The Global Vaccine Action Plan identifies workforce capacity building as a key strategy to achieve strong immunization programs. The Strengthening Technical Assistance for Routine Immunization Training (START) approach aimed to utilize practical training methods to build capacity of district and health center staff to implement routine immunization (RI) planning and monitoring activities, as well as build supportive supervision skills of district staff.First implemented in Uganda, the START approach was executed by trained external consultants who used existing tools, resources, and experiences to mentor district-level counterparts and, with them, conducted on-the-job training and mentorship of health center staff over several site visits. Implementation was routinely monitored using daily activity reports, pre and post surveys of resources and systems at districts and health centers and interviews with START consultants.From July 2013 through December 2014 three START teams of four consultants per team, worked 6 months each across 50 districts in Uganda including the five divisions of Kampala district . They conducted on-the-job training in 444 selected under-performing health centers, with a median of two visits to each . More than half of these visits were conducted in collaboration with the district immunization officer, providing the opportunity for mentorship of district immunization officers. Changes in staff motivation and awareness of challenges; availability and completion of RI planning and monitoring tools and systems were observed. However, the START consultants felt that potential durability of these changes may be limited by contextual factors, including external accountability, availability of resources, and individual staff attitude.Mentoring and on-the-job training offer promising alternatives to traditional classroom training and audit-focused supervision for building health workforce capacity. Further evidence regarding comparative effectiveness of these strategies and durability of observed positive change is needed. START was initially implemented in Uganda, one of 10 countries with the most un-immunized children in 2012 22.1The START approach to in-service training was designed to build individual capacity Three different START teams consisting of four international consultants (START consultants) were deployed in Uganda from July 2013-December 2014 . The criSTART teams were deployed in all four geographical regions of Uganda . Each STBefore the START teams were deployed, a meeting was held with leadership from the selected districts, including Health Directors, UNEPI staff, and START partner organizations to introduce the START consultants, gain support for the START approach, and develop a district-specific implementation plan, including selection of low-performing health centers, timeline for initial and re-visits to each. Before the end of the 6-month deployment, each START consultant met again with district leadership to plan for continuation of the START approach, to provide feedback on experiences and recommendations for strengthening ongoing planning and monitoring of the RI system. A similar meeting was also held with each START team, UNEPI staff and other national stakeholders, where results of routine monitoring (reported below) were shared and discussed.From the outset, START consultants worked with district UNEPI staff to identify 5–6 low-performing health centers in each district to visit. The criteria for selection of low-performing health centers was the same as that used for the districts. In selected health centers, START consultants worked jointly with district UNEPI staff, and used an approach that included supportive supervision and on the job training to build HCW skills and to foster health facility processes to strengthen key elements of planning and monitoring for the RI system that could continue to function after training from the START consultant was finished (START approach). Tools used to facilitate the START approach included the UNEPI template for RI microplanning and standard administrative vaccination data collection forms . A new questionnaire was developed to assess the availability and congruence between different sources of administrative vaccination data reported in the immunization information system. The START approach was designed to (1) minimize the HCW’s time away from their regular duties; (2) involve all interested facility staff to enhance continuity and sustainability; (3) tailor content to address individual HCW and facility organizational gaps; (4) allow for use of interactive training methods ; (5) provide an opportunity for repeat exposure to knowledge and skills and to practice new skills in the context in which they would be eventually be performed.During the initial visit to health centers, START consultants modeled the START approach to district UNEPI staff; during follow-up visits, they mentored and encouraged district UNEPI staff to lead the START approach at health centers to enhance their retention of knowledge and skills. START consultants and district UNEPI staff conducted at least one follow-up visit to all selected health centers in the districts where they worked. More frequent follow up visits were conducted if needed . The follow-up visits provided the opportunity to cover topics in more detail at different visits, re-inforce previous learning, address gaps in learning and motivate staff, all of which increases the likelihood of retention and implementation of the learning When requested by district leadership, START consultants supported other RI activities . In addition, when requested by district leadership, START consultants occasionally led or presented at one time off-site group training workshops in order to provide the opportunity for staff from health centers not targeted for the START approach to receive training on RI planning and monitoring.2.2Implementation of START in Uganda was monitored using a mixed methods utilization-focused methodology Each week, START consultants reported location, type, and frequency of their activities to CDC through a standardized spreadsheet with the names of districts and health centers where START activities were conducted, presence and role of national and district staff in these activities (START team 1 and 3 only), type of activity, and topics covered during each activity. Activity type was defined based on anticipated approaches to training, either group or on-the-job. Topics were defined based on the elements of RI planning and monitoring on which START activities were focused: microplanning, administrative data recording and reporting, using administrative data for action, vaccination monitoring chart, use of the Reaching Every District (RED) tool to prioritize health centers for supportive supervision In the latter half of each team’s deployment, CDC staff members accompanied each START consultant to observe their work, and conduct individual semi-structured interviews with them. Interview questions were predominantly open-ended and aimed to elicit START consultants’ feedback about implementation of the START approach, adaptations to improve the approach, and perceived effects of their work.To further understand change in RI planning and monitoring tools and systems, resulting from implementation of the START approach, semi-structured organizational-level assessment (OA) questionnaire was implemented at all districts and the selected health centers visited by START Uganda team 3. The OA aimed to measure presence of RI planning and monitoring tools and extent of implementation of RI systems using both closed and open questions. OAs were conducted for all districts where START consultants worked and in a minimum of five purposively selected health centers in each district; at least one health center from each of the four types of health centers in the Ugandan health service classification system CDC and the UNEPI considered the monitoring activities for START approach to be routine public health program evaluation thus full institutional review board approval was not required.3Results from the three START teams deployed in Uganda during July–December 2013 (Team 1), January–June 2014 (Team 2), and July–December 2014 (Team 3)  were aggThe three START teams reached 50 (45%) of the 112 districts in Uganda, including the five divisions within Kampala district. START team 1 consultants found that there was insufficient time to fully implement multiple on-the-job visits needed for the START approach in all selected health centers in the 22 districts. Thus, fewer districts were selected for START team 2 (n = 16) and START team 3 (n = 12). All 50 districts received at least one visit from the START consultant : 5–9)) with the majority of districts  receiving three or more visits. START consultants trained and mentored 162 district UNEPI staff (mean = 3 per district).Together, START consultants and district UNEPI staff reached > 2000 HCWs in 792 health centers ; 410 (52%) of these were initially reached through on-the-job training visits (median = 7 centers per district) and 382 (48%) were initially reached through group training workshops (median = 13 centers per district). Health centers initially reached through group training received fewer repeat visits  compared with health centers initially reached through on-the-job training . Among all 792 health centers visited 444 (56%) received at least one on-the-job training visit , and among these, 59% (260/444) received two or more on-the-job training visits. The START consultants reported that visit frequency was influenced by geographical location of the targeted health centers, engagement of the district EPI staff, rate and extent of improvement in skills, and frequency of group training, which left less time for repeat visits.Across all three START teams 1771 activities were reported by START consultants. Activities that were not a START training activity or focused on a START specific topic were excluded . Of 1771 START training activities (group or on-the-job) reported, 366 (21%) were at the district-level and 1405 (79%) were at health center level. Of the district-level activities, 99% (361/366) were on-the-job mentoring and training, and the remainder  were group workshops for district staff. Two-thirds  of health center activities were on-the-job training, and the remainder  were group workshops for staff from different health centers .Fig. 2FrAcross all reported START training activities (n = 1771), the most frequently covered RI planning and monitoring topic was microplanning , followed by those topics covering collection, monitoring, and use of administrative vaccination data . Only STIn START teams 1 and 3, district UNEPI staff accompanied the START consultant to more than half of the health center training activities  (information not available for START team 2). START consultants reported that the capacity of the district UNEPI staff to accompany the START consultant was affected by the extent of competition for their time and district leadership’s support of the strategy. Additionally, some district EPI staff visited different health centers from the START consultants to increase the reach of the strategy and disseminate updated information about the EPI program, as was the usual focus for supportive supervision visits. District UNEPI staff took a lead role in on-the-job training at 30% of jointly conducted health center visits, though an upward trend was observed throughout the 6-month START deployment from 24% in the first month to 43% in the sixth  month.This is the third time (since I began working that) we’ve been trained in (RI) micro-planning. The first time we