, and technological advancements that encourage sedentary activities ,9. For iInternationally, countries recognize the importance of improving obesity treatment . For insDigitizing such programs or offering electronic health  programs, is a promising alternative overcoming the limitations of conventional programs. E-Health is the delivery of health-related information and/or healthcare services in a digital format or platform, and may serve as a standalone or adjunct intervention to conventional healthcare interventions, delivered face-to-face ,22,33. EE-Health programs may serve as a favorable alternative to in-person programs, including for children. Children are avid users of the internet, including accessing the internet for health-related advice and services ,23,27,28p < 0.001) in children aged 3 to 16 years [There is a developing body of evidence examining the effectiveness of e-Health interventions for the treatment of children with overweight and/or obesity. A 2021 meta-analysis of 19 randomized controlled trials (RCT) found that e-Health childhood obesity interventions significantly reduced BMI z-score  is a web-based program with health professional coaching sessions for the treatment of childhood overweight or obesity. The BHPO is the online adaptation of the in-person, group-based version, which is an evidence-based, family-centered lifestyle program for primary school aged children aged 7–13 years living with overweight or obesity, which has been successfully delivered and evaluated in Australia for over a decade. The in-person program is consistent with evidence-based guidelines on healthy eating, physical activity, and behavior changes . An RCT This protocol paper details the methodology of a study that aims to evaluate the effectiveness of a 10-week e-Health (web-based) healthy lifestyle program for primary-school-aged children aged 7–13 years (referred to hereon as “web-based program”). The primary aim of this study is to evaluate the effectiveness of a web-based program on the participating child’s health outcomes, including the impact of the web-based program on the child’s body mass index z-score (BMI z-score), waist circumference (WC), dietary intake, physical activity, and quality of life post-program-completion . This study also aims to explore the experience of families completing a web-based lifestyle program.The study protocol received ethics approval from the Monash University Ethics Committee (Project Number: 30472) and is registered with the Australian New Zealand Clinical Trial Registry (ACTRN12621001762842).The intervention will run in Victoria, Australia, where the Better Health Program has not been delivered via e-Health modalities for the treatment of childhood overweight or obesity. All data collection and study/program activities will be undertaken via e-Health and with families living in Victoria. The obesity rate in Victoria is comparable to the obesity rate of developed countries with the highest rates of obesity, with 2 in 3 adults and 1 in 4 primary-school-aged children living with overweight or obesity . This study is an RCT with a qualitative component and a waitlisted control group . This stThe 10-week web-based program will be administered by the administrating organization, Better Health Company (BHC), and is delivered during the year at primary school terms and midterms. In Australia, there are four school terms per year. The midterm programs will start approximately 6 weeks into the school term. Participants will be recruited for a school term or midterm program; a new recruitment cycle will begin, at the latest, 2 weeks prior to the commencement of the next earliest term or midterm program. Participants recruited during a school term or midterm recruitment cycle will only be considered for a school term or midterm program, respectively. Following study enrolment, participants allocated to the intervention group (Cohort 1) will complete the program in the subsequent commencing school term or midterm, whereas participants allocated to the control group (Cohort 2) will complete the waitlist control period in the next commencing school term or midterm. Participants allocated to the control group will not receive any intervention during the 10 weeks control period and will receive the (same) web-based program in the school term or midterm following the waitlist control term. Study involvement for each participant will run from baseline to 12-months post-program completion. Families who consent to the study will be randomized into the intervention or waitlisted control group. The randomization schedule was generated using block randomization (1:1 ratio) from Research Randomizer . Group aThis study/program focuses on the family unit. Study participants