Diabetes self-management education and support can improve outcomes in people with diabetes. Providing health interventions via digital modes of delivery can extend the reach of programs delivered through traditional means. The web-based version of the Diabetes Education and Self-Management for Ongoing and Newly Diagnosed (MyDESMOND) is a digital diabetes education and support program for people with type 2 diabetes. The program was originally developed in the United Kingdom and is evidence-based, grounded in behavioral theory, and designed through a rigorous process of intervention mapping. As such, MyDESMOND was considered an ideal candidate for adaptation to the Australian setting. Program content and the digital platform were modified to suit the local context to increase the likelihood that the revised version of MyDESMOND will deliver similar outcomes to the original program. The aim of this paper is to describe the systematic processes undertaken to adapt the digital MyDESMOND diabetes education and support program for people with type 2 diabetes to the Australian setting. The adaptation involved a multidisciplinary group with a diverse range of skills and expertise—a governance structure was established, a skilled project team was appointed, and stakeholder engagement was strategically planned. The adaptation of the program content included modifications to the clinical recommendations, the inclusion of local resources, practical changes, and revisions to optimize readability. A 2-stage independent review of the modified content was enacted. Digital adaptations were informed by relevant standards, local legislative requirements, and considerations of data sovereignty. The digital platform was extensively tested before deployment to the production setting. MyDESMOND is the first evidence-based digital diabetes education and support program for Australians with type 2 diabetes. This paper provides a road map for the adaptation of digital health interventions to new contexts. Diabetes is a chronic condition defined by high plasma glucose levels that can lead to an increased risk of serious health complications and premature mortality . The incA high proportion of people with T2DM experience long-term complications, including kidney disease, retinopathy, amputations, heart attacks, and stroke, associated with reduced life expectancy . Optimal1c (HbA1c) levels [Diabetes self-management education and support (DSMES) programs empower people with diabetes to be actively involved in their own self-care by supporting informed decision-making and the adoption and maintenance of self-care strategies and behaviors . DSMES h) levels  and decr) levels , as well) levels . One suc) levels ,13. This) levels . DESMOND) levels .Despite the utility and cost-effectiveness of DSMES programs such as DESMOND, face-to-face programs may not be accessible or suitable for all people with diabetes. In addition, particularly during COVID-19, web-based delivery as an option has been very attractive ,17. Comm2 [In Australia in particular, access to programs can be affected by geographic remoteness, which affects the availability of health resources, accessibility, and the financial viability of facilitating programs and services in remote areas. Australia’s population is dispersed over almost 7.7 million km2 . To demo2 , with ag2 .Web-based delivery of DSMES offers an opportunity to provide comprehensive coverage of education and support to otherwise difficult to reach populations. Such programs can mitigate many of the barriers associated with attendance to face-to-face programs, particularly in the Australian context where the population is dispersed over a vast geographical area.ask the expert; integration with commercially available activity trackers; a decision maker ; and tracking of HbA1c, blood pressure, cholesterol, weight, and waist measurements.Participation in DSMES via web-based modes of delivery has increased significantly in recent years . Such prThe aim of this paper is to describe the systematic process undertaken to adapt MyDESMOND to the Australian setting in readiness for consumer pilot-testing. This systematic approach considered the relevant social, cultural, environmental, and policy-level factors of influence to develop the first web-based DSMES program for people with T2DM in Australia. The description of this work provides a road map for others to follow when adapting comprehensive digital self-management programs to local contexts to ensure that such programs meet the needs and priorities of all stakeholders  and are fit for purpose for implementation in a new setting.request-for-quote process, the Australian Government Department of Health (hereon referred to as the Department) commissioned Diabetes WA, National Diabetes Services Scheme (NDSS) Agent for WA, to adapt, pilot, evaluate, and implement MyDESMOND in the Australian setting. The process undertaken to adapt the program to the Australian context is the focus of this paper.In December 2018, following a The adaptation of MyDESMOND to the Australian context involved three key areas of focus: (1) establishment of the project team and carefully planned engagement with stakeholders, (2) content adaptation, and (3) digital adaptation. These areas of focus are summarized in the project road map presented in The first stage of the project to adapt MyDESMOND involved the establishment of a governance structure, appointment of the project team, and planning for stakeholder engagement. An organizational chart portraying the roles and responsibilities of the governing bodies, project management team, and key stakeholders is presented in A steering committee of senior stakeholders was established to provide overall governance of the project, including the Chief Executives from Diabetes WA, Diabetes Australia, and Diabetes Tasmania; the General Manager of the NDSS; and the Directors of Diabetes Products, NDSS Enhancements, and Chronic Disease Policy from the Department. The role of the steering committee was to make recommendations in relation to project plans, budgets, and timelines and to broadly monitor progress and risks throughout the life of the project. This included recommendations as to how MyDESMOND (1) integrated with and complemented without duplicating existing NDSS services delivered by Diabetes Australia and Agents of the NDSS across Australia; (2) complied with relevant government policy, the overarching NDSS service agreement, and individual NDSS Agent agreements; (3) met relevant standards for NDSS content, review, and approvals; (4) complied with local data privacy, cyber security, and other internet technology security requirements of the NDSS and government policy; (5) managed risks, defined as any event or condition with the potential to affect achievement of project objectives; and (6) could be delivered in accordance with agreed budgets and time frames.Diabetes WA was responsible for the day-to-day operation of the project. A project management team was appointed. The team, led by an experienced project manager, included Credentialled (accredited) Diabetes Educators (CDEs); content, marketing, and evaluation analysts; and a digital systems consultant. The team met weekly and was responsible for all aspects of developing, managing, and monitoring the project work plan and for securing appropriate resources to ensure the successful completion of the project.A working group comprising representatives of the state and territory Agents of the NDSS, Diabetes Australia, and the Department was also established. The purpose of the group was to foster communication, collaboration, and input into planning for the adaptation, eventual pilot-testing, and implementation of MyDESMOND at the operational level. The group provided advice and support to the project management team to ensure that the program complemented and integrated with existing education and support services and materials provided through the NDSS, met appropriate standards for content, and included appropriate processes for approval and review.A plan to guide stakeholder engagement and communication was developed and approved by the Agent working group and steering committee to ensure optimal stakeholder awareness, engagement, motivation, and satisfaction. The development of the plan involved four key processes: (1) identification of internal and external stakeholders likely to be affected by project processes or outcomes; (2) analysis of the level of interest, influence, and involvement in the project; (3) consideration of how to best manage stakeholder expectations during the project to maximize support and minimize the potential for conflict; and (4) planning to regularly update and review stakeholder expectations and building strategies to maintain stakeholder engagement and support throughout the life of the project. The plan included a matrix identifying key project stakeholders in addition to the type of information to be communicated, appropriate channels for communication, and the planned frequency and timing of communication activities. The matrix can be viewed in DESMOND Newly Diagnosed and Foundation: Educator Manual and Curriculum 2015 [The content of MyDESMOND was adapted to ensure that the program was (1) culturally and contextually appropriate for the Australian setting, (2) consistent with the content of the face-to-face version of DESMOND already being delivered in Australia, and (3) aligned with Australian clinical guidelines for the management of T2DM. The content was adapted by a CDE who was also accredited to facilitate the face-to-face adaptation of DESMOND in Australia and by an experienced content analyst. The process initially involved a detailed review of