We calculated descriptive statistics and applied structural coding and content analysis to qualitative data. Results: At least 75% of participating centers secured health care system administrative, clinical, and IT leadership buy-in and support. Six themes emerged from interviews: engaging leadership, access to resources, leveraging federal funding support to build leadership interest, designating champions, identifying training needs, and ensuring staff roles and IT systems support workflows. Conclusions: Buy-in among staff and clinicians is defined by the belief that the TTP is necessary, valuable, and evidence based. Recognizing and securing these dimensions of buy-in can facilitate implementation success, leading to improved cancer outcomes.Background: Delivering evidence-based tobacco dependence treatment in oncology settings improves smoking abstinence and cancer outcomes. Leadership engagement/buy-in is critical for implementation success, but few studies have defined buy-in or described how to secure buy-in for tobacco treatment programs (TTPs) in cancer care. This study examines buy-in during the establishment of tobacco treatment programs at National Cancer Institute (NCI)-designated cancer centers. Methods: We utilized a sequential, explanatory mixed-methods approach to analyze quantitative data and qualitative interviews with program leads in the U.S.-based NCI Moonshot-supported Cancer Center Cessation Initiative ( Approximately 24% of patients with cancer smoke cigarettes at the time of diagnosis . DeliverMultiple factors at the patient, clinician, and health system levels influence the success of tobacco dependence treatment program implementation. Patients diagnosed with cancer may not be ready to quit, want to quit smoking on their own , or be aMitigating such barriers requires obtaining buy-in to successfully implement and integrate TTPs as part of routine cancer care. Buy-in from clinical leadership and oncology clinicians specifically is a critical factor for the implementation success of evidence-based programs in behavioral health and primary care settings ,13. EvidIn 2017, the U.S.-based National Cancer Institute (NCI) initiated the Cancer Center Cessation Initiative (C3I) as part of the Moonshot program with the goal of integrating and enhancing TTPs in routine oncology care . C3I hasIn this mixed-methods sequential explanatory study , we condEvery six months, the C3I Coordinating Center collects data from C3I cancer centers via a web-based Qualtrics survey. Quantitative items assess cancer center and TTP characteristics, staffing, the status of implementation activities, and aggregate data of program reach and effectiveness among patients for the prior 6-month period. The biannual report is described in more detail elsewhere .For the current study, to answer our first research aim , we analyzed 5 items evaluating implementation activities to assess cancer center/health system leadership and clinician and staff buy-in with the following response options: not applicable, not started, in progress, completed, and in maintenance . In addiTo address the second aim of our study , we performed secondary data analysis on interview transcripts of C3I program leads and co-leads. The C3I coordinating center principal investigator (BR) and project scientist (HD), both PhD-level researchers with training in qualitative approaches, conducted in-person interviews with up to 10 program team members at each center between September 2018 and October 2019. The purpose of the 30–60 min interviews was to obtain in-depth perspectives on the TTP and its implementation across C3I centers. The interview guide (available upon request) included 12 main questions with probes to better understand the process, barriers, and facilitators of implementing an evidence-based TTP in oncology care. Interview participants were informed of the purpose of the interviews, which were audio-recorded and professionally transcribed. For this analysis, we included only transcripts from program leads representing the 20 (of 22) Cohort 1 C3I centers that participated in the qualitative interviews and submitted quantitative report data for the July to December 2019 reporting period. One Cohort 1 C3I center did not submit quantitative report data for this reporting period, and one did not participate in qualitative interviews, so both of those centers were excluded from the current analysis.The aim of the qualitative analysis was to understand how program leads described buy-in, how buy-in was obtained, and the ways in which levels of cancer center leadership and clinician buy-in influenced TTP implementation. We utilized a homogenous, purposive sampling approach for this analysis , in whicQuantitative data were analyzed using SPSS (Version 27). Descriptive statistics were calculated for program characteristics (items are listed in n = 30) of program lead/co-lead interviews across 20 C3I centers that submitted data reports for the June–December 2019 reporting period were uploaded into NVivo (2020)  staff were also willing to work with us. Although the time pressures and demands on the EHR staff on the numerable other things that they need to be collecting, I think, puts a little bit of a pressure on this”.-Respondent 10, Center 8Another program leader echoed that gaining this buy-in from cancer center leadership helped expedite this process of further engaging other partners across the health system:“As we were able to get buy-in from the cancer center leadership, the amount of support seemed to move, and the support from the administrative people and from both [hospital] administration and our own departmental administration in being able to do simple things as find the space around the clinic and work out billing issues, all of that moved much faster once we had buy-in from the cancer center leadership, knowing that this was something that was important to the cancer center”.-Respondent 15, Center 11The four centers for whom securing leadership buy-in was not completed described specific challenges regarding turnover throughout the health system that impacted the level of buy-in and the effort required to obtain it, as illustrated by the following program lead:“One of the things that hurt us a lot here is that during the past two years, we have gone through a lot of changes and transition in leadership. So, every time we have a meeting with leadership members, by the time we go back, the [previous leadership is] not there or they have forgotten […] Every time, it was like starting from scratch, and a new approval is required from someone that we never heard of before”.-Respondent 6, Center 5“We need leadership to provide resources. We need institutional support for these two full-time positions and to cover nicotine replacement therapy and to cover the space”.-Respondent 1, Center 1Beyond obtaining verbal support for the TTP, program leads across all 20 centers said leadership buy-in was demonstrated through the allocation of tangible resources, such as staff time—including IT staff time, which is often a shared resource at cancer centers—designated office space within the cancer clinics, and funds for evidence-based treatment that was not reimbursed by health insurance. Program leads saw their own role as asking for what they needed from clinic and cancer center leadership to implement and sustain a successful TTP, even when those asks required significant time and effort. For example, this program lead explained that the“…biggest test of this program going forward is, Do we have enough staff? We’ll find out very quickly. […] For now, we’ll get the main leadership buy-in to go to their faculty meetings, go to their nurse meetings. That’s basically going to be a full-time job for all of probably January and February”.-Respondent 28, Center 9Program leads said that integrating referral systems and the TTP into routine workflows and monitoring its progress required significant IT support. More than a third of program leads indicated that their IT teams prioritized time-sensitive requests from other cancer center programs over those of the TTP, creating delays and impeding progress towards implementation. Program leads said that identifying IT leaders who would advocate for the program was an essential step in obtaining buy-in from those leaders and their teams. A program lead at one center who had engaged the IT team successfully described the cancer center IT director as being:“…like our quarterback in the IT world. […] He just knows who to talk to. They had their annual system-wide IT meeting [IT Director] invited us to present about this program because he noted IT people usually work behind the scenes. They don’t always learn how their work impacts patient care. After the presentation, his words literally were, ‘My inbox is flooded with people wanting to know how they can get involved in this project’”.-Respondent 8, Center 6In 2019, 17 (85%) centers were offering in-person evidence-based counseling, which required designated physical space to deliver that treatment. At most cancer centers, the TTP spanned multiple clinics where space was a limited resource. However, the relationships and buy-in program leads had established with clinic and cancer center leadership helped mitigate space issues, as illustrated by the following program lead:“The director of the ambulatory operations in our cancer clinics controls the space in our hematology-oncology clinics, which is where they have like a rotating schedule of space that [the tobacco treatment specialist] can use. If it becomes a problem, she will reach out very practically and let him know like, ‘Hey, this is what happened today’. […] They’re supporting us in finding that space. […] We have her set up to have a mobile office capability [with a] laptop. [Cancer center director] got her a cellphone for use inhouse”.-Respondent 7, Center 6A total of 17 program leads representing 15 (75%) centers highlighted the critical role that funding and program endorsement from NCI played in bolstering cancer center leadership support and facilitating early implementation success. Of those, over half described specifically leveraging NCI’s backing of the program as a key discussion point in meetings with cancer center leadership, who program leads perceived to be highly motivated to demonstrate progress in NCI priority areas. This respondent explained that achieving implementation success for the TTP was now an institutional priority:“… I’ve been doing this for a really long time and have had a very hard time convincing people that tobacco dependence services are a critical part of a health system’s role. As soon as the NCI spoke up, that changed”.-Respondent 21, Center 15Program leads described NCI funding itself as a net benefit to initiating the implementation of TTPs at their centers, particularly to designate staff time to develop and scale-up successful programs while devising a longer-term strategy for sustainability. Illustrating this concept, this program lead offered: “The NCI being willing to be involved in this and to put in, even if only a small amount of money to get this jump started, is a very big deal. […] Without that, we wouldn’t have seen the program success that has happened in this past year. Now I’m fully confident that we can continue to keep this up and running over the next years to decades”.-Center 8, Respondent 10However, the end of the grant period presented difficulties at some centers, regardless of if they reported having secured leadership buy-in, as staff would need to be funded outside of the grant model on which the program originated. This program lead explained:“We had a long, arduous negotiation with the hospital over making good on their commitment in the proposal to hire a [tobacco treatment specialist]. […] It required the addition of an FTE to their hard budget…to absorb the people who had already been hired and had been paid for four years on grant funds. It’s just, you know, anything they don’t have to, if they can’t get reimbursement and it’s going to cost them money, they’re skeptical”.