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Background: A multiple sclerosis (MS) diagnosis urges decision-making on immunotherapies, while persons with MS (PwMS) need to develop a coping concept in parallel. At this stage, PwMS ask how they themselves may contribute to controlling the disease. Evidence suggests that maintaining a healthy lifestyle (e.g. physical activity and stress management) is a key factor for healthy aging and preserving activity, while data on MS are complex. Objectives: Following the Medical Research Council framework, this study aimed to develop and investigate the feasibility of a new digital health application that conveys evidence-based patient information about lifestyle factors in MS and engages PwMS in relevant behaviour change techniques. Methods: Based on a digital health application promoting lifestyle management in breast cancer survivors, an MS-specific adaptation (‘levidex’) was developed. Feasibility was tested with 15 PwMS and eight MS experts. Subsequently, a six-week pilot study with eight PwMS was conducted. All participants provided feedback on practicability and acceptability via a questionnaire and took part in a semi-structured telephone interview. Levidex was revised after each test phase. Results: The final levidex tool includes 16 modules, 177 references and several other functions. Feasibility results showed that PwMS and MS experts perceived levidex as understandable (14 out of 15; 6 out of 8), trustworthy (15 out of 15; 8 out of 8), and relevant (10 out of 15; 8 out of 8). Interviews revealed potential for improvement regarding the length and complexity of some content. Piloting of the revised version confirmed good feasibility and high acceptance. Most participants felt inspired to initiate (7 out of 8) or had already implemented (5 out of 8) lifestyle changes after working with levidex. Conclusion: Results suggest that levidex is feasible and well-accepted by PwMS and MS experts. It might be a useful tool to support PwMS in adapting to their diagnosis and initiating health-promoting lifestyle changes.

IntroductionRelapsing-remitting multiple sclerosis (MS) is characterized by relapses of new or worsening neurological symptoms and periods of recovery. We developed a web-based program (POWER@MS2) to support people with MS (PwMS) in decision-making regarding relapse management. The program consists of three components (dialogue-based decision aid (DA), nurse- led webinar, online chat). POWER@MS2 was evaluated in a randomized controlled trial (RCT) accompanied by a process evaluation (PE), aiming to identify implementation barriers and facilitators and to understand change mechanisms.MethodsThe mixed-methods PE is based on the MRC complex interventions framework. PwMS and experts (neurologists, study nurses) participated in the study. During the RCT, participants received questionnaires about the intervention and study organization. Based on the results, semi-structured interview guides were developed. Expert interviews were recorded and transcribed. Currently, we are analyzing the expert interviews thematically and recruiting PwMS for the interviews. We will use joint displays to merge quantitative and qualitative findings.ResultsQuantitative data are available from n=72 experts and n=159 PwMS (intervention n=79, control n=80). After six months 90% of n=38 neurologists stated that PwMS participated more actively in relapse management. We interviewed 11 experts, who stated that the program promotes shared decision- making in relapse management. In the intervention group, the program was used by 98% of participants. After three months, 97% stated to like the dialogue-based approach of the DA. 34 PwMS in the intervention group had one or more relapses during the observation period. Of these, 71% (n=24) used the DA for acute relapses and all found it helpful.DiscussionThe interviews with PwMS will address selected aspects based on quantitative study results and characteristics of participants, aiming to optimize the intervention and to further explore study findings.ConclusionDecision aids with a dialogue-based approach are suitable to support PwMS in making decisions regarding relapse management.

IntroductionProcess evaluations accompanying complex interventions examine the implementation process of the underlying intervention, identify mechanisms of impact and assess contextual factors. This paper presents the protocol for a process evaluation conducted alongside the randomised controlled trial POWER@MS2. The trial comprises the evaluation of a web-based complex intervention on relapse management in 188 people with multiple sclerosis conducted in 20 centres. The web-based intervention programme focuses on relapse treatment decision making and includes a decision aid, a nurse-led webinar and an online chat. With the process evaluation presented here, we aim to assess participants’ responses to and interactions with the intervention to understand how and why the intervention produces change.Methods and analysisA mixed methods design is used to explore the acceptance of the intervention as well as its use and impact on participants. Participants are people with multiple sclerosis, neurologists, nurses and stakeholders. Quantitative semistandardised evaluation forms will be collected throughout the study. Qualitative semistructured telephone interviews will be conducted at the end of the study with selected participants, especially people with multiple sclerosis and neurologists. Quantitative data will be collected and analysed descriptively. Based on the results, the qualitative interviews will be conducted and analysed thematically, and the results will be merged in a joint display table.Ethics and disseminationThe process evaluation has received ethical approval from the Ethical Committee of the University of Lübeck (reference 19–024). Findings will be disseminated in peer-reviewed journals, at conferences, meetings and on relevant patient websites.Trial registration numberNCT04233970.

