Antimicrobial stewardship (AMS) has emerged as a systematic approach to optimize antimicrobial use and reduce antimicrobial resistance. To support the implementation of AMS programs, the World Health Organization developed a draft toolkit for health care facility AMS programs in low- and middle-income countries. A feasibility study was conducted in Bhutan, the Federated States of Micronesia, Malawi, and Nepal to obtain local input on toolkit content and implementation of AMS programs. This descriptive qualitative study included semi-structured interviews with national- and facility-level stakeholders. Respondents identified AMS as a priority and perceived the draft toolkit as a much-needed document to further AMS program implementation. Facilitators for implementing AMS included strong national and facility leadership and clinical staff engagement. Barriers included lack of human and financial resources, inadequate regulations for prescription antibiotic sales, and insufficient AMS training. Action items for AMS implementation included improved laboratory surveillance, establishment of a stepwise approach for implementation, and mechanisms for reporting and feedback. Recommendations to improve the AMS toolkit’s content included additional guidance on defining the responsibilities of the committees and how to prioritize AMS programming based on local context. The AMS toolkit was perceived to be an important asset as countries and health care facilities move forward to implement AMS programs. The misuse of antimicrobials is one of the main drivers for the development of antimicrobial resistance (AMR) ,2. AntimIn 2015, at the 68th World Health Assembly, AMR was recognized as a threat to public health. A global action plan, including an objective to optimize the use of antimicrobials, was endorsed during the Assembly. AMS programs aim not only to optimize antimicrobial use, but also to improve patient outcomes, decrease rates of AMR, and reduce health care costs ,10,11. WThe AMS toolkit is divided into six sections: (1) Structural Core Elements for AMS Implementation at the National Level; (2) Structural Core Elements for AMS Implementation at the Facility Level; (3) Planning AMS programs; (4) Performing AMS interventions; (5) Assessing AMS programs; (6) Education and Training. As part of the AMS toolkit’s development, a feasibility study was undertaken in Bhutan, the Federated States of Micronesia (FSM), Malawi, and Nepal. The study objectives were to (1) assess local knowledge and perceptions regarding AMR, AMS, and key concepts of the AMS toolkit; (2) identify barriers and facilitators for the implementation of AMS programs and policies; (3) identify recommendations to revise the AMS toolkit draft to ensure it meets the needs of a broad range of LMIC settings; (4) to provide recommendations to the countries on initiating and strengthening AMS programs. The study countries were selected based on geographic regions where AMR is a significant issue and where, to date, there are limited resources and AMS programs. These countries also represent different regions and varying healthcare systems .The following results are organized by national and health care facility core elements and health care facility-based interventions as described within the AMS toolkit. In addition, we have included data on actionable items and recommendations for the draft toolkit. A summary of demographic information is found in Key findings from this study are shown in The national core elements include (1) National Plan and Strategies; (2) Regulations and Guidelines; (3) Education and Training; (4) Supporting Technologies and Data.All study countries identified AMR as a growing threat and have drafted an AMR National Action Plan (NAP); however, the countries were at various levels in terms of NAP implementation. Relatively few respondents outside of the national government were aware of the NAP content.Remark 1.“I have heard of the National Plan, but it is not being implemented in our medical college….” Study participants aware of the NAP reported dedicated high-level national leadership in support of the NAP. In addition, some countries have obtained outside funding to support portions of the NAP. However, across the four countries, numerous barriers were identified that affected the implementation of NAP policies and programs. These barriers included the need for additional financial support and technical assistance, limited laboratory capacity, including infrastructure and expertise, and lack of technical expertise on AMR-specific issues. Remark 2.“…again, it involves a lot of resources. You need to see the sensitivity and (do) surveillance …to review sensitivities…A lot of budget is involved in that. So, funding is another part (in terms of) feasibility or not. And of course, the human side and human resources are also important....” Facilitators for AMR regulations and guidelines included the existence of drafted standard antibiotic prescribing guidelines, which have been developed in Bhutan, Malawi, and Nepal. In FSM, there is an antibiotic prescribing guideline that has been reviewed with national stakeholders and external technical expertise. FSM, Malawi, and Nepal are in the process of developing and implementing policies for prescription-only antibiotic sales. In Bhutan, prescription-only regulations are implemented and enforced. The key barriers identified included inadequate monitoring and evaluation at the national and regional levels for infection prevention and control (IPC) and AMS including adherence to guidelines, inadequate laboratory facilities to provide empiric diagnostic data and support, implementation of the AWaRe  classification of antibiotics, challenges with the supply chain of medications in hospital pharmacies, and lack of prescribers (physicians) in remote areas. Remark 3.“….I’m not claiming that just writing in law will be sufficient to really restrict prescriptions for selling…we have so many pharmacies which have been already selling without prescriptions… we need to really go and then take action against those who are selling the antibiotics…at the same time in the public sector we are promoting some antibiotics to be used by [non-physicians]…because neonatal mortality [is] very high…” Remark 4.“…If we don’t have the drugs [in the hospital], the doctor will prescribe and then the patient is obligated to buy in a pharmacy….” At the national level, there was strong support to enhance education and training in AMR/AMS for physicians, nurses, pharmacists, and laboratory staff. At the broader community level, AMS awareness, training, and education included public antibiotic information campaigns. Barriers included lack of dedicated financial support and limited training and technical expertise. Respondents also reported the need for more community advocacy and awareness of AMR.Remark 5.“…and we are also thinking to develop some sort of dramatizing…learning materials and publishing to the media (for the community). So that type of materials we’re planning to do. That requires a little bit budget so we are constrained with budget so we’re planning anyway…and also planning to do some training for health professionals…primary, community levels–upper-level health professionals also need to have training….” Bhutan, Malawi, and Nepal are recipients of Fleming Fund grants to expand microbiology laboratory capacity and strengthen surveillance systems . RespondRemark 6.“So, we are so glad that at least one of our key priorities for the NAP–AMR surveillance—we have a country grant to support improving lab capacity and surveillance. So, that’s a very good plus for us….” Health care facility core elements include (1) Leadership Commitment; (2) Accountability and Responsibilities; (3) Education and Training; (4) Monitoring and Surveillance; (5) Reporting and Feedback. A key component of facility-based AMS is dedicated support from facility leadership to encourage the development of AMS and IPC committees and implement programs. Facility leaders stated that the recommended AMS activities in the toolkit are feasible and necessary to decrease AMR. Barriers to leadership commitment included inadequate dedicated human and financial resources for AMS programs, and inadequate internal communication between administrators, management, and staff.Remark 7.“A successful stewardship program can only work when there is good collaboration between top management and middle-level management. Because middle-level management, they are the ones that are in touch with the staff on the ground there.” Remark 8.“Stressing the importance of leadership commitment is really important. Because nothing really happens without leadership commitment.” Respondents described active IPC committees, quality improvement teams, and drug and therapeutic committees. These committees are engaged in routine activities and provide important feedback and training to clinical personnel. Building on these committees, leaders and clinical staff were enthusiastic about future implementation of AMS committees and antibiotic prescribing guidelines. Remark 9.“…we don’t have an AMS team but the infection control committee they have nurse staff. They do regular monitoring of cultures of different areas of the theatre…they take a routine culture on a regular basis….” Barriers included physicians’ reluctance to change their prescribing practices, even with the available evidence-based guidelines, and provider-heavy workloads, which decreased interest in devoting time to an AMS committee. Remark 10.“We have an issue of shortages of staff…we also have issues of people wearing too many hats, so that is part of, I guess, it’s kind of like we’re not sure who’s going to take care of it, and wonder who which program is.” There was a high level of enthusiasm for expanding AMS education and training within health care facilities. Currently, some study facilities have an established education infrastructure  that can support additional AMR/AMS training. However, despite enthusiasm, time and resources were barriers. Many facilities lack space and available expertise to support trainings. At some sites, even IPC trainings are limited due to inadequate resources. In addition, some respondents emphasized the need for a ‘hands-on’ approach to support sustained knowledge. Remark 11.