The term “stromal cells” refers to a highly heterogeneous class of connective tissue cells that build the infrastructure of any organ and fulfill a variety of fundamental roles in health and disease. Embedded into the framework of stromal cells are parenchymal cells, which define the specific function of an organ. Distinctive populations of stromal cells with different morphologies and functions include (i) fibroblasts, pericytes, and telocytes that are widely distributed throughout various organ systems; (ii) cells with stemness features, such as bone-marrow-derived mesenchymal stem/stromal cells (MSCs) and adipose tissue-derived stem/stromal cells (ASCs); and (iii) stromal cells specifically restricted to some organs, such as interstitial cells of Cajal in the gastrointestinal tract muscularis and fibroblastic reticular cells in secondary lymphoid organs, among others.In recent years, there have been substantial advances in our understanding of stromal cell biology, especially the molecular signals underlying their contribution to several biological processes in different tissues, including tissue morphogenesis and development, maintenance of local tissue homeostasis, tissue injury, regeneration, immune responses, cancer, and other pathologies. Increasing evidence indicates that stromal cells are leading actors in shaping the organization, integrity, and dynamics of their own microenvironment, but their phenotype and functions are tightly dependent on the specific tissue microenvironment wherein they reside. Expanding our knowledge of the cellular and molecular mechanisms regulating the interactions of stromal cells among themselves and with neighbor parenchymal cells or tissue-resident stem cells in physiological and pathophysiological contexts is crucial to gain insights into their potential clinical relevance as therapeutic targets or tools in the translational field of tissue engineering and regenerative medicine.International Journal of Molecular Sciences, “Molecular Morphology and Function of Stromal Cells”, consisting of seven original articles and three reviews, cover different aspects of stromal cell biology/pathobiology, including the role of the stromal microenvironment and stromal cells in diseases and novel therapeutic strategies.In such a scenario, the collected contributions of this Special Issue of the In this collection, Acar and colleagues  present In another original study with a similar approach, Aasebø and co-authors  performe+ stromal cells, a distinctive stromal cell type thought to play an important “nursing” role for these myogenic cells [The original contribution of Squecco et al.  demonstric cells . Collectic cells .+ stromal cells.The in vivo study by Rocha and colleagues  reports + stromal cells. In the original work, telocytes/CD34+ stromal cells were revealed as an important, though previously neglected, source of cancer-associated fibroblasts in invasive lobular carcinoma of the breast [+ stromal cells in skin pathology [+ stromal cells were analyzed in normal skin tissue, and their distribution was compared with that observed in different kinds of skin lesions, including tumor or tumor-like conditions and non-tumoral skin pathologies, such as fibrosing/sclerosing diseases, basophilic degeneration of collagen, dermatitis, vasculitis, folliculitis, and perifolliculitis, among others [+ stromal cells are still a poorly characterized cell type because of their relatively recent identification, and, hence, these contributions pave the way for further research addressing the possible implication of these peculiar cells in other pathophysiological processes.Díaz-Flores and colleagues contributed to this Special Issue with one original paper  and one e breast . The revathology . Telocytg others . TelocytA comprehensive review written by Rautiainen et al.  is dedicIn the field of tissue engineering for regenerative-medicine purposes, Martinez-Garcia and colleagues  investigThrough in vivo research, Lu et al.  discloseFinally, the review by Sadeghi et al. gives an overview of the signaling pathways that regulate lymphoma cell migration and interaction with stromal cells within the tumor microenvironment, with a focus on Mantle cell lymphoma, and highlights the fundamental role of epigenetic mechanisms in integrating signals at the level of gene expression throughout the genome .International Journal of Molecular Sciences Editorial Office for their professional work in making this Special Issue successful. A “Molecular Morphology and Function of Stromal Cells 2.0” Special Issue is now open for submission of original manuscripts and reviews authored by outstanding experts dealing with any aspects of stromal cell biology.In aggregate, the contributions published within the Special Issue “Molecular Morphology and Function of Stromal Cells” are excellent examples of the recent advances made in the broad field of stromal cell research and will hopefully open new avenues for the exploration of stromal cell pathobiology, providing important discoveries into novel therapeutic approaches for different kinds of diseases. I thank all the authors and reviewers for their valuable work and the time dedicated to providing these excellent contributions to this Special Issue of the journal. I also acknowledge Ansel Liu and the


Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5) defines echolalia as a pathological, parrotlike, and apparently senseless repetition (echoing) of a word or phrase just uttered by another person and classifies this condition among the “restrictive and repetitive behaviours” of Autism Spectrum Disorder (ASD). The authors reviewed the existing literature on echolalia and its role in the development of children with ASD. Current conceptualizations include echolalia among repetitive behaviors and stereotypies and thus interpret this symptom as lacking any communicative significance, with negative effects on learning and sensory processing. Echoic behaviors, however, have been described in neurotypical infants and children as having a substantial effect on the consequent development of language and communication. Relevant research has documented a functional role of echolalia in ASD children as well since it facilitates the acquisition of verbal competencies and affords a higher degree of semantic generalization. This developmental function could be restricted to specific contexts. Considering echolalia as stereotypy and treating it as a disturbing symptom could impair the development of ASD-specific learning and communication processes. In light of this evidence, the authors propose a different conceptualization of echolalia and suggest that this symptom be considered among atypical communication patterns in children with ASD, with implications for treatment and prognosis.The  Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by difficulties in reciprocal social communication and interaction (criterion A) and by repetitive, restricted behaviors and interests . Frequent comorbidities have been documented between ASD and mental health conditions such as anxiety disorders , attentiStereotyped or repetitive motor movements, use of objects or speech;Insistence on sameness, inflexible adherence to routines, or ritualized patterns of verbal or nonverbal behavior;Highly restricted, fixated interests with abnormal intensity or focus;Hyper- or hypo-reactivity to sensory input or unusual interest in sensory elements.RRBs represent a major clinical element for neuropsychology, diagnosis, and treatment of ASD . RRBs coAs for the frequency of specific subtypes of these symptoms, stereotypies were documented as the most frequent early RRBs in a recent study of 105 individuals with ASD . StereotDiagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5), echolalia can be described as the pathological, parrotlike, and apparently senseless repetition (echoing) of a word or phrase just spoken by another person [Criterion B1 for ASD in the DSM-5 lists echolalia among stereotyped/repetitive modalities of speech . Accordir person . Despiter person , dementir person , and intr person , echolalr person .This article provides a narrative review of the existing literature on the nature of RRBs as signs and symptoms of ASD, focusing particularly on phonic stereotypies, language development, and echolalia. The main reasons and issues behind the current conceptualization of echolalia as a stereotyped and apparently meaningless behavior are explored, and possible alternative theoretical perspectives are discussed.An extensive web-based search was conducted using PubMed, Web of Science, and Google Scholar. Key search terms included “Autism spectrum disorder AND echolalia” and “Autism spectrum disorder AND stereotypies”, and variations, combined with study filters for original research, case reports, and case series. A total of 1538 articles were identified. All articles were screened manually for content appropriateness. Additional articles were identified from the reference lists of screened papers. Duplicates were removed. At the end of the selection process, a total of 76 articles were included in this review. Only papers published in English were reviewed. The flow chart of the study is shown in According to the aforementioned general description, any