East African countries face significant societal challenges related to sustainable development goals but have limited resources to address these problems, including a shortage of nutrition experts and health care workers, limited access to physical and digital infrastructure, and a shortage of advanced educational programs and continuing professional development.This study aimed to develop a web-based program for sustainable development with a focus on digital learning, digital health literacy, and child nutrition, targeting government officials and decision-makers at nongovernmental organizations (NGOs) in Ethiopia and Rwanda.A web-based program—OneLearns (Online Education for Leaders in Nutrition and Sustainability)—uses a question-based learning methodology. This is a research-based pedagogical method developed within the open learning initiative at Carnegie Mellon University, United States. Participants were recruited during the fall of 2020 from ministries of health, education, and agriculture and NGOs that have public health, nutrition, and education in their missions. The program was conducted during the spring of 2021.to large extent or to a very large extent. Furthermore, 17  and 18  participants reported that their capacity to drive change related to digital health literacy and digital learning had increased to a large extent and to a very large extent, respectively.Of the 70 applicants, 25 (36%) were selected and remained active throughout the entire program and filled out a pre- and postassessment questionnaire. After the program, of the 25 applicants, 20  participants reported that their capacity to drive change related to the sustainable development goals as well as child nutrition in their organizations had increased Digital learning based on a question-based learning methodology was perceived as a useful method for increasing the capacity to drive change regarding sustainable development among government officials and decision-makers at NGOs in Ethiopia and Rwanda. East African countries face significant societal challenges covered by the global sustainable development goals (SDG) . A totalAlthough information and communication technology (ICT) is central to meeting new skills and training demands in most low- and middle-income countries , interneSimilar to digital learning, digital health literacy is a fundamental aspect of any country’s economic development and a major contributor to the realization of SDGs . DigitalRwanda encourages web-based learning and the digitization of several other service sectors, such as health care, commerce, and governance . HoweverThe OneLearns program targeted government officials and decision-makers in nongovernmental organizations (NGOs) in Ethiopia and Rwanda and covered the SDGs with a focus on digital learning, digital health literacy, and nutrition. We described the development of the OneLearns program, learning objectives, question-based learning methodology, process of recruiting participants, and the results of the program evaluation. Finally, we highlighted some lessons learned and ways to improve the program in the future.The OneLearns program was designed and developed by a team of 6 experts at the KTH Royal Institute of Technology and Mälardalen University, Sweden, between September 2020 and December 2020. The team included a professor, 2 associate professors, a postdoctoral researcher, a PhD student, and a research assistant with a master’s degree. The team had expertise in different domains including digital learning technologies, digital health literacy, sustainable development, public health, and nutrition. The program was based on the team’s research fields, but to ensure that the program would be relevant for the target participants from Rwanda and Ethiopia, the content was discussed with research colleagues from Rwanda and Ethiopia, including members of the teaching team from Ethiopia and Rwanda.The program used a question-based learning methodology in which the learning material was organized around formative questions linked to one or more skills, which in turn were linked to the learning objectives . More coThe program was designed for participants’ self-paced studies of digital material followed by web-based video seminars at the end of each unit, in line with the principle of the flipped classroom. The program comprised 3 units . The firunderstanding level of the Bloom taxonomy of learning, which is a hierarchical model that categorizes learning objectives into varying levels of complexity, and the level of “understanding” is the second lowest level [To ensure that the material was relevant to the target group and countries, half  of the OneLearns teachers were from Ethiopia or Rwanda. Moreover, policy documents and other teaching materials were reviewed to ensure that the topics included in the program were relevant for and adjusted to their corresponding countries. The first step in the development of the program was to determine the learning objectives and related skills for each module. In total, 17 learning objectives and 47 skills were identified; an example of a skill can be as follows: “Explain the pros and cons of web-based learning.” Thereafter, program designers formulated a series of formative questions for each skill. The formative questions formed the backbone of the digital learning material  and werest level . Each fost level  , and the rest was based on the teaching team’s own research. Finally, questions for the final assessment tests were formulated. The final assessment tests took place at the end of modules B, C, D, and E  and werePrinciples of good questionsQuestion is from the program domain .Question is targeted toward a misconception.Question is not based on a reference lookup.Question is reasonable to solve without external systems.Principles of good answering alternativesThree or more answer alternatives are provided.Answer alternatives are plausible and linked to the misconception.Answer alternatives are formulated to maximize readability.Principles of good feedbackFeedback is constructive.Feedback is unique and provided for each answer alternative.Feedback for answer alternatives does not reveal the answer.The recruitment process continued between September 2020 and December 2020, targeting potential participants from various ministries with a focus on the ministries of health, education, and agriculture and NGOs with public health, nutrition, and education in their missions. We collaborated with the embassies of Rwanda and Ethiopia in Stockholm, who distributed calls for applications to ministries and NGOs in their respective countries. To reach the different ministries, the information had to go via the ministry of foreign affairs, whereas the NGOs were reached via less formal networks. In addition, we sent information to our own network of NGO contact persons and to the Swedish embassies in Ethiopia and Rwanda, which they then shared further.We received 70 applications, including 42 from Ethiopia and 28 from Rwanda. Applicants were screened and scored according to the professional field, leadership experience, educational background, current job position, and their potential for decision-making, as well as the ability to express oneself in English. Furthermore, we aimed to achieve a gender balance of close to 1:1 ratio for men and women. On the basis of applicant scoring, 27 applicants were selected for the second phase of recruitment, where web-based interviews were conducted primarily to verify sufficient communication and verbal skills in English. Although 3 (11%) participants were recognized as having less experience communicating orally in English, none of them were excluded. Of the 27 participants, 13 (48%) were men, 14 (52%) women, 15 (56%) from Ethiopia, and 12 (44%) from Rwanda. Of these, 26 (96%) successfully registered to the program, but 1 (4%) requested withdrawal from the program after the registration, leaving 25 active participants. For the 2 (7%) participants who did not start the program, one reported a change in work circumstances that conflicted with the program’s schedule, while the other did not communicate a reason and failed to register completely.The program continued between January 29, 2021, and May 11, 2021 , and it Each unit was supposed to be completed within approximately 25 days. The participants began by working with the digital material and answering formative questions, followed by a web-based video seminar with teachers from Sweden and a final group assignment and module test. In the absence of physical interaction, it was important to ensure that the participants interacted and networked with each other. Therefore, 1 group assignment per program unit was included. Reminders were sent weekly with deadlines, including a general group progress report. The program ended on May 11, 2021, with a full-day web-based workshop and included invited speakers from Sweden, Rwanda, and Ethiopia and “learning by doing” activities. Unlimited data packages were provided to all participants in Ethiopia and Rwanda to ensure that they could be involved in the workshop. In addition, the participants in Rwanda were invited to meet in a large conference room at a hotel in Kigali and take part in the workshop from there, whereas the COVID-19 pandemic restrictions in Ethiopia did not allow for physical gatherings at that point in time.The predominant means of communicating program information, progress updates, and deadline reminders to the participants was email. For less formal communication, that is, sharing scientific articles or pertinent seminars, a WhatsApp group was set up so that the participants could network as well. Google Docs was used for group assignment submissions, and teachers used the comment function to provide feedback on assignments. The initial kickoff, video seminars at the end of each module, and final workshop were conducted via Zoom . Moreover, during the final workshop, a Miro board, a web-based creative collaboration platform , was usebefore and after the program. These web-based surveys included questions provided by the grant provider and the national foreign aid agency (Swedish Institute). To the best of our knowledge, these questions have not been validated but are used in all programs that they support. The surveys were distributed using the survey software Survey Generator and included automatic reminders to nonresponders. The first survey had 17 questions, whereas the latter had 9  to some extent, and (3) to a large or to a very large extent. Descriptive data were generated by Survey Generator from Alstra or analyzed using IBM SPSS 26 Statistics or Microsoft Excel Analysis ToolPak.The overall aim of the preassessment survey was to capture the participants’ demographic and professional profiles and their own perception of their capacity in the various topics, that is, the current level of knowledge and confidence to bring about change. Questions such as “To what extent do you have sufficient knowledge and skills to drive change regarding digital learning” were used, with a nominal scale with options “not at all,” “to a small extent,” “to some extent,” “to a large extent,” or “to a very large extent” or “not applicable.” Owing to the small number of participants, categories were merged into three main categories  and 5,  and 18 (72%) participants responded, respectively. Questions such as “Which section did you learn the most from?’ and ‘What did you think was missing from the unit?” were used to identify areas of improvement for future programs; however, an analysis of the results was beyond the scope of this study.To evaluate the program material, an