Application of the Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) framework to evaluate workforce education and training programs targeting clinical health care staff has received relatively little attention. This paper aims to contribute to this area with RE-AIM findings from a women's health-focused workforce training program implemented by the U.S. Department of Veterans Affairs (VA). Over the past two decades, the rapid expansion of the women Veteran population in VA has necessitated a quick response to meet clinical demand. To address this health care need, the VA Offices of Rural Health (ORH) and Women's Health (OWH) partnered to deploy a primary care workforce development initiative for Rural Providers and Nurses—the Rural Women's Health Mini-Residency —to train VA clinicians in rural locations in skills for the care of women Veterans. Here we assess the applicability of RE-AIM as an evaluation framework in this context.We evaluated the Rural WH-MR, relying on a primarily quantitative approach, rooted in RE-AIM. It included longitudinal and cross-sectional measurements from multiple quantitative and qualitative data sources to develop selected metrics. Data collection instruments consisted of pre-, post-, and follow-up training surveys, course evaluations, existing VA databases, and implementation reports. We developed metrics for and assessed each RE-AIM component by combining data from multiple instruments and then triangulating findings.Results from the Rural WH-MR program for fiscal years 2018–2020 indicate that RE-AIM provides an instructive evaluation framework for a rural workforce training program, particularly in eliciting clarity between measures of Reach vs. Adoption and focusing attention on both provider- and patient-level outcomes.We describe evaluation metric development and barriers to and facilitators of utilizing RE-AIM as an evaluation framework for a provider- and nurse-facing intervention such as this workforce training program. We also reflect upon RE-AIM benefits for highlighting process and outcomes indicators of a training program's success and lessons learned for evaluating rural workforce development innovations. Several of our observations have implications for training and evaluation approaches in rural areas with more limited access to health care services. Since 2008, the U.S. Department of Veterans Affairs (VA) has been growing its workforce of trained Women's Health Primary Care Providers (WH-PCPs)  via a naTo address these barriers, in fiscal year 2018 (FY 2018) VA implemented an adapted version of the WH-MR workforce training program, called the Rural WH-MR, described in detail elsewhere . By traiAs shown in Evaluation of an innovative program adaptation like this is essential to inform ongoing program improvements and to determine the value of continuing to invest resources in the program. As a VA Office of Rural Health (ORH) funded program and in partnership with VA's Office of Women's Health (OWH), the Rural WH-MR training program developed an evaluation plan built on the Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) framework. RE-AIM has several advantages, including that it is widely used to evaluate behavioral health change interventions  and provThis evaluation included aspects of both quantitative and qualitative program assessment. More details described elsewhere  delineatORH provides an online calculator that OWH uses to determine site- and Health Care System (HCS)-specific rurality for program eligibility. VA uses the Rural-Urban Commuting Areas (RUCA) system to define rurality .In addition, OWH tracks a variety of implementation and adoption processes with the following data sources:As described elsewhere , OWH admIn parallel, VA's Institute for Learning, Education and Development (ILEAD) evaluations capture participant satisfaction, trainer performance, and course objectives achieved. Specifically, ILEAD evaluations are completed by participants within 30 days after training completion of the bifold program and after each part of the trifold program (due to separate program accreditations). These use 5-point Likert scales  to reflect participant satisfaction with respect to training applicability and delivery. Similarly, these evaluations report mean Likert scale scores showing whether participants feel that trainers met program-specific objectives. ILEAD evaluations also include open-ended items on these topics.VA's Women's Health Evaluation Initiative (WHEI) compiles a longitudinal master ORH database of baseline and follow-up data  that uses the training completion date as an index for measures taken pre-training, and 1- and 2-years post-training. The database taps into multiple existing national VA data sources via the WHEI Master Database supplemented with files from VA's Corporate Data Warehouse, Primary Care Management Module (PCMM), VA Support Service Center Capital Assets (VSSC), and national Women's Health Assessment of Workforce Capacity—Primary Care (WAWC-PC) data.Additionally, the training site points of contact, site-observers, and contract trainers complete templated OWH post-training reports to reflect on implementation processes, while OWH also conducts a debriefing call with the site planning team to discuss implementation successes and challenges and to review post-training responsibilities .OWH had a site-observer  at many trainings given by new trainers and some given by repeat trainers. Data assessing the participating sites and training sessions were recorded in OWH Tracking Spreadsheets listing communications with sites and other site-specific details, including attendance of a site-observer . FurtherSite-observers provided immediate implementation feedback critiques to the trainers, and their quality assurance reports were used to assess trainers' adherence to training protocol and delivery to insure fidelity in training implementation .To track the number of live and online courses offered in OWH's learning portfolio, OWH uses a central course-tracking system and lists available courses in VA internal communications to disseminate learning opportunities to clinical staff, also posting courses on the VA Training Management System.To assess contraceptive prescribing practices by PCPs, VA contraception pharmacy data were used in combination with a series of medical codes from outpatient utilization data to determine all types of contraception usage. Medical procedure and diagnostic codes came from a list compiled annually by Health and Human Services Office of Population Affairs , which u•HCSs examined include those that sent at least one PCP or nurse to the training.•Sites refer to divisions within a HCS .•Clinical staff analyses examine PCPs  and nurses from participating sites.•Women Veteran panel analyses examine women Veterans receiving care from a particular PCP.All the data sources and collection processes described above were used to examine measures at multiple levels.Reach as “The absolute number, proportion and representativeness of individuals who are willing to participate in a given initiative, intervention or program”, and asks the evaluator to consider several issues, including whether the program reached the intended rural population. It also states that Effectiveness is “The impact of an intervention on important outcomes, including potential negative effects, quality of life, and economic outcomes”, followed with inquiries about how the intervention improves on current practice with respect to identified outcomes. The information sheet indicates that Adoption consists of “The absolute number, proportion and representativeness of settings and staff who actually initiate a program” and asks the evaluator several questions including whether the selected sites proved to be appropriate. Additionally, it states that Implementation specifically covers how closely the facilities and staff adhere to the various elements of an intervention's protocol, including consistency of delivery as intended and the time and cost of the intervention. The information sheet further notes that evaluators should account for whether the intervention was delivered with fidelity to the program's core elements and goals. Finally, it gives this definition of Maintenance: “The extent to which a program or policy becomes institutionalized or part of the routine organizational practices and policies” and asks the evaluator “What plans were developed to incorporate the intervention, so that it will be delivered over the long term?”In 2018, ORH's evaluation unit  providedoperationalize the RE-AIM components. We did this by carefully defining each component as it applied to the Rural WH-MR and selecting specific measures to assess program progress and impact. While our measures may not follow the RE-AIM framework exactly as applied to patient-facing interventions, we offer considerations for how we operationalized each component of the framework for our provider- and nurse-facing training program based on definitions provided by ORH.To apply RE-AIM to the Rural WH-MR, we first had to Reach of the Rural WH-MR generally as the percentage of rural women Veterans receiving care from PCPs and nurses with women's health expertise, which in turn was defined as being (a) a WH-PCP and/or (b) completing the Rural WH-MR training program. We examined the effectiveness of the program's Reach according to increases in the following measure:R1. The percentage of rural women Veterans on panels of WH-PCPs or PCP participants at program baseline and one- and two-years post-training.We defined the To determine the percentage of rural women Veterans on panels of WH-PCPs or trained PCPs at program baseline and one- and two-years post-training, we considered each FY group of participants as a cohort. We then defined provider-specific training years such that T0 = training baseline date, T1 = one-year post-training follow-up date, and T2 = two-year post-training follow-up date. We took the first day of the training month for each provider as T0, which served as the index date; we added one and two years to create T1 and T2, respectively. We then used VA administrative data to link the records of all patients found at the training sites to their providers; we looked at those who were on the panels of trained PCPs at the specific timepoints, T0, T1, and T2. By selecting the rural women Veterans on PCPs' panels at each timepoint, we could determine the percentage point increase from T0 to T1 and T2.Effectiveness, we felt the program evaluation should reflect the program goal of increasing training participants' women's health expertise in order to improve the quality of rural women's health care. This led us to document two separate outcomes measures of Effectiveness:E1. The changes over time in the Likert scale scores of participants’ self-reported comfort with training related KAPS.E2. The percentage of women Veterans seen by trained PCPs provided with contraception by these participants at program baseline and one-year post-training.To show To determine the PCPs' and nurses' changes in KAPS over time, we analyzed OWH survey data. Wilcoxon signed rank tests conducted in SAS  were used to analyze linked 5-point Likert scale data for all KAPS areas for pre- and post-training changes as well as pre- and 6-months post-training changes. Positive Likert scale scores indicated higher levels of comfort.Subsequently, to determine contraception provision rates, we created provider-specific baseline and follow-up years with the baseline year, Y0, equal to the one-year period preceding T0, and Y1 equal to the one-year period starting with T0. Next, we identified all women Veterans seen by PCPs during each provider specific year (Y0 or Y1) by linking VA outpatient data to PCP identifying information for each visit with trained PCPs. To analyze changes from Y0 to Y1, we used a fixed effects logistic regression model with terms for year and dummy variables for stations to account for correlation. This allowed us to calculate the odds ratio of PCPs at 17 HCSs providing contraception at Y1 compared to Y0.More specifically, pharmacy-based contraceptives include oral contraceptive pills, the depot medroxyprogesterone acetate injection, the vaginal ring, and the contraceptive patch. Other types of contraception from pharmacy data are not included in this measure because they are available over the counter , come from VA prosthetics  or are intended as back-up contraception (emergency contraception) and are not consistently reported in pharmacy data across sites. The WHEI list of medical codes is selected for the following types of contraception provision: any contraception, cervical cap, condom, diaphragm, implant, injectable, intrauterine device, oral contraception pills, patch, ring, spermicide, and sterilization; and does not include in the list of contraception provision any codes for contraception counseling, natural family planning, emergency contraception, abortion, pregnancy, live birth, non-live birth, or infecund.Prior to operationalizing adoption measures, we defined different units of analysis, counting these measures first by the fiscal year of each training cohort, and then for the program overall across all years cumulatively. For the Adoption measures, we defined and counted participating HCSs as those that hosted the Rural WH-MR and sent one or more PCPs to the training within given fiscal years. Similarly, participating sites were those VA Community-Based Outpatient Clinics (CBOCs) or VA Medical Centers (VAMCs) that sent at least one PCP to the training within that fiscal year. Training sessions counted for analysis comprised either the bifold one-day training date, or the second or third part of the trifold training dates. We also tracked the numbers of PCPs and nurses who partially and fully completed training .Adoption as:A1. The percentage of eligible sites participating.A2. The median percent rurality of participating sites.A3. The percentage availability of WH-PCPs and trained PCPs in participating rural sites at program baseline and one-year post-training.We measured the extent of program Sites eligible for the Rural WH-MR training are those primary care CBOCs and VAMCs where ≥50% of VA enrollees have a rural residence . However, with ORH permission, non-rural primary care sites can also participate if they form part of a subset of sites with ≥50% rurality or they are sending participants to fill training spots that would otherwise go unfilled. The full denominator of eligible rural sites comes from the annual WAWC list of all VA primary care sites cross-referenced with the ORH rurality calculator. We included pilot sites in this measure.To determine how well the set of the sites that adopted (participated in) the training aligned with the goal of reaching rural sites, we looked at participating sites' median rurality and the percentage that qualified officially as rural . We included pilot sites in this measure as well.To be counted as a trained PCP, for bifold trainings, participants completed the one-day, in-person training session, but for trifold trainings, we tracked PCPs separately who partially vs. fully completed the training. We then examined the number of WH-PCPs before and after the trainings as well as participants who completed the training but may not have obtained WH-PCP status according to VA workforce data. However, since PCPs could qualify as WH-PCPs prior to the training, we reviewed the changes in percentages of WH-PCPs and/or training participants as an indicator of adoption. To assess the changes in availability of WH-PCPs at specific participating sites, we also relied on the annual WAWC counts of WH-PCPs at the sites in the year prior to and the year following the training to determine which participants were or became WH-PCPs after training.Implementation as consistently delivering a women's health training program that meets the needs of rural-based PCPs and Nurses. To do so, the Rural WH-MR needed to maintain fidelity to core program elements and cross-site consistency while allowing flexibility for site-specific tailoring. We monitored several measures to assess Implementation processes. These include:I1. The percentage of trainings attended by site observers.I2. Likert scale scores from participants regarding usefulness of training activities.I3. The percentages of participants satisfied with the training and program learning objectives.We defined program As noted above in the Data Sources and Collection Processes section, OWH had site-observers attend select trainings and complete quality assurance reports to critique trainers and reflect upon their fidelity to training implementation protocols. The total number of site-observers was monitored in the OWH Tracking Spreadsheets also described earlier.We analyzed the quantitative OWH Survey 6-month post-training usefulness and relevance data with Wilcoxon signed ranks tests for participants' mean Likert scale scores (higher scores indicating more usefulness and relevance), while we also reviewed the qualitative data for commonly cited themes.As noted earlier, ILEAD evaluations are completed by participants within 30 days after training completion of the bifold program and after each part of the trifold program. The 5-point Likert scales were used to assess participant satisfaction and to measure whether participants felt that trainers met program-specific objectives.Maintenance as promoting ongoing local and virtual women's health training opportunities to sustain high levels of women's health services capacity in rural areas. We used the following process measures for FY 2018-FY 2020 to assess effective program Maintenance:M1. The percentage of the Rural WH-MR trainings attended by local leaders.M2. The number of HCSs granted funding for subsequent local trainings.M3. The number of live and online courses maintained and added to the OWH learning portfolio.Finally, we defined We postulate that local leaders who attended trainings are more likely to provide future local in-services, that additional funding of HCSs propagates the intervention, and that maintaining the courses online allows for rural sites to use the curriculum locally for their own in-services. We monitored local leader attendance via the OWH Tracking Spreadsheets described in the Data Sources and Collection Process section above. All HCSs applying for and receiving grant funding to host local trainings were tracked in a similar manner by OWH. To document the number of live and online courses offered in OWH's learning portfolio, OWH uses its central course-tracking system .With the RE-AIM components operationalized and specific measures defined, we assessed the Rural WH-MR program's progress and impact. Here, we share results from FY 2018-FY 2020 showing that the RE-AIM approach successfully identified effective implementation and positive program performance.R1. The percentage of rural women Veterans on panels of WH-PCPs or PCP participants at program baseline and one- and two-years post-training.Using the described measures and methods, the percentage of rural women Veterans on trained PCPs' patient panels generally increased over time for all training cohorts. E1. The changes over time in the Likert scale scores of participants’ self-reported comfort with training related KAPS.N = 184 FY 2018–2020 PCP participants who completed the bifold program, none were lost to follow-up at the 1-month post-training time, and 74 (40%) had linked data available for both pre- and immediate post-training. Wilcoxon signed rank test analyses reveal significant improvements for all 22 PCP KAPS areas assessed  immediately post-training. For the 6-month post-training mark, 9 PCPs were lost to follow-up, with N = 175 PCPs remaining. As previously reported for the FY 2018 and FY 2019 PCP participant cohorts, 52 PCPs had linked data for pre- and 6-month post-training surveys. No new linked surveys were collected for the FY 2020 cohort. At 6-months post-training, none of the 22 KAPS means scores declined. Specifically, 18 increased significantly , while four did not show statically significant improvement.Of N = 327 FY 2018–2020 nurse participants who completed the bifold program, none were lost to follow-up at the 1-month post-training time, and 186 (57%) had linked data available for both pre- and immediate post-training. Of the 17 nurse KAPS areas assessed, Wilcoxon signed rank test analyses indicate significant improvements for all of them  among those nurses immediately post-training. As previously reported for the FY 2018 and FY 2019 nurse participant cohorts, 93 nurses had linked data for pre- and 6-month post-training surveys. No new linked surveys were collected for the FY 2020 cohort. At 6-months post-training all 17 nurse KAPS areas assessed increased significantly .E2. The percentage of women Veterans seen by trained PCPs provided with contraception by these participants at program baseline and one-year post-training.Likewise, of the p = 0.0009].As shown in A1. The percentage of eligible sites participating.N = 1,055 primary care sites found in the ORH Rurality Calculator FY 2020 list of sites, 510 (48.3%) primary care sites were ≥50% rural and therefore eligible to participate in the Rural WH-MR on the basis of rurality. Of those 510 eligible primary care rural sites, 65 (12.7%) had sent PCPs to the Rural WH-MR during pilot or FY 2018-FY 2020 trainings.At the end of FY 2020, of the A2. The median percent rurality of participating sites.On top of those 65 eligible rural sites, an additional 41 other sites sent PCPs. Among them, one was rural , 39 did not meet the rurality threshold in the ORH Rurality Calculator but had received permission from ORH to send participants to the Rural WH-MR, and one had unknown rural status .A total of 106 unique sites sent PCPs to a pilot or FY 2018-FY 2020 training.  Excluding the one site missing from ORH's Rurality Calculator, the participating 105 sites had a median rurality of 69.5% . Specifically, 66 participating sites (62.9%) were ≥50% rural, and 39 participating sites (37.1%) did not meet the rurality threshold.A3. The percentage availability of WH-PCPs and trained PCPs in participating rural sites at program baseline and one-year post-training.N = 202 FY 2018-FY 2020 PCP participants , 87 (43%) were WH-PCPs before their training. At the one-year follow-up point, among the original 202 PCP participants:•168 (83.2%) were WH-PCPs.•17 (8.4%) PCPs had left VA or changed positions.•6 (3.0%) anticipated completing the training in the following fiscal year due to delays imposed by the Coronavirus pandemic.•10 (5.0%) were either float providers or home-based PCPs functioning as WH-PCPs.•Only 1 (0.5%) decided not to become a WH-PCP.The availability of WH-PCPs and trained PCPs improved from baseline to one-year follow-up for the FY 2018-FY 2020 cohorts as assessed by WHEI using the annual WAWC surveys to determine WH-PCP status of participants prior and subsequent to training. Among the I1. The percentage of trainings attended by site observersIn FY 2018, 54% (7 out of 13) of trainings were attended by a site observer. In FY 2019 and FY 2020, 44% and 50%  of trainings had site observers, respectively. A decreased frequency reflects a year in which more trainings were delivered by previously observed training teams, seen in the past without noted deficiencies and therefore not needing close observation. In fact, among trainings from FY 2018-FY 2020 that had at least one new training team member, 54% (7 out of 13) received observation from an OWH representative or designee.I2. Likert scale scores from participants regarding usefulness of training activities.N = 106 responding) from FY 2018-FY 2020 rated case studies, simulation equipment, MammaCare®, live female model  experience, and supply demonstration as 4.49–4.69. In the words of a FY 2019 PCP post-training: “It is really wonderful to have access to a GTA. I always feel like I am able to improve my skills with constructive feedback”. Nurses (N = 251 responding) from these cohorts rated case studies, exam set-up activity, gynecologic procedure videos, live female model experience, and supply demonstration as 4.71–4.82. A nurse from the FY 2019 cohort reported post-training: “The case studies were very useful in learning how to interact with a patient regarding sensitive subjects as well as line of questioning that will help the provider give a more clear course of care”. Finally, FY 2018-FY 2020 OWH survey data demonstrated strength of the training's relevance to rural practice, with ratings of 4.50 among PCPs (N = 110 responding) and 4.71 among nurses (N = 256 responding).Using a scale in which 1 = poor and 5 = excellent, PCPs (I3. The percentages of participants satisfied with the training and program learning objectives.N = 173) and 89.3% . Cumulative FY 2018-FY 2020 data showed high participant satisfaction . Similarly, 93.4% of PCPs indicated satisfaction across 10 PCP program-specific objectives, while 94.9% of nurses showed satisfaction across 8 nurse program-specific objectives.Response rates for the Rural WH-MR ILEAD Evaluations for FY 2018-FY 2020 were 94.0%  received additional funding from OWH, training materials, and program support to host their own local women's health trainings in subsequent years (2 HCSs were funded multiple times). Additionally, at least 11 FY 2018-FY 2020 Rural WH-MR-participating HCSs also participated in regional-wide women's health trainings supported by OWH in the years after having the Rural WH-MR.M3. The number of Online courses maintained & added to the OWH learning portfolio.By FY 2020, there were more than 40 hours of online training content available for local trainers in the OWH online library including on-demand courses, slide decks, breast and pelvic exam instructional videos, simulation equipment instructions, and other supporting training-related materials. OWH ensures training content is regularly reviewed and updated to reflect the most up-to-date, evidence-based medical guidance available. Additionally, over 100 women's health clinically oriented online, on-demand courses were widely available for VA staff to take advantage of for their ongoing learning needs.•Enlist evaluation expertise prior to program onset to ensure consistent and accurate use of RE-AIM for the program's duration.•Ensure that flexibility is built into the training's structure so that implementation and evaluation can weather unforeseen events  while remaining aligned with RE-AIM.