“Major barriers as of right now is lack of knowledge mainly. We have high staff turnover, so in the last three years there have been no new trainings. Almost 75% of the staff may not be aware of the IP (infection prevention) practices….” Remark 12.“So hands-on is a very, very important part of it. As compared to just reading and looking at the modules. But you have to apply, the application of that knowledge needs to be implemented as well. With the hands-on skills I think it will stick and will stay there longer, and be more useful to the people. In my opinion, I think two or more models of education is probably the best suitable for us in this setting.”Among microbiologists and laboratory staff, there was a strong desire for capacity building and international support for up-to-date equipment and supplies and development of AMR surveillance systems. However, in most health care facility sites, there was inadequate capacity to conduct point prevalence surveys and routine surveillance of susceptibility patterns, including health care facility-specific antibiogram data. Remark 13.“For the lab, our major challenges are both human and material resources…we have a very big challenge procuring laboratory microbiology supplies. Either maybe because of the budget or our major supplier—the central medical stores—they don’t have them in stock……we have the knowledge, but resources are not there….” In health care facilities with developed IPC committees, there are existing reporting and feedback structures in place that can be expanded to include AMS. However, in most facilities, there are inadequate structures for reporting these data to facility management and clinical staff. Study participants noted there was little communication between laboratory and clinical personnel, decreasing opportunities for information exchange about AMR patterns and impact of the use of specific antibiotics.Remark 14.“…We are very much lacking in reporting and feedback. We can do something but this is one area we really have to really have to think and discuss with regards to core elements…there are so many challenges, which we have to sit together and discuss and see how to move things forward.” Multiple action items were identified at both the national and facility level to move forward with implementation of the NAP and the WHO toolkit and development and implementation of AMS committees and other supporting programs and policies. Identification of sustainable funding and technical expertise in human, animal, and environmental health was essential across each of the core elements. Action items at the national and facility level are found in Box 1Establish terms of reference for National AMR technical working groups.Perform needs assessments of local laboratory capacity at the national and local levels.Update National Essential Medicine Lists or equivalent documents, including integration of the WHO AWaRe categories.Sensitize health care providers about AwaRE categories.Review, update, and implement national and district/state/regional antibiotic prescribing guidelines informed by available AMR surveillance data.Develop needed resources for health care facility leadership to ensure antibiotic prescribing guidelines are followed consistently across the country.Increase national antibiotic awareness campaigns.Develop or expand age-relevant education AMR/AMS programs in public school systems.Strengthen microbiology laboratory capacity and expand training to facility-based laboratory staff to support and encourage engagement in AMS and national surveillance.AMR—antimicrobial resistance; AMS—antimicrobial stewardship.Box 2Identify funding sources to support facility-level AMS.Sensitize facility leaders about the urgency of AMR as a health risk.Increase facility leaders’ awareness of National Action Plan (NAP) content, government roll out plans, and potential funding and resources to support facility-based AMS.Develop stepwise approaches to implement AMS considering facility capacities throughout the country.Standardize IPC committee roles and responsibilities.Identify dedicated leaders and champions within facilities who will take responsibility for establishing AMS committees and implement AMS programs. In many instances, individuals involved in IPC, QIT, and DTC committees can serve as key stakeholders in this process.Develop/adapt standard antibiotic prescribing guidelines informed by local AMR surveillance data patterns.Strengthen laboratory capacity to ensure annual output of aggregate antibiograms and support regular reporting to national laboratories for AMR surveillance.Establish mechanisms for reporting and feedback on the implementation of AMS interventions and adherence to antibiotic prescribing guidelines based on international consensus and local input.Integrate AMS training into existing CME programs and IPC training initiatives across all health disciplines.Develop interdisciplinary training programs to support increased understanding and communication between wards and departments.Develop training-of-trainer workshops on AMS and cascade training to other health care providers in the health care facilities.AMR—antimicrobial resistance; AMS—antimicrobial stewardship; CME—continuing medical education; DTC—drug and therapeutic committees; IPC—infection prevention and control; QIT—quality improvement teams.The WHO toolkit provides a detailed overview of evidence-based health care facility AMS interventions including (1) persuasive, educational, and feedback; (2) restrictive; (3) structural interventions. The toolkit also includes information on planning, implementing, and assessing AMS programs. Identified enablers to support AMS interventions included strong leadership support at the health care facility administration level, overall strong interest in education and training in IPC, AMR, and AMS among clinical staff, and perceptions among staff that AMS interventions decrease unnecessary antibiotic use. Barriers included inadequate local infectious disease, AMR and AMS expertise, and limited financial and human resources to implement interventions and conduct program monitoring and evaluation.Remark 15.“When it comes to interventions I think they are very much appropriate because many of these problems do exist in our…day-to-day practices. But we are not really assessing them…to the fullest extent about the interventions.” Study participants suggested recommendations on the improvement of content, organization, and presentation of materials, which were incorporated into the final version of the WHO AMS toolkit . ParticiRemark 16.“I think it’s a good start. It has more stuff, areas that need to be stringent, if we kind of have an impact on this issue. And I think it’s pretty comprehensive in a sense… But I think it should be an organic process, as we move along and identify issues, we address them and continue to make improvements.” The toolkit was universally well-received by policy makers, facility management, and clinical staff levels throughout the four study countries. Data were obtained from a diverse multinational and interdisciplinary group of stakeholders. Identification of possible enablers and barriers for toolkit implementation at the national and facility level supported revisions to ensure that the toolkit meets the needs of a broad range of LMIC settings. Each study country presented different contextual factors to consider regarding AMS implementation and use of the AMS toolkit. Varying factors included different health priorities at both the national and facility level, current status of nationalized universal health care plans, variances in public health funding, availability and use of antibiotics, and development and enforcement of prescription-only regulations. These factors must be considered on a country-by-country basis for stakeholder engagement and evaluating pathways to toolkit implementation.Key facilitators and enablers included strong leadership commitment at the national, local, and facility levels, increases in funding mechanisms to support development of surveillance systems within countries, and increased awareness of AMR. Key barriers to AMS implementation included limited human and financial resources, inadequate supporting technologies , and communication challenges between facility administration and staff, and between staff members. These barriers can be mitigated using a clear step-by-step approach, as indicated in the WHO AMS toolkit, tailored to specific country and facility contexts and needs. In addition, a multidisciplinary training and education approach can potentially strengthen AMS commitment and communication within health care facilities. Prior studies have described the core elements of AMS programs in LMIC settings, including the need to build laboratory capacity, enhance IPC, and establish surveillance systems of both infections and antibiotic use ,23,24,25Respondents reported the need for increased and consistent education and training. A first step towards strengthening educational initiatives includes understanding current clinical staff competencies and building tailored projects and programs that emphasize and develop knowledge and skills. Education must be ongoing, hands on, and practical, and include incentives and a broad range of resources .Respondents felt the toolkit provided important information on appropriate antibiotic use and consumption and the means to utilize less expensive and technologically based approaches appropriate to LMIC contexts. AMS committees were considered at the heart of effective facility-based stewardship. Therefore, these committees must be