end-of-unit evaluation with open-ended questions was sent to the 25 participants after the Data on the performance of the participants, that is, their engagement with the learning material and learning objectives, were automatically collected by the open learning initiative system. Response rates and answering patterns of the formative questions were assessed; for example, how many times different answer alternatives were selected for the multiple-choice questions. In addition, based on the data that the open learning initiative system collected from participant engagement with the program material, it automatically generated learning curves for each of the 47 skills in the program.Paragraph 2 of the Swedish Ethical Review Authority states that ethics approval is only necessary if a project collects sensitive personal data from the participants, involves physical procedures, uses a method that will impact the participants physically or physiologically or if there is a risk of harm, or involves biological material . None ofAll 25 participants remained active and participated throughout the entire program, but 3 (12%) did not complete all the tasks required by the program, such as formative questions and module tests. Divided by units, of the 25 participants, 24 (96%) successfully completed all the requirements of units 1 and 2, and 23 (92%) completed those of unit 3. Participants who completed all the tasks were given a certificate of completion, and the 3 (%) participants who remained active but did not complete all the tasks required by the program received a certificate of participation.none or very little knowledge before the program started. In addition, 12  participants reported having none or very little knowledge about digital learning before the program started. Corresponding numbers for knowledge level rated as none or very little for child nutrition and SDGs were 2  participants and 1  participant, respectively.On the basis of the results from the preassessment survey, the topic that the participants self-reported having the least previous knowledge about was digital health literacy, and 17 of the 25  participants expressed having to a large extent or to a very large extent for digital health literacy and 5  participants regarding digital learning. The corresponding numbers for SDGs and child nutrition were 10  and 13  participants, respectively  participants replied ectively .to a large extent or to a very large extent after the program, and 23  reported that their knowledge regarding digital learning increased to large extent or to a very large extent. Moreover, despite having extensive self-reported knowledge about the SDGs before the program, the postassessment survey showed that all 25 participants reported that their knowledge regarding the SDGs had increased to a large extent or to a very large extent after the program, whereas 20  participants reported that their knowledge regarding child nutrition increased to large extent or to a very large extent. Regarding the participants’ capacity to drive change in their organizations after completing the program, 20  participants reported that their capacity related to the SDGs had increased to large extent or to a very large extent, and 20  reported that their capacity to drive change related to child nutrition increased to large extent or to a very large extent. Furthermore, 18  participants reported that their capacity to drive change related to digital health literacy had increased to a large extent or to a very large extent, and 17  reported that their capacity to drive change regarding digital learning had increased “to a large extent or to a very large extent”  reported that their knowledge regarding the digital health literacy had increased  extent” .Different types of digital learning materials were provided and participants were asked in the postassessment survey about which materials had been the most helpful. Multiple answers were allowed, and almost all participants reported that they found the formative questions helpful , followed by module test questions , reading the program text and web pages , watching videos , and web-based workshops , and more than half  of the participants reported that group assignments were helpful. Overall, approximately three-fourths  of the participants felt that their participation in the program was worth the time and effort they had put in.The postassessment survey included 2 open-ended questions: (1) “Did you miss something in the program?” and (2) “Did the program meet your expectations?” For the first question, more than half  of the participants reported that they did not feel anything was missing in the program. The second most common response was that the participants felt that they would have benefited from physical interactions. The second open-ended question yielded more uniform results, in which all but 1 (4%) respondent felt that the program met their expectations. For example, one of the participants wrote the following:...The content and topics were beyond my expectations. For some modules, it was my first time to hear about them especially in Unit 1  and unit 2 (module 3 and 4) digital health literacy in digital ecosystem was an eye opener. I am looking forward to explore it in my routine work…I am now confidently organizing a Facebook campaign on Covid-19 in Haiti...I do not feel intimidated anymore. Even if it’s something I do not understand, I search online, YouTube and get hands-on...”Regarding web-based networking and interaction, more than half  of the participants reported having been in contact with other program participants on a monthly or weekly basis. In addition, more than half  of the participants reported having been in contact on a monthly or weekly basis with teachers participating in the program. No participant had been completely out of touch with the other participants, whereas 1 (4%) participant reported that they had never been in contact with teachers outside of the class.The OneLearns program showed that a digital program is a useful approach to enhance knowledge about issues related to sustainable development among government officials and leaders of NGOs in Ethiopia and Rwanda. All participants  reported that their knowledge regarding the SDGs had increased to a large extent or more after the program, and 80% (20/25) reported that their capacity to drive change in their organizations related to the SDGs had increased to a large extent or more. In this program, midlevel to high-ranking government officials and leaders of NGOs were targeted because they influence policy making in their respective countries and often collaborate to bring about changes in communities and policies . Hence, Knowledge, skills, and abilities after completion of a web-based learning experience are common ways to define the effectiveness of a web-based education program ; the resParticipants also reported that they gained substantial knowledge on topics in which they had initially believed they were already well-versed, such as in the case of the SDGs. At the same time, for topics that the participants reported as having low previous knowledge, such as digital learning and digital health literacy, 92% (23/25) and 96% (24/25), respectively, of the participants reported that their knowledge regarding these issues increased to a large extent or to a very large extent. This indicated the importance of offering advanced professional development to experts in the ministries and NGOs in these countries.The participants were expected to spend 40 hours on the program over a 3-month period at the same time as they were working in their regular jobs. An advantage of self-study of digital material is that it was possible for the participants to adjust their reading to their own schedules. However, the disadvantage was time management issues, such as interference of daily life routines in studies and some personal problems, which have previously been reported from similar programs  and wereAn example of a digital barrier was that we provided unlimited data packages for all participants for the final workshop, but the poor infrastructure from the local service provider impeded a few participants from having reliable connectivity during this full-day collaborative event. In addition, although weekly reminders were sent containing deadline dates and a general group progress report, deadlines for all 4 module tests had to be extended for some of the participants based on their personal needs. This was done to accommodate the needs of the participants, as the program was a professional development program and not a formal academic course. The foremost goal of the program was to ensure that the participants learned the course material.An incentive to fulfill all the requirements, announced at the first kickoff seminar, was that the participants in OneLearns were promised a printed and digital certificate at the end of the program. Moreover, a few ambitious and high-performing participants were appointed as course ambassadors. This initiative was implemented after the program started to recognize their efforts and form long-lasting relations between participants and teachers. For example, 2 ambassadors were invited to speak at the kickoff of the second edition of the OneLearns program, which started in September 2021. In addition, all participants were invited to become alumni members of the international network run by the Swedish Institute.Regarding communication with the participants, the WhatsApp group proved useful and easy to use. All participants had previous experience with the app, and it was their preferred method of communication with the teachers as compared with email. Sending reminders via WhatsApp ensured faster responses or follow-ups than expected from the participants; thus, we increased the use of the app for smoother and faster communication during the course of the program. WhatsApp was used for informal communication among the participants, contributing to networking among professionals in different areas and countries and was available for future communication after the end of the program.In the open learning initiative platform, data were collected when students answered questions, that is, click-data, and these are used in a machine learning model to predict students’ mastery of the learning objectives ,22. FurtOpen learning initiative courses using question-based learning methodology are being used at more than a hundred colleges and universities in the United States, but their spread outside North America is limited . We knowA potential limitation of this program was selection bias in the recruitment process because participants need to be able to communicate in English, although this is not the official language in Ethiopia and has just recently become one in Rwanda . AlthougThe next step for participants is to implement what they learned and build capacity for change in their organizations. If done on a large scale, it will take time, but may include, for example, increased use of digital learning in schools, universities, and other educational organizations. Digital health literacy may lead to increased ability of the general population and professionals to seek information on self-care, access to care, increased use of internet-based medical consultations to reduce emergency department visits, and electronic receipts of drugs . In addiDigital learning based on question-based learning methodology is a useful method to increase knowledge and the capacity to drive change related to sustainable development among government officials and decision-makers at NGOs in Rwanda and Ethiopia.