•Distinguish the difference between Reach and Adoption measures early in the evaluation to devise separate measures reflecting these RE-AIM components differently.Sanders et al. (2022)  delineatThe latter point emphasizes one of the benefits of RE-AIM for evaluation–it helps to highlight opportunities to measure patient vs. clinician program outcomes.Utilizing RE-AIM to guide the Rural WH-MR's evaluation plan enabled us to take a systematic approach to developing our program's metrics and ultimately facilitated effective data collection for evaluation of this provider- and nurse-facing workforce training initiative. Along the way, the application of RE-AIM to our program evaluation also brought to light some challenges. Initially, our evaluation team defined our intended populations as both (1) PCPs and nurses serving rural women Veterans, and (2) rural women Veteran patients. As such we sought to measure the percentage of eligible PCPs and nurses “reached”  as well as the percentage of rural women Veterans reached (on the panels of designated WH-PCPs). Both measures introduced challenges. For the former, we struggled with the selection of an appropriate denominator for PCPs and nurses, as sites frequently replaced selected participants due to scheduling conflicts. For the latter, since PCPs could be WH-PCPs prior to the training and not all trained PCPs became designated WH-PCPs, we needed two outcome measures, one reflecting rural women Veterans on WH-PCP panels and the other accounting for rural women Veterans on WH-PCP and/or participant panels. After further discussion with ORH about operationalization of Reach and Adoption, we reframed Reach in terms of patient-level outcomes and Adoption in terms of health care staff-level and health care facilities-level outcomes. We hope that our experience with applying RE-AIM in a rural setting and identifying rural-specific measures  will benefit those applying RE-AIM to rural settings, and that our experience with this application of RE-AIM will expand a relatively limited existing literature on the use of RE-AIM for PCP/nurse training initiatives.When tracking the numbers and percentages of rural women Veterans on panels of PCPs with women's health expertise for each Rural WH-MR training cohort over time, we see general improvement longitudinally through increasing rates of patient coverage. The trend points to program success, although without a comparison group, we cannot conclude definitively that the program increased the percentages of rural women Veterans on panels of WH-PCPs and/or participants. Future evaluation activities may involve creating an intervention and a comparison group to allow for difference-in-difference analyses.We have seen in the literature that RE-AIM measures do not always align across different evaluations, with the evaluators citing different types of measures as indicators of varying RE-AIM components. Holtrop et al. (2021)  outline Specifically, in 2020, we began to examine women's health outcome indicators that we could measure to reflect the program Effectiveness. We considered as possibilities the percentages of rural women Veterans receiving appropriate: (1) contraception, (2) cancer screenings, and (3) cancer screening results follow-up, among others. To determine clinical appropriateness, all measures required complex algorithms, but in the case of contraception, we felt that given the apparent needs around contraception among women Veterans generally  we couldFor our contraception provision rates, we see that, although the rates before and after the training are small, the large relative percentage increase in contraception provision is clinically meaningful and statistically significant. However, future work should examine contraception provision in intervention groups and appropriately selected comparison groups.Regarding program Adoption, as our results show approximately 13% of eligible sites sent PCPs and/or nurses to the Rural WH-MR for pilot or FY 2018-FY 2020 trainings, leaving many eligible sites yet to receive training. Nevertheless, given that the program accomplished this participation rate in essentially 3 years , the Rural WH-MR has shown high program Adoption in a relatively short time.Further, with respect to program Adoption, the median rurality of participating sites was just under 70%. It would have been even higher except that some less rural sites were accommodated on a case-by-case basis to optimize use of available training spaces. Furthermore, although the majority of participating sites were rural, the less rural sites that sent PCPs and/or nurses still serve rural women Veterans among their patient population, thus allowing program benefits to disseminate. These Adoption metrics all suggest that the site selection process effectively identified rural sites appropriate for the program goal of increasing access for rural women Veterans to PCPs and nurses with women's health expertise.Among PCP participants with pre/post data, the percentage serving in a designated WH-PCP role nearly doubled from pre-training to post-training, such that 83% were designated WH-PCPs at follow-up, an additional 5% essentially functioned as WH-PCPs, and 3% could not finish until the following year due to the Coronavirus pandemic. All, even those without the formal WH-PCP designation, were now better positioned to serve rural women Veterans with increased women's health expertise due to their exposure to up-to-date women's health training activities and content.During the FY 2018-FY 2020 trainings, the Rural WH-MR was well implemented throughout the country as per our metrics. For example, we report that over one half of trainings in which there was at least one new training team member were monitored by OWH representatives or designees ensuring high program implementation fidelity and quality. Other measures used to evaluate the Rural WH-MR's Implementation such as usefulness of the training activities, the training's relevance to rural practice, and participant satisfaction, reflect a well-targeted curriculum and appropriate set of skills development exercises.Lastly, RE-AIM asks whether programs reflect widespread Maintenance as well as Reach, Adoption, and Implementation. While we acknowledge that our Maintenance measures may not follow the RE-AIM framework in the traditional sense as used for patient-facing interventions, we offer considerations for how we defined Maintenance for our Rural WH-MR provider- and nurse-facing training. An Effective program should continue to thrive after the initial efforts, so we looked for indicators that the Rural WH-MR could be sustained. These measures became more evident during program implementation, as we realized which types of efforts contribute to ongoing trainings of rural PCPs and nurses. For example, after engaging with the Rural WH-MR, at least 15 HCSs either hosted their own local women's health trainings or participated in regional trainings, both of which provide opportunities for participants to use their experience to disseminate more training information to additional staff.Very helpful to attend to update my own knowledge. In addition, valuable for me as the physician team lead to join in the experience to be able to continue to teach/mentor my colleagues”.With 100% of in-person trainings attended by local leaders, Rural WH-MR training sessions became more tailored to local sites because these leaders could speak to site-specific concerns. This in turn improved the quality of the trainings and the likelihood of maintaining aspects of the training over longer time periods. As one PCP stated after training in FY 2020: “To further support ongoing dissemination of training after participating in the Rural WH-MR, we note that the number of online courses maintained and added to the OWH online library grew impressively in response to the demand. Making these materials available and maintaining them so that they contain the most recent recommendations requires ongoing curation by OWH, but the benefits of the expansive offerings include easy accessibility and allowing for further propagation of women's health knowledge and skills development activities within VA.As a result of all program metrics—defined within the RE-AIM framework—showing positive program progress through FY 2020, ORH Leadership in FY 2021 committed to continue the OWH-ORH partnership to support the Rural WH-MR for 5 additional years (FY 2022-FY 2026). As discussed, many eligible rural sites have yet to benefit from this program, and the additional funds will allow for ongoing program Maintenance, while in the meantime, OWH explores ways in which the Rural WH-MR can be partially absorbed and implemented within the grander national WH-MR training program structure.Other education-focused initiatives for health professionals may build upon our experience using RE-AIM as an evaluation framework for a workforce training program. The framework helped to distinguish provider- and patient-level program outcomes of interest and created the context for understanding other aspects of the program assessment.With respect to the overall evaluation challenges and benefits of RE-AIM, and lessons learned for evaluating training programs in rural areas, OWH confirmed that enlisting evaluation expertise from the start has substantially enhanced all stages of program development and implementation. This aligns with the principle that the evaluation cycle should occur in concert with all stages of program design and rollout , 33. In Additionally, OWH learned that ensuring that flexibility is built into the training's structure can help both the program implementation and evaluation to weather unforeseen events such as COVID-19. The pandemic, in fact, proved the biggest obstacle to program implementation and evaluation by precluding numerous in-person trainings until they were deemed safe to implement. To overcome the obstacle of the COVID-19 pandemic, OWH offered the trifold program in addition to the bifold program. This enabled HCSs to continue a path towards completing the training in full, though extended over time, by participating in the in-person training when COVID-19-safe conditions arose locally.RE-AIM has only recently been more widely suggested as a framework for health care workforce training programs –22. MostAmong individual examples of RE-AIM used to assess training programs –22, evalIn so far as limitations of the evaluation, we note that while the Rural WH-MR specified delineated goals, it did not set numerical objectives at the outset, which would have provided useful milestones and is recommended for similar future work. We mentioned above the lack of a comparison group, and the relatively small number of PCPs for whom we have measures both before and after the training, making KAPS changes more difficult to detect. We also found that although the program evaluation efforts thoroughly captured metrics for all RE-AIM components, this labor-intensive approach requires significant involvement from administrative, clinical, and evaluation partners to sustain it. Efforts to develop a master tracking database currently under construction will reduce the time needed to continue ongoing monitoring and automate aspects of program evaluation. In that regard, the program evaluation will more easily be maintained and sustained in the future.In addition, we found the following limitations of the evaluation work hold. First, our solution to the COVID-19 pandemic delays complicated metrics assessment. For example, women Veterans on the panels of PCPs who partially completed the training but not fully, remain in the denominator of the R1 measure for our current analyses. This could lead to an underestimate of the program Reach because partially trained PCPs could be less inclined to increase the numbers of rural women Veterans on their panels than the fully trained PCPs. In other words, we may have a conservative estimate of program Reach. Second, after we developed our metrics, VA began its data migration to the Cerner Millennium information management system. While only one participating HCS migrated to Cerner during the training evaluation period, this change meant that some administrative data became unavailable via processes we relied upon. Third, measuring the degree to which providers and nurses engage in the training opportunity has proven challenging because the scheduling continues to be highly complex, with participants frequently replaced by their facilities due to changes in staff availability, interest, or need. On one hand, flexible scheduling allowed OWH to maximize training spaces but, on the other hand, it hindered our ability to definitively characterize the program Adoption at the PCP and nurse levels because the denominators represented a combination of participants either replaced or removed.Application of the RE-AIM framework proved valuable in the evaluation of the Rural WH-MR, demonstrating Effectiveness of this PCP- and nurse-facing training program. Our experience brought to light both pros and cons for RE-AIM's use to evaluate a workforce training program such as ours. On the positive side, the RE-AIM framework highlights both process and outcomes indicators of program successes and challenges. On the negative side, applying the framework to a provider- and nurse-facing intervention proved more complex. That is because, in the Rural WH-MR, PCPs and nurses represent a key target population of the intervention since the program seeks to improve their KAPS and comfort with women's health to improve outcomes for patients. However, in that regard, patients form a distal target population of the intervention as well. Once we decided to apply Reach to patients only and Adoption to PCPs/Nurses and HCSs/sites per ORH definitions, the framework demonstrated utility. RE-AIM enabled us to highlight all aspects of program development, execution, and evaluation, as well as generate some lessons learned—several of which have implications for similar workforce training programs in rural areas.