formed and members must receive regular training in antimicrobial prescribing practices and stewardship. The committee should be responsible for reviewing and auditing courses of therapy for specified antimicrobial agents and clinical conditions. There is also the need for an established and effective communication strategy between the AMS committee, leadership, and clinical staff.In terms of health care facility-based AMS, evidence-based antibiotic treatment guidelines were identified as a key component of AMS. Where possible, guidelines should be based on local antibiotic resistance patterns and availability and cost-effectiveness of agents. Day-to-day guidelines should be kept simple and include empiric antibiotic selection, definitive antibiotic selection, organism and disease states, intravenous to oral conversion, renal dosing, and duration of therapy. In conjunction with those guidelines, AMS programs are needed to reduce the overuse and overprescribing of antibiotics, the use of broad-spectrum antibiotics and dose combinations, and delayed prescribing.Health care facilities in LMIC need capacity building both in terms of human and technological resources to develop a formulary and auditing process, antibiotic prescribing documentation policies and procedures, and regulations regarding drug restrictions including use of the WHO AWaRe  classifications. Health care facility monitoring and surveillance capabilities need to be developed to support AMS initiatives including measures to monitor quality/quantity of antimicrobial use at the unit and facility-wide level, compliance with specific interventions, and identification of antibiotic susceptibility rates for locally significant pathogens. The feasibility study was conducted in only four countries with a sample size of 12 national leaders, 21 facility administrators, and 65 clinical staff. Only one country was selected from Africa and there were no LMIC from Latin America, the Caribbean, the Middle East, or Europe included. Despite the small sample size, purposeful sampling was undertaken to ensure that different regions of the study countries were included with a diverse group of national- and facility-based stakeholders. These data provide a general overview of barriers and facilitators for implementation of AMS programs and the AMS toolkit. As implementation of the toolkit moves forward, additional data from other countries will continue to contribute to future versions. In addition, the feasibility study was focused on health facilities which provide inpatient care. Respondents discussed the need for AMS within community health facilities and education for patients. Future research and development of community-based AMS training and interventions are needed to address the high consumption of antibiotics outside of inpatient facilities.The feasibility study was conducted from February 2019 to May 2019. The project was a partnership inclusive of a multinational and interdisciplinary team with expertise in AMR and AMS, infectious diseases, IPC, public health, nursing sciences, pharmacy, and social sciences. The study countries were selected by both WHO staff and the HFHS feasibility study team, based on geographic regions where AMR is a significant issue and where, to date, there are limited resources and AMS programs. These countries represent diverse contexts and challenges associated with the implementation of health care facility-based AMS programs. In addition, WHO and/or HFHS had worked with AMS leaders in the four selected countries, which facilitated rapid implementation of the feasibility study.The study population included national- and local-level policymakers, facility administrators, and clinical staff. Study health care facilities were identified by in-country investigators and coordinators, and represented various facilities  and diverse geographic regions within each country. All facilities included inpatient care and ranged in size from 36 to 850 beds. Participating clinical staff included physicians, nurses, pharmacists, microbiologists, and laboratory technicians.The study used a qualitative design based on key domains for program feasibility studies ,27. ThesIn each country, the project was undertaken after an initial meeting with in-country study investigators and local governmental, nongovernmental, and health care facility stakeholders. After completion of the study, dissemination stakeholder workshops were convened within each country. These workshops provided opportunity for local input on (1) the interpretation of the feasibility study data; (2) ways to address facilitators and barriers to implementation of the AMS toolkit and AMS programs and policies; (3) identification of actionable items to promote implementation. This input from each country is reflected in the final reports and subsequently, in this paper.Overall, 12 policy makers were recruited and interviewed, and 15 health care facilities were selected between the four countries. With the facilities, a total of 21 administrators, 20 physicians, 21 nurses, 11 pharmacists, and 13 laboratory personnel were interviewed . When thNational-level respondents were identified by in-country principal investigators and coordinators as well as recommendations from the WHO Country Offices and included individuals involved in the development of AMS NAP and other experts in AMR and AMS. At the facility level, administrators or managers were invited to participate in the study. Clinical staff selection criteria included individuals engaged in current or past IPC programs and/or those engaged in existing AMS committees. A range of staff were interviewed, including ward physicians and nurses, laboratory staff, and pharmacists. In each country, the international and local partners worked closely together to approach potential respondents to explain the purpose of the study and request their participation. At the policy and hospital administration level, all of those approached made themselves available for the interviews. At the clinical level, the study team requested interviews with representatives from nursing, medicine, pharmacy, and microbiology/laboratory staff . PotentiThree interview guides and demographic forms were developed specific to the population groups . Draft interview guides and demographic forms were provided to in-country investigators to review and revise to ensure they reflected local contexts. Interview guide items and probes focused on the research objectives, the toolkit core elements for health care facility-based AMS in LMIC, and the 6 program feasibility key domains. Demographic forms included items on current institutional affiliation , respondents’ education and employment , and engagement in AMR, AMS, and IPC programs at the health care facility or national levels see .Data collection was led by team members from the Henry Ford Health System in partnership with local staff. In Bhutan, additional data collection support was provided by investigators/infectious disease specialists from Christian Medical College, Vellore, India. Interviews were conducted in English, with interpretation to local language verbally as required. Interviews were audiotaped and transcribed. Transcribed data were entered into Ethnograph, version 6, a qualitative data management software. A data coding dictionary was developed based on the interview guides and emergent themes from team members’ field experiences and the transcribed text.After initial coding was completed, groups of code words were organized under common topics including the AMS core elements, the key domains for the feasibility study, and emergent themes. Searches were conducted within common themes, study country, and population . Search documents were saved and reviewed to identify key findings and recommendations within and across countries in terms of barriers and facilitators for health care facility-based AMS policies and programs, action items to strengthen AMS policies and programs including implementation of the AMS toolkit, and specific recommendations for the AMS toolkit’s content and organization. Illustrative text within the transcripts were identified to support the summary conclusions. Country-specific draft reports were sent to in-country investigators and other stakeholders for their review and input.The project was approved by ethical review boards in each country, the Henry Ford Health System Institutional Review Board , and the WHO Ethical Review Committee (Geneva) ]. All participants provided written informed consent.There was clear consensus that optimal implementation and use of the toolkit requires recognition of country-specific contexts. These include diagnostic challenges, laboratory capacity, and high burdens of infectious diseases. Health care workers responsible for prescribing antibiotics have a broad range of education, training, and experience. Development of antibiotic prescribing guidelines may often be limited by inadequate local data on disease burden and susceptibility patterns. Many LMIC have poorly regulated prescription-only policies or limited access to essential antibioticsDespite these challenges, the consensus among study respondents was that the toolkit will be an important asset as countries and health care facilities move forward to combat AMR and implement AMS programs. More information will be needed to address implementation strategies and many barriers need to be addressed to increase likelihood of successful implementation within the study countries and other LMIC. The road ahead must include commitment at the national and facility levels to prioritize AMR and develop sustainable national and local initiatives. The WHO toolkit provides a comprehensive review of core elements of AMS, strategies for intervention adaptation and implementation, and expansion of training and educational platforms. With growing global concerns regarding AMR, the WHO toolkit can provide practical guidance and support to LMIC worldwide .


