Abstract Background Methotrexate (MTX) is recommended as first-line therapy in patients with rheumatoid arthritis (RA), proven to be effective, safe and inexpensive. However, a significant proportion of patients does not achieve disease remission with MTX monotherapy. Main reasons include insufficient dose up-titration to the maximal recommended oral dose or the delayed switch to a subcutaneous administration route. We hypothesise, that by dose and route optimisation, a higher proportion of patients can achieve remission. Further, exploratory biomarkers will give new insights on individual MTX metabolism and drug adherence. Methods The MethMax trial is a prospective, randomised, assessor-blinded, parallel-group, superiority, low-intervention trial, including 182 patients across 7 European countries. Patients with active RA, naïve to biologic (except tumour necrosis factor alpha inhibitors; TNFi) or targeted synthetic antirheumatic drugs, who have been on a stable oral MTX therapy for the past 3 months are randomised in a 1:1 ratio to 25 mg MTX weekly, either administered orally or subcutaneously. Additionally, both arms receive a short-term glucocorticoid regimen with a four-week tapering and withdrawal protocol. The primary endpoint is the difference in proportion of patients achieving remission defined as the Clinical Disease Activity Index (CDAI) ≤ 2.8 at week 24, comparing the dose/route optimisation and oral dose optimisation. The active study duration for each patient is 24 weeks. Study visits take place at baseline, weeks 4, 12, 16 and 24. Clinical efficacy and safety parameters are obtained at each visit. Patient-reported outcomes, exploratory biomarkers as well as medication adherence are assessed. Written consent is obtained for all participants. The study has received regulatory approval via the Clinical Trials Information System and Medicines and Healthcare products Regulatory Agency and has included the first patient in August 2024. Discussion The anticipated results will provide insights whether the subcutaneous administration of 25 mg MTX is advantageous in achieving CDAI remission when compared to the oral intake after 24 weeks and inform the community regarding the utility of established and newly developed biomarkers, as well as the potential impact of inadequate drug adherence. The MethMax study is aimed to optimise individual therapy in RA and provide more precise pharmacological MTX management recommendations.

The SMILe (allogeneic SteM cell transplantation faciLitated by eHealth) integrated care model (ICM) offers a transformative approach to routine transplantation care by combining eHealth technology (a patient-facing App for home symptom registration) with monitoring, self-management support and care coordination carried out by an advanced practice nurse (APN) team. Implementing the SMILe-ICM in a setting with an existing eHealth infrastructure and APN support requires context-specific adaptations. Our aim was to adapt the SMILe-ICM to our local setting, guided by a prior context analysis. We followed the ADAPT guidelines, with stakeholder involvement from patients, informal caregivers and the local clinical, IT and legal teams. Using the Framework for Reporting Adaptations and Modifications-Expanded (FRAME), we documented key adaptations. We used the Expert Recommendations for Implementing Change (ERIC) taxonomy to select promising implementation strategies. Key required adaptations included using the local electronic eHealth platform to enhance usability and enable multiple provider access to patient documented data and reducing APN intervention sessions from 12 to six during the first year post-alloSCT to address financial constraints. Minor adaptations included revising content and simplifying language. Further, we selected 20 tailored implementation strategies focused on understanding the local context, involving key stakeholders, preparing a pilot trial, and training healthcare providers and patients for implementation. Real-world adaptation requires balancing the intervention's core components with the technical, regulatory, and resource constraints of the local context. Structured adaptation and strategic implementation planning were essential to support long-term sustainability.