the UK version of MyDESMOND to identify program elements requiring adaptation. The program content was also compared with the Australian lum 2015  previous1c levels were amended from 6.5% to 7% (48-53 mmol/mol) [The clinical guidelines for the management of T2DM cited throughout MyDESMOND were amended in accordance with Australian recommendations and guidelines. Targeted HbAmol/mol) . Blood gmol/mol) . Referenmol/mol) ,30. Smokmol/mol) . Contentmol/mol) . Australmol/mol)  in additmol/mol) .Links and references to UK-focused consumer resources were replaced with links and references to Australian resources. For example, references to services and resources provided through the National Health Service (NHS) in the United Kingdom were replaced with references and links to the services and resources provided through the NDSS in Australia. These included references to the NDSS website landing page and information about blood glucose monitoring; management of hypoglycemia; sick days; medications; food labels; physical activity; sexual health and diabetes; the diabetes annual cycle of care; and advice on driving, travel, healthy cooking, and eating out . Other lprogramme was changed to program). Branding throughout the program was amended from that of the NHS and the Leicester Diabetes Centre to that of the Australian Government Department of Health and the NDSS. References accrediting the Leicester Diabetes Centre for the original program design were retained. Embedded videos were refilmed to reflect the changes to program content and local language accents and included the stories of Australian people living with T2DM. Images were adapted to suit the Australian context. To ensure consistent formatting throughout the program, the images were edited by the Leicester Diabetes Centre. Processes for registration were also updated to be contextually relevant. This included data to be collected in relation to the participants’ postcode information , gender , ethnicity , and registrant identification .A variety of additional practical adaptations were also made to MyDESMOND. These included the conversion of all units of measurement to be consistent with Australian standards. For example, calories were changed to kilojoules, and ounces were changed to grams. Spelling and grammar were also edited to reflect locally accepted conventions , sentence structure , type of information to be included , design features , and pictures .Given Australia’s multicultural diversity, including migrants of non–English-speaking background, it was important to ensure that MyDESMOND was appropriate for people with lower levels of English literacy. Each learning session and booster session throughout the program was reviewed against the NDSS readability checklist . The purThe readability of MyDESMOND was also assessed using the Flesch–Kincaid Scale , a scaleUpon completion of the amendments to the program content, MyDESMOND was subjected to a 2-stage process of independent assessment to confirm that the content was appropriate for the Australian context and complied with all relevant standards and guidelines. First, a review was conducted by 2 external CDEs . The program was then sent to the Medical Education and Scientific Advisory Council for review. The Medical Education and Scientific Advisory Council is a body maintained by the Australian Diabetes Educators Association and the Australian Diabetes Society and provides strategic advice to the NDSS on medical, educational, and scientific matters. The results of these 2 stages of review confirmed that the content of MyDESMOND was consistent with relevant standards and guidelines and, therefore, likely to be suitable for Australian consumers.The digital specifications of MyDESMOND were modified to suit the Australian setting. This part of the project was overseen by a member of the project management team who was an experienced project systems consultant. Coding and development work outside of the content management system was undertaken by the UK-based developers of the original MyDESMOND platform. The modifications were guided by a software and system development life cycle approach. Such approaches offer a stage-based conceptualization of the life of a system or software from inception to maintenance . The forreal life. Deployment occurs when system functionality is verified and involves the release of the software or system to end users. When a system is deployed and users start to interact with it, issues or defects may be identified, at which point the life cycle continues to evolve.The requirement gathering and analysis phase of a life cycle typically involves identification of stakeholder needs and building understanding of how users will interact with the system and how the system should function. Given that MyDESMOND had been developed and offered to people with T2DM in the United Kingdom, this phase of the project involved ensuring that the program met local standards and legislative requirements for information and data management. The design phase of the life cycle usually involves the determination of a high-level system design, whereas the development phase involves the configuration of the infrastructure as well as database and system coding. In the case of MyDESMOND, this work had been undertaken by a UK-based web developer when the program was originally developed. The next phase of the life cycle involved testing to verify that the system worked as expected under conditions simulating Privacy Act 1988 [MyDESMOND was adapted to meet relevant standards and local legislative requirements for best-practice information and data management. Relevant standards and legislation informing local adaptations included (1) the National Institute of Standards and Technology  informatAct 1988  and PrivAct 1988 , includiAct 1988  for the The review of relevant standards and local legislation resulted in changes to the program privacy policy and terms and conditions and the addition of a feature to enable users to opt in or out to receive future direct marketing campaigns. More specifically, the amendments included (1) strengthening passphrase (password) management practices for user accounts, including the adoption of protocols for the frequency of required changes to passphrases and limitations on the frequency of user-instigated daily password changes, the reuse of passphrases, and the use of sequential passphrases; (2) implementation of multifactor authentication; (3) recording of relevant information for logged events, including a description of the event, the date and time it occurred, and the users, processes, and equipment involved; and (4) implementation of the Secure Hash Algorithm 2 family of Secure Hash Algorithms  for enhaTo ensure data sovereignty, whereby MyDESMOND data were stored and accessible only from within Australia , the appproduction-ready. A test plan outlining the strategies for testing and execution and the processes for test management was developed. The plan was reviewed by key stakeholders before its execution to foster commitment to resourcing and time frames.The Australian MyDESMOND platform was tested to validate that the program functioned as specified and, thus, could be considered Testing focused on the functionality of the platform , capacity for backup and recovery , and penetration . Additional nonfunctional testing typically conducted at this stage of the development life cycle  was not required as the MyDESMOND Australia installation had been configured to replicate the UK environment, which had been operating nationally in the United Kingdom since 2018 with >15,000 users .high. Examples of issues included duplication of words, poor rendering of display, inaccurate or unhelpful error messages, incorrect navigation, inappropriate or missing verification and validation, and problems connecting with third-party services. Upon completion of testing, MyDESMOND was profiled as low-risk and determined as functionally fit for purpose in the Australian setting. The disaster recovery plan was successfully tested, with the system fully recovered and restored. Specialist internet technology security consultants conducted penetration testing to simulate a malicious user both with and without credentials. This test demonstrated that MyDESMOND was not susceptible to cyberattacks and would not expose users to unacceptable risk. Upon completion of functional, disaster recovery, and penetration testing, MyDESMOND was recommended for deployment to the production environment in preparation for consumer pilot-testing.The project team developed test cases for each function and feature of MyDESMOND to identify inputs and expected outputs, allow for remediation of issues where the actual output varied from anticipated outputs, and identify opportunities to improve user experience. The cases were manually executed by professional test engineers using a range of common web browsers  and devices . Project team members participated in testing . Testing was repeated when system shortfalls were identified and rectified. In total, 736 test cases were executed on web browsers, and 566 were executed on devices. More than 100 issues were reported and categorized according to severity . No issues were categorized as The steps outlined in this paper facilitated the cultural adaptation of MyDESMOND, the first evidence-based web-based DSMES program for Australian people living with T2DM. By documenting the systematic approach, including the appointment of a multidisciplinary project management team, active stakeholder engagement, and the specific processes undertaken to adapt program content and the digital platform, this paper provides a road map for others to follow when adapting