IntroductionMultiple sclerosis (MS) is an inflammatory and degenerative disease of the central nervous system that mainly affects young adults. Uncertainty is a major psychological burden of the disease from diagnosis to prognosis, enhanced by the pressure to make early decisions on a diverse set of immunotherapies. Watchful waiting for 1–2 years while adapting goals and lifestyle habits to life with a chronic disease represents another reasonable option for persons with MS (PwMS). A behaviour change programme based on evidence-based patient information (EBPI) is not available in standard care. This randomised controlled trial (RCT) with an embedded process evaluation investigates the efficacy and cost-effectiveness of a web-based behavioural lifestyle programme to change lifestyle behaviour and reduce inflammatory disease activity in PwMS.Methods and analysisA web-based behavioural intervention will be evaluated in an RCT aiming to recruit 328 persons with clinically isolated syndrome, suspected MS or confirmed MS for less than 1 year, who have not yet started immunotherapy. Moreover, a mixed-methods process evaluation and a health economic evaluation will be carried out. Participants will be recruited in at least 16 MS centres across Germany and randomised to an intervention group with 12 months of access to EBPI about lifestyle factors in MS, combined with a complex behaviour change programme or to a control group (optimised standard care). The combined primary endpoint is the incidence of new T2 lesions on MRI or confirmed relapses.Ethics and disseminationThe study has been approved by the Ethics Committee of the Hamburg Chamber of Physicians (PV6015). Trial results will be communicated at scientific conferences and meetings and presented on relevant patient websites and in patient education seminars.Trial registration numberClinicalTrials.gov Registry (NCT03968172); Pre-results.

We analysed whole-genome sequences of 560 breast cancers to advance understanding of the driver mutations conferring clonal advantage and the mutational processes generating somatic mutations. We found that 93 protein-coding cancer genes carried probable driver mutations. Some non-coding regions exhibited high mutation frequencies, but most have distinctive structural features probably causing elevated mutation rates and do not contain driver mutations. Mutational signature analysis was extended to genome rearrangements and revealed twelve base substitution and six rearrangement signatures. Three rearrangement signatures, characterized by tandem duplications or deletions, appear associated with defective homologous-recombination-based DNA repair: one with deficient BRCA1 function, another with deficient BRCA1 or BRCA2 function, the cause of the third is unknown. This analysis of all classes of somatic mutation across exons, introns and intergenic regions highlights the repertoire of cancer genes and mutational processes operating, and progresses towards a comprehensive account of the somatic genetic basis of breast cancer. Whole-genome sequencing of tumours from 560 breast cancer cases provides a comprehensive genome-wide view of recurrent somatic mutations and mutation frequencies across both protein coding and non-coding regions; several mutational signatures in these cancer genomes are associated with BRCA1 or BRCA2 function and defective homologous-recombination-based DNA repair. Mutational signatures of breast cancers This study reports whole-genome sequencing of tumours and normal tissue from 560 breast cancer cases, providing a comprehensive genome-wide view of recurrent somatic mutations and mutation frequencies across both protein coding and non-coding regions. The authors analyse mutational signatures in these cancer genomes, including a new investigation of rearrangement mutational processes, and find several that are associated with BRCA1 or BRCA2 function and defective homologous-recombination-based DNA repair. They also find mutational signatures showing distinct DNA replication strand biases.

BackgroundHemoconcentration has been identified as a risk factor for a complicated course in Shiga toxin-producing E. coli-hemolytic uremic syndrome (STEC-HUS). This single-center study assesses hemoconcentration and predictors at presentation in STEC-HUS treated from 2009–2017.MethodsData of 107 pediatric patients with STEC-HUS were analyzed retrospectively. Patients with mild HUS (mHUS, definition: max. serum creatinine < 1.5 mg/dL and no major neurological symptoms) were compared to patients with severe HUS (sHUS, definition: max. serum creatinine ≥ 1.5 mg/dL ± major neurological symptoms). Additionally, predictors of complicated HUS (dialysis ± major neurological symptoms) were analyzed.ResultsSixteen of one hundred seven (15%) patients had mHUS. Admission of patients with sHUS occurred median 2 days earlier after the onset of symptoms than in patients with mHUS. On admission, patients with subsequent sHUS had significantly higher median hemoglobin (9.5 g/dL (3.6–15.7) vs. 8.5 g/dL (4.2–11.5), p = 0.016) than patients with mHUS. The product of hemoglobin (g/dL) and LDH (U/L) (cutoff value 13,302, sensitivity 78.0%, specificity of 87.5%) was a predictor of severe vs. mild HUS. Creatinine (AUC 0.86, 95% CI 0.79–0.93) and the previously published score hemoglobin (g/dL) + 2 × creatinine (mg/dL) showed a good prediction for development of complicated HUS (AUC 0.87, 95% CI 0.80–0.93).ConclusionsAt presentation, patients with subsequent severe STEC-HUS had a higher degree of hemoconcentration. This underlines that fluid loss or reduced fluid intake/administration may be a risk factor for severe HUS. The good predictive value of the score hemoglobin (g/dL) + 2 × creatinine (mg/dL) for complicated HUS could be validated in our cohort.