P. aeruginosa.Using polyclonal IgM-enriched immunoglobulin (IgM-IG) as adjuvant therapy to colistin appears useful in the treatment of pneumonia caused by multidrug-resistant strains of  Pseudomonas aeruginosa strains, both ceftazidime-susceptible and one colistin-resistant. Pharmacodynamically optimised antimicrobials were administered for 72 h, and intravenous IgM-IG was given as a single dose. Bacterial tissues count and the mortality were analysed. Ceftazidime was more effective than colistin for both strains. In mice infected with the colistin-susceptible strain, ceftazidime reduced the bacterial concentration in the lungs and blood (−2.42 and −3.87 log10 CFU/ml) compared with colistin  and with the controls. Colistin plus IgM-IG reduced the bacterial lung concentrations of both colistin-susceptible and resistant strains  and the bacteraemia rate of the colistin-resistant strain (−44%). These results suggest that IgM-IG might be useful as an adjuvant to colistin in the treatment of pneumonia caused by multidrug-resistant P. aeruginosa.We evaluated the efficacy of ceftazidime or colistin in combination with polyclonal IgM-enriched immunoglobulin (IgM-IG), in an experimental pneumonia model  using two multidrug-resistant  Pseudomonas aeruginosa is a Gram-negative bacillus (GNB) that causes community- and healthcare-associated infections, especially in intensive care units  preparation containing IgG, IgM, and IgA as an adjunctive therapy were associated with significantly improved survival in patients with septic shock . GiamareP. aeruginosa.Therefore, the aim of this study was to evaluate the efficacy of ceftazidime or colistin in combination with IgM-enriched immunoglobulins (IgM-IG) in treating pneumonia in a murine model, where infection was induced using clinical strains of multidrug-resistant MICs and MBCs for the two clinical strains are shown in P < 0.001).Motility assays are shown in When grown alone, both bacterial strains showed similar growth at 24 h. The colistin-resistant PaM1 strain showed a loss of fitness compared with the colistin-susceptible Pa147 strain  .The colistin-susceptible Pa147 strain showed higher biofilm formation (97.1%) than the colistin-resistant PaM1 strain (41.2%) .10 CFU/g) and blood (−3.87 log10 CFU/ml) as well as the mortality (−40%). Colistin monotherapy and IgM-IG administered alone only reduced the bacterial concentrations of the colistin-susceptible Pa147 strain in the lungs . In mice infected with the colistin-resistant PaM1 strain, ceftazidime monotherapy reduced the bacterial concentration in the lungs (−1.42 log10 CFU/g) and the mortality (−40%). Colistin monotherapy and IgM-IG administered alone did not have a therapeutic effect on any variables in mice infected with the PaM1 strain.The efficacies of colistin and ceftazidime as monotherapies and in combination with IgM-IG are shown in 10 CFU/ml) and the mortality (−20%) in mice infected with the Pa147 strain, and it decreased the bacterial concentration in the lungs (−0.8 log10 CFU/g) and blood (−0.89 log10 CFU/ml) in those infected with the PaM1 strain, but the effects were not significant in any of these cases. In the secondary analysis, IgM-IG plus ceftazidime decreased bacterial concentrations in lungs  and blood , and the mortality  respect to colistin monotherapy against the Pa147 strain, without differences with colistin for the PaM1 strain.Compared with ceftazidime monotherapy, IgM-IG plus ceftazidime reduced the bacterial concentration in the blood (−0.83 log10 CFU/g). This combination also reduced, although not significantly, the bacterial concentration in the blood (−1.29 log10 CFU/ml) and the frequencies of bacteraemia and mortality (−30%) against the same strain. In mice infected with the colistin-resistant PaM1 strain, IgM-IG plus colistin reduced, although not significantly, the bacterial concentration in the lungs (−1.04 log10 CFU/g) and blood (−1.88 log10 CFU/ml) and the frequency of bacteraemia (−44%). In the secondary analysis IgM-IG plus colistin compared with ceftazidime monotherapy only decreased the bacteraemia rate  for the PaM1 strain.Finally, compared with colistin monotherapy, IgM-IG plus colistin significantly reduced the bacterial concentration of the colistin-susceptible Pa147 strain in the lungs  and in blood .P. aeruginosa, regardless of the MIC. The weak efficacy of colistin monotherapy in treating infections with the colistin-susceptible strain was significantly improved when combined with IgM-IG in terms of bacterial clearance from the lungs and blood and the bacteraemia and mortality rates. However, the combination of IgM-IG and ceftazidime led to only modest improvements compared with ceftazidime monotherapy, and the difference was not significant.Our results show that ceftazidime monotherapy was better than colistin in treating experimental murine pneumonia caused by both strains of 10 CFU/g) when compared with the control group. IgM is the first line of defense against infection by inhibiting bacterial adhesion to epithelial cells and neutralizing toxins  are T-cell–independent antigens, being antibodies induced in response to them mostly of the IgM isotype. In acute P. aeruginosa infection, the LPS-phenotype predominates and, as such, might be that treating the infection with antibiotics in combination with IgM-IG could be an option for acute infections because IgM-IG could awaken the immune response faster, helping to resolve it along with antibiotics. In this regard, a murine pneumonia model in BALB/c mice  significantly the bacterial lungs concentration. IgM KBPA101 could be detected in the bronchoalveolar lavage fluid of infected mice but not in uninfected animals. In addition, this monoclonal antibody increased the neutrophils recruitment in the lungs compared with control PBS-treated infected mice, whereas macrophage/monocyte recruitment did not  . Nevertheumoniae , and in eumoniae . One expvaluated . In addivaluated .10 higher with the colistin-resistant strain than the colistin-susceptible strain. These results are in accordance with other studies showing that the decrease in both the in vitro and in vivo fitness and virulence of Acinetobacter baumannii after acquisition of colistin resistance was due to a pmrA mutation  susceptibilities were used for inducing pneumonia in mice: Pa147 (MIC 0.5 mg/l) and PaM1 (MIC >128 mg/l). For biofilm assays, A. baumannii ATCC 19606 and A. baumannii CR17 . In vivo experiments were approved by the Committee on the Ethics of Animal Experiments of the University Hospital Virgen del Rocío (0784-N-15) and the Ministry of Agricultura, Pesca y Desarrollo Rural (11-09-15-322). The animal model experimental study design is represented in Male immunocompetent C57BL/6J mice  were used . Animals had a sanitary status of murine pathogen free and were assessed for genetic authenticity. Mice were housed in an individually ventilated cage system under specific pathogen-free conditions, with ad libitum access to water and food. The study was carried out following the recommendations of the Guide for the Care and Use of Laboratory Animals  https://For the in vitro studies, antimicrobials were used as standard laboratory powders (Sigma-Aldrich). For the efficacy studies, clinical formulations were used: colistimethate sodium , ceftazidime , and IgM-IG .https://www.eucast.org/clinical_breakpoints/). MBCs were determined by subculturing onto 100 μl of antimicrobial-free Mueller–Hinton agar in wells containing antimicrobial concentrations greater than or equal to the MIC of the corresponding agent. Studies were performed in triplicate.MICs were determined using the broth microdilution method following the EUCAST recommendations and interpreted according to EUCAST breakpoints  (https:/Surface motility was measured as previously described . Briefly5 CFU/ml) was grown in 10 ml of MHBII (Sigma-Aldrich) at 37°C. Then, at different time points , 100 μl aliquots were taken, and twofold dilutions were plated on blood agar plates. Competitive growth between the two strains was assessed in MHB by mixing 5 × 105 CFU/ml of each strain in the same culture. After 24 h, aliquots from the cultures were seeded on both blood agar and Mueller–Hinton plates with 2 mg/l colistin to differentiate the colonies  was added to each well. After 10-min incubation at room temperature, the wells we washed twice and 200 μl of 96% ethanol added to each. After 15 min of incubation at room temperature, biofilm formation was quantified by measuring the OD at 580 nm . Assays were performed in triplicate. The results are represented with normalisation to the positive control strain, which was taken as 100%.Biofilm production was measured as previously described . A. baumBefore performing the efficacy studies, all therapies were evaluated in five healthy male immunocompetent C57BL/6J mice (20 g), which were treated with the dosage and regimen to be used. Mice were evaluated for 7 d, and no weight loss or changes in motility and/or mortality were observed.10 CFU/ml, and animals were observed for 7 d. Then, groups of mice were ip anesthetised (ketamine/diazepam) and intratracheally infected