digital health programs for delivery in new contexts.Adaptation of existing evidence-based health programs to new settings has the potential to introduce services into new environments in a cost-effective and timely manner with reasonable prospects of successful outcomes . Howeverbuy-in from funders, service providers, health professionals, and others who stood to be affected by the implementation of the program in the short and long term. Inclusion of these parties from project instigation to piloting, evaluation, and implementation improves the likelihood of ongoing buy in and support from those who have influence over program delivery, thereby enhancing the potential sustainability of the program in the future.The incorporation of stakeholder input into the design of behavioral interventions to improve public health is critical, as is the development of strategies for optimal and sustained stakeholder engagement . The eng1c levels, self-efficacy, diabetes knowledge, and self-care behaviors in people with T2DM [A strength of this work is the adoption of an existing evidence-based program grounded in behavioral theory and designed using a systematic intervention-mapping approach . It is rith T2DM . Thus, wRobust security and privacy protections for the rights of consumers are key to ensure that digital health interventions are effective, safe, and trusted by users; a proactive approach that considers potential and emerging threats, relevant standards and legislative requirements, and evolving ethical issues is essential . AccordiWe followed a systematic approach to adapt MyDESMOND to the Australian setting. However, there are limitations that need to be acknowledged. When working with project stakeholders, it is critical to collaboratively establish and agree on detailed timelines, systematic work plans, and goal-setting processes with continual revision of standards set and group norms . DespiteDelays were also experienced in adapting the MyDESMOND digital platform owing to a lack of system administrator training or hand over and lack of architectural diagrams and administrator guides or description of access levels. This resulted in a process of trial and error as the local project team learned how to navigate the system. To mitigate this unforeseen issue, we engaged a content editor experienced in technology and digital communications to ensure that our team developed and followed robust system user guides. Involving the UK developers of the original MyDESMOND platform in the project from the outset also provided an additional source of knowledge and expertise to overcome this issue. Consequently, we recommend involving original program developers as stakeholders when adapting digital programs to new settings, where possible.Although the adaptation of MyDESMOND Australia involved a collaborative approach and extensive stakeholder engagement, program users  were not directly involved in the adaptation at this stage. However, follow-up pilot-testing involves an initial exploratory phase to seek preliminary feedback about program acceptability from users before advancing to more comprehensive phases of pilot-testing.We provide a list of recommendations to consider for future adaptation work in digital self-management programs . These rKey recommendations for the adaptation of digital self-management programsInvolve individuals with multidisciplinary skills and expertise in the project management team. This may include those experienced in project management, program or clinical content, and digital systems and processes in addition to the original program developers.Involve stakeholders across multiple levels of influence. This might include funding or commissioning bodies, senior executives and operational-level employees of service-providing organizations, health professionals and clinicians, original program developers, and others who may have an interest in or be affected by program implementation.When working with independent advisors and bodies, it is critical to establish workable time frames and deadlines and seek agreement to those time frames by all concerned.Create a clear plan for how stakeholder engagement will be sustained throughout the life of the project. Consider the priorities and agendas of each of the stakeholders.Use information and resources from a range of credible local sources to inform content adaptations. These may include government guidelines and recommendations as well as information and resources from peak industry bodies, advisory councils, and professional societies.When adapting an existing digital program to a new setting, it is important to ensure that the relevant team members have been provided with adequate system administration training and that appropriate technical user guides and resources are supplied.Incorporate a process for external or independent review of program content to ensure that it is culturally appropriate and relevant to the target population.Adopt a systematic approach to digital adaptations to ensure optimal performance in the local environment. Consider all relevant standards, local legislative requirements, and matters surrounding data sovereignty.Conduct rigorous testing of the digital program to ensure that it performs as intended in the local setting.Further work is needed to ensure the feasibility of delivering MyDESMOND in the Australian setting in addition to establishing the acceptability and potential effectiveness of the program among Australian people with T2DM. Consumer pilot-testing was undertaken upon completion of the adaptation project described in this paper and will be reported in detail at a later date. Briefly, the aims of the 2-phase pilot were to (1) determine if MyDESMOND provided a useful, engaging, and relevant learning experience for people in Australia living with T2DM; (2) obtain consumer feedback on the functional and technical aspects of the program; (3) determine the potential effectiveness of MyDESMOND in increasing diabetes empowerment and reducing diabetes-related distress among Australians with T2DM; and (4) further assess consumer satisfaction with MyDESMOND after further adaptations were made based on the findings of phase 1 of pilot-testing. Should consumer pilot-testing indicate that MyDESMOND is acceptable, feasible, and likely to be effective, the program will be recommended for inclusion in the suite of programs and services provided to people with T2DM throughout Australia via the NDSS.This paper provides a road map for the adaptation of digital health programs for delivery in new contexts, including recommendations for engaging the project management team and stakeholders and processes for adapting content and the digital platform. We believe that the systematic approach that we adopted to adapt MyDESMOND to the Australian setting would be applicable to other development studies that aim to contextually adapt an existing digital program.


ARID1A belongs to a class of chromatin regulatory proteins that function by maintaining accessibility at most promoters and enhancers, thereby regulating gene expression. The high frequency of ARID1A alterations in human cancers has highlighted its significance in tumorigenesis. The precise role of ARID1A in cancer is highly variable since ARID1A alterations can have a tumor suppressive or oncogenic role, depending on the tumor type and context. ARID1A is mutated in about 10% of all tumor types including endometrial, bladder, gastric, liver, biliopancreatic cancer, some ovarian cancer subtypes, and the extremely aggressive cancers of unknown primary. Its loss is generally associated with disease progression more often than onset. In some cancers, ARID1A loss is associated with worse prognostic features, thus supporting a major tumor suppressive role. However, some exceptions have been reported. Thus, the association of ARID1A genetic alterations with patient prognosis is controversial. However, ARID1A loss of function is considered conducive for the use of inhibitory drugs which are based on synthetic lethality mechanisms. In this review we summarize the current knowledge on the role of ARID1A as tumor suppressor or oncogene in different tumor types and discuss the strategies for treating ARID1A mutated cancers. Nucleosomes are composed of 147 base-pairs of DNA wrapped around histone octamers , 3. The The SWI/SNF complex was identified in yeast in 1984 , suggestARID1A deletion on one allele leads to embryonic lethality  is a key component of the mammalian SWI/SNF protein complex. ARID1A directly binds DNA with low sequence specificity , even thethality .In addition, ARID1A can modulate gene transcription in cells, either directly controlling the expression of cancer related genes or indirectly by regulating the recruitment or activity of histone modifier enzymes, which add or remove histone modifications at gene regulatory regions. For example, ARID1A can regulate the immune response by modulating the interferon-responsive gene methylation profile in multiple tumor types . ARID1A The immunoprecipitation assay for ATR (ataxia telangiectasia and RAD3-related protein) followed by mass spectrometry, revealed that ARID1A is also an interacting partner and enriched in double strand brake (DSB) sites, further demonstrating that ARID1A is required to create the proper chromatin profile that facilitates the histone variant H2AX phosphorylation, mediated by ATR .ARID1A genetic alterations are linked to tumor development. For this reason, we examined the literature describing ARID1A alterations in human cancer, highlighting its double role as a tumor suppressor or oncogene in different tumor types and stages and focusing on its current use in cancer therapy.Considering the