Serious mental illness (SMI) can have devastating consequences. Unfortunately, many patients with SMI do not receive evidence-based psychological treatment (EBPTs) in routine practice settings. One barrier is poor “fit” between EBPTs and contexts in which they are implemented. The present study will evaluate implementation and effectiveness outcomes of the Transdiagnostic Intervention for Sleep and Circadian Dysfunction (TranS-C) implemented in community mental health centers (CMHCs). TranS-C was designed to target a range of SMI diagnoses by addressing a probable mechanism and predictor of SMI: sleep and circadian problems. We will investigate whether adapting TranS-C to fit CMHC contexts improves providers’ perceptions of fit and patient outcomes.N = 96 providers; N = 576 clients), via facilitation. CMHC sites are cluster-randomized by county to Adapted TranS-C or Standard TranS-C. Within each county, patients are randomized to immediate TranS-C or usual care followed by delayed treatment with TranS-C (UC-DT). Aim 1 will compare TranS-C (combined Adapted and Standard) with UC-DT on improvements in sleep and circadian problems, functional impairment, and psychiatric symptoms. Sleep and circadian problems will also be tested as a mediator between treatment condition (combined TranS-C versus UC-DT) and functional impairment/psychiatric symptoms. Aim 2 will evaluate whether Adapted TranS-C is superior to Standard TranS-C with respect to provider perceptions of fit. Aim 3 will evaluate whether the relation between TranS-C treatment condition (Adapted versus Standard) and patient outcomes is mediated by better provider perceptions of fit in the Adapted condition. Exploratory analyses will (1) compare Adapted versus Standard TranS-C on patient perceptions of credibility/improvement and select PhenX Toolkit outcomes and (2) evaluate possible moderators.TranS-C will be implemented in at least ten counties in California, USA  expand support for TranS-C, a promising transdiagnostic treatment delivered to patients with SMI in CMHCs; (b) take steps toward addressing challenges faced by providers in delivering EBPTs ; and (c) advance evidence on causal strategies  in implementation science.https://clinicaltrials.gov/ct2/show/NCT04154631Clinicaltrials.gov NCT04154631. Registered on 6 November 2019. The online version contains supplementary material available at 10.1186/s13063-023-07148-9. Serious mental illness (SMI) can have devastating psychosocial and health consequences –3. SMI cThus, large-scale implementation of EBPTs could have a tremendous positive impact. However, barriers have been identified. One barrier is that the context for implementation  typically differs from the context in which EBPTs are developed . This causes poor “fit,” operationalized herein as provider perceptions of EBPT acceptability, appropriateness, and feasibility within their routine practice setting –14. ImpoIn the present study, we sought to determine if fit of an EBPT for SMI could be improved in the context of community mental health centers (CMHCs). CMHCs are major, publicly funded providers of treatment for SMI. CMHC providers carry heavy caseloads with high rates of comorbidity and complexity , 19. AltA related challenge for CMHC providers and SMI treatment is that, in the proliferation of EBPTs, many focus on treating a single diagnosis . Consequtransdiagnostic approach to treatment. The transdiagnostic approach holds that disorders co-occur in part due to common processes that drive symptoms [A promising alternative to single-diagnosis treatments is the symptoms –26. By tsleep and circadian problems as an important transdiagnostic contributor to SMI. First, sleep and circadian problems, including insomnia, hypersomnia, and evening circadian preference, predate and predict a range of mental illness, including depression, substance use, anxiety, and psychosis [n = 50), bipolar disorder (n = 35), and major depressive disorder (n = 26) exhibited 25, 24, and 21 distinct patterns of sleep and circadian problems, respectively [number of sleep or circadian problems—including those at the subdiagnostic level—was more predictive of impairment than diagnostic threshold of those problems [Circling back to SMI treatment in CMHCs, a question arises: what common mechanisms could be targeted by a transdiagnostic treatment to address a range of SMI diagnoses? Four lines of evidence highlight sychosis –32. Secosychosis , 33, 34.sychosis –37. Fourectively . Moreoveproblems . Collectproblems .Building on this evidence, the Transdiagnostic Intervention for Sleep and Circadian Dysfunction (TranS-C) was developed . Based oCMHC providers [. This is particularly important because CMHC providers are responsible for the day-to-day delivery of clinical services, including EBPTs. Thus, ensuring that TranS-C is acceptable to CMHC providers, as well as effective for their patients, is essential. There is already promising evidence that cognitive behavior therapy for insomnia can be delivered in routine practice [The preliminary evidence for TranS-C in CMHCs has been promising. Specifically, among adult CMHC patients, TranS-C relative to usual care followed by delayed treatment with TranS-C (UC-DT) was associated with improvements in sleep and circadian problems, functional impairment, and psychiatric symptoms . Howeverroviders . This ispractice , includipractice , 45, andPertinent to this next step, TranS-C as it is typically delivered—henceforth “Standard TranS-C”—involves relatively high-intensity procedures similar to other EBPTs. Specifically, TranS-C consists of eight weekly, 50-min sessions. Indeed, in a process evaluation, CMHC staff identified dose and complexity as barriers to implementing Standard TranS-C . In respTogether, the goal of the present hybrid type 2 effectiveness-implementation study , 49 is tDuring the Implementation Phase, sites are cluster-randomized by county to Adapted TranS-C or Standard TranS-C with 1:1 allocation. Then, within each county, patients are randomized to immediate TranS-C or UC-DT. The first aim is to assess the effectiveness of TranS-C, compared to UC-DT. We hypothesize that, compared to UC-DT, TranS-C (combined Adapted and Standard) will be associated with larger reductions in the primary patient outcome of sleep disturbance and the secondary patient outcomes of sleep-related impairment, functional impairment, and psychiatric symptoms. We also hypothesize that TranS-C’s benefits for functional impairment and psychiatric symptoms will be mediated by improvements in sleep and circadian problems. The second aim is to evaluate whether TranS-C treatment condition (Adapted versus Standard TranS-C) is associated with fit to the CMHC context, operationalized as provider ratings of acceptability, appropriateness, and feasibility. We hypothesize that Adapted TranS-C will be superior to Standard TranS-C with respect to the primary provider outcome of acceptability and the secondary provider outcomes of appropriateness and feasibility. The third aim is to evaluate whether better fit mediates the relation between TranS-C treatment condition and patient outcome. We hypothesize that relative to Standard TranS-C, Adapted TranS-C will be associated with greater reductions in the primary and secondary patient outcomes indirectly through higher provider ratings of acceptability, appropriateness, and feasibility. Exploratory analyses will (1) compare Adapted and Standard TranS-C on patient perceptions of credibility/improvement and select PhenX Toolkit outcomes and (2) determine whether treatment effects are moderated by risk factors including age, sex, and sleep and circadian and psychiatric symptoms at baseline , 51.This study was preregistered on clinicaltrials.gov (identifier: NCT04154631) and received approval from the Committee for the Protection of Human Subjects at the University of California, Berkeley. Any protocol changes will be submitted to clinicaltrials.gov and the Committee for the Protection of Human Subjects. The research team will communicate relevant changes to the CMHCs and in appropriate publications . If there are too many findings to reasonably interpret in one paper, we may separate some of the findings into two or more papers. This research is funded by the National Institute of Mental Health R01MH120147). The present protocol used the SPIRIT reporting guidelines   and a clinical science graduate student (CAC) with expertise in TranS-C and SMI. Fourth, consultation is provided on an ongoing, as-needed basis by the facilitators via phone calls, text messaging, and emails. Fifth, the facilitators organize and lead regular presentations to the CMHCs on advanced topics related to sleep and mental health . Sixth, facilitators help with administrative barriers, such as working to ensure that TranS-C trainings count toward Continuing Education credits. Seventh, facilitators offer a sleep treatment certification that CMHC providers can achieve via three supervised TranS-C cases. Eighth, facilitators maintain an active website with supplemental treatment-related resources for CMHC providers. Ninth, facilitators develop and distribute materials  related to sleep knowledge and mental health at the request of CMHC leadership and providers. Tenth, facilitators hold regular and as-needed meetings with CMHC leadership and key providers to provide progress updates, collaborate on decision-making, and problem-solve barriers to effective intervention delivery such as organizational burnout, site cultures that are resistant to change, lack of resources or funding, oversaturation of treatment options, and logistical barriers. Eleventh, facilitators identify and cultivate intervention “champions” who can model effective treatment delivery and support their colleagues in using Trans-C.Participants in the present study are drawn from CMHCs and consist of CMHC providers and CMHC patients CMHCs preferred to determine which providers are eligible to receive TranS-C training at each site , because this aligns with their real-world practice. The other inclusion criteria for providers are as follows: (1) employed or able to deliver client-facing services to patients within the CMHC, (2) interest in learning and delivering TranS-C, and (3) volunteer to participate and formally consent to participate.The inclusion criteria for patients are as follows: (1) aged 18 years and older; (2) meet criteria for an SMI per self-report and confirmed by referring provider or administration of the Mini International Neuropsychiatric Interview  by a licensed clinical social worker on the research team; (3) exhibit a sleep or circadian disturbance as determined by endorsing 4 (quite a bit) or 5 (very much), or the equivalent for reverse-scored items, on one or more PROMIS-Sleep Disturbance questions , 62; (4)Patients will be excluded if they meet any of the following criteria: (1) presence of an active and progressive physical illness or neurological degenerative disease that is directly related to the onset and course of the sleep and circadian problems, or making participation in the study unfeasible, as assessed by the Checklist of Medical Conditions and Symptoms on the Duke Structured Interview for Sleep Disorders  and clinBuilding the CMHC network that forms the basis for this study began in August 2013 with outreach by the PI. The network has been maintained via newsletters, meetings, and workshops on EBPTs. Originally, eight counties agreed to participate. At various stages of the study, we have continued to focus on recruiting new counties and new CMHC sites to maximize provider and patient sample size goals. Most counties consist of three to 10 CMHC sites. Sites in the following ten