repetitive, rigid, and invariable action with a tendency to be inappropriate for the context could be classified as a stereotypy . ClassicPhonic stereotypies are fixed, chronic, and non-propositional acoustic behaviors . PS may Simple: any straightforward and distinct sound whose utterance requires little effort;Complex: any sound that mimics physiological functions such as hyperventilation, nonsensical word repetitions, or any other sound that is notably complex in nature. Classification of PS based on the quality of phonation:Vocal: communicative vocalizations, syllables, echolalia ;Non-vocal: guttural emissions and non-communicative vocalizations such as throat clearing, grunting, buzzing, whistling, laughing, and coughing .Classification of PS based on the complexity of phonation :Simple: The lack of a unanimous classification makes it difficult to obtain definitive data on the prevalence and impact of such behaviors both in ASD individuals and neurotypical children, a population that may still manifest stereotyped behaviors . An accuEven though atypical early vocalization is not pathognomonic for ASD, its manifestation represents the first reason why ASD children access health services . A serieDespite being included in the same category and sharing many characteristics with other phonic stereotypies, echolalia shows distinctive traits. A proper characterization of echolalia should be based on an exact distinction between echolalia in children with ASD and echoic behaviors in non-ASD children .Echoic behavior is commonly found in neurotypical children below the age of 30 months ,56 and iSix behavioral and linguistic core attributes of different echolalic responses were identified: evidence of attention, echo directed/not directed to a person, degree of change, the timing of change, evidence of comprehension, the expectation of a response from an adult. According to this framework, seven functional categories of echolalic responses were identified: (1) Non-focused ; (2) Turn-taking ; (3) Declarative ; (4) Rehearsal ; (5) Self-regulatory ; (6) Yes-Answer ; (7) Request .It was also hypothesized that the number of functions attributed to immediate echolalia might vary according to the linguistic competence of ASD children . EcholalThe context of the communicative act is of crucial importance, as it can significantly influence the responses of ASD children. In fact, these vary in terms of adequacy and repetitiveness depending on the appropriateness of the linguistic expressions uttered by the adult interlocutor . SpecifiEcholalia is included among the “restrictive and repetitive behaviours” criterion B1 for ASD . This deEcholalia in children with ASD appears to have specific functional qualities, which set it apart from other stereotypies. Whereas RRBs were traditionally considered as interfering factors in learning new skills ,74, echoStereotyped behaviors such as the majority of currently recognized RRBs negatively affect children with ASD , contribFor the abovementioned reasons, we suggest that the inclusion of echolalia in the “RRB” criterion B1 for ASD is only partially appropriate and that echolalia should not be considered as a mere phonic stereotypy. The potential social and communicative function of echolalia sets it apart from other kinds of stereotypies and makes it more akin to atypical social communication features as listed in the diagnostic criterion A . HoweverTo date, a number of questions regarding echolalia and its functional role in ASD individuals remain unanswered. A change in the conceptualization of this peculiar phonic feature may represent the starting point for future studies searching for more effective therapeutic interventions for ASD children. The thorough categorization of paralinguistic and behavioral features accompanying echolalia would provide specialists with useful tools for determining whether a specific phonic behavior is to be discouraged or could be taken advantage of for the development of alternative communicative strategies.


The majority of the world’s poorest women (income < $1.90/day) reside in fragile, conflict and violence (FCV)-affected countries, like the Democratic Republic of the Congo. Health services in these settings have traditionally focused on immediate relief efforts, communicable diseases and malnutrition. Recent data suggests there is need to widen the focus to include cancer, as its incidence and mortality rates are rising.Employing competency-based learning strategies, Congolese health professionals were trained to perform same-day cervical cancer screening and treatment of precancerous lesions of the cervix; same-day clinical breast examination and breast ultrasound diagnostics; surgical treatment of invasive cancers of the breast and cervix; and infusion of cytotoxic chemotherapy. Outpatient breast and cervical cancer care clinics, a chemotherapy suite and surgical theatres were outfitted with equipment and supplies.Combining local and regional hands-on training seminars with wise infrastructure investments, a team of US and Zambian oncology experts successfully implemented a clinical service platform for women’s cancers in a private sector health facility in the Democratic Republic of the Congo.We forged a novel partnership between oncology health professionals from Africa and its Diaspora, international philanthropic organisations, a cancer medicine access initiative and an established African cancer centre to build women’s cancer services in a FVC-affected African setting. Two billion people live in areas plagued by violence and conflict, among whom are the majority of the global poor (income < $1.90/day) and a third of the world’s women . Since 1Motivated by the need and our previous successes in establishing cancer care services for marginalised women in Africa and its Diaspora –13, we eThe DRC is the second largest country on the African continent and major African continental crossroad being bordered by Rwanda, Uganda, Burundi and Tanzania to the east, Central African Republic and South Sudan to the north, Angola and Zambia to the south and Republic of Congo to the west. Formally established as a Belgian colony in 1908, the DRC gained independence from Belgium in 1960, became Zaire in 1972 and formally DRC in 1997. The population of 84 million people is now host to over 200 different ethnic groups and distinct languages with Lingala, Kingwana, Kikongo, Tshiluba and French considered the national languages . The DRCAgainst this backdrop of economic deprivation, political instability and infectious disease epidemics, a cancer crisis is also unfolding in the DRC. Cancer is among the leading causes of death worldwide. In 2018, there were 18.1 million new cancer cases and 9.5 million cancer-related deaths globally, far exceeding the number of deaths from human immunodeficiency virus/AIDS, malaria and tuberculosis combined . World HWith the common goal of improving healthcare in Africa, a partnership was formed between the Dikembe Mutombo Foundation (DMF)  and the Our primary objective was to increase access to women’s cancer (cervix and breast) services in the DRC by building a contextually-appropriate and sustainable diagnostic and therapeutic service platform.The first step in assessing the local conditions and circumstances was to convene a broad cross section of stakeholders for a Consensus Meeting. In March 2016, key Congolese stakeholders from the government, civil society, private and public health sectors and academia were convened over a 3-day period in the capital city of Kinshasa. The format of the meeting consisted of formal presentations of peer-reviewed, gray literature and unpublished data on the following topics: (1) epidemiology of women’s cancers in the African region with a focus on the DRC, , 37–45 aFollowing the Consensus Meeting, a site visit was conducted at BMMH by a visiting US gynaecologic oncologist (Groesbeck Parham). Discussions were held with hospital administrators, clinicians , clinical managers, procurement specialists, data managers and DMF leadership. An assessment was made of the physical plant, clinical capacity, infrastructure and interest among staff in participating in a women’s cancer care initiative.Informed by the findings from the situational assessment, a team of US and Zambian surgical and clinical oncologists and nurse specialists was tasked by the FOA to design an implementation strategy that encompassed training a local oncology workforce, developing clinical services and building a clinical infrastructure for women’s cancer care services.Stakeholders attending the Consensus Meeting listed the following as major barriers to the implementation of women’s cancer care services in the DRC: (1) low levels of cancer awareness among health professionals and the general population; (2) lack of trained oncology human resources of all types, including ancillary personnel; (3) lack of financing and unreliable systems for the procurement, storage and dispersal of equipment and supplies; (4) poor access to affordable cancer medicines and (5) properly outfitted clinics and surgical theatres .The above findings, coupled with a wide variation in the backgrounds and clinical experiences of the designated BMMH staff-trainees, prompted the FOA team to adopt competency-based