Background Adverse late health outcomes after multimodal treatment for pediatric cancer are diverse and of prime interest. Currently available evidence and survivorship care guidelines are largely based on studies addressing side‐effects of two dimensional planned radiotherapy. Aims The Dutch pediatric 3D‐planned radiotherapy (3D‐RT) study aims to gain insight in the long‐term health outcomes among children who had radiotherapy in the 3D era. Here, we describe the study design, data‐collection methods, and baseline cohort characteristics. Methods and Results The 3D‐RT study represents an expansion of the Dutch Childhood Cancer Survivor study (DCCSS) LATER cohort, including pediatric cancer patients diagnosed during 2000–2012, who survived at least 5 years after initial diagnosis and 2 years post external beam radiotherapy. Individual cancer treatment parameters were obtained from medical files. A national infrastructure for uniform collection and archival of digital radiotherapy files (Computed Tomography [CT]‐scans, delineations, plan, and dose files) was established. Health outcome information, including subsequent tumors, originated from medical records at the LATER outpatient clinics, and national registry‐linkage. With a median follow‐up of 10.9 (interquartile range [IQR]: 7.9–14.3) years after childhood cancer diagnosis, 711 eligible survivors were identified. The most common cancer types were Hodgkin lymphoma, medulloblastoma, and nephroblastoma. Most survivors received radiotherapy directed to the head/cranium only, the craniospinal axis, or the abdominopelvic region. Conclusion The 3D‐RT study will provide knowledge on the risk of adverse late health outcomes and radiation‐associated dose‐effect relationships. This information is valuable to guide follow‐up care of childhood cancer survivors and to refine future treatment protocols.

Background and Aims Endoscopic ultrasound‐guided portal pressure gradient (EUS‐PPG) measurement is a promising alternative to hepatic venous pressure gradient (HVPG) assessment, especially in settings where HVPG is unavailable or limited. The commercial 25‐gauge (25G) system showed good correlation with the hepatic venous pressure gradient (HVPG). However, the 25G has drawbacks due to its small caliber and the proprietary pressure transducer. The aim of this study was to validate a custom‐built 22G conventional intravascular pressure transducer system (22G EUS‐PPG). Methods In this prospective cohort study, 26 patients underwent EUS‐PPG measurement using both systems during the same session. The primary outcome was the correlation of PPG values. Secondary outcomes included the correlation and variability of portal vein pressure (PVP) and hepatic vein pressure (HVP) measured by both systems. Results PPG values showed excellent correlation of both systems (r = 0.901, p < 0.001). 25G EUS‐PPG correctly identified clinically significant portal hypertension (CSPH, defined as PPG ≥ 10mmHg) in 25 of 26 (96.2%) cases. Portal vein and hepatic vein pressures also correlated significantly (r = 0.776 and r = 0.673, respectively) between both systems. Variability within both systems was very low to low. Conclusion EUS‐PPG measurements obtained using the commercial 25G and custom‐built 22G EUS‐PPG systems were validated. The custom‐built 22G system excels due to pressure‐tracing based quality control, availability and cost‐efficiency. Key Summary Summarize the established knowledge on this subject ◦ EUS‐guided portal pressure gradient (EUS‐PPG) measurement using a commercial 25G system is a minimally invasive alternative to hepatic venous pressure gradient (HVPG) for evaluating portal hypertension. ◦ The commercial 25G device lacks real‐time pressure tracing due to a propietary transducer system. ◦ Limited availability and reimbursement of this device restrict the clinical adoption of EUS‐PPG in many healthcare systems. ◦ No adaptable alternative has previously been validated against the commercial system in a same‐session setting. What are the significant and/or new findings of this study? ◦ This is the first prospective same‐session validation of a custom‐built 22G EUS‐PPG system against a commercial 25G device under identical conditions. ◦ The 22G system showed excellent correlation with the commercial device and equivalent diagnostic performance for clinically significant portal hypertension. ◦ Integration with a standard intravascular pressure transducer enables real‐time pressure tracing and broader technical flexibility. ◦ The system provides a reliable, safe and cost‐efficient alternative that can expand access to EUS‐PPG across diverse healthcare environments.

In the Methods section of this Article, ‘greater than’ should have been ‘less than’ in the sentence ‘Putative regions of clustered rearrangements were identified as having an average inter-rearrangement distance that was at least 10 times greater than the whole-genome average for the individual sample. ’. The Article has not been corrected.