Antimicrobial peptides (AMPs) are promising molecules to treat infectious diseases caused by multi-drug resistance pathogens, some types of cancer, and other conditions. Computer-aided strategies are efficient tools for the high-throughput screening of AMPs.StarPep Toolbox, an open-source and user-friendly software to study the bioactive chemical space of AMPs using complex network-based representations, clustering, and similarity-searching models. The novelty of this research lies in the combination of network science and similarity-searching techniques, distinguishing it from conventional methods based on machine learning and other computational approaches. The network-based representation of the AMP chemical space presents promising opportunities for peptide drug repurposing, development, and optimization. This approach could serve as a baseline for the discovery of a new generation of therapeutics peptides.This report highlights https://github.com/Grupo-Medicina-Molecular-y-Traslacional/StarPep) under the Apache 2.0 license.All underlying code and installation files are accessible through GitHub ( The functionalities of each module are explained in detail below.StarPep toolbox allows users to retrieve a subset of AMPs from the StarPepDB using their metadata . It is also possible to find AMPs that share a given sequence identity above a threshold with single or multiple queries from the StarPepDB or an external sequence. Moreover, the software can create a non-redundant set of AMPs where any pair of sequences share no more than a given threshold of sequence identity. The user can choose the parameters to calculate the sequence identity . Finally, the software enables filtering out AMPs from the StarPepDB by peptide attributes (sequence or length), physicochemical properties, metadata node names, and PDB availability. The filtering module supports complex queries with AND/OR/NOT operators. https://grupo-medicina-molecular-y-traslacional.github.io/StarPep_doc/networks.html). In addition, specific use cases have been reported by StarPep toolbox integrates an option to compute protein/peptide sequence-based MDs. These MDs are calculated by applying statistical , fuzzy , and non-fuzzy (e.g. GOWAWA) aggregation operators on physicochemical amino acid properties  [see SI1–4 in StarPep toolbox takes peptide sequences as input to project all these n compounds into an m-dimensional space of hundreds of MDs. These sequence-based MDs showed better behavior  metadata (METNs), (ii) chemical space (CSNs), and (iii) half-space proximal (HSPNs). METNs are knowledge graphs where the edges represent semantic relationships  between the AMPs and their metadata [see Fig. 1 in k-means, expectation–maximization, and Uclust), for detecting potential AMPs families with similar MD profiles. Zooming into the detected clusters helps to identify central nodes representing relevant AMPs within communities. Moreover, the clustering analysis offers the possibility of identifying singleton  nodes, representing isolated peptides with distinct characteristics from the grouped ones. These important nodes facilitate the identification of shared motifs among potential AMP families organized into distinct communities. Previous research identified such motifs for different AMPs, including antiparasitic , or by applying different layouts that spatialize and rearrange nodes. Furthermore, the networks can be represented with the principal components, which are linear combinations of the MDs calculated with the software. The online documentation of the software presents a comprehensive description of most of the features from this section.After creating the similarity networks, the software provides global properties  and calculates centrality measures  that give a notion of the importance of nodes (peptides) in a complex network. Moreover, the program includes community detection algorithms  8 and integrating functionalities from other Java-based open-source projects. For instance, the graphical user interface was built on top of Gephi (NetBeans Platform (https://platform.netbeans.org/). The graph database structure was implemented in Neo4j (https://neo4j.com/). The visualization engine and some network-based metrics and methods were imported from Gephi (BioJava (Jmol (http://www.jmol.org/).StarPep toolbox is an open-source and user-friendly software to explore the AMP chemical space by querying, filtering, visualizing, and analyzing network-based representations. This application opens many possibilities for peptide drug repurposing, design, and optimization. We plan to add new functionalities to the software, such as new centrality metrics, more global and node-specific network properties, a module for structural motifs searching, and a web version of the StarPepDB with some tools of the software.


To date, nanomaterials have been widely used for the treatment and diagnosis of rheumatoid arthritis. Amongst various nanomaterials, polymer-based nanomaterials are becoming increasingly popular in nanomedicine due to their functionalised fabrication and easy synthesis, making them biocompatible, cost-effective, biodegradable, and efficient nanocarriers for the delivery of drugs to a specific target cell. They act as photothermal reagents with high absorption in the near-infrared region that can transform near-infrared light into localised heat with fewer side effects, provide easier integration with existing therapies, and offer increased effectiveness. They have been combined with photothermal therapy to understand the chemical and physical activities behind the stimuli-responsiveness of polymer nanomaterials. In this review article, we provide detailed information regarding the recent advances in polymer nanomaterials for the non-invasive photothermal treatment of arthritis. The synergistic effect of polymer nanomaterials and photothermal therapy has enhanced the treatment and diagnosis of arthritis and reduced the side effects of drugs in the joint cavity. In addition, further novel challenges and future perspectives must be resolved to advance polymer nanomaterials for the photothermal therapy of arthritis. Rheumatoid arthritis (RA) is a chronic autoimmune condition that is correlated with a high death rate and affects nearly 1% of the population worldwide. It is distinguished by the infiltration of inflammatory cells, synovial hyperplasia, pannus development, persistent cartilage, and bone deterioration .The quality of life for many patients has increased thanks to recent developments and novel treatment modalities that have significantly weakened disease progression . The advHealthy bone is made up of two neighbouring bones that are covered in cartilage. The articular cavity is the area between the ends that carries synovial fluid and is delineated by the synovial membrane on both sides. The synovial membrane is a thin layer of cells made up of two types of synovial cells: type A, which resemble macrophages, and type B, which resemble fibroblasts. Due to the porous structure of the synovial membrane, nutrients in the serum can diffuse cartilage while also producing synovial fluid. The development of rheumatoid arthritis and immunological reactions are complicated and involve interaction between elements of innate and adaptive immune systems. Numerous inflammatory cells are present in the synovial membrane, where they interact to promote joint degeneration . The exiAnother mechanism involved in RA is an antigen-nonspecific pathway that requires cell-to-cell interaction between fibroblasts and macrophages with activated T-cells . AdaptivPTT uses the near infra-red wavelength  of the electromagnetic spectrum to treat diseases such as cancers and arthritis. Upon exposure to NIR, the tissue temperature increases due to the conversion of light energy to heat, thereby killing cancerous cells or tissue. Three photophysical steps are involved in the conversion of NIR energy into heat. In the first and second steps, upon absorbing light, NMs convert into hot lattices, resulting in charge separation particle oscillation. Once light has been absorbed and transformed into heat, electron–photon relaxation occurs. The final step is cooling, during which heat is emitted from metal NMs into the surrounding environment. . Thus, sOwing to the small size of NMs, the restriction of electronic motion differs from that of bulk material. When light energy is incident on the NMs, the electrons on the NMs’ surface become excited, and an electron cloud forms over this surface. Here, the free electrons transfer from the valence band to the conduction band, which leads to the enhancement of the resonance peak. NMs, including graphene, carbon nanotubes, and gold nanoparticles (NPs), are the subject of preclinical investigation as possible agents for the photothermal treatment of cancer, particularly tumours. However, there are still obstacles to be overcome to improve light conversion efficiency and decrease damage to healthy cells and tissues. A new class of drugs called biological response modifiers targets inflammatory mediators in the treatment of RA. At optical frequencies, metal NPs effectively scatter and absorb visible light. Recent advancements in the synthesis, conjugation, and fabrication of NPs have prompted a greater interest in employing plasmon-resonant NPs. Additionally, their optical and photonic usage for biological purposes has been developed . To control biological autoimmune systems and treat diseases, a novel therapeutic strategy has recently arisen due to its