-Respondent 3, Center 2Yet, the persistent engagement of cancer center leadership enabled program leads to begin conversations about securing funding beyond that provided by NCI. This program lead explained:“We knew we would have to have [cancer center administrative and clinic directors] on board. […] It’s really not hard to sell treating tobacco [dependence] to oncologists, you know, at least in the head-nod version of doing it. Now, when it comes to the wallet version, I’m not so sure”.-Respondent 16, Center 12Between 85 and 95% of centers had trained clinicians and staff in the new clinical workflow and to implement the TTP . Three tIn quantitative surveys, 19 (95%) centers reported having fully or somewhat integrated clinical champions into the TTP; however, respondents at just 12 (60%) centers discussed champions during qualitative interviews. Program leads representing those centers emphasized champions’ expertise in building enthusiasm among their peers for the program, which they accomplished through leading training and education, answering questions, and helping clinicians overcome TTP ambiguity and indifference. A few program leads also asserted that champions played a pivotal role in achieving buy-in from cancer center and clinic-level leadership in addition to that from clinicians and staff. Program leads said champions were designated this role because they were trusted and respected among their peers and leadership, knowledgeable about tobacco dependence treatment, and dedicated to its implementation. They described two ways that champions were identified. At some centers, program leads recognized promise in nurse practitioners or oncologists themselves. For example, this program lead explained:“The cancer clinicians are so consumed by the active treatment, they weren’t considering tobacco as part of treatment. This project is a tremendous opportunity to change that culture […] When this project came up, I said, ‘[champion name], you seem to get it, and you seem to be a perfect person for this sort of project.’ […] There was no question she is someone who was able to have relationships and come as an insider and bring this part in to start changing the culture”.-Respondent 23, Center 16In contrast, at other centers, program leads relied on the relationships they had developed with cancer center leadership to recommend a person who fit the criteria stated above. This respondent described that the cancer center director:“…was really instrumental in identifying a champion for the program. [We] said, ‘You know, who do you recommend?’ And he recommended two of the very best champions in the cancer center, one on the medical side, one on the radiation side, who have been part of this from the beginning”.-Respondent 2, Center 2Regardless of the presence of champions at their centers, program leads emphasized the importance of providing clinicians and staff—and when possible, cancer center leadership—with opportunities for training to encourage buy-in and increase the likelihood, frequency, and quality of TTP implementation. Program leads highlighted four critical areas in which they perceived that clinicians and staff required ongoing education and training. First, they perceived a need for education on the evidence for tobacco dependence treatment effectiveness among patients with cancer. For example, this program lead recalled:“Some of the people that have been here for a very long time have kind of hardened to the idea that smoking is something that they’re going to be able to change in our cancer patient population and in our culture. They’re pessimistic, and it’s just not a priority”.-Respondent 15, Center 11Second, program leads observed that leadership, clinicians, and staff were largely unaware of evidence for the effectiveness of tobacco cessation in improving cancer treatment and survivorship outcomes. This program lead articulated:“One of the other challenges is just getting people to understand the importance of intervening early in a person’s cancer experience. […] They’re still worrying about, ‘Let’s get to survivorship, and then we’ll start talking about this,’ which the evidence doesn’t support that. I mean, they’re less likely to get to survivorship, is what we’ve been pointing out, if we wait until then”.-Respondent 1, Center 1Third, program leads remarked that many providers were skeptical that patients with cancer would participate in tobacco dependence treatment, given these patients’ unique considerations, such as treatment side effects and smoking as means for coping with a cancer diagnosis. Finally, program leads said clinicians and staff required training on how to refer patients and effectively implement the TTP. Training sessions to address these four areas were implemented in a multitude of ways across cancer centers. At one center, for example, program leads utilized weekly in-services among clinicians“…to increase awareness of the program and create a more personalized relationship with the oncologists to be able to get those referrals”.-Respondent 6, Center 5Champions also commonly delivered training, relying on the trust and relationships they had established among peers to garner interest in program implementation. Several program leads described leveraging the C3I network to send staff to training offered at other C3I centers or to develop joint training programs. For example, this program lead asserted:“We were very fortunate in that we paired up with [other C3I center] to create the tobacco treatment specialist program, and now all of our providers go through that program. We provide them specialized training, which we’ve had to develop for medical providers, specialized training for behavioral providers, and then a lot of just hand holding as well”.-Respondent 9, Center 7Program leads were cognizant that clinician and staff buy-in for the TTP was influenced by who was responsible for referring patients, how easy the referral process was to use, and how well the TTP was integrated into their clinical workflows. In 2019, fewer than half of centers were utilizing automatic EHR referrals; most centers utilized either optional EHR or clinician-initiated referrals , which r“I think for us, the biggest problem is the rate at which the oncologists are canceling the [referral]. I think it’s upwards of two-thirds, so we’ve still got a long way to go. And many of them may be new patients or inpatients”.-Respondent 21, Center 15Many program leads said they mitigated this challenge by giving the responsibility for referrals to nurses, medical assistants, or tobacco treatment specialists. Illustrating this theme, this program lead described hiring a full-time nurse practitioner who“…would show the physicians the best practice advisory and orient them to how to prescribe. However, we’d say, ‘If you don’t want to prescribe, we’re happy to, but let’s set up [electronic] links so that we can see these patients’”.-Respondent 30, Center 20Program leads observed that unless the referral process was both perceived as important and easy to use, clinicians would likely not use it. As this program lead reflected:“We don’t have an alert culture. Physicians ignore it anyway. I will admit to that also. You know how to bypass it, and you’ll just ignore it”.-Respondent 23, Center 16Program leads who perceived themselves as the most successful in addressing clinician resistance persistently engaged their cancer centers’ IT leadership and staff and facilitated exchange between IT teams and the clinicians. This program lead explained:“I was surprised how willing and how supportive [the IT staff] were in the process of getting providers engaged in the tobacco treatment program. [They pulled] some of the data on the Quality Oncology Practice Initiative, analyzed the workflows. They even made small tests of change to support implementation”.-Respondent 14, Center 10In this sequential, explanatory mixed-methods study, we utilized data from quantitative reports and qualitative interviews with 30 program leads at 20 cancer centers throughout the U.S. participating in the Cancer Center Cessation Initiative. Centers offered a range of evidence-based tobacco dependence treatment interventions in inpatient and outpatient clinics, including counseling, pharmacotherapy, and referrals to Quitlines. In quantitative reports, 75% or more centers reported having secured multiple levels of leadership buy-in and having trained clinicians/staff in areas relevant to the TTP. Qualitative data further elucidated components of buy-in across levels of cancer center leadership and clinician/staff levels that were critical to ensuring the successful implementation of TTPs in cancer care settings and the implications of securing each component for TTP implementation . These cOur work both corroborates and builds on prior studies that have examined leadership and clinician buy-in for implementing new programs in primary care, behavioral health, and oncology settings. Published work in implementation science has characterized buy-in as providing support and advocacy . In a stPrior work suggests that implementing new programs for cancer patients and survivors requires buy-in characterized by the belief that this population needs the program and would use it . MoreoveProgram leads described the process of obtaining buy-in from multiple levels as iterative in nature. Although it was possible to have leadership buy-in without staff/clinician buy-in and vice versa, program leads who had secured cancer center leadership’s verbal support for the program, received financial resources and office space, and were provided IT support to implement new workflows and program monitoring indicated that securing staff buy-in came more easily. Centers that did not report having secured all three levels of leadership buy-in tended to focus more on obtaining buy-in among staff and clinicians who would implement the program, particularly as some managed leadership turnover. Future research is needed to determine the extent to which buy-in at the leadership and clinician/staff level influenced the longer-term program sustainability, reach, and effectiveness of programs in C3I.Our study is the first to examine buy-in across a diverse network of cancer centers committed to integrating tobacco dependence treatment into routine oncology care. We used both quantitative and qualitative data to characterize and operationalize this concept. Despite its strengths, there are some limitations to this work. No survey item specifically assessed clinician buy-in, nor did our analysis differentiate between clinician and staff buy-in. The two questions regarding training served as proxies for staff and clinician buy-in. This is consistent with prior work that has found that training improves buy-in among clinicians and those implementing or supporting a new program ,31. The Obtaining buy-in from cancer center and clinical leadership is critical to the successful implementation of tobacco dependence treatment into routine oncology care, but buy-in has not been clearly defined or operationalized. Despite 75% or more of the centers reporting having secured all levels of buy-in and training in quantitative reports, nuances emerged in qualitative data, which offered a deeper understanding of the what, how, and why of buy-in. Our findings suggest that buy-in from leadership is defined as verbal support, access to tangible resources , and access to power  that facilitate TTP implementation. Buy-in among staff and clinicians is defined by the belief that the TTP is necessary, valuable, and evidence based; the belief that patients served will utilize the TTP; and self-efficacy and willingness to refer and deliver evidence-based tobacco dependence treatment to patients with cancer who smoke. Securing these dimensions of buy-in are likely to facilitate implementation success, leading to increased rates of cessation and improved short- and long-term tobacco and cancer outcomes for patients.