were trained, it was not clear at all. The second time (the division) convened another training but still we never understood, and that is why we planned at the division without health centers first sharing their micro-plans. It is now with the START support that I have understood micro-planning and practiced it.” “Feedback from START consultant interviews and observational visits identified factors affecting implementation . START cThree months into their work, and after several re-visits, the most commonly reported changes observed by START consultants were related to positive staff motivation towards RI, completion of planning and monitoring tools, implementation of new systems for archiving, and checking of accuracy of vaccine administration data. START consultants felt their support had increased district and health centers’ awareness of the underlying reasons for challenges experienced, and what they could do to address or work within them.START team 3 completed OAs in 16 districts (100%) and 90 health centers (17%). OAs were immediately used to inform the focus of the START consultant’s work with that district or health center. Improvement was seen in all indicators , althoug4To be effective, in-service training of the health workforce should focus on their specific training needs, be job-based and practical, and involve regular follow-up to ensure knowledge and skills are understood and continually practiced. The START approach was designed to achieve this, using techniques of on-the-job training and mentoring within the platform of supportive supervision. Positive changes in staff motivation, awareness of challenges, availability and completion of planning and monitoring tools were observed at district and health center levels. However, START consultants felt the potential for sustainability of these and newly introduced processes was limited by various contextual factors, including limited external accountability for supportive supervision activities; competition for staff time; availability of material, human, and financial resources; and individual staff motivation.The START approach used on-the-job training because it could be implemented as part of an existing supportive supervision platform and had strong evidence of positive learning outcomes While mentorship has been less frequently used and evaluated outside of clinical practice, it was incorporated in the START approach at the district level to enhance potential for sustainability. Mentorship in the START approach was done through development of a collaborative working relationship between START consultants and district EPI officers, on-site observation, and the provision of targeted and individualized feedback, which together have been shown to improve knowledge, skills, and motivation in mentees The START approach differs from previously reported in-service workforce capacity building strategies to strengthen RI systems in the African region, which have favored several days of off-site classroom style training on a broad range of topics related to program management, vaccine management and delivery, vaccination program planning, and monitoring of RI Strengthening supportive supervision is a key strategy to build and sustain workforce capacity at individual and organizational levels The financial, material, and human resource shortages reported to inhibit the ability of district UNEPI staff to implement routine supportive supervision visits are similar to those reported in other LMICs Since the implementation of START Uganda, the START approach has been implemented in three additional low- and middle income countries 4.1Monitoring was built into the START approach from the beginning and collected self-reported data to inform adjustments to the START approach and measuring effects of the START consultants work in selected districts and health centers 5A stable, availabe, well-trained and motivated health workforce; sufficient financial and material resources; and routine implementation of supportive supervision and accountability measures would help to optimize RI planning and monitoring activities. Despite the GVAP recommendation to strengthen sub-national planning, monitoring, and workforce capacity as well as extensive investment in in-service training of health care workers using class-room style didactic approaches, further evidence of optimal methods for, and the longer term effects of, in-service workforce capacity building is needed. Current evidence suggests a move away from group, didactic, classroom-style training of health care workers and audit-focused supportive supervision in LMICs would enhance outcomes and sustainability of these interventions All authors have no conflicts of interest to declare.


Despite advances in digital technology to generate demand for health services, considerable gaps remain in our understanding of which interventions are effective, which characteristics mediate their benefit for different target populations and health domains, and what is necessary to ensure effective deployment. Future research should examine the long-term effects of, equity in access to, and cost-effectiveness and efficiency of digital demand generation interventions. Despite advances in digital technology to generate demand for health services, considerable gaps remain in our understanding of which interventions are effective, which characteristics mediate their benefit for different target populations and health domains, and what is necessary to ensure effective deployment. Future research should examine the long-term effects of, equity in access to, and cost-effectiveness and efficiency of digital demand generation interventions. The recent introduction of digital health into generating demand for health commodities and services has provided practitioners with an expanded universe of potential tools to strengthen demand and ensure service delivery receipt. However, considerable gaps remain in our understanding of which interventions are effective, which characteristics mediate their benefit for different target populations and health domains, and what is necessary to ensure effective deployment. This paper first provides an overview of the types of digital health interventions for demand generation, including untargeted client communication, client-to-client communication, on-demand information services, personal health tracking, client financial transactions, and targeted client communication. It then provides a general overview of 118 studies published between January 1, 2010, and October 3, 2017, that used digital interventions to generate demand for health interventions. The majority (61%) of these studies used targeted client communication to provide health education or reminders to improve treatment adherence, and the most frequently (27%) studied health condition was HIV/AIDS. Intervention characteristics that have been found to have some effect on gains in demand generation include modality, directionality, tailoring, phrasing, and schedule. The paper also explores new emergent digital approaches that expand the potential effect of traditional demand generation in terms of personalization of content and services, continuity of care, and accountability tracking. Applying existing frameworks for monitoring and evaluation and reporting, research on emerging approaches will need to consider not only their feasibility but also their effectiveness in achieving demand generation outcomes. We propose a research agenda to help guide the field of digital demand generation studies and programs within a broader health systems strengthening agenda, including establishing and documenting the influence of intervention characteristics within different populations and health domains and examining the long-term effects and cost-effectiveness of digital demand generation interventions, as well as equity in access to such interventions. Global efforts to strengthen health systems have predominantly focused on ensuring adequate supply of, and access to, health commodities and services. Yet inadequate coverage on several key indicators of health use persists. Interventions that generate awareness and demand for health commodities and services in an equitable manner are often overlooked but show much promise for addressing ‘last mile’ populations and achieving the Sustainable Development Goals. Additionally, by increasing demand for health services, there is the potential to improve the quality of health care and to reduce inequities in health services.The unprecedented reach and use of ubiquitous mobile technology by the general populationThis paper explores the variety of ways in which digital tools have been use to create demand in low- and middle- income countries (LMICs) as well as the factors that have contributed to variability in the evidence base. Additionally, we offer the reader guidance for documenting specific characteristics of demand generation interventions, an overview of emerging approaches aimed at strengthening the potential value of digital demand generation, and a proposed research agenda to further advance this promising field.–Interventions that generate awareness and demand for health services are a staple in public health.,,,,,Untargeted client communication, often referred to as mass communication, is defined here as the transmission of untargeted health promotion content in which relatively undifferentiated audiences receive identical communication material.The Senegal MOHSA sent >4 million SMS messages during the 2014-2015 Ebola outbreak to warn the population about the dangers of the disease and provide prevention guidance.––Client-to-client communication, also known as peer communication, is the interaction between people who share common attributes, such as having similar health conditions, demographics, or prescribed treatments.7—are available via websites, helplines, SMS/text-messaging menus, or client applications, among other channels, and may be used to inform decision making. However, the defining feature of on-demand information services is that it relies on individuals to proactively initiate contact with the health system or information service. In its online form, on-demand information services can be as pervasive as the use of medical information websites such as WebMD. Increasingly, these types of health information services are being optimized for mobile devices and use in areas with low Internet connectivity, thus overcoming barriers related to Internet accessibility. Through these mobile phone-based modalities, clients can access health information by sending a message to an advertised number known as a short code. Documented examples of this intervention include platforms used by the Engage-TB approach and the Mobile for Reproductive Health (M4RH) project, whereby clients navigate through a menu of options by texting codes to specify the type of information they are seeking.–On-demand information services—defined here as health information accessible to the general public when triggered by the clientThe use of on-demand information services enables clients to determine the timing and content of the health information and reduces concerns related to client confidentiality.,Personal health tracking uses digital devices, such as mobile applications, wearables, and sensors, to document and monitor a client's health status.