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Most genetic variants associated with complex traits are hypothesized to regulate gene expression. To understand the genetics underlying gene expression variability, we characterized 14,324 RNA-sequencing samples from the Trans-Omics for Precision Medicine program and performed expression and splicing quantitative trait locus (e/sQTL) analyses in six tissues and cell types, including whole blood ( n = 6454) and lung ( n = 1291). We detected tens of thousands of secondary cis-e/sQTLs, showing that secondary cis-e/sQTL discovery remains unsaturated. We fine-mapped UK Biobank–derived genome-wide association study (GWAS) signals from 164 traits and identified e/sQTL colocalizations for 10,611 GWAS signals, including 7096 that colocalize with secondary e/sQTLs. Our results suggest that even larger e/sQTL analyses will uncover additional secondary e/sQTLs, further benefiting GWAS interpretation.

Post–liver transplant (LT) weight gain and metabolic dysfunction predispose to cardiovascular (CV) morbidity, allograft steatosis, and reduced long-term survival. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) promote weight loss and improve cardiometabolic health, yet evidence in liver transplant recipients (LTRs) is limited. We aimed to evaluate the safety, tolerability, and efficacy of GLP-1 RAs in post-LT weight management. We performed a multicenter retrospective cohort study of adult LTRs treated with GLP-1 RAs across 4 international centers (January 1, 2010–June 30, 2025). Regular GLP-1 RA users were compared with matched non-users by age, sex, obesity, and diabetes status, transplant year, and center. The primary outcome was the change in body weight 1-year post-exposure. Secondary outcomes included glycemic and lipid profiles, kidney and allograft function, immunosuppression effects, major adverse cardiovascular events (MACE), and adverse effects. Longitudinal analyses used linear mixed models with multiple imputation. Among 104 GLP-1 RA users, 68.3% initiated therapy for diabetes; subcutaneous semaglutide was most used at a median dose of 0.82±0.46 mg weekly. Treatment led to significant reductions in body weight (−3.8 kg; −3.9%, p <0.001), body mass index (BMI) (−1.6 kg/m 2 ; −5.0%, p <0.001), and glycated hemoglobin (HbA1c) (−0.48%, p =0.002), with modest lipid improvement. Liver function tests and immunosuppression trough levels remained stable, and no treatment-limiting adverse events occurred. In matched analyses (80 GLP-1 RA users vs. 116 non-users), GLP-1 RAs facilitated greater weight loss (−3.4 kg difference, p =0.009) and HbA1c reduction (−0.43% difference in HbA1c, p =0.042) without increased risk of allograft dysfunction, T-cell–mediated rejection (TCMR), or MACE. This multicenter, international study demonstrates GLP-1 RAs are safe and moderately effective in reducing weight and improving metabolic parameters post-LT, without adverse effects on allograft function or immunosuppression, despite limitations of low dosing. Prospective, randomized trials of GLP-1 RAs in LTRs are thus warranted.

ABSTRACT Background Immune checkpoint inhibitors (ICIs) have emerged as promising agents for the management of advanced HCC. By reducing tumour burden, ICIs may serve as a downstaging/bridging tool to improve transplant candidacy. The aim of this study was to assess the safety of patients receiving pre‐LT ICIs. Methods Multicenter, retrospective cohort study from January 2018 to December 2024, including 48 patients who received ICIs prior to LT (ICI cohort). A control cohort (non‐ICI cohort) was built (1:3) using propensity score matching including 144 patients who underwent LT for HCC without prior ICI. Results Within the ICI cohort ( N = 48) rejection occurred in 9 patients (18.8%), all biopsy‐proven, with a median onset of 31 days post‐LT (12.0–182.0). The median washout period was 60 days (13–96). Patients experiencing rejection had shorter washout periods ( p = 0.029). All rejection episodes were successfully managed; two were steroid‐resistant, one requiring re‐transplantation. There were no rejection‐related deaths. Of the 5 patients with HCC recurrence, 60% received ICI for < 90 days ( p = 0.027). Comparison between the ICI and non‐ICI cohort revealed no significant differences in rejection rates (18.8% vs. 19.4%, p = 0.916), graft failure, HCC recurrence, or overall mortality. Overall survival (OS) did not differ between ICI and non‐ICI patients ( p = 0.625) or between those with and without rejection ( p = 0.119). Rejection was not associated with increased mortality, with deaths primarily attributed to infection or HCC recurrence. Conclusion Our results demonstrate that rejection rates were similar in patients receiving ICIs pre‐LT and it can be safely managed.