will, therefore, involve the child(ren) who meet the following inclusion criteria and at least one parent/caregiver. The eligibility criteria accounts for the inclusion criteria of the web-based program and the characteristics of participants who would benefit most from a family-centered program and are developmentally mature enough to complete research activities. The inclusion criteria are children aged 7–13 years (inclusive) with overweight or obesity, as defined by the Centers for Disease Control and Prevention , and living in Victoria, Australia . ChildreChildren will be excluded if they are within their healthy weight range or underweight . Children will also be excluded if they are engaging in other weight management programs (structured or referred) and will not be discontinuing the program during the study time period. Children who have participated in or completed other program(s) delivered by BHC in the past 12 months will be excluded. Other exclusion criteria include having a sibling who is completing or already completed the study, being unable to understand or communicate in English, or lacking access to a device to access online resources and complete study/program activities.t-test. The sample size estimation accounted for a possible reduction in BMI z-score within the control group, an effect size based on BHC’s pilot data, and a 30% attrition rate based on previous trials on a similar program  [n = 118 participants  to observe a difference in the primary outcome measure between groups with this effect size using a t-test. The primary outcome will be the change in BMI z-score from baseline to 10 weeks. An a priori power analysis was conducted using G*Power version 3.1.9.4  to estimtrition) . The efftrition)  criteriaBHC will recruit participants to complete the web-based program from their established networks in Victoria, including promoting the study among local government councils, schools, non-profit or private organizations, general practitioners, and other health professionals. BHC will advertise through flyers, posters, newsletters, social media posts , and/or electronic correspondence. BHC will also use promotional strategies, including running family-focused media campaigns, keeping social media accounts up-to-date with recruitment information , and reaching out to youth/parent-focused groups and/or health professionals in regional areas of Victoria.Study investigators will also support recruitment by communicating with and disseminating promotional resources to professional networks.Interested families can self-refer by completing an online registration form. Healthcare professionals may also refer participants by completing an online referral form. Once an online referral is received, a profile will be generated in BHC’s data system, including the participant’s unique identifier number. BHC will contact the families to outline the program and the relationship with the research, provide key information on the study, and conduct initial screening with participants for eligibility in the program and research. If families are willing to participate in this study, BHC will obtain verbal consent from the families for their contact details to be provided to study investigators. Study investigators will contact the families to address their queries or concerns if received and noted by BHC, confirm their eligibility for the research, and obtain written consent from the parent/caregiver and assent from the child(ren) prior to randomization.The BHPO is a 10-week web-based program designed for families that aims to promote healthy behavior changes. The program is a multi-component program, primarily delivered via a website where participants have access to weekly modules/activity sessions. There are 10 modules covering topics such as the five food groups, healthy eating behaviors/habits, reading food labels, the importance of and ways to increase movement, and healthy family routines. The participating child(ren) and at least one parent/caregiver will apply the information presented in each module by completing weekly online activities/exercises, available to families at the end of each module. Families participating in the program also receive weekly phone coaching calls with qualified health professionals such as dietitians, nutritionists, and exercise physiologists to set weekly targets on and develop action plans to achieve healthy behavior changes. Families also receive email/SMS communication to follow up with their progress throughout the program, access to a closed Facebook group with posts shared by other families who have previously participated or are currently participating in the program, and prize incentives upon completion. The program activities are designed