potential to minimize side effects. In recent decades, conjugated, polymer-based nanomaterials have been used in photothermal therapy . ConjugaSo far, numerous switches have been used to control a drug’s release from the formulation. Amongst them all, the use of a light-triggered sequential release system stands out from the rest of the stimuli. The combination of the use of conjugated, polymer-based nanomaterial with laser therapy can achieve controlled drug release. The release of an anti-rheumatic drug incorporated into the polymeric material upon laser irradiation is depicted in For instance, polyethylene glycol (PEG), primarily, is used for the surface modification of NMs. In one study, Quindeel and co-workers prepared a polycaprolactone–polyethylene glycol–polycaprolactone (PCL-PEG-PCL) triblock copolymer via a ring-opening copolymerization reaction and utilised such polymer NMs as nano vehicles for the delivery of the drug MTX. Their results revealed the excellent efficacy of NMs with respect to an RA mouse model compared to those models of free MTX. These fabricated NMs decrease the expression of the inflammatory factors and recover the behavioural response capability of mice . Another study by Chen and colleagues  demonstrAnother study by Lee et al.  revealedIR780, a lipophilic, cationic, heptamethine dye with an emission wavelength of 780 nm, generates heat upon its irradiation with NIR light. NIR780 is a NIR bioactive dye that is usually conjugated with a polymer for photothermal therapy . PTT canFor example, in one report, researchers developed a nanogold core multifunctional dendrimer nanocomposite that was conjugated with the drug MTX, wherein the latter acts as a targeting ligand for receptors in arthritic tissues. In addition, NIR-780 was also loaded with this nanocomposite to provide PTT via light irradiation. Their results showed the sustained release of MTX and the enhanced anti-inflammatory efficacy of the nanocomposite via its combination with PTT towards mouse macrophage RAW 265.7 cells and CIA mice model. Hence, their multifunctional, targeted nanocomposite proved to be a potent therapeutic strategy for improved RA therapy . Gold nanoparticles number among the FDA-approved metallic nanoparticles. They are widely used for diverse biomedical applications owing to the simplicity of their synthesis, their biocompatible nature, the ease with which their surfaces can be modified, and their remarkable optical activities . The tunTriptolide (TP) is a disease-modifying anti-rheumatic drug (DMARD). Owing to the NIR irradiation of AuNPs, TP can be released to specific inflammatory joint tissues and improve the treatment of RA in vivo. Moreover, these modified materials successfully minimised the invasion and migration of RA fibroblast-like synoviocytes in vitro. NIR irradiation increased the temperature and generated heat that accelerated the release rate of TP from the hybrid hydrogels . This inAnother study demonstrated the combined effect of PTT and MTX-loaded PLGA Au/Fe/Au NPs conjugated with arginine-glycine-aspartic acid (RGD) for RA therapy applied to CIA mice . This stLike AuNPs, Cu-based NPs also play a vital role in various biomedical applications because of their superior biocompatibility, ease of synthesis, and PTT alteration efficacy. In addition, Cu aids osteogenic differentiation and bone development and improves chondrocyte proliferation . Therefo7.2S4 NPs under the influence of NIR reduced the intrusion of synovial liquid and enhanced anti-inflammatory effects in the arthritic joints of CIA rats. This also inhibited C-reactive protein and tumour necrosis factor (TNF-α). As the concentration of NPs increases, the solution temperature rises from 41 °C (125 mg/mL) to 55 °C (500 mg/mL). Singlet oxygen and reactive oxygen species generation were investigated to study their photodynamic effects.The combination of PTT and photodynamic therapy (PDT) with Cu7.2S4 NPs + NIR) on the inflamed paws of rats was reported. In this study, the researchers revealed the significantly greater therapeutic effect of (Cu7.2S4 NPs + NIR) compared to (NaCl + NIR). In another approach, Huang and associates designed a CuS shell and Au nanorod core (Au NR@CuS) together with PTT and PDT for RA treatment to reduce the hyperplasia of the synovium [Moreover, a comparative study between the impact of (NaCl + NIR) and  and vasoactive intestinal peptide (VIP) for the loading of MTX and its release in a controlled manner to a specific arthritic site. VIP-HA-Au NR@CuS-MTX demonstrated excellent therapeutic effects in vivo and higher NIR absorption than Au NR@CuS. Furthermore, both HA and VIP played a significant part in controlling or regulating the release of MTX. Hence, this investigation suggests that the synergistic activity of NPs and PTT improved RA treatment .Due to their outstanding biocompatibility and low toxicity, iron oxide NPs (IONPs) have generated a great deal of interest with respect to biological applications. One intriguing characteristic of IONPs is their special superparamagnetism, which allows them to simultaneously function as heat therapy transducers, carriers for targeted drug delivery, and magnetic resonance imaging (MRI) contrast agents for diagnosis. Iron-based NPs can be used to magnetically transport NPs to a targeted region for the more concentrated, more potent, and longer-lasting retention of NPs in the targeted tissue and, subsequently, improved therapeutic efficacy . IO has Researchers found that colloidal gold-coated superparamagnetic IONPs, also known as AuSPIONs, had a significant therapeutic effect on RA murine models and also caused a reduction in the circulation of substantial organs .3O4 NPs in the range of 70–350 nm. However, it was observed that smaller NPs were quickly engulfed by the normal cells, leading to off-targeting. While the NPs with 220 nm size showed a rise in temperature under laser irradiation and gave exact targeting, they could not be engulfed by the normal cells. Still, they easily penetrated the inflamed arthritic tissue and were retained within it with as little difficulty. As a result, the use of NPs of the appropriate size benefits the PTT of RA, which should be appropriately tuned to produce the desired results.To improve the targeting efficacy of SPIONs, researchers have studied the effects of NPs’ size on the efficiency of PTT for arthritis treatment, as shown in Black phosphorous nanosheets (BPNs) are superior photo-responsive materials. They are widely used because of their excellent phototherapy effects, strong biocompatibility, and promising osteogenic qualities; they have drawn a great deal of attention ,33. DuriRecently, researchers prepared a black phosphorous nanosheet-based thermos-responsive hydrogel with the help of platelet-rich plasma (PRP)-chitosan as a temperature-responsive polymer . It was Semiconducting polymeric quantum dots are a new class of functional nanomaterials being developed for photothermal therapy. Recently, scientists have prepared folate receptors that target semiconductive polymeric quantum dots . To stabPTT has recently received recognition as an effective RA treatment method . Dual or multiple stimuli-responsive drug delivery systems, compared to single stimuli-responsive drug systems, offer greater control over medication release since they are more flexible and sensitive in terms of reacting to inflammatory situations. In one study, the investigators provided a method for constructing a dual or multiple-stimuli-responsive drug delivery system to treat RA. In the past, lipid NPs were produced by assembling triglycerol monostearate (TGMS) and 1,2-rdistearoyl-sn-glycero-3-phosphoethanolamine-carboxyl (DSPEPEG). In the current study, the matrix metalloproteinases’ cleavable TGMS segment was conjugated with PEG-COOH using 3-amino phenophenyl boronic acid (PBA) as a linker.Compared to other stimuli-responsive drug delivery systems that have been previously discussed in the literature, the PEG has stealth features. They show that the PEG shell’s defence stabilizes Dex-loaded PPT micelles’ circulation. In addition, it accurately recognizes scavenger receptors through ligand–receptor interaction, wherein hydrophilic block Dextran Sulfate (DS) was selected as the active target. In one study, Polycaprolactone (PCL) and DS were combined to generate DS-b-PCL, which demonstrated improved biodistribution in the rear feet of CIA mice following each systemic injection compared to little in wild-type animals. Wang et al.  demonstrIn order to deliver MTX, researchers have conjugated a sialic acid-dextran-octadecanoic acid to MTX and prepared a MTX-loaded micelle. These micelles were able to enhance bone healing while also obtaining an anti-inflammatory benefit. Through the interaction of sialic acid and vascular endothelial cells, this MTX-loaded micelle greatly increased the drug’s accumulation in arthritic joints while showing good therapeutic advantages and few side effects. Effective therapies for RA include PTT and antioxidant combination therapy using Pd and Se NP co-delivery devices . During 3O4) NPs have been utilised to treat and diagnose RA. Their biodistribution is ultimately impacted by the differences in their properties concerning size, charge, roughness, and elemental makeup, as depicted in 3O4 NPs exhibit remarkable biocompatibility and stability upon exposure to NIR light at higher temperatures [MTX and gold-based nanomaterials are routinely used for treating RA using PTT and chemotherapy, which induce a significant drop in