Citations

Abstract TP53 and PPM1D are key regulators of DNA damage response and repair, and somatic mutations in these genes often co-occur in hematopoietic cells, expanding under genotoxic stress. Unlike TP53 mutations, where mechanisms of progression are defined, pathways underlying clonal fitness and transformation in PPM1D mutant cells remain unclear. In collaboration with 5 academic institutions, we analyzed the clinical and molecular landscape of 337 patients with clonal hematopoiesis (CH) and clonal cytopenia of undetermined significance (CCUS) across 4 genotypes: PPM1Dmt/TP53wt (n = 170 [50%]), PPM1Dmt/TP53mt (n = 25 [7%]), TP53mt/PPM1Dwt (n = 17 [5%]), and TP53wt/PPM1Dwt (n = 125 [38%]). All PPM1D variants were truncating, located in exon 6 of the gene, with a median variant allele frequency (VAF) of 6% (range, 0.3%-64%). The PPM1Dmt/TP53mt genotype was most frequently encountered in therapy-related CH/CCUS (t-CH/t-CCUS; 80%, 66.5%, 76.5%, and 19%; P ≤ .001) and had a shorter time interval to detection from last genotoxic exposure (6.2, 5.9, 11.25, and 24.5 months; P ≤ .001) compared with PPM1Dmt/TP53wt, TP53mt/PPM1Dwt, and TP53wt/PPM1Dwt genotypes, respectively. Acknowledging the short follow-up duration, rates of malignant transformation were lower in the PPM1Dmt/TP53wt (2%) and PPM1Dmt/TP53mt (4%) groups compared with PPM1Dwt/TP53wt (12%) and PPM1Dwt/TP53mt (17%) groups (P ≤ .001), respectively. In summary, PPM1D mutations are frequently observed in t-CH/t-CCUS, with low median VAFs, and are associated with low rates of progression, even when comutated with TP53.

Abstract The purpose of this study was to evaluate the incidence and outcomes of traumatic lunate fractures in a Level I trauma center over a 20-year period. Traumatic lunate fractures are rare, making it difficult to determine their frequency, outcomes, and patterns in clinical practice. A retrospective evaluation of 57 patients was conducted at a single institution from 2000 to 2022. Imaging studies, including radiographs, computed tomography, and magnetic resonance imaging, were reviewed to confirm traumatic etiology and fracture pattern. Fifty-seven lunate fractures met inclusion criteria: 11 were isolated and 46 had associated carpal fractures. Treatment included immobilization in 31 patients and surgery in 26. At a mean follow-up of 20.5 months (range, 2–186), average wrist flexion–extension range of motion was 90 degrees (range, 45–160), and grip strength averaged 26 kg (range, 6–48). Patient-reported outcomes were collected at a mean of 105 months (range, 12–226), with mean scores of 27 for the Disabilities of the Arm, Shoulder, and Hand, 19 for the Patient-Rated Wrist Evaluation, and 77 for the Mayo Wrist Score. Complications included 25 cases of posttraumatic arthritis, 2 cases each of avascular necrosis (AVN), nonunion, and complex regional pain syndrome, and 1 hardware infection. Posttraumatic arthritis was more frequently observed in patients with dorsal intercalated segment instability (DISI), age over 50 years, and displaced fractures. Lunate fractures occur in conjunction with greater arc injuries. Volar pole fractures were the most common fracture type observed. Predictors of long-term osteoarthritis included age over 50 years, DISI deformity, and displaced fractures at the time of diagnosis. Surgical fixation methods resulted in comparable outcomes. Two lunates progressed to AVN, both of which occurred following open operative fixation. Prognostic, Level IV