The strawberry tree fruit and leaf are a rich source of minerals, easily digestible sugars, dietary fibers, vitamins  and many bioactive compounds of significant functional value. Due to their favorable chemical composition, fruits have recently become increasingly popular in consumption. The aim of this study was to determine the physical-chemical composition, content of bioactive compounds, and also the antioxidant capacity of the fruit and leaves of wild strawberry tree populations among the Adriatic coast in Croatia, as well as to investigate the influence of location on the content of specific bioactive compounds. According to the obtained results, both fruit and leaves are pronouncedly high in vitamin C content, the average value for fruits amounted to 224.21 mg/100 g FW, while that for leaves amounted to 138.08 mg/100 g FW. Additionally, significantly high values of total polyphenolic compounds were recorded both in fruits  and especially in leaves . Several pigments from different categories were determined in the fruit depending on fruit maturity, including: total anthocyanins, β-carotene and lycopene; while in leaves chlorophylls and carotenoids. Given the high content of different bioactive compounds high values of antioxidant capacity were determined . Location strongly influenced the physical-chemical composition and also the content of specialized metabolites; populations collected from southern areas  of the Adriatic coast tended to have higher amounts of vitamin C, total phenols, total anthocyanins and β-carotene. Arbutus unedo L., fam. Ericaceae) is a neglected fruit species in Croatia and its potential for cultivation and consumption has not been sufficiently utilized. Namely, the fruit and leaves of the strawberry tree are of significant functional importance and many studies have proven high contents of minerals, easily digestible sugars, dietary fibers, vitamins  and also many other bioactive compounds with significant antioxidant activity in strawberry fruit and leaves 50]. PigmFor the purposes of antioxidant capacity determination ethanolic extracts, obtained from total phenol determination, were used. Antioxidant capacity was determined spectrophotometrically using an ABTS radical cation ) at 734 nm according to method described in . As an ap = 1% was considered the statistical level of significance. In addition to the results, the tables show different letters that indicate significant statistical differences between the varied treatments at p ≤ 0.0001. The average deviation of the results from the mean value for each investigated parameter with the values of standard deviation is also presented.A sample of 20 fruits and 20 leaves were included in three repetitions . Laboratory analyses of chemical composition and bioactive compounds for each sample were performed in triplicate. According to a randomized block design (with three replicates), to determine the significance of differences within the examined factor ANOVA and Duncan’s multiple range tests were performed using statistical software . Mean vaBased on the obtained results, it can be concluded that both strawberry tree fruit and leaves are nutritionally important sources, since in analyzed plant material samples high contents of bioactive compounds, especially vitamin C and phenols, but also different plant pigments: β-carotene, anthocyanins and lycopene in fruits and chlorophylls in leaves were identified. Based on the valuable nutritional composition and high level of bioactive compounds, high values of antioxidant capacity, both for fruits and leaves were determined. In strawberry tree populations collected from southern areas  of the Adriatic coast, higher contents of important nutrients such as vitamin C, total phenols, anthocyanins and β-carotene were found. Additionally, populations collected on the Mediterranean islands off the southern Adriatic coast tended to accumulate more phytochemicals in fruits and leaves. Therefore, it can be concluded that location, but also micro-location significantly influenced the nutritional quality of the edible parts—fruits and leaves—of the strawberry tree. Additionally, further studies of individual bioactive compounds from categories of polyphenols and pigments by more precise analytical methods (HPLC) are necessary in order to provide more detailed information of the potential use and quality of strawberry tree fruit and leaves. According to the results, fruits and leaves of the strawberry tree’s natural populations show significant biological potential, rich nutritional composition, and thus, a functional value ofgreat importance for the human diet.


Community pharmacists (CPs) continue to have an important role in improving public health, however, advances in telehealth and digital technology mean that the methods by which they support their customers and patients are changing. The primary aim of this study was to identify which telehealth and digital technology tools are used by CPs for public health purposes and determine if these have a positive impact on public health outcomes. A systematic review was carried out using databases including PubMed and ScienceDirect, covering a time period from April 2005 until April 2020. The search criteria were the following: randomized controlled trials, published in English, investigating the delivery of public health services by community pharmacists using a telehealth or digital tool. Thirteen studies were included out of 719 initially identified. Nine studies detailed the use of telephone prompts or calls, one study detailed the use of a mobile health application, two studies detailed the use of a remote monitoring device, and one study detailed the use of photo-aging software. Public health topics that were addressed included vaccination uptake (n = 2), smoking cessation (n = 1), hypertension management (n = 2), and medication adherence and counseling (n = 8). More studies are needed to demonstrate whether or not the use of novel technology by CPs can improve public health.  At a time when the world is in the midst of a global pandemic , communiIn addition to the immediate public health concerns of the coronavirus, other important global health issues still remain, including both communicable  and noncommunicable diseases. According to the World Health Organization’s (WHO) 2016 global report on causes of deaths , six of Countries worldwide take a multipronged approach to addressing the abovementioned modifiable risk factors. Strategies employed have included increasing taxes on tobacco, sugar and alcohol, restricting marketing of these products, restricting access to these products through licensing laws, and raising public awareness about the harm that these products can cause ,8,9,10. Those working in the primary health sector, such as community pharmacists, form a key part of the public awareness strategy and, in addition, have an important role to play in treating, screening, and providing brief interventions to those who may be at risk of harm . This asRecent research has highlighted the continued role of pharmacy teams to improve public health and has discussed how digital technology could be used to enhance their role in this domain ,26. The Working to integrate telehealth and digital health concepts into healthcare interventions introduces challenges related to both health literacy and digital literacy. Health literacy describes, “… the degree to which individuals have the capacity to obtain, process, and understand basic health information and services needed to make appropriate health decisions” . In laymTherefore, we conducted a systematic review of the literature to understand how pharmacists have used telehealth and digital technologies to improve public health related outcomes, addressing NCDs as well as communicable diseases and medication-related topics. This systematic review was carried out following the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement .The review was carried out between March 2020 and May 2020 to identify any papers published between April 2005 and the end of April 2020. PubMed, Medline, Science Direct, Web of Science, and Scopus were searched for articles that reported outcomes associated with the use of telecommunication or digital communication technologies by pharmacists for the purposes of improving public health. Medical Subject Heading (MeSH) terms and keywords (KW) were identified and a search strategy was developed using the PICO  framework. MeSH terms and KWs for community pharmacy included pharmacy (MESH), pharmacies (MeSH), community pharmacy services (MeSH), and retail pharmacy (KW). MeSH terms and KWs for telecommunicaitons and digital communication technology included telephone (MeSH), social media (MeSH), mobile applications (MeSH), internet (MeSH), Facebook (KW), Twitter (KW), Instagram (KW), and YouTube (KW). MeSH terms and KWs for public health interventions and outcomes included public health (MeSH), smoking cessation (MeSH), weight-loss (MeSH), health (MeSH), sexual health (MeSH), and alcohol brief intervention (KW). The full PICO search criteria used on PubMed is available in For this systematic review, we included the following studies that were: (1) randomized controlled trials (RCTs); (2) full articles published in peer-reviewed journals; (3) included a telehealth or digital technology element used for either interaction between a community pharmacist and customer/patient, such as telephone, email, online discussion boards, social media, smartphone mobile application, or for patient use alone as part of a community pharmacy intervention; and (4) reported public health interventions and outcomes. The authors (P.C. and R.K.) identified studies’ titles that suggested that they met the inclusion criteria of the review. Further to the initial screening, abstracts and full articles were reviewed and removed if the primary objectives of the paper did not investigate the use of telehealth and digital technologies by community pharmacists for public health purposes and were not run as RCTs. A template was created in Excel, which both authors used to extract data including intervention variables , participant variables , outcomes variables . Face-to-face meetings were conducted between the authors to compare each other’s identified studies. The Jadad scale , which gUsing the criteria outlined, the initial search identified 719 potential papers. Duplicates were removed, and then papers were quickly screened by title. Articles not meeting the eligibility criteria were removed. This left 223 potential papers. Articles were, then, screened by abstract for inclusion