inflammatory cytokine levels. When combined, gold nanorods and shells produce heat. Therefore, they are treated with NIR light and have improved therapeutic efficacy when combined with MTX. Magnetic iron oxide . They depend on Perovskite quantum dots and MOF-loaded polydopamine to enable Hrheating .Chemotherapy is the primary method of treatment for RA, along with surgery. Most patients can enter remission after employing treatments, biological agents, glucocorticoids, non-steroidal anti-inflammatory medications (NSAIDs), and disease-modifying anti-rheumatic pharmaceuticals. NSAIDs such as aspirin reduce the signs and symptoms of inflammation by inhibiting COX-2 activity . The curOne of the most well-supported nanocarriers, liposomes, have been used to successfully distribute Dex, an anti-RA drug, to RA patients. Liposomes incorporating synthetic materials of 100 nm in diameter and surface functionalised with 10% 5 kDa PEG that is slightly negatively charged have been shown to improve their in vivo half-life and capacity to target inflamed joints. In addition, the anti-arthritic activity of Dex is significantly boosted after being enclosed within liposomes according to pharmacodynamic studies using CIA mice . For theIn this regard, Kim et al.  used PLGAn innovative method among the phototherapeutic approaches is the image-guided application of light, in which only the target region with a high photosensitizer concentration should be illuminated. Several procedures have involved the provision of WS2 or Au NPs to CT-PTT . TriggerA multipurpose imaging tool that can “picture” and “trigger” the targeted, controlled release of medication from ENCs is required. Only a handful of proof-of-concept studies have examined the efficacy of these RA therapeutic options, which are currently in the early stages of development.Due to the progressive, debilitating nature of the disease; its unknown cause; and its initial similarities to other inflammatory diseases, RA is notoriously difficult to diagnose in its early stages. NIR-II photoacoustic molecular imaging (PMI) is being developed as a promising new strategy for the precise diagnosis and direction of RA treatment due to its exceptional sensitivity and specificity upon deep penetration.In one study, TCZ, a targeted anti-rheumatic drug, was combined with polymer NPs to provide the first NIR-II-based theragnostic nanoplatform, or TCZ-Polymer NPs, for the PA-imaging-guided therapy of RA. NIR-II PMI data have shown that TCZ-Polymer NPs have better targeting capabilities for the effective non-invasive diagnosis of RA joint tissue, with a high signal-to-noise ratio (SNR) of 35.8 dB in 3D PA tomography images. Additionally, it has been demonstrated that the results of clinical micro-CT and histological analyses are in agreement with respect to the NIR-II PMI treatment evaluation of RA mice.Six Harlan rats developed arthritis in their knee and ankle joints with the assistance of peptidoglycan polysaccharide polymers. Three rats comprised the untreated controls. Before and up to 24 h after the intravenous administration of 10 mg/kg ICG, optical imaging of the knee and ankle joints was performed using an integrated OI/X-ray system. The fluorescence signal intensities of the joints with and without arthritis were analysed for any discernible differences using generalised estimating equation models. Joint samples from the knee and ankle were further examined and evaluated using histology .Nimesulide and low-dose MTX would be present in therapeutic RGD-mediated polymeric micelles that would be used to actively and passively target RA. As a result, they adhered RGD to NHS-PEG3400-PLA2000, an FDA-approved amphiphilic copolymer that is biocompatible and biodegradable. Additionally, we conducted real-time fluorescence imaging analysis to examine the in vivo distribution of the fluorescence-labeled R-M/N-PMs and in vivo investigations in a rat model of adjuvant-induced arthritis to evaluate the anti-inflammatory activity of R-M/N-PMs.This problem may be resolved through the creation and application of magnetic NPs, namely, ultrasmall paramagnetic iron oxide (USPIO)  was created, coated with USPIO, and conjugated with folic acid (FA) with a targeted function towards the PEG-b-PAA/USPIO surface; subsequently, researchers were able to develop a highly stable and focused nanocomposite contrast agent (referred as FA-PEG-b-PA). Herein, the authors also investigated the impact of FA-PEG-b-PAA/USPIO on RA’s early diagnosis.3O4 NPs on the effectiveness of PTT for RA treatment to improve biosafety and its targeting impact.When PTT is used with external magnetic field-targeted therapy, therapeutic efficacy increases, and adverse effects are reduced with fewer doses. Additionally, iron-based parts enabled T2-weighted magnetic resonance imaging (MRI) in vivo, thus supplying the RA treatment’s guiding and monitoring capability. Magnetic iron oxide NPs (IONPs) have a unique ability to convert light to heat. The FDA has approved IO as a contrast agent for MRI because of the high biocompatibility of its iron-based composition. Colloidal gold-coated superparamagnetic IONPs, also known as AuSPIONs, were found to have a significant therapeutic effect on RA murine models and provoke a reduction in circulation in the principal organs by  investigPhotodynamic therapy, which uses photosensitizers or non-toxic dyes along with safe, visible light, has been used for more than a century, but is just now gaining popularity ,43. In aPDT primarily relies on the presence of oxygen present inside the cells. When a photosensitizer enters the cell, it is exposed to light at a wavelength that coincides with the photosensitizer’s absorption spectrum. The absorption of a photon causes the excitation of the photosensitizer from the ground state to the excited state. The energy is released as fluorescence while the residual energy causes the excitation of the photosensitizer towards the excited triplet state, thus generating phosphorescence . Co-deliAs a result, they are frequently co-delivered with conventional agents. Palladium (Pd) blue was the term given to the hexagonal palladium nanosheets developed by Chen et al.  with a b2. This was associated with a significant reduction in the toxicity issues associated with MTX. It was advocated that, like MTX, other therapeutic agents can be combined with PTT to amplify its medicinal benefits  NPs employed PEI as a stabilizer. The created PPY-PEI NPs showed significant NIR absorption and exhibited good photothermal stability and performance . A methyA unique method for the treatment of RA involved the use of CuS NPs based on copper NPs and a novel l-cysteine-assisted synthesis. In addition to stimulating chondrogenesis and osteogenesis, copper acts as a photothermal and photosensitizer. In vitro investigations have shown outstanding biocompatibility and excellent photothermal and photodynamic effects.RNA interference (RNAi) is a cellular process that silences messenger RNA (mRNA)-based genes post-transcriptionally, and small interference RNA (siRNA)-based silencing is only temporary. Hence, new methods have been devised and described to produce longer-lasting silencing. The use of short hairpin RNA (shRNA), for example, is a vector-encoded technique that can be employed for long-lasting, reliable cell silencing. Small interfering RNA (siRNA), which is highly specific and effective in terms of silencing genes, is a critical component that is mediated by RNA interference . An intrRGD-functionalised, siRNA-loaded poly (lactide-co-glycolide) NPs were created by Scheinman et al.  as a nanFor the treatment of RA, Park et al. created PLGA NPs that were loaded with Dex and siRNA. In this study, PLGA NPs were first loaded with Dex before being combined with PEI/siRNA . Then, gPolymer-based NMs and PTT have led to tremendous growth in nanomedicine, which has been proven through various publications and clinical trials over the past years. The combined effect of PTT and polymer NMs has revealed multiple advantages compared to conventional therapies such as radiotherapy, chemotherapy, and immunotherapy for treating diseases such as cancers and RA. Polymer-based NMs are cost-effective, biocompatible, and beneficial materials that are easily functionalised with functional groups. They can convert light to heat energy and thus enhance their own photothermal conversion efficiency. They are used as nanocarriers for controlled drug release that improve the efficacy of RA treatment and reduce the disease’s side effects. With the help of NMs, drugs bind to specific target sites, produce signals for imaging determinations, and generate ROS to support PTT and PDT performance. This review expounds on various polymer-based NMs for the photothermal therapy of RA, including Au, Cu, iron oxide, black phosphorous, quantum dots, and palladium. These NMs have achieved excellent improvement in the treatment of RA via their combination with PTT. However, many issues still need to be discussed, such as their low photothermal conversion efficacy, safety, and low in vivo efficiency, which limit their clinical applications. In addition, their accumulation in non-targeted cells or tissues is another problematic issue. Thus, besides their effective treatment efficiency, the interaction of such polymer NMs with tissues is a matter of concern that requires further investigation to determine their potential applications. In the future, we believe that nanotechnology and advanced polymer-based NMs will play a vital role in treating RA.