training enfolded into a matrix of self-directed learning and bedside mentoring as the strategy for workforce capacity building. Mastery of the various clinical and surgical procedures was facilitated by using the following skills-building techniques: deconstruction (each procedure was broken down into its subcomponents); high volume repetition ; pre- and post-case review and mental narration . South-south professional exchange programmes were also felt to represent potential opportunities for skill building. Onsite mentoring was led by the visiting FOA oncology team on an intermittent basis, as conditions permitted.Given the low socioeconomic status of the target population and their lack of access to cancer prevention and treatment services, the clinical services deemed to be of greatest value were the following: (1) cervical cancer screening using visual inspection with acetic acid (VIA) and digital cervicography; (2) treatment of cervical cancer precursors using thermal ablation and large loop excision of the transformation zone (LLETZ); (3) evaluation of symptomatic women with clinical breast exam, breast ultrasound and ultrasound-guided core needle biopsy/fine needle aspiration; (4) surgical treatment of cervical and breast cancers; (5) breast oncoplastic procedures; (6) palliative surgery and (7) infusion of chemotherapy for advanced cervical and breast cancers .Investments were made in outpatient clinics and surgical theatres to ensure that the trainers and trainees had well-equipped clinical facilities for both teaching and clinical care, respectively. Dedicated space for the new clinical services was assigned by the hospital administration, after which it was remodelled and furnished with the necessary equipment, supplies and furniture .The initial plan was to implement workforce training, clinical service and infrastructure development through quarterly visits over a 12-month period. The intended timeline was significantly altered from 12 to 24 months (January 2017–December 2019) due to travel restrictions related to multiple episodes of political unrest within the DRC and Ebola outbreaks. Mentorship was continued in between visits through electronic communication [Following approval by the DRC Ministry of Health, the DMF and FOA, in collaboration with the United Nations Population Fund, co-sponsored a cervical cancer awareness campaign in Kinshasa (May–June 2016). Awareness activities, led by teams of nurses and doctors from the BMMH, were comprised of television and radio announcements and talk shows, combined with community-based educational sessions at large public gathering sites (markets and religious services) throughout the city. Immediately following the campaign, a small team of BMMH staff doctors and nurses attended a hands-on cervical cancer prevention educational seminar at the University Teaching Hospital in Lusaka, Zambia (20 June–1 July 2016), where they were trained to perform ‘single-visit cervical cancer screening and treatment’ procedures using VIA, digital cervicography, thermal ablation and LLETZ . Upon coAs of January 2020, 28,417 women have been screened for cervical cancer, of which 2,153 (1 of every 13 screened) were found to have cervical abnormalities suggestive of cervical pre-cancer. More than 90% were treated on the same day with either thermal ablation or LLETZ. Invasive cervical cancer was pathologically confirmed in 284 (1%) of the screened population . of whicFollowing the initial cervical cancer screening camp in July 2016, four additional visits were made to the DRC by the FOA team of mentors from January 2017–December 2019. During these visits, they were joined by a US breast surgical oncologist (Ronda Henry-Tillman) who implemented a hands-on training curriculum for BMMH staff general surgeons and nurses, designed to teach clinical breast examination, ultrasound imaging of the breast and axilla ultrasound-guided core needle biopsies and fine need aspirations. A surgical training curriculum for staff general surgeons was initiated by the US breast surgical oncologist with the goal of building their capacity to perform breast lumpectomy, modified radical mastectomy, axillary node dissections, breast oncoplastic procedures and palliative surgery. The curriculum for teaching breast diagnostic and surgical procedures was previously developed and implemented in Zambia .As of December 2019, 5,211 women have been evaluated using clinical breast examination and breast ultrasound. The vast majority presented with symptoms, elicited by nurses during cervical cancer screening. Clinical abnormalities were detected in 1,420 (27%) women, of which 516 (36%) met the criteria for ultrasound-guided core needle biopsy. Pathology reports were available on 368 (71%), of which 164 (44%) were malignant and 204 (55%) benign. Approximately 90% of the breast cancers were advanced stage (stage 3 or 4) . A totalAfrican Access Initiative [Some of the chemotherapeutic agents indicated for the treatment of breast cancer were available for purchase from local private vendors in Kinshasa; however, their prices made them unaffordable for the vast majority of patients. Neither was there a mechanism for verifying their quality. Access to cytotoxic cancer medicines at a discounted price became available through a partnership with the Bioventures for Global Health (BVGH) itiative , a nonpritiative . Since fitiative .A wide variety of 21 BMMH staff members were trained during the course of the initiative .We report one of the few real-world efforts to implement detection and treatment services for cervical and breast cancer in a fragile nation torn by war, outbreaks of infectious diseases, political unrest and devastating poverty.Using a unique matrix of self-directed learning, onsite and regional hands-on training seminars, south-south professional exchange programmes and teleconferencing, Congolese-led women’s cancer services were established in a private healthcare facility in Kinshasa. Skills transfer was facilitated through a process of clinical and surgical bedside mentoring, rendered by a close-knit team of highly skilled university-based US and Zambian oncologists and Zambian nurse-specialists who had a history of working together in resource-constrained African environments. Through wise investments, the physical and clinical infrastructure needed to support the newly trained workforce was simultaneously established. In between onsite visits, modern forms of telecommunication  were used to facilitate continuing medical education. Central to the success of the effort was the support of the hospital’s administrative staff and the sponsoring organisation (DMF), coupled with the leadership, clinical knowledge and logistical guidance provided by local professional colleagues.Fragility and violent conflict are on the rise worldwide. When protracted, their consequences extend beyond the war-wounded, impacting the health of entire communities. By 2030, up to two-thirds of the global extreme poor will live in societies affected by fragility, conflict and violence . Noncommprevent those cases that can be prevented (e.g. ablation of precancerous conditions of the cervix), treat those cases that can be treated  and relieve suffering in the others. These recommendations were in line with the humanitarian principles embedded in the ‘Four Pillars of Oncology’: prevent all cancers that can be prevented; treat all cancers that can be treated; cure all cancers that can be cured; provide palliation whenever palliation is required [Building the pathway for cancer care in severely resource-constrained settings is a difficult task, as it involves the integration of a cancer care platforms into healthcare systems whose supportive services  are often quite meagre. Yet, these are the circumstances under which one must operate when faced with the task of implementing cancer care services in the world’s poorest nations. When working in settings that are severely resource-constrained, a key ethical question that must be addressed is whether attempts should be made to implement only certain parts of the cancer care pathway if the system cannot be implemented in its entirety. In our particular situation, the outstanding question was whether cancer detection, diagnostic and surgical services should be implemented in the absence of radiation therapy services, given the likelihood of uncovering large numbers of cases of advanced disease that would require these adjunctive therapeutic modalities. When posed to key local stakeholders and organisations in attendance at the Consensus Meeting, the consensus opinion was to begin, immediately, by training the workforce and building the clinical services and infrastructure needed for delivery of early detection and surgical treatment services. The underlying rationale was that the present inability to treat all cancer cases should not impede efforts to required . There wMotivated by a commitment to actively engage the problem by implementing contextually-appropriate and evidence-based solutions, and to learn on the go, we started with the resources that were available. We made frequent use of the various sets of resource-stratified management guidelines for cervical and breast cancer developed by the WHO, Breast Health Global Initiative, National