criteria, and then the remaining articles were screened as full articles for inclusion. In total, 13 studies were included in this review. The search process is outlined in The main types of teledigital health interventions and outcomes found in this review were medication adherence and counseling, hypertension management, vaccination uptake, and smoking cessation. Most of the reviewed studies showed a positive impact of the use of telehealth and digital health tools, such as telephones and mobile health applications, on participants’ health outcomes.Two studies ,47, bothp < 0.001).One study, based in Australia, investigated how photo-aging software could be used by community pharmacists to promote smoking cessation . ParticiSeven studies investigated the impact of telehealth or digital interventions by community pharmacists to improve medication adherence ,55,57,58The USA studies investigated patient adherence to antidepressants  and mediThe Canadian study looked specifically at antibiotic counseling with patients in the intervention group being telephoned by the pharmacist on day three of their antibiotic therapy . The telp = 0.04) but did not affect patient quality of life or asthma control [The earlier of the Netherlands’ studies  investig control . The medication counseling study was carried out in the Netherlands  and was (p < 0.001)), 12 months ), and 18 months ) and the intervention was noted to have sustained effects for at least 24 months. The intervention group sustained significantly lower SBP and DBP versus control group for 24 months from baseline.Two studies , based in the USA, investigated the use of home blood pressure telemonitoring with community pharmacist management ,51. PatiThe Jadad tool (see Supplementary) indicated that while all of the reviewed studies were randomized, and included details about the method of randomization, only one study  was doubThis systematic review of RCTs evaluating the use of telehealth and digital technology by community pharmacists to improve public health has identified a number of studies that demonstrated the effective use of these tools. The telephone was found to be the most commonly used intervention tool. Of note, no studies used social media as an intervention tool. These findings match those of a previous review which highlighted that there was very little evidence of measurable health outcomes following the use of social media, in particular, by community pharmacists to improve public health . The use of telehealth and digital technology by community pharmacists is not a new research area ,34,61,62The lack of use of video conferencing technology is interesting; however, one study that did not meet the inclusion criteria for this review did show promise in the use of video conferencing software . Video cAnother point highlighted in this review was the limited use of “novel” technology by community pharmacists. A mobile health application was only used in one study , whereasThe public health topics for which pharmacists used telehealth or digital technology in studies in this review were limited in scope. Many topics focused on medication counseling and adherence which are more traditional roles of the community pharmacist ,56,57,58This review has highlighted the positive role that telehealth and digital technology can play in supporting community pharmacists to deliver public health services. As such, these tools need to continue to be integrated within community pharmacy services. These tools will be particularly useful for those patients and customers who are not able to visit community pharmacies in person. Given that the world is currently in the grips of a global pandemic, it is clear that offering community pharmacy users’ methods of communication other than only face-to-face would allow the profession to continue to have an impact on public health regardless of the ability to physically meet ,3. The uThe use of more novel telehealth and digital technology such as mobile health applications, social media, and video conferencing would benefit from further research. Anecdotal evidence exists suggesting that community pharmacists do use these tools for public health purposes; however, future studies need to address how these compare to usual care and telephone only interactions ,34,61.This study has demonstrated that if community pharmacy is to progress beyond the traditional face-to-face method of communication, then, more studies are needed that address the use of novel technology for a variety of public health topics. Those who commission public health services should be consulted to determine whether a framework for delivering community pharmacy public health services is needed. A blueprint could be created that community pharmacists could use to develop new services. This blueprint would detail how to engage particular demographics, which types of technology are best suited for addressing particular health topics and whether combining technology with face-to-face interaction is needed. Public awareness of the role of community pharmacy in public health also needs to be raised, as a recent study noted that the public would visit their GP or use an online resource to look for health advice rather than consulting a pharmacist . As suchThere were a number of limitations associated with this systematic review. Firstly, this review was interested only in RCTs. As a result, some other interesting studies that used alternative methods may have been missed. Secondly, each of the studies identified had different primary outcomes, therefore, direct comparison of the results was not possible. Finally, due to the everchanging nature of telehealth and digital technology, some novel tools used by community pharmacists for public health purposes may have been missed. This systematic review highlights how telehealth and digital technology is being used by community pharmacists to improve public health. We found that telephone calls and automated telephonic prompts were the most commonly used alternative method of communication to face-to-face discussions. There were limited studies on the use of more novel technology, with only one study using a mobile health app, one study using a remote health monitoring device, and no studies using social media. In addition, medication adherence was the main public health topic addressed in the studies, with other public health issues such as overweight and obesity, mental health, and sexual health not being investigated at all. Studies that evaluate the use of more novel technology and a broader range of public health topics are needed to understand if community pharmacists can enhance their role in these domains and meet the needs of a digitally literate customer base.


The ongoing SARS-CoV-2 pandemic has highlighted both the importance of One Health, i.e., the interactions and transmission of pathogens between animals and humans, and the potential power of gene-based vaccines, specifically nucleic acid vaccines. This review will highlight key aspects of the development of plasmid DNA Nucleic Acid (NA) vaccines, which have been licensed for several veterinary uses, and tested for a number of human diseases, and will explain how an understanding of their immunological and real-world attributes are important for their efficacy, and how they helped pave the way for mRNA vaccines. The review highlights how combining efforts for vaccine development for both animals and humans is crucial for advancing new technologies and for combatting emerging diseases. It has now been three decades since Felgner and colleagues published that nucleic acid constructs, i.e., both plasmid DNA and mRNA could be directly injected in vivo into mice resulting in the encoded protein made in situ . The potSignificant enthusiasm was raised by pre-clinical and clinical studies showing promising results for using plasmid DNA to prevent or treat diseases as varied as infectious diseases, cancer, autoimmune diseases, and allergy  . FurtherThe licensed veterinary plasmid DNA vaccines (as described in the next section) and those certain of the human clinical trials, in diseases as diverse as emerging pathogens to cancer ,16,17,18This review will describe the advances first in veterinary plasmid DNA vaccines, and will review the relevant aspects of human plasmid DNA vaccines and immunotherapies that have set the stage both for other gene-based vaccines such as mRNA and viral vectors, and for the hoped-for expanded development of plasmid DNA vaccines. All of this will be done in the increasingly important context of One Health, which is the interactions of animal and human health. Understanding the importance of the human and animal ecosystem for the emergence of pathogens and of the immune preventions and therapies for both humans and animals are crucial for anticipating, preventing, and responding to novel pathogens. Within the veterinary field, nucleic acid vaccines have promoted a revolution in the concept of vaccination, which has been previously dominated by inactivated or live vaccines. The improvement of immunogenicity and the easy efficient delivery of NA vaccines provide several rationales for NA vaccination of companion and production animals against classical and emerging veterinary virus diseases, as well as new zoonotic viruses. In general, plasmids seem cost-effective for veterinary use . The road to obtaining useful veterinary DNA vaccine candidates has been long but with many promising observations , and a vIn recent years, there seems to be an increased frequency of emerging virus outbreaks among humans. Most of these novel viruses are zoonotic RNA viruses with high mutation potential emerging from wild animals. This is a consequence of increased contact with wild animals and their viruses. This cross-species infection is either directly or after virus amplification and super-spreading events in flocks of humans of flocks of production animals. Examples of this are the 2003 Sars-CoV from bats and mammals , the 200The challenge of novel zoonotic virus infections in production animals is the transmission in herds of often thousands of animals with possible spread to many new farms. In addition, several new virus variants can arise by mutations during the spreading through many thousands of individual animals in farms. Such mutations could be adaptation mutations, increased infectivity, and/or pathogenicity in the animals, which may affect also humans, as seen, for example, with influenza  and SarsAvian influenza viruses from migrating birds can acquire the multiple basic amino acid mutations in the HA1-HA2 cleavage site