Candida, the most common species of which is Candida albicans. The ergosterol pathway in yeast is a common target by many antifungal agents, as ergosterol is an essential component of the cell membrane. The current antifungal agent of choice for the treatment of candidiasis is fluconazole, which is classified under the azole antifungals. In recent years, the significant increase of fluconazole-resistant C. albicans in clinical samples has revealed the need for a search for other possible drug targets. In this study, we constructed a mathematical model of the ergosterol pathway of C. albicans using ordinary differential equations with mass action kinetics. From the model simulations, we found the following results: (i) a partial inhibition of the sterol-methyltransferase enzyme yields a fair amount of fluconazole resistance; (ii) the overexpression of the ERG6 gene, which leads to an increased sterol-methyltransferase enzyme, is a good target of antifungals as an adjunct to fluconazole; (iii) a partial inhibition of lanosterol yields a fair amount of fluconazole resistance; (iv) the C5-desaturase enzyme is not a good target of antifungals as an adjunct to fluconazole; (v) the C14α-demethylase enzyme is confirmed to be a good target of fluconazole; and (vi) the dose-dependent effect of fluconazole is confirmed. This study hopes to aid experimenters in narrowing down possible drug targets prior to costly and time-consuming experiments and serve as a cross-validation tool for experimental data.Candidiasis is reported to be the most common fungal infection in the critical care setting. The causative agent of this infection is a commensal pathogen belonging to the genus IMPORTANCE Candidiasis is reported to be the most common fungal infection in the critical care setting, and it is caused by a commensal pathogen belonging to the genus Candida, the most common species of which is Candida albicans. The current antifungal agent of choice for the treatment of candidiasis is fluconazole, which is classified under the azole antifungals. There has been a significant increase in fluconazole-resistant C. albicans in recent years, which has revealed the need for a search for other possible drug targets. We constructed a mathematical model of the ergosterol pathway in C. albicans using ordinary differential equations with mass action kinetics. In our simulations, we found that by increasing the amount of the sterol-methyltransferase enzyme, C. albicans becomes more susceptible to fluconazole. This study hopes to aid experimenters in narrowing down the possible drug targets prior to costly and time-consuming experiments and to serve as a cross-validation tool for experimental data. Candida. The following Candida species are all reported to cause cutaneous, mucosal, bloodstream, and deep-seated tissue infections: Candida albicans, C. glabrata, C. tropicalis, C. parapsilosis, and C. krusei. The most common of these is Candida albicans  noted several risk factors for invasive candidiasis that include the use of broad-spectrum antimicrobials, immunosuppressive drugs, total parenteral nutrition, iatrogenic interventions, along with several challenges in the critical care setting, namely, the shift to more resistant  therapy . Among tstration . The mec species . The che species .Candida species, and some nonalbican Candida species have already been reported to have intrinsic resistance to azoles  noted a high level of resistance to azoles among o azoles . In fact noted a C. albicans, which can be costly and time-consuming. In this study, we propose a different approach to investigating fluconazole resistance in C. albicans, namely, using mathematical models to determine possible drug targets within the ergosterol pathway. The aim of this study is to narrow down possible drug targets prior to costly and time-consuming experiments and to serve as a cross-validation tool for experimental data. To our knowledge, this is the first study to investigate the fluconazole resistance in the ergosterol pathway of Candida albicans using mathematical modeling.There is an abundance of experimental investigations into azole resistance mechanisms in The rest of the paper is organized as follows: The results of the model simulations are shown in the Results section. These are followed by a discussion on how the results compare with previous literature, the conclusions drawn, and further recommendations that are proposed in the Discussion section. Then, in the Materials and Methods section, we discuss, in detail, the mathematical modeling process.C. albicans.The model was run to simulate several scenarios to investigate possible drug targets in the ergosterol pathway in C. albicans, as no ergosterol was produced, and ergosterol is essential for yeast survival. Cases 2 (0.01×) and 3 (0.1×) simulate the partial inhibition of lanosterol. They yield a higher percentage of the toxic sterol and ergosterol as the dominant metabolite but a lower percentage of ergosterol reduction, satisfying 2 out of 3 criteria which denote fair fluconazole resistance. Case 4 (1×) denotes the default case, which serves as our baseline. Cases 5 (10×) and 6 (100×) simulate the overproduction of lanosterol. They yield a lower percentage of the toxic sterol but a higher percentage of ergosterol reduction, satisfying 1 out of 3 criteria and denoting an equivocal result. The lanosterol concentration was varied as follows: 0×, 0.01×, 0.1×, 1×, 10×, and 100× the baseline value see , represe10.1128/msystems.00691-22.4FIG S2x axes denote the time in hours, and the y axes represent the concentrations in μM. The last two subplots, emphasized in dark borders, reiterate the pertinent plots of ergosterol and the toxic sterol  for easier comparison. Download FIG S2, PDF file, 0.1 MB.Plots generated by the simulation of variations in lanosterol concentration. The variations are as follows: 0× (red solid line), 0.01× (orange dashed line), 0.1× (yellow dotted line), 1× (green dashed dotted line), 10× (blue dense dashed dotted line), and 100× (purple dashed double dotted line). The Copyright © 2022 Yu et al.2022Yu et al.https://creativecommons.org/licenses/by/4.0/Creative Commons Attribution 4.0 International license.This content is distributed under the terms of the C. albicans, as no ergosterol was produced, and ergosterol is essential for yeast survival. Cases 2 (0.01×) and 3 (0.1×) simulate the partial inhibition of C14α-demethylase. They yield a higher percentage of toxic sterol and a higher percentage of ergosterol reduction, satisfying 0 out of 3 criteria, which denotes a good target for antifungals as an adjunct to fluconazole. Case 4 (1×) denotes the default case, which serves as our baseline. Cases 5 (10×) and 6 (100×) simulate the overexpression of the ERG11 gene. They yield a lower percentage of the toxic sterol and a lower percentage of ergosterol reduction, satisfying 2 out of 3 criteria and denoting fair fluconazole resistance. The C14α-demethylase enzyme concentration was varied as follows: 0×, 0.01×, 0.1×, 1×, 10×, and 100× the baseline value see , represe10.1128/msystems.00691-22.5FIG S3x axes denote the time in hours, and the y axes represent the concentrations in μM. The last two subplots, emphasized in dark borders, reiterate the pertinent plots of ergosterol and the toxic sterol  for easier comparison. Download FIG S3, PDF file, 0.1 MB.Plots generated by the simulation of variations in C14α-demethylase concentration. The variations are as follows: 0× (red solid line), 0.01× (orange dashed line), 0.1× (yellow dotted line), 1× (green dashed dotted line), 10× (blue dense dashed dotted line), and 100× (purple dashed double dotted line). The Copyright © 2022 Yu et al.2022Yu et al.https://creativecommons.org/licenses/by/4.0/Creative Commons Attribution 4.0 International license.This content is distributed under the terms of the C. albicans, as the dominant metabolite is ergosterol, and ergosterol is essential for yeast survival. Cases 2 (0.01×) and 3 (0.1×) simulate giving fluconazole with a dose lower than its minimum inhibitory concentration (MIC) . They yield a lower percentage of toxic sterol and a lower percentage of ergosterol reduction, satisfying 2 out of 3 criteria, which denotes fair fluconazole resistance. Case 4 (1×) denotes the default case, which serves as our baseline. Cases 5 (10×) and 6 (100×) simulate giving fluconazole with a dose higher than its MIC. They yield a higher percentage of toxic sterol and a higher percentage of ergosterol reduction, satisfying 0 out of 3 criteria and denoting a good target for antifungals as an adjunct to fluconazole. The fluconazole concentration was varied as follows: 0×, 0.01×, 0.1×, 1×, 10×, and 100× the baseline value see , represe10.1128/msystems.00691-22.6FIG S4x axes denote the time in hours, and the y axes represent the concentrations in μM. The last two subplots, emphasized in dark borders, reiterate the pertinent plots of ergosterol and the toxic sterol  for easier comparison. Download FIG S4, PDF file, 0.1 MB.Plots generated by the simulation of variations in fluconazole concentration. The variations are as follows: 0× (red solid line), 0.01× (orange dashed line), 0.1× (yellow dotted line), 1× (green dashed dotted line), 10× (blue dense dashed dotted line), and 100× (purple dashed double dotted line). The Copyright © 2022 Yu et al.2022Yu et al.https://creativecommons.org/licenses/by/4.0/Creative Commons Attribution 4.0 International license.This content is distributed under the terms of the C. albicans, as no ergosterol was produced, and ergosterol is essential for yeast survival. Cases 2 (0.01×) and 3 (0.1×) simulate the partial inhibition of sterol-methyltransferase. They yield a lower percentage of toxic sterol and a lower percentage of ergosterol reduction, satisfying 2 out of 3 criteria, which denotes fair fluconazole resistance. Case 4 (1×) denotes the default case, which serves as our baseline. Cases 5 (10×) and 6 (100×) simulate the overexpression of the ERG6 gene. They yield a higher percentage of toxic sterol and a higher percentage of ergosterol reduction, satisfying 0 out of 3 criteria and denoting a good target for antifungals as an adjunct to fluconazole. The sterol-methyltransferase enzyme concentration was varied as follows: 0×, 0.01×, 0.1×, 1×, 10×, and 100× the baseline value see , represe10.1128/msystems.00691-22.7FIG S5x axes denote the time in hours, and the y axes represent the concentrations in μM. The last two subplots, emphasized in dark borders, reiterate the pertinent plots of ergosterol and the toxic sterol  for easier comparison. Download FIG S5, PDF file, 0.1 MB.Plots generated by the simulation of variations in sterol-methyltransferase concentration. The variations are as follows: 0× (red solid line), 0.01× (orange dashed line), 0.1× (yellow dotted line), 1× (green dashed dotted line), 10× (blue dense dashed dotted line), and 100× (purple dashed double dotted line). The Copyright © 2022 Yu et al.2022Yu et al.https://creativecommons.org/licenses/by/4.0/Creative Commons Attribution 4.0 International license.This content is distributed under the terms of the C. albicans, as no ergosterol was produced, and ergosterol is essential for yeast survival. Cases 2 (0.01×) and 3 (0.1×) simulate the partial inhibition of C5-desaturase. They yield a lower percentage of the toxic sterol but a higher percentage of ergosterol reduction, satisfying 1 out of 3 criteria, which denotes an equivocal result. Case 4 (1×) denotes the default case, which serves as our baseline. Cases 5 (10×) and 6 (100×) simulate the overexpression of the ERG3 gene. They yield a higher percentage of the toxic sterol but a lower percentage of ergosterol reduction and ergosterol as the dominant metabolite, satisfying 2 out of 3 criteria and denoting fair fluconazole resistance. The C5-desaturase enzyme concentration was varied as follows: 0×, 0.01×, 0.1×, 1×, 10×, and 100× the baseline value see , represe10.1128/msystems.00691-22.8FIG S6x axes denote the time in hours, and the y axes represent the concentrations in μM. The last two subplots, emphasized in dark borders, reiterate the pertinent plots of ergosterol and the toxic sterol  for easier comparison. Download FIG S6, PDF file, 0.05 MB.Plots generated by the simulation of variations in C5-desaturase concentration. The variations are as follows: 0× (red solid line), 0.01× (orange dashed line), 0.1× (yellow dotted line), 1× (green dashed dotted line), 10× (blue dense