Comprehensive Cancer Network and American Society of Clinical Oncology –57. SimiCancer care as a human right is in accordance with human rights instruments adopted by the United Nations Human Rights Council . We recoSome of the challenges encountered and solutions derived during the course of our work were as follows:In order to increase the availability and accessibility of cancer detection services, quarterly week-long mobile outreach cervical cancer early detection camps were sponsored by the BMMH. To date, six such outreach camps have been held, all in densely populated areas around Kinshasa, led by hospital nursing staff, through which over 5,000 women have been screened for cervical cancer. Three of the outreach camps were mentored, onsite, by visiting Zambian nurse-trainers.The costs of pathology services were unaffordable for most patients, resulting in significant delays, and impacting timely treatment. As a short-term solution, we negotiated reduced fees with private sector pathologists in Kinshasa, however, most patients still had difficulty paying the residual costs. These circumstances helped to motivate the formation of a partnership between the DMF and American Society of Clinical Pathology, resulting in a venture to build chemistry and pathology laboratory infrastructure at the BMMH. All equipment has been purchased, installed and a local pathologist hired to lead the programme. Expectations are that the laboratory will be fully operational in April 2021.The World Health Organization has an Essential Medicines List that contains several chemotherapeutic and palliative agents used in the treatment and palliation of breast and cervical cancer . Other tRadiation therapy is an essential pillar in the treatment of cervical and breast cancer. Early-stage cervical cancers with low disease volume can often be cured with surgery alone. Others require adjunctive treatment with radiation. Radiation therapy is also essential in the management of breast cancer patients who are treated with conservation therapy as well as those with advanced disease. We were aware that we would encounter patients that could not be optimally treated because of the lack of radiation therapy. This problem is not just limited to the DRC but across the region as only 23 of 52 African countries are known to have radiation therapy facilities . This waLimited, one-time investments such as ours can be very beneficial in that they can provide the capital outlay for training and infrastructure development that can be continually realised. The presence of women’s cancer care at BMMH can now be used to offset expenses by offering services at affordable but profitable fees. It can also be presented as a model of cancer care to investors interested in promoting the growth of for-profit health enterprises in low-income nations, particularly those affected by conflict and violence. Services can be leveraged to advocate for government-led national health promotion and awareness campaigns for cervical and breast cancer control; public sector breast and cervical cancer early detection and treatment services; national Human Papilloma Virus vaccination programmes for adolescent girls; expansion of national laboratory and pathology services; public sector radiation therapy services; partnerships with pharmaceutical firms to help ensure access to essential cancer medicines and the development of a national strategic plan for cancer control.Private enterprises can help break the cycle of fragility, conflict and poverty. Businesses create jobs and income and support livelihoods, and in doing so can contribute to social cohesion and stability. Private investments in cancer care in resource-constrained environments deserve further consideration . This maUsing a novel partnership consisting of oncology health professionals from Africa and its Diaspora, international philanthropic organisations, a cancer medicine access initiative and an established African cancer centre, we successfully trained the workforce and built the clinical services and infrastructure for women’s cancer care services in a private sector health facility in the DRC.BMMH, Biamba Marie Mutombo Hospital; BVGH, Bioventures for Global Health; DMF, Dikembe Mutombo Foundation; DRC, Democratic Republic of the Congo; FCV, Fragile, Conflict and Violence; FOA, Friends of Africa, Inc.; HPV, Human papilloma virus; LLETZ, Large loop excision of the transformation zone; LND, Lymph node dissection; VIA, Visual inspection with acetic acid; WHO, World Health Organization.None of the authors declare any conflicts of interest.Funding for the initiative was provided by a generous grant from the Howard G. Buffett Foundation , whose m


The success rate for translation of newly engineered medical technologies into clinical practice is low. Traversing the “translational valleys of death” requires a high level of knowledge of the complex landscape of technical, ethical, regulatory, and commercialization challenges along a multi-agency path of approvals. The Indiana Clinical and Translational Sciences Institute developed a program targeted at increasing that success rate through comprehensive training, education, and resourcing. The Medical Technology Advance Program (MTAP) provides technical, educational, and consultative assistance to investigators that leverages partnerships with experts in the health products industry to speed progress toward clinical implementation. The training, resourcing, and guidance are integrated through the entire journey of medical technology translation. Investigators are supported through a set of courses that cover bioethics, ethical engineering, preclinical and clinical study design, regulatory submissions, entrepreneurship, and commercialization. In addition to the integrated technical and educational resources, program experts provide direct consultation for planning each phase along the life cycle of translation. Since 2008, nearly 200 investigators have gained assistance from MTAP resulting in over 100 publications and patents. This support via medicine–engineering–industry partnership provides a unique and novel opportunity to expedite new medical technologies into clinical and product implementation. Investigators face many significant challenges in their efforts to reach clinical translation of their innovative medical technologies. The success rate for translation of newly engineered medical technologies into clinical practice is low –4. TraveIn 2008, Purdue University, a member of the Indiana CTSI research consortium, developed MTAP with the specific goal of assisting Indiana CTSI investigators with advancing toward clinical translation of their medical technologies. Advancement support can be provided at any point during the early stages of research and development. The medical technologies being developed can range widely from clinical monitoring, surgical and imaging technologies, to implantable, wearable, point of care, and remote sensing diagnostic and therapeutic devices, to assistive and rehabilitative technologies. Technology research and translation projects can also include digital health, biologics, drug delivery, and combination devices but are not typically stand-alone drugs as development of these are supported in other aspects of the Indiana CTSI. MTAP enables investigators to develop technologies and speed their progress toward commercialization and clinical implementation by providing integrated technical and educational support augmented by partnerships with experienced and successful professionals in the medical device and health products industry in Indiana. Recognizing that most medical technologies follow unique pathways and timelines to full development and translation, MTAP supports investigators with determining the specific resources they will need for their particular stage of development toward commercialization. MTAP then connects investigators to these educational and technical resources.The goal of this communication is to describe the novel MTAP model for advancing translation, with the intent of disseminating a potential best practice for the advancement of all programs with Clinical and Translational Science Awards (CTSAs). A brief review of current challenges and the published models attempting to address the many challenges to advancing innovation and translation of medical technology will set the context for the description of MTAP.Medical technologies form an increasingly important component of healthcare, especially in the move to more distributed and complex delivery systems. The development of medical technologies requires a rich and diverse set of resources – from engineering design through preclinical evaluation to human clinical testing to manufacture, marketing, distribution, and post-market evaluation – all of which are subject to unique regulatory and commercialization processes.Early on, the developers of the National Institutes of Health (NIH) CTSA program recognized the potential for advanced training through partnerships to overcome some of these challenges to translation, encouraging partnerships between medicine and schools of business, law, engineering, and communications. Other investigators have also recognized the critical role of internal and external experts