An irregular vessel pattern with DFI-EUS was a significant predictor of malignant gallbladder lesions (p = 0.002). DFI-EUS is more sensitive than e-FLOW-EUS for vessel detection and the differential diagnosis of gallbladder lesions and IPMNs. Vessel evaluation using DFI-EUS may be a useful and simple method for differentiating between mural nodules and mucous clots in IPMN, between solid gallbladder lesions and sludge, and between malignant and benign gallbladder lesions.Detective flow imaging endoscopic ultrasonography (DFI-EUS) is an innovative imaging modality that was developed to detect fine vessels and low-velocity blood flow without contrast agents. We evaluate its utility for the differential diagnosis of gallbladder lesions and intraductal papillary mucinous neoplasms (IPMNs). We enrolled patients who underwent DFI-EUS, e-FLOW EUS, and contrast-enhanced EUS for gallbladder lesions or IPMNs. The detection of vessels using DFI-EUS and e-FLOW EUS was compared with that via contrast-enhanced EUS and pathological findings. The vessel pattern was also categorized as regular or irregular. Of the 33 lesions included, there were final diagnoses of 13 IPMNs and 20 gallbladder lesions. DFI-EUS was significantly superior to e-FLOW EUS for discriminating between mural nodules and mucous clots and between solid gallbladder lesions and sludge using the presence or absence of vessel detection in lesions ( Pancreatobiliary diseases are important causes of morbidity and mortality worldwide. Among the imaging modalities, transabdominal ultrasonography is the most non-invasive, cheapest and widely used method. However, it has some limitations. When performing transabdominal ultrasonography imaging, the intervention of gas, bone and fat can create problems. Endoscopic ultrasonography (EUS) was developed as a solution to these issues. EUS is the most reliable and efficient diagnostic modality for pancreatobiliary disease owing to its high spatial resolution, which allows for the detection of small lesions in pancreatobiliary disease. There is difficulty in making differential diagnoses based on EUS imaging characteristics alone, however, because the majority of lesions are hypoechoic. The assessment of vascularity is another approach that can be used for differential diagnosis. Doppler imaging modalities, such as color-Doppler EUS, power Doppler EUS, and e-FLOW EUS, are used in real-time checking of vascularity. Of these methods, e-FLOW EUS is a directional power Doppler ultrasonography method that has better spatial and temporal resolutions than the others. However, conventional EUS Doppler modes, including e-FLOW EUS, are not suited to the visualization of fine vessels and slow flow. On the other hand, contrast-enhanced EUS (CE-EUS) is better for detecting blood flow and does not have some of these limitations. Assessments of the utility of CE-EUS for detecting intraductal papillary mucinous neoplasms (IPMNs) and gallbladder lesions have been reported in many articles ,9,10,11.Between January 2020 and December 2021, 58 patients who underwent DFI-EUS, e-FLOW EUS, and CE-EUS at Wakayama Medical University Hospital for gallbladder lesions or IPMNs detected by CT, MRI, and/or transabdominal ultrasonography were prospectively enrolled.The inclusion criteria for this study were: age >20 years, and DFI-EUS, e-FLOW EUS, and CE-EUS imaging all being performed on the same day. CE-EUS was done at the end of examination because it affected DFI-EUS and e-FLOW EUS images. Patients suspected of having gallbladder sludge or mucous clots in the IPMN after CE-EUS were followed-up for at least 1 year to confirm an absence of change. Patients with a mural nodule in IPMN underwent surgical resection for diagnosis. Patients with a solid gallbladder lesion underwent surgical resection or EUS-guided fine needle aspiration (EUS-FNA) for diagnosis. Finally, 33 patients were included in this study according to inclusion criteria as surgical resection was not performed for 19 patients with mural nodules in IPMN and 6 patients with solid gallbladder lesions . There wThis study was approved by the Wakayama Medical University Ethics Committee (Nos. 2492 and 2496), and all patients provided informed consent.This study evaluated the utility of DFI-EUS for the differential diagnosis of IPMN and gallbladder lesions. The primary aim was to measure the accuracy of DFI-EUS for differentiating between mural nodules and mucous clots in IPMN, and to differentiate between solid gallbladder lesions and sludge. A lesion with vessels was defined as a mural nodule or a solid gallbladder lesion, and a lesion without vessels was defined as a mucous clot or sludge. The accuracy of DFI-EUS in the differential diagnoses was compared with that of e-FLOW EUS. For mucous clots and sludge, the absence of blood flow was confirmed by CE-EUS. A secondary outcome measure was the ability to differentiate between malignant and benign variations of IPMN and gallbladder lesions. A lesion with a regular vessel pattern was defined as benign, and a lesion with an irregular vessel pattern was defined as malignant.Convex-type endoscopes  with ultrasound observation systems  were used. The patient was placed in the left lateral position under diazepam-induced sedation for EUS, and heart rate, saturation, and blood pressure were monitored. The color gain, dynamic range, and transmission frequency were set to 65, 83, and 5.0 MHz, respectively, for DFI-EUS, and 52, 83, and 5.0 MHz for e-FLOW EUS. The color gain settings were optimized before starting the study to minimize the noise in lesions in either mode, and these values were then fixed across all patients. EUS images were recorded for the subsequent evaluation of vascularity. Assessment of vessels was performed on the recorded EUS images by three endosonographers who had at least 10 years of EUS experience, and who were blinded to all other imaging and patient information. Vessels were assessed as absent/present or regular/irregular vessels. The terms regular vessel images refers to smooth and linear vessels in the tumor, while irregular vessels are defined as tortuous vessels with a caliber change .DFI-EUS, an innovative Doppler US technique, can detect very slow flow and microvascular vessels, doing so without motion artifacts or the need for contrast agents. In terms of Doppler ultrasonography, the ultrasonic Doppler signals represent not only blood flow, but also motion artifacts. Therefore, the signals from the motion artifact overlap with low-speed flow components . The slo® GE Healthcare Pharm, Tokyo, Japan), which is a second-generation ultrasonography contrast agent composed of perfluorobutane microbubbles with a median diameter of 2–3 μm. After reconstitution with 2 mL of sterile water for injection, 0.7 mL of the agent was administered through a peripheral vein. For CH-EUS, the extended pure harmonic detection method was used with the mechanical index set at 0.3.The CE-EUS used Perflubutane  was used for statical analysis. The comparison of vessel detection between DFI-EUS and e-FLOW EUS was performed with McNemar’s test. Inter-rater agreement was evaluated with Landis and Koch proposals . The qualitative variables were used to compare categorical variables with Fisher’s exact test. A n = 1) or intraductal papillary mucinous carcinoma (IPMC) . The assessment of the differences in vessel type (regular/irregular vessel) between malignant and benign IPMN was not performed because there were only four surgical IPMN lesions, including one benign IPMN. The examination of gallbladder lesions by CE-EUS led to a diagnosis of gallbladder sludge in 8 cases and solid lesions in 12 cases. Histopathological examination of the solid gallbladder lesions with EUS-FNA (n = 5) or surgery (n = 7) revealed carcinoma (n = 8), metastasis of renal cancer (n = 1), adenoma (n = 1), cholesterol polyp (n = 1), and chronic cholecystitis (n = 1). Inter-rater agreement regarding the assessment of vascularity was high . The accuracies of DFI-EUS and e-FLOW-EUS for differentiating mural nodules from mucous clots in IPMN were 100% (13/13) and 77% (10/13), respectively. The accuracies of DFI-EUS and e-FLOW EUS for discriminating between solid lesions and sludge in gallbladder lesions were 95% (19/20) and 70% (14/20), respectively. DFI-EUS  was thus significantly superior to e-FLOW EUS in discriminating between mural nodules and mucous clots in IPMN, and also between solid gallbladder lesions and gallbladder sludge  (p = 0.005). In 9 of 33 cases (27%), lesions were not adequately diagnosed on e-FLOW EUS. The median size of lesions missed on e-FLOW EUS was 15 mm . We find it particularly concerning that gallbladder cancer, measuring 35 mm in size, was missed on e-FLOW EUS (p = 0.002) (The patient characteristics are shown in FLOW EUS . Irregul= 0.002) . DFI-EUS= 0.002) . The sen= 0.002) .According IPMN guidelines, EUS plays an important role in addressing worrisome features including cyst ≥3 cm, thickened and enhanced cyst wall, mural nodule < 5 mm, a main pancreatic duct 5–9 mm, lymphadenopathy, abrupt changes in the caliber of the pancreatic duct with distal pancreatic atrophy, cyst growth rate ≥5 mm in two years, and elevated CA 19-9 . In partIn this study, we evaluated the vascularity of IPMN and gallbladder lesions using DFI-EUS. In 32 of 33 lesions, DFI-EUS facilitated correct discrimination between mural nodules and mucous clots and between solid gallbladder lesions and gallbladder sludge. By contrast, e-FLOW EUS, which has the best resolution among the three conventional Doppler modes, missed diagnosis in 9 of 33 cases (27%). DFI-EUS was therefore found to be significantly superior to e-FLOW EUS in the differential diagnosis in IPMN and gallbladder lesions. We found it particularly concerning that gallbladder cancer measuring 35 mm in size was missed on e-FLOW EUS. A reason for detection with e-FLOW-EUS being difficult in advanced cancer could be because the blood flow in advanced cancers with neovascular attributes is slow or often intermittent . DFI-EUSWe also evaluated the effectiveness of DFI-EUS for discriminating between malignant and benign gallbladder lesions . Irregular vessel patterns were detected in 89% of malignant gallbladder lesions, and regular vessel patterns were detected in 100% of benign lesions. An irregular vessel pattern was therefore found to be a significant predictor of malignancy in gallbladder lesions. Unnecessary surgical resection was performed for three benign gallbladder lesions in this study because gallbladder lesions >10 mm in diameter had the potential for malignancy. On the other hand, it was possible to diagnose gallbladder lesions as benign in all cases with DFI-EUS. In the previous report, the sensitivity, specificity, and accuracy were 77%, 88%, and 86%, respectively, when the lesion size classification  was defined as a malignant gallbladder lesion . In termWe also examined the optimal settings for Doppler imaging including DFI-EUS and e-FLOW EUS. When the color gain is too low, the detection of vessels is difficult. However, the stronger the vessel signal becomes, the stronger noise only occurs without detecting the other vessels with a slower flow . In thisIt is important to compare the results of DFI-EUS with those obtained via transabdominal ultrasonography, another microvascular imaging technique. Diagnostic studies on various diseases have shown that the utility of transabdominal ultrasonography for microvascular imaging is similar to that of DFI ,27,28,29This study has three main limitations. First, it is a single-center study with a small study population, meaning that further studies of DFI-EUS with larger cohorts from multiple centers are needed in the future. Second, sludge and mucous clots were confirmed by CE-EUS rather than by pathological analysis. However, it is difficult to perform surgical resection because in clinical practice, mucous clots and gallbladder sludge are evaluated by CE-EUS and then followed-up. In these cases, we confirmed that there was no change after one year. Third, we fixed the optimal color gains to compare both modes under the same conditions; however, the optimal color gains for both modes differed from case to case.DFI-EUS was found to be more sensitive than e-FLOW-EUS for vessel detection and the differential diagnosis of gallbladder lesions and IPMN. We determined that an irregular vessel pattern with DFI-EUS also predicts malignant gallbladder lesions. The evaluation of vessels using DFI-EUS may be a useful and simple method for differentiating between mural nodules and mucous clots in IPMN, between solid gallbladder lesions and gallbladder sludge, and between malignant and benign gallbladder lesions.