dashed dotted line), and 100× (purple dashed double dotted line). The Copyright © 2022 Yu et al.2022Yu et al.https://creativecommons.org/licenses/by/4.0/Creative Commons Attribution 4.0 International license.This content is distributed under the terms of the The local one-at-a-time sensitivity analysis was plotted using a tornado chart for ergosterol, as shown in 10.1128/msystems.00691-22.2TABLE S1Table S1, PDF file, 0.05 MB.Model parameters. Download Copyright © 2022 Yu et al.2022Yu et al.https://creativecommons.org/licenses/by/4.0/Creative Commons Attribution 4.0 International license.This content is distributed under the terms of the ERG1 gene deletion results in the demise of C. albicans due to its lack of ergosterol. This agrees with the results of the study by Pasrija et al. (2005) that the erg1 mutant showed a total lack of ergosterol and led to increased azole susceptibility  a partial inhibition of lanosterol yields a fair amount of fluconazole resistance; (iv) C5-desaturase is not a good target of antifungals as an adjunct to fluconazole; (v) C14α-demethylase is confirmed to be a good target for fluconazole; and (vi) the dose-dependent effect of fluconazole is confirmed. This study hopes to aid experimenters in narrowing down the possible drug targets prior to costly and time-consuming experiments and to serve as a cross-validation tool for experimental data.From the model simulations, we found the following results: (i) a partial inhibition of sterol-methyltransferase yields a fair amount of fluconazole resistance; (ii) overexpression of the ERG1 gene that expresses squalene epoxidase, which is the target of antifungal allylamine. Moreover, the computational approach used in our study is also applicable to other, completely different pathways involved in the azole resistance mechanism, such as the CDR1, CDR2, and MDR1 genes, which are involved in the drug efflux transporter. We also recommend doing further experiments on the sterol-methyltransferase enzyme to confirm that its overexpression is a possible target for antifungals as an adjunct to fluconazole in order to validate our simulation result.We recommend extending the model to include other genes involved in the ergosterol biosynthesis pathway, such as the C. albicans is built by adopting the pathways of Sanglard et al. (2003) , and Maure 1 in ). We notERG11, ERG3, and ERG6. Various point mutations in the ERG11 gene were shown to alter the binding abilities of azoles to the C14α-demethylase enzyme  , which compared the sterol compositions of  (GC/MS) .The model uses ordinary differential equations (ODEs) with mass-action kinetics, as first described in , which hThe ODEs for the model with azole  are shown in The constraint equations are shown in C. albicans strain, it is mainly composed of ergosterol (98%), while the rest is classified as unknown (2%). We distribute the unknown 2% to the remaining metabolites in the pathway. In a fluconazole-resistant strain, the sterol composition is as follows: ergosterol (2%), eburicol (16.1%), obtusifoliol (34.5%), 14α-methyl-3,6-diol (45.2%), and unknown (2.2%). We again distribute the unknown 2.2% to the remaining metabolites in the pathway , they used a molar ratio of 1:2:50 for the enzyme, inhibitor, and substrate, respectively . We testble 8 in ). Follow10.1128/msystems.00691-22.3FIG S1x axes denote the time in hours, and the y axes represent the concentrations in μM. The last two subplots, emphasized in dark borders, reiterate the pertinent plots of ergosterol and the toxic sterol  for easier comparison. Download FIG S1, PDF file, 0.04 MB.Plots generated by the model calibrated from Kelly et al., (1997) . The norCopyright © 2022 Yu et al.2022Yu et al.https://creativecommons.org/licenses/by/4.0/Creative Commons Attribution 4.0 International license.This content is distributed under the terms of the C. albicans are as follows: Susceptible (MIC ≤ 2 μg/mL), Dose-dependent (MIC = 4 μg/mL), and Resistant (MIC ≥ 8 μg/mL)  M27-A3  broth mi8 μg/mL) . We recaThe recalibrated model generated the plots shown in A local one-at-a-time sensitivity analysis was performed on the model parameters. We took −10% and +10% of the baseline values of the parameters, as shown in In experimental studies, antifungal susceptibility is quantified via a visual spotting assay on yeast extract peptone dextrose (YEPD) medium , the disC. albicans  proposed the use of percent ergosterol reduction as a quantitative method by which to evaluate antifungal susceptibility . Howeveralbicans . Anotheralbicans .C. albicans: (i) when the percent toxic sterol  is less than 17.73%; (ii) when the percent ergosterol reduction is less than 94.69%; and (iii) when ergosterol is the dominant fraction among the metabolites.Considering the above methods for antifungal susceptibility, we propose the following criteria, based on the data gathered in When all three criteria are satisfied, we designate it as good fluconazole resistance. When two out of three are satisfied, we designate it as fair fluconazole resistance. When only one out of three is satisfied, we designate it as an equivocal result such that no conclusion can be drawn. Conversely, when none of the criteria are satisfied, we designate it as a good target for antifungals as an adjunct to fluconazole.https://github.com/dlsu-scomb/candida-amr.The source code is available at


In January 2010, Haiti was hit by a 7.0-magnitude earthquake. The impact of the earthquake on Universal Health Coverage in mothers remains unclear. This study explores the association between the 2010 Haiti earthquake and access to the five quality essential health services among women who gave birth in the two years before and after the earthquake.From the Sixth Demographic and Health Survey in Haiti, we extracted data for women aged 15–49 who had reported a live birth in the two years before and after the 2010 Haiti earthquake. We used difference-in-difference analyses for antenatal care, delivery care, and vaccination, and multivariate logistic regression analyses for family planning and malaria prevention, to assess the impact of the acute damage  of the earthquake on these mothers’ access to quality essential health services.Mothers who had not suffered acute earthquake damage were more likely to live in rural areas and had less education and household wealth. The difference-in-difference and multivariate logistic regression analyses did not show strong evidence of any significant association between acute earthquake damage and access to quality health services. However, after the earthquake, access to quality health services deteriorated for both mothers with and without acute earthquake damage .The earthquake adversely affected mothers’ access to quality essential health services regardless of their exposure to acute earthquake damage. Mothers in rural areas who avoided such damage might also have experienced long-term negative effects from the earthquake, which was likely exacerbated by other structural factors such as lower education and economic status. Since tAchieving or sustaining UHC even in the context of the emergency  is imperative to minimizing the suffering related to disrupted access to essential health services, especially for vulnerable populations, such as mothers and infants . For exaIn January 2010, Haiti was hit by a 7.0-magnitude earthquake, causing an estimated 316,000 deaths and 300,000 injuries, displacing 1.3 million people, and destroying 97,294 houses . This deTo achieve and sustain UHC even under an emergency like an earthquake, it is critical to identify the weaknesses in the system that cause limited access to quality services for the wide array of essential health services for mothers. In this study, we explored associations between the 2010 Haiti earthquake and the access to quality health services in family planning, antenatal care, delivery care, vaccination, and malaria prevention. We hypothesize that the mothers exposed to acute damage from the earthquake, such as household-level housing damage and/or loss of a family member or region-level collapse of houses, had more deteriorated access to quality health services compared to mothers who did not.We used the Sixth Demographic and Health Survey (DHS) in Haiti, which comprised retrospective data collected after the earthquake for 14,287 women aged 15–49. The DHS is a nationally representative household survey conducted in more than 85 countries worldwide since 1984. DHS has high response rates  [We included women who reported a live birth in the two years before and after the 2010 Haiti earthquake . We included only the latest birth if a woman had multiple births because the DHS collected detailed data on pregnancy or delivery of the latest birth. The women who reported a live birth more than two years before the earthquake were excluded to minimize potential recall bias. We applied additional inclusion and exclusion criteria to make the sub-cohort for each outcome because the mothers’ need for health services were different depending on the type of services  and/or loss of a family member (yes or no) due to the earthquake. If mothers experienced housing damage and/or loss of a family member due to the earthquake, they were defined as having suffered household damage. We measured both based on the retrospective self-report by mothers who answered the Haiti sixth DHS questionnaire. Regional damage was defined as living in the region where 50% or more of houses had been damaged. This definition was used in the previous study that explored the impact of the 2010 Haiti earthquake on birth outcomes . To the First, as a primary definition, mothers who had experienced at least one of household damage or regional damage were defined as the exposed group. Second, mothers who had suffered household damage were defined as exposed regardless of their exposure to regional damage. Third, mothers who had experienced regional damage were defined as exposed regardless of their exposure to household damage. To measure short-term damage from the earthquake in antenatal care, delivery care, and vaccination, we limited the exposed group to mothers who reported a live birth within six months after the earthquake.The outcomes were: access to quality health services in family planning, antenatal care, delivery care, child vaccination, and malaria prevention because these are considered essential health services under UHC  and coulWe assessed several individual-level characteristics of mothers: age (continuous variable), smoking status (yes or no), education status , urban or rural, region of residence , decision maker for health care (not mother or mother), household wealth , alcohol drinking , mothers’ occupation , and fathers’ occupation .Mothers’ characteristics were described as the mean and SD for continuous variables and as the number and percentage for categorical variables. These characteristics were compared between the earthquake exposed group and the unexposed group stratified by before and after earthquake using Mann–Whitney test for continuous variables and Fisher’s exact test for categorical variables.For antenatal care, delivery care, and vaccination, we used the difference-in-difference (DID) analysis. The DID design requires two differences: the difference in the outcomes comparing after and before the event in the group exposed to the event (A1), and the same difference in the group unexposed to the event (A2). The change in outcomes associated with the event unexplained by the secular trends could be estimated as A1–A2. In our study, the effect of the Haiti 2010 earthquake on EC in each health service was analyzed using the logistic regression model and the equation below:ί is the possibility of experiencing the outcome of interest for participant i; (2) Exposureί is 1 if the participant i experienced the earthquake; (3) Postperiodί is 1 if the participant i gave birth after the earthquake; (4) the interaction between Exposureί and Postperiodί captures the effect of the earthquake  on outcomes of interest after excluding the effect of temporal trend on the outcomes; (5) Cί is the vector notation of mothers’ age and education status.where  PRί is tIn the DID analysis, we included mothers’ age and education status and did not include other covariates because the latter were measured after the earthquake and were probably affected by it; hence, if they were adjusted, the effect estimate would have been underestimated. To evaluate