to support translational efforts across the product life cycle, including design, prototyping, nonclinical studies, and regulatory activities . Since ihttps://www.prf.org/otc/). For a number of years, Purdue has led all public academic institutions in commercialization of technologies, ranking first nationally among universities without a medical school, and 12th overall for “Best Universities for Technology Transfer” [Through an intentional focus on innovation, invention, and impact, Purdue technologies have been commercialized in the USA and used globally in more than 100 countries, to the benefit of millions of people , one of the most advanced technology transfer systems associated with academic institutions in the USA , operateAmong the leaders in technology transfer at Purdue, the Weldon School of Biomedical Engineering develops more than half of the over 100 US patents successfully licensed to company partners, and more than 25 related technology start-ups raising in excess of $75 million in venture capital. Although the medical technologies resulting from this substantial transfer have touched over 2 million patients worldwide, the full capacity for clinical translation has not yet been reached.Strategically, to develop the highest level of translational impact, the Purdue College of Engineering and Indiana University School of Medicine (IUSM) have established an important partnership that leverages the strengths of technology development and clinical research. Recent record-setting research and facilities growth at both institutions have positioned the IUSM and Purdue engineering partnership to be one of the most productive translational research enterprises in the world. MTAP represents a central component of the innovation ecosystem linking these two institutions – providing essential support for medical technology design, development, and translation.In 2000, Balas and Boren  reportedEarly-stage ideation and innovation of new medical technologies often require rapid iterations of prototypes for testing for functionality and ability to meet the clinical needs ,13. HoweIn the realm of clinical translation of innovative medical technologies, several obstacles have been recognized. Central to these is preclinical testing and “a critical need for early trans-disciplinary communication and collaboration in the development and execution of research approaches” . In the Regulatory knowledge and support has been identified as one of the key barriers to actual translation to clinical practice. In 2014, 56% of translational research hubs indicated some type of regulatory support for investigators related to investigational new drugs and device regulations (IND/IDE) through online training . RegulatInvestigators ,17 have In another key arena of medical technology, biomedical imaging, Wilson, Jermyn, and Leblond  identifiInvestigators –21 have Biomedical Entrepreneurship and Ethical Development of Medical Technologies, had been initiated a few years prior, and the three regulatory courses focused on medical technologies were developed and initiated in alignment with MTAP. Each of the technical resources were assembled as part of MTAP formulation from existing technical staff and facilities across multiple colleges and centers of Purdue University. MTAP resource areas are staffed by more than a dozen faculty and staff members with specific expertise. Direct funding from the Indiana CTSI grant/cost share covers 1.5 FTE spread across seven key lead positions. Two professors with expertise in biomedical engineering and pharmacy are co-directors at 0.15 FTE each. Four other faculty and staff with expertise in engineering prototyping, preclinical studies, veterinary pathology, and regulatory science support the MTAP at 0.20 FTE each, and one administrative support staff provided at 0.40 FTE. All technical and educational resources are provided to Indiana CTSI investigators without charge.Creation of MTAP in 2008 was based on the challenges recognized for investigators seeking to translate technology, the growing needs of technology innovation projects in the Indiana CTSI, and an informal assessment of available key technical and educational resources at Purdue that could be rapidly deployed and made available to investigators. Five technical resource areas were examined, selected, and improved under Indiana CTSI guidance. In addition, these technical resources were supplemented with five courses in three educational resource areas to fill the support gap in training and address the identified challenges in ethics, entrepreneurship, and regulatory knowledge and application ;Devices, biomaterials, and tissue engineering technologies (29%);Magnetic resonance imaging and other imaging technologies (22%);Diagnostics, biosensors, and signal processing technologies (20%).Many of the projects were highly collaborative in nature with one-third being of an interdepartmental or inter-institutional nature. Initially, many of the projects had critical, challenging technical or preclinical needs and thus were focused within one stage of technology development. More recently, almost 30 of the most promising projects have moved through at least 1 development stage toward results suitable for inclusion in FDA submissions. The overwhelming majority of projects yielded data as part of a larger research effort as reflected in 129 reported scientific publications, 20 reported conference presentations, 5 reported IP filings, and 3 reported textbook contributions. The types of technologies supported by MTAP based on publications includeThese data do not include internal IP disclosures, transmission of results directly to a local or regional company partner, or other deliverables not reported back to our program.With an NIH grant to investigate if external cues could be used to improve the loudness and pace of speech in patients suffering from Parkinson’s disease, Dr. Huber found that a natural external cue stimulated patients to produce a higher intensity voice with more normal physiologic function. She was directed to MTAP with an idea for a therapeutic technology. A first-generation prototype device was designed and constructed with support from MTAP Design, Prototyping, and Evaluation core. Powered by a battery and micro-computer worn with a belt clip, the device resides at the external auditory canal of the patient and emits noise when the patient talks thereby encouraging louder speech. With multistage support from MTAP, the device, named “SpeechVive,” was advanced to a 38-patient study evaluating clinical use. A behind-the-ear model has been designed and is being manufactured for use in a large multi-site clinical trial. This novel technology  has the Case Example 1: While detection methods for food-borne pathogens are available, all require days. An effective prevention strategy requires that the pathogens be detected in less than one 8-hour work shift. Professor Ladisch engaged the technical design and development resources of MTAP to develop a solution to this challenging problem. The team together with the Design, Prototyping, and Evaluation core developed a novel microfiltration system that utilizes nanopore membranes to concentrate pathogens rapidly. Through numerous design iterations and detailed evaluations through all seven stages of project development, previously confounding issues such as pore blockage and cavity fouling were overcome, yielding a high-throughput approach with two orders of magnitude pathogen concentration amplification to detectable levels for routine assays. A working, computer-controlled prototype of the pathogen amplification system was then entered into the FDA Food Safety Challenge. The system designed with MTAP support won the $300,000 first prize. The prize gave the team members unprecedented and ongoing access to FDA scientists to target current efforts to meet the needs of the FDA laboratories across the country that are responsible for detecting pathogens in our food supply [. With pertinent intellectual property protection recently secured and the needs of the FDA in mind, licensing negotiations to produce the first generation of the system are well underway.Case Example 2: d supply . With peAn essential component of this novel paradigm for investigator training and technical resourcing is the integration of expertise from the medical device and biotechnologies industries. Such experts provide years of experience with technology development, nonclinical and clinical evaluations, regulatory approvals, and commercialization strategies.Industry partners regularly contribute their expertise on these topics through coursework by discussing real-world examples, experiences, and case studies. The industry experts are primarily from local and regional medical device and biotechnology companies. In 2019, Indiana had the fifth largest medical devices sector in the USA with over 275 establishments in the state . Many ofAdvertising the specialized capabilities of MTAP is accomplished via the creation of an electronic brochure with dissemination to faculty members, postdoctoral fellows, staff members, and graduate students at Indiana CTSI institutions – Indiana University, Purdue University, and the University of Notre Dame. Such efforts are followed by the posting