–––Client financial transactions are another common mechanism to generate demand for the use of health care services and to improve health outcomes. Traditionally, these type of transactions included the provision of vouchers, monetary incentives, or nonmonetary incentives to assist with out-of-pocket payments incurred by clients when seeking health services. With increasing mobile phone penetration, financial services—including savings, insurance, credit, banking, and payments—have rapidly been integrated into mobile phone applications and mobile network operators in what is known as mobile money.,–Targeted client communication is defined here as the transmission of targeted health information “in which separate audience segments (often demographic categories) benefit from a shared message.”Targeted client communication originates from the health system and can be tailored to address the needs and preferences of an individual client.–Although postal and email reminders have demonstrated value in high-income countries, limited access to such services in LMICs hinders their implementation and viability. The increasing global availability of mobile phones provides alternative avenues for targeted client communication through the use of SMS and voice messages, mobile phone apps, and social media channels. Moreover, a growing body of literature has documented the efficacy of digital targeted client communication interventions, particularly through SMS, to improve health system performance and health outcomes in LMICs.We conducted a landscape literature review to identify published studies that used digital client communication to improve health outcomes in LMICs . Since tBOX AND(“Randomized” OR “randomised” OR “RCT”) ANDCountry names for all LMICsOn October 3, 2017, we searched the PubMed database for the following terms:Randomized study design with a comparison groupSMS or voice messages used to remind or inform clients about a health behaviorStudy conducted in an LMIC, as defined by the World BankStudy published from January 1, 2010, to October 3, 2017Titles and abstracts were screened for the following inclusion criteria:Year of publicationRegion: Latin America, Eastern Mediterranean region, sub-Saharan Africa, East Asia Pacific, Southeast Asia, South AsiaHealth outcome: Treatment adherence was defined as studies sending messages (reminders or information) to promote a health behavior that did not require participants to attend a health facility. Health care use was defined as a study that required participants to attend a clinic for a provided service.Type of health conditionData for included studies were abstracted by one of the authors and were tabulated for each of the following variables:Limitations: This was not an exhaustive literature review and its findings should be interpreted with caution. We only searched 1 database, did not include information from gray literature, and only included English language articles. The aim of this review was to provide a general overview of intervention studies using SMS or voice messages to generate demand for health interventions. WHO is currently developing guidelines on the comparative value of different digital health interventions based on a series of systematic reviews that are currently underway.Abbreviations: IVR, interactive voice response; LMIC, low- and middle-income country; RCT, randomized controlled trial; SMS, short message service.–,,,Of the 118 studies identified, the majority (61%) used targeted client communication to provide health education or reminders in order to improve treatment adherence and other health behaviors that do not require clinic visits. In terms of geographic scope, 51% (n=60) of studies were conducted in 4 countries: China (n=25), Iran (n=14), Kenya (n=12), and India (n=9). The most frequently studied health condition was HIV/AIDS . The majority of identified studies were 2-arm studies, where the intervention's effect on the study outcome was compared to a control or standard of care group. Within this field, trials have evaluated the effect of client communication interventions on, for example, HIV treatment adherence,,With the likely exception of SMS reminders for HIV-treatment adherence,Approaches to digital demand generation are distinguished by characteristics of the intervention. Key intervention characteristics of digital client communication that have been studied and found to have some effect on gains in demand generation include: (1) modality, (2) directionality, (3) tailoring, (4) phrasing, and (5) schedule . In thisKey intervention characteristics of digital client communication that have been found to have some effect on gains in demand generation include modality, directionality, tailoring, phrasing, and schedule.–The vast majority of client communication interventions rely on SMS or USSD (unstructured supplementary service data), though interactive voice response and communication via social media platforms are gaining prominence.Interactive, or two-way, messaging may be preferred by implementers, as it allows for an exchange of information between client and provider and also between clients. In South Africa, participants randomized to either one-way SMS or interactive SMS groups had similar reductions in systolic blood pressure, compared to the control group.Tailoring is defined as “any of a number of methods for creating communications individualized for their receivers with the expectation that this individualization will lead to larger intended effects of these communications.”The scheduling of messages is an important characteristic of targeted client messaging. Scheduling refers to the time of day, frequency, and timing of messages sent in relation to an event or behavior, such as an SMS sent 3 days before an immunization appointment. In rural Kenya, investigators found that participants who received weekly SMS reminders were more likely to adhere to HIV treatment at 48 weeks than those who were not sent reminders or those who were randomized to receive daily SMS reminders.Research results have highlighted that there may be a minimum and maximum threshold for the number of messages to produce an effect.Like scheduling, the phrasing of the messages has been associated with the uptake of health services. In the same Kenyan study described earlier, no significant differences were shown between short and long messages—“This is your reminder.” versus “This is your reminder. Be strong and courageous, we care about you.”—on HIV treatment adherence measured at 48 weeks.The observed heterogeneity in digital demand generation efficacy studies may be explained by both the content and the characteristics of the intervention. To that end, it is important that researchers and practitioners document the details of digital interventions so others can replicate the studies and so we can better understand what elements of digital demand generation approaches do and do not work. To that end, the WHO mHealth Technical Evidence Review Group has published an mHealth evidence reporting and assessment checklist to help improve the quality and reporting of digital interventions.Although they have not yet been captured in the scientific literature, a number of emerging approaches aim to strengthen the value of digital demand generation interventions and reflect the evolving sophistication of digital solutions globally and the growing familiarity of users with digital tools locally. These approaches include integrating demand generation with systems focused on unique identification and persistent health records, capturing information about receipt and effect, leveraging new messaging platform channels to reach additional users, and using artificial intelligence for enhanced personalization, wearables, and natural language chatbots.With the advent of social media platforms and the integration of digital demand generation approaches with identification systems and persistent records, including electronic medical record systems, digital demand generation approaches could be better positioned to also account for services received. Such systems could facilitate informing actual demand generation content and support measuring the effectiveness of specific digital demand generation interventions on expected and unintended outcomes, which, in turn, could inform personalization strategies. Furthermore, digital demand generation interventions that support client registration can link clients into national record systems and populate reporting indicators. The challenge of integrating these systems is ensuring that ethical data standards and client privacy concerns are appropriately addressed.Integrating digital demand generation approaches with identification and record systems could help inform demand generation content and support measurement of expected and unintended outcomes.The increasing familiarity with SMS and interactive voice response, access to mobile-money systems, and the availability and use of WhatsApp, Facebook, Weibo, and other social media platforms has facilitated narrowcasting messages to specific target audiences and personalizing autonomous interactive demand generation messaging through natural language processing and use of artificial intelligence in LMICs. Increasingly, digital demand generation approaches will be able to apply algorithms to identify clients in need of information or at risk of not adhering to their treatment protocols, who would, for example, benefit from a customized combination of financial incentives and personalized messaging delivered through specific channels with content designed for the intended beneficiary based on their personal motivations, health profile, and history of care.The growing evidence base has begun to show that many digital demand generation approaches offer value; however, to what extent depends on the health program area, message content, and population and intervention characteristics. Future research will need to establish and document the influence of intervention characteristics, as highlighted above, within different populations and health domain areas. Rigorous studies that evaluate novel applications of digital demand generation approaches are still needed, as are studies that assess the additive benefits of each of the described intervention characteristics. This could be done through randomized controlled trials or, for scaled programs, implementation science or adaptive randomized studies. Although the majority of the identified literature has come from efficacy trials, many of which could be described as small pilots, digital interventions are gradually being brought to scale. To ensure rigorous evaluations of digital health interventions along each stage of its maturity, WHO recently released a monitoring and evaluation guide for digital interventions.To ensure rigorous evaluations of digital health interventions along each stage of its maturity, WHO recently released guidance for monitoring and assessing digital interventions.,,Aside from conducting additional efficacy trials, larger questions must be asked about the generalizability and equity of previously conducted studies . Much ofThe recent introduction of digital health into demand generation has provided practitioners with an expanded set of potential tools to strengthen demand and ensure service delivery receipt. Although this paper primarily discussed the predominant forms of digital demand generation interventions in the published literature, the field of digital health is rife with innovations and continues to evolve with the rapid sophistication of digital tools. As the capabilities of digital tools advance, a new wave of research will need to explore the emerging trends of digital technologies and how they may be harnessed to improve demand generation. Applying existing frameworks for monitoring and evaluation and reporting, research on emerging approaches will not only need to consider their feasibility but also their effectiveness on achieving demand generation outcomes.