with 50 μl of the MLD: 8.59 and 9.66 log10 CFU/ml for Pa147 and PaM1 strains, respectively. Then, mice were randomly assigned to one of the following groups: (i) control, infected and untreated; (ii) CMS (20 mg/kg/q8h/ip); (iii) CAZ (100 mg/kg/q12h/ip); (iv) IgM-IG (430 mg/kg/iv), single dose administered 30 min post-infection; (v) IgM-IG plus CMS; and (vi) IgM-IG plus CAZ. Antibiotic treatments were initiated 4 h post-infection and lasted 72 h. Antibiotics dosages were based on previous PK/PD data and their proven efficacy in experimental models of infection (A previously characterised murine pneumonia model was used . Firstlynfection . IgM-IG nfection .10 CFU/g and log10 CFU/ml). Blood samples were also studied for qualitative cultures.Mortality was recorded for 72 h after beginning the treatments. Immediately after animal death, or on euthanasia at the end of the experiment , lungs and blood samples were aseptically obtained and processed for quantitative cultures (log10 CFU/g), expressed as means ± SEM, were compared by Tukey’s post hoc tests, after confirming the homogeneity of variance between groups using Levene’s test . For the quantitative blood cultures (log10 CFU/ml), the Games–Howell test post hoc tests was used . As the hypothesis of the study was that combining IgM-IG with antibiotics improves their therapeutic efficacy, in the primary analysis we compared each combination with the corresponding monotherapies and controls. Moreover, as a secondary analysis, we made the comparison between the CMS and CAZ treatment groups. Finally, the eta-squared for treatment comparisons was calculated. P < 0.05 was considered to indicate significance. SPSS v24.0 software was used (SPSS Inc.).Mortality rates and positive qualitative blood cultures are expressed as percentages, and differences between groups were compared using the two-tailed Fisher’s test. Quantitative bacterial cultures in the lungs  and the Ministry of Agricultura, Pesca y Desarrollo Rural (11-09-15-322).https://grants.nih.gov/grants/olaw/guide-for-the-care-and-use-of-laboratory-animals.pdf).The present study followed the recommendations of the Guide for the Care and Use of Laboratory Animals (


In recent years, the preferentially expressed antigen in melanoma (PRAME) has also been used in the histopathological diagnosis of melanocytic lesions, in order to understand if it could constitute a valid, inexpensive, and useful resource in dermatopathological fields. We performed a double-center study to evaluate whether the data on the usefulness and possible limitations of PRAME could also be confirmed by our group. From 1 December 2021 to 29 March 2022, we collected 275 cases of melanocytic lesions that were immunostained with PRAME (Ab219650) and rabbit monoclonal antibody (Abcam). To better correlate the PRAME expression with its nature , we categorized PRAME tumor cells’ percentage positivity and intensity of immunostaining in a cumulative score obtained by adding the quartile of positive tumor cells  to the PRAME expression intensity in tumor cells . Of these 275 lesions, 136 were benign, 12 were of uncertain potential for malignancy (MELTUMP or SAMPUS or SPARK nevus), and 127 were malignant. The immunoexpression of PRAME was completely negative in 125/136 benign lesions (91.9%), with only a few positive melanocytes (1+) and intensity 1+ in the remaining 11 cases (8.1%). Of the 127 cases of melanoma , PRAME was strongly positive in 104/127 cases (81.8%) with intensity 4+ and 3+. In 17 cases , PRAME was positive in percentage 2+ and with intensity ranging from 2+ to 3+. In 7 cases (5.5%) of desmoplastic melanoma, PRAME was 1+ positive and/or completely negative. Of the 12 cases of lesions with uncertain potential for malignancy, the immunoexpression of PRAME was much more heterogeneous and irregularly distributed throughout the lesion. These data are perfectly in agreement with the current literature, and they demonstrate that the reliability of PRAME is quite high, but its use cannot cause physicians to disregard the morphological information and the execution of other ancillary immunohistochemical stains such as Melan-A, HMB-45, MiTF, and SOX-10. Allen–Spitz criteria, various ancillary immunohistochemical techniques have become more and more widespread, allowing an additional possibly helpful resource in challenging melanocytic lesions Allen–Spi lesions , and, re lesions . In the  lesions ,12,13. IWe consulted the archives of two pathological anatomy departments planning to extrapolate their cases from 1 December 2021 to 29 March 2022, on which it was necessary, in addition to immunostaining with other antibodies , to run PRAME to gain a further indication of the benignity/malignancy of the lesions. We identified 323 melanocytic lesions, which were all diagnosed by two dermatopathologists at the time of diagnosis and double-blinded for the execution of this study (A.C and G.C.). After screening, only the cases in which the diagnosis was concordant between both dermatopathologists were considered.This study was approved by the local ethical committee.First, 5-micron thick tissue sections were cut from formalin-fixed paraffin-embedded (FFPE) blocks. The cases in question were all stained with anti-PRAME antibody Ab219650, rabbit monoclonal, in 1:250 dilution.To better correlate the PRAME expression with its nature , we categorized PRAME tumor cells’ percentage positivity and intensity of immunostaining in a cumulative score obtained by adding the quartile of positive tumor cells  to the PRAME expression intensity in tumor cells . More specifically, we used the following scores for the percentage positivity of tumor cells: 0% (score 0), 1% to 25% (score 1+), 26% to 50% (score 2+), 51% to 75% (score 3+), and 76% to 100% (score 4+). Furthermore, we used a score for intensity by measuring the nuclear immunostaining for PRAME as weak, moderate, or strong . Sebaceous glands were used as an internal control to confirm the functioning of the PRAME antibody stain. These characteristics of immunoexpression were estimated by both dermatopathologists during the review of the cases.A total of 275 melanocytic proliferations were examined, including 136 benign lesions, 12 lesions of the uncertain potential of malignancy, and 127 malignant lesions. In total, 156 (56.7%) patients were male, and 119 (43.2%) patients were female, with a mean age of 56.8 in the first group and 43.7 in the second group. Of the 136 melanocytic benign lesions, 84 (61.7%) were nevi with low-grade dysplasia (according to WHO 2018 ), and 52Of the 136 benign melanocytic lesions, divided into 84 with low-grade dysplasia and 52 with high-grade dysplasia, 81/84 (96.4%) were negative or had a score of 1+ for PRAME, while 4/52  nevi with high-grade dysplasia were positive for PRAME with an immunoscore of 1+/2+ A. RegardIn recent years, the continuous need to refine the diagnosis of MM associated with the difficulty and inter-observer variability of atypical pigmented lesions has made it possible to search for new markers that are useful in both the diagnostic and potentially therapeutic fields .Although initially discovered in tumor-reactive T-cell clones with cutaneous melanoma  and usedRegarding the pigmented melanocytic lesions, of the 145 cases reported by Lezcano et al., 86.4% were completely negative for PRAME, with 13.6% of mild and focal positivity in some nevi such as dysplastic, recurrent, etc. In our work, we found a slightly higher negative value, equal to 96.4% for nevi with low-grade dysplasia (according to WHO 2018), and we reported a positivity rate for PRAME (7.6%) in nevi with high-grade dysplasia with a score of 1+/2+. These data are particularly interesting because they seem to confirm the trend of the results reported in the paper by Gassenmaier et al.  in whichRegarding the 12 lesions with uncertain potential for malignancy comprising 4 MELTUMP, 3 SAMPUS, and 5 SPARK nevus, we also reported a certain degree of heterogeneity of immunostaining for PRAME, characterized by areas of greater positivity (score 3+) and areas of positivity equal to 2+ or also 1+. As already addressed by Raghavan et al. , the lesIn conclusion, our study also supports the evidence already present in the literature, attributing a definitely significant role to PRAME in the complex differential diagnosis between dysplastic melanocytic nevi and malignant melanomas, while remembering that there is a subgroup of lesions that can express, even quite intensely, this immunomarker. In the various histotypes of malignant melanoma, PRAME appears to be quite reliable, even considering that some particular types, including nevoid melanoma, spindle cell melanoma, and desmoplastic melanoma , tend to lose immunopositivity, and therefore, the dermatopathologist must know this eventuality. Overall, PRAME is useful but not conclusive when applied to lesions with an uncertain potential for malignancy such as MELTUMP, SAMPUS, and SPARK nevus. Future studies with more case series and other data are needed to elucidate and better understand the usefulness of PRAME in other MM subtypes and other primary skin lesions.