literature findings discussed so far, we can conclude that the role of ARID1A is fundamental in different cellular processes by regulating the transcription of genes involved in cell differentiation and development, although many mechanisms are not completely clarified yet. Several recent studies reported that One of the most interesting results from the -omics characterization of human cancers was the discovery that chromatin regulation and epigenetic processes are tightly linked to the development of cancer . Indeed,ARID1A , 56% of uterine endometrioid cancer (EC)  , 40% of cer (EC) , but in cer (EC) , 45. WieD1A loss . ARID1A etriosis . These dARID1A mutations since the early stages of tumor development .Gibson et al. analyzed the genomic landscape of endometrial cancer progression and reported the presence of elopment . Among t lesions . Reviewi lesions , we obseARID1A mutations contribute to the final inactivation of the apoptosis-promoting function of P53 by suppressing apoptosis-promoting P53K120Ac. This finding suggests that either the transcriptional repression of oncogenic genes or the transcriptional activation of tumor suppressor genes contribute to the tumor suppressive role of ARID1A.Bitler et al. demonstrated that ARID1A inactivation upregulates HDAC6 expression, which in turn deacetylates Lys120 of P53 . P53K120Unexpectedly, ARID1A inactivation in association with APC and PTEN absence in mouse ovarian cancer models, prompted tumor cells towards epithelial differentiation . This obARID1A haploinsufficiency is enough to drive tumor progression.Aberrant SWI/SNF mediated chromatin-remodeling can sustain the activity of both oncogenic and tumor suppressive networks, resulting in directionally opposite effects. A double functional role for ARID1A in tumorigenesis has been described in hepatocellular carcinoma (HCC). Indeed, a recent finding by Sun et al. demonstrated that the gain of ARID1A function triggers tumor initiation by enhancing CYP450-mediated oxidative stress, while the loss of ARID1A during the later phases of tumor growth decreases the DNA accessibility and inhibits the transcription of genes associated with migration, invasion, and metastasis . In thisZhao et al. reported that 10–15% of HCCs harbor loss-of-function mutations in this gene and that 83% of HCC show ARID1A mRNA overexpression if compared to adjacent normal tissues . Accordi1. the change in ARID1A expression could be an early event during the development of HCC, since the silencing of ARID1A enhances cellular proliferation. However, this hypothesis cannot explain the up regulation of ARID1A in most HCC tumors compared with adjacent normal liver tissues.2. the expression of ARID1A is very low in normal tissues, and at the early stages of the tumorigenesis ARID1A increases to prevent cellular proliferation. Whereas, during the late stages of HCC progression, the ARID1A loss due to acquired mutations, elicits tumor escape and enhance cell proliferation.The second hypothesis seems to be more reasonable if we consider that ARID1A expression levels negatively correlated with survival in HCC patients .in vivo, while ARID1A overexpression had the opposite effect, increasing survival and slowing tumor growth.To test the functional role of ARID1A, Zhang and colleagues used the hepatocellular carcinoma model induced by hydrodynamic transfection of tumor cells with activated AKT/NRAS combined with either ARID1A overexpression or knockdown . They obGastric carcinoma (GC) is classified by The Cancer Genome Atlas (TCGA) project into four molecular subtypes: Epstein-Barr virus (EBV) positive with extreme DNA hypermethylation; microsatellite instability (MSI); genomically stable (GS), and chromosomal instability (CIN) .ARID1A genetic alterations in gastric cancer (GC) were first reported by Abe et al. and Wang et al. . ARID1A copy number loss is the most frequent genetic alteration and involves 13–35% of BC cases. In addition, Zhang et al. demonstrated that in a variety of primary invasive BCs, ARID1A expression was epigenetically regulated. , ERBB2 (17q12), KRAS (12p12.1), AKT2 (19q13) and MYC (8q24.2), and deletion of CDKN2A (9p21.3), SMAD4 (18q21.2), ARID1A (1p36.11) and PTEN (10q23.31)  .ARID1A mutated pancreatic cancers carry KRAS hotspot mutation G12D, suggesting that the inactivation of ARID1A may cooperate with KRAS in the early stages of pancreatic cancer formation  carry about 20% ive PDAC .0/G1 to G2/M phase. In this study, they proved that ARID1A knockdown or deficiency was associated with decreased apoptosis and increased cell proliferation . To define the effects of ARID1A in renal carcinogenesis, Somsuan et al. used a non-malignant kidney epithelial (MDCK) cell line to demonstrate that ARID1A silencing using siRNAs significantly reduced cell death while increasing cell proliferation, with a cell cycle shift from Gferation . MoreoveAnother study in patients affected by RCC, revealed lower ARID1A protein expression in 67% of samples and decreased ARID1A messenger RNA (mRNA) levels in 68% of samples if compared to normal kidney . The losARID1A mutation frequency of 12-16%.Cancers of unknown primary origin (CUP) comprise newly diagnosed tumors presenting as metastatic cancers, whose primary site cannot be identified after detailed standardized physical examinations, blood analyses, imaging, and immunohistochemical (IHC) testing . This tuARID1A mutations accounted for 11% of 200 archive CUPs  samples of a CUP case with ARID1A mutations. The study reports how the fractional abundance of ARID1A mutation (p.R1276_) in ccfDNA decreases during the initial treatment and then increases again during disease worsening, thus suggesting a role in the expansion of the more aggressive subclones . ARID1A mutations were evenly distributed across the gene without clustering or hotspots. Despite the increased TMB, no statistical significance was noticed in ARID1A mutated patients receiving targeted therapies or immune-checkpoint inhibitors for what concerns progression-free and overall survival. However, ARID1A mutated tumors revealed UV-induced mutation signatures, showing a higher frequency of C>T substitutions in comparison with ARID1A wild-type melanomas. This finding suggests that the impact of ARID1A mutations in immune-checkpoint inhibitors response needs to be better elucidated.Many genetic alterations occur during the development of melanoma. Thielmann et al. analyzed the clinical pathological features of 116 patients diagnosed with melanoma in association with the most common genetic alterations, including mutations in D1A gene . They deARID1A expression is progressively lost during colorectal cancer (CRC) development: Wei et al. showed that the loss of ARID1A expression was associated to distant metastasis and late TNM stage of CRC. However, the survival analyses indicated that the loss of ARID1A protein expression was a better prognostic factor for stage IV CRC . In lineARID1A mutations are detectable in about 6-7.5% of lung cancers. Hung et al. demonstrated that ARID1A loss-of-function mutations and biallelic inactivation induce the complete loss of ARID1A expression in non-small cell lung cancer (NSCLC) ( (NSCLC) . Another (NSCLC) . Moreove (NSCLC) , 63, 74.In addition to survival rate, other clinicopathological factors such as lymph node metastasis and tumor infiltration have been positively correlated with loss of ARID1A expression . The autARID1A mutations among different cancer types, made this gene a very appealing research object for target therapy investigations.The high frequency of ARID1A in target therapy was investigated within the context of synthetic lethality. Synthetic lethality is based on essential gene interactions where a genetic alteration, such as a defect in a tumor suppressor gene (genetic context), influence a second gene essential for cell survival   . The use target)  and Kael target) , after t target) –93. As fhenotype  for the https://clinicaltrials.gov/) concerning ARID1A, ranging from phase I to phase II. Currently there are 23 clinical trials registered in the clinical trials website  deficiency and PARP inhibitors. In this context Shen et al. demonstrated both hibitors . The POLhibitors . AuthorsARID1A (court B). Preliminary results of the study were presented at ASCO 2022 and described that in the court B patients who had stable disease were ARID1A mutated . Despite ENMD- 2076 did not meet the efficacy bar set in this trial, this AURKA inhibitor has been reported as potentially advantageous for ovarian clear cell carcinomas patients with ARID1A deficiency .ARID1A acts predominantly as a tumor suppressor gene in many solid tumors, although its functional role seems to be stage and tumor type dependent. For example, ARID1A expression is initially upregulated in HCC and then lost by acquisitions of truncating/missense mutations. The loss of ARID1A expression in human cancers is generally associated with negative prognostic features, tumor progression and increased tumor growth and invasion. The lack of ARID1A in tumors is associated with an increased tumor mutational burden and genomic instability, which is currently pharmacologically exploited according to synthetic lethality principles. Although the exact mechanisms are still elusive, clinical trials with small inhibitors directed toward DNA damage response (DDR), immune checkpoint blockade (ICB), kinase inhibitors and epigenetics effectors are showing promising results and are worth investigating in future studies.MF contributed to conception and design of the study. BF, IS, GG, and RR wrote the first draft of the manuscript. IP wrote sections of the manuscript. All authors contributed to manuscript revision, read, and approved the submitted version.