Over recent decades, multifaceted nurse-led care models have been developed to reduce unplanned hospital transfers from long-term care facilities (LTCFs). In Switzerland, the INTERCARE model has demonstrated effectiveness, with core components including deployment of nurses in expanded roles (INTERCARE nurses), evidence-based communication tools, and advance care planning. However, resource-intensive implementation strategies such as 1:1 support meetings for model implementers pose challenges for scale-up, underscoring the need for more scalable implementation support. The INTERSCALE study compares two modes of delivering implementation support—an individualized and a collective-oriented approach—testing the hypothesis that the latter achieves non-inferior fidelity to the INTERCARE model and comparable reductions in unplanned hospital transfers at the LTCF level. Secondary aims are to compare implementation (acceptability, feasibility), economic (costs, cost-effectiveness), clinical (unplanned transfers), and organizational (staff absences, turnover) outcomes. This non-inferiority, effectiveness–implementation hybrid type III trial uses a cluster-randomized controlled design, with LTCFs as the unit of randomization. Forty German-speaking LTCFs in Switzerland (≥20 long-term care beds; cantonal accreditation) will be randomized (1:1) after formal consent to either individualized or collective implementation support, without blinding of LTCFs or the research team. In the individualized arm (20 LTCFs), leadership receives 1:1 support meetings, and INTERCARE nurses receive 1:1 coaching, mirroring the original INTERCARE trial. In the collective arm (20 LTCFs), leadership support and INTERCARE nurse coaching are delivered in group formats involving several LTCFs/INTERCARE nurses together at two-monthly intervals. The primary outcome is LTCF-level fidelity to the INTERCARE core components, analyzed with a binomial generalized linear mixed model including a random LTCF effect. Non-inferiority of the collective mode will be concluded if the lower bound of its 95

INTRODUCTION:Allogeneic hematopoietic stem cell transplantation (HSCT) offers curative potential for many hematological malignancies; however, outcomes may be adversely affected by infections and transplant-associated complications, contributing to non-relapse mortality (NRM). Innovative digital approaches for outpatient surveillance may support earlier detection of complications and thereby help reduce NRM. CASE PRESENTATION:We report on a 73 year-old Caucasian patient who underwent allogeneic HSCT for acute myeloid leukemia in complete remission following non-myeloablative conditioning. The patient participated in the interventional study "Cross-sectoral care for patients with hematological diseases following innovative cell therapy" (SPIZ), which evaluates digital surveillance after cellular therapies. SPIZ comprises daily remote monitoring of vital signs, medication adherence, and symptoms using a multimodal approach integrating an eHealth system (patient smartphone app and caregiver monitoring dashboard), home visits, video consultations, and regular case conferences with referring physicians during follow-up. Eight months post-HSCT, during an inpatient stay at an orthopedic rehabilitation center, the patient reported increasing dyspnea and cough via the app. In response, the SPIZ team initiated immediate transfer to the transplant center. Diagnostic work-up revealed pneumonia caused by aspergillus fumigatus and coronavirus, and progression of pre-existing pulmonary graft-versus-host disease (GvHD), confirmed by computed tomography and spiroergometry. Early detection and prompt transfer enabled rapid initiation of antifungal therapy and intensified GvHD management. The patient was discharged with improved general condition and respiratory function, without further septic complications. CONCLUSION:Innovative digital surveillance is an effective tool for outpatient monitoring after cellular therapies, facilitating early detection and intervention and potentially reducing NRM, particularly in high-risk patients.

BACKGROUND:Nonadherence to heart transplantation-related medications involves both immunosuppressant drugs and co-medications; yet the correlates of heart transplantation patients' overall medication nonadherence remain unclear. OBJECTIVES:We aimed to (1) describe nonadherence to both immunosuppressive and co-medication among Spanish heart transplantation patients, (2) to identify individual-level predictors of co-medication nonadherence, and (3) to describe nonadherence to non-pharmacological advice (eg, sun protection, physical activity, alcohol use) and clinical practice patterns of transplant centers. METHODS:For this multicenter cross-sectional study, we surveyed 224 adult patients attending 5 Spanish centers 1 to 5 years post-transplantation. We assessed nonadherence to immunosuppressants and co-medications using the Basel Assessment of Adherence to Immunosuppressive Medication Scale (BAASIS©). Correlates of nonadherence to co-medications were derived from the Integrative Model of Behavioral Prediction using self-report instruments, as were non-pharmacological treatment adherence and treatment centers' practice patterns. Supported by causal mapping, multiple logistic regression analysis allowed adjustment for relevant confounders. RESULTS:Nonadherence prevalence was 16.5% for co-medications (range across centers: 7.4%-25.0%), versus 9.4% (range: 2.6%-22.2%) for immunosuppressants. Adherence support varied across centers. Barriers to immunosuppressant nonadherence predicted co-medication nonadherence (odds ratio = 11.80; 95% CI, 2.59-53.69). Nonadherence to non-pharmacological treatments, particularly sunscreen use (59.3%) and physical activity (31.8%), were also common. CONCLUSIONS:Post-heart transplantation co-medication nonadherence surpasses immunosuppressant nonadherence. Barriers to immunosuppressant adherence strongly predict co-medication nonadherence. While no direct causal relationship is clear, immunosuppressant nonadherence may prove useful for identifying patients prone to co-medication nonadherence.