counties in California, USA, are currently participating in the Implementation Phase: Alameda, Contra Costa, Kings, Monterey, Placer, Santa Cruz, Solano, Santa ClaraFacilitators meet with key CMHC leadership, who help to engage and recruit providers in their CMHC. In some CMHCs, this involves leadership requiring all staff to complete the TranS-C training, whereas in other CMHCs, leadership advertises the opportunity and allows anyone who is interested to register. During the TranS-C trainings, facilitators continue to engage and recruit providers by describing the benefits of participating in the study. These benefits include possible improvement in sleep and mental health for patients, certification in TranS-C for providers, expert consultation from the UC Berkeley research team, hard copies of the treatment materials, enrollment prizes, and financial compensation received by participating patients. After TranS-C trainings, facilitators follow up with weekly emails for 1 month that highlight each of these benefits and present other resources related to TranS-C, sleep, and mental health. Providers are also recruited through flyers posted in CMHCs, announcements at staff meetings, meetings organized by the facilitators, and appointments by leadership. Strategies to maintain relationships with providers and optimize data collection are ongoing by facilitators, including workshops and trainings, “enrollment challenges” and prizes , continuing education credits for participation, and distributing newsletters or other topical resources.Patients are recruited through a variety of methods, based on each CMHC’s preference. These methods include the following: (1) posting flyers from the research team in waiting rooms and providers’ offices; (2) integrating a sleep screener into intake paperwork; (3) asking providers to screen patients on their caseload; and (4) encouraging word of mouth between patients. Potentially eligible patients are typically identified by their provider. With the patient’s consent, the provider contacts the facilitators, who connect the patient with the assessment team so that the patient can be formally evaluated for eligibility and enrolled in the study. After eligibility has been confirmed and consent to participate in the study has been given, the patient is matched to a CMHC TranS-C provider. Ideally, the TranS-C provider is the patient’s own provider . If this is not possible, an alternative provider is identified. Patient retention is maximized via collaborative efforts between the providers, facilitators, and assessment team. Considerable efforts are made by the facilitators and assessors to answer questions and troubleshoot challenges  to prevent attrition.Two variations of TranS-C are tested in the present research: Standard TranS-C and Adapted TranS-C. Both are delivered alongside the usual care offered by each CMHC. The control condition is usual care followed by delayed treatment with Adapted or Standard TranS-C (UC-DT). In the CMHCs, usual care consists of working with a service provider  who provides direct mental health support from within their scope of practice. The patient might also be referred by that provider for other services as needed . Occasionally patients receive treatment from interdisciplinary or residential teams, meaning their services are coordinated across multiple service providers. Although most providers delivered TranS-C via individual sessions, some chose to deliver it in a group setting. Note that TranS-C was originally developed in English, then translated into Spanish about four months into data collection to expand access and subsequently offered by Spanish-speaking providers. The treatment conditions, along with the adaptation process for Adapted TranS-C, are described below.cross-cutting modules are case formulation, sleep and circadian education, motivational enhancement, and goal setting. Core module 1 targets irregular sleep–wake times, difficulty winding down, and difficulty waking up. Core module 2 aims to reduce daytime impairment. Core module 3 focuses on unhelpful beliefs about sleep. Core module 4 aims to promote maintenance of changes made during treatment. Optional module 1 addresses poor sleep efficiency via stimulus control [Optional module 2 helps patients reduce time in bed. Optional module 3 addresses delayed or advanced phase problems . Optional module 4 helps patients manage worries about sleep. Optional Module 5 promotes compliance with Continuous Positive Airways Pressure (CPAP) for patients with sleep apnea. Optional Module 6 helps patients negotiate sleep in complicated environments . Optional Module 7 is for patients who experience nightmares. Training for the Standard TranS-C condition consists of a 1-day workshop  or two, 3-h training blocks.Standard TranS-C is delivered by CMHC providers across eight 50-min, weekly sessions . It is c control  and slee control . Optionacross-cutting and core modules as in Standard TranS-C, but the core modules are split up into five, rather than four, modules. Core module 1 targets irregular sleep–wake times. Core module 2 targets difficulty winding down. Core module 3 targets difficulty waking up. Core module 4 aims to reduce daytime impairment. Core module 5 promotes the maintenance of change. The one optional module focuses on reducing sleep-related worry and can be integrated with the core modules, based on clinical presentation, treatment goals, and provider case conceptualization. Training for the Adapted TranS-C condition consists of four, 1-h workshops or two, 2-h workshops, based on CMHC preferences.Adapted TranS-C is delivered by CMHC staff across four, 20-min, weekly sessions. Treatment consists of the same four There have been calls for rigorous approaches to treatment adaptation , 67. In all participants receive what we hypothesize to be an active treatment (TranS-C); and (c) maximizing efficiency in terms of study duration, budget, and participants’ time investment. Notably, usual care has been the comparison group in several influential studies [In UC-DT, patients begin with usual care for 4 weeks if their CMHC is randomized to Adapted TranS-C and 8 weeks of usual care if their CMHC has been randomized to Standard TranS-C. After the delay, they receive Adapted or Standard TranS-C, also based on the condition to which their CMHC has been randomized see Fig. . The dec studies –75.In addition to the measures below, a sociodemographics form is completed by providers and patients. Only measures that will be analyzed for the primary aims of the Implementation Phase (see above) are reported below. See Table Acceptability: Providers rate the acceptability of TranS-C via the Acceptability of Intervention Measure [ Measure . This 4- Measure .Appropriateness and feasibility: Providers rate the appropriateness and feasibility of TranS-C via the following 4-item measures: Intervention Appropriateness Measure and Feasibility of Intervention Measure [ Measure . Both me Measure .Number of TranS-C Sessions: The number of sessions delivered to each enrolled patient by each provider will be counted.Occupation: Providers are asked to report their current position, professional degree, and work history, including their caseload, theoretical orientation, licensure status, and previous training in sleep treatment.Sleep disturbance: The 8-item PROMIS-Sleep Disturbance (PROMIS-SD) assesses disruption to sleep  over the past 7 days [t 7 days . Items at 7 days , 62.Sleep-related impairment: The 16-item PROMIS-Sleep Related Impairment (PROMIS-SRI) assesses daytime impairment related to sleep problems over the past 7 days on a scale from 1  to 5  [/always) . Scores /always) , 62.Functional impairment: Functional impairment is assessed via the Sheehan Disability Scale (SDS) [le (SDS) . Impairmle (SDS) , 78.Overall sleep health: The Sleep Health Composite is proposed to capture overall sleep health for the complexity of sleep problems in SMI that are covered by TranS-C [In the past week, what time have you usually woken up in the morning?). Scores range from 0 to 6, with higher scores indicating better sleep health. Initial validity of this measure has been established [ TranS-C . It is dablished .Psychiatric symptoms: The DSM-5 Cross-Cutting Measure assesses psychiatric symptoms across 13 mental health domains. Participants rate how often they were bothered by each symptom on a scale from 0  to 4 (nearly every day). Scores range from 0 to 52, with higher scores indicating more severe symptoms. This measure has demonstrated good test–retest reliability and clinical utility [ utility , 81.PhenX Toolkit: substance use and suicidality—Scales from the PhenX Toolkit [ Toolkit  are used Toolkit . To asseCredibility and perceived improvement: Perceptions of TranS-C credibility and symptom improvement are assessed by four questions adapted from the Credibility/Expectancy Questionnaire (CEQ) [re (CEQ) . These qProviders and patients are consented by the assessment team prior to participation. All participants are informed that they can withdraw from the study at any time. All patients are compensated for their participation, and providers are compensated if permitted by their CMHC. The assessments are completed by the assessment team, comprised of experienced assessors. Note that assessors complete the consent process to minimize burden on participants . Because the assessors need to provide study-related information—such as number of assessments and treatment sessions—to the patients during the consent process, the assessors are not blind to condition at pre-treatment. However, at post-treatment and 6FU, we endeavor to keep assessors blind to condition. As is common in clinical trials, there are ways that assessors may be able to infer treatment condition . Assessors receive ongoing supervision and are thoroughly trained to deliver the surveys with integrity and minimal bias.Provider assessments are completed after TranS-C training, at mid-treatment, and at post-treatment. See Fig. Patient assessments in the immediate TranS-C treatment conditions are completed at pre-treatment, mid-treatment, post-treatment, and 6 months after treatment (6FU). Patient assessments in the UC-DT condition are completed at pre-treatment and 4 or 8 weeks after pre-treatment , depending on whether their county has been randomized to Adapted or Standard TranS-C, respectively. After the post-UC-DT assessment, patients start delayed treatment with TranS-C. They subsequently complete assessments at mid-treatment, post-treatment, and 6FU. Note that patients do not complete a 6FU assessment after the delayed portion of UC-DT. This was a compromise made with CMCH partners, so that patients would not need to wait 7–8 months to receive treatment. See Fig. CMHCs and patients are randomized through a computerized randomization sequence. We do not stratify during randomizing at the county level. When randomizing patients, we stratify for the presence of psychosis or not (current), presence of substance use or not (current), and age ≥ 50 or not), as there is evidence that these variables can impact sleep or treatment outcome  or not, , 85. OnlN = 8 counties that agreed to participate, though as noted above, new counties have since been recruited to meet sample size goals determined by the following calculations. For Aims 1 and 3, 60 patients from eight randomized clusters/CMHCs were found to provide over 90% power to detect large effects (average d = 0.89) between TranS-C and UC-DT [d = 0.50) between Standard and Adapted TranS-C. For Aim 2, based on a prior study with a similar aim/measure [d = 0.80) between Standard and Adapted TranS-C on the primary outcome of acceptability. Prior