of key information and points of contact on the Indiana CTSI website, along with numerous presentations and posters at Indiana CTSI-sponsored workshops, and by word of mouth.Different IP pathways among different institutions. Within the Indiana CTSI, each university has its own OTC, such that there is no standardized route for technology commercialization, and sharing IP between universities can present its own unique challenges. While MTAP helps bridge the gap and inform investigators, future innovative programs and agreements are needed to align and streamline IP sharing across universities.Lack of seed funding for innovation. While some funds are available to support biomedical innovations, these are often limited to certain disease areas or institutions, and many gaps exist in the preclinical, pre-commercialization stages of innovation development. Future initiatives seek to develop tracking and funding opportunities to fill these gaps and maximize seed funding for small studies that fall outside existing funding opportunities. MTAP offers support for both patentable as well as nonpatentable innovations.Lack of progress tracking. Across Indiana CTSI programs that currently support innovation, work is needed to enhance tracking and streamline processes toward innovation, particularly in the context of medical device development. Future initiatives are in development to provide robust tracking and coordination along both drug and device development processes.MTAP has been successfully implemented within the Indiana CTSI. Although relatively new, the program has assisted many investigators along the translational science spectrum. Despite this vast array of resources available to investigators, several barriers remainTo date, MTAP has greatly assisted numerous investigators to overcome translational challenges associated with their innovative technology research programs. The program’s integrated medical device design, bionanotechnology development, and preclinical study capabilities, together with supporting educational resources, facilitate the movement of projects through early technology development and evaluation stages toward clinical translation. Key to broadening impact will be to expand connections between Indiana CTSI investigators and MTAP resources and continue to facilitate novel medical technology projects. This expansion will support not only technology innovation but also drive innovation in regulatory science, and related instruction, to match the growing complexities of the medical technology–patient interface and healthcare system integration.


SM-funded multilevel intervention (MLI) project to increase screening in Appalachian Kentucky and Ohio primary care clinics.Colorectal cancer (CRC) screening rates are lower in Appalachian regions of the United States than in non-Appalachian regions. Given the availability of various screening modalities, there is critical need for culturally relevant interventions addressing multiple socioecological levels to reduce the regional CRC burden. In this report, we describe the development and baseline findings from year 1 of “Accelerating Colorectal Cancer Screening through Implementation Science (ACCSIS) in Appalachia,” a 5-year, National Cancer Institute Cancer MoonshotProject development was theory-driven and included the establishment of both an external Scientific Advisory Board and a Community Advisory Board to provide guidance in conducting formative activities in two Appalachian counties: one in Kentucky and one in Ohio. Activities included identifying and describing the study communities and primary care clinics, selecting appropriate evidence-based interventions (EBIs), and conducting a pilot test of MLI strategies addressing patient, provider, clinic, and community needs.p = .003), enhancement of electronic health record (EHR) systems and development of clinic screening protocols, and implementation of community CRC awareness events, all of which promoted stool-based screening . Variability among clinics, including differences in EHR systems, was the most salient barrier to EBI implementation, particularly in terms of tracking follow-up of positive screening results, whereas the development of clinic-wide screening protocols was found to promote fidelity to EBI components.Key informant interviews identified multiple barriers to CRC screening, including fear of screening, test results, and financial concerns (patient level); lack of time and competing priorities (provider level); lack of reminder or tracking systems and staff burden (clinic level); and cultural issues, societal norms, and transportation (community level). With this information, investigators then offered clinics a menu of EBIs and strategies to address barriers at each level. Clinics selected individually tailored MLIs, including improvement of patient education materials, provision of provider education (resulting in increased knowledge, Lessons learned from year 1 included increased recognition of variability among the clinics and how they function, appreciation for clinic staff and provider workload, and development of strategies to utilize EHR systems. These findings necessitated a modification of study design for subsequent years.NCT04427527 is registered at https://clinicaltrials.gov and was registered on June 11, 2020.Trial  Contributions to the literatureWe describe the formation of a multicomponent multilevel intervention (MLI) in rural Appalachian primary care clinics.Pilot year findings informed strategies and adaptations that will be implemented during years 2 through 5 of the multiyear intervention.Lessons learned from the first year of ACCSIS Appalachia can inform other researchers seeking to implement evidence-based colorectal cancer screening programs in low-resource, rural settings.Colorectal cancer (CRC) is a significant public health problem in several areas of the United States (U.S.), including the Appalachian region . AppalacAlthough screening tests for CRC  that can reduce both incidence and mortality from CRC have been available, CRC screening prevalence is lower in Appalachian regions of Kentucky and Ohio as compared to non-Appalachian regions . Low CRCMulticomponent interventions that use a combination of two or more approaches in three strategic areas—increasing community demand, increasing community access, and improving provider delivery of screening services—have been found to be effective in increasing CRC screening . HoweverSM initiative promoting acceleration of cancer research.Researchers at the University of Kentucky (UK) and Ohio State University (OSU) have conducted prior research in Appalachia addressing each of these levels of influence across Appalachian Kentucky and Ohio. From 2003 to 2018, they implemented the “Appalachia Community Cancer Network,” a National Cancer Institute (NCI)-funded effort to address cancer disparities in the region that included, among other programs, a faith-based initiative to decrease cancer burden in rural Kentucky and Ohio by reducing obesity and increasing cancer screening rates , 24. InvThe overall aim of ACCSIS is to conduct multi-site, coordinated, transdisciplinary research to evaluate and improve colorectal cancer screening processes using implementation science strategies. In this report, we describe the developmental process and year 1 pilot findings for ACCSIS Appalachia and how we plan to test our approach in a randomized controlled trial in 10 additional counties in Appalachian Ohio and Kentucky during years 2–5.ACCSIS Appalachia was developed in two phases, and all components of the project were approved by the institutional review board of The Ohio State University prior to engaging in project activities. Phase I focused on establishing the project and conducting activities needed to develop and test an MLI. These activities were conducted in one Appalachian county in Kentucky and one county in Appalachian Ohio and included a series of activities: (1) identifying and describing the study communities and primary care clinics; (2) planning the MLI; and (3) conducting a pilot test of the MLI using customized clinic-specific implementation strategies for EBIs at each level. As an MLI project, the focus is on the patient, provider, clinic, and community levels, with intervention delivery mainly occurring within the primary care clinic setting and community-level strategies often being supported by clinic staff and efforts. The main outcomes from ACCSIS are CRC screening, follow-up of abnormal tests, and referral to care; data to assess outcomes will come from the electronic health record (EHR) systems of the participating primary care clinics. Secondary outcomes include community-level assessment of self-reported CRC screening collected from serial random-digit-dialed telephone surveys. During year 1 activities, our primary foci included assessment of factors  affecting implementation of evidence-based interventions (EBIs) and pilot testing our research strategy for refinement prior to full project trial implementation during Phase II in years 2–5.Development of the ACCSIS project was guided by three theoretical frameworks. First, the Social Determinants of Health Model provided the overall conceptual foundation for the project. Second, the Model for the