To describe structural changes that can be made in an emergency medicine residency program to increase diversity and foster an inclusive environment.  We established a diversity committee to introduce several simultaneous structural changes focusing on resident recruitment, education and engagement. Some of these changes include establishment of a scholarship to recruit visiting students from diverse backgrounds and a second look weekend for minority applicants. Others focused on ensuring residency didactics, were inclusive and addressed topics pertaining to diversity in emergency medicine.  We increased the number of minority residents underrepresented in medicine matching in our program from zero to between 2 and 4 annually. We increased the percentage of women matching in our program from 33% to 47%. We worked with residency leadership to increase the number of didactics focusing on diversity and inclusion.  Implementation of a Diversity Committee in emergency medicine training programs can be an important tool to improve diversity on a structural level.  The benefits of a diverse physician workforce are well known. There is evidence that patients from racial and ethnic minority backgrounds have better interactions with physicians from similar backgrounds with respect to patient-centered outcomes, and that physicians who are underrepresented in medicine (URiM) are more likely to meet the needs of minority and underserved communities  , 2. PrIn 2019, the Accreditation Council for Graduate Medical Education (ACGME) established Common Program Requirements focusing on improving diversity and inclusion in residency training programs  . These There are many structural barriers that must be addressed to create, support, and sustain a diverse and inclusive residency program. In 2009, the Council of Emergency Medicine Residency Directors (CORD) recommended 8 key recruitment strategies in order to increase diversity in EM. These strategies include active recruitment of students from diverse backgrounds, validation of the importance of applicants meeting with residents and faculty from underrepresented groups during recruitment, development of curricula to address topics on diversity equity and inclusion, and celebration of successful institutional diversity initiatives  , 7. InIndividuals identifying as racial/ethnic minorities, women, and sexual/gender minorities face increased discrimination during medical training, including overt mistreatment and implicit bias  , 11. I The Diversity Committee was established to introduce structural changes that would increase diversity and inclusion in our EM residency program. Led by two faculty co-chairs, one resident chair and open to all residents who wanted to participate, the committee discussed, developed, and instituted several simultaneous initiatives intended to synergistically recruit and support a more diverse cohort of residents. Based on the success of other EM diversity recruitment programs, and the personal experiences of our resident members, the Diversity Committee established a multifaceted effort to recruit a diverse class of residents at different stages of the recruitment process  , 9. WeWe successfully petitioned the emergency department chair to provide a budget to defray the cost of travel and lodging associated with a visiting sub-internship. Five scholarships of $1500 were awarded annually to URiM visiting students. Applicants for the scholarship were asked to provide a CV and a written statement explaining their interest in leadership and academics. Scholarship applications were reviewed by a committee consisting of the Diversity Committee faculty and resident chairs, and the residency program director. Scholarships were then awarded on a rolling basis. Residents on our Diversity Committee identified sustained and frequent outreach emphasizing a commitment to diversity equity and inclusion to be an important factor in their own decisions about where to apply for residency training and where they wanted to match. We therefore decided to begin our outreach early- well before residency applications were completed. We selected residents on the Diversity Committee to represent our program at the Student National Medical Association and to speak at events sponsored by EM interest groups at medical schools affiliated with historically Black colleges and universities such as Howard University College of Medicine and Meharry Medical College. Our goal at this stage of recruitment was to attract visiting students and residency applicants identifying as URiM and to clearly establish our program’s commitment to recruiting a diverse cohort of residents. Any student doing a sub-internship at our program, whether as a URiM scholarship recipient or not, was informed via email of our program’s commitment to diversity, equity and inclusion and was invited to seek information pertaining to life as a racial, ethnic, gender and/or sexual minority in our program and city. Resident volunteers met with rotators who self-identified as women, URiM and sexual/gender minorities to provide information about the inclusive culture fostered by our program. We emphasized that these meetings were informal and unrelated to assessment or grading during the sub-internship. After being selected to interview, all applicants to our EM residency program were also invited via email to seek information pertaining to life as a racial, ethnic, gender and/or sexual minority from the residents. Interested applicants were matched with resident volunteers who could share personal experience about their individual concerns either via email, on the phone, or during the interview day. These meetings were also informal, and sometimes would take place at the casual dinner prior to the interview day. Again, we emphasized that these meetings were for the purpose of providing information and fostering connections and that they were not part of the interview assessment. Prior to the establishment of the Diversity Committee, the materials and presentations provided on the interview day did not explicitly emphasize a commitment to diversity and inclusion in our program, and focused mainly on the details of the training program and on academic research. Our Diversity Committee quickly identified this as a missed opportunity for program leadership to build commitment to diversity into the structure of the interview day and to provide a clear message to diverse applicants that their identities were valued on an institutional level. We revamped the materials provided to interviewees to include information about the minority house staff office, LGBTQ life in our city, and the importance and contributions of women leaders in our department. Our resident Diversity Committee members identified the interval between interviews and the finalization of residency match lists as an important time to re-emphasize an institutional commitment to diversity. Additional departmental funds were secured to invite interested URiM students for a second look after interviewing but before the match rank order lists were finalized. Programming for the second look included meeting with key departmental leadership such as the department chair, the residency program director, the assistant program directors and senior faculty members identifying as URiM. Applicants attending second look participated in a medical simulation activity at our Center for Medical Simulation, and were invited to shadow faculty working clinically in the emergency department. We also arranged for attendees to have dinner with the Diversity Committee