The scarcity of evidence-based research on non-communicable diseases (NCDs) among Syrian refugees has hampered efforts to address the high burden of these diseases in host countries. The objective of this study is to examine published research on NCDs among Syrian refugees in order to inform future research, practice, programs, and policy. .Using the scoping review framework proposed by Arksey et al., 17 different databases were searched to identify studies reporting on NCDs among Syrian refugees. The number of relevant documents found was 34, with the earliest going back to 2013—2 years after the beginning of the Syrian conflict.The majority of these documents were descriptive in nature and only two studies addressed the effectiveness of interventions in the management of NCDs. No studies investigated the prevention of these diseases. Furthermore, only 7 studies addressed the host community and only one research article, conducted in Lebanon, included subjects from the host community. The increasing number of documents over the past 5 years illustrates a growing interest in studying NCDs among Syrian refugees. Examination of the papers showed high prevalence of NCDs among Syrian refugees as well as unmet healthcare needs.The findings of this review highlighted the dire need for further research on the burden of NCDs among Syrian refugees. Future studies should diversify research design to include interventions, address the host community in addition to the refugees, tackle prevention as well as treatment of NCDs, and explore strategies to enhance the resilience of the host country’s health system while ensuring quality of care for NCDs. The increasing momentum for research found in this review presents an opportunity to fill current knowledge gaps, which could result in preventing, controlling and ultimately reducing the burden of NCDs among Syrian refugees and their host communities.The online version of this article (10.1186/s12889-019-6977-9) contains supplementary material, which is available to authorized users. Worldwide, approximately 70% of total deaths are attributed to non-communicable diseases (NCDs), mainly cardiovascular diseases (CVD), cancers, diabetes and chronic respiratory diseases . This siToday, the Syrian refugee crisis is considered to be the largest displacement emergency in the world . Up untiIn view of the unremitting nature of the crisis in Syria and the high prevalence of NCDs burden among both Syrian refugees and host communities, there is an imminent need for evidence based interventions and recommendations to address the burden of these diseases, both at the prevention and management levels. Although previous research has suggested a few successful examples of interventions in the context of NCDs in humanitarian crises –21, theiA recent systematic review of the effectiveness of interventions for NCDs in humanitarian crises concluded that interventions that included standardization of care and improvement of patient follow up yielded positive results. However this systematic review also raised concerns that quantity and quality of evidence on the topic were extremely limited and that substantially more research is needed . AccordiThis scoping review followed the Arksey et al. framework for knowledge synthesis of research which consists of five iterative steps: (1) identifying the research question;(2) identifying relevant studies; (3) selecting relevant studies; (4) data charting and finally; (5) collating, summarizing, and reporting the results . Unlike interventions aiming to address NCDs in this population. This research question will lead to the identification of gaps and opportunities in the existing knowledge of NCDs’ burden among Syrian refugees.The primary research question that guided this study was ‘what has been published with regards to NCDs among Syrian refugees? more specifically, ‘what is the current evidence with regards to available (Syria* OR Syrie*) AND refuge*(Syria* OR Syrie*) AND (asylum* OR camp OR camps OR deport* OR diaspora OR displaced OR emigrant* OR emigre* OR escapee* OR evacuee* OR exile* OR expatriate* OR immigrant* OR runaway* OR survivor* OR transient* OR victim*) AND (conflict* OR war OR wars)Studies reporting on NCDs among Syrian refugees were identified by searching 17 different databases, including Academic Search Complete (by EBSCO), CINAHL Plus with Full Text, Directory of Open Access Journals , Embase, Global Health Library, Historical Abstracts, ProQuest Central, PsycINFO, PubMed, ScienceDirect, Scopus, Sociological Abstracts, Web of Science, and Worldwide Political Science Abstracts, as well as three Middle Eastern studies related databases—AlManhal, E-Marefa, and Middle Eastern & Central Asian Studies. The search strategy consisted of two broad queries, in the title, abstract, and keyword fields, as follows:The two searches, which were carried out in late September 2017, targeted all types of literature in Arabic, English and French, and the union of both resulted in a total of 3630 documents; the number was reduced to 1500 after removing all duplicate records.The main topic of the document was Syrian refugees, regardless of their locationThe document had to be a journal article, conference paper, book chapter, short paper, report, or case studyThe study had to focus on any NCD, such as CVD , cancers, chronic respiratory diseases ), and diabetes or any of the NCDs’ risk factors in relation to Syrian refugeesThe study had to include an outcome related to NCDs and/ or their complicationsThe document had to be published from 2011 on, that is, from the time the Syrian conflict started (March 2011) For a document to be included in the study, it had to meet the following criteria:A document was excluded from the study if it was an authored book, editorial, letter, note, abstract, news piece, or book review published before 2011 or was in a language other than Arabic, English, or French.Two reviewers (HC and RA) independently reviewed the titles and abstracts and screened the documents for eligibility. The full text versions of eligible documents were retrieved and independently screened by the two reviewers to determine whether they met the inclusion criteria. Disagreements about whether the inclusion criteria were met were resolved through discussion with a third reviewer (FN).A comprehensive data extraction form was developed using an inclusive approach in order to avoid omitting any findings of potential value to the scoping review. The development of this form was followed by an iterative review process by an expert panel consisting of a health system expert, an epidemiologist and a statistician. Following its development and review, the data extraction form was pilot tested on five randomly selected documents. The panel further reviewed this form in light of the pilot test results. The final version of the form contained descriptive information about: 1) general information; (2) authors’ affiliations; (3) country where the study took place; (4) NCDs and their risk factors; (5) study design; (6) study population; (7) funding source; and (8) health system indicators addressed. The data extraction form can be found in Additional file  general Data entry and analysis were conducted using the Statistical Package for the Social Sciences (SPSS) software version 23.0 for Windows . After eOf the 1500 documents screened for inclusion based on the title and abstract, only 94 were found relevant (i.e. met the eligibility criteria). The main reason for excluding the 1406 documents was that they did not address NCDs. The examination of the full text of the 94 documents resulted in 34 that were eligible for inclusion in the study  and the second in Jordan (n = 1550 households). Both studies aimed at estimating the prevalence of NCDs among Syrian refugees living in a non-camp setting and found that almost one in two households had a member with NCDs in both Lebanon and Jordan [Regarding the prevalence of NCDs among adult Syrian refugees, two cross-sectional, population-based surveys were conducted, one in Lebanon . The majority of these studies were descriptive and only two studies addressed the effectiveness of interventions. Such a limited number of studies on interventions is not in line with the recurrent calls urging a better understanding of effectiveness of interventions tackling NCDs among Syrian refugees , 51, 52.Furthermore, of the 34 reviewed papers, seven addressed the host communities and their challenges and only one research article, conducted in Lebanon, included subjects from the host community . This fiIn this review, the synthesis of results of original articles addressing NCDs among Syrian refugees led to two main findings that warrant further discussion: a high prevalence of NCDs among Syrian refugees and unmet healthcare needs. It is important to note however that these findings ought to be considered with caution due to the limited number of studies and the heterogeneity of their results. This review showed that one in two Syrian refugee households had a member with NCDs. Such a significant prevalence was also noted by the Disaster and Emergency Management Survey, which showed that 10.0% of Syrian refugees reported a form of NCDs . This fipeople with life-threatening and chronic disease, due to their particular needs, should be included in the design of policies and plans to manage their risks before, during, and after disasters, including having access to life-saving services”. This statement underlines the need to include NCDs’ care as an integral part of policy design and implementation of plans to manage risks among Syrian refugees, including having sufficient access to healthcare [This review highlighted insufficient healthcare for NCDs’ patients among Syrian refugees. The massive influx of Syrian refugees to neighboring countries has put enormous pressures on their already fragile health systems . In this situation, these health systems struggled to cope with the acute healthcare needs and often neglected the treatment and management for NCDs resulting in disruption of care, reduced functional capacity, disease exacerbation, worsening of disease prognosis, or even death , 61. Sucalthcare , 63. DesIn all reviewed papers in this study, primary healthcare centers in host countries were found to be at the forefront of healthcare delivery for NCDs among Syrian refugees. This finding is in accordance with previous literature citing the national health systems particularly primary healthcare centers as the first line of defense against health crises . The impIn this review, the main barrier to sufficient healthcare for NCDs among Syrian refugees was related to healthcare costs or the absence of medical insurance. This finding is in line with previous studies that showed that cost is the main barrier for refugees seeking healthcare for NCD , 67. In The findings of this review ought to be considered in light of a couple of limitations. First, the search for documents was limited to those available electronically and could have missed relevant information not archived in this format. The search employed in this review however was comprehensive and thus provided a clear depiction of overall NCDs’ burden among Syrian refugees and their host communities. Second, similar to other scoping reviews, reviewed documents were not screened for quality and, thus, have large variations in study methodologies and sampling.Focus on identifying quality interventions: The focus should be on intervention-based research, in addition to cross-sectional survey based investigations, to better inform policies and properly guide humanitarian assistance. In addition, interventions aiming to improve standards and quality of NCDs’ care are needed.Consider the full intervention spectrum: Attention should be given to the prevention of NCDs in addition to their management and treatmentInclude