causing a highly pathogenic avian influenza virus with high mortality in chickens and other susceptible bird species. In addition, reassortment of influenza virus during infection of swine, bird, and human may cause antigenic shifts creating new influenza viruses with pandemic potential. Until 2020, Denmark had about 1300 mink farms each with approximately 10,000–30,000 mink, a number that increases at the time of new puppies. Thus, Denmark was the largest mink producer in Europe with more than 17 million mink concentrated in specific geographic areas in a relatively small country of 5.8 million people. In June 2020, SARS-Cov-2 caused an unstoppable increase in the numbers of infected mink farms in Denmark to more than 288 in the fall of 2020 causing a significant parallel increase in human infections with mink-variant viruses . To imprSimilar concerns may be true during a new human influenza pandemic where exchange of influenza viruses between humans and flocks of production pigs and chickens may develop into multiple uncontrollable virus reservoirs of human concern. A recent example is the triple reassortant H1N1pdm09, composed of genes from three known swine viruses, which was detected in Mexico and the USA. This new virus variant rapidly spread among humans during the 2009 pandemic and was later transmitted from humans into pig populations worldwide .The spillover from infected production animals to humans and back and into wild fauna may contribute to an uncontrollable spread of zoonotic pathogenic viruses and could establish new virus reservoirs among new animal species. Thus, increased and improved broadly reacting NA vaccinations of animals may be useful to protect them from zoonotic viruses and benefit production animal health. This would also protect humans from an occupational risk and reduce the risk to public health. “To protect the humans, vaccinate the animals”.Zoonotic viruses may cause disease in the animals and/or cause a negative impact on animal production. Swine influenza (SIV) causes reproductive problems, weight loss, and aggravation of secondary infections in pigs, and SIV is a leading infection affecting the majority of herds in modern swine production .Current circulating endemic swine influenza virus strains of, e.g., H1(av)N1, H1N1pdm09, H1(av)N2, H3(hu)N2(sw) may differ slightly from the similar human influenza virus variants . HoweverEscherichia coli, and the induction of a long-lasting Th1-biased immune response with broad-reacting antibodies and strong cellular immunity, mimicking live attenuated vaccines without the same biohazards. Since the emergence of the NA vaccination platform in the early 1990s , DNA vacThe intracellular production of antigens may explain the efficient induction of protective cell-mediated immunity (CMI) also in primates; however, the lower antibody immunogenicity of plasmid DNA vaccines in primates  have sloIn some cases, DNA vaccines have failed to produce measurable antibodies but with protection of the host which may represent a limitation in measuring protective antibodies or demonstrate a major role for CMI ,44. EffoThe recent improvement in gene design, optimized codon-change in the vaccine genes and improved plasmid vectors ,72, or tMany veterinary DNA vaccine candidates have been evaluated over the years leading to valuable observations and three licensed vaccines . Cattle: These include vaccine candidates against viral diseases of bovines where the use of DNA vaccines encoding the VP4 protein of bovine rotavirus (BRV) was first found effective in stimulating a Th1-like immune response . In 1999Small Ruminants: DNA vaccine candidates were developed for preventing viral diseases of small ruminants. Thus, protection was obtained against diseases like caprine arthritis-encephalitis (CAE) , foot anSwine: In swine, plasmid DNA vaccines could protect against classical swine fever (CSF), which causes significant losses to the pig industry ,52. ImmuDogs: For dogs the important viral diseases are rabies, canine distemper, and parvoviral infections, and many groups have studied the use of DNA vaccines. For example, DNA vaccines encoding the rabies virus glycoprotein (G) induced strong and durable virus-neutralizing antibody titers in dogs ,37. A biHorses: In horses DNA vaccine constructs encoding the envelope proteins (prM and E) have prevented the West Nile virus (WNV) infection , and as Poultry: In poultry, DNA vaccine candidates have been studied against major viral infections like avian influenza, using the haemagglutinin (HA) gene ,42. SimiIn various animal species the plasmid DNA vaccines have worked very well, and plasmid DNA vaccines have been approved and licensed for veterinary use. Three plasmid DNA vaccines for prevention of infectious diseases have received approval, including two for fish and one for horses. These included two for fish  : one forGiven the strong effect in animals, the marked advantages of NA vaccines, and the increase in new virus threats for animals and in cases of zoonotic viruses for humans, the development and usage of more preventive NA vaccines in animals, especially in large flocks of production animals, is important.The purpose of vaccinations is twofold: to protect the individual and to protect the flock. The individual argument in humans is influenced by some individual-specific risk factors relevant for the different virus diseases, e.g., chronic lung disease as a risk factor for Covid-19 infection, which affect the risk/benefit ratio for any disease and its prophylactic vaccine. Protection of a flock or a population may be determined by certain health measures and political strategies. For production animals, protection of the herd seems more relevant than the individual animal. In addition, protection by vaccines against infectious diseases may lower the general use of antibiotics and improve production in general, e.g., decrease the need to slaughter chickens during influenza outbreaks . These fFor these reasons, two different designs of a broad protective influenza NA vaccine candidate may be considered. The version of a broad influenza DNA vaccine for production pigs may induce mostly antibodies (against HA and/or NA) to prevent infection and spread by shedding of influenza virus. In contrast, the version for humans should also contain genes for conserved internal virus proteins for additional CMI induction (against M and/or NP) to protect humans from disease and death, as well ,86,87, aFor DNA vaccines, there is a dose–response correlation, and in some cases a higher DNA dose is needed for obtaining cross-protection against variant viruses . In addiEfficacy of DNA Vaccines in Target Animals vs. Animal Models: The development and testing for efficacy and relevant dose of NA vaccines is much easier using exclusively the actual target animal. Although the best animal model for human influenza and thus influenza vaccine candidates are ferrets it may not be the best model for a DNA vaccine since DNA works very well in ferrets but perhaps suboptimally in primates like humans. In contrast, the best model for influenza NA vaccines for pigs may be pigs. Plasmid DNA vaccines work extremely well in pigs and only one vaccination of a very low DNA dose can protect pigs from influenza challenge ,87,88. MDelivery Modalities: The delivery of a plasmid DNA vaccine and vaccine organ may be crucial for its immunogenicity, optimal dose, schedule, and effect. Whereas intradermal injection followed by electroporation was earlier shown to be superior to just needle injection, especially in case of a suboptimal working DNA vaccine ,90,91,92In addition, alternative delivery methods like suppositories , mucosalE. coli is fast and simple, this likely requires an in-house GMP DNA vaccine production facility of large capacity with QA and filling, since at present, most Clinical Manufacturing Organization prices exceed this. However, effective, safe, and economically viable nucleic acid vaccines for animal use are indeed possible and needed.The vaccine cost, including the actual time per animal needed to perform the immunization, is among the most crucial parameters for determining the use of a safe and efficient NA vaccine in production animals. Depending on the disease and country, a vaccine for production animals should probably cost less than one dollar. Although plasmid production in A number of the early targets for DNA vaccines are focused on diseases for which traditional approaches have not yielded successful vaccines, such as HIV and malaria, but also cancer in the form of immunotherapeutic vaccines as treatments. The ability to generate Cytotoxic T Lymphocyte responses (CTL) by DNA vaccines was a significant reason for the excitement because CTL are thought to be important for controlling diseases by pathogens that invade cells  and cancer. CTL responses cannot prevent initial infection, since CTLs can only kill virally infected cells, but not directly viruses, but this activity is important in many viral infections for limiting disease even if CTLs cannot provide “sterilizing immunity” against initial infection.  