Kidney transplant recipients (KTR) may experience burdensome symptoms, including tremor, nausea, and bruises, sometimes caused by immunosuppressive medication, which can negatively influence health-related quality of life. The 59-item Revised Modified Transplant Symptom Occurrence and Symptom Distress scale (MTSOSD-59R) captures patients' symptom experience but has not been validated in Brazil. We evaluated the Brazilian Portuguese MTSOSD-59R regarding content validity (expert panel), internal structure (factor analysis), and associations with other variables (known-groups approach). Symptom occurrence and distress by sex and age were assessed using ridit analyses. 485 KTR (42.2% women; 50.2 ± 12.8 years) were included at median 7.4 [3.2-13.0] years post-transplantation. The expert-rated scale-content validity index was 0.49. Construct validity and known-group associations were confirmed. The most occurring symptoms were anxiety [ridit score: 0.697], tiredness [0.653], and difficulty seeing well [0.652]. The most distressing symptoms were menstrual problems [0.635], difficulty seeing well [0.606], and genital warts [0.595]. Female/younger KTR tended to report more (distress from) psychological/aesthetic symptoms; male/older KTR tended to report more (distress from) physical symptoms. The MTSOSD-59R showed validity for internal structure and relationships to other variables, but insufficient expert-rated content validity for immunosuppression-specific side effects, suggesting it may better reflect general symptom burden in this population.

BACKGROUND:Implementation science recognises that health innovations must be adapted to local contexts. Context analysis is a critical foundational phase for tailoring interventions and implementation strategies, yet remains underutilised in pharmaceutical sciences, limiting successful translation and scale-up of proven services in interprofessional settings. AIM:This paper provides a methodological roadmap highlighting the foundational role of context analysis in guiding real-world adaptation of a known service - the New Medicine Service - to form the myCare Start service in Switzerland. METHODS:Guided by the Basel Approach for coNtextual ANAlysis (BANANA), a mixed-methods context analysis was enacted including individual interviews and online quantitative surveys to understand the current patient journey, interprofessional practice patterns, and readiness of pharmacists and physicians to deliver enhanced medication adherence services. RESULTS:Between September 2023 and February 2024, individual interviews were conducted with 16 patients, 22 physicians, 11 pharmacists and 11 pharmacy technicians from French and German speaking regions of Switzerland. In addition, online surveys were completed by 48 pharmacists and 49 pharmacy technicians. Outputs includes a context report presenting the current state of long-term medication initiation in Swiss community pharmacies and other ambulatory care settings, a comprehensive list of multi-level contextual factors (barriers/facilitators) affecting implementation of myCare Start and stakeholder preferences relating to intervention design and delivery which will inform the adaptation of myCare Start and the selection of multilevel implementation strategies to facilitate implementation in Switzerland. DISCUSSION AND CONCLUSION:This study offers a replicable methodology prioritising contextual understanding as a basis for optimising care processes and real world translation. TRIAL REGISTRATION:ClinicalTrials.gov, Implementation of a New Model of Care for Supporting Long-term Medication Adherence (myCareStart-I) - NCT06191835.