all relevant populations: The host communities should be included in NCDs’ programs and interventionsStrengthen service delivery: Future research should examine strategies to enhance the resilience of primary healthcare centers in host countries , given their strategic role in healthcare delivery for Syrian refugees. Such strategies could address the centers’ medicines management capacity, health workforce, infrastructure and financing systems, as well as leadership & governance capacity Current health policies and interventions among Syrian refugees seem to be lagging behind the profound global changes in humanitarian crises. Mainly, these crises became more protracted in nature with infectious diseases and malnutrition being replaced with longer term health conditions such as NCDs. Findings from this review highlight two main issues related to NCD among Syrian refugees: first a significant prevalence of NCDs and second the largely unmet healthcare needs of Syrian refugees. As a result, this review underscores the call for a better understanding of NCDs and interventions in humanitarian crises. More specifically, future research on NCDs among Syrian refugees ought to consider the following issues:Although solutions to alleviate the burden of NCDs among Syrian may seem as an intractable task, the impressive progress that has been made in the management of communicable diseases clearly illustrates that large-scale change could be feasible with global collaboration, research and advocacy. In fact, the research momentum for NCDs’ prevention and management found in this review presented an opportunity, which if geared towards feasible and effective interventions, could lead to improved humanitarian national and international actions to prevent, control and ultimately reduce the burden of NCDs.Additional file 1:Data Extraction Form. (DOCX 26 kb)Additional file 2:n = 19)*. (DOCX 38 kb)Characteristics of original studies included in the scoping review (


The role of molecular size selectivity in the onset and progression of osteoarthritis (OA), a degenerative disease of the musculoskeletal system and the most common cause of disability in aging adults, is unknown. Here we delivered a mixture of Texas-red (70 kDa), and Rhodamine-green (10 kDa) tagged, dextrans of neutral charge in a single bolus via heart injection to middle aged (8–10 months) and aged (17–19 months) Dunkin-Hartley Guinea pigs, a natural model for OA. We quantified tracer transport in serial-sectioned, cryofixed block specimens after five minutes’ circulation. A remarkable separation of the molecules was observed in serial fluorescent images of whole joint sections. The larger, 70 kDa red tracer was abundant in the marrow cavity albeit less prevalent or absent in the bone, cartilage, meniscus and other tissues of the joint. Tissues of the meniscus, ligament, and tendon exhibited abundant 10 kDa tracer; volumes of tissue containing this molecular tracer were significantly lower in older than in younger animals. Surprisingly, muscle fiber bundles exhibited little fluorescence, while their bounding fasciae fluoresced either red or green. Small caliber channels through the articular cartilage appeared to show a degree of green fluorescence not observed in the surrounding cartilage matrix. This study opens up new avenues for study of musculoskeletal physiology in health and disease as well as new strategies for drug delivery. A recent study correlates aging with increased intestinal permeability to solutes but not macromolecules, which modulates “innate mucosal immune responsiveness [of] elderly humans“3. Osteoarthritis (OA), a degenerative disease of the musculoskeletal system and the most common cause of disability in aging adults, is a multifactorial disease involving complex interactions between tissues of articular joints and the immune system. The role of size selectivity in the onset and progression of OA is unknown. Molecular transport between tissue compartments of the musculoskeletal system occurs via blood, interstitial fluid and lymphatic flow6. An understanding of changes to molecular transport associated with aging and disease of musculoskeletal organs, such as the knee joint, may have important implications for unraveling the etiology and pathogenesis of osteoarthritis (OA) and other degenerative diseases associated with aging.Tissues of the braini.e. cartilage, subchondral bone, bone, meniscus, synovium) depend on molecular transport via blood flow, as well as interstitial transport between vascular and avascular tissues, to survive. The closed circulatory system of vertebrates provides a means for molecular transport to the respective vascularized tissues of the musculoskeletal system via the blood, with delivery to and from the heart via respective venous and arterial systems and interstitial fluid shunting via the lymphatic system7. Yet it is currently not known how molecules such as pro-inflammatory cytokines, growth factors, nutrients and proteolytic enzymes are transported from the blood, to and between different tissue compartments within articular joints.The resident cells of different musculoskeletal tissues making up a given articular joint  as a putative means to control relative drainage of interstitial fluid via the lymphatic system, in particular during development, and in (patho-)physiology9. The relative contributions of arterial and venous circulation, as well as the lymphatic circulation, to interstitial flow and molecular transport in the tissues of the musculoskeletal system are not clearly delineated.It is currently unknown whether the bounding layers of bone and cartilage  actively modulate transport into and out of tissue compartments of the joint and musculoskeletal system. The expression of ZO-1 proteins by periosteal cells12, although small channels have been postulated to physically link cartilage to the subchondral bone interface13. Assessment of the transport to/from and between tissue compartments via blood and interstitial fluid flow necessitates the use of an imaging modality that allows for seamless imaging of transport across organ, tissue, cellular and molecular length scales. Visualization of molecular transport at organ, tissue, cellular, and molecular length scales in healthy and OA tissue compartments is expected to uncover the underpinnings of OA onset and progression. Hence, we aimed to quantify differences in transport between tissue compartments of the knee joint, to test the hypothesis that boundary tissues exhibit molecular size dependent barrier properties similar to those observed in the brain, lung and gut.Furthermore, diffusion and convection are putative transport mechanisms to and from avascular articular joint cartilage tissue17, ligament18, and cartilage13 and in consideration of physiologically relevant biological analogs in a similar range of molecular sizes. The Dunkin-Hartley strain of Guinea pig serves as a model for naturally occurring osteoarthritis, where cartilage lesions increase in frequency and size with increasing age21. Two cohorts were studied, including skeletally mature male GP at 8–10 (corresponding to middle age in humans) and 17–19 (corresponding to aging humans) months20. After five minutes’ circulation, animals were sacrificed and knee joints were immediately frozen in vivo in OCT medium using liquid nitrogen, after which cryosectioning and high resolution, three-dimensional imaging of block faces was carried out in reflection and fluorescence modes.We assessed molecular communication in knee joints comprising bone, cartilage, and the vascular system, with particular interest in transport across tissue boundaries including the bone-cartilage interface of the joint. We injected, in a single bolus to the heart of anaesthetized Guinea pigs, a mixture of fluorescent-red tagged, 70 kDa, and fluorescent-green tagged, 10 kDa, dextrans of neutral charge and allowed for five minutes circulation before sacrifice. Molecular tracer sizes were chosen based on previous experiments showing molecular sieving in unloaded and loaded cortical bone tissue22, a semi-quantitative multi-feature evaluation used to assess disease progression in human patients. This comprised of individual scores for five tibiofemoral sub-regions  for each of the medial and lateral compartments for knee OA features. The features assessed in each sub-region, included cartilage morphology (scored out of six), bone cysts and bone attrition (scored out of three) and osteophytes (scored out of seven), for a maximum total score of 190. The total WORMS score for younger animals was significantly lower than that of the older age group oup Fig. . All anioup Fig. . The dis23. The characteristics of interest were osteophytes, bone end deformity and cartilage loss, representative of joint space narrowing. The younger animals exhibited multiple osteophytes and varied regions of both partial and full depth cartilage loss with some deformity of tibial plateau; the mean KL score was 2.67 for the younger animals. The older animals also exhibited multiple osteophytes but areas of cartilage loss were larger with marked bone-on-bone cartilage erosion; the mean KL score was four for the older animals.In addition, a coronal view of the imaging data set was constructed, analogous to anterior-posterior radiographs, for qualitative analysis with the commonly used Kellgren-Lawrence (KL) system for classification of knee OARespective tissues of the knee joint exhibited size selective partitioning of molecules, even though the molecular tracers were injected to the heart as a single, mixed bolus of sizes. Although dextrans were delivered as a single mixture of green small and red large molecular weights, a remarkable separation of the two sizes of molecules (red and green) was observed in fluorescent images of whole joint sections, indicative of size separation by the tissues of the joint and greater musculoskeletal system Figs –3. Volumvice versa24. Furthermore, after five minutes circulation in anaesthetized animals, molecular transport to musculature surrounding the knee joint was markedly less than that observed in the tissue compartments of the bone and joint, providing further evidence for the suggestion that bone provides an important role in maintenance of muscle26. Finally, articular lesions exhibit disruption to molecular transport, which may have important implications in the etiology and pathogenesis of osteoarthritis, the most common musculoskeletal disease and disability in aging adults. This is in stark contrast to studies reporting increased transport in OA joints for very small molecular weight tracers (less than 1 kDa)25. Additionally, recent literature implicates the role of intraarticular structures on the pathogenesis of OA, e.g. inflammation of the synovium28.These data indicate that tissues of the musculoskeletal system exhibit active compartmentalization similar to other organ systems of the body. Our results point to a previously unappreciated capacity of different musculoskeletal compartments to separate molecules based on size. These data further implicate barrier membrane functions of the periosteum, growth plate and synovial membrane. Interestingly, recent studies demonstrate higher permeability of the periosteum in the bone to muscle direction than 31. Furthermore, extracellular matrices of different joint tissues exhibit independent filttration properties; we hypothesize that the relative compositions of ECMs in health and disease can effectively shift the balance between transport of matrix degrading proteolytic enzymes (of molecular weight less than 50 kDa) and their inhibitors that are transported via the blood and are too large to penetrate healthy tissues5. It is currently not known how molecules such as inflammatory cytokines, growth factors, nutrients and proteolytic enzymes are transported from the blood, to and between