studies have reported high correlation coefficients between acceptability, feasibility, and appropriateness (rs = 0.67–0.90) [n − 1) × ICC. Eight clusters with an average cluster size of 10 were found to be needed to achieve over 80% power to detect a large effect for the outcome (acceptability) at the provider level. Thus, to test this aim, we would need at least 80 CMHC providers: 10 providers from 8 CMHCs (at least 4 CMHCs per randomized arm).Sample size was determined via power analyses with Optimal Design , 87 and nd UC-DT , and ove67–0.90) , 90; thu67–0.90) , 92, we In sum, we aimed to randomize at least eight CMHC clinics to either Standard or Adapted TranS-C, with at least 80 providers (10 per CMHC). The goal for patients is 240 patients (30 per CMHC) randomized to immediate Standard or Adapted TranS-C and 240 randomized to UC-DT (30 per CMHC). Adding 20% to account for attrition, the total target sample size for providers is 96 and for patients is 576.All patient-identifiable data are saved by the assessment team on password-protected fillable PDFs on a secure password-protected and HIPAA-compliant website. On these PDFs, patients and providers are assigned identification numbers. These identification numbers are then used to link anonymized data that is collected via password-protected Qualtrics. When collecting assessments, assessors call participants and enter the data into Qualtrics. Participants also have the option of entering their data directly into a participant-facing version of the surveys via a HIPAA-compliant version of Qualtrics. Patient-identifiable data is not shared with outside entities during or after the trial. A data management team supervised by the PI, biostatistician (LD), and postdoctoral scholar (LDS) is responsible for downloading, collating, and analyzing the data.A Data Safety Monitoring Board has been formed to help prevent and manage adverse events. The board includes members with expertise in SMI, psychosocial treatments, and randomized controlled trials. Members are independent from the PI and competing interests. A report was made to the board bi-annually for the first year of the research. Since then, it has shifted to annual reports. However, if safety issues arise, it will be changed to monthly meetings. Yearly reports are submitted to the Committee for the Protection of Human Subjects at UC Berkeley and National Institute of Mental Health.Outcomes specifically of interest to our partners are presented to CMHC leadership as part of the widely used implementation strategy, audit, and feedback . HoweverResults from the trial, as well as analysis code, will be shared via peer-reviewed publications, professional conference presentations, and meetings and newsletters to CMHCs, as relevant. Other than the authors and compliance with data-sharing agreements stipulated by the National Institutes of Health, no other entities have contractual agreements to access the final dataset. Deidentified data are submitted to the National Institute of Mental Health Data Archive twice per year, per their requirements.This trial is supervised by the PI (AGH), who manages the facilitation team, assessment team, and the data management team. The PI meets with members of each team as needed in addition to daily email communication. Within each team, there is at least one trained lead  who supervises the day-to-day activities of other team members. There is no coordinating center, trial steering committee, or Stakeholder and Public Involvement Group. The responsibilities of each team are detailed elsewhere in this protocol. In summary, the facilitators execute the implementation of TranS-C via numerous activities, including training and supervising CMHC providers in the delivery of TranS-C. The assessment team is responsible for the informed consent process and conducting participant  evaluations. CMHC leadership and enrolled providers work with the facilitation team to recruit additional providers. CMHC providers help to identify potentially eligible patients, who are then connected with the assessment team for formal eligibility evaluation.In December 2022, updates relevant to the present protocol were made to the clinicaltrials.gov protocol (identifier: NCT04154631). These updates can be summarized as follows. First, minor changes were made to four inclusion and exclusion criteria, based on feasibility and preferred practices of CMHC partners. For instance, as described above, CMHCs preferred to determine which providers were eligible to deliver TranS-C, and thus, providers held a wider range of positions than we had originally anticipated. Additionally, in rare cases, providers outside of CMHCs participated in the study . Thus, we changed the provider criteria to be more inclusive (see provider inclusion criterion 1 above). Second, as the study unfolded, rich data emerged. To maximize the resources invested in this study, we decided to systematically capture these data with additional measures, now included in the “Analyses will use all available data (intent-to-treat) . If dropDistributions will be evaluated to detect outliers, and we will ensure that assumptions of planned analyses are met. Covariates will include the patient variables for which we stratified . For all statistical models, counties will be entered as dummy variables rather than a level of analysis due to the relatively small number of clusters. The average intraclass correlation on provider and patient-level outcomes will be reported. The Benjamini–Hochberg procedure  will be N by stage of dropout will be reported for the following: dropout after randomization but before the first treatment session, dropout after treatment has begun but attended half or fewer of the intended number of sessions , dropout after attended more than half the intended number of sessions  but before treatment has been completed, and dropout after treatment has been completed but prior to post-treatment or 6FU assessments. The number of patients who completed a post-treatment assessment but were lost to 6FU will also be reported. When available, the reasons for dropout and improvement among patients who drop out will be reported.The Multilevel modeling (MLM) –103 willMLM will be used to account for multiple observations nested within providers. TranS-C treatment condition (Adapted versus Standard TranS-C) will be evaluated as a predictor of fit, operationalized as provider ratings of acceptability, feasibility, and appropriateness. The level 1 equation will include dummy-coded time indicators as the predictor . The level 2 equation will include dummy-coded treatment condition , treatment-by-time interaction terms, and dummy-coded counties  as predictors. The treatment effects of interest will be significant treatment-by-time interactions at the 5% level on the primary outcome of acceptability and the secondary outcomes of feasibility and appropriateness, all modeled as continuous variables. Significant treatment-by-time interactions indicate that change in perceptions of fit is significantly different comparing Adapted to Standard TranS-C. Significant interactions will be interpreted using planned contrasts  and graphs.Multilevel structural equation modeling will be used to test whether improved perceptions of fit  mediate the relation between TranS-C treatment condition  and change in the primary patient outcome of sleep disturbance and the secondary patient outcomes of sleep-related impairment, functional impairment, and psychiatric symptoms. Models will evaluate change in outcomes from pre-treatment to post-treatment and pre-treatment to 6FU.Three sets of sensitivity analyses will be run to help account for the complexities of the COVID-19 pandemic and the CMHC context. In the first set, the analyses for Aims 1–3 will be conducted with (a) treatment completers, (b) patients who completed more than half the number of the suggested sessions , and (c) patients who completed half or fewer of suggested sessions. In other words, these analyses will test the effectiveness of TranS-C at varying doses, which may be important considering evidence on “early responders”  and “reaMLM will be used to test TranS-C treatment condition (Adapted vs. Standard TranS-C) predicting PhenX Toolkit outcomes of substance use and suicidality at post-treatment and 6FU. The approach to MLM will mirror Aim 2, except the outcomes will be substance use and suicidality from the PhenX Toolkit. Linear regression will be used to test treatment condition (Adapted vs. Standard TranS-C) predicting patient perceptions of TranS-C’s credibility and perceived improvement at post-treatment.Using MLM, three-way interactions between treatment condition (Adapted or Standard TranS-C versus UC-DT), time, and risk factors will be used to evaluate moderators of patient outcome . Each moderator and outcome will be tested in a separate model. Moderators will include age, sex, and sleep/circadian and psychiatric symptoms at baseline. The level 1 equation will include the moderator and dummy-coded time indicators as the predictors . The level 2 equation will include dummy-coded treatment condition , treatment-by-time by moderator interaction terms, and dummy-coded counties  as predictors. A significant interaction indicates a moderating effect and will be probed with planned contrasts  and graphs.This study aims to evaluate the implementation and effectiveness outcomes of the Transdiagnostic Intervention for Sleep and Circadian Dysfunction (TranS-C) delivered to patients in community mental health centers (CMHCs) by CMHC providers. Findings will address several research priorities. First, TranS-C was designed to target a wide range of serious mental illness (SMI) diagnoses through addressing a wide range of sleep and circadian problems , 40. As and pre- to 6FU. Depending on the outcomes from the trial, an important direction for future research will be testing the long-term effects of TranS-C relative to a control . Fifth, unforeseen challenges arose related to the COVID-19 pandemic and subsequent mandates in California . For some patients, sleep and circadian treatment became secondary to coping with other mental health ramifications of the pandemic  or even meeting basic needs of secure access to food and shelter [These potential contributions should be considered alongside the protocol’s methodological limitations. First, we did not collect data from leadership at our partner CMHCs. The primary reason was that these leaders have many demands on their time and already had generously collaborated with us on the design and implementation of the study. However, we recognize that leadership-level factors can meaningfully impact implementation outcomes . Thus, e shelter . Additio shelter –98. At tThese challenges and limitations notwithstanding, in testing the implementation and effectiveness outcomes of TranS-C delivered by CMHC providers, this study has the potential to (a) expand support for a promising transdiagnostic treatment delivered to patients with SMI in routine practice settings, (b) take steps toward addressing some of the major challenges faced by providers in delivering evidence-based treatments , and (c) advance evidence on causal strategies in implementation science.Protocol version 1, December 12, 2022. Data collection started in February 2020. Recruitment was completed in August 2022, but patient visits/assessments will continue through August 2023. Publishing of this protocol was delayed because of unforeseen challenges and uncertainties related to the COVID-19 pandemic and subsequent mandates , which began in California shortly after data collection started for this study.Additional file 1. SPIRIT checklist.