to involve the family unit; the activities  are expected to be completed by the participating child(ren) and at least one parent/caregiver. The program is also designed and expected to allow the flexibility for household members other than the participating child and parent/caregiver to engage with the program contents . The program is delivered free of charge to participating families by BHC. The BHPO is adapted from the in-person, group-based version, which has been successfully delivered and evaluated in Australia for over a decade, and consistent with evidence-based guidelines on healthy eating, physical activity, and behavior changes .No advice is provided to participants allocated to the control group during the waitlisted control period.Data collection and management follows the Monash Research Data Management Policy and data will be stored securely on Monash University supported servers and at the Monash University Be Active Sleep Eat (BASE) facility. All information collected by BHC at recruitment and during program administration will be stored in BHC’s online, password- and firewall-protected data system and will follow BHC’s privacy policy. All data and results will be deidentified and managed confidentially at all stages during the study.Information on data collection and management is provided to participants (children and parents/caregivers) in the study explanatory statements (both parent/caregiver and child versions); these forms are emailed to parents/caregivers along with the study consent forms, and when study investigators are obtaining written consent from participants and prior to randomization.Outcome measures will be self-reported via surveys administered online, at baseline, post-program completion (10 weeks), and 6- and 12-months post-program completion. Participants allocated to the control group will be asked to complete an additional set of surveys following the 10 week control period. All study assessments will be administered online via a Research Electronic Data Capture (REDCap) ,47 link,Qualitative data will also be collected online through video conferencing and real-time transcribing platforms  the child’s BMI z-score, waist circumference, dietary intake, physical activity, quality of life, and the participating child and parent/caregiver’s experience of completing the program. Details on the collection of the outcome measures are summarized in The web-based program also includes surveys to be completed by participants as a part of the program activities. Data collected from these surveys may supplement data collected by study investigators, to inform outcome measures. All statistical analysis of quantitative data will be performed using IBM SPSS Statistics version 25  and metht-test will be used to compare the difference in the mean change in BMI z-score between Cohort 1 and 2 from baseline to 10 weeks. Independent t-tests will also be used to compare the differences in the quantitative outcome measures between cohorts from baseline to 10 weeks. A 2 × 2 mixed ANOVA will be conducted to investigate the impact of the web-based program (between factor: web-based program vs. control) on BMI z-score from baseline to 10 weeks (within factor). Separately, mixed model ANOVAs will also investigate the impact of the web-based program on the secondary outcome measures  from baseline to 10 weeks. The impact of being waitlisted (Cohort 2) will be explored to ascertain whether receiving the web-based program following 10 weeks of waiting will differ on the quantitative outcome measures from Cohort 1 over time. If being waitlisted does not have an impact on the quantitative outcome measures (as anticipated), a one-way repeated measures ANOVA will be used to assess the effect size of the web-based program on quantitative outcome measures overtime with greater certainty . Independent t-tests may also be used to compare the differences in the mean changes in quantitative outcome measures between cohorts or compare the mean differences in quantitative outcome measures for all participants at immediately pre-program (baseline or post-10-weeks waitlisted period) and post-program completion. The primary focus of this study is to test whether the web-based program has an effect on BMI z-score over a 10-week period. An independent As the goal of including a qualitative component in this study is to understand lived experience, reflexive thematic analysis will be used to explore participants’ experiences of the web-based program ,55. EvalUrgent action is needed to improve the treatment of childhood obesity. Few multidisciplinary weight management services currently exist for children outside the realm of primary health care, which, with limited resources, is predominantly focused