tissue compartments within articular joints. Assessment of the transport to and from and betweeen tissue compartments via blood and interstitial fluid flow necessitates the use of an imaging modality such as that presented here, which allows for seamless imaging of transport across organ, tissue, cellular and molecular length scales. Given previous studies that demonstrate size and charge separation in the different caliber porosities of bone17, as well as studies showing active barrier function of boundary tissues (e.g. periosteum), these studies may open a new avenues to elucidate joint physiology in health and disease, the role of intraarticular and extraarticular transport of inflammatory cytokines on tissue permeability, as well as physical (exercise) and chemical  measures to modulate joint tissue health with age.Our current working hypothesis is that inflammatory cytokines actively modulate molecular barrier properties of boundary tissues, enabling active control of transport between tissue compartments, similar to that observed in the brain, lung and gutper previous protocols18 albeit mixed in a single solution prior to injection. Two additional animals (one from each age cohort) served as baseline controls, where one was injected with a single tracer bolus of rhodamine green alone and one was injected with lactated Ringer’s solution (pH 7.3–7.4). Animals were euthanized 5 min after bolus injection.This study was approved by the Case Western Reserve University IACUC (Protocol #2012-0100). All experiments and methods were performed in accordance with relevant guidelines and regulations of this IACUC. Three anaesthetized 8–10 month old (mo) and three 17–19 mo male, Dunkin-Hartley retired breeder Guinea pigs were injected via the heart with a single bolus containing 10 kDa rhodamine green tagged and 70 kDa Texas red tagged dextrans , prepared and delivered on a per gram basis, 32. Serial sections of each sample block  were reconstructed as animated gif files .Immediately after euthanasia, knees were resected and frozen (liquid nitrogen) in OCT embedding compound  before transfer to BioInVision  for concomitant cryosectioning and imaging using an automated microtome-blockface episcopic imaging system  that allows for microscopic, three dimensional resolution of fluorophores in macroscopic specimensDataset 1Dataset 2Dataset 3


Neuroimaging plays a pivotal role in Transient Ischemic Attack (TIA). Generally, clinicians focus on the specific changes in morphology and function, but the diagnosis of TIA often depends on imaging evidence. Whereas Traditional Chinese Medicine (TCM) is concerned with the performance of clinical symptoms, they began to use imaging methods to diagnose TIA. CT and MRI are the recommended modality to diagnose TIA and image ischemic lesions. In addition, Transcranial Doppler sonography (TCD) and Digital Subtraction Angiography (DSA) are two acceptable alternatives for diagnosing TIA patients. This article elaborates the update of imaging modalities in clinic and the development of imaging modalities in TCM. Besides, multiple joint imaging technologies also will be evaluated whether enhanced diagnostic yields availably. Currently, cerebrovascular disease is the third commonest cause of death following malignant tumors and cancer, especially ischemic cerebrovascular disease, which has a high risk of paralysis .There arClinicians tend to diagnose TIA with the collection of imaging evidence and duration of cerebral ischemia. With the increased recognition of TIA, update diverse imaging techniques have been used to improve the early diagnosis rate and accurate location of TIA, whereas TCM generally attributes TIA to the aura of stroke, starting from the earliest “The yellow Emperor' Classic of Internal Medicine” to the “Su Wen Men Tune Classics” and “Medical Forest Reform Mistakes” . NowadayThe largest obstacle clinicians and TCM doctors must overcome is how to confirm the evaluation and management of TIA with multiple neuroimaging technologies and joint application . For exaBy combining different kinds of imaging, one may discover that neuroimaging focus cannot be separated from the three aspects of the ischemic penumbra (IP), cerebrovascular conditions  (CVC), and cerebrovascular reserve (CVR). Further, if clinicians can obtain accurate imaging diagnosis of TIA, the prediction of early stroke and individualized therapeutic planning could be effective by implementation .As early as 1977, Astrup defined the IP as perfused brain tissue at a level within the thresholds of functional impairment and morphological integrity . It has Cerebral vascular conditions include the location of stenosis, the degree of stenosis, the time of formation, the collateral circulation, the luminal diameter, and blood flow. Some literatures point out that the establishment of good collateral circulation can minify low perfusion area and enhance the survival time of IP. Besides, it also contributes to endovascular treatment and reduction of infarct volume, which reduces the risk of recurrence and improve prognosis . For cliCVR refers to the intracranial arterial blood pressure changes, which can have semiautomatic self-regulation within a certain range . The abiPositron emission tomography (PET) is a unique nuclear medicine test using positron emitters to show the pathophysiological process of the IP. Because of its long time and low resolution, PET is not suitable for the use of patients with acute cerebral infarction.αvβ3-integrin via Positron emission tomography (PET). Therefore, PET provides a promising target for semiquantitative monitoring of the disease . In. In82]. In conclusion, the complexity of the patient's condition determines that multiple imaging diagnostic modality should be used in TIA patients. The combined use of multiple imaging methods will be able to solve the current “individualized” needs of patients for treatment and provide sufficient basic work for targeted and advanced treatment plans . We conf


Of late, however, TransCelerate, acollaborative effort of 19 member companies,2 including most of the largest pharmaceutical companies, has identified aconcerning trend of diverging regulations with regard to handling of pharmacovigilancefindings from ongoing clinical trials.April 1990 marked the inception of the International Council for Harmonisation (ICH), anorganization created through the joint efforts of regulatory authorities andpharmaceutical companies, with the mission to align global pharmaceutical regulatoryrequirements. Over the ensuing quarter century, among other accomplishments, harmonizedprocesses for submission of new drug applications and standardized coding of adverseevents have been accepted globally.3 while US Food and Drug Administration (FDA) guidance restrict reporting to key(sponsor-adjudicated) related events.4 While in isolation, the rationale for each of the above guidelines ismeritorious, the divergence of these requirements is complicating consistentcommunication of safety profiles to stakeholders.Examples include the processes for determining whether adverse events reported byinvestigators are related to investigational drug and expected (i.e. consistent with theknown safety profile of the product and/or events anticipated in the population).Unexpected and related serious adverse events may be subject to expedited reporting toapprise investigators and regulators of potential risks. Recent European guidelinesrequire comprehensive expedited reporting of serious events,Over the last two decades, the clinical trial landscape has evolved considerably: (1)many more countries are participating; (2) diverse populations, often with significantunderlying comorbidities, are being evaluated; and (3) new technologies are beingdeveloped. Consequently, optimal benefit–risk assessment requires close collaborationbetween all stakeholders from the investigators with their deep expertise of the diseaseand individual patient data, to the sponsor with their in-depth knowledge of thespecific molecules and to the various regulatory authorities who oversee safety andefficacy of drugs from various sponsors. To that end, communication of congruous safetydata (by sponsors) to other stakeholders has become especially important; in this way,investigators and regulators across all regions will have comparable insight into theevolving safety profile of new products. To meet these goals, we at TransCelerateimplore representatives for regulatory authorities to work with industry sponsors, inthe spirit of ICH, to identify potential ways to re-harmonize global pharmacovigilanceprocesses and requirements.


Efficacious psychiatric treatments are not consistently deployed in community practice, and clinical outcomes are attenuated compared with those achieved in clinical trials. A major focus for mental health services research is to develop effective and cost-effective strategies that increase the use of evidence-based assessment, prevention, and treatment approaches in community settings.The goal of this program of research is to apply insights from behavioral economics and participatory design to advance the science and practice of implementing evidence-based practice (EBP) for individuals with psychiatric disorders across the life span.Project 1 (Assisting Depressed Adults in Primary care Treatment [ADAPT]) is patient-focused and leverages decision-making heuristics to compare ways to incentivize adherence to antidepressant medications in the first 6 weeks of treatment among adults newly diagnosed with depression. Project 2  is provider-focused and utilizes normative pressure and social status to increase data collection among community mental health workers treating children with autism. Project 3  explores how participatory design can be used to design organizational-level implementation strategies to increase clinician use of EBPs. The projects are supported by a Methods Core that provides expertise in implementation science, behavioral economics, participatory design, measurement, and associated statistical approaches.Enrollment for project ADAPT started in 2018; results are expected in 2020. Enrollment for project ASSISTS will begin in 2019; results are expected in 2021. Enrollment for project MOTIVATE started in 2018; results are expected in 2019. Data collection had begun for ADAPT and MOTIVATE when this protocol was submitted.This research will advance the science of implementation through efforts to improve implementation strategy design, measurement, and statistical methods. First, we will test and refine approaches to collaboratively design implementation strategies with stakeholders . Second, we will refine the measurement of mechanisms related to heuristics used in decision making. Third, we will develop new ways to test mechanisms in multilevel implementation trials. This trifecta, coupled with findings from our 3 exploratory projects, will lead to improvements in our knowledge of what causes successful implementation, what variables moderate and mediate the effects of those causal factors, and how best to leverage this knowledge to increase the quality of care for people with psychiatric disorders.ClinicalTrials.gov NCT03441399; https://www.clinicaltrials.gov/ct2/show/NCT03441399 (Archived by WebCite at http://www.webcitation.org/74dRbonBD)DERR1-10.2196/12121 Worldwide, psychiatric disorders account for more years lived with disability than any other category of disease . The risOn average, it takes 17 years for 14% of research to make its way into practice, with the majority of research findings never deployed in the community . This fiImplementation research in both health and mental health care began prioritizing the identification of determinants at clinician, organization, and system levels that affect implementation success or failure. Several heuristic implementation frameworks that attempted to capture