Out-of-hospital cardiac arrest (OHCA) is a significant global cause of mortality, and Emergency Medical Services (EMS) response interval is critical for survival and a neurologically-favorable outcome. Currently, it is unclear whether EMS response interval, neurologically-intact survival, and overall survival differ between snowy and non-snowy periods at heavy snowfall areas.A nation-wide population-based cohort of OHCA patients, registered from 2017 through 2019 in the All-Japan Utstein Registry, was divided into four groups according to areas  and seasons (winter or non-winter): heavy snowfall-winter, heavy snowfall-non-winter, other area-winter, and other area-non-winter. The first coprimary outcome was EMS response interval, and the secondary coprimary outcome was one-month survival and a neurologically-favorable outcome at one month.A total of 337,781 OHCA patients were divided into four groups: heavy snowfall-winter , heavy snowfall-non-winter , other area-winter , and other area-non-winter . Longer EMS response intervals (>13 minutes) were most likely in the heavy snowfall-winter group , and also more likely in heavy snowfall areas in non-winter . One-month survival in winter was worse not only in the heavy snowfall area  but also in other areas . One-month neurologically-favorable outcomes were also comparable between heavy snowfall-winter and other area-non-winter groups.This study showed OHCA in heavy snowfall areas in winter resulted in longer EMS response intervals. However, heavy snowfall had little effect on one-month survival or neurologically-favorable outcome at one month. Despite the improvement and implementation of various treatment strategies to improve survival from OHCA, there is still an inadequate favorable neurological prognosis for survivors after OHCA, and global survival rates are less than 10%. To enhance survival after OHCA, implementation of steps in the “chain of survival” concept are required, such as immediate recognition of cardiac arrest and activation of the Emergency Medical Services (EMS), early cardiopulmonary resuscitation (CPR), rapid defibrillation, and effective Advanced Life Support (ALS). Therefore, early EMS intervention is critical for survival from OHCA.Out-of-hospital cardiac arrest (OHCA) is a significant global cause of mortality and a pressing public health concern. The EMS response interval is also an important determinant of survival after OHCA. An upper limit of 13 minutes for EMS response interval, when bystanders provide defibrillation, is reportedly associated with improved one-month neurologically-intact survival. Therefore, an EMS response interval as short as possible is needed for a favorable neurologically-intact survival and overall survival. However, several factors can lengthen EMS response interval, such as traffic conditions, distance from the EMS station to the scene, an increased number of cases, and population density. In addition to these factors, weather conditions may affect EMS response interval due to disruptions or delays in the transportation network.The EMS response interval, defined as the interval between receipt of an emergency call and the arrival of EMS on the scene, is a traditional performance measure for EMS systems in developed countries. and trauma injury. Heavy snowfall or a deep freeze may affect performance in components of the “chain of survival.” Worsened traffic conditions resulting from heavy snowfall may impede EMS response intervals and transport to hospital times, potentially leading to an adverse impact on outcomes following OHCA. In addition, there is reported to be an increased onset of OHCA during the winter season, and also an increase in poor outcomes associated with the winter season and cold environment. Moreover, an association between snowfall and onset of OHCA was reported from studies in the United States and Europe. Based on these findings, the risk of onset of OHCA increases in the winter season, while adverse weather conditions in snowy areas may prolong EMS response intervals and reduce neurologically-intact survival and overall survival.In general, so-called “bad weather conditions” often refer to heavy rain, strong wind, storm, or typhoon, but many of these are transient weather changes. On the other hand, there are seasonal weather conditions that produce changes in weather that persist over a certain period of time, especially low temperatures in the winter season. In fact, many Western countries, such as the United States and Europe, are hit by deep freezes several times during the winter season, which often cause disruptions in transportation networks and traffic jams. Snowfall is associated with an increased incidence of traffic disruptionsSo far, it is unclear whether EMS response interval, neurologically-intact survival, and overall survival differ between snowy and non-snowy periods at heavy snowfall areas, or whether there is a difference between heavy snowfall areas and non-heavy snowfall areas. The aims of the present study were to clarify whether there were any differences in EMS response interval and OHCA prognosis: (1) between heavy snowfall and non-heavy snowfall regions, and (2) between snowfall and non-snowfall seasons in heavy snowfall regions. The FDMA of Japan supervises the nation-wide EMS system, while local government fire departments operate the local EMS systems, which cover 99% of the population. Most EMS units contain at least one emergency life-saving technician (ELST), a highly trained individual who can practice some aspects of ALS. During the study period, all the EMS providers performed CPR and ALS according to the Japanese Resuscitation Council  guideline.This study was a retrospective, nation-wide population-based cohort study using data from the All-Japan Utstein Registry. The All-Japan Utstein Registry, maintained by the Fire and Disaster Management Agency , is a nation-wide population-based registry of OHCA that adheres to the standardized Utstein-style.In Japan, patients with emergencies can make emergency calls without hesitation because ambulances are a part of administrative services and ambulance transport is free of charge. The study period was set from 2017 through 2019 to avoid the strain on EMS produced by the global coronavirus disease 2019 (COVID-19) pandemic in 2020, which may have impacted this research. In 2005, the FDMA initiated an on-going, nation-wide, population-based registry of all OHCA patients resuscitated by EMS. The data were collected by EMS personnel in collaboration with the OHCA patients’ treating physicians and submitted to the local fire department. The data were then integrated into the registry system on the FDMA database server. The data were checked for consistency by the database software program. If the data form was incomplete, the FDMA returned it to the local fire department and the data form was completed. The FDMA provided all the anonymous data to the study group. The database included the following data: event date and location (prefecture); sex; age; cause of OHCA; initial rhythm; bystander witness status, presence, and type of bystander CPR and/or public-access defibrillation (PAD) use; advanced airway management (AAM) and/or adrenaline administration by ELST; time of arrest; EMS call receipt; arrival time at the scene and CPR by EMS; prehospital return of spontaneous circulation; one-month survival; and neurological outcomes at one month after OHCA. The cause of OHCA was presumed to be of cardiac origin unless evidence suggested cerebrovascular disease, respiratory disease, malignant tumor, evident external cause, or other non-cardiac cause. The physicians in charge and EMS personnel determined the cause of the arrest. Neurological outcome was defined using the Cerebral Performance Category score. The EMS response interval was calculated as the duration from the call receipt by a dispatch center to ambulance arrival at the scene of the OHCA, as previously reported.These OHCA data were obtained using a form that included patient information recommended by the Utstein-style reporting guidelines for cardiac arrest.This study included adult patients (age ≥18 years) with an episode of OHCA who received attempted resuscitation by EMS personnel in Japan from January 1, 2017 through December 31, 2019. The following patients were excluded: patients for whom cardiac arrests were witnessed by EMS personnel or for whom no resuscitation was attempted by EMS personnel, patients with inappropriate records of EMS responses , and patients with transport time >180 minutes. Although there are some prefectures where partial heavy snowfall zones exist, ten prefectures have a heavy snowfall zone over the whole area. The Japanese Ministry of Land, Infrastructure, Transport, and Tourism  has designated these ten prefectures as “heavy snowfall areas” . Therefore, the cohort of the present study was divided into four groups according to areas  and seasons (winter or non-winter). Winter was defined as December through February.Japan, an island nation, is divided into 47 prefectures. Snowfall is prevalent during winter in Japan, except for some limited prefectures located in the south. The secondary coprimary outcome was one-month prognosis, indicated by both one-month survival and a one-month neurologically-favorable outcome. A neurologically-favorable outcome was defined as a Cerebral Performance Category score of CPC1 or CPC2.The first coprimary outcome was EMS response interval, and a cutoff time of 13 minutes was used according to results from previous studies. In addition, multivariate logistic regression analysis was performed to compare one-month outcomes by area-season. Potential prehospital confounders for the analytic model were selected based on biological plausibility and data from previous studies. The 12 selected variables included age, sex, witnessed arrest by bystander, some type of bystander CPR initiation, initial shockable rhythm, presumed cardiac cause, defibrillation by EMS, AAM by ELSTs, adrenaline administration by ELSTs, day of week (weekday as Monday-Friday), time of day (daytime as 9:00am-4:59pm), and area-season.Categorical variables are presented as counts (proportions), and continuous variables are presented as medians (interquartile range [IQR]). Baseline characteristics and study outcomes of categorical variables were compared using Chi-square tests and Kruskal-Wallis tests. Multivariate logistic regression analyses were performed to evaluate the association between groups and EMS response interval (<13 minutes). Potential confounders prior to EMS arrival in the analytical model were adjusted for the day of the week and the time of day when the OHCA occurred, based on data from previous studies.All statistical analyses were performed using JMP Pro 16.1.0 software . The level of significance was set at P <.05.The FDMA and the institutional ethical review board of Niigata University  approved this study with a waiver of patient informed consent (#2021-0112).A total of 381,007 OHCA episodes were entered in the All-Japan Utstein Registry from 2017 through 2019, and 337,781 patients were eligible for enrollment in this study .The study cohort was divided into four groups according to area  and season (winter or non-winter): heavy snowfall-winter N = 15,627), heavy snowfall-non-winter , other area-winter , and other area-non-winter , as shown in Figure 5,627, heS3 - available online only). An EMS response interval of >13 minutes occurred in 4,400 of 48,582 patients (9.1%) in the heavy snowfall areas and in 17,465 of 289,199 patients (6.0%) in other areas  in heavy snowfall areas and 97,441 of 289,199 patients (33.7%) in other areas . Survival at one month was more likely in cases of bystander-witnessed arrest , bystander CPR , initial shockable rhythm , defibrillation by EMS , or a daytime event . On the other hand, one-month survival was significantly lower in cases of AAM by ELSTs  or adrenaline administration by ELSTs .One-month survival throughout the year in heavy snowfall areas and other areas was 4.2%  and 4.7% , respectively  and in other areas . In the non-winter seasons, one-month survival was comparable between the heavy snowfall areas and other areas Figure .S8 - available online only). The neurologically-favorable outcome at one month was significantly more prevalent in males , bystander-witnessed arrests , bystander CPR , initial shockable rhythm , cardiac causes , defibrillation by EMS , or daytime events . Meanwhile, a one-month neurologically-favorable outcome was significantly less likely in cases of AAM by ELSTs  or adrenaline administration by ELSTs .A neurologically-favorable outcome at one month after OHCA throughout the year in heavy snowfall areas and other areas was 2.0%  and 2.3% , respectively .This survey period was set from 2017 through 2019, before the outbreak of the global COVID-19 pandemic, when emergency systems around the world, including Japan, were responding to an extraordinary situation. Since the COVID-19 pandemic is easing and societies are returning to the previous emergency situations, the emergency system that existed before the pandemic needs to be re-assessed. This target period was believed to be suitable for this study because the total number of OHCAs and the numbers in the four groups divided by area and season remained almost constant each year during the research period  was significantly most likely to occur in heavy snowfall areas in winter (10.6%), it was also likely to occur even in the non-winter season (8.3%). There were more instances of EMS response intervals >13 minutes in the heavy snowfall area (9.1%) than in other areas (6.0%) throughout the year, suggesting some factors may lengthen EMS response intervals in heavy snowfall areas compared with other areas throughout the year. However, while the EMS response interval was not affected by the winter season in other areas, it is conceivable that the effect of winter on EMS response interval is stronger in the heavy snowfall area. The distribution of EMS centers in Japan is almost proportional to population density. Previous studies have shown that OHCA survival rates were lower in low-density areas due to longer EMS response intervals in these areas.S7). Meanwhile, one-month survival was decreased in both heavy snowfall areas and other areas in winter . This outcome might not be affected by the winter season as results were comparable between heavy snowfall-winter and other area-non-winter groups.A neurologically-favorable outcome at one month after OHCA throughout the year in heavy snowfall areas and other areas was 2.0% and 2.3%, respectively (Table The rate of bystander CPR was slightly higher in heavy snowfall area either in winter or non-winter. In addition, the rate of ALS by ELSTs was higher in heavy snowfall areas. However, it is possible that these aggressive interventions were not performed in a timely manner. Thus, the execution of key elements of the “chain of survival” might be negatively affected if OHCA occurred in heavy snowfall area. Several studies have shown that a shorter EMS response interval is a critical determinant of survival after OHCA, and bystander CPR and PAD prolong the upper limit of EMS response interval. Third, the low PAD rates in heavy snowfall areas indicate the need for more effectively placed automated external defibrillators to improve OHCA outcomes.These findings suggest that several approaches are needed to reduce seasonal and regional differences in prolonged EMS response interval and outcomes after OHCA. First, residents need to understand that EMS response interval will be prolonged during the heavy snowfall periods and act to avoid increasing EMS demand. Second, strengthening of bystander CPR training may be effective for improving the survival of OHCA in the area with longer EMS response intervals. The development of more highly trained rescuers, such as “first-responder,” may also contribute to an improved OHCA survival rate.This study has some limitations. First, the categories for the All-Japan Utstein Registry data included the prefectures where OHCA occurred but not detailed location information. Second, the actual amount of snowfall was not measured because it was extremely difficult to obtain the exact information on the amount of snowfall at the point where OHCA occurred at that time. Therefore, the effects of snowfall outside of heavy snowfall areas could not be excluded. Third, these results were based on the Japanese health care system. In Japan, emergency calls and patient transport are free of charge. In countries where emergency calls and transportation fees are charged, hesitation to make emergency calls due to costs may also be a factor. However, these results will serve as a useful reference for countries with heavy snowfall in winter. Finally, as with all observational studies, data integrity validity and ascertainment bias are potentials.Cases of OHCA in heavy snowfall areas in winter resulted in longer EMS response intervals. However, heavy snowfall had little effect on one-month survival or neurologically-favorable outcome at one month.