Importantly for viral infections, CTLs can target epitopes from proteins that are more highly conserved such as viral enzymes or other internal proteins, which are less likely to mutate (since they must conserve their function or structure) than are surface proteins. Excellent examples of this are the diversity and mutations seen for influenza hemagglutinin and HIV Env, compared to, for example, influenza Nucleoprotein or HIV Gag. This makes the role of CTL potentially of great importance for an immune response that can be effective against different strains of a virus, such as those occurring for influenza with the annual shifts and periodic drifts of the strains .Results of Select Illustrative Human Clinical Trials of DNA Vaccines: Relevance of Veterinary Successes: The human clinical trials of DNA vaccines for many different targets, and by having been in thousands of people ,11, haveThus, the licensure of a plasmid DNA vaccine for West Nile virus for horses  and the While plasmid DNA vaccines generated immune responses in a variety of vaccine trials, the challenge for demonstrating human efficacy appeared to be in part due to the limitation of needing up to three doses to generate sufficient neutralizing antibody. In the case of vaccines where CTLs were thought to be important such as for HIV, malaria, and Tb, at least part of the challenge is that the necessary protective immune responses, and any correlates for cellular responses, are not really known and the diseases themselves have additional challenges compared to, e.g., WNV, in that HIV integrates, and for Tb, as the mycobacterium can infect cells latently. Thus, the problem appears to be a combination of lack of potency for the DNA vaccines combined with the difficulty of knowing exactly what immune responses are needed and the difficulty of diseases for which most of the clinical trials have been done.Potency of DNA vaccines as Priming for Heterologous Prime-Boost Regimens: One of the most interesting observations has been that plasmid DNA vaccines work extremely well as a priming agent for heterologous prime-boosting protocols in which plasmid DNA encoding an antigen is given initially, with a subsequent boost being a different form of the antigen, whether a recombinant protein, or even a viral vector encoding the same antigen (reviewed in ). This rOne obvious advantage of NA vaccines, whether plasmid DNA or mRNA, is the speed with which they can be designed and redesigned , constructed and manufactured. This is because either can be easily made from knowledge of the gene sequence of the pathogen without having to deal with the actual pathogen itself. Of course, understanding aspects of the antigenicity is important, such as the approach for SARS-CoV-2 vaccines where the pre-fusion form of the spike protein is thought to be key . The manTwo key aspects stand out for nucleic acid vaccines in the context of One Health: vaccines for infectious diseases whose spread involves both animal and human hosts (such as the West Nile virus discussed above) and vaccines for diseases which may arise as new species in animals which then cross into humans, as apparently happened with SARS-CoV-2. For the former, scientific progress will advance much more rapidly with more collaborations between vaccinologists who focus on animal and human vaccines. There are many areas of overlap in addition to the virus-specific aspects of immunity. For example, given the size of pigs and cattle, the lessons learned for potency will possibly be more synergistic than trying to predict from murine studies how well a vaccine will work in humans. The usage of biolistics devices with delivery to pig skin is another example where there may be relevance for human i.d. delivery and vice versa. Additionally, of course, a number of pathogens are specifically shared or are very similar between humans and animals, whether viruses such as influenza, parasites, or mycobacteria. The other urgent One Health aspect that drives the development of rapid-deployment technologies such as NA vaccines are the emerging diseases that cross from animal species to humans (and then back in the other direction as has been seen with SARS-CoV-2 in mink farms). Of course, development of platform technologies such as nucleic acid vaccines is only half of the equation, as the ability to respond quickly to any new pathogen will also require expanded surveillance efforts and the infrastructure for massive vaccine delivery campaigns both for humans and animals. It is clear that Nucleic Acid vaccines are a platform technology for new emergency vaccines, both in terms of design and manufacture. While for humans this has only been proven through Phase 3 efficacy trials for mRNA vaccines, the speed and early clinical trial results for DNA vaccines What must continue to be studied as these technologies are used more and more, are the One Health aspects of disease emergence, containment, and immunization, remembering that humans are but one part of the ecosystem. Large data sets are being generated now for NA vaccines’ safety, efficacy and effectiveness, optimal doses, vaccination scheme, prime-boost use, and possible correlates of protection against sars-Cov-2/Covid-19 infection and disease. In addition, the WHO has developed, with the input of regulators worldwide, guidelines for DNA vaccines . All the


Infants admitted to neonatal intensive care units (NICU) require carefully designed risk-adjusted management encompassing a broad spectrum of neonatal subgroups. Key components of an optimal neuroprotective healing NICU environment are presented to support consistent quality of care delivery across NICU settings and levels of care. This article presents a perspective on the role of neonatal therapists—occupational therapists, physical therapists, and speech–language pathologists—in the provision of elemental risk-adjusted neuroprotective care services. In alignment with professional organization competency recommendations from these disciplines, a broad overview of neonatal therapy services is described. Recognizing the staffing budget as one of the more difficult challenges hospital department leaders face, the authors present a formula-based approach to address staff allocations for neonatal therapists working in NICU settings. The article has been reviewed and endorsed by the National Association of Neonatal Therapists, National Association of Neonatal Nurses, and the National Perinatal Association. Infants requiring neonatal intensive care are a particularly vulnerable population secondary to prematurity and/or significant medical conditions. Risk-adjusted care considers the broad spectrum of medical, neurologic, developmental, and psychosocial outcomes experienced by neonatal subgroups . The effNeonatal therapy encompasses the art and science of integrating typical development of the infant and family into the environment of the NICU –16. IncoThe Universe of Developmental Care (UDC) Model provides a useful framework to underscore the value of including neonatal therapy as an elemental component of quality service delivery in the NICU . RecogniDefining the necessary components required to provide risk-adjusted age-appropriate neonatal care for complex and critically ill infants will facilitate implementation of standardized care practices consistent with the central tenets of developmental care philosophy and the demonstrable effect on perinatal outcomes. The American Occupational Therapy Association (AOTA), American Physical Therapy Association (APTA), American Speech–Language–Hearing Association (ASHA) define the NICU as a specialized practice setting due to the medical and developmental fragility of the infants, the vulnerable emotional status of the families, and the intricacy of medical, cultural, and social factors that impact the family-infant unit –23, 40. Level I well newborn nurseries (WNNs) provide basic routine care including state-mandated newborn assessment, management of minor medical problems, and screenings and medical stabilization to prepare for transport when needed for low risk, full-term, and late-preterm infants born 35–37 weeks gestational age.Level II special care nurseries (SCN) provide intermediate level care for moderately preterm infants born at greater than or equal to 32 weeks gestational age with birth weight greater than 1500 g or management of full-term infants requiring careful postnatal monitoring, IV antibiotics, or short-term respiratory support.Level III or IV NICUs provide a full range of subspecialty staffing with advanced diagnostic imaging and respiratory support equipment adequate to provide the highest-level intensive care services for critically ill infants of all viable gestational ages. Level IV NICUs additionally provide requisite surgical subspecialties for surgical repair of complex conditions as well as a full range capacity of respiratory support including extracorporeal mechanical oxygenation .In accordance with the American Academy of Pediatrics (AAP), NTs contribute to the provision of care in each of the four levels of nurseries as defined below :Level I As essential members of the SCNs and NICU teams, NTs provide family-centered neuroprotective care services to infants at increased risk for developmental compromise and their families. Infants with lower medical acuity admitted to the NBN (WNN) or Level II SCN who benefit from neonatal therapy services include—but are not limited to—neonates born at 32 weeks gestation or older, neonates who have been exposed prenatally to recreational or prescription drugs, infants with birth injuries/anomalies, late preterm infants, infants born to young teen parents or mothers with inadequate prenatal care. Per AAP recommendations, all infants with higher medical acuity at increased risk for developmental compromise admitted to Level III or IV NICUs merit support through comprehensive services by NTs . NeonataThe provision of therapy services in the NICU requires specialized orientation, training, continuing education, and mentoring. Discipline-specific competencies exist that support the presence of all three disciplines in the NICU to best address the unique needs of the infants and their families in this complex treatment environment. While each NT  brings neuroprotective developmental support tasks that fall specifically within the scope of practice of their discipline, there are foundational neonatal therapy service skills included within the scope of practice across all three disciplines of OT, PT, and SLP. While the presence of more than one neonatal therapy discipline may offer the best practice, staffing patterns may vary among hospitals based on a combination of availability of therapy staff members who possess the requisite advanced discipline-specific competencies to provide the specialized services required in the NICU practice setting and service needs. The competencies common to all three discipline’s scope of practice are optimally provided in a manner that reflects the discipline-specific perspective of each professional while avoiding redundant overlap of services.