Analysis of Population Health and Health Disparities, developed by the Center for Population Health and Health Disparities (CPHHD), was used to understand not only the multilevel factors that hinder and facilitate adherence to CRC screening recommendations, but help understand the relationships between levels . As showThird, a model described by Proctor et al.  that guiData for 2010–2014 showed that, compared to non-Appalachian counties, Appalachian counties of Kentucky and Ohio had higher CRC incidence  and mortality  . With suWe selected 12 counties, six in Appalachian Kentucky and six in Appalachian Ohio, to participate in ACCSIS in Appalachia  and provide input on project development and implementation. ESAB members were provided with the project protocol and data collection tools to review, and they provided the ACCSIS team with recommendations and suggested subsequent steps.Additionally, the ACCSIS team recruited community advisory board (CAB) members from the identified project counties in KY and OH. Participants were identified via word of mouth, clinic recommendations, and key informant interviews. Members include clinic and community champions, community leaders, health department and cooperative extension representatives, and community health workers.After incorporating ESAB and CAB suggestions, investigators conducted key informant interviews with community members and clinical stakeholders to help develop a locally relevant menu of EBIs from which pilot clinics could select MLIs. Informed consent was obtained from each key informant who completed a brief demographic survey prior to beginning the discussion. Interviews were audio-recorded and supplemented by handwritten notes. For the community and clinical key informant groups, the research team created a coding spreadsheet, identifying high-level themes and overarching findings for each broad category in the respective interview guide. Investigators conducted interviews in-person, via telephone, or via web-conferencing. Semi-structured interview guides, informed by a review of the literature and the research team’s prior experience in Appalachia, were used to organize the interview discussions with the community members and clinical stakeholders, respectively. Interview guides concentrated on a SWOT  analysis for CRC screening at the patient, provider, clinic, and community levels.Community key informants were recruited using multiple strategies including personal email invitations and referrals from existing partners . Recruited community members represented local agencies committed to serving area residents, including cooperative extension, community health worker programs, local health departments, hospitals, and cancer coalitions. The interview guide for community members focused on perceptions of their community’s health, socioeconomic status, culture, CRC awareness, personal and community knowledge of CRC screening tests, barriers to CRC screening in their communities, community assets and/or programming that could be leveraged to promote CRC screening, and preferences for messaging and channels for delivery of community-based CRC screening education.Clinical stakeholders were individuals from participating health centers including doctors, nurses, certified medical assistants, administrators, quality improvement coordinators, and front desk staff. Similarly, the interview guide for clinical stakeholders asked about perceptions of community- and patient-oriented challenges to CRC screening, clinic- and provider-related practices , and preferences for patient, provider, and community messaging and formats for CRC screening education.Phase I activities occurred during year 1 of the project with Phase II activities scheduled for years 2 through 5. Phase I activities were pilot tested in one Appalachian Kentucky and one Appalachian Ohio county. Phase II activities will include review and revision of the MLI approach tested in Phase I and evaluation of effectiveness in a group randomized trial implemented in five additional counties in Appalachian Kentucky and five additional counties in Appalachian Ohio. Results from Phase II will be reported in a future publication.A total of 12 CAB members in Kentucky and 10 in Ohio were recruited to the project, and to date, we have held four CAB meetings: in January 2019 (Kentucky), March 2019 (Ohio), May 2019 (Kentucky), and August 2019 (Ohio). Meetings provided CAB members with the opportunity to offer input and recommendations on the proposed objectives and processes of Phase I of ACCSIS Appalachia. Topics for CAB meetings included an overview of the initiative and themes reflected in key informant interviews, summary of clinic and community intervention activities, and requests for feedback on telephone survey materials, as well as suggestions for increasing community participation and engagement at future events.n = 13 in Kentucky, n = 11 in Ohio) and 51 clinical stakeholders  in the 12 intervention counties between February and May 2019. On average, the interviews took 45–60 min. Key informant interviews identified strengths such as providers encouraging CRC screening among patients and positive and strong community connections, among others. Common CRC screening barriers were described at the (A) patient level ; (B) provider level ; (C) clinic level ; and (D) community level  [We conducted interviews with 24 community members (rtation) , 36. OppUltimately, the qualitative findings guided the research team’s decision to create a menu of multilevel , evidence-based strategies for clinics to choose from to implement in the year 1 pilot. In addition, pilot community events held in year 1 focused on provision of CRC and screening education in a creative and engaging manner at a well-regarded community location. For example, in Kentucky, the ACCSIS team partnered with a federally qualified health center (FQHC) and cooperative extension to host a community luncheon that included an expert speaker  and tours of an inflatable colon. Subsequent discussions of community-level approaches focused on the need to raise community awareness via multiple communication methods, including health fairs and mass communication mediums , that CRC is both preventable and treatable.After formative evaluation activities were complete, year 1 pilot project activities commenced in two clinics/communities . Project staff and clinic champions conducted in-person implementation meetings with clinic staff and providers, project team members, and any other interested stakeholders with the goal of reviewing relevant national and local CRC statistics, discussing themes identified in the key informant interviews and environmental scans, reviewing baseline CRC screening rates based on EHR reports, describing the levels of implementation on which to focus, and highlighting possible strategies for each level. In Ohio, the pilot clinic chose patient education (patient level), provider education (provider level), and improving EHR reports and alerts and creating a written pathway to care for CRC screening (clinic level) as strategies to improve CRC screening in their patient population. In Kentucky, the pilot clinic champion, in consultation with clinic staff, selected patient education and fecal immunochemical testing (FIT) reminders/follow-up (patient-level), feedback/assessment and provider education (academic detailing), and developing a screening protocol and improving EHR reporting to increase annual wellness visits (AWVs) (clinic level). Specific details about each intervention level are displayed in Table The Ohio pilot clinic implementation team chose Healthy Colon, Healthy Life as the patient-level EBI to implement in their clinic because it offered the potential to reach those patients who do not present in clinic at regular intervals . Componep = 0.003).At the provider level, the Ohio clinic chose to implement a provider education EBI that focused on follow-up of abnormal CRC screening tests, consistent with the clinic’s goal of 100% follow-up . ComponeSimilarly, an intervention kickoff event was held by UK researchers in November 2019 to present clinic staff details of their chosen EBIs, which included scheduled biannual expert speakers to provide detail on high-level, pertinent CRC screening topics for providers. The kickoff presentation concluded with an educational session to assist providers with motivating patients to complete CRC screening. However, in previous discussions, the clinic indicated that provider knowledge of screening modalities and guidelines was excellent and should not be the focus of any provider education EBI sessions. Citing patient adherence as a primary factor in low screening rates, the Kentucky clinic chose to implement a provider education EBI that focused on communication strategies providers could utilize to motivate both willing and reluctant patients to complete CRC screening. The education session was provided by UK researchers with expertise in CRC research and communication strategies.The pilot clinics in Kentucky and Ohio selected clinic-level EBIs they felt would increase CRC screening and were best suited to their needs. The Ohio clinic fine-tuned their use of eClinicalWorks (eCW) to identify patients in need of CRC screening and follow-up and