SM objectives by reducing the burden of CRC on the US population. Specifically, SMARTER CRC aims to test the implementation, effectiveness, and maintenance of a mailed fecal test and patient navigation program to improve rates of CRC screening, follow-up colonoscopy, and referral to care in clinics serving rural Medicaid enrollees.Screening reduces incidence and mortality from colorectal cancer (CRC), yet US screening rates are low, particularly among Medicaid enrollees in rural communities. We describe a two-phase project, SMARTER CRC, designed to achieve the National Cancer Institute Cancer MoonshotPhase I activities in SMARTER CRC include a two-arm cluster-randomized controlled trial of a mailed fecal test and patient navigation program involving three Medicaid health plans and 30 rural primary care practices in Oregon and Idaho; the implementation of the program is supported by training and practice facilitation. Participating clinic units were randomized 1:1 into the intervention or usual care. The intervention combines (1) mailed fecal testing outreach supported by clinics, health plans, and vendors and (2) patient navigation for colonoscopy following an abnormal fecal test result. We will evaluate the effectiveness, implementation, and maintenance of the intervention and track adaptations to the intervention and to implementation strategies, using quantitative and qualitative methods. Our primary effectiveness outcome is receipt of any CRC screening within 6 months of enrollee identification. Our primary implementation outcome is health plan- and clinic-level rates of program delivery, by component (mailed FIT and patient navigation). Trial results will inform phase II activities to scale up the program through partnerships with health plans, primary care clinics, and regional and national organizations that serve rural primary care clinics; scale-up will include webinars, train-the-trainer workshops, and collaborative learning activities.This study will test the implementation, effectiveness, and scale-up of a multi-component mailed fecal testing and patient navigation program to improve CRC screening rates in rural Medicaid enrollees. Our findings may inform approaches for adapting and scaling evidence-based approaches to promote CRC screening participation in underserved populations and settings.clinicaltrial.gov (NCT04890054) and at the NCI’s Clinical Trials Reporting Program (CTRP #: NCI-2021-01032) on May 11, 2021.Registered at  Contributions to the literatureOur study will contribute new data on the effectiveness, implementation, and maintenance of a program of mailed fecal test outreach and patient navigation to improve screening rates in rural settings.We use a collaborative model that involves health plans, clinics, and vendors. Our findings will provide evidence for the scalability of this model across similar US settings.Our evaluation will track multi-level adaptations to the intervention and to implementation strategies using novel frameworks, contributing to scant prior research in this area.We will scale up the study to over 130 rural clinics and assess the program adoptions and adaptations (both planned and executed).Colorectal cancer (CRC) is the third-leading cause of cancer death in the USA , 2. CRC Rates of CRC screening are particularly low among adults in rural communities and among specific sub-populations within these settings, including Medicaid enrollees , 10–12. Interventions are needed to address disparities in CRC screening and follow-up in rural Medicaid enrollees. Fecal immunochemical testing (FIT) is a convenient at-home screening strategy recommended by the US Preventive Services Task Force; adults with an abnormal FIT result must obtain a follow-up colonoscopy to find and remove polyps or find cancers at early stages. Several systematic reviews have highlighted the success of mailed FIT outreach as a strategy to improve rates of CRC screening, demonstrating greater CRC screening improvements than with other strategies –27. PatiSM objectives by developing a model for how to rapidly adapt and scale-up multi-level interventions through clinic-health plan-vendor partnerships to reduce the burden of CRC on the US population.Our study, Screening More patients for CRC through Adapting and Refining Targeted Evidence-based Interventions in Rural settings (SMARTER CRC), evaluates the implementation of a targeted, multi-level program that incorporates tailored mailed FIT outreach and patient navigation to address CRC disparities in rural Medicaid populations. Through the course of a large-scale pragmatic trial plus a scale-up study, we anticipate working with more than 20 regional and national organizations to facilitate the program’s implementation in an estimated 160 rural primary care clinics . We will assess adaptations and drivers of program success at the patient, clinic, health plan, vendor, and policy levels. This study fills key evidence and implementation gaps and will support President Biden’s Cancer MoonshotSMARTER CRC is being conducted as part of the NCI-funded consortium, the Accelerating Colorectal Cancer Screening and Follow-up through Implementation Science (ACCSIS) Program. The overall aim of ACCSIS is to conduct multi-site, coordinated, transdisciplinary research to evaluate and improve CRC screening processes using implementation science strategies. SMARTER CRC is a large-scale, parallel, cluster-randomized study involving three Medicaid health plans and 30 rural clinics, followed by a scale-up study involving 130 rural practices. A cluster-randomized design was chosen because it could minimize the potential for contamination  and could minimize bias due to changes in secular trends (versus stepped-wedge designs). Clinic units were randomized either to implement mailed FIT outreach along with a tailored patient navigation program to promote timely follow-up for abnormal FIT or to continue providing usual care. The intervention program was tailored for rural Medicaid populations using Boot Camp Translation , with coSMARTER CRC has obtained approval from the Oregon Health & Science University’s Institutional Review Board (protocol number: 20681), which has granted a waiver of informed consent because the study involves minimal risks to enrollees and could not practicably be conducted without the waiver. A ceding agreement was obtained from Kaiser Permanente Center for Health Research. The study will be monitored by the MPIs, following an established internal data safety monitoring plan.The project team invited participation from eight health plans that serve rural counties in Oregon; three health plans agreed to participate (37.5%). All three health plans are Coordinated Care Organizations (CCOs), networks of heath care providers  who work with local communities to provide coordinated care to individuals covered on Medicaid. The three participating CCOs are Eastern Oregon CCO (EOCCO), Cascade Health Alliance (CHA), and PacificSource. PacificSource is organized into administrative entities that cover three distinct regions participating in SMARTER CRC: PacificSource-Central, PacificSource-Gorge, and PacificSource-Marion and Polk Counties. In 2021, these CCOs provided Medicaid and dual-eligible coverage to 296,047 people in Oregon . The 2019 Medicaid CRC screening rate was 51% for EOCCO and 52% for CHA, and the 2021 Medicaid CRC screening rate was 62% for PacificSource .All participating CCOs provide coverage with no out-of-pocket costs to Medicaid enrollees for FIT, colonoscopy, sigmoidoscopy, CT colonography, and follow-up colonoscopy after an abnormal test result in alignment with Oregon policy , 52. Forn = 6795 in 2021), and in 2019 expanded the program to include prior-year FIT-screened Medicaid enrollees (n = 239 in 2021). The SMARTER CRC intervention will be overlaid on these existing screening promotion efforts.Participating CCOs promote CRC screening in a variety of ways. In prior years, a subset of EOCCO clinics  conducted a mailed FIT outreach program using the collaborative clinic-health plan-vendor model from the BeneFIT study  –57. ImplThe project team  collaborated with the participating CCOs to recruit affiliated clinics. To be eligible for participation in the study, clinics had to have at least 30 age-eligible Medicaid or dual-eligible enrollees, have a CRC screening rate of 60% or lower, and be in a geographic region designated as rural or frontier by the Oregon Office of Rural Health or have a Rural-Urban Commuting Area code of 4 or higher –60. For n ~ 3960 patients aged 50–64), using practice facilitation to support implementation. Using a mixed methods approach, identify patient-, clinic/health system-, and payer/policy/community-level factors that are associated with reach, effectiveness, implementation, and maintenance of the program, and assess program adaptations.Aim 1: Conduct a large-scale pragmatic study, using a two-arm cluster-randomized design, to assess the implementation, effectiveness, and maintenance of a direct mail and patient navigation CRC screening program in 30 rural primary care clinics (n ~ 20) to scale up the program to clinics serving rural and underserved patients in high-priority geographic regions of the USA  using webinars, train-the-trainer workshops, and collaborative learning approaches. Assess trainings delivered, program adoption and adaptations, and determinants of dissemination success.Aim 2: Partner with regional and national organizations  within the same health system to serve as randomization units. These clinics had common staff or enrollees, lacked claims data at the level of individual clinics, or were too small to otherwise meet eligibility criteria. This resulted in 29 clinic units for randomization.Units were randomized 1:1 into intervention