Limited information on the business practices of liver transplant (LT) centers worldwide has been published. Characterizing this data could help identify best practices as well as opportunities for improvement. As such, the International Liver Transplant Society (ILTS) Business Practice Committee conducted a global online survey of LT centers, which was sent to the ILTS membership. Questions focused on 5 main domains: transplant practice and volumes, workforce, finances, quality assessment and performance improvement, and overall program function. Data was compared across program geographic regions and transplant volume. A total of 89 discrete centers were represented, of which 76.4% were academic/university-affiliated, and about one-third each were from Europe (36.0%) and North America (31.5%). The top 3 problems programs reported were finances/funding (60.7%), adequate program support/guidance (48.3%), and transplant volumes (43.8%). In all, 59.6% of respondents felt their salary was undercompensated, consistent across geographic regions. In addition, 69.7% felt their center was not adequately funded to meet program goals, with programs in Europe (N=28/32, 87.5%) and Oceania (N=2/3, 66.7%) most impacted. Transplant surgeon retainment was noted as more difficult for lower volume programs (<50 liver transplants/year, N=13/31). Nearly half (42.7%) of all programs felt under-resourced to provide high-quality care, and the majority (80.9%) felt there was room for growth and improvement under their current model. While international concerns varied widely among LT centers, inadequate salary and center funding, low transplant and referral volumes, and staff retainment were persistent themes. Focusing on adopting region-specific best practices and developing transplant systems of care that focus on these elements is critical to provide optimal care to LT patients worldwide.

Living liver donation is a critical component for addressing organ shortage and improving outcomes for patients with end-stage liver disease. As the prevalence of living donor liver transplantation (LDLT) increases worldwide, understanding and optimizing long-term donor health is paramount. The 2025 International Liver Transplantation Society and International Living Donor Liver Transplantation Society (ILTS-iLDLT) Consensus Conference convened experts in the field of liver transplantation to establish evidence-based guidelines focused on the long-term medical, psychological, and social considerations following living liver donation. The aim of this working group was to integrate current evidence and expert consensus on donor follow-up protocols, risk assessment, and management strategies to promote long-term donor health, quality of life, and living liver donor programs globally to safeguard the welfare of this unique population.

Background. As cancer therapeutics improve, more liver transplant (LT) candidates will have a history of prior to transplant malignancy (PTM), an established risk for cancer posttransplant. Methods. This study provides granular analysis (with focus on nonliver PTM) of posttransplant cancer risk relating to PTM in 1105 consecutive adult LT recipients (2009–2019, N = 542 with PTM). Results. PTM prevalence increased from 37.8% to 63.2% during this timeframe. Post-LT survival was lower (10 y: 61.2% versus 75.1%; P < 0.001) with higher cancer-related mortality (17.6% versus 2.2%; P < 0.001) in patients with any PTM. The higher cumulative incidence of cancer post-LT associated with PTM (59.7% versus 37.6%; P < 0.001) was not attributable to de novo cancer (38.5% versus 37.7%; P = 0.21) but to recurrence. Cancer recurrence rate (10 y) was lowest in nonliver/nonskin (“other”) PTM (10.6%) with mortality rates from recurrence of only 4% in this cohort. De novo cancers may present at more advanced stage in patients with PTM and lung cancer the most common nonskin de novo malignancy (PTM 21%, no PTM 7%). Family history of cancer was an independent predictor for de novo cancer. Conclusions. PTM associated post-LT cancer outcomes are dominated by skin and liver cancer recurrence and not recurrence of “other” cancers or de novo cancer. This data supports the guidance proposals for cautious liberalization of “other” cancer remission requirements before transplantation. As post-LT cancer is highly prevalent regardless of PTM status, adherence to posttransplant cancer screening and surveillance is critical to identify early cancer after transplant.

Background. Metabolic dysfunction–associated steatotic liver disease (MASLD) is increasingly recognized as a significant indication for liver transplantation (LT) in North America. Yet data on its impact in other countries, such as Spain, remain limited. This study aimed to evaluate the prevalence and trajectory of MASLD-related LT in Spain and compare these findings with broader national data and international data sets. Methods. Multicenter retrospective cohort study including adults (18 y and older) undergoing LT for MASLD between 2010 and 2023 in 5 large Spanish centers. Additional data were obtained from the Spanish Transplant Registry (Organización Nacional de Trasplantes) and high-prevalence LT centers in the United States (n = 7) and Canada (n = 1). Results. Among 3448 LTs performed in the 5 Spanish centers, 3.4% (n = 117) were MASLD-related. An increasing trajectory of MASLD-related LT was observed, with predictions suggesting a rise to 5.4%–10.8% of LTs for MASLD by 2028. These trends were consistent with Organización Nacional de Trasplantes data. Compared with North American data, the growth trajectory in Spain showed a less steep increase. Hepatocellular carcinoma rates were higher in the Spanish MASLD-LT recipients, yet metabolic comorbidities were frequent in all populations. Conclusions. The burden of MASLD-related LT in Spain is growing, yet at a less pronounced rate than in the United States/Canada. Whether this slower increase will persist or decline in the future as newer antiobesity and MASLD-related drugs are increasingly used is still unknown. In the meantime, our results highlight the need for tailored approaches to management and prevention in the Spanish population and underscore the importance of continued monitoring and research into the evolving impact of MASLD on LT in Spain and beyond.