resident and faculty members, and to attend a party hosted by the minority house staff association. Once recruited, it is important to ensure an inclusive learning environment in which a diverse group of residents can thrive. To that end, the Diversity Committee began to address structures within the educational milieu of the classroom and hospital. We worked closely with the associate program director in charge of residency didactics to identify areas related to diversity, equity and inclusion that were lacking in our curriculum, and expanded the didactic curriculum to include these areas structurally as a recurring curricular objective. We successfully incorporated implicit bias training into our curricula to mitigate the effect of implicit bias in our interactions as colleagues and clinicians. We also created a bystander intervention workshop so that allies could support colleagues and junior trainees when subjected to mistreatment related to race, ethnicity, gender, and sexual orientation. Speakers were invited to share their experiences as members of diverse groups. For example, we hosted a panel on the experience of transgender healthcare workers. Finally, we initiated a grand rounds lecture series focusing on diversity equity and inclusion. Subjects ranged from political advocacy as a physician, to trauma informed care in the emergency department, to the care of incarcerated populations. In addition to creating new didactic content focusing on diversity equity and inclusion, we also sought ways to make existing didactic offerings more inclusive. For example, we recognized the importance of including patients of diverse skin tones in dermatology lectures and ensured that the example slides of skin findings were inclusive. We incorporated subjects pertaining to diversity, equity and inclusion in healthcare into our monthly journal club, and are currently examining our simulation curriculum to ensure that same sex couples are represented in simulated cases requiring collateral information from a spouse. The Diversity Committee continually reassess the needs of the residency program based on input from committee members annually. New resident chairs and junior members bring in new ideas for improving diversity recruitment and inclusivity in our residency, while the faculty co-chairs provide ongoing experience, institutional memory, and guidance when liaising with departmental and residency leadership. Our Diversity Committee was created, in part, due to the low numbers of URiM and women residents in our 2014 and 2015 classes. Between 2016 and 2019 we awarded 19 scholarships to support visiting rotators from underrepresented backgrounds, increasing our number of URiM visiting students from 2 to an average of 7 annually. We have recruited 5 scholarship recipients to our program in total, and have increased our number of URiM residents from zero in 2014 and 2015 to between 2 and 4 annually for the last four years. As of November 2020, URiM residents comprise 18% of our residency cohort. In 2014 and 2015, 33% of matched residents were women. Since establishing the Diversity Committee, 47% of matched residents are women. Data about sexual and gender minorities has not been collected. Prior to 2016 we did not have any didactic conferences in our residency focusing explicitly on diversity and inclusion. Since the establishment of the Diversity Committee, we have had four grand rounds speakers, one panel discussion and one journal club focusing on diversity and inclusion. We have also provided implicit bias training and bystander intervention training for the entire residency and faculty. The Diversity Committee continually scrutinizes the didactic program to ensure that educational programming is structurally inclusive, even when the content does not explicitly pertain to diversity equity and inclusion. Many residency programs struggle to recruit diverse residency classes. Developing diversity where there is little or no diversity is a challenging task. Programs with existing resident and faculty diversity may be more attractive to underrepresented minority and female residency applicants. This leaves programs that have not already established diversity at a disadvantage in recruiting diverse applicants, and lack of diversity becomes self-perpetuating. Our Diversity Committee initiatives were successful in mitigating the effects of two application cycles in which no URiM residents were recruited and only 33% of residents recruited were women. These efforts have proven to be sustainable over four years. Program leaders seeking to improve their resident diversity will need buy-in from key stakeholders. The active participation of women, URiM and sexual/gender minority residents on our Diversity Committee was important in identifying what outreach strategies to implement, and what information about our program to emphasize to recruit diverse residency applicants. They also gave key input as to what changes should be made to our didactic curriculum to foster a more inclusive residency program. Departmental leaders are also important stakeholders. In order to secure funding to implement our recruitment strategies, we made a formal presentation to our department chair. We presented published evidence showing the success of other recruitment programs and continue to provide annual data documenting our success to demonstrate the need for ongoing funding. We also worked closely with the associate program director in charge of resident conference to make changes to the didactic curriculum. We emphasized shared common goals of fostering diversity equity and inclusion in the residency to convey the importance of dedicating many hours of conference time to these curricular initiatives. Programs without existing diversity can look to university or hospital-based groups, such as the minority house staff association, to partner with in their recruitment efforts. Our partnership with the minority house staff association at our hospital allowed second look participants to appreciate a wider institutional commitment to supporting URiM residents outside of our individual EM department. Next steps for our Diversity Committee include a focus on creating and supporting opportunities for advocacy and community outreach, an area identified as important by our residents. The COVID-19 pandemic has impacted some of our recruitment strategies. We are currently looking at what virtual outreach strategies have been most effective in the 2021 academic year and how they might be carried forward to support diversity recruitment at multiple stages of the application process. We are also discussing ways to sensitively recruit sexual and gender minorities, a group that has not typically been the focus of pipeline programs. We anticipate that it may be more difficult to collect data on the success of recruitment initiatives for sexual and gender minorities, since these demographics are not routinely collected on residency applications. Institution of a Diversity Committee to make structural changes in residency programs can increase recruitment of URiM and women residents. Our Diversity Committee has demonstrated sustained success in recruiting a more diverse cohort of residents over four years. The approach of our Diversity Committee can be generalized to residencies in other specialties to increase recruitment and inclusion of a diverse cohort of residents. More work is needed to address the way recruitment is changing in response to COVID-19 and to sensitively identify and recruit sexual and gender minorities. None Declared.