on helping children with co-morbidities associated with weight and not the general population.E-Health interventions are promising strategies for the treatment of childhood obesity. With modifiable risk factors, including engaging in excessive sedentary, digital-based activities, influencing the rising childhood obesity rates, family-focused e-Health treatment programs may serve as means to upscale conventional treatment interventions. Such programs may also adapt to the increased demands of healthcare services and (young) people’s way of living during the COVID-19 pandemic. Though there is a growing body of evidence suggesting the effectiveness of e-Health interventions for the treatment of childhood overweight and/or obesity, studies have largely focused on parent- or child-focused programs and short-term impacts on weight-based outcomes and/or lifestyle behaviors/habits ,22,37. EThere are also strengths in the assessed intervention. This study involves a unique partnership between academics and industry to deliver a real-world family-focused e-Health intervention. The e-Health adaptation of the face-to-face, group-based program is expected to support family engagement; the web-based program includes elements expected from and favored by parents of children with overweight or obesity of  childhood obesity treatment programs ,39. ProgFuture findings from this study are expected to add to the evidence regarding e-Health childhood obesity treatment interventions, including novel insights on ways to improve the treatment of childhood overweight and obesity. This study’s purpose also aligns with global commitments to achieve United Nations’ sustainable development goals. The results of this study will be published in peer-reviewed journals and presented at scientific meetings and conferences. No identifiable information will be disclosed.


BCR::ABL1 transcript, the hallmark of the disease, by RT-qPCR. Considering that almost half of the patients who discontinue the treatment experience a molecular relapse, the identification of new approaches for the improvement of the selection of the best-responding CML patients is needed. In the present pilot study, we compared the gold standard with two additional MRD techniques: the quantification of the BCR::ABL1 transcript by digital PCR and the quantification of leukemic stem cells by flowcytometry. In fact, this cell population is one of the factors driving relapses. Although no linear regression was observed, a correlation between the lowest levels obtained using the three methods was noted. To the best of our knowledge, this is the first time that these methods have been compared in the CML setting.The monitoring of the minimal residual disease (MRD) in Chronic Myeloid Leukemia is a key element in the management of affected patients because it reflects the response to therapy and allows for the selection of the best responders who may benefit from the suspension of the therapy. The gold-standard method of MRD monitoring is the quantification of the BCR::ABL1 transcript at levels ≤ 0.01% by RT-qPCR, is the prerequisite for the successful interruption of treatment among patients with Chronic Myeloid Leukemia (CML). However, approximately 50% of patients in Treatment-Free Remission (TFR) studies had to resume therapy after their BCR::ABL1 transcript levels rose above the 0.1% threshold. To improve transcript detection sensitivity and accuracy, transcript levels can be analyzed using digital PCR (dPCR). dPCR increases BCR::ABL1 transcript detection sensitivity 10–100 fold; however, its ability to better select successful TFR patients remains unclear. Beyond the role of the immune system, relapses may be due to the presence of residual leukemic stem cells (LSCs) that are transcriptionally silent. Flow cytometry can be used to identify and quantify circulating bone marrow Ph+ LSCs CD34+/CD38− co-expressing CD26 (dipeptidylpeptidase-IV). To date, the significance of circulating Ph+ LSCs in TFR is unclear. The aim of this work is to compare and examine the values obtained using the three different methods of detecting minimal residual disease (MRD) in CML at RNA (RT-qPCR and dPCR) and LSC (flowcytometry) levels among patients in TFR or exhibiting a DMR. The twenty-seven patients enrolled received treatment with either imatinib (12), dasatinib (6), nilotinib (7), bosutinib (1), or interferon (1). Twelve patients were in TFR, while the rest exhibited a DMR. The TFR patients had stopped therapy for less than 1 year (3), <3 years (2), 6 years (6), and 17 years (1). Blood samples were collected and tested using the three methods at the same time. Both d-PCR and LSCs showed higher sensitivity than RT-qPCR, exhibiting positive results in samples that were