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Introduction: As one means to avoid waste in research investment, involving patients as full partners in research has become increasingly frequent. There is clearly a low level of investment in palliative care research. Following the guidance from the James Lind Alliance and the UK public consultation ('Palliative and End of Life Care Research Priorities Project'), we developed a 3-step protocol aimed at prioritising 10 unanswered questions in palliative care (PC) research in France, from the viewpoint of patients, volunteers, healthcare professionals and family caregivers., Methods and Analysis: To identify unanswered questions in PC (stage 1), an unstructured questionnaire will be used. This questionnaire will be tested on patients and healthcare professionals and modified, if necessary, before being made available online for a period of 6 months. A multidisciplinary steering committee including board-certified PC physicians, methodologists, nurses, a sociologist, an anthropologist and an information specialist will analyse the data collected in order to delete duplicate questions, do a thematic and population classification of the responses, modify questions using the PICO (patient problem, intervention, comparison and outcome) format and perform a literature review on each question to identify any relevant systematic review., Ethics and Dissemination: We expect the results to have wide-ranging benefits, for example, by prompting investment in the 10 prioritised research questions. There are also potential benefits for patients and caregivers, by including them as partners in future research. Regarding the current bill being examined by the government planning to legalise euthanasia and assisted suicide in France, this study will provide new insights into how patients and caregivers are prioritising those themes. The major benefit of this study is to involve patients and family caregivers as partners in PC research. They will be consulted and their choices will be valuable resources and may prompt researchers to focus on different topics. In view of the limited funding available, PC research needs to prioritise major issues and raise its visibility.The second stage of the study is the first-round prioritisation using a fixed format questionnaire, which will last 4 months. The third stage will consist of reaching a consensus regarding the top 10 unanswered questions in PC research, using the nominal group technique. A secondary objective during this third step is to study the reasons for the prioritisation., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2025. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ Group.)

Objectives: Sarcopenia increases the risk of nonalcoholic steatohepatitis (NASH) and cirrhosis in patients with nonalcoholic fatty liver disease (NAFLD). Subsequently, poorly managed NAFLD can result in adverse health outcomes. Lifestyle interventions are effective for both NAFLD and sarcopenia; however, diagnosis of sarcopenia in this population is not well defined. This review aimed to examine current methods to diagnose sarcopenia in NAFLD patients., Methods: MEDLINE, EMBASE, and CINAHL databases were searched for articles published until July 2023 using the terms "Non-alcoholic fatty liver disease," "NAFLD," "fatty liver," "sarcopenia," and "myoatrophy." Studies were excluded if they included pediatric populations, did not diagnose both sarcopenia and NAFLD, or included patients with alternate causes of liver disease., Results: Twenty studies, predominantly from Asian countries (14 [70.0%]), involving 68 848 participants (45.5% females) were included. In 15 studies, most participants had a BMI > 25 kg/m 2 . Heterogeneity in the tools used to diagnose NAFLD was identified, with abdominal ultrasound being the most commonly used. European, Asian, and Australasian Sarcopenia Working Groups had differing diagnostic definitions of sarcopenia. Of the three potential diagnostic elements of sarcopenia (muscle mass, strength, function), all studies measured muscle mass, commonly through bioelectrical impedance analysis (12 [60.0%]). Seven studies (35.0%) measured muscle strength, with the majority (n = 6) utilizing hand grip strength. Four (20.0%) measured muscle function, through gait speed or a timed up-and-go test., Conclusions: The lack of standardization in sarcopenia diagnosis for NAFLD patients is concerning. A consistent definition is necessary to prevent this comorbidity from being overlooked, improve care, and outcomes., (© 2025 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.)