The perioperative management of the surgical instruments and implants that comprise sets for trauma surgeries has been identified as a complex and resource-intensive activity due to non-standardized inventories, redundant surgical instruments and unnecessary sterilization cycles. The 4S Intelligent Trauma Care program aims to improve perioperative management and thereby reduce environmental impact by utilizing standardized inventories, a sterile implant portfolio, a barcode that enables a digital safety certification, and a digitized restocking service.The objective of this study was to investigate the impact of the introduction of the 4S program for the management of surgical sets in open reduction internal fixation (ORIF) trauma surgeries.This was a single-center, quality improvement study of ORIF trauma surgeries, comparing the current practice (30 procedures) to the procedure following the introduction of the 4S program (30 procedures). The primary outcome was the proportion of procedures requiring only one sterilization cycle. Secondary outcomes were the number of sterilization cycles per procedure, set processing time across departments, total set processing costs, number of missing or damaged implants, number of cleaning cycles per procedure, time taken to assemble containers for sterilization, number of containers entering the autoclave per procedure, environmental impact, number of baskets entering the cleaning machine per procedure, and staff satisfaction.Introduction of the 4S program resulted in a reduction in the mean number of sterilization cycles required from 2.1 to 1.0 (p < 0.001). In the current practice, only 30.0% of procedure sets were sterilized within one cycle, compared to 100.0% following introduction of the 4S program (p < 0.001). A reduction in the mean set processing time of 24.1% in the OR and 35.3% in the sterilization department was observed. Mean set processing costs for the current practice were €81.23, compared to €50.30 following introduction of the 4S program. Furthermore, following the introduction of the 4S program, procedures were associated with significant reductions in water and electricity usage, and increased staff satisfaction.This quality improvement study demonstrates the substantial time and cost savings, positive environmental impact and staff satisfaction that could be achieved by streamlining surgical set management through the 4S program. To our knowledge, this is the first study of this type and our findings may be instructive to other hospitals and surgical specialties. The perioperative management of surgical instruments and implants has been identified as a complex and resource-intensive activity frequently associated with substantial administrative and financial burden. –4 In ourUnderutilization of instruments during surgery has been observed in multiple studies, likely resulting in unnecessary reprocessing of unused equipment. , 3–7 In In traumatology, the inclusion of implants alongside instruments within surgical sets introduces additional complexity. In our experience, frequently, implants are added after the initial sterilization of instruments as they were not on site at the time of the first sterilization, resulting in the requirement for an additional sterilization cycle. EU Medical Device Regulations (MDR) enforce traceability requirements for all implants used.  CommonlyThe absence of standardized inventories, the redundancy of and in surgical sets and unnecessary sterilization cycles all contribute to an increase in health resource utilization, and raise concerns over environmental impact and sustainability of these practices. –5, 7 ThiStandardized Inventory: Surgical sets are standardized to create new lightweight versions that contain the instruments only, eliminating all implants (plates and screws). These smaller sets are designed to be used across a wide range of traumatological surgical indications, creating a simplified inventory and removing the need for procedure-specific sets.Sterile Portfolio: Pre-sterilized, individually packed, ready-to-use, bar- and color-coded implants separate to the instrument sets are used.Safety Certification: Implants can be traced from manufacturers to patients through the use of barcoding and a digital management system, resulting in clear and precise documentationService and Advanced Planning: The program introduces digital management of restocking, reducing personnel time required.Previous cost and quality improvement studies have shown that the introduction of programs to improve the management of surgical sets have resulted in substantial cost and time savings via reductions in instrument reprocessing. , 9, 10 HThe objective of this study was to investigate the impact of the introduction of the 4S program for the management of surgical sets in open reduction internal fixation (ORIF) surgeries. The first hypothesis was that the introduction of the 4S program would reduce the number of sterilization cycles of the required surgical sets, thereby reducing the environmental impact and increasing the sustainability of surgical set processing. It was further hypothesized that the 4S program would improve perioperative processes by reducing staff and set turnover time, reducing hospital costs, and improving staff satisfaction for activities related to the management of surgical instruments and implants used in ORIF procedures. The reporting of this study was designed to align with the Standards for Quality Improvement Reporting Excellence (SQUIRE) 2.0 guidelines, which provides guidance on reporting systematic efforts to improve the quality, value and safety of healthcare. .This was a single-center, pre-post quality improvement study of trauma surgeries, comparing procedures performed with the current practice to those performed following the introduction of the 4S program, from November 2019 to November 2020. Both cohorts consisted of 30 trauma procedures and were selected using convenience sampling.The study was conducted at a tertiary hospital in Spain, serving a population of around 250,000 people. In 2018, approximately 17,000 surgeries were performed, 2,000 of which were trauma surgeries.Due to COVID-19 restrictions on external personnel access within the hospital, the study was paused for four months between March 2020 and July 2020.Data specific to procedures for all consecutive adult patients (aged 18 and older) undergoing ORIF surgeries with locking plates using the DePuy Synthes (a Johnson and Johnson company) Small Fragment System were included. No patient data were collected. There were no exclusion criteria. No pediatrics were included as these patients undergo conservative treatment rather than ORIF surgery.The intervention was the introduction of the 4S program. The new standardized surgical set was provided by DePuy Synthes (a Johnson and Johnson company). The composition of the implant trays was designed by a dedicated 4S team at the manufacturer, based on four years of consumption data both at the national and customer level in Spain [unpublished data]. The introduction of the 4S program was facilitated by this 4S team in collaboration with hospital personnel. In order to introduce the 4S program, certain resources were required, including multi-purpose instruments, sterile implants, and storage equipment such as cabinets and trolleys. The staff that worked in the department prior to the introduction of the 4S program were identical to those after the intervention was introduced.Table Data concerning processing times were collected following each activity through in-person direct observation by a trained investigator using a calibrated stopwatch. The investigator was trained on the definitions of each of the outcome measures. The investigator could not be blinded to the intervention in this study, due to the nature of data collection in a pre- and post- study design, which involved a change of practice.The primary outcome was the proportion of procedures requiring only one sterilization cycle. The secondary outcomes Table  were i) Staff satisfaction was evaluated through two methods. In order to assess improvement by changing processes, a questionnaire developed in The Netherlands was used.  For stafThe primary endpoint was powered to 80% based on (i) a two-sided z-test, (ii) type 1 error = 0.05, (iii) 30 procedures per group and that (iv) 30% of the procedures prior to the 4S program would require less than two sterilization cycles and 70% after the 4S program. The sample size chosen (30 procedures per group) was informed based on this hypothesis only. All study variables were analyzed descriptively. A two-sided z-test was used for the comparison for the primary endpoint. A p value < 0.05 was considered statistically significant. Fisher’s Exact test was used for categorical data and Wilcoxon rank sum test was used to compare the distributions of continuous data, unless otherwise specified. Analyses were conducted using R version 3.6.3. .p = 0.020). There were no cancellations of the planned procedures in the study.In total, 60 procedures were observed: 30 with the current practice and 30 following the introduction of the 4S program. Table p < 0.001).With the current practice, only 30.0% of procedure sets were sterilized within one cycle, compared to 100.0% after the introduction of the 4S program (p < 0.001). The maximum number of sterilization cycles per procedure for a single set with the current practice was 4, compared to 1 following the introduction of the 4S program.The introduction of the 4S program resulted in a reduction in the mean number of sterilization cycles required per procedure from 2.1 to 1.0 (p = 0.040) and 35.3%  in the sterilization department. No significant differences in the set processing time in the purchasing department were noted as a result of the intervention (Table p = 0.014) following the introduction of the 4S program.The introduction of the 4S program resulted in a reduction in the mean set processing time of 24.1% in the OR .With the current practice, an implant was unavailable or damaged in 40% of procedures, compared to 3.3% following the introduction of the 4S program (p = 0.121). The mean number of cleaning cycles per procedure was similar with the current practice and following the introduction of the 4S program . The introduction of the 4S program significantly reduced the mean assembly time of containers for sterilization per procedure by 43.3% . There was a significant difference in the mean number of containers entering the autoclave per procedure per cycle, which was reduced from 14.2 containers with the current practice, to 5.6 following the introduction of the 4S program (p < 0.001).The mean number of baskets placed into the cleaning machines per procedure per cycle was numerically lower following introduction of