undetectable using RT-qPCR (17/27). None of the patients tested negative with d-PCR; however, 23/27 were under the threshold of 0.468 copies/μL, corresponding to a stable DMR. The results were divided into quartiles, and the lowest quartiles defined the lowest MRD. These data were strongly correlated in 15/27 patients, corresponding to almost half of the TFR patients. Indeed, the TFR patients, some lasting up to 17 years, corresponded to the lowest detectable DMR categories. To the best of our knowledge, this is the first attempt to analyze and compare DMRs in a CML population using standard (RT-qPCR) and highly sensitive (dPCR and LSCs) methods.A Deep Molecular Response (DMR), defined as a  BCR-ABL1 oncogene are generated by this rearrangement. The disease marker is its chimeric transcript [A t9; 22) q34; q11) balanced reciprocal translocation is the cause of the chimeric BCR-ABL1 oncoprotein and generates chronic myeloid leukemia (CML), a clonal myeloproliferative disorder. The Philadelphia (Ph) chromosome and the 1 balance2 q34; q1Since the successful introduction of Tyrosine Kinase Inhibitors (TKIs), the monitoring of the minimal residual disease (MRD) in Chronic Myeloid Leukemia (CML) adult cases has become pivotally important for patients’ management and therapeutic strategy choices.BCR::ABL1 transcript levels using RT-qPCR, normalized for the quantification of a housekeeper gene , in peripheral blood (PB) cells. A stable Deep Molecular Response (DMR), defined as BCR::ABL1 transcript levels ≤0.01% determined via RT-qPCR, is the prerequisite for a successful interruption of treatment among patients with CML. However, approximately 50% of patients enrolled in Treatment-Free Remission (TFR) studies had to resume therapy after their BCR::ABL1 transcript levels rose above the 0.1% threshold, which is known as Major Molecular Remission (MMR). These events are experienced regardless of other variables like the risk upon diagnosis, the duration of TKI therapy, the duration of the DMR, and so on. Thus, it appears that DMR quantified via RT-qPCR is not an optimal parameter for the selection of patients who can safely discontinue treatment and maintain TFR.MRD is conventionally monitored by quantifying BCR::ABL1 transcript levels. This technique is based on the partitioning of a reaction mix into thousands of micro-PCR reactions. Amplification, independently of the dPCR platform (which is either chip-based or droplet-based), reveals the presence of the target through fluorescence, and this allows for the absolute quantification through the counting of the positive micro-reactions. Moreover, it seems to surpass the sensitivity of RT-qPCR by 10–100 fold and its accuracy as well [Digital PCR (dPCR) has recently emerged as a more precise and accurate technique for detecting MRD among CML patients by absolutely quantifying  as well , thus in as well . At pres as well ,9,10,11.BCR::ABL1 transcript levels unable to monitor the residual quiescent CML LSCs. In fact, LSCs may present very low levels of transcripts or even be transcriptionally silent while also surviving indefinitely in tumor-specific hypoxic niches and circulating in the PB. Hematopoietic stem cells are characterized by the CD34+/CD38−/Lin− immunophenotype. CD26 (dipeptidylpeptidase IV) has been identified as a biomarker for the quantification and isolation of CML LSCs in the bone marrow (BM) of CML patients, as CD26+-sorted LSCs have been demonstrated to be entirely BCR-ABL1-positive at the genomic level. Recently, LSCs have been successfully quantified in PB samples as well, and the use of PB CD26+ LSCs flow cytometry assays appears to be feasible, reproducible, specific, and sensitive [However, the possibility that a relapse after the discontinuation of TKI administration may be due to the persistence of leukemic stem cells (LSCs) that are insensitive to TKIs renders even the most sensitive PCR-based assay for monitoring ensitive ,13. ThisBCR::ABL1 transcript quantification by RT-qPCR, (ii) the quantification of the same transcriptby dPCR, and (iii) the quantification of circulating LSC in patients in TFR or exhibiting a DMR.In the present preliminary study, we compared and examined the results obtained using three different methods of detecting MRD in CML: (i) Twenty-seven adult patients afflicted with CML were enrolled in two biological, clinical, non-pharmacological trials, namely, “AIRC IG 20133” and “NP-DPCR-CML_1603”, approved by the Ethics Committees of Siena and Brescia , respectively. The studies were conducted in accordance with the Declaration of Helsinki, and the enrolled patients provided their written informed consent. They received treatment with either imatinib , dasatinib , nilotinib , bosutinib , or interferon . Upon