created a written pathway to clinical care for CRC screening and follow-up of abnormal tests. The written pathway documented the combination of the chosen EBIs and how their respective components were assimilated into their existing clinic operations. It also specified the process of identifying patients eligible for screening, ensuring that patients received a CRC screening recommendation (either in-person or via mail), tracking completion of CRC screening in eCW and referral follow-up, monitoring progress, and making improvements, as needed.The Kentucky clinic also developed a CRC screening protocol to ensure implementation fidelity, and they decided to focus on increasing the number of patients who visit the clinic for annual wellness visits (AWV). In making this decision to leverage AWVs to increase CRC screening rates, the clinic pointed out the limited time that providers have to discuss CRC with patients during acute care visits, and also that AWVs are underutilized by patients. AWVs provide the best opportunity and time for providers to discuss CRC and other screenings with patients in detail and use motivational communication techniques to encourage patients to follow through and complete screening. To implement this strategy, the clinic decided on a two-pronged approach: (1) at the patient level, the clinic will send birthday card reminders to patients encouraging them to schedule AWVs; and (2) at the provider/clinic level, the clinic will set goals and provide incentives for providers and staff who increase their respective AWV numbers.The pilot clinics in both states chose to use the “inflatable colon”  to educaA similar event was held in Lewis County, Kentucky, in May 2019. The outreach event was held in conjunction with the local county extension office. The event included a presentation from a clinic provider on how to complete FIT and Cologuard tests, a healthy cooking demonstration, a testimonial from a community member about her personal colonoscopy experience, and guided tours of the inflatable colon. Forty-six community members attended the event. Additionally, to help reach patients who may not visit the clinic regularly, members of the Kentucky CAB in the pilot county decided to use mass media to deliver a message that CRC is “preventable, treatable, and beatable.” To that end, a billboard was collaboratively designed with input from Kentucky ACCSIS project team members, clinic staff, and university marketing staff. The billboard was erected in December 2019 in a high-visibility location along a main highway, and it included the aforementioned simple message; the logos of the university, project, and local clinic; a contact phone number for community members to inquire about screening; and a photo of a known practitioner from the clinic.Throughout the course of these multilevel program activities, it became apparent that supporting clinics throughout EBI implementation requires more resources than we initially anticipated. We originally planned on evaluating our MLI using a group randomized trial. Two counties per state would be randomized to an early intervention arm, and two counties would be randomized to a delayed intervention arm which would receive our MLI 12 months later. Counties in each study arm would experience a 12-month active intervention period and then be observed for sustainability of the MLI for either 12 or 24 months depending on the arm. However, based on our experience in the pilot year, the design was altered to introduce the intervention in a staggered fashion  will be the first to receive the intervention with the order of the other pairs (pairs 2 and 3) randomly determined. Study group  will also be randomly assigned within pairs 2 and 3. Thus, across the two states, we will have eight counties that will be randomized to study group and four whose group assignment will not be randomly determined. Figure Lastly, our pilot work indicated that a change in primary outcomes was necessary. Originally, our primary outcome was the county-level CRC screening rate which would be determined using telephone surveys conducted every 12 months in each county. However, most of the intervention activities occurred in the clinics, not in county-wide community settings, so assessing county-level CRC screening rates did not seem to reflect the effects of our partners’ greatest efforts. Given our study design, we would expect stronger effects on clinic-level rates than county-level rates which may demonstrate lagged effects due to the time required for the intervention to permeate from the clinic to the community. We also realized during the pilot period that in order to reach our target sample size of 100 participants per county, data collection required more time than anticipated and would span both the active intervention and sustainability period in the early intervention arm as well as the control and active intervention periods in the delayed intervention arm, which is not ideal for estimating an intervention effect. As a result, we changed our primary outcome to clinic-level CRC screening rates determined via EHR. Since exact screening dates are available in the EHR, we can easily determine the number of patients screened during the control, active intervention, and sustainability periods.In this report, we have described our experiences during year 1 of a 5-year project that will deliver an MLI to increase CRC screening and follow-up in underserved areas of the U.S., specifically Appalachian Kentucky and Appalachian Ohio. Preliminary tasks included selecting rural primary care sites in Appalachian counties and developing relationships to serve as a foundation for implementing the program. A theory-guided approach used by the investigators focused on careful assessment of community and clinic assets and barriers that would influence intervention implementation. The structure and management of the primary care clinics, the EHRs that they use, and community context were important drivers of progress in developing the project. The pilot phase proceeded as planned and provided important information on how to move forward with the full-scale trial.A strength of the process was that the investigators have extensive history of working in partnership with Appalachian communities , 23–33 aOne of the primary lessons learned was the extent of the challenges associated with the range of administrative structures of the primary care clinics. Although community structures were relatively uniform and characteristic of rural Appalachia, the primary care clinics had distinctly different structures. Several clinics are FQHCs and others are satellite primary care clinics of regional hospitals. The satellite primary care clinics are governed by the corporate policies of the regional hospitals and have varying degrees of decision-making authority. Additionally, as health care delivery in rural areas has been in flux in recent years , change Finally, differences in EHRs among the clinics also presented challenges. A total of eight different EHRs are currently used among the 12 participating clinics and the clinics engaging in year 1 each had different EHRs. Further, none of the clinic partners maintain on-site technical support for their EHR. As a result, while clinics can generate pre-defined reports, they frequently have no ability to customize those reports or change the systems to facilitate the intervention. Such changes reportedly require the use of consultants who function remotely from the clinic. Thus, efforts to obtain screening data or add intervention components through the clinic EHRs were problematic and required extensive interactions with our staff, including health IT experts from the universities. Due to privacy concerns and institutional health system policies, efforts to assist clinic and health system staff with this activity were not successful. Given that underuse of EHR functionality tends to be more prevalent in rural areas , researc.Although all counties and clinics participating in the project are in Appalachian Kentucky and Appalachian Ohio, there are important differences in each clinic and county that may affect CRC screening and follow-up of abnormal findings. Health care in the counties is provided by primary care practices and access to specialty care such as colonoscopy, surgery, and medical oncology is only available in large population centers. Thus, for most community residents, local access to CRC screening is limited to stool blood testing by FOBT, FIT, or Cologuard. We have plans to work with clinics to address these limitationsThe experience gained through working with the pilot clinics in year 1 of the project provided significant lessons, including recognition of variability among the primary care clinics and how they function, appreciation for the workload of the providers and clinic staff, and understanding of barriers to gaining access to EHR data for evaluation. The experience also led to recognition that the resources needed to implement the intervention with fidelity required revision of the study design. Collectively, this formative research has informed project activities and implementation strategies for years 2 through 5 of ACCSIS Appalachia to ultimately address the problem of CRC disparities in Appalachia.