constructs at each of these levels supported these studies ,9,17. BrImplementation studies historically have been premised on the assumption that clinicians make rational clinical choices that maximize utility for themselves and their patients . A growiTo date, implementation research has not leveraged insights from behavioral economics to design implementation strategies. This approach is promising and has been applied outside of the scope of implementation science with regard to physician and patient behavior in health care -34. The Although implementation science underscores the importance of stakeholder involvement in the implementation process , there hcomplex moderated mediation or conditional indirect effects in a multilevel context, thus limiting the forward movement of the field in understanding how or when implementation strategies are most effective.Causal theory is largely underdeveloped in implementation science ,39, and A second factor that limits the development of causal theory in implementation science is the lack of standardized and validated measures that assess putative mechanisms that link strategies to outcomes. Important work is currently underway to address this measurement gap in some areas of implementation science ; howeverEven when measures are available to assess putative mediating mechanisms and investigators test these variables as mediators within randomized controlled trials, a third factor that limits the development of causal theory in implementation science is the failure of many implementation strategies to engage the targeted mechanisms . A recenThe center is funded as part of the National Institute of Mental Health ALACRITY P50 to support the rapid development, testing, and refinement of novel and integrative approaches for optimizing the effectiveness of treatments for and prevention of mental disorders and organizing and delivering mental health services in community settings . The majThe Methods Core is the foundation of the Penn ALACRITY center. Specifically, it supports 3 incubators related to implementation strategy design, measurement, and statistical methods: (1) optimization of implementation strategy design through our design incubator, (2) refinement of measurement of mechanisms through our measurement incubator, and (3) development of novel approaches to test mechanisms in multilevel implementation trials through our statistical methods incubator. The Methods Core supports 3 exploratory projects that are wide in scope and span the most salient levels at which implementation takes place—the individual in treatment, the clinician, and the organization. Although each project stands alone, they are linked through common methods and measurement tools see .Project 1 (Assisting Depressed Adults in Primary care Treatment [ADAPT]) compares the effectiveness of different schedules of financial incentives to increase medication adherence among adults recently diagnosed with depression in primary care settings. Project 2  examines the effectiveness of normative pressure in increasing the use of EBP among frontline clinicians working with children with autism in schools. Project 3  develops and tests the acceptability of organization-focused implementation strategies to increase clinicians’ use of EBPs in community mental health clinics. In the section that follows, we will describe the major activities of the Methods Core, followed by more in-depth descriptions of each project.The design incubator will test several participatory approaches to develop implementation strategies. Here, we describe 4 methods including innovation tournaments, behavioral design, rapid-cycle prototyping, and discrete choice experiments.Innovation tournaments ,45 take Easy, Attractive, Social, and Timely [Behavioral design is a systematic approach, informed by engineering and human-centered design principles, to understand human behavior and apply those insights to the design of behavior change interventions ,47. In td Timely . For exaRapid-cycle prototyping is an industry innovation that has recently been applied to health care and is a complementary approach to behavioral design. The goal of rapid-cycle prototyping is to test potential innovations more efficiently, less expensively, and more reliably than traditional clinical trials . These aDiscrete choice experiments ,52 are ftake a gamble on innovative practices that may put quality at risk. Present bias refers to the tendency of individuals to overvalue immediate or current rewards compared with future rewards [behavioral phenotype [Implementation science frameworks posit that individual factors such as motivation, self-efficacy, knowledge, and attitudes are important in the implementation process ,9. To da rewards . Present rewards . An indihenotype  and may Implementation science frameworks also posit the importance of organizational factors in explaining implementation success, emphasizing constructs such as organizational culture (the collective sense of how work is done in an organization), organizational climate , implementation climate , and implementation leadership (group beliefs about how capably a leader supports EBP implementation) -62. ThesWe will refine existing, validated measures from the behavioral economics literature for assessing psychological heuristics. Once measured in patients, providers, and administrators, these phenotypes can be evaluated as mediators and moderators of implementation strategy effects.processes that are responsible for change [active ingredients that explain the specific ways in which implementation strategies affect implementation and client outcomes. The identification of mechanisms can lead to more efficient and tailored strategies based on the EBP of interest and the context in which it is implemented. The goals of the statistical methods incubator are to develop methods that quantify the magnitude and statistical significance of cross-level indirect effects in mediation models (the approach needed to test mechanisms) that span patient, clinician, and organizational levels and develop methods and guidelines for designing studies that have adequate statistical power to detect mediation effects in these multilevel trials. These methods are necessary to rigorously test the implementation strategies that are developed through our exploratory projects and pilot studies.Mechanisms refer to r change ; they caAlthough some research has begun to identify challenges and propose solutions for addressing mediation in simple 2-level mediation models (patients nested within providers) , little centered within context with means reintroduced approach [There are no good guidelines to help investigators design multilevel studies so that they have adequate power to detect indirect effects of clinical interest. The importance of designing studies with adequate statistical power to detect meaningful effects is well understood  and acceapproach —to addreImproving the management of adult depression is one of the great challenges facing outpatient mental health care. As continuous antidepressant treatment tends to improve symptoms of depression -76, qualTangible financial patient rewards have successfully increased a wide range of health behaviors ,34,81-84Behavioral economics research has highlighted that the design and delivery of financial incentives significantly influence effectiveness ,92. AntiWe will compare the effects of usual care, escalating, and de-escalating patient financial incentives on daily antidepressant medication adherence and depression symptom control of nonelderly adults with clinical depression see . A threeElementary school children with autism often need intensive support throughout the day . ConcernPhiladelphia’s Medicaid system spends more than US $80 million a year on TSS, about a third of the children’s mental health services budget. Although children with autism comprise 7% of all children served through this system, they account for 40% of TSS services. Administrators, advocates, and parents have decried the poor or unknown quality of care and outcomes associated with it, yet the very nature of the work they do makes it difficult to monitor. Our observations of TSS in the community , combineThis project will develop and test strategies to increase TSS’s self-efficacy, supervision, and sense of belonging to a professional community, with opportunities for peer comparison and supervisor recognition as mechanisms to increase the use of EBP. The target practice for this study is data collection. We chose data collection because (1) it is a component of every EBP for children with autism and is common to many mental health interventions for other children as well, (2) this foundational practice is essential to measuring and monitoring outcomes and has been associated with more positive outcomes in and of itself, and (3) it makes possible the objective assessment of the effectiveness of implementation strategies and supports iteration and improvement.Our clinician-focused implementation strategy is based on 3 psychological principles informed by behavioral economics. The first is bounded rationality, defined as limited information, cognitive capacity, and willpower . TSS mayPhiladelphia’s Department of Behavioral Health is making substantial investments in establishing and enforcing standards for autism intervention. Data collection will be an important part of these new standards. We will use a participatory design approach to build a digital app on the Penn Way to Health platform that allows TSS to (1) receive frequent communication and reminders about how and when to collect data, (2) easily collect and upload data, (3) observe how the child in their care is progressing, (4) observe how they compare with their peers in data collection, and (5) receive positive recognition from their supervisors and employers in response to frequent and accurate data collection.We will use rapid-cycle prototyping, an iterative development process that involves multiple tests of our intervention’s utility, feasibility, acceptability, and potential for long-term system-wide implementation. To develop the components of this new tool, we will (1) conduct an innovation tournament among TSS and their supervisors to identify ways to increase TSS’s data collection; (2) observe and query 10 TSS workers in the field to examine how they collect data, the functional and structural barriers that impede their ability and willingness to collect data, and their intentions, attitudes, subjective norms, and self-efficacy regarding data collection; (3) use rapid prototyping and testing to create an app through Way to Health that makes data collection easier, more rewarding, and socially desirable and refine the app based on observation and data collection; (4) test the refined app with 30 TSS from 3 agencies; and (5) explore broader applicability of this technology with our partners to determine how use of other EBPs can be objectively and inexpensively measured and rewarded.In project MOTIVATE, we will partner with stakeholders to develop implementation strategies that target organizations and leverage established principles from behavioral economics to improve EBP implementation in community mental health clinics. In our work investigating the implementation of EBP over the past 5 years ,104, ageIn response to this challenge, payers, including Philadelphia’s Department of Behavioral Health and Intellectual disAbility Services (DBHIDS), are beginning to use financial incentives to motivate organizations to encourage EBP implementation. These efforts are based in part on evidence from a few published studies, which show that pay-for-performance schemes, that is, paying clinicians directly for the implementation of EBPs, result in greater use of EBP and higher fidelity -111. HowThe limited impact of paying organizations to change clinician behavior