Current non-invasive diagnostic modalities of iatrogenic bile leak (BL) are not particularly sensitive and often fail to localise the BL origin. Percutaneous transhepatic cholangiography (PTC) and endoscopic retrograde cholangiopancreatography (ERCP) are considered the gold standard, yet are invasive studies with potential complications. Ce-MRCP has been not comprehensively studied in this setting but may prove particularly helpful given its non-invasive nature and the anatomical dynamic detail. This paper reports a monocentric retrospective study of BL patients referred between January 2018 and November 2022 submitted to Ce-MRCP followed by PTC. The primary outcome was the accuracy of Ce-MRCP in detecting and localising BL compared to PTC and ERCP. Blood tests, coexisting cholangitis features and time for leak resolution were also investigated. Thirty-nine patients were included. Liver-specific contrast-enhanced MRCP detected BL in 69% of cases. The BL localisation was 100% accurate. Total bilirubin above 4 mg/dL was significantly associated with false negative results of Ce-MRCP. Ce-MRCP is highly accurate in detecting and localising BL, but sensitivity is significantly reduced by a high bilirubin level. Ce-MRCP may be very useful in early BL diagnosis and in accurate pre-treatment planning, but can only be reliably used in selected patients with TB < 4 mg/dL. Non-surgical techniques, both radiological and endoscopic, are proven to be effective in terms of leak resolution. Iatrogenic bile leak (BL) is a rather common complication that can occur after biliary, hepatic and pancreatic surgery. Biliary complications are common after liver transplantation 10–30%), major hepatic surgery, pancreaticoduodenectomy (PD) and cholecystectomy, particularly if the latter is performed laparoscopically up to 1.2%) [0–30%, ma% [0–30%,BL can cause significant morbidity and mortality so it requires prompt diagnosis and treatment. Accurate diagnosis of BL is crucial to optimise post-operative management in an effort to significantly reduce morbidity and mortality related to this condition. However, documenting the presence and extent of BL can be difficult, often requiring multiple investigations before reaching a definitive diagnosis.Current techniques to evaluate the biliary tree for suspected bile duct injuries include ultrasound (US), computed tomography (CT), magnetic resonance cholangiography-pancreatography (MRCP), chole-scintigraphy, percutaneous transhepatic cholangiography (PTC) and endoscopic retrograde cholangiopancreatography (ERCP).US and CT can determine the presence of fluid collection, while conventional MRCP is highly sensitive for the diagnosis of anatomic abnormalities but does not provide functional assessment of the biliary tree. Historically, chole-scintigraphy was employed to confirm leaks. Scintigraphy is highly sensitive for leak detection but lacks the anatomical detail necessary for treatment planning. ERCP and PTC are usually necessary to document the exact location of the leak, providing an opportunity for treatment delivery at the same time. Although both techniques are considered minimally invasive, they can be complicated by potentially serious procedure-related adverse events ,4.®; Bayer) is an intravenous MRI contrast agent that demonstrates hepatocyte uptake and dynamic biliary excretion. Bile enhancement is seen 20 min after intravenous injection of the contrast medium. In the excretory phase of liver-specific contrast-enhanced magnetic resonance cholangiopancreatography (Ce-MRCP), the biliary tree is well depicted, with detailed images that can even demonstrate leaks from small peripheral branches [Gadoxetic acid disodium  Ce-MRCP for the early detection of postoperative BL in a group of patients later studied with PTC and ERCP for further characterisation and treatment of the leakage.This was a monocentric retrospective study including patients who developed bile leaks as a postoperative complication of hepato-pancreatico-biliary (HPB) surgery at a single tertiary referral centre, Policlinico Tor Vergata.Patients were identified retrospectively through the hospital’s database. All consecutive patients operated on between 1 January 2018 and 30 November 2022 were eligible for inclusion.All patients with an abdominal  drainage positive for the presence of bilirubin undergoing Ce-MRCP investigation followed by PTC/ERCP were included.-Patients under 18 years old-Patients who were pregnant-Patients who had not undergone both Ce-MRCP and PTC/ERCP.Exclusion criteria were:This was a retrospective single-centre study evaluating the accuracy of Ce-MRCP in detecting and describing postoperative bile leak by comparison with PTC/ERCP, considered as a standard of reference. Factors influencing Ce-MRCP performance were also evaluated.All patients had undergone HPB surgery and had clinical diagnosis/suspicion of BL .All patients underwent liver Ce-MRCP to confirm the clinical suspicion of leakage and to plan further treatment, and then were studied with PTC/ERCP to confirm BL and, when possible, to deliver interventional radiological/endoscopic treatment. In all cases where trans-oral access to the biliary tract was compromised, PTC was used. Where both techniques were available, a choice was made by a multidisciplinary team including a surgeon, gastroenterologist and interventional radiologist based on the predicted BL localisation, ease of therapeutic intervention with either technique, concomitant dilatation of intrahepatic peripheral bile ducts, patient’s general conditions and specific vulnerabilities .The results of the Ce-MRCP investigation were compared with those of PTC/ERCP in terms of leak detection and leak localisation.Correlations between the serum total bilirubin (TB) levels and drainage output and Ce-MRCP results were investigated.TM, Best, The Netherlands) using a 16-channel phased-array surface coil and respiratory gating, with the patient in a supine position and fasting for at least 4 h before acquisition. Abdominal drainage was clamped closed at least 1 h before Gd-MRI. Basal imaging was acquired with T1 GRE (gradient echo) “in phase” and “out of phase” in the axial plane and half-Fourier acquisition single-shot turbo spin echo (HASTE) sequences for MRCP and multiplanar/maximum intensity projection (MPR/MIP) reconstructions specially designed to directly view the content of the biliary and pancreatic ducts.MRI examinations were performed on a 1.5 T MR system , followed by a bolus of 20 mL of saline injected at a flow rate of 2 mL/s. Arterial, late arterial, portal and equilibrium phases were acquired, respectively, 15, 35, 70 and 150 s after the administration of Gd-EOB-DTPA. Subsequently, other sequences were acquired in the axial plane: T2 TSE (turbo spin-echo), T2 adiabatic spectral inversion recovery (SPAIR) and diffusion-weighted imaging (DWI). After at least 20 min, the hepatobiliary phases, recognised by the excretion of the contrast agent into the bile duct, were acquired with the use of the T1 and T1 SPGR fat-sat spoiled gradient echo (GRE) “in phase” on the axial plane. Additional delayed MR imaging at 60, 120 and 180 min was performed only if the visualisation of the biliary ducts was not sufficient for anatomical diagnosis within 30 min after the administration of Gd-EOB-DTPA. MRI images were evaluated in consensus by two experienced radiologists; specifically, for each patient, the type of surgical intervention and the possible bile duct lesion were defined, and the grade of liver parenchymal enhancement was evaluated, together with the level and timing of contrast enhancement of the biliary system.Dynamic phases were acquired after the intravenous administration of 0.1 mL/kg of gadoxetic acid . The patient was placed in a supine position, the field was sterilised and local anaesthetic was injected at the puncture site before starting the procedure. Biliary system access was achieved with a combined approach, advancing a 21 G needle under US and fluoroscopic guidance. After the puncture of a subsegmentary/segmentary bile duct, a 0.018″ guidewire and 6 Fr introducer were inserted. All patients required the placement of an internal–external biliary drainage as well as further percutaneous procedures to treat the leak.ERCP was performed in a dedicated operating room by an experienced gastroenterologist (>20 years of experience). The patient was placed in a supine position and a dedicated endoscope was advanced into the second part of the duodenum. Sphincterotomy at the level of the major papilla was performed, and a retrograde cholangiography was acquired after cannulation of the common bile duct (CBD) evaluating the site of biliary leakage. Contemporary therapeutic procedures were also performed.The primary outcome was the accuracy of Ce-MRCP in detecting and localising BL, defined as concordance with the results of PTC/ERCP. Bile leak was defined as per the International Study Group on Liver Surgery .The secondary outcomes were the association between serum TB levels and MRCP sensitivity for BL and drainage output and MRCP sensitivity for BL. High TB levels were defined as total bilirubin > 2 mg/dL. Moreover, the coexistence of cholangitis and time for leak resolution were also evaluated.Data were extrapolated from a prospectively maintained database recording continuous and discrete variables regarding baseline characteristics, surgical procedure, in-hospital blood test, postoperative course and complications with a 90-day follow-up.According to the IRB of Policlinico Tor Vergata, research studies conducted retrospectively from data obtained for clinical purposes do not need ethical approval.This study was conducted according to the international ethical recommendations on clinical research established by the Helsinki Declaration and in accordance with the STROBE criteria  p value was determined, and the null hypothesis was rejected at p < 0.05. The analysis was performed using R software (R Core Team (2020). R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. URL https://www.R-project.org/, accessed on 1 January 2022).Characteristics were summarised by means of the levels for categorical variables or by means of quantiles for continuous variables. Fisher’s exact test was used to analyse the correlation between the presence or absence of biliary leak and patients’ clinical laboratory parameters. In particular, bilirubin levels and drainage output were compared to define their statistical value. In all cases, a two-tailed Among a total of 70 patients with postoperative BL diagnosis, thirty-nine met the inclusion criteria: twenty-three undergoing Ce-MRCP and PTC and sixteen Ce-MRCP and ERCP .Twenty-six patients (67%) were male, while thirteen (33%) were female. Mean age at the time of the investigation was 61 years old. Index surgical procedures included liver transplantation (38%), liver resection (26%), PD (13%) and cholecystectomy (23%). Mean time of BL onset from index surgery was 6.3 days. The BL site was the common bile duct in 62% of patients, left hepatic duct in 13%, cystic duct in 8%, right posterior hepatic duct in 5% and aberrant right posterior hepatic duct, S-IV duct, S-VII duct, right anterior hepatic duct or right hepatic duct in 3% of cases. Bile leak patients’ characteristics are summarised in ® in the biliary tract from 20 to 30 min after