The success of living donor liver transplantation (LDLT) has bridged the growing gap between organ demand and availability in patients with liver failure or liver cancer. Safety of the living liver donor (LLD) is paramount, and astute intraoperative management plays a critical role in ensuring optimal outcomes for them. Given that intraoperative surgical and anesthesia practices vary widely across centers, the International Liver Transplantation Society (ILTS) and the International Living Donor Liver Transplantation Group (iLDLT Group) convened a global consensus conference in Toronto in March 2025 to develop guidelines for intraoperative management of the LLD. This manuscript details the recommendations on intraoperative considerations for the safety of LLD developed by Working Group II of the Consensus Scientific Committee, using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system for assessment of recommendations, and the Danish model of consensus. Working Group II focused on intraoperative monitoring, fluid and ventilation strategies, surgical techniques for vascular and biliary division, surgeon and center-specific experience, and intraoperative crises planning. These guidelines aim to support both established and emerging LDLT teams to ensure high-quality and safe intraoperative care for the LLD.

Abstract Background The associations between bilateral oophorectomy or hysterectomy with ovarian conservation and the risk of Parkinson's disease (PD) remain inconclusive. Objectives To evaluate the evidence on these two associations. Methods We conducted a systematic search across Embase, PubMed, Scopus, MEDLINE, and Web of Science through May 15, 2024. Data were extracted independently by two reviewers, and random‐effects meta‐analyses were performed. Results Eight studies with a total of 242,275 women were included. For bilateral oophorectomy, the effect size (ES) was greater than 1.0 in 5 of 8 studies. The pooled analysis showed a significant association between premenopausal bilateral oophorectomy and an increased risk of PD in cohort studies (hazard ratio [HR] 1.32; 95% CI 1.12–1.56) but not in case–control studies or combining both cohort and case–control studies. There was a suggestive trend of increasing risk with younger age at bilateral oophorectomy. For hysterectomy with ovarian conservation, the ES was greater than 1.0 in all six studies. The pooled analysis showed a non‐significant association in cohort studies and in case–control studies; however, the association was significant when combining both cohort studies and case–control studies (ES 1.19; 95% CI 1.01–1.41). Conclusions Current studies provided low to moderate evidence for the associations between bilateral oophorectomy and hysterectomy with ovarian conservation and increased risk of PD. However, the evidence was only observational and there was important heterogeneity across the case–control studies. Future studies should focus on surgeries performed at younger ages and on the possible effects of estrogen replacement therapy.

Introduction: Adult hepatitis B vaccination coverage in the United States remains low despite updated national recommendations supporting universal adult immunization. Many adults remain unaware of their susceptibility to hepatitis B virus (HBV) infection. This quality improvement (QI) study evaluated a stepwise “Offer–Offer–Test–Vaccinate” workflow designed to improve hepatitis B vaccine uptake among vaccine-hesitant adults in a primary care setting. Methods: This retrospective QI study was conducted at a single primary care clinic in Rochester, Minnesota. Adult patients (≥19 years) seen between October 1, 2022, and October 1, 2024, were routinely offered hepatitis B vaccination during rooming. Two participating physicians implemented an enhanced workflow in which patients who declined vaccination were counseled and then offered serologic screening using the 2023 CDC-recommended triple panel (HBsAg, anti-HBs, and total anti-HBc). Patients with negative serology were notified via the patient portal and reoffered vaccination along with a link to the CDC Vaccine Information Statement. The primary endpoint was initiation of the hepatitis B vaccine series following receipt of negative serology results. Preliminary series-completion data through October 1, 2025, were also assessed. Results: Among 501 eligible adults, 104 (20.8%) accepted vaccination at the initial offer. Of the 397 who declined, 106 (26.7%) agreed to serologic testing; 91 (85.8%) were seronegative. Among seronegative patients, 41 (45.1%) subsequently accepted vaccination. Integrating serologic testing increased overall vaccination uptake from 20.8% to 28.9%, an absolute increase of 8.2 percentage points and a relative increase of 39.4%. Approximately 2.6 serologic tests were required to generate 1 additional first-dose vaccination. Preliminary series-completion rates were 74.0% among those vaccinated at the initial offer and 87.8% among those vaccinated following serologic testing. Discussion: In this primary care setting, incorporating serologic testing into the workflow was associated with modestly improved hepatitis B vaccination uptake among vaccine-hesitant adults. Serologic results may help re-engage patients by providing personalized immunity information. Implementation considerations include staffing needs, laboratory access, patient portal engagement, and insurance coverage. Conclusion: The “Offer–Offer–Test–Vaccinate” strategy was associated with a modest increase in hepatitis B vaccine uptake among hesitant adults. This EMR-integrated, stepwise approach may offer a feasible and scalable strategy to reduce missed vaccination opportunities and support HBV prevention in adult primary care.