and control groups. Randomization was stratified on health system designation  and performed by the project statistician in two batches in April 2021 (2 CCOs) and May 2021 (1 CCO), with timing based on data availability. Each batch consisted of five strata, with 2–6 clinic units within a stratum. The randomized allocation sequence was generated using STATA version 16 . The study condition  was randomly assigned during a virtual ‘roll of dice’ meeting attended by health plan and clinic representatives, with the intervention group being offered the intervention during year 1 of the study (April 2021) and the control group being offered the intervention during year 2 of the study (April 2022). Fifteen units were assigned to intervention and 14 units were assigned to usual care. For practical reasons, the research team and the clinic staff were unblinded to randomization assignment.On an annual basis, CCO staff use claims data to generate a list of eligible enrollees for each clinic assigned to the intervention; eligible enrollees are aged 50–75, enrolled in Medicaid or dually enrolled in Medicaid and Medicare, and due for CRC screening . The study team enters the list into a cloud-based database, REDCap . Clinic staff then may use the list to conduct a “scrub” of the data to remove the names of any enrollee who, based on electronic health record (EHR) data, is not due for CRC screening, has life-limiting comorbid conditions, is otherwise ineligible for FIT testing, or has not established care at the clinic .Mailed FIT outreachFor the mailed FIT outreach component, scrubbed lists are sent to a vendor  who delivers outreach to enrollees on the list. For EOCCO and CHA, the vendor mails introduction letters Intervention clinic staff are encouraged to make a live outreach call to enrollees, either before or after the FIT mailing, in accordance with mailed FIT program best practices . Phone cPatient navigationThe adapted patient navigation program is phone-based and covers four topic areas  , 61, 62.Implementation facilitationStudy activities will be primarily facilitated by the project manager, practice facilitators (who are members of the research team), and other study team members with relevant expertise . Practice facilitation is increasingly used as a centralized and unifying strategy to build practice capacity , 66 and CCO and clinic staff trainingIntervention training activities cover how to scrub patient lists for mailed FIT eligibility and how to conduct patient navigation. For the scrub training, two research team members (a project manager and research associate or practice facilitator) train clinical staff from each intervention clinic in how to review lists of enrollees and remove names of enrollees determined to be ineligible based on health record data (two training sessions were held to accommodate the roll-out timing of the different CCO FIT mailings) with supplemental follow-up to answer questions as needed. The scrub training lasts about 60 min, and a recorded version of the training is offered via a web link to participants for later viewing or to train new staff. In addition, a 5-h patient navigation training is provided; this training was adapted from the PRECISE study . The patWorkflow assessmentsTo understand current CRC screening and follow-up practices within a given clinic, practice facilitators conduct workflow assessments in collaboration with staff at clinics assigned to the intervention. Two workflow assessment meetings are held: The initial meeting primarily focuses on the mailed FIT component; the second meeting primarily focuses on the patient navigation component. During these meetings, practice facilitators create visual ‘swim lane’ diagrams using Lucidchart© . As part of the facilitated workflow assessment, clinic staff describe their current CRC screening process, choose program components to implement  and aspects of program implementation , and discuss any planned adaptations. Workflow diagrams are then reviewed with clinic staff and research team members and refined based on feedback. Based on the workflow, clinic staff assign leads for the mailed FIT and patient navigation components.Effectivenessn adenomas, cancers detected) and referral to cancer care among those with cancer detected. To obtain data for outcomes unavailable in claims data , practice facilitators will conduct chart audits in each participating clinic (at 1 year after the FIT mailing date). Primary analyses will rely on intention-to-treat; that is, enrollees will retain their unit at the time of randomization assignment irrespective of whether they received the mailed FIT and patient navigation intervention  or transfer care to another randomization unit during follow-up. Because we do not anticipate having auxiliary variables that correlate greater than .50 with the outcome that would allow us to use multiple imputation [We will evaluate intervention effectiveness by assessing whether enrollees in the intervention clinics are more likely to obtain any CRC screening compared to patients in the usual care clinics within 6 months of the date the enrollees were identified as eligible (claims list pull date) Table . Additioputation , 75, we We will use hierarchical generalized linear modeling to account for clustering of enrollees within clinics in our assessment of intervention effectiveness (clinic level), implementation, and maintenance  . BecauseSample size and powerAssuming a balanced, two-arm, cluster-randomized trial, 106 patients per clinic, an intra-class correlation (ICC) of .03, and a pre-implementation (baseline) CRC screening rate of 44.6%, we will have 79.5% power to detect a clinically meaningful change in screening rates as small as 10% in the intervention group (an increase to 54.6%) following program implementation using a two-tailed alpha level of .05. Pre-implementation (baseline) CRC screening rates were determined by reviewing clinic-level data from EOCCO and excluding clinics with a CRC screening rate above 60%. The minimum detectable effect size (MDES) to achieve 80% power is 10.1%, using the same assumptions. For ICC values ranging between .01 and .05, power ranges from 97.7 to 62.1%, and MDES to achieve 80% power range from 7.1 to 12.3%, indicating moderate sensitivity to the value of the ICC , 78. PowImplementation outcomesWe will evaluate intervention implementation by assessing the extent to which intervention clinics deliver the program, by component (for mailed FIT: within 6 months of the date the enrollees were identified as eligible (claims list pull date); for patient navigation within 6 months of the abnormal FIT result date). Additional implementation outcomes include implementation of non-core components , reach, acceptability , barriers and facilitators, and program adaptations (desired and executed). We will also track the number of CCO and clinic staff who participate in the scrub training and patient navigation training. Implementation will be assessed using mixed methods, that is, data in REDCap (intervention activities) and vendor data (intervention activities and screening events) as well as findings from a baseline intake survey, one-on-one qualitative interviews (conducted before and after implementation), field notes taken by practice facilitators, and periodic reflections among members of the study team.Clinic intake surveyPrior to randomization, a clinic intake survey was completed by all participating clinics. The clinic intake survey was developed using common data elements from the ACCSIS consortium. The survey asks about what CRC screening tests the clinic uses, CRC screening rates, rates of follow-up colonoscopy, and characteristics of the health system to which the clinic belongs. The survey was managed using REDCap; links to the survey were distributed by email to the primary point of contact in all recruited clinics ; practice facilitators followed up with clinic staff, as needed, to obtain answers to any skipped questions and to document survey questions for which the answer could not be easily obtained.Qualitative interviewsn ~ 3), clinic staff , and clinicians and staff from colonoscopy facilities  are conducted prior to the FIT mailing and after implementation. These interviews will be conducted in intervention and usual care clinics. Practice facilitators will conduct informal qualitative interviews with enrolled clinics 6–9 months from the year 1 FIT mailing for the purpose of informing year 2 implementation. Interviews with clinic and CCO staff seek to understand contextual factors, barriers and facilitators to implementation and maintenance, program acceptability and adaptations (both desired and executed), and unanticipated consequences (positive or negative). Interviews with clinicians performing colonoscopy and their staff seek to understand their awareness of and reaction to the program. Interviews will also be conducted with participating CCOs and clinics 9 months following the post-implementation interview to assess maintenance of the intervention. Interviews are conducted via videoconference and generally last 30–60 min. All qualitative interviews will be digitally recorded, professionally transcribed, uploaded to ATLAS.ti, and then analyzed by the research team using an immersion crystallization approach to identify salient findings [Semi-structured qualitative interviews among CCO leaders in quality improvement roles (findings . FindingPeriodic reflections and field notesWe will conduct monthly periodic reflection meetings with the practice facilitators and other members of the research team to track adaptations (to the intervention and to implementation strategies) and to understand barriers, facilitators, and contextual factors at the clinic and CCO levels . In addiImplementation