the 4S program compared to the current practice  within the current practice was €81.23 USD$85.59), compared to €50.30 (USD$53.00) following the introduction of the 4S program  and 5.77 kW (p < 0.001), respectively. These translated into cost savings per procedure of €0.61 (USD$0.64) and €0.70 (USD$0.74), respectively.Mean values for the water and electricity consumption of the cleaning machines and steam autoclaves were obtained and used to calculate water and electricity usage within the current practice and following the introduction of the 4S program. Introduction of the 4S program was associated with reductions in mean water and electricity usage per procedure of 320 L .The NASA-TLX results from five staff members showed that mental, physical and time demands, along with performance and frustration levels, were all significantly improved with the 4S program  a standardized inventory, 2) a sterile implant portfolio, 3) a barcode system that enables a digital safety certification, and 4) a digital service for restocking. Its introduction in the perioperative process management of surgical sets for ORIF trauma surgeries resulted in a reduction in set processing times, number of sterilization cycles, and processing costs. Furthermore, following the introduction of the 4S program, staff satisfaction was increased and there was a positive sustainability effect due to the reduction in water and electricity usage.A key improvement noted after the introduction of the 4S program was the increased speed of set processing. Following the 4S program introduction, total time spent in the OR, sterilization and purchasing departments decreased by 10.5 min, freeing up staff to undertake other tasks. Over 1,000 surgeries, this equates to a time saving of 174 h. The removal of all implants (screws and plates) from the sets leads to a reduction in size and variability of sets, thereby optimizing inventory management and allowing for the use of one central depository per OR. Surgeons may have concerns about the additional time burden of opening separately packaged implants, thus increasing OR time. However, a hospital in Germany assessed how the 4S program impacted surgical set management practices in trauma surgeries. It was reported that there was no significant difference in median incision-to-suture time after the change in surgical set management practice, and a numerical reduction of 4 min following introduction of the 4S program, indicating that separately packaged implants and screws did not confer an additional time burden during surgery, contrary to the authors' initial expectations. .The introduction of a stock management system and the digitalization of supply chain procedures such as consumption, purchasing and invoicing, aims to reduce the timings in the purchasing department. However, in this study, timings reported for the purchasing department were not significantly decreased following introduction of the 4S program. One possible explanation for this could be the reduced productivity of one employee who suffered an injury (not related to the study) in the period after the 4S program was introduced. Another explanation might be that the 4S stock management tool (eSims) was not fully integrated with the hospital’s enterprise resource planning (ERP) system. System integration may have eliminated all manual transactions in the hospital’s ERP system, since each report would have been automatically sent to the system instead of being sent via email to the responsible team.The provision of pre-sterilized implants separately to the surgical instrument sets reduces the number of sterilization cycles required in the hospital and results in fewer containers requiring sterilization per procedure, reducing the workload for sterilization staff. Sterilized surgical sets no longer need to be opened to add new or missing implants, thereby avoiding unnecessary reprocessing and further reducing the burden on hospital staff.The combination of decreased set processing times and the requirement for fewer sterilization cycles translates into measurable cost savings. Analysis found that the whole process was €30.93 (USD$32.59) more expensive within the current practice compared to the process following the introduction of the 4S program. Over 1,000 procedures, the mean process cost saving was calculated to be €30,930 . This may be of particular importance for healthcare systems, given the growing concern over the increasing rates of healthcare expenditure in Spain and other developed countries. .2 per capita. [2 per capita, a smaller but still substantial contributor to overall emissions. [Reduced environmental impact is another important outcome of the introduction of the 4S program. The United States' healthcare system and has the world’s highest healthcare emissions, both in absolute and per capita terms, producing 1.72 metric tons of CO capita.  Spain’s issions. .Hospitals have a key role to play in addressing resource consumption levels and must find ways to reduce their carbon footprint.  Studies The final improvement observed was in staff satisfaction. The new standardized sets in the 4S program are much lighter than those typically used (6 kg versus approximately 12 kg), making them easier for OR personnel to transport and set up, and potentially reducing the risk of injury from transporting heavy sets. With the standardization of sets, there are fewer procedure-specific sets which simplifies the overall process. Carrying out inventory of every implant used is also easier, since surgical personnel only need to read the barcode label on the packaging. These improvements were captured in the results of the NASA-TLX and the questionnaire. Staff reported reduced physical and mental demands and an overall reduction in workload following introduction of the 4S program. They also noted that it was easier to trace implants following introduction of the program and that fewer administrative errors occurred in the purchasing department. The utilization of barcoding allows for tracking of implants, increases the ease with which hospitals can comply with MDR traceability requirements and simplifies the purchasing process as single items can be easily identified and reordered. Digitalization of the stock management results in the immediate flow of information from the OR to the administrative teams, with enhanced security compared to paper-based methods which are more easily damaged or lost.This study was performed in Spain, where there has been a recent increase in the proportion of hospitals using sterile instruments and implants. In the authors’ experience, in 2019 only six departments in Spain were operating with sterile osteosynthesis material; by 2022 there were 44. It is therefore likely that wider implementation of the 4S program would be beneficial.The findings of our study are in line with published literature in that several studies have reported measurable time and cost savings when changes are made to the management of surgical sets. Introduction of a perioperative management program for elective orthopedic surgeries, which involved the optimization of surgical tray contents, resulted in a reduction in instrument processing time and associated costs.  A reviewThis study has some limitations. A convenience sample was used, and although this sampling method is commonly used in clinical trials and observational studies, the sample may not be representative of the total population. Any inferences made in this study are limited to the data presented and may not be generalizable to other settings. As the intervention received (before or after the introduction of the 4S program) was based on a convenience sample of consecutive cases and not randomly assigned, it is only possible to infer correlation between the intervention and outcomes, again limiting the conclusions that can be drawn from this study. Additional work will be required to test the hypothesis that the 4S program drives efficiency and cost savings in other settings.Only procedure-related data were collected during the study, and no patient baseline characteristics were recorded, e.g. comorbidities. It was therefore not possible to control for potential confounders in the analyses. Additional confounding factors that may have influenced surgical set processing were not recorded but had the potential to have a significant impact on findings . In-person observation of OR staff may have influenced behavior and subsequent outcomes .  SurgeonsAlthough the surgical procedures remained consistent throughout the study, patient outcomes were not recorded. In future studies, it would be valuable to collect data on surgical and safety endpoints for patients. Whilst the program introduction described here is specific to DePuy Synthes Trauma (a subsidiary of Johnson & Johnson), it is our belief that the principles underpinning the 4S program are nonetheless transferable to other surgical specialties to realize similar benefits from the perspective of reduced resource use and costs, and improved sustainability of these procedures. Further research would be advisable to understand the potential benefits after a complete integration of the stock management tool.Key strengths of this study include the prospective study design and broad patient inclusion criteria, mitigating selection bias, and standardized data collection instruments. The same hospital staff were present for procedures using the current practice and for those following the introduction of the 4S program, thereby reducing variability in potential confounding factors, despite the necessary pause of the study during the COVID-19 pandemic.To our knowledge, this is the first study evaluating time management, cost savings and the environmental impact of streamlining perioperative management of surgical sets via the 4S program in trauma surgery. Further research should be undertaken, to demonstrate whether the positive impact of the broad and comprehensive changes made to surgical set management demonstrated in this single-center study in Spain, focusing on ORIF surgeries, is generalizable to other surgical specialties across the world.In conclusion, this study demonstrated substantial time and cost savings that could be achieved by the introduction of the 4S program. Furthermore, the 4S program may contribute to net positive environmental impact and results in increased staff satisfaction. The introduction of a lean management program such as the 4S approach is of paramount importance, given the shift towards a value-based approach to management within healthcare systems and the necessity to minimize costs. Scaling the 4S program to other specialties and settings may improve the management of surgical instruments and implants, resulting in lower costs for hospitals, payers, and ultimately, patients.