may be due to a number of factors ranging from poor incentive design to organizational incentives not being translated into incentives for frontline clinicians . Organizbehavioral diagnosis process. We will use a structured tool developed by ideas42 to comprehensively analyze the ideas submitted in the tournament and identify specific behavioral barriers impeding the use of EBPs by clinicians. For example, tournament ideas that indicate that clinicians run out of time to implement EBPs during the standard 50-min therapy session may suggest that the planning fallacy  contributes to incomplete or infrequent use of EBPs in session. The behavioral diagnosis step will yield multiple hypothesized behavioral bottlenecks that, once confirmed or disconfirmed by stakeholders, will inform implementation strategy design.Our participatory design approach incorporates 3 novel and promising methods for systematically eliciting and leveraging end-user input to design effective interventions. First, we will use an innovation tournament (described previously) to generate ideas from clinicians (the end users) about the best ways for organizations to use financial and nonfinancial incentives to facilitate clinician implementation of EBP (see description above). Second, we will refine the ideas generated through the innovation tournament using a Third, once a set of implementation strategies have been identified as potentially useful, we will use a discrete choice experiment to systematically elicit and quantify stakeholders’ preferences regarding how these strategies should be designed and structured . DiscretWe have begun recruitment and data collection for Projects 1 and 3; data collection is ongoing for both projects. Project 2 recruitment and data collection will begin in 2019. No publications containing the results of this study have been submitted or published in any journal.The institutional review boards of the University of Pennsylvania and the City of Philadelphia approved all study procedures, and all ethical guidelines were followed. All individuals interested in participating in the research described in this protocol will provide written informed consent.This work is occurring in close collaboration with community stakeholders vested in mental health in the City of Philadelphia. Our major partners include the DBHIDS, the School District of Philadelphia, the nonprofit organizations that serve the mental health needs of Philadelphia residents in the DBHIDS network, and the University of Pennsylvania Health System. Philadelphia is a city of 1.6 million racially and ethnically diverse communities, approximately a third of who are enrolled in Medicaid. Philadelphia manages the behavioral health care of its Medicaid enrollees through Community Behavioral Health (CBH), a not-for-profit corporation that falls within the organizational structure of DBHIDS. CBH pays for mental health and substance use care for more than 100,000 consumers annually and has more than 250 organizations in network, including approximately 50 CBH centers and other specialized mental health and substance use agencies providing outpatient services.The School District of Philadelphia serves approximately 140,000 students educated in 214 schools annually, making it the eighth largest school district in the United States. Furthermore, three-quarters of its students are eligible for free or reduced-price lunch. About two-thirds of students are African American and 10% are Latinx, and 107 languages other than English are spoken at home by District students.The University of Pennsylvania Health System is the largest health system in the Delaware Valley. It includes 6 hospitals and 2 regional medical centers. Last year, the health system accommodated more than 5 million outpatient visits, 135,000 adult hospital admissions, and 350,000 emergency room visits.All projects are approved by the appropriate institutional review boards.Enrollment for project ADAPT started in 2018; results are expected in 2020. Enrollment for project ASSISTS will begin in 2019; results are expected in 2021. Enrollment for project MOTIVATE started in 2018; results are expected in 2019. Data collection had begun for ADAPT and MOTIVATE when this protocol was submitted.Although hundreds of treatments for common psychiatric disorders have demonstrated efficacy, problems persist in optimizing their implementation in community practice ,118. WheOne innovation of our Penn ALACRITY center is the merging of mental health treatment, implementation science, behavioral economics, and participatory design. Implementation research in mental health has identified important, malleable characteristics of treatments, the individuals using them, and the organizations in which they work that affect their use and outcomes. Behavioral economists have identified a wide range of patterns in human decision making that may contribute to poor health outcomes as well as methods of designing the environment to optimize optimal decision making ,119-127.We anticipate that our Penn ALACRITY center will result in the following outcomes. First, through the design, measurement, and statistical methods incubators, the Methods Core will generate guidelines for using participatory design approaches  in the development of implementation strategies; a set of publicly available measures of behavioral phenotypes and a database that pools deidentified patient, provider, and organizational data; and practical statistical tools, guidelines, and information that facilitate the design of the next generation of mechanism-focused randomized trials in implementation science. Second, through our exploratory projects, we will generate data that will seed future implementation science studies that incorporate advances from behavioral economics and participatory design . Third,


Alzheimer’s disease (AD) is the most common type of dementia affecting regions of the central nervous system that exhibit synaptic plasticity and are involved in higher brain functions such as learning and memory. AD is characterized by progressive cognitive dysfunction, memory loss and behavioral disturbances of synaptic plasticity and energy metabolism. Cell therapy has emerged as an alternative treatment of AD. The use of adult stem cells, such as neural stem cells and Mesenchymal Stem Cells (MSCs) from bone marrow and adipose tissue, have the potential to decrease cognitive deficits, possibly by reducing neuronal loss through blocking apoptosis, increasing neurogenesis, synaptogenesis and angiogenesis. These processes are mediated primarily by the secretion of many growth factors, anti-inflammatory proteins, membrane receptors, microRNAs (miRNA) and exosomes. Exosomes encapsulate and transfer several functional molecules like proteins, lipids and regulatory RNA which can modify cell metabolism. In the proteomic characterization of the content of MSC-derived exosomes, more than 730 proteins have been identified, some of which are specific cell type markers and others are involved in the regulation of binding and fusion of exosomes with adjacent cells. Furthermore, some factors were found that promote the recruitment, proliferation and differentiation of other cells like neural stem cells. Moreover, within exosomal cargo, a wide range of miRNAs were found, which can control functions related to neural remodeling as well as angiogenic and neurogenic processes. Taking this into consideration, the use of exosomes could be part of a strategy to promote neuroplasticity, improve cognitive impairment and neural replacement in AD. In this review, we describe how exosomes are involved in AD pathology and discuss the therapeutic potential of MSC-derived exosomes mediated by miRNA and protein cargo. Alzheimer’s disease (AD) is characterized by the progressive deposition of β-amyloid (Aβ) around neurons and the intracellular accumulation of neurofibrillary tangles (NFT) of hyperphosphorylated tau, mainly in areas implicated in memory and learning, such as the prefrontal cortex and hippocampus. In advanced stages of the disease, aggregates of Aβ are present in motor areas, cerebrospinal fluid, as well as in eyes and neuromuscular joints  and oligodendrocyte precursor cells. The interaction between the administered cells and resident cells promote neuroplastic events such angiogenesis stimulation, neurogenesis and axonal remodeling, result in a neurological recovery  treatment in several neurodegenerative diseases  membrane-enclosed vesicles of endosomal origin, released by a variety of cell types, capable of transferring biologically active macromolecules, such as proteins, lipids and RNA, to other cells , lncRNA), however, determining the exact composition and content of the exosomal content (cargo) produced by different cell types is hard to establish due to differences in the conditions which the cells are found. It should be mentioned that cellular homeostasis is an important factor that controls exosome cargo and secretion, therefore the exosomes will present characteristics that reflect its cellular origin , forming aggregates of Aβ , increases this potential. Besides, MSCs are the most efficient exosome producing cells , which regulates transcription factors and cofactor deacetylation involved in angiogenesis, inflammation, response to oxidative stress and in neural development, associated with NPC proliferation and differentiation  best known as collapsing response mediator protein 2 also is found in the exosomal cargo. DPYSL2 is a member of a family named for their roles in axonal growth cone collapse. Its main function is stabilizing microtubules, promoting neuritic outgrowth and modulating signaling processes  is another protein found in exosomes  and CXCL2 , NGF (UniProt code P01138) and BDNF (UniProt code P23560) that modulate cell death cascades, increase production of proteins responsible for proliferation and maintenance of neurons. These factors also have roles in the outgrowth of dendrites and stabilizing synapses between neurons. In recent years, these neurotrophins have been considered as key regulators of adult neurogenesis and the changes in expression have been related to occurrence and development of cognitive impairments, even though the molecular mechanism is not completely elucidated  and cell division control protein 42 (CDC42 UniProt code P60953). It is known that tau is accumulated in the growth cone and its presence persists during the axonal elongation, however, understand the role of tau in axonogenesis is complicated because tau exists in different phosphorylation states and these states influence the subsequent localization of tau within neurons without implication of its role in the progression of AD .The second most important process for our analysis is axonogenesis with 10 members and an FDR of 8.91e−06) where they can modulate the processes like the responses to stimuli previously described. The main pathway of this interactome network was the Rap1 signaling pathway (FDR 2.3e−05) which has been reported to regulate vesicle secretion, cytoskeletal dynamics, proliferation and cell adhesion,  combined with the proteomic and bioinformatic analysis of those pathways that participate in this therapeutic modulation.The bioinformatic analysis performed, allowed us to focus on possible candidates with an important role in neurogenesis and neuroplasticity or even identify some potential pathways implicated in AD’s patient’s progress. This would allow us to use exosomes with different therapeutic approaches, for example, the modification of exosomes with some classes of proteins or miRNAs, with effects on tissue repair, maintenance of cellular homeostasis or impairing the disease progression.ER-Z, MH-S, BM, YG-M, AM-A and AC-A: equal contribution for the literature search, writing and correcting of this review article.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.