i.v. administration.In our study cohort, 69% of patients (27/39) were found to be positive for BL at the Ce-MRCP with excretion of PrimovistIn all patients, segmentary and subsegmentary intrahepatic and extrahepatic bile ducts, as well as bilomas, were opacified using contrast medium.Moreover, Ce-MRCP was able to detect the site of BL in all positive patients.Lesions occurred in the CBD in 17 patients, in the left hepatic duct in 2 patients, in the right posterior hepatic duct in 2 patients, in the right anterior hepatic duct in 1 patient, in segment VII of the hepatic duct in 1 patient, in the cystic duct in 3 patients and in the aberrant right posterior hepatic duct in the remaining 1 patient. BL location results matched with those observed during PTC and ERCP in 100% of cases.Among the twelve Ce-MRCP-negative patients, BL location was revealed at PTC in six  and at ERCP in another six (CBD in five patients and right hepatic duct in one patient).Ce-MRCP detected a bile leak in 63% and 74% of patients who were later positive at ERCP and PTC, respectively.p: 0.0001). Daily drainage output was not found to be correlated to BL detection with Ce-MRCP, with no particular cut-off being significant.High levels of serum TB were found in 24 patients, and this group included the 12 patients negative on Ce-MRCP. A strong correlation between Ce-MRCP BL detection and serum TB < 4 mg/dL was found  successfully treated the leak, resulting in complete cessation of biliary output from the abdominal drainage.In more detail, in 18 patients, internal–external biliary drainage alone was sufficient to treat the leak; biliary drainage was kept open and connected to a proper drainage bag until the biloma output drainage ended. At this time, the biliary drainage was closed. Finally, if biloma drainage remained silent and control cholangiography did not demonstrate residual leakage and/or stenosis, all the drainages were removed.Moreover, further procedures were required in specific patients; among the 18 aforementioned patients, three required further insertion of a plastic stent to prevent stenosis at the leak level, two patients required a radiological–endoscopic rendezvous for total transection/disconnection at the level of the CBD-Luschka duct along with final positioning of two to four plastic stents, two patients with leak in the right hepatic duct and CBD were managed with the positioning of metal-covered stents and, finally, in just one patient with a peripheral low-flow leakage due to hepatic wedge resection, direct embolisation with a mixture of Glubran–Lipiodol was performed, with immediate leak resolution.The average time for leak resolution was 14 days (range 1–45 days). One patient died during the observational period due to hepatic failure.In all ERCP patients, a stent  was placed, resulting in complete cessation of bile leak from the percutaneous biloma drainage. In detail, 15 patients required the positioning of one or more plastic stents, while a covered metal stent was implanted in only one patient.The average time for leak resolution was 24 days.E. Faecalis, E. Faecium, C. Freundii and C. Albicans being the most commonly isolated.Human bile is normally sterile, but may become infected due to incomplete biliary obstruction or as a iatrogenic complication of operative or non-operative interventions . Clinical presentation can be subtle, particularly in the early phase, where abnormal liver function is the most common alteration. All patients included in this study were evaluated for the possible presence of cholangitis; complete blood count, liver function and inflammatory markers such as erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and procalcitonin (PCT) were included, as well as microbiological evaluation of the bile after drainage. Overall, among the 39 patients included in the study, 12 manifested evidence of infection. The test results are summarised in Treatment of cholangitis was achieved using antibiotic therapy and biliary drainage (in the PTC group). A combination of ampicillin and aminoglycoside provides good cover for Gram-positive cocci and Gram-negative bacteria, respectively. In patients who had previous biliary intervention, the addiction of metronidazole to cover anaerobes can be useful. Sometimes, mezlocillin and piperacillin can also be administered due to their high bile concentration excretion. However, an effective therapy should always be based on blood or bile culture, especially in patients who have undergone previous biliary intervention. The mean time for the normalisation of blood parameters and resolution of the cholangitis (with negative bile culture) was 14 days.Early treatment and resolution of postsurgical biliary complications strongly depends on a rapid and accurate diagnosis. First-line investigations in most patients with suspected BL are usually US or CT. However, both modalities lack the ability to differentiate bilomas from other types of fluid collections and to eventually locate the site of BL .Therefore, when BL is suspected using these modalities, usually, ERCP has to be performed to precisely identify the site of the leak and initiate treatment. ERCP has a sensitivity of more than 90% in detecting bile leaks and can also be used to demonstrate additional biliary pathology, yet it is intrinsically unable to evaluate extra-biliary structures, resulting in a significant rate of false negatives due to the non-visualisation of ducts that are disconnected from the main biliary tree . MoreoveAn important diagnostic contribution can, therefore, be provided by Ce-MRCP, which represents an accurate and dynamic study, providing functional as well as morphological information about biliary lesions. When Primovist is injected intravenously, it is incorporated into hepatocytes by an anionic transport system after the vascular phase. Glutathione-S-transferase has been identified as an intracellular transport protein for Gd-EOB-DTPA . ExcretiIn our study, Ce-MRCP was able to detect bile leak in approximately 66% of patients, while the remaining cases required PTC to confirm and treat the BL. In fact, as reported in other studies, adequate bile duct filling by the contrast material requires conserved liver function ,21. PrevThese results demonstrate that in patients with normal liver function, ce-MRCP is highly able to identify the presence and the location of the leak, approaching a sensitivity of a 100%.As mentioned above, this could be explained by the high affinity of bilirubin for the glutathione-S-transferase transport system, which is also the intracellular transport for the Gd-EOB-DTPA in the hepatocyte. High TB levels act as a competitor binder, preventing the contrast molecule from entering hepatocytes. Alternatively, high levels of TB could simply indicate a condition of impaired liver function, resulting in the deficient excretion of Primovist in bile. The identified cut-off is higher than that found, for example, by Tschirch, but this difference may have been profoundly influenced by the patient cohort, which, in the present study, was mostly composed of non-cirrhotic patients.In this study, in all patients with a positive Ce-MRCP, BL location was anatomically accurate, matching the PTC/ERCP results. This may significantly influence clinical practice, as Ce-MRCP could play a fundamental role in rapidly achieving a precise anatomical diagnosis, simplifying the choice of the most appropriate treatment approach based on BL location. In turn, this could expedite the up-front delivery of the most suitable treatment for each patient’s specific condition, which may help in decreasing condition- and treatment-related complications such as cholangitis, peritonitis, sepsis and bleeding due to vascular erosion at the biloma site. Re-operative management of BL, especially in delayed diagnosis, is usually not first-line in order to avoid further surgical stress in a patient in a precarious clinical condition and with a high risk of a hostile abdomen. Therefore, PTC and ERPC have a fundamental role, and exploiting Ce-MRCP may be extremely useful. PTC can, thus, be planned with greater detail, permitting faster and better-targeted management of multi-ductal percutaneous access. Furthermore, knowledge of the precise anatomical location of BL can aid the logistics of intervention: for example, radiological–endoscopic rendezvous can be the treatment of choice for complete transection of the common biliary duct ,24,25,26In three cases in this series, BL developed after left hepatectomy with double bilio-enteric anastomosis for a 3b Bismuth-Corlette Klatskin tumour. Anastomoses had been performed between the jejunum and right anterior and right posterior bile ducts. Ce-MRCP was able to depict the precise location of the single-anastomosis BL, demonstrating dehiscence exclusively in the right anterior or posterior bile duct .These results allowed a specific percutaneous approach leading to puncturing of the exact biliary system requiring drainage. This granted minimisation of biliary system punctures, potentially reducing complications such as arterial intrahepatic bleeding.Another situation in which Ce-MRCP would undoubtedly be useful is in the assessment of suspected BL after cholecystectomy. In this case, identification of a Luschka duct BL could avoid further invasive treatment, as this situation usually recovers spontaneously, while identification of different injuries to the biliary tree may optimise pre-operative planning, obviating the need for invasive diagnostic modalities altogether.In general, in view of the considerations above, the authors believe Ce-MRCP to deserve consideration in all patients with suspicion of BL without obvious cause and localisation and with TB < 4 for non-cirrhotic patients and TB < 1.5 for cirrhotic patients, to permit the non-invasive precise anatomic definition of biliary injury and consequent tailor-made treatment planning.The most common complication reported in the study was the intercurrent onset of cholangitis.The management of this complication was achieved mainly with antibiotics therapy. However, we believe that keeping the biliary drainage opened even after BL resolution could result in a faster normalisation of laboratory parameters and, hence, bile culture negativisation. The mean time for leak resolution was approximately 28 days for the PTC group and 24 days for the ERCP group, independently of treatment type. To the best of our knowledge, these data seem to be in accordance with the literature ,27,28.The current study has some limitations, including the retrospective nature and small sample size, hampering reliability of the results, and the monocentric experience, limiting their generalisability.Ce-MRCP can accurately diagnose the presence of BL. Diagnostic accuracy is substantially reduced by high serum TB concentrations. These patients may benefit from up-front third-level investigations. The localisation of BL with Ce-MRCP is very precise and perfectly concordant with PTC evaluation, and this may be particularly helpful for pre-interventional planning. PTC/ERCP preserve a higher diagnostic value, especially in cases of high serum TB, yet due to their invasive nature, their first-line use is probably best reserved for patients with impaired liver function or for BLs that require expedited interventional treatment.