Symptom-related distress after allogeneic stem cell transplantation (alloSCT) significantly impairs quality of life and long-term health. However, symptom distress evolution is not substantiated and potential influences of patient-related factors remain unclear. This study's aims were to (A1) describe first-year post-alloSCT symptom distress evolution, (A2) explore that evolution in view of three patient factors: graft-versus-host-disease (GvHD), gender, age group. This prospective longitudinal observational sub-study of the main SMILe (SteM cell transplantatIon faciLitated by eHealth) study used demographic and clinical data of patients receiving the SMILe Integrated Care Model, and their electronic patient-reported symptom distress outcomes. Patients reporting ≥ 1 time pre- and regularly post-alloSCT on 10 relevant symptoms (distress = 1–10 scale, none = 0), were included. We calculated distress point prevalences at 10 time points and plotted distress score trajectories, determining distress durations and distress persisting > 30 days uninterrupted throughout the first year post-alloSCT (A1). We used boxplot faceting visualising distress persistence by patient factors, and sought parallel-evolving GvHD and distress point prevalences (A2). Four symptoms contributed to the highest distress point prevalences (fatigue 48.2–76.9 https://trialsearch.who.int/Trial2.aspx?TrialID=DRKS00020347 , date of registration: 03/01/2020 (Freiburg) and clinicaltrials.gov: NCT04789863, https://clinicaltrials.gov/expert-search?term=NCT04789863 , first posted: 03/10/2021 (Basel).

BACKGROUND:After kidney transplantation adherence to immunosuppressive medication is crucial for graft survival and its assessment requires valid measurements. The Basel Assessment of Adherence-to Immunosuppressive Medications Scale (BAASIS) is a validated self-report tool to detect non-adherence, however, its ability to predict clinically relevant outcomes remains to be established. METHODS:In this prospective cohort study including 226 consecutive kidney graft recipients transplanted at the Medical University of Vienna between 2018 and 2019 the adherence toward immunosuppressive medication was monitored for 2 years after transplantation. The BAASIS was applied at the first outpatient visit and at months 3, 6, 9, 12, and 24 post-transplant to assess the implementation and persistence phase of adherence. Non-adherence was defined by any positive response to one of the BAASIS-items. The primary endpoint was biopsy-proven allograft rejection defined by the Banff meeting report during a maximum follow-up of 4 years. RESULTS:Of the total study cohort [median age 56 years (IQR 46-63), 75 (33%) female], 125 recipients (55%) reported non-adherence at least once. Self-reported non-adherence increased within the first 3 months from 11% to 31% and remained between 27% and 32% at months 6 to 24 post-transplant. Non-adherent recipients experienced more allograft rejections than adherent patients (24%, n = 30 vs. 7%, n = 7; P < .001) during a median follow-up of 3.7 years (IQR 1.0-4.0). Using a time-dependent Cox regression model, the adjusted hazard ratio for allograft rejection associated with previously reported non-adherence was 2.90 (95% confidence interval (CI) 1.51-5.58; P = .001) accounting for recipient sex, age at transplantation, and history of previous transplantation. CONCLUSION:Our findings support the clinical value of the BAASIS. Its implementation into routine post-transplant care may facilitate the identification of clinically relevant medication non-adherence, enabling timely interventions.

Background:Cardiovascular (CV) disease represents a leading cause of death in kidney transplant recipients (KTRs). Poor physical fitness adds to the increased CV risk of KTRs. Exercise-based rehabilitation and physical activity interventions may prove pivotal in both short and long-term outcomes after kidney transplantation. Methods:PHOENIX-Kidney is a prospective, multicentre, randomized, controlled, single-blinded trial with parallel groups. A total of 147 adult de novo KTRs from two independent Belgian transplant centres will be randomized to one of three groups with different exercise intensity: (i) 6 months moderate-intensity aerobic and muscle strengthening exercise training followed by a physical activity intervention (MIT, n = 49), (ii) 6 months moderate- and high-intensity aerobic exercise training and moderate-intensity muscle strengthening exercise training followed by a physical activity intervention (MHIT, n = 49), or (iii) sham exercise training, not followed by a physical activity intervention (CON, n = 49). The training and physical activity interventions are home-based programmes, which will be initiated at 3 and 9 months after transplantation, respectively. Study participants will be followed up until 2 years after transplantation. The primary hypothesis is that peak oxygen uptake (VO2peak) assessed after the 6-month home-based training programme (the primary outcome) will increase more in MHIT than in CON. Secondary hypotheses are that VO2peak will increase more in MIT compared to CON, and more in MHIT compared to MIT. Secondary endpoints encompass changes in 6-minute walking distance, endothelial function (flow-mediated dilation of the arteria brachialis), health-related quality of life, physical activity, and safety. Conclusion:PHOENIX-Kidney is the first adequately powered RCT to address the question of optimal training intensity in KTRs. Moreover, the implementation potential of a home-based exercise programme followed by a physical activity intervention will be formally assessed in a real-world clinical setting. Clinical Trial Registration:Clinicaltrials.gov identifier number: NCT06260579.