Transcription factors (TFs) such as RBPJ in Notch signaling bind to specific DNA sequences to regulate transcription. How TF-DNA binding kinetics and cofactor interactions modulate gene regulation is mostly unknown. We determine the binding kinetics, transcriptional activity, and genome-wide chromatin occupation of RBPJ and mutant variants by live-cell single-molecule tracking, reporter assays, and ChIP-Seq. Importantly, the search time of RBPJ exceeds its residence time, indicating kinetic rather than thermodynamic binding stability. Impaired RBPJ-DNA binding as in Adams-Oliver-Syndrome affect both target site association and dissociation, while impaired cofactor binding mainly alters association and unspecific binding. Moreover, our data point to the possibility that cofactor binding contributes to target site specificity. Findings for other TFs comparable to RBPJ indicate that kinetic rather than thermodynamic DNA binding stability might prevail in vivo. We propose an effective in vivo binding energy landscape of TF-DNA interactions as instructive visualization of binding kinetics and mutation-induced changes., Competing Interests: Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Binimetinib is a MEK1/2 inhibitor particularly active in cells harboring activating mutations in the MAP kinase pathway, especially in BRAF and NRAS. Binimetinib, in combination with encorafenib, has received marketing approval in several jurisdictions for the treatment of patients with BRAF V600E or V600K mutant melanoma. The absorption, distribution, metabolism, and excretion of binimetinib were evaluated by administering a carbon 14-labeled binimetinib 45 mg dose (containing 40 μCi of radiolabeled material) to 6 healthy male participants. A total of 62.3% of the radioactivity was eliminated in the feces, while 31.4% was eliminated in the urine. The overall recovery of radioactivity in the excreta for all 6 participants was 93.6% (3.27%), indicating that good mass balance was achieved. The total percentage of the dose in the excreta of all metabolites containing the N-demethylation clearance of binimetinib by CYP1A2 and CYP2C19 was approximately 17.8%. The contribution of direct glucuronidation to the clearance of binimetinib was estimated to be 61.2% and represented the majority of the clearance. Additionally, excretion of unchanged binimetinib into the urine was estimated to have contributed 6.9% to the overall clearance. Based on study results, binimetinib is at least ≈ 50% absorbed, but based on its PK properties and because its glucuronide conjugates are unstable in the GI tract, absorption is thought to be significantly higher., (© 2025 The Author(s). Pharmacology Research & Perspectives published by British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics and John Wiley & Sons Ltd.)

Introduction: Obesity is a known risk factor for postoperative complication after ventral or incisional hernia repair (VIHR). Whether minimally invasive techniques can mitigate this risk for certain patients remains unknown. This study investigates whether MIS approaches offer advantages in reducing any medical or surgical complication after VIHR across clinically meaningful BMI categories., Methods: This study analyzes data from the Michigan Surgical Quality Collaborative Core Optimization Hernia Registry (MSQC COHR). The registry is a representative, random sample of adult patients from 70 Hospitals across the state of Michigan. This study includes adult patients receiving VIHR between Jan 2020 and September 2023. All elective VIHRs captured in the MSQC database were included in analysis. Univariate statistics were used for cohort summary and multivariate logistic regression was used to estimate the probability of any 30-day postoperative complication while controlling for age, sex, the interaction of BMI and surgical approach, medical comorbidities, hernia size, mesh use, use of component separation, and previous hernia repair., Results: A total of 11,886 people met the study inclusion criteria. The median (IQR) age was 55.0 (44-65) and 5,111(43.0%) were female. The median (IQR) BMI was 31.7 (27.6-36.3). 5,260(44.3%) cases were performed with an MIS approach and 6,626(55.7%) were performed with an open approach. The adjusted relative risk of experiencing a complication after open repair when compared to MIS repair was 1.34 (95% CI [1.04-1.70], p = .02) in Obesity Class I, 1.62 (95% CI [1.23-2.14], p < .001) in Obesity Class II, and 2.31 (95% CI[1.49-3.56]) for Obesity Class III., Conclusions: MIS repair was associated with improved 30-day outcomes for patients with class I, II, and III obesity, but not for healthy to overweight patients. In clinical scenarios where delay for severely obese patients may be difficult, electing to use an MIS repair may be the optimal strategy to reduce risk of complications., Competing Interests: Declarations. Disclosures: The authors report no conflicts of interest or financial ties to disclose., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Hepatitis E virus (HEV) is a globally distributed pathogen that causes acute hepatitis in people. Recent human cases of HEV arising after contact with urban rats (Rattus spp.) have raised concerns regarding whether rats may be a source of HEV infection. We investigated whether urban Norway rats (Rattus norvegicus) could be a source of HEV in an underserved urban neighborhood of Vancouver, Canada. We found that 15% of rats tested positive for rat HEV, and that HEV status was associated with increasing rat body length and family relationships. Rat HEV isolates were clustered according to their location on either the east or west side of a busy roadway bisecting this neighborhood, suggesting that this street is a barrier to HEV spread. Widespread distribution of HEV among rats in this neighborhood poses potential human health risks, emphasizing the need to reduce close contact of people with rats and their excreta., (© Wildlife Disease Association 2025.)