To describe quality and outcomes of patient-reported outcome (PRO) measures (PROMs) used in patients with refractory hormone-producing pituitary adenomas, and to provide an overview of PROs in these challenging pituitary adenomas.Three databases were searched for studies reporting on refractory pituitary adenomas. For the purpose of this review, refractory adenomas were defined as tumors resistant to primary therapy. General risk of bias was assessed using a component approach and the quality of PROM reporting was assessed using the International Society for Quality of Life Research (ISOQOL) criteria.20 studies reported on PROMs in refractory pituitary adenomas, using 14 different PROMs, of which 4 were disease specific  and ISOQOL score: 46% (range 29–62%)). SF-36/RAND-36 and AcroQoL were most frequently used. Health-related quality of life in refractory patients  varied greatly across studies, and was not always impaired compared to patients in remission.There is a scarcity of data on PROs in the subset of pituitary adenomas that is more difficult to treat, e.g., refractory and these patients are difficult to isolate from the total cohort. The patients' perspective on quality of life, therefore, remains largely unknown in refractory patients. Thus, PROs in refractory pituitary adenomas require adequate analysis using properly reported disease specific PROMs in large cohorts to enable appropriate interpretation for use in clinical practice.The online version contains supplementary material available at 10.1007/s11102-023-01309-4. The definition of refractory hormone-producing pituitary adenomas is ambiguous. Moreover, ‘refractory tumors’ or refractoriness was not defined in the 4th edition of the World Health Organization Guidelines for Classification of Pituitary Tumors . ThroughRegardless of the exact definition, refractoriness can theoretically result in prolonged treatment, more interventions, higher disease burden, longer exposure to supraphysiological hormone levels, and higher risk of hypopituitarism. Therefore, refractory patients might be more prone to impaired quality of life (QoL) and functional disability compared to patients with pituitary tumors who are cured by a single intervention , 8. BiocVarious generic, and disease-specific patient-reported outcome measures (PROMs) have been developed, which are increasingly being used in the field of pituitary care and research. Moreover, PROMs are used to classify patients holistically, e.g., using SAGIT and ACRODAT in patients with acromegaly , 15. DesThis systematic review was performed in accordance with the Preferred Reporting Items for Systemic Reviews and Meta-Analyses (PRISMA) guidelines .A literature search was conducted on 16-09-2022 . The full search strategy, and in- and exclusion criteria are shown in Supplement 1 and 2, respectively. In brief, articles reporting on PROMs in patients with refractory hormone-producing pituitary adenomas in English were included. Articles were excluded if no full text was available, if they reported on < 5 refractory patients per disease, or on non-original data.difficult-to-treat adenomas, meeting the following criteria: hormone-producing adenomas not responding to first-line therapy—either pituitary surgery for acromegaly, CD, thyrotrophic adenomas (TSH-oma) and gonadotropinomas, or the maximum tolerated dose of DAs for prolactinomas. Studies on prolactinomas resistant to surgical treatment, and studies on pituitary adenomas for which surgery was the primary treatment option, but not performed in all patients (due to contraindications), were also included. Consequently, due to paucity of data, the definition of refractory adenoma was highly inclusive. Notably, no PRO studies on patients with aggressive pituitary tumors were available.Following consensus amongst the authors, for this review, refractory adenomas were defined as All identified studies were imported into Endnote X9. Studies were screened by title and abstract and those of interest were reviewed by full-text screening. An overview of extracted data was shown in Supplement 3. If data was only presented in figures without absolute values, numerical values were estimated.Questionnaires were the only type of PROMs used in the included articles, and therefore solely these results were reported. All PROMs were described briefly below and elaborately in Supplement 4.The validated Acromegaly Quality of Life Questionnaire (AcroQoL) assesses four domains of HR-QoL  . TuebingPituitary Quality of Life Questionnaire (PIT QOL) describes HR-QoL in patients with pituitary disease .The 36-item short-form (SF-36) and Research and Development-36 (RAND-36) measure eight domains of HR-QoL and two component scales  , 23. SF-novelty seeking (range 0–34), harm avoidance (range 0–34) an reward dependence (range 0–30), with higher scores indicating stronger emphasis on the behavior [Beck Depression Inventory (BDI) determines signs and intensity of depression . The Multidimensional Body-Self Relations Questionnaire (MBSRQ) measures body satisfaction , 27. SCLbehavior , 30. Hosbehavior .The quality of selected articles was assessed using a component approach for the general risk of bias , and theMicrosoft Excel  was used for data collection. The primary study outcome were PROMs. The secondary outcomes were the quality of reporting on PROMs and PRO results. Statistical analysis could not be performed, due to insufficient data to perform a meta-analysis.A total of 4554 articles were screened for eligibility, as depicted in the flowchart of article screening and inclusion in Supplement 6. Twenty articles were included in the systematic review, of which 14 were cross-sectional studies, 5 were cohort studies, and 1 article reported on cross-sectional and cohort data (study characteristics: Supplement 7). As some studies reported on multiple types of refractory adenomas, the number of studies reporting on patients with the included pituitary diseases were 14 for refractory acromegaly, 6 for refractory CD, and 4 for refractory prolactinoma. No studies reported on TSH-oma or gonadotropinoma. In total, 14 different PROMs reported on refractory adenomas, of which 4 were disease-specific  (Supplement 8). None of the studies defined refractoriness. Two studies explicitly stated that patients with active disease were symptomatic, although none included a definition of the symptoms. Four studies reported on missing PROM data, of which only one reported < 10% missing data . QualityAcroQoL and SF-36 were most frequently used. In 8/20 studies, absolute PRO results were not reported, with only conclusions being reported on whether refractory patients scored higher or lower than patients in remission or healthy controls , 39–43.personal relations in another study [AcroQoL was used in nine studies Fig. , of whicer study   CushingQoL scores in refractory CD patients compared to patients in remission . AbsolutPIT QOL scores, solely reported in one study and without presenting absolute values, were comparable in refractory acromegaly patients and patients in remission .physical functioning and general health [role physical, bodily pain and vitality domains [SF-12/36 and RAND-36 were reported in nine studies  , and the. used a score of > 17 points to indicate presence of depression) [. described a score of ≥ 18 points as a severe depression) [BDI was reported in two studies, using different cut-off values. In refractory acromegaly, mean BDI scores were 18.9 ± 10.9   (Supplemression) .hostility scores in refractory AC and CD than in healthy controls, and psychoticism in refractory CD [obsessive–compulsive scores in refractory acromegaly patients compared to patients in remission 3 months after surgery, whereas no differences were observed at 12 months [Two studies reported on SCL-90-R. One found higher ctory CD   patients is scarce. A plethora of PROMs were used in research and care of pituitary adenomas, of which few were disease specific. The quality of reporting in the available studies was low, with high risk of bias, leading to inconsistent PRO outcomes. Due to the paucity of data, no conclusions on HR-QoL and the contributing factors in refractory patients could be made.Currently, no consensus on the definition of refractory is available in the literature, resulting in the application of the present definition  for data selection. Using this definition, it should be noted that the status of refractoriness is not only dependent on tumor characteristics, but also on the surgical experience within the treating center, as more experienced surgeons may have somewhat better outcomes. However, from a patient's perspective, this definition might implicitly reflect the impact of the disease, due to prolonged absence of disease remission and the need for secondary treatment. Furthermore, the scarcity of data influenced the present, inclusive definition, as studies reporting on PROs in the most challenging patients  were lacking. Consequently, these most challenging cases could not be identified at present, and therefore warrant future in-depth systematic investigation.Nevertheless, there were some studies reported on PROs in patients with persistent disease after primary treatment—the present definition of refractory patients—to address our clinical question. The next challenge was the use of plethora of PROMs, which were mostly generic and sometimes disease-specific. Disease-specific PROMs focus on quality of life domains specifically impaired in the disease of interest, allowing identification of more subtle impairments than generic questionnaires , 55, 56.Despite their better sensitivity, results of the disease specific questionnaires  were equally ambiguous compared to those of the less sensitive, pituitary-specific (PIT QOL), and generic HQ-QoL questionnaires . Surprisingly, independent of the type of questionnaire used, results of refractory patients compared to patients in remission were inconsistent; being lower in some, yet comparable in other studies. A possible explanation may lie in the well-known fact that patients in remission report ongoing impaired quality of life.bodily pain and physical functioning  and appearance (AcroQoL), expected to be most affected [Furthermore, there was no clear difference in outcomes between the types of adenomas. HR-QoL measured by SF-12/36 and RAND-36 varied greatly between the studies within same type of adenomas. Previous literature reported the worst HR-QoL in active CD compared to other pituitary adenomas , improviaffected , 59, werThe well-known Wilson and Cleary model (WCM)  states tIn agreement with the WCM, we found HR-QoL in refractory acromegaly and CD was not always worse than in patients in remission. This may be caused by ongoing symptoms in patients in biochemical remission, resulting from permanent complications  leadThe importance of the use of PROs in addition to clinician-reported outcomes is well recognized in care for pituitary disease, as well as other diseases , 13. IdeAn important limitation to this systematic review was the high risk of bias and low quality of PRO reporting, limiting proper interpretation and comparability. Secondly, isolating the patients who met our definition of refractory was challenging, as information on treatment was not always presented. This led to an inhomogeneous population. Due to the quality of data, no conclusions could be drawn about HR-QoL in refractory patients, compared to those in remission. Lastly, comparison of PROs with biochemical outcomes lay beyond the scope of this review, which would be interesting to place the PRO results in perspective. To adequately treat and support refractory patients, future studies using disease specific PROMs in large cohorts of patients with pituitary adenomas should be performed, with subgroup analyses for patients who are not in remission after primary therapy.The current systematic review demonstrated a scarcity of high-quality data on PROs in the subset of refractory pituitary adenomas—defined as adenomas being difficult to treat. Additionally, in the current literature, data from refractory patients was difficult to isolate from the rest of the cohort, and the patients' perspective on quality of life therefore remains largely unknown in refractory patients. Thus, PROs in patients with refractory hormone-producing pituitary adenomas require adequate analysis using properly reported disease-specific PROMs in large cohorts to enable appropriate interpretation and use for clinical practice.Supplementary file1 (PDF 659 kb)Below is the link to the electronic supplementary material.