Immune checkpoint inhibitors (ICIs) have improved cancer prognosis significantly, but their use has been avoided in liver transplant recipients (LTr) due to poorly characterized rejection risk. Data surrounding rejection risk are extremely suboptimal, with highly variable immunosuppression approaches and follow-up, and do not account for the learning curve in managing immunosuppression in the setting of ICI. A standardized institutional clinical practice protocol was developed in 2021 for immunosuppression management to facilitate ICI therapy with prospective close follow-up for immunosuppression levels and allograft function. Of 20 LTr, 12 (60%) were male, 18 (90%) were Caucasian, with a mean age of 54.0 (SD 11.2) years. However, 13/20 had 2 or more failed cancer therapies before ICI. Hepatocellular carcinoma ​(HCC) (N=7), lung (N=3), and melanoma (N=3) were the most frequent. Time from first ICI treatment to death was <30 days (N=5), 30–59 days (N=4), 60–89 days (N=1), and >90 days (N=6). Most deaths were cancer-related, reflecting the late stage of disease. ICI toxicity occurred in 3 LTr; pneumonitis (N=1, 5%), myocarditis (N=1, 5%), and acute cellular rejection (N=1, 5%). Four patients remain alive 178–341 days with stable allograft function and slow reduction in immunosuppression. Three out of 4 patients have a partial cancer response, and 1 with slowed progression of disease. ICI treatment in the immunosuppressed LTr is feasible with careful immunosuppression management and follow-up. Demonstrating a low rejection risk should allow for earlier utilization of these agents to improve cancer prognosis. Optimizing rejection risk with cancer response requires ongoing study.

Opioids are often prescribed to children for pain relief related to procedures, acute injuries, and chronic conditions. Around-the-clock dosing of opioids can produce physiologic opioid dependence within 5 days. According to a 2001 consensus paper from the American Academy of Pain Medicine, American Pain Society, and American Society of Addiction Medicine, dependence is defined as “a state of adaptation that is manifested by a drug class specific withdrawal syndrome that can be produced by abrupt cessation, rapid dose reduction, decreasing blood level of the drug, or administration of an antagonist.” The experience of children undergoing iatrogenic withdrawal symptoms is variable and may be mild and go unreported or can be severe and even life threatening. Guidance on opioid withdrawal is available only for adults and primarily for adults with substance use disorders. This report will summarize existing literature and provide readers with information on how to screen for symptoms of iatrogenic opioid withdrawal as well as mechanisms for opioid withdrawal prevention.

Abstract Objectives The aim of this study was to compare the measured physiological factors that limit running performance with real marathon results from world-class distance runners, evaluating the compatibility between measured data and predicted results based on the previously suggested model. Methods Four world-class East African marathon runners (three male, one female) underwent physiological running assessments to predict marathon performance times using a model based on V ˙ $\dot {\mathrm{V}}$ O 2 peak, percentage of V ˙ $\dot {\mathrm{V}}$ O 2 peak at the second ventilatory threshold, and running economy. Predictions were then compared to participants’ best marathon times. Results The measured V ˙ $\dot {\mathrm{V}}$ O 2 peak of the world-class runners was 75.1 ± 2.7 mL/kg/min. The second ventilatory threshold occurred at 85 ± 3 % of the peak, with a running economy of 63.7 ± 2.4 mL/kg/min at 19.6 ± 0.9 km/h. The predicted marathon performance time was 2:06:51 ± 0:03:17 h:min:s for the males and 2:17:36 h:min:s for the female. Comparing these predictions to their personal best times, the average difference was 00:55 ± 00:51 min:s (range: 00:20-02:08). Conclusions This research provides laboratory data on world-class road running athletes, reinforcing the link between marathon performance and V ˙ $\dot {\mathrm{V}}$ O 2 peak, the percentage of V ˙ $\dot {\mathrm{V}}$ O 2 peak at the second ventilatory threshold, and running economy. The examined athletes had lower V ˙ $\dot {\mathrm{V}}$ O 2 peak compared to predicted values, highlighting the importance of running economy and fractional utilization of V ˙ $\dot {\mathrm{V}}$ O 2 peak in achieving such performances. Future studies should continue to advance the field by including additional bioenergetic parameters measured during race conditions and expanding the participant cohort of elite marathoners, encompassing both sexes.