©, which highlights the ‘shared’ common ground of all three disciplines but is not intended to represent the unique aspects of service inherent to each individual discipline [Intervention requires continuous assessment.Assessment includes pre/during/postintervention.Assessment can be formal and/or informal and includes observational assessment.The development of subsystems is connected one to another.Medical status, diagnoses, age, and medications affect assessment/intervention.To clarify differences and commonalities among the scopes of practice of the therapy disciplines providing neonatal therapy services, OT, PT, and SLP benefit from their state licensure scope of practice guidelines as well as advanced neonatal therapy competency recommendations endorsed by the discipline-specific professional organizations . In addition, the National Association of Neonatal Therapists (NANT) empaneled the NANT Professional Collaborative (NPC) to identify the common knowledge, skills, and abilities needed for a NT to practice safely and competently in the NICU regardless of his or her professional affiliation. The NPC is a multidisciplinary professional task force of NTs  established to advise and assist in defining, creating and reviewing emerging standards, practices, and guidelines. The NPC has defined a Neonatal Therapy Core Scope of Practicescipline . It is cscipline , 42. The© additionally provides foundational definitions of neonatal therapy and subsequent services required to provide risk-adjusted age-appropriate neonatal care for medically fragile infants and families [The Neonatal Therapy Core Scope of Practicefamilies . The NT families .In alignment with professional organizations , including the Neonatal Therapy National Certification Board (NTNCB), and in attending to the AAP leveling of neonatal care, the following recommendations are made for neonatal staffing –59, 61.Neonatal Abstinence Syndrome resulting from prenatal exposure to recreational or prescription drugs.Birth injuries or structural anomalies.Neuromotor or orthopedic diagnoses.Genetic disorders, fetal distress, or neurodevelopmental immaturity affecting safe transition to oral feeding.For Level I WNNs, therapists may serve a consultative role. For Level I units in hospitals with Levels II–IV NICUs, a process of access to NTs should be established. For hospitals without a NICU, NTs may offer consultative work to the WNN as part of an outside institution to provide in-person consultation, and/or direct patient care as part of a service arrangement between entities. For remote consultation to the Level I WNN, the process should be a formal and established system for consultative input via phone/telemedicine with specialized NT(s) from a level III or IV NICU. The process should establish how to access a trained NT  who can be available for remote and/or in-person consultation (preferred) within a timely manner based on acuity to meet the infant and family needs. Consulting services may vary by discipline based on diagnosis or presenting clinical problems, scope of practice, and state regulations depending on the practice patterns of the consulting institution. Examples of presenting problems/diagnoses appropriate for referral for neonatal therapy services in the Level I WNN may include—but are not limited to:The developmental care needs of infants admitted for intermediate level care to a Level II SCN vary according to degree of prematurity and medical acuity. Serving infants born as young as 32 weeks gestational age, as well as infants requiring short-term respiratory support or recovering from intrauterine drug exposure, the SCN merits careful attention to the delivery of consistent high-quality developmental care. Service delivery models may vary according to number of beds and patient acuity level, however, ensuring availability of neonatal therapy expertize is important in this setting to optimize neurodevelopmental outcomes and prevent iatrogenic complications. For smaller SCNs located in a community hospital that do not have in-house access to neonatal therapy expertize, establishing a formal process for providing consulting services by qualified NTs as described above may be considered. For SCNs that serve as a step-down unit for higher acuity level NICUs in the same facility, staffing should be considered as part of the FTE calculation as stated below. A process to ensure consistent transfer of neuroprotective care principles between units should be implemented.Historically neonatal therapy services in NICU Levels III and IV evolved through application of a multidisciplinary rehabilitative/consultative model of care approach. However, the classic rehabilitative/consultative model does not adequately address the complex developmental needs of the preterm or medically fragile neonate. Similar to the benefits documented for primary care nursing staffing patterns, current best practice for intensive care neonatal therapy service delivery emphasizes an expanded integrated model , 44. FocNeonatal Therapists working in Levels III–IV NICU settings under an integrated model should have consistent dedicated days/time in the NICU to assess and address age-appropriate patient and family needs, from any viable gestational age through discharge. The AAP Guidelines for Perinatal Care (8th edition) recommends at least one OT or PT with neonatal expertize and at least one individual skilled in evaluation and management of feeding and swallowing disorders in Level III/IV NICUs , p. 58. All vulnerable survivors of a complicated perinatal course designated as ‘high risk’ for medical, neurologic, developmental, or psychosocial outcomes following discharge from Levels II to IV care units merit follow-up care to mitigate adverse outcomes associated with their physiologic compromise and to track, record, and analyze medical and neurodevelopmental outcomes. The AAP Guidelines for Perinatal Care, 8th edition, recommends that follow-up services are an ‘essential’ component of Levels III and IV NICU services . ServiceThe staffing budget is one of the most difficult challenges hospital department leaders face in their work as labor consumes the majority of an organization’s financial resources , p. 25. Neonatal care has become technically advanced and requires a sufficient supply of specially trained professionals . The risEarly therapy services in the NICU that are continued routinely until NICU discharge optimizes outcomes , 50. BorNursing and NTs alike require highly specialized knowledge for work in the labor-intensive NICU, as newborns are totally dependent and require complex technologic and personnel support for even routine functions such as breathing, thermoregulation, and feeding . InterdiThe preponderance of evidence establishing the relationship between staffing and quality patient outcomes is currently recognized by many. However, there is marked variability across units and states in staffing of NT and limited resources to inform managers and administrators on how to allocate NT efficiently. Staffing model complexities include variables such as unit function variances and organization-related variances to name a few .Patient experience and NICU-related outcomes are associated with both direct and indirect therapy services of NTs. Indirect services are essential to the preventative/habilitative model of care and are often overlooked in NT staffing as therapists are most typically staffed using a rehabilitative lens. Examples of NT services that contribute to infant neurodevelopmental outcomes, staff support, and psychosocial support of families include, staff/family education regarding positioning and handling, management of environmental factors, participation in unit-wide program development, and preparation of the family for discharge and follow-up services. Given outcomes related to neuroprotective care utilizing a preventative/habilitative model, NT staffing should allow for a minimum of 25% nonbillable time for the continuous quality improvement activities that address these infants’ unique and complex issues.Although staffing calculations that include both (1) worked hour per unit of service (WHPUOS) and (2) hours per patient day (HPPD) are commonly utilized for hospital staffing of rehabilitation departments, the preventive/habilitative model of care of the NICU necessitates a different formula for staffing NTs. Staffing must include allotment for direct and indirect services (billable and nonbillable care) to include collaborative care with MD/RN/RT/parents, planning, staff support/education/mentoring, bedside rounds, discharge planning, parent education/support, and NBN consultation. Table For hospitals where services are needed that include research, weekend coverage, higher acuity, or increased NT presence, an adjustment to the formula in Step 2 is recommended . This formula, when used to determine adequate staffing of NTs, supports the provision of quality care that facilitates optimal development and support of infants and their families in the NICU.The clinical and professional reasoning that NTs bring to the NICU is based on the understanding of medical factors, human development, and the interplay between the environment and the sensory system. The AAP Committee on Fetus and Newborn and American College of Obstetricians and Gynecologists Committee on Obstetric Practice 2017 Perinatal Guidelines (AAP and ACOG), eighth edition, recommends that services of at least one OT or PT with neonatal expertize in addition to a professional with neonatal feeding expertize be available in Levels III and IV NICUs [© of practice of NTs [The AOTA, APTA, and ASHA organizations have developed discipline-specific NICU competency resources to support the professional development of their membership. In 2018, the AOTA Practice Council reauthorized a description of the role of OTs in the NICU , 22. In e of NTs , 42. Dese of NTs . LicenseUpon completion of prerequisite competency requirements and successfully passing a written examination, the NTNCB awards the specialty designation of CNT to duly licensed OT, PT, or SLP who have demonstrated evidence that they have attained the specialized professional qualifications needed to provide competent neonatal therapeutic services in the NICU. The CNT designation applies only to NTs who maintain current licensure/credentialing or permission to practice as a therapist under the jurisdiction of the respective licensing boards for OT, PT, and SLP. The NTNCB neonatal certification process is endorsed by the NANT . The preA rapidly expanding body of evidence supports the improved scope of outcomes for all involved stakeholders when a comprehensive neuroprotective developmental care model is applied in the NICU setting. Recommendations include neonatal therapy expertize as essential for optimal delivery of an integrated family-centered neuroprotective care model. Provision of therapy services in the NICU is an advanced area of practice for OT, PT, and SLP that requires specialized knowledge and experience to function independently as an expert NT in the NICU. Recommended preparation resources are available to assist licensed professionals to acquire the discipline-specific expertize needed to meet practice standards in this acute medical practice setting. It is incumbent on the individual therapist to work collaboratively within a transdisciplinary service delivery model to maximize the effectiveness of services of all care providers while simultaneously working to gain the requisite discipline-specific advanced training needed to fulfill the unique contributions the respective disciplines offer in this complex acute care setting.