evaluationTo guide our evaluation of the implementation process, we will use elements of the Proctor Implementation Framework and RE-AIM , 83. We MaintenanceWe will assess maintenance at the CCO, clinic, and enrollee levels. Maintenance will be defined as the proportion of CCOs and clinics that implemented the program in year 1 that also implemented it in year 2. For those CCOs and clinics that continue the program in the second year, we will descriptively compare the screening rates at year 2 to that of year 1. At the enrollee level, maintenance is defined as the proportion of enrollees who completed a FIT in year 1 also completed one in year 2 (with censoring for those who received a colonoscopy and thus are ineligible for FIT in year 2).We will work with a national advisory board to develop a plan to scale up the program and disseminate training products to a national audience. Findings from the cluster-randomized study will be used to inform scale-up planning. Partnering regional and national organizations will receive a small stipend to participate in program training sessions to facilitate outreach and implementation of the mailed FIT and patient navigation intervention in 5–10 clinics they serve and to support program evaluation and tracking activities. The plan will likely include training sessions on mailed FIT outreach, patient navigation, and practice facilitation delivered to health systems, as well as to technical assistance and advocacy-organizations, using webinars, train-the-trainer workshops, and learning collaboratives informed by the Extension for Community Healthcare Outcomes (ECHO) format Fig. . The 5-hAs part of the registration process for webinars, training workshops, and learning collaboratives, participants will be asked to complete a brief (15-min) survey. Survey questions will assess adoption of the program, program adaptations implemented or planned, and current clinical practices related to CRC screening and follow-up . Participants who represent community organizations will be asked about their organization’s current CRC screening and follow-up facilitation activities and future plans. For all participants, we will gather demographic information , professional role, affiliated organization name and location, and email address. We will ask permission to recontact participants in 6 months for a follow-up survey. Participants of multiple SMARTER CRC training events will only be asked to complete a single baseline survey.Six months following the administration of the baseline survey, project staff will email respondents an invitation to complete a follow-up survey. This survey will ask respondents about their clinical practices related to CRC screening and follow-up, the extent to which implementation of the SMARTER CRC program is being planned or executed, planned or implemented adaptations to the program, and their participation in SMARTER CRC trainings or workshops.Our plan to evaluate the scale-up trial will be developed with guidance from the national advisory board. We will track the number of health plan, clinic, and community organization staff who attend our train-the-trainer workshops, mailed-FIT workshops, and patient navigation workshops, ECHO-informed learning forums, and project-specific training events. We will report the number of individuals trained on each component by role . Using 6-month follow-up survey data, we will assess the number of community organizations whose staff have facilitated health plans or clinics to deliver the program and the number of health plans or clinics who have begun to implement each component of the program. Among those who have implemented the program, we will collect and report information about adaptations to the program and the reasons adaptations were made. We will assess determinants of dissemination success, using methods from systems science or configurational comparative methods , 88. We SMARTER CRC is a pragmatic study that will test the implementation, effectiveness, and scale-up of a multi-component mailed FIT and patient navigation program delivered to rural Medicaid and dual Medicaid-Medicare enrollees using a partnership among clinics, health plans, and vendors. We will test the program in three Medicaid health plans and 29 rural clinic units, then scale up the program by delivering tailored trainings and implementation support to health systems and organizations, assessing program adoption and adaptations. Our findings may have a profound impact on how to broadly scale evidence-based CRC screening programs in rural and frontier settings and may be particularly valuable in the context of COVID-19-related care disruptions and recent changes to the US Preventive Services Task Force CRC screening guidelines.


Substance abuse has been an intractable societal concern in the US for more than half a century. The recent opioid epidemic has only accentuated this problem. Adolescents are significant long-term contributors to the crisis due to their susceptibilities to drug abuse and impressionable age. This review examines the particular vulnerabilities of the adolescent brain to drug abuse and the risk and protective factors thereof, especially in light of the Rat Park studies. In addition, the article provides an overview of the evidence-based prevention program registries and offers detailed summaries of two: Blueprints for Healthy Youth Development (Blueprints) and the Washington State Institute for Public Policy (WSIPP). By combining inputs from Blueprints and WSIPP, five programs with the highest benefit-cost ratios (BCR) were identified: Functional Family Therapy, Positive Family Support, Lifeskills Training, Positive Action, and Good Behavior Game. In light of their outstanding characteristics, these programs are poised to be widely implemented and to make a measurable difference in the fight against substance and opioid abuse. Substance abuse and addiction is a protracted societal problem that has long defied attempts to tame it. Since the War on Drugs was declared more than 50 years ago, the situation has not improved. In fact, it has worsened with the recent opioid crisis. According to the National Institute on Drug Abuse, the cost of substance abuse in the United States, including that of healthcare, lost productivity, addiction treatment, and criminal justice involvement, is approximately $600 billion annually , with prThe adolescent brain: susceptibility and vulnerabilityAdolescence is a critical time for the development of the brain. During this period, which continues until the mid-twenties, cognitive and social skills develop, and the brain changes to prepare the teenager for the independence of adulthood ,5. NumerMore concerningly, the developing adolescent brain is also more vulnerable to addiction and the damaging effects of substance abuse than the adult brain. In an experiment designed to model the effects of adolescent drug use, it was found that cocaine use altered the gene expression patterns and histone modification in the PFC of the rats, suggesting that cocaine exposure during adolescence has profound and long-lasting cellular and behavioral consequences even after the drug is no longer administered . Human sCommon socially and culturally tolerated substances affect the development of the brain. Alcohol, for example, can cause long-lasting neurophysiological changes, including alterations in both gray-matter and white-matter brain structures, as well as aberrations in brain activity. These structural and functional differences translate into poorer performances in neurocognitive tests of attention, working memory, spatial functioning, verbal and visual memory, and executive functioning . NicotinThe adolescent brain is a dynamic and changing organ, second only to the infant brain in terms of synaptogenesis . With itNew ideas in SUD prevention and treatmentOne of the most influential new ideas in SUD research is actually more than 40 years old: In the late 1970s, Canadian researchers Bruce K. Alexander and colleagues housed rats either individually in small cages known as Skinner boxes or socially in a mixed-sex colony known as the Rat Park, which was 200 times larger than normal cages and offered a variety of compartments for play and social enrichment. The experiments showed that, while the socially isolated rats obsessively self-administered morphine until they died, the Rat Park rats mostly abstained from morphine water; they would try it, but not to the point of addiction and overdose. In fact, they showed a statistically greater preference for plain water over morphine water ,15. In aAlexander’s landmark studies were ignored for more than 30 years. However, they have enjoyed renewed research interests in the last decade. In a recent study, researchers revisited the Rat Park experiments, but with a twist: Instead of choosing between drugs and no drugs, the rats had to choose between drugs and social interaction. In this scenario, the rats pressed the lever to enter the “social peer chamber” instead of the “drug self-administration chamber” more than 90% of the time - even for the rats that had previously been exposed to methamphetamine for three weeks and exhibited signs of addictive behavior. This finding corroborated with Alexander’s finding that addicted rats in Rat Park preferred plain water to morphine. The research also highlighted a qualitative difference in rat addiction behaviors, initially identified by Alexander, between the voluntary abstinence rats that chose social reward and the involuntary abstinence rats that had their drugs removed - with the former showing little or no signs of drug craving behavior while the latter showing an intensification of drug craving behaviors over time known as the “incubation of craving” . This suStudies in