enrollment, 12 patients (44%) were in TFR, while the rest (66%) exhibited a DMR. The TFR patients had stopped receiving therapy for less than 1 year , <3 years , 6 years , and 17 years . A total of 10 mL of Peripheral Blood (PB) was collected using EDTA tubes and centrifuged in order to obtain the buffy coat within 24 h of sampling for RT-qPCR analysis. A total of 5 mL of fresh PB from the samples was sent to Azienda Ospedaliera Universitaria in Siena for LSC CD26+ quantification. A total of 10 mL of fresh PB collected in EDTA tubes was sent to ASST Spedali Civili of Brescia for dPCR analysis. All the shipments were carried out by an express courier within 24 h.RNA extraction was performed after the PB samples were centrifuged to obtain PB cells using NucleoSpin RNA plus , as specified in the manufacturers’ instructions. This procedure has been approved for clinical diagnostic application in Italy. Extracted RNA was immediately quantified using a Qubit RNA high-sensitivity kit  and retrotranscribed using the following method.2O was retrotranscribed after being incubated at 70 °C for 10′, followed by ice incubation. Then, 100 U of Reverse transcriptase (Superscript I or II), 1 mM of dNTP, 10 mM of DTT, 25 μM of Random hexamers, and 20 U of RNAse inhibitor and RT buffer (according to the enzyme used) were added to a final volume of 20 μL. This step was followed by three subsequent incubations: at room temperature for 10′, at 42 °C for 45′, and at 99 °C for 3′, with a final holding period at 4 °C. The cDNA was quantified using Qubit ssDNA kit (ThermoFisher Scientific) and then stored at −20 °C until analysis. Retrotranscription was performed as described in Bernardi S. et al. (2019) [A total of 1 μg of total RNA in 10 μL of DNA- and RNA-free HBCR::ABL1 transcript quantification was performed using the automated Xpert Ultra BCR-ABL1 MonitorTM Cepheid method and calibrated for the transcript of the ABL1 reference gene and the BCR-ABL1 target gene, with a PCR sensitivity of 5.0 . Samples were analyzed according to the manufacturer’s instructions and by following the internationally standardized methods of MRD monitoring for CML. Accordingly, molecular responses were expressed and reported as BCR::ABL1 % on a log scale, where 0.1%, 0.01%, 0.0032%, and 0.001% corresponding to MR3.0, MR4.0, MR4.5, and MR5.0, respectively. The minimum sum of the ABL1 reference gene transcripts, irrespective of whether BCR::ABL1 was detected, should be 10.000 for MR4.0, 32.000 for MR4.5, and 100.000 for MR5.0. In fact, DMR classes may be assessed even in the case of undetectable BCR::ABL1 transcript levels (U). In this case, the MR classes are determined according to the ABL1 transcript copy number, i.e., 10.000, 32.000, and 100.000 for MR4.0, MR4.5, and MR5.0, respectively [ectively .BCR::ABL1 transcript. The entire procedure was conducted as previously published [BCR::ABL1 quantifications were performed by analyzing 50 ng of cDNA using a QuantStudio 3D Digital PCR System (ThermoFisher Scientific). The fixed quantity of cDNA considered during the analysis allowed for the normalization of the results and the non-saturation of the instrument, as previously reported by our group [BCR::ABL1 transcript values determined using dPCR were expressed as numbers of copies/μL. The secondary analysis was carried out using AnalysisSuite Cloud Software (V 3.1) (ThermoFisher Scientific). A value of 0.468 copies/μL of BCR::ABL1 transcript is a previously calculated cut-off capable of identifying patients presenting optimal response to TKIs [BCR::ABL1 transcript levels above the cut-off present a significantly lower probability of obtaining stable TFR than patients presenting BCR::ABL1 transcript levels below the cut-off.d-PCR analysis was performed using a TaqMan-MGB probe targeting the ublished ,15, and ublished . A custour group . BCR::AB to TKIs . In partTo detect circulating CD34+/CD38−/CD26+ LSCs, PB cells of CML patients were incubated with a mixture of pre-titred lyophilized antibodies containing anti-CD45 , anti-CD34 (581), anti-CD38 (HIT2), and anti-CD26 (M-A261) (BD Bioscience). Isotype controls were included in each staining procedure. Acquisition and analysis were performed using a FACSCanto II flow cytometer coupled with FACSDiva software (Ver 8.0) . To obtain a sensitivity comparable with and superimposable to molecular assays, 1,000,000 CD45+ events were acquired. Median absolute number of CD26+ cells/μL was calculated as follows: (# WBCs/μL) × (% CD34+/CD38−/CD26+ stained CD45+ cells) ,13.A descriptive statistical analysis was conducted in order to evaluate the demographic and clinical variables, such as the therapy and the TFR. A linear regression analysis was performed to evaluate the correlation between the results