BACKGROUND: Mortality atlases provide insight into the health burdens a society is facing and help visualise them spatially. Here we estimate the geographical distribution of different mortality causes in the elderly population (≥75 years) in Switzerland. Knowledge of the spatial patterns enables better identification of high-risk areas for specific causes of death and potential risk factors, and can help guide policy, allocate resources and raise awareness in a more targeted manner. METHODS: We analysed Swiss mortality data, provided by the Swiss Federal Statistical Office, for the elderly population (≥75 years) for the period 2010–2020. We employed Bayesian spatial models for areal data to produce smoothed maps presenting the age- and sex-adjusted standardised mortality rates for the 25 main causes of death at the municipality level. Additionally, we evaluated the effects of language, urbanisation and income levels on cause-specific mortality. RESULTS: Language regions are associated with mortality rates for many causes of death. In particular, the French-and Italian-speaking regions are associated with a lower burden of mortality due to cardiovascular diseases and diabetes compared to German-speaking Switzerland, but this is offset by increased rates of certain cancers. In 2020, most COVID-19 deaths were concentrated in the French- and Italian-speaking regions. Higher income levels tend to be a protective factor for most causes of death. CONCLUSIONS: We have provided the first model-based mortality maps focusing on the elderly population (≥75 years) in Switzerland. Our estimates identify areas with the highest cause-specific mortality rates and indicate potential health services that are needed in specific areas. The maps can also raise awareness of the most prominent health problems of the ageing population in different parts of the country and guide targeted health interventions.

Switzerland invests substantially in research, yet many innovations fail to reach routine healthcare. This paper argues that embedding implementation science into national research infrastructures is key to closing this gap, reducing research waste and accelerating translation into practice. By strengthening initiatives such as IMPACT and national funding programmes, Switzerland can ensure its innovations deliver timely, sustainable benefits for patients and society.

BackgroundeHealth technologies, including remote patient monitoring (RPM) applications, have the potential to improve care for diseases such as cancer and cardiovascular conditions. However, they also raise ethical aspects that are often inadequately addressed in eHealth evaluation research. This is problematic, as evaluations guide decision-making at multiple levels. To improve evaluation practices, it is essential to understand how ethical aspects are addressed in terms of both content and methodology, enabling the development of tailored recommendations for enhancement. ObjectiveThis scoping review systematically examines how ethical aspects are addressed in eHealth research, focusing on original studies evaluating RPM applications for cancer and cardiovascular diseases. MethodsUsing Joanna Briggs Institute (JBI) methodology and PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews) guidelines, this review implemented a comprehensive search strategy with the terms “cancer or cardiovascular diseases,” “eHealth or telemonitoring,” and “evaluation designs.” Searches included MEDLINE, Embase, CINAHL, SocINDEX, Philosopher’s Index, PsycINFO, and Google Scholar. Data extraction will emphasize ethical aspects and methodological approaches to consider them. The analysis will apply inductive-deductive qualitative content analysis. ResultsInitial searches identified 3321 articles published between 2014 and August 2024. Screening and analysis will be completed in the first quarter of 2025, with results anticipated by summer 2025. ConclusionsOverlooking ethical aspects in evaluation studies can significantly impact eHealth practices. This scoping review will map ethical considerations in original evaluation research, identifying opportunities for more holistic integration of ethics and informing future practical guidance. Trial RegistrationOSF Registries OSF.IO/7XAFV; https://osf.io/7xafv/ International Registered Report Identifier (IRRID)DERR1-10.2196/60849