the validity of the DID design, we examined pre-earthquake trends in the outcomes and assessed the plausibility of the parallel trend assumption . For famFor both DID and multivariable logistic regression analyses, we applied a mixed effect model with the random effect of region (11 regions in Haiti). To address potential bias due to missing data, we applied the multiple imputation method in which we used the chained equations to create 10 imputed datasets . The estimates from the 10 imputed datasets were then combined using Rubin’s rules .We conducted several sensitivity analyses. First, for the outcome of antenatal care, we excluded births within 10 months after the earthquake because these mothers likely received antenatal care both before and after the earthquake; hence, the outcomes may be misclassified in terms of the temporal relationship with the exposure. Second, we conducted DID and multiple regression analyses with the outcomes in continuous variable . All methods were carried out in accordance with relevant guidelines and regulations.The final sample included 5703 mothers; 3229 reported a live birth before the earthquake and 1844 reported a live birth after. The earthquake-exposed mothers were more likely to live in urban area, have higher education and household wealth status, and have non-agricultural occupations  and -6.2% for mothers with acute earthquake damage (mothers who suffered from household damage or lived in hugely damaged areas) in antenatal care, -6.5% and 0% in delivery care, and -9.5% and -13.1% in vaccination, respectively Table . Figure We conducted this retrospective study to explore the impact of the 2010 Haiti earthquake on quality health services in mothers. Contrary to our hypothesis, we did not observe strong evidence that mothers with acute damage from the earthquake experienced lower access to quality health services compared to mothers without it. This may be because the acute earthquake damage did not cause any negative impact, or the earthquake equally impacted both groups. Because both groups of mothers' access to quality health services were found to have deteriorated in the descriptive analyses Table , the earTo the best of our knowledge, this is the first study that shows that mothers who did not suffer from household damage or did not live in hugely damaged areas also experienced deterioration of access to quality health services. Previous studies show that mothers exposed to the earthquake were more likely to have adverse reproductive health outcomes compared to unexposed or less exposed mothers –8. This There could be several explanations for the deterioration of access to quality health services even for mothers who did not suffer from household damage or did not live in hugely damaged areas. First, long-term structural damage on the health care system may have adversely affected the access to quality health services even for mothers who avoided acute earthquake damage. Well-known long-term structural damages involve the spread of communicable diseases. Even before the earthquake, it was only less than 10% of the population who had access to potable tap water, and less than one-third that had access to electricity . HoweverSecond, mothers who did not suffer from household damage or did not live in hugely damaged areas were relatively more exposed to the long-term structural damages due to pre-existing vulnerabilities. In our study, mothers who did not suffer from household damage or did not live in hugely damaged areas mainly lived in rural areas and had lower education or wealth status than the exposed mothers. There is evidence that poorer and less educated people are more vulnerable to the disaster , 29. ThuThird, although mothers who suffered from household damage or lived in hugely damaged areas suffered the most , the overall effect could have been mitigated slightly due to the intensive foreign aid and reconstruction efforts in urban areas, compared to mothers without acute earthquake damage as they were mainly in rural areas .Our study has several strengths. First, we used the large-scale nationally representative household data, which were constructed with well-established sampling and data collection methods. Second, we applied DID, a statistically robust natural experimental method, which could appropriately consider unmeasured non-time varying confounders. Third, multiple analyses with different definitions of earthquake exposure showed similar tendencies, strengthening the robustness of our results.Alongside this, several limitations should be acknowledged. First, our study targeted mothers in Haiti, and the generalizability of our results to mothers in other countries should be carefully interpreted. Second, if mothers suffered other impacts at the same time as the earthquake, the DID method could not appropriately estimate the impact of the earthquake (common shock assumption) . HoweverThe 2010 earthquake negatively affected Haitian women’s access to quality essential health services regardless of their exposure to acute earthquake damage. Furthermore, mothers who did not suffer from household damage or did not live in hugely damaged areas may have suffered from the long-term structural damages of the earthquake, which were likely exacerbated by other structural factors such as their lower education and economic status. As part of recovery efforts for UHC in Haiti, government and emergency aid need to pay attention not only to mothers who suffered from acute earthquake damage, but also to mothers who did not but were nonetheless exposed to long-term structural damages and rendered vulnerable. Further studies that use longitudinal data with robust balancing methods such as matching are required.


Few addiction treatment options are available in Arctic Canada, leading many Inuit to seek treatment programs in southern cities. We conducted a case study to understand what contributes to a culturally safe experience for Inuit in a mainstream addiction rehabilitation centre in Southern Canada. We carried out more than 700 hours of participant observation, in addition to semi-structured interviews and member-checking activities with 20 Inuit residents, 18 staff and four managers. Data were analysed using an inductive interpretative process. Throughout their journey in the program, Inuit navigated through contrasting situations and feelings that we grouped under six broad themes: having Inuit peers, having limitations imposed on one’s ways of being and doing, facing ignorance and misperceptions, having conversations and dialogue, facing language barriers and being in a supportive and caring environment. This study highlights how cultural safety varies according to people, context and time, and relates to developing trustful relationships. Significant health disparities exist between Indigenous and non-Indigenous populations worldwide , with coResponses to addictions are largely provided through systems and mechanisms that can reinforce disparities. Health systems are social spaces in which power relations intersect with social categories such as race, class and gender . It is gThe recognition of pervasive inequity and discrimination led Maori nurses in New Zealand to propose ‘Cultural Safety’ as a guiding principle and an analytical perspective for considering the influence of the broader historical, sociocultural, political and economic context in the delivery of health services and the creation of health disparities . CulturaTo date, studies that have used cultural safety as an analytical lens examined experience of care cross-sectionally e.g. . We knowThis article is part of a larger project which aims to explore the contribution of cultural safety to identify ways to improve access and services offered to Inuit in mainstream residential addiction rehabilitation programs . We condThe study was conducted in an addiction rehabilitation centre with residential programs in the southern part of the province of Quebec, Canada. As a private institution with agreements with the Quebec Ministry of Health and Social Services, the centre offered voluntary mainstream outpatient and residential addiction rehabilitation programs, as well as aftercare and continuing care programs, social and employment reintegration services, and family services. It served different population groups: adolescents, adults, pregnant women and mothers with young children, adults with mental health issues and individuals referred by the justice system. Over time, the centre had worked with individuals from different ethno-cultural backgrounds including Indigenous peoples, with Inuit representing less than five percent of its program users.Within a therapeutic community approach , programWithin special projects intended for them, Inuit in the residential programs (‘Inuit residents’) gathered approximately once a month in one location outside the centre’s premises, where they could eat traditional foods; the group also met with visiting Inuit Elders who came quarterly to share their life experiences with Inuit who were in institutions in the South (treatment or detention centres). Starting in 2018, a few staff had also been visiting selected villages in northern Quebec, approximately monthly, to offer aftercare support to former Inuit residents.Data collection and analysis were informed by ethnographic and creative research methods . The worOver a 2-year period, the PhD candidate (Julie Lauzière) collected data using participant observation, document review and in-depth interviews, followed by member-checking activities. Participant observation helped the PhD candidate to become familiar with the centre’s activities, functioning and context of intervention, and to establish rapport with its various actors . At the Inuit residents in three of the centre’s adult programs as well as staff and managers were purposively invited to participate in in-depth interviews. Invitations to Inuit residents were made to maximize diversity based on age, sex/gender and life experiences. Other participants were selected based on their role and the intensity of their contact with Inuit residents. The research team developed semi-structured, open-ended interview guides based on the literature and preliminary understanding of the therapeutic context. The interview guides were discussed with an Inuit community organization director before pretesting with one Inuit resident from the case who later agreed for her interview to be retained for analysis. Interview guides evolved over time based on collected data.n = 3), minimal notes were taken during the interview and expanded thereafter.All interviews were conducted by the PhD candidate in English or French, according to each participant’s preference, in closed rooms on the centre’s premises. In-depth interviews lasted 35–110 minutes with Inuit participants and 25–200 minutes with staff participants. Interviews were audio-recorded and transcribed verbatim. For participants who were uncomfortable with audio-recording  from five of the centre’s residential programs. A total of 20 Inuit residents (19 women and one man) aged 18–61 years participated in interviews and/or member-checking activities. All were originally from the Inuit Nunangat and two of them had been living in southern Quebec for over 2 years. Staff participants included 18 clinical/specialized staff and four clinical/administrative managers (15 women and seven men) aged 24–67 years. None of them self-identified as Indigenous. Two-thirds had a lifetime’s experience of problematic alcohol and/or drug use, with some of them being former residents of the centre’s programs. Staff participants had from 1 to 33 years of experience in the field of addiction treatment, including 6 months to 23 years in their current job.Through their narratives, Inuit participants spoke about their experience of navigating between contrasting yet interrelated situations and feelings throughout their program. We grouped these into six broad themes based on the interpretative analysis: having Inuit peers, having limitations imposed on one’s ways of being and doing, facing ignorance and misperceptions, having conversations and dialogue, facing language barriers and being in a supportive and caring environment. After giving an overview of Inuit participants’ journey into the program, we provide a detailed and nuanced description of when and how these interrelated elements manifested and operated in the program to either foster or hinder their cultural safety. The themes are presented in a way that is meant to emphasize the dynamic interplay between them. Data from staff interviews and participant observation are brought into the narrative presented here, when they shed additional light on the context or relational dynamics in the program. All quotes are from Inuit residents, identified by pseudonyms. Quotes from Francophone participants were translated into English by the research team after data analysis was completed.Most residents followed similar stages during their journey into the program see ; each jo“First came here, I felt very insecure. Because I didn’t know what’s going on, I didn’t know the people. But then I got to know them. I felt more secure.” (Elisapie)For Inuit participants, working with “addicts” who “need fixing themselves” (in their words) was especially upsetting at first. Many Inuit needed two to three months – representing a third to a half of their program – before starting to settle down and to use the proposed therapeutic tools. “Getting to know” the place, the people and the program was a key process for Inuit participants to feel more comfortable and safer in their new environment.