obtained via RT-qPCR, dPCR, and CD26+ cell quantification. Moreover, the data were subdivided into quartiles for their analysis. Statistical analysis was performed using GraphPad (Ver. 9.5.1).The TFR status, the type of TKI treatment, the RT-qPCR results, the dPCR data, and LSCs quantification were employed as variables, and their details are summarized in BCR::ABL1 copies/μL), and the LSC values ranged from 0 to 0.156 (cells/μL). Both d-PCR and LSCs showed higher sensitivity than RT-qPCR, exhibiting positive results in samples presenting undetectable levels of BCR::ABL1 transcript by RT-qPCR . None of the patients tested negative via d-PCR. However, 23/27 (85%) were under the threshold of 0.468 copies/μL of BCR::ABL1 transcript, which has previously been described as corresponding to a “true” DMR. LSC levels were negative in six patients (22%), four of which  also tested negative by RT-qPCR. Considering the entirety of the results, the RT-qPCR values ranged from 0–0.0068 (%IS), the d-PCR values ranged from 0.073 to 0.943  samples presented total concordance among the three methods A. In addanscript B.The two lowest quartiles, together with the levels corresponding to undetectability, defined the lowest detectable DMR. Considering these levels altogether, a strong correlation of these data was noted in 15/27 patients. Among them, 7/15 (46.6%) concordant cases were in TFR, corresponding to 58.3% of the total patients in TFR enrolled in this study. Among the 26 DMR patients, defined using the gold standard, 11 (42%) were discordant. BCR::ABL1 transcript levels was the gold-standard method for monitoring minimal residual disease (MRD) in CML and for the best management of CML patients [BCR::ABL1 transcript levels have been widely reported along with their overcomes via dPCR. In fact, in recent years, the molecular surveillance of MRD in hematological malignances has been transformed by dPCR. In addition, the inability to detect LSCs that are still present in the BMs of patients who have sustained undetectable molecular residual disease is one of the major limitations of CML MRD surveillance [BCR::ABL1 transcript quantification via dPCR and LSC CD26+ detection and quantification. The enrolled patients had been undergoing different treatments. In particular, 15/27 patients were receiving TKI therapy, while 12/27 were in TFR. Among the TFR patients, some lasting up to 17 years, almost half were in the lowest-detectable DMR categories by all three MRD techniques. This is a notable result since the enrolled TFR patients presented at least 2 years of sustained TFR. The reported timing of molecular relapse after the discontinuation of TKI administration was within 1 year from therapy suspension [BCR::ABL1 transcript. The RT-qPCR and dPCR approaches reported in the present manuscript consider a relative and an absolute quantification of BCR::ABL1 transcript, respectively. This is a very important point since BCR::ABL1 is conventionally quantified by considering normalization with a reference gene in order to confirm the quality of the pre-analytic steps and identify the MR classes following the IS. In the case of the presented dPCR quantification, BCR::ABL1 was absolutely quantified, and the comparability of the results was facilitated by the normalization of the quantity of RNA retrotranscribed and by the quantity of cDNA analyzed via dPCR, as stated in the Materials and Methods section. Moreover, dPCR is less sensitive than RT-qPCR to nucleic acid degradation thanks to its ability to amplify short sequences detected by MGB probes. Notably, the aim of BCR::ABL1 dPCR quantification is the improvement of accuracy and sensitivity, not the simple transfer of the IS from RT-qPCR to a new technology. Despite this difference, the two molecular techniques turned out to be the most concordant in the identification of patients presenting very low MRD levels. In part, this is not surprising since leukemic stem cells are known to be almost quiescent and non-expressing BCR-ABL1. In this context, a recent study aiming to evaluate CD26 expression in suspected cases of CML in the chronic phase and correlating CD26+ stem cells at baseline and their kinetics with tyrosine kinase inhibitor (TKI) treatment on a further follow-up at 12 months led to an interesting result [BCR-ABL1 [BCR::ABL1 transcript levels relating to the identification of new CML patient sub-settings is warranted.The improvement of MRD monitoring for adult CML patients is one of the main goals of the current CML management strategy. Until a few years ago, the quantitative reverse polymerase chain reaction (RT-qPCR) determination of patients ; nowadayeillance . Particueillance ,20,21,22eillance . To the spension . Indeed,g result . Of the BCR-ABL1 ,27. The