Social media addiction has increasingly been a critical social problem. We explored the association between peer pressure on mobile phone use and adolescent mobile social media addiction and tested whether self-esteem and self-concept clarity could buffer the effect of peer pressure.Mage = 14.480, SDage = 1.789) participated in our anonymous cross-sectional questionnaire study.830 adolescents (The results showed that peer pressure significantly predicted adolescent mobile social media addiction. Self-esteem moderated the effect of peer pressure on mobile social media addiction in that peer pressure had a weaker effect for adolescents with higher self-esteem. Self-concept clarity moderated the effect of peer pressure on mobile social media addiction in that peer pressure had a weaker effect for adolescents with higher self-esteem. The two moderators also interact in that the moderation of self-esteem was stronger for adolescents with higher self-concept clarity and the moderation of self-concept clarity for adolescents with higher self-esteem.The results highlight the critical role of self-esteem and self-concept clarity in buffering the impact of peer pressure on mobile social media addiction. The findings promote a better understanding of how to buffer the undesirable effect of peer pressure and reduce the risk of mobile social media addiction among adolescents. Social Peer pressure may be an essential predictor of adolescent mobile social media addiction. Peer pressure refers to the pressure that individuals feel when they are directly or indirectly asked to think and act according to the rules or requirements of their peers , 7. SincIn addition, according to the individual-environment interaction model , 12, envMoreover, self-esteem and self-concept clarity may act as protective factors to alleviate the impact of negative environmental factors on individuals. According to sociometer theory , self-esPrevious studies have also confirmed the protective effects of self-esteem and self-concept clarity in buffering negative interpersonal factors. For instance, self-esteem moderated the effect of relational victimization on children’s internal problem behaviors, with the effect being stronger for children with lower levels of self-esteem . IndividHypothesis 1: Self-esteem would moderate the association between peer pressure and mobile social media addiction in that peer pressure had a weaker effect for individuals with high self-esteem than for those with low self-esteem.Hypothesis 2: Self-concept clarity would moderate the association between peer pressure and mobile social media addiction in that peer pressure had a weaker effect for individuals with high self-concept clarity than for those with low self-concept clarity.Although peer pressure has been proven to have a significant predictive effect on adolescents’ Internet addiction , the effIn conclusion, the present study explored the association between peer pressure on mobile phone use and mobile social media addiction and further tested whether self-esteem and self-concept clarity could moderate the effect of peer pressure. In addition to the two simple moderating effects, the present study also examined whether there were significant gender differences in the two moderating effects and whether the two moderators interacted. The results can better reveal the complex protective roles of self-teem and self-concept clarity.2.2.1.Mage = 14.480, SDage = 1.789). The detailed demographic data analysis of participants is presented in We invited 896 adolescents from two high schools in South China. They participated in our anonymous survey in the classrooms. Thirty-eight students did not complete all the psychological scales. Twenty-eight students provided invalid responses. Data from 830 adolescents were analyzed to test our hypotheses. Three hundred and seventy-seven adolescents were boys (45.40%), and 453 adolescents (54.60%) were girls. These participants’ age range from 11 to 18 years old  was used . This sc2.2.3.The Chinese version  of the R2.2.4.The Chinese version  of the S2.3.The Pearson correlation analysis was conducted before the model test. We adopted the PROCESS macro for SPSS  to analy3.3.1.3.2.We conducted two moderation analyses to test the moderating roles of self-esteem and self-concept clarity. The three-way interaction analysis was also performed to examine whether the two moderators interacted with each other.β = 0.196, p < 0.001), self-esteem negatively predicted mobile social media addiction , and the interaction of peer pressure and self-esteem showed a significant effect on mobile social media addiction . The association between peer pressure and mobile social media addiction was strong in adolescents with low self-esteem  but was not significant for adolescents with high self-esteem . The effect of peer pressure on mobile social media addiction at different levels of self-esteem is depicted in β = 0.174, p < 0.001), self-concept clarity negatively predicted mobile social media addiction , and the interaction of peer pressure and self-concept clarity showed a significant effect on mobile social media addiction . The association between peer pressure and mobile social media addiction was strong in adolescents with low self-concept clarity  but was not significant for adolescents with high self-concept clarity . The effect of peer pressure on mobile social media addiction at different levels of self-concept clarity is depicted in β = −0.113, p < 0.001). β = −0.286, p < 0.001) but was not significant in adolescents with low self-concept clarity . The interaction of peer pressure and self-concept clarity was stronger in adolescents with high self-esteem  but was not significant in adolescents with low self-esteem .After controlling for age, gender, and daily mobile phone use time, there was significant three-way interaction between peer pressure, self-esteem, and self-concept clarity  and high levels of self-esteem . For adolescents with high self-concept clarity, the effect of peer pressure on mobile social media addiction was significant at low self-esteem  but was not significant at moderate self-esteem . Peer pressure even negatively predicted mobile social media addiction at high self-esteem for adolescents with high self-concept clarity . Similarly, for adolescents with low self-esteem, the effect of peer pressure on mobile social media addiction was significant at low self-concept clarity  and high self-concept clarity . For adolescents with high self-esteem, the effect of peer pressure on mobile social media addiction was significant at low self-concept clarity  but was not significant at moderate self-concept clarity . Peer pressure even negatively predicted mobile social media addiction at high self-concept clarity for adolescents with high self-esteem .Specifically see , for adoβ = 0.075, p = 0.062). The three-way interaction of peer pressure, self-concept clarity, and gender was also insignificant . In other ways, there were no significant gender differences in the moderating effects of self-esteem and self-concept clarity.4.Social media is increasingly playing a critical role in people’s daily life. Mobile social network services have become an essential core function of mobile phones. However, the following problem of mobile social media addiction occurs and develops into one of the typical problem behaviors among adolescents. This study examined the effect of peer pressure on adolescents’ mobile social media addiction and the moderating effects of self-esteem and self-concept clarity. The results showed that both self-esteem and self-concept clarity significantly alleviated the effect of peer pressure on mobile social media addiction, and there was a significant interaction between the two moderators. The reasons and implications of the results are discussed below.First, this study found that peer pressure on mobile phone use significantly predicted adolescent mobile phone addiction. Consistent with this result, previous research has shown that peer pressure on Internet use was positively associated with adolescent Internet addiction . Mobile Second, this study revealed that self-esteem buffered the association between peer pressure on mobile phone use and social media addiction. The effect of peer pressure on mobile social media addiction was significant only in adolescents with low self-esteem rather than high self-esteem. This result is consistent with sociometer theory , which hThird, this study also demonstrated that self-concept clarity buffered the association between peer pressure on mobile phone use and social media addiction. The effect of peer pressure on mobile social media addiction was significant only in adolescents with low self-concept clarity rather than high self-concept clarity. This result also coincides with previous research indicating the protective effect of self-concept clarity in buffering negative environmental factors . Self-coIn addition, the present study found no gender differences in the moderating roles of self-esteem and self-concept clarity, but the two moderators  significantly interact. The moderating role of self-esteem was more potent in adolescents with high self-concept clarity than those with low self-concept clarity. Similarly, the moderating role of self-concept clarity was more potent in adolescents with high self-esteem than in those with low self-esteem. In other words, the two protective factors can mutually enhance. Previous studies have found that the negative impact of risk factors on self-evaluation is stronger in individuals with lower self-concept clarity . The resSome limitations should be noted. First, the causal relationship between peer pressure and mobile social media addiction cannot be strictly confirmed by the cross-sectional design we used. Future research should consider using a longitudinal design or experimental study. Second, this study only focused on social media addiction without including different types of mobile phone addiction. In addition to mobile social media addiction, peer pressure may cause other types of mobile phone addiction, such as mobile game addiction. Future research should consider testing whether peer pressure exerts different effects on different mobile phone addictions and whether the moderating effects of self-esteem and self-concept clarity will show differences in different types of mobile phone addiction. Third, academic performance is an important factor in adolescence, but we did not include it in the analysis. Academic performance was closely associated with self-esteem and mobile phone addiction , 52. FutDespite the above limitations, our findings still bring about important implications. First, this is one of the first studies documenting the impact of peer pressure on mobile social media addiction. The findings expand previous research on the association between peer pressure and Internet addiction. Second, this study further uncovers the critical roles of self-esteem and self-concept clarity in buffering the impact of peer pressure. These results contribute to understanding how to buffer the effect of peer pressure and how to reduce mobile social media addiction. Third, this study has specific implications for preventing and intervening in mobile social media addiction. Since peer pressure directly increases the risk for mobile social media addiction, parents and educators should help adolescents understand the harm of peer pressure, stay away from deviant peers, and avoid the impact of negative peer pressure. Besides, since self-esteem and self-concept clarity can effectively buffer the influence of peer pressure, parents and educators should help adolescents develop positive self-evaluations and clear self-concepts.In conclusion, we conducted a moderation analysis to analyze the moderating roles of self-esteem and self-concept clarity in the association between peer pressure on mobile phone use and mobile social media addiction. Peer pressure directly predicted adolescent mobile social media addiction. Both self-esteem and self-concept clarity effectively moderated the effect of peer pressure. Peer pressure had a significant impact on mobile social media addiction only in adolescents with low self-esteem or self-concept clarity. In addition, there was a significant interaction between the two moderators. The moderating role of self-esteem was more potent in adolescents with high self-concept clarity but not significant in low self-concept clarity adolescents. The moderating role of self-concept clarity was more potent in adolescents with high self-esteem but not significant in low self-esteem adolescents. The findings highlight the protective roles of self-esteem and self-concept clarity in the mobile Internet era. Enhancing self-esteem and self-concept clarity will be an effective way to protect adolescents who experience high peer pressure from mobile social media addiction.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by the Ethics Committee of Guangzhou University. Written informed consent to participate in this study was provided by the participants’ legal guardian/next of kin.XX contributed to the conceptualization, methodology, investigation, and writing—original draft, review, and editing. WH contributed to the resources, and writing—review and editing. QL contributed to the conceptualization, methodology, investigation, formal analysis, and writing—original draft, review, and editing. All authors contributed to the article and approved the submitted version.This work was supported by the Programs of the National Social Science Fund of China (No. 21BDJ054 and No.18CRK009) and the Program of the Fund of Philosophy and Social Science of Guangdong Province (No. GD20CXL05).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.