humans also support the link between social factors and SUDs. For example, negative experiences such as bullying, social conflict, and economic stress are found to be common triggers of drug relapse. On the other hand, positive social experiences, such as having friends and social support, can be restorative factors over relapse -25. TherAnother well-supported evidence-based drug treatment method, community reinforcement approach (CRA), also takes advantage of the therapeutic benefits of positive social interactions. It focuses on helping clients to become more positively engaged with their families, friends, school, work, and community organizations and to enhance the enjoyment and frequency of non-drug-related social activities. A meta-analysis of six outcome studies shows CRA’s effect size for SUD to be large (ES=-0.58) and highly significant ,27.Risk and protective factors of SUDOver the years, addiction researchers have identified many factors associated with SUD. Some are risk factors that make an individual more prone to develop the disorder while others are protective factors that make an individual less likely to do so ,29. In lAnother way to look at the two categories in Table Risk and protective factors are correlated and cumulative over time . For exaEvidence-based prevention program registriesEBPPs work by reducing risk factors of SUD or strengthening protective factors ,31. The In the past 30 years, there has been an explosion in the development and evaluation of EBPPs. In response to this flood of data, a number of EBPP registries have emerged to evaluate, catalog, and rank these programs, as shown in Table Of these programs, Blueprints and WSIPP deserve special mention.Blueprints, founded in 1996, was one of the earliest efforts to evaluate EBPPs according to a clear set of scientific standards and a rigorous expert review process. It has been recognized by practitioners and researchers as a premier registry for EBPPs for adolescents ,35 and iBlueprints certified programs are rated as Promising, Model, or Model Plus. The Promising programs must meet a minimum standard of effectiveness and require either one randomized control trial or two quasi-experimental trials. The Model programs are programs whose results are replicated by additional randomized and/or quasi-experimental trials. The highest-tier Model Plus programs must meet Blueprints’ most rigorous scientific evaluation and require the program outcome to be independently replicated by researchers who are not affiliated with the program developer . AdditioWSIPP takes a unique approach to EBPP evaluation. In addition to reviewing the research literature to identify effective EBPPs, it also estimates their economic benefits, providing policymakers with the requisite numbers to make policy or funding decisions. The WSIPP benefit-cost model does this by valuing changes in outcomes produced by the programs and comparing them to the costs of providing those programs. The benefit and cost estimates reflect the difference between a person who participates in the program and one who does not. Finally, WSIPP runs a sensitivity analysis, known as Monte Carlo analysis, to account for the risk and uncertainty around many of the inputs and assumptions of the model. As a part of this analysis, the model calculates the benefit-cost results of an EBPP 10,000 different times, each time varying the inputs randomly within a defined range. The output of this calculation - “the chance the program will produce benefits greater than the costs” - reflects the percentage of those runs in which the benefits minus the costs are greater than zero . TherefoIt should be noted that the unit of measurement of benefit-cost analysis is the “value of a statistical life” (VSL). This means that the benefits calculated are limited to the lifetime of the intervention recipients . HoweverBlueprints and WSIPP recommended EBPPsWith Blueprints  providinAll three Model Plus programs have positive BCRs, and two of the three have outstanding numbers: Every dollar of investment yields $19 in benefits from the Functional Family Therapy (FFT) program and $13 in benefits from LifeSkills Training (LST). Among Model Programs, Positive Action (PA) stands out with a BCR of $29. It also has the most wide-ranging positive outcomes, from improved academic performance to reduced bullying, to reduced substance abuse. Among Promising programs, Good Behavior Game (GBG) and Positive Family Support (PFS) stand out with returns of more than $63 and $198 for every dollar invested - the two highest BCRs amongst all Blueprints-certified programs related to SUD. Except for FFT (a selective/indicated program) and PFS , all programs are universal interventions delivered in school settings. Below is a brief description of each program:Functional Family Therapy (FFT)FFT is a selective EBPP targeting at-risk adolescents who have been referred by juvenile justice systems, healthcare providers, child welfare agencies, or schools. It is a strength-based short-term family counseling program that is provided primarily in clinical settings but may also be provided at home, schools, child welfare agencies, and probation and parole systems. At 100%, it has the highest predictability rating amongst all Blueprints programs, meaning that it is a near certainty that benefits will exceed costs and that the program will succeed .Lifeskills Training (LST)Developed by Dr. Gil Botvin at Cornell University, LST is a three-year universal substance abuse and violence EBPP designed to be implemented with middle school students. It consists of 15 core sessions in Level 1, 10 booster sessions in Level 2, and five booster sessions in Level 3. Additional topic-specific supplemental lessons  also are available for each level. Units are taught sequentially and delivered primarily by classroom teachers. LST provides students with training in personal self-management, social skills, and drug resistance skills. Skills are taught using instruction, demonstration, feedback, reinforcement, and practice . It has Positive Action (PA)PA was developed by Carol Gerber Allred, Ph.D., a public school teacher and administrator, more than 30 years ago. The program is based on the intuitive philosophy that positive actions lead to positive feelings, leading to more positive actions. It consists of seven units, and every grade level is taught the same lessons but in an age-appropriate manner. The seven units are self-concept, mind and body, self-management, social conduct, self-honesty, self-improvement, and review. Supplemental modules help educators integrate other topics into the program such as SUD and bullying prevention . PA has Good Behavior Game (GBG)First described and tested in 1969, GBG is a universal intervention originally designed as a classroom management strategy that rewards children for appropriate behavior during instructional times. The class is divided into two teams; points are given to the team with inappropriate behavior displayed by any of its members. Like golf, the team with the lowest score wins . Even thPositive Family Support (PFS)PFS is an EBPP targeted toward at-risk middle school-aged children. Its goal is to reduce problem behavior and drug use by improving the parents' family management and communication skills and by addressing dysfunctional family dynamics. PFS is the only program in Table It is also interesting to note that, of the three highly rated universal, school-based programs listed above , only LST was designed specifically to be a SUD EBPP. The other two, PA and GBG, had other intents but nonetheless had the effect of reducing substance use as one of their outcomes, a likely result of the Rat Park Effect - that social and environmental enrichments in themselves reduce substance abuse and addiction. The GBG program, for example, is most strongly indicated for aggressive male elementary school students, who, as a result of the intervention, exhibited significantly less aggressive and disruptive behavior than their control classroom counterparts. This reduction in aggression yielded subsequent long-term benefits; by the time they reached young adulthood, the formerly aggressive GBG kids were less likely to develop SUDs (29% vs 83% in controls) and less likely to display violent and criminal behavior (34% vs 50%) . By reduSubstance use amongst adolescents has long been a serious public health concern. To address this issue, decades were spent on the development and testing of substance use EBPPs. We finally now have effective, proven, and economically-sensible prevention programs. According to WSIPP, the net program cost of LST was $105 per student. As such, it costs just $5 billion dollars to roll out the highest-rated Blueprints program to all 50 million students in the country and generate societal benefits of more than $65 billion dollars. Therefore, at minimal costs, school-based universal interventions such as LST, PA, and GBG have the potential to transform our schools, turning environments of academic stress, bullying, and social exclusion, where adolescents first encountered and are hooked on drugs, into spaces where practical life and social skills are mastered. At the same time, effective family-focused programs such as PFS and FFT reduce familial dysfunction and improve the communication and relationship between the parent and child. Given that the Rat Park experiments and more recent studies have suggested that substance use may be related to the absence of fulfilling relationships, improving familial bonds and peer relationships work to effectively diminish the attraction of substances ranging from alcohol to opioids. A sense of urgency is needed to muster the necessary resources and implement these valuable programs in schools across the country.