Background and Aims: Improving the care of decompensated cirrhosis is a significant clinical challenge. The primary aim of this trial was to assess the efficacy of a chronic disease management (CDM) model to reduce liver-related emergency admissions (LREA). The secondary aims were to assess model effects on quality-of-care and patient-reported outcomes., Approach and Results: The study design was a 2-year, multicenter, randomized controlled study with 1:1 allocation of a CDM model versus usual care. The study setting involved both tertiary and community care. Participants were randomly allocated following a decompensated cirrhosis admission. The intervention was a multifaceted CDM model coordinated by a liver nurse. A total of 147 participants (intervention=75, control=71) were recruited with a median Model for End-Stage Liver Disease score of 19. For the primary outcome, there was no difference in the overall LREA rate for the intervention group versus the control group (incident rate ratio 0.89; 95% CI: 0.53-1.50, p =0.666) or in actuarial survival (HR=1.14; 95% CI: 0.66-1.96, p =0.646). However, there was a reduced risk of LREA due to encephalopathy in the intervention versus control group (HR=1.87; 95% CI: 1.18-2.96, p =0.007). Significant improvement in quality-of-care measures was seen for the performance of bone density ( p <0.001), vitamin D testing ( p <0.001), and HCC surveillance adherence ( p =0.050). For assessable participants (44/74 intervention, 32/71 controls) significant improvements in patient-reported outcomes at 3 months were seen in self-management ability and quality of life as assessed by visual analog scale ( p =0.044)., Conclusions: This CDM intervention did not reduce overall LREA events and may not be effective in decompensated cirrhosis for this end point., (Copyright © 2024 American Association for the Study of Liver Diseases.)

Introduction: Current evidence demonstrates questionable incremental benefit of robotic abdominal wall (ventral) hernia repair when compared to other approaches. However, data are mainly limited to 30-day outcomes and do not capture long-term patient reported outcomes (PROs) where the robotic may provide distinct advantages., Methods: We analyzed patients who underwent ventral hernia repair from January 2020-September 30, 2022 in the Michigan Surgical Quality Collaborative Core Optimization Hernia Registry (MSQC-COHR). Validated PROs included the Ventral Hernia Recurrence Inventory (VHRI), PROMIS Pain Intensity 3a (Pain 3a), and HerQLes quality of life measures. Survey weighting was employed to reduce non-response bias and balance respondents with the overall COHR population. Logistic regression was used to assess the relationship of operative approach with answering "Yes" to the 3 VHRI questions, reporting a worse than average Pain 3a score, and reporting a below median HerQLes score. Models accounted for patient, hernia, and operative characteristics., Results: Our sample included 1583 patients undergoing hernia repair, of which 507 (32.0%) were robotic, 202 (12.8%) were laparoscopic, and 874 (55.2%) were open. Median follow up time was 1.3 years (IQR 1.2-1.5). Patient characteristics were similar across approaches. Robotic repairs were more often performed electively, on larger hernias, and with mesh. After controlling for covariates, a robotic approach was associated with a lower predicted probability of reporting a bulge [19.5% (95% CI 15.7-23.2%)] than a laparoscopic approach [26.8% (95% CI 20.4-33.2%)], but was no different than an open approach [18.8% (95% CI 16.1-21.6%)]. No other differences in PROs were found by approach., Conclusions: We found a lower likelihood of reporting a bulge after robotic ventral hernia repair when compared with a laparoscopic approach, but no difference when compared with an open approach. No other differences in long-term PROs were found when comparing robotic to laparoscopic or open approaches., Competing Interests: Disclosures. Brian T Fry, Abigail L Kappelman, Joshua K Sinamo, Desmond Huynh, Leah J Schoel, Alexander K Hallway, Anne P Ehlers, Sean M O’Neill, Michael A Rubyan, Jenny M Shao, and Dana A Telemhave no conflicts of interest or financial ties to disclose., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)