“As far as I’m concerned, this is my second family.” (Mae)Inuit participants who stayed in the program eventually got “used to it” and came to better understand and appreciate the program. Along their journey, they also made personal realizations that led them to commit more to the program. By interacting more with the other residents and staff using the program tools, Inuit participants developed new relationships based on having experienced similar life situations and emotions. When further developed and sustained over time, such connections eventually led Inuit participants to feel that they belonged to the ‘family’ or ‘community’ of program residents.While the above provides a general overview of a ‘typical’ journey in the program, it should not be understood as the journey of all Inuit participants, nor as a linear one. The stories we heard highlight that all residents had ups and downs at all stages of the program, yet all experiences were unique. Not all residents we met completed their program, and some had returned for another program, regardless of whether or not they had completed the previous one.“First time when I arrived, I saw [name of a particular Inuit resident]. I was all safe.” (Annie)Having Inuit peers, especially when first arriving in the program, was valuable to most Inuit participants as it helped them to be more at ease in this unfamiliar environment. In addition to offering the opportunity to speak in their first language, Inuit participants reported that they were more open to talk to Inuit peers and felt better understood by them given their common understanding of Inuit historical experience and present situation. In contrast, conversations with non-Inuit were sometimes described as “awkward” due to language barriers or having different sociocultural referents.“[When we meet with Elders], they think we’re getting special treatment. I try to explain to some of the girls that you know, we do our therapy too, it’s not like we’re just going out to have fun and eat country food. We have our own little therapeutic community too.” (Minnie)In the same way, Inuit participants were greatly appreciative of and touched by the occasional visits by Inuit Elders, and deplored the comments they received every now and again from some non-Inuit residents who seemed to see this activity as a privilege and/or did not recognize its therapeutic value. Among other things, these meetings with Elders and other Inuit residents provided them with meaningful support and motivation to continue their healing journey.Having Inuit peers was also important to Inuit participants because it helped them to develop relationships with fellow Inuit while sober. Nevertheless, these relationships were sometimes conflictual, as some Inuit participants reported being “put down” by Inuit peers at times, a situation that resulted in acute feelings of loneliness and isolation.The presence of Inuit residents in programs fluctuated over time, depending on demand and available space. There were periods when there was only one Inuit resident and others when there were several (up to eight) or none. Some reported feeling alone and isolated when they were the lone Inuk in their program, whereas some others, while they also found the situation difficult, nevertheless saw it as an opportunity to connect with non-Inuit. In all cases, Inuit participants were concerned when leaving the program meant there would be a single Inuk remaining.From the staff, there was a clear recognition of the importance and benefits of having more than one Inuk at a time in the program to facilitate their integration. However, some staff questioned the depth or quality of the relationship between Inuit residents, particularly when they came from the same northern village or were related otherwise, with some of these relationships in the program being seen as mostly based on convenience.“It was very difficult for me at first because I was told… I don’t know how many times, not to be around Inuit, as much. [...] It was very difficult for me. I can’t just seem to… not be around them, because I’m so used to them. Like even though I didn’t know them for, like, a long time. Like if there’s Inuit, I’ll go to them.” (Maggie)At different points in their program, Inuit participants felt forced to do things they did not want to or that they did not understand. Likewise, some reported they felt prevented from acting according to their personal and/or collective ways of being and doing:“In the beginning, I wasn't hanging out with the French girls or English girls or... either talking to them. I was just talking to [name of a given Inuit resident] and the other Inuit girls, mostly. And they would tell us, like ‘you Inuit girls’, ‘you Inuit girls’... And… I just felt like they were racist. And that they wanted us differently than the other girls. [...] And, I feel, I just felt watched.” (Elisapie)In some situations, Inuit participants felt they were treated differently specifically because they were Inuit, such as when they were asked to stay away from fellow Inuit and to mix more with other residents or when they were asked not to speak in Inuktitut so everybody could understand their conversations. When experienced or perceived by Inuit residents as manifestations of racism, these situations impinged on their experience of cultural safety in the program:Staff rather explained that they would intervene whenever they perceived that a “negative alliance” or an “unhealthy dynamic” existed between residents or group of residents in order to preserve the safety aspect of community dynamics and the integrity of the therapeutic approach. Although this course of action was not specific to Inuit residents, it was said to be likely happening with them because of their inclination to group together, sometimes without letting other people into their circle.In situations where Inuit were asked to stay apart from each other, they would usually come to see benefits in that they were able to develop relationships with at least some non-Inuit residents; however, if the same intervention was made too early in their program or at a time when they had not yet developed a basic relationship with at least one other resident in the program, Inuit participants felt isolated and not listened to.In contrast to the community dynamics that made them feel different or controlled, Inuit participants appreciated being able to have some input in their own individual plans of care in terms of what they felt they needed to improve instead of being told what to do, as this made them feel that their view matters.[laughing] And they understand that I live in a lot of places where there is alcohol and drugs.” (Louisa)“They only understand I live in a violent home. In a cold [climate]. With animals. For Inuit participants, having to live and work with non-Inuit was uncomfortable at times due to their ignorance of, and misperceptions about, the northern/Inuit context. From the Inuit participants’ perspective, non-Inuit residents and staff had a very limited knowledge and understanding of Inuit history and ways, the kind of life Inuit go through every day, and resources available in their communities. Staff acknowledged this perception describing how judgemental and reluctant they were at first to change their ways. Some staff have had (or still had) concerns over some Inuit customary practices. This sometimes led them to try to change Inuit residents’ ways, including how they take care of their loved ones or spend their money, even when it was not related to the reason for their participation in the program.Throughout their program, Inuit participants faced many situations where the ignorance or misperceptions of non-Inuit residents and staff translated into negative experiences for them. As an example, staff participants shared their perception over how the northern environment is challenging for anyone who struggles with alcohol or drug issues to stay sober. Combined with an absence of knowledge of the resources available in Inuit communities, this concern led some staff – and non-Inuit residents as well – to adopt an overprotective approach towards Inuit residents and to suggest that they should consider not returning home after their program. In this view, there was little recognition of how wrenching a choice between home and sobriety could be, nor of the challenges Inuit would likely face by moving to a southern city (e.g. living without one’s relatives around and finding an apartment and a job). Inuit participants were hurt whenever staff and non-Inuit residents verbalized or acted as if they were thinking that all Inuit will relapse at the end of their program and/or they did not believe in their ability to stay sober in their home community. They felt mistrusted in such situations, which resulted in strong feelings of sadness, bitterness and anger. Inuit participants also felt uncomfortable, different or judged in situations where others were reacting to or asking them to change their ways, as described above. These negative experiences were usually associated with Inuit closing themselves off to others and/or to the program.Many of the challenging situations faced by Inuit participants sparked conversations and open dialogue among staff and residents, which helped to reduce tensions and to foster openness and trust. Staff participants reported the need to better understand Inuit life context and culture to be able to adjust their interventions accordingly, and they view interactions with Inuit residents as opportunities for non-Inuit to create relationships with Inuit while learning more about them individually and collectively. In that respect, staff often encouraged Inuit residents to talk about where they come from to non-Inuit residents and staff. Some Inuit participants were more open and comfortable to do so than others, depending on their personal traits and life experiences, as well as the context and subject matter.