Stakeholder involvement (SI) is essential for effective and sustainable intervention implementation, yet practical guidance is lacking. This study mapped SI use in implementation science studies, identified gaps, and proposed a practical framework for improved SI planning. Using an evidence gap map approach, this study built on Mielke et al.'s (2022) methodology, which identified implementation studies from 2015-2020. The search was updated to include studies from 2021-2023 from PubMed, using the same search strategy and inclusion criteria. Data extraction followed the Guidance for Reporting on Involvement of Patients and the Public reporting checklist. From 10,184 studies, a random sample of 2,005 was screened, adding 162 implementation science studies to Mielke et al.'s 110, totaling 272 studies for SI analysis. SI was reported in 89% of studies, but often lacked depth and strategic planning. Stakeholders were mainly engaged during the preparatory phase. Most studies involved micro- and meso-level stakeholders, rarely including macro-level stakeholders. Few described stakeholder selection or preparation. SI was mostly consultative, via interviews, surveys, and focus groups, with limited active collaboration. SI processes and costs were rarely evaluated. Our findings underscore the need for structured, comprehensive SI planning and offer practical recommendations to strengthen SI efforts in implementation research.

Introduction:eHealth-facilitated integrated care models (eICMs) offer promising enhancements to healthcare delivery in stem cell transplantation, but entail implementation and ethical challenges. While qualitative process evaluation methodologies can effectively address such issues through interdisciplinary collaboration, no previous studies have integrated approaches from implementation science and applied ethics into eICM evaluations. Objective:Exploring an integrated approach to the qualitative process evaluation of a stem cell transplantation eICM (SMILe-ICM), our objectives were threefold: (1) assess the current SMILe-ICM's implementation through stakeholder perceptions; (2) examine relevant ethical issues; and (3) develop strategies to mitigate identified implementation and ethical challenges. Methods:Semistructured individual interviews were conducted with 12 patients and 3 relatives. Additionally, 8 clinicians in total participated in two focus groups. Data analysis followed an inductive-deductive thematic approach built on interpretative frameworks from implementation science and medical ethics and supported by ethical consultations. Results:We isolated three main themes, centered on the patient's treatment journey and recovery, to explain patients', their relatives' and clinicians' perceptions regarding the SMILe-ICM. While the SMILe-ICM was generally viewed as valuable, perspectives varied regarding standardized procedures, including eHealth, and care coordination practices. These themes encompass implementation and ethical issues related to individual, intervention, inner setting, and outer setting factors, leading to the development of 17 implementation strategies. Conclusion:This study provides nuanced insights into patient- and provider-level eICM implementation and ethical challenges. By identifying these issues early, the integrated research design and resulting strategies facilitated well-informed, timely solutions.

RATIONALE:Nonadherence to routine outpatient appointments (NApp) post kidney transplantation (KT) is a poorly studied health behavior associated with unfavorable outcomes. In the ADHERE BRAZIL Study, we previously reported a high prevalence of this behavior (12.7%). AIMS AND OBJECTIVE:This study aimed to identify the multilevel factors associated with NApp after KT. METHOD:A cross-sectional study, subproject of the ADHERE BRAZIL Study, was performed. We studied a randomized and multi-stage sample of 1105 patients from 20 transplant centers. Patients who missed one or more of the last five scheduled appointments were considered nonadherent. Multivariate analysis was performed using sequential logistic regression, evaluating 49 multilevel variables, according to the Ecological Model (patient, micro, meso, and macro levels). RESULTS:Most patients were male (58.5%), with a mean age of 47.6 ± 12.6 years. The independent factors associated with NApp were, at the patient level: age (OR 0.97; 95% CI 0.96-0.99; p = 0.001), more than 5 years after KT (OR 2.03; 95% CI 1.38-3.00; p < 0.001), and nonadherence to immunosuppressives (OR 2.41; 95% CI 1.66-3.50; p < 0.001); at the micro level (health professionals): higher scores on the team trust scale (0-100) (OR 0.98; 95% CI 0.95-1.00; p < 0.079), and at the meso level (KT center): frequent (monthly) consultations (OR 1.75; 95% CI 1.10-2.77; p < 0.018) and scheduling difficulties (OR 1.91; 95% CI 1.16-3.17; p < 0.011). CONCLUSION:This study is the first to examine the association of health system factors with missed appointments after KT. The identified patient factors allow us to recognize patients at risk for NApp. Modifiable variables at the health professional and KT center levels suggest targets for effective interventions aiming to reduce this behavior and improve outcomes. TRIAL REGISTRATION:ClinicalTrials.gov on 10/10/2013, NCT02066935.