The pathologic triangle formed by chronic heart failure (HF), chronic kidney disease (CKD), and anemia carries high morbidity and mortality rates and decreases quality of life. Anemia represents a common condition in patients with advanced HF and CKD, with a total prevalence in cardiorenal syndrome (CRS) ranging from 5% to 55%. Searching for a pragmatic approach for these patients with guided and disease-specific recommendations beyond just targeted hemoglobin therapeutic behavior represents the core of research for ongoing clinical trials. It is well known that the prevalence of anemia increases with the advancement of CKD and HF. The physiopathological mechanisms of anemia, such as the reduction of endogenous erythropoietin and the decrease in oxygen transport, are leading to tissue hypoxia, peripheral vasodilation, stimulating neurohormonal activity, and maintenance of the progressive renal and cardiac dysfunction. Given the challenges with the treatment options for patients with cardiorenal anemia syndrome (CRSA), new therapeutic agents such as hypoxia-inducible factor–prolyl hydroxylase domain inhibitors (HIF-PH) or hepcidin antagonists are emerging in the light of recent research. This review summarizes the potential therapeutic tools for anemia therapy in the cardiorenal population. Cardiorenal syndrome (CRS), first described in 1836 by Robert Bright, includes hemodynamic interactions of the heart and kidney in which acute or chronic dysfunction in one organ may induce acute or chronic dysfunction in the other organ . . 17]. Hypoxia, as a secondary effect of anemia, increases inflammation and oxidative stress in CKD patients. Further, the reduced renal perfusion activates the renin-angiotensin system, changes that reduce cardiac output and contribute to the process of left ventricular hypertrophy. As in a vicious circle, these changes decrease organ perfusion (including the kidney), making cardiorenal-anemia syndrome a serious and complex disease .2 have increased levels that could explain the iron deficiency ..75].Recent studies showed that roxadustat could reduce ACE2 expression and mRNA in several cells of a mouse model lung tissue, contributing to the inhibition of SARS-CoV-2 and being a potential tool for the prevention and treatment of COVID-19. Another effect of roxadustat reported by Zhu et al. is the improvement of wound healing in diabetic rats . RoxadusSeveral studies have established the beneficial role of daprodustat in the management of renal anemia and its non-inferiority to erythropoiesis-stimulating agents. Tsubakihara et al. demonstrated an increase in hemoglobin level (10~12 g/dL) in the ESA-naive population using daprodustat . DaproduVadadustat inhibits all three PHDs and was approved in 2020 in Japan for the treatment of anemia secondary to CKD. In the phase-3 PRO2TECT clinical trial, vadadustat did not fulfil the pre-specified non-inferiority criteria for non-fatal stroke, non-fatal myocardial infarction, or all-cause death . A phaseMolidustat: for pre-dialysis patients, studies showed a reduction in ferritin, hepcidin, and LDL cholesterol levels, with an improvement in renal anemia in the hemodialysis population as well ,84. OnlyEnarodustat, a newly approved HIF-PH inhibitor, as studies indicate, shows efficacy and safety in correcting hemoglobin in anemic patients with CKD. Comparing to ESAs, enarodustat improved iron utilization without hyper-producing EPO. Phase III comparative studies (SYMPHONY ND and HD studies) showed that enarodustat is non-inferior to darbepoietin alfa in reducing hepcidin levels and controlling hemoglobin, with a total iron-binding capacity higher for enarodustat . Desidustat, another hypoxia-inducible factor–prolyl hydroxylase (HIF-PH) inhibitor, was approved in March 2022 in India for CKD patients on dialysis and non-dialysis-dependent. It is also used for the treatment of anemia induced by chemotherapy and anemia associated with COVID-2019 infections. In rat models, desidustat decreased liver hepcidin levels and increased plasma EPO and reticulocytes. In the phase-3 DREAM-ND study, patients with CKD  were randomized to receive desidustat or darbepoetin alfa for 24 weeks, with no inferiority in the desidustat group regarding the treatment of anemia (hemoglobin 7.0–10 g/dL). The same findings were shown in the Phase-3 DREAM-D Study, where desidustat was noninferior to epoetin alfa (hemoglobin 8.0–11.0 g/dL) in CKD dialysis-dependent patients .The use of HIF stabilizers in clinical practice according to Japanese Society of Nephrology (JSN) are: cardiorenal-anemia syndrome, ESA-resistant anemia, and MIA syndrome. The appropriate choice of anemia therapy, either ESA or HIF represents a correct option together with iron therapy, contributing significantly to the prevention of CRA syndrome .Several studies showed that SGLT2 inhibitors diminished hypoxia in the kidney cortex. Layton et al. studied the effects of acute and chronic SGLT2 inhibition and demonstrated reduced oxygen consumption and sodium transport in diabetic proximal tubules and nephrons in a rat model.By controlling mitochondrial oxygen consumption, luseogliflozin inhibits HIF-1α expression, leading to restoration of hypoxia in the intracellular environment, and further promotes HIF-1α proteasomal degradation in human renal proximal tubular epithelial cells .The benefit of SGLT2 inhibition in enhancing HIF 1 and 2 has relevant implication as HIF-PH may have a variable biological response. The HIF-PH class of drugs is based on molecules that differ in T1/2, so they have different activity duration and their effect is strictly limited to the time they are present in the circulation. Importantly, the efficacy of HIF-PH in restoring the hemoglobin level is also linked to the improved iron assimilation in the gut, providing a perspective to restrict the need to add iron supplementation in CKD and perhaps in HF anemia management .Hepcidin, a regulator of iron homeostasis, may be responsible for erythropoietin resistance by directly inhibiting the proliferation of erythroid progenitors . Due to the main site of elimination of hepcidin (the kidney), patients with CKD will have increased levels of hepcidin. Ashby et al. demonstrated that in hemodialysis (HD) patients, the EPO dose is inversely correlated with hepcidin levels . Regarding hepcidin levels, anemias can be divided into anemias with high and low hepcidin. While in the first group, the anemia is due to the inhibitory effect of hepcidin on the absorption of iron, leading to iron deficiency anemia, in the second group, the anemia is the cause of the suppression of hepcidin due to an abnormal erythropoiesis . PatientIt was observed that there was a reduction in hepcidin levels during EPO treatment in CKD patients, which was associated with an increase in hemoglobin response, a fact that can be used to predict EPO responsiveness in HF patients . In the Interleukin 6 (IL-6) is a regulator of hepcidin synthesis. In patients with rheumatoid arthritis, the administration of tocilizumab (a humanized anti-IL-6 receptor antibody) reduces Il-6 levels and increases hemoglobin levels . ConsideOther possibilities for hepcidin inhibition, as studies suggest, are thiazolidinediones, vitamin D, estrogens, and testosterone. Direct hepcidin inhibitors are those drugs that inhibit hepcidin-binding to ferroportin: anticalin proteins , guanosine 5’-diphosphate (GDP), monoclonal antibodies (AB 12B9M), or aptamers .PRS080#022 is a polyethylene glycol-bound anticalin protein that could represent a potential tool in anemia treatment for CKD patients. This class of proteins is a novel class of stable, small proteins that transport and store vitamins or hormones in many organisms. Repeated doses of PRS-080#022 in cynomolgus monkeys demonstrated the suppression of hepcidin.Renders et al. showed that for the CKD group treated with PRS080#022, TSAT and iron levels increased, with maximum values after 19 h and a dose-dependent duration of effect until 72 h post-PRS-080 administration for the highest dose group .Multiple trials and studies are necessary to evaluate the beneficial and adverse reactions of all therapeutic agents regarding anemia treatment in both HF and CKD patients. Comparisons between ESA and PHD inhibitors were made on CKD patients , but did not include the vast majority of the heart failure population. Data from both pathological conditions are needed in order to obtain a specific treatment plan for cardiorenal anemia syndrome. Anemia complicates both heart failure and chronic kidney disease and is a negative prognostic factor. Treating anemia in the context of the cardiorenal syndrome could be challenging due to the multiple interactions and pathophysiologic complexity. From iron therapy, ESA therapy, to hepcidin inhibitors, or HIF-PH inhibitors, beyond the therapeutic targets, there is a reduction in complications and decreased mortality rates. Several drugs that are under clinical evaluation have shown good results in terms of safety and efficacy, but more data are needed to confirm their utility in the CRA syndrome therapeutic plan.