“I used to be so wishing that staff could go up North. Now they have after-care group. Now they understand more what we go through with up North. So that is really helping too.” (Jeannie)Dialogue did help, most of the time, although educating non-Inuit represented an additional burden on Inuit participants. One thing that helped to alleviate this burden was the fact that some staff members had begun to travel regularly to the North to offer aftercare support. For Inuit participants, this contributed to a sense of being better understood, and for the staff who had gained this work experience in the North, it made it easier to build connections with Inuit residents thereafter. These staff usually became ‘allies’ for Inuit participants as they had witnessed and could corroborate information regarding their living conditions and realities:Throughout their program, language barriers presented significant challenges for many Inuit participants. At the time of data collection, most Inuit were more comfortable speaking in Inuktitut than in English, and only a few were fluent in French. In contrast, most non-Inuit residents were Francophones and had limited proficiency of English. Most staff were fluent in French and English, but none spoke Inuktitut. For Inuit, being in such a place contributed to a lack of comfort, being closed off and loneliness. Some had the sense of not being in the right place, especially at the beginning of their program.Language barriers created a gap among the residents because of limited verbal interaction and communication, which contributed to misunderstandings and hindered the development of relationships with non-Inuit residents. To some extent, the language barriers also impacted the understanding that Inuit participants had of the program structure, routines and therapeutic tools, as well as their retention, participation and/or progression in the program. Having to use English or French represented an additional challenge when they wanted to express themselves, particularly when it came to sharing their feelings. Some Inuit were afraid to be judged or laughed at for the way they express themselves in another language, whereas others were hard on themselves for being slow or remaining silent in their interactions with non-Inuit. As most everyday conversations were in French and not everything was automatically translated into English during group meetings, Inuit reported being annoyed or frustrated having to constantly ask other residents or staff for translation into English (or Inuktitut) when their need for translation was known by all. Conversely, the staff saw these interactions as opportunities to learn how to be assertive and take one’s place in a group. Inuit participants were greatly appreciative when translation was readily offered, including during celebrations and at times when decisions about the affairs of the resident community were being made. This gave them access to the information that was being shared and made them feel that they were considered as full members of the resident community.[Name of an Inuit resident] told me that he does “not trust White people” and that he does not speak to them. Although he studied French in school and understands it very well, he said that nobody knows about it in the program and he acts as if he always needs the translation. (excerpt from field notes)Beyond these considerations, language and communication issues reflected the level of relational comfort with residents and staff. When they first came into the program, some Inuit participants were not comfortable enough to let people know that they understood or spoke some French or, in a few cases, that they were actually fluent in French. Part of this was explained by the fact that they have limited opportunities to learn and use French in the North and needed time to be more confident in their abilities to use it in their interactions with Francophones. This was also the case for English although there was greater familiarity and fluency. Language was nevertheless intertwined with closedness and mistrust. Some Inuit participants have hidden, sometimes for weeks or even months, the fact that they were understanding what was going on in French to protect their distance from others and the program because of trust issues and/or to resist to the program:Language issues usually receded over time as Inuit residents became more familiar with the people and the program structure.“There’s a lot of care. […] I don’t see care… much at home, as much as they do here. It makes me… I’m part of the group. Just the feeling of the thing they care for me. And that they’re there for me. Just makes me I’m part of this, the community.” (Elisapie)Ultimately, Inuit participants found support and care through the relationships they developed with other residents and staff. For Inuit participants, being cared for meant having people who were there for them, to support them. Such people were described as sober, honest, well-meaning, helpful, empathetic and caring. They were welcoming and inclusive, reaching out to them and sharing their life story with them. They were taking an interest in them, listening to them and showing consideration and understanding of their situation.These attributes contributed to feelings of trust and safety among Inuit participants. Being cared for made Inuit participants “feel important”. It helped them to feel less lonely, increased their self-esteem and gave them a reason to be hopeful for the future. Many Inuit participants had gone through traumatic events and had relatives and friends who were less available to offer appropriate support, especially emotional support, because of their own drinking and/or drug problems. In turn, following their experience in the program, several Inuit participants have said they wanted to be a caring person for their loved ones and/or to support other Inuit who are struggling with addiction as they did.From the overall experience of Inuit participants, we developed a model which proposes a way of understanding the relational interplay influencing their cultural safety in this setting see . The quaWe examined the experiences of Inuit in a mainstream addiction rehabilitation centre to understand how cultural safety develops and unfolds in this context, using a case study design. The unique characteristics of the selected case allowed for a longitudinal examination of factors contributing to cultural safety within a complex intervention setting; in this case, long-term mainstream residential programs based on a therapeutic community approach. Our findings highlight that the relational dimension is central to understanding the Inuit experience of programs in a longitudinal perspective. The quality and outcome of the multiple encounters they had with the staff and other residents was a major influence on the development of trust and cultural safety over the course of their program. Key elements to promoting cultural safety in this context included having Inuit peers, having conversations and dialogue, and being in a supportive and caring environment, whereas having limitations imposed on one’s ways of being and doing, facing ignorance and misperceptions and facing language barriers were rather hindering cultural safety. Our study emphasizes the need to consider the dynamic interplay between contexts and practices that promote and hinder cultural safety, particularly in long-term care programs, to enhance the care experience of Inuit and likely of other population groups.Historical and ongoing experiences of oppression and marginalization of Indigenous peoples resulted in a loss of trust in self, family/clan, community, and government and outsiders, all of which impacts the way Indigenous people engage in life, build relationships and participate in various activities, including treatment programs . Like otBy emphasizing the central role of trust in fostering a sense of cultural safety in Inuit, our findings point to its dynamic nature as a relational process outcome. Trust needs to be established for “exotic differences” in the care relationship be exposed, discussed and negotiated , p. 179.Opportunities to develop trust are generally more limited in programs characterized by rigidity and restrictions imposed on its users, which may contribute to perpetuating mistrust of the system . CollectLanguage barriers and cross-cultural misunderstandings have been observed to negatively impact the self-esteem of Inuit when interacting with southern mainstream health services , which iProviding culturally safe care implies being able not only to notice, recognize and interpret correctly various communication cues including verbal, body and gestural language and silence; but also being knowledgeable and reflexive about our own communication patterns . Not knoCommunication is a medium through which power can be exercised . In our To the extent that the therapeutic community approach is essentially based on peer support, the relational dynamics are necessarily different from those in other contexts where a care provider has a status and knowledge that places him or her in an expert position relative to the care recipient. That said, therapeutic communities remain places where power issues are present, tied to the structure and program modalities that involve certain types of interactions among their members, residents and staff included. That all staff and most residents were non-Inuit also points to the need to explicitly consider the macro context influences on interactions and power dynamics . This isMost participants had a very limited awareness or understanding of the historical and socio-political context in which their interactions in the program took place. Raised and socialized in different yet interconnected social worlds, Inuit and non-Inuit inevitably have different embodied experiences of life and of the persistent legacies streaming from colonial history, which could lead to very different interpretations or actions in response to a same situation. In some cases, the pervasiveness of racism and discrimination may have played a role in Inuit participants’ lives, including in the very pathways that brought them into treatment at the centre. As most Inuit participants were women, it should also be noted that compared to Indigenous men, Indigenous women and girls are known to be disproportionately impacted by prejudice and discrimination and feel less safe in their interactions with the health care system due to the intersection of racism against Indigenous peoples, misogyny and gender discrimination . As for To foster a therapeutic community spirit, the staff focused on the commonalities in residents’ experiences. Although this strategy had some benefits, it also entails potential risks to cultural safety as it may result in situations where individuals’ experiences are being examined and understood only in the light of these commonalities . For example, some staff were likely to interpret the fact that Inuit residents felt judged or misunderstood as a common trait of people who use alcohol/drugs, without necessarily considering the ways in which multiple systems of oppression such as racism, colonialism, classism and sexism intersect to structure the unique life experiences of each resident . For InuAlthough the responsibility of providing a culturally safe environment lies with the care providers and institutions, the actual outcome of their efforts also depends on the care recipients who have to engage themselves in the relational care process to actualize cultural safety. For managers and care providers serving Inuit, it is essential to understand and consider the gap in trust and to create the conditions for mutual trust to develop. A closer attention to communication issues and power imbalances would also be warranted. A better understanding of the immediate and broader contexts in which care is provided could help moving forward in this direction. Finally, care providers and institutions can refer to equity-oriented initiatives and tools to foster the critical reflexivity and organizational changes necessary to create culturally safe care environments e.g. .This study contributes to the understanding of key features of culturally safe addiction rehabilitation programs for Inuit, especially women. Further research with Inuit men is warranted as their care experiences might be different. Our observations are also intrinsically linked to the therapeutic context and approach in the participating centre. During data analysis, it was difficult at times to distinguish the relational dynamics associated with cultural safety from the recovery process in group therapy which involves self-identification or self-affiliation to the group. The transferability of study findings to other settings, especially where programs are shorter and/or focusing on individual counselling, would need further exploration. Finally, we cannot completely avoid the risk of essentialization in the way we represented Inuit and non-Inuit participants in the study, although we have tried to minimize distortions by using reflexivity and perspective throughout the research process.Our study reinforces the idea that being culturally safe relates to developing trustful relationships with the people around oneself. In a place that is likely to pose a cultural risk due to a marked sociocultural distance and power differentials, some encounters or situations would foster a sense of cultural safety while others will go the other way, depending on people, context and time. Consequently, we find that cultural safety cannot be conceptualized as a simple dichotomous outcome of care nor as a consistent one, especially in a complex long-term intervention.


Existing educational programs typically include limited information on traditional, complementary, and integrative medicine (TCIM) for survivors of childhood cancer.This brief report presents the preliminary results of an educational program that aims to promote the safe and effective use of Chinese medicine (CM) among survivors in Hong Kong.Survivors of childhood cancer, their caregivers, and oncology practitioners were invited to participate in a program that consists of two didactic seminars and a written educational booklet that disseminated information on the use of CM. A structured questionnaire was used to evaluate participants' receptivity toward and perceived relevance of the program. The Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) framework was used to discuss the impact of the intervention.Reach: A total of 174 participants attended the seminars, and the seminar recording received over 380 views on social media platforms since April 2021. The hardcopy of the educational booklet was distributed to 43 recipients. The web-version of the booklet was sent to 67 participants and downloaded 143 times. Efficacy: The majority found that the content of the seminar useful (mean score = 5.04/6 points), especially the CM exercise (mean score = 4.88/6 points) and dietary advice (mean score = 4.99/6 points). Intention to adopt: The survivors (or their caregivers) reported that they would adopt advice on food therapies (83.3%) and traditional Chinese health exercises (55.6%) during survivorship.The preliminary data on patient preferences will be applied to further develop educational materials and to establish a TCIM referral network within the cancer survivor community. Advances in contemporary treatment strategies have led to a significant improvement in the 5 year survival rate of children with cancer, leading to an emerging population of survivors globally . HoweverWhile some of the late effects may require lifelong pharmacological interventions , survivoIn Hong Kong, the use of TCIM is increasingly prevalent among patients and survivors of cancer. This popularity is fueled by the recognition of Chinese medicine practitioners as a licensed profession and the incorporation of the citywide Chinese Medicine Clinic cum Training and Research Centers into the public healthcare service in Hong Kong . FurtherCancer survivors and their families are often highly receptive to knowledge about lifestyles optimization during the early survivorship period. Previous research has demonstrated the short-term efficacy of health education programs in increasing health-promoting behaviors, such as nutrition and physical activities, among survivors of childhood cancer , 15. In The research-to-practice gap in translating knowledge of TCIM to practice models has been widely recognized. Health authorities, such as the National Center for Complementary and Integrative Health, support the implementation and dissemination of research on TCIM interventions . In receIn March 2021, our group initiated a program that aimed to deliver educational resources to promote the safe and effective use of CM and to develop a framework for providing advice on CM for survivors of childhood cancer. This report aims to present: (1) an overview of the educational program; and (2) an initial evaluation of the participants' receptivity toward the program and their content preferences. We aimed to incorporate elements from the RE-AIM model to describe the impact of the program thus far, to discuss the application of these preliminary findings in advising future implementation strategies and the development of the educational program, and to identify future opportunities for integrative care in survivorship care.The educational program, entitled “Promoting Safe and Appropriate Use of TCM in Survivors of Childhood Cancer” (19B1-2/017A_R1), was supported by Hong Kong Food and Health Bureau under the Chinese Medicine Development Fund. The core study team consisted of two pediatric oncologists (AWL and CKL), two pharmacists (CSL and HWC), two licensed Chinese Medicine practitioners specializing in integrative oncology (HKK and KYA), and one methodologist (YTC). The program specifically targeted individuals who were diagnosed with cancer before the age of 18 years and had completed anti-cancer treatment . As the majority of patients and survivors were still under the age of 18 years, the content of the program was designed mainly for their parents and caregivers. Healthcare professionals specializing in oncology and/or TCIM were also invited to participate in the program. The overall framework of the program is presented in As part of the program, a series of didactic seminars are held to disseminate information on CM use to childhood cancer survivors and their families/caregivers. The seminars are advertised through local pediatric oncology groups, non-governmental organizations, and social media platforms (WhatsApp and Facebook). The seminars were delivered by registered CM practitioner focusing on the field of integrative oncology. The selection of seminar topics and contents was based on clinical consensus among the study team members and our previous report on the most common TCIM modalities among local cancer survivors .Due to the COVID-19 pandemic, the first seminar was delivered by video conference using Zoom  on April 15, 2021. The contents of the first seminar were mainly focused on: (1) CM perspectives on children physiology and cancer; (2) the body constitution characteristics according to CM theories; (3) CM principles of health promotion in cancer in both physical and psychological aspects; and (4) CM advice  for survivor. The second seminar was delivered at the CUHK Medical Center, a non-profit, private teaching hospital, and livestreamed over Zoom. The second seminar focused on non-oral therapies  for survivors of childhood cancer.Both seminars also involved clinical sharing of healthcare professionals and an interactive question-and-answer session at the end. Recordings of the seminars were uploaded to social media platforms and made available to the public. The presentation slides were also disseminated to the participants after the seminars. A summary of the content covered in the seminars is presented in A set of educational materials was developed to provide information on CM theories and advice on CM use during the post-treatment phase. The materials was integrated as a part of the survivorship care plan, which currently contains personalized information on survivors' cancer diagnosis and treatment history, as well as late effects and health promotion advice adapted from the Children Oncology Group , 21. TheTo evaluate attendees' receptivity toward the educational seminars, a post-event feedback questionnaire was developed using Qualtrics XM . The questionnaire mainly evaluated the perceived usefulness of the overall content and each topic using a seven-point scale . The participants were asked whether they were interested in joining future events and to provide any additional comments or further suggestions. We also asked individuals diagnosed with pediatric cancer, and/or their families/caregivers if they would adopt any of the advice (“yes” or “no”) provided in the seminars, including: (1) incorporating recommended foods/herbs into their diets; (2) taking herbal tea; (3) performing traditional Chinese health exercises; and (4) using acupressure/massage.The feedback questionnaire for the written educational resources included evaluating the participants' perceived usefulness of the content and if recipients would adopt any of the advice (“yes” or “no”) included in the booklet. In addition, we also asked whether the materials would affect their attitudes toward CM.Applying the RE-AIM framework into our program evaluation based on the original definitions, “Reach” referred to the number or proportion of individuals who received or were affected by the program. “Effectiveness” was defined as the impact of intervention including the delivery of the education content. We referred “Intention to adopt” as the proportion of participants that intended to adopt the suggestions in the program as it was not feasible to measure the actual adoption right after the education program. Similarly, we were not able to evaluate the program using the “Implementation” and “Maintenance” components in a short timeframe.® Statistics Ver. 26.0 . Descriptive statistics from the evaluation questionnaire are presented as means, standard deviations, and percentage values. In addition, an exploratory analysis was conducted to compare the feedback from caregivers/families vs. other participants  using Mann–Whitney U-test for continuous variables and Fisher's exact test for categorical variables to advice future program planning that may target specific subgroups.Data were analyzed using SPSSBased on the latest statistics , 23, we The hardcopy of the educational booklet was distributed to 43 recipients through the clinics and NGO network. In addition, the web-version of the booklet was sent to 67 participants who joined the seminars and downloaded 143 times from November 2021 to January 2022.Of the 174 attendees, 94 (response rate = 54.0%) provided their feedback on the seminars. The results are presented in n = 17, 94.4%) and they would consider receiving CM treatment in the future during the cancer survivorship phase .With regard to the written educational resources, 18 recipients (response rate = 41.9%) completed the feedback survey . Most ofn = 15/18, 83.3%), try the recommended traditional Chinese health exercises , take herbal tea , and perform the recommended acupressure on their children . Similar results were obtained from the feedback related to the educational materials; nearly all of the respondents  reported that they would adopt the advice provided in the materials.Attendees of the seminars who were caregivers reported that they would help their children to incorporate the recommended foods or herbs in their diet (n = 29). Their suggestions included CM dietary therapy; non-oral therapies, including exercises and acupressure; and precautions, such as herb-drug interactions and foods or herbs unsuitable for cancer survivors. The respondents also recommended the use of illustrations with more concrete case studies to improve their understanding of the material presented. Most of the respondents expressed their interest in attending future events . A higher proportion of caregivers or families of survivors/patients expressed interest as compared to other participants (P = 0.02).Besides, some respondents provided free-text responses on their preferences for future seminar topics . The patients/participants provided their written informed consent to participate in this study.CSL and HWC performed data analysis. CSL and YTC prepared the first draft of the manuscript. All authors contributed to the study conception, study design, and acquisition of data. All authors commented on previous versions of the manuscript, read, and approved the final manuscript.This study was funded by the Chinese Medicine Development Fund (19B1-2/017A_R1), which is a Commissioned Budget by the Food and Health Bureau, the Government of the Hong Kong Special Administrative Region.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflictof interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.