Objective: The objective of this investigation was to evaluate the agreement rate on judgments made using the Murad tool by different systematic review teams. Introduction: Evaluating the methodological quality of case reports and case series is challenging but some tools do exist for this purpose. We leveraged the presence of studies that have been evaluated by different systematic review teams to assess the inter-consensus agreement among different teams on Murad tool domains. Methods: Using a back-citation method, we identified systematic reviews that used the Murad tool and retrieved all the included primary studies. We selected studies that were assessed by more than 1 systematic review team. We calculated observed agreement and Gwet’s agreement coefficient on judgments made about each signaling question. Results: We identified 982 systematic reviews that cited the Murad tool and collectively cited 59,080 references. The final data comprised of 81 duplicated case reports and series assessed by more than 1 systematic review team. Overall, the signaling questions had very high observed agreement with 5 of the 8 questions having agreement over 75%. The signaling questions with the highest agreement addressed the adequacy of the ascertainment of the exposure (coefficient 0.959), ascertainment of the outcome (coefficient 0.829), presence of a dose-response gradient (perfect agreement), and clarity of reporting (coefficient 0.755). Conclusion: The current study demonstrates overall high agreement among different systematic review teams that used the Murad tool for appraisal of the same case series and case reports. Leveraging duplicated studies across systematic reviews is a feasible way to retrospectively assess the reliability of the tool.

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.

PURPOSE Venetoclax, an oral BCL-2 inhibitor, has efficacy in t(11;14)-positive relapsed/refractory multiple myeloma (RRMM), which is enhanced by dexamethasone, which promotes BCL-2 dependency. METHODS The randomized, open-label, phase III CANOVA study (ClinicalTrials.gov identifier: NCT03539744 ) enrolled adults with t(11;14)-positive RRMM who had received ≥2 previous lines of therapy. Patients were randomly assigned (1:1) to venetoclax-dexamethasone or pomalidomide-dexamethasone until progression or intolerable toxicity. The primary end point was independent review committee assessed–progression-free survival (PFS) in the intention-to-treat population analyzed by stratified log-rank test (two-sided type I error rate, α = .05), with hazard ratio (HR) and 95% CI estimated by stratified Cox proportional hazard model. Secondary end points included response rates, overall survival (OS), minimal residual disease (MRD) negativity rate (<10 –5 ), and safety. RESULTS Overall, 263 patients were randomly assigned (venetoclax-dexamethasone, n = 133; pomalidomide-dexamethasone, n = 130). Median PFS was 9.9 months (95% CI, 6.9 to 12.6) with venetoclax-dexamethasone versus 5.8 months (95% CI, 3.8 to 9.2) with pomalidomide-dexamethasone (HR, 0.823 [95% CI, 0.596 to 1.136]; P = .24). Overall response and very good partial response or better rates were 62% and 39%, respectively, with venetoclax-dexamethasone versus 35% and 14% with pomalidomide-dexamethasone. MRD negativity rate was 8% with venetoclax-dexamethasone and 0% with pomalidomide-dexamethasone. Median OS was 32.4 months (95% CI, 26.4 to 40.7) with venetoclax-dexamethasone and 26.9 months (95% CI, 20.4 to 38.9) with pomalidomide-dexamethasone (HR, 0.856 [95% CI, 0.612 to 1.197]). Grade ≥3 treatment-emergent adverse event rates were 67% with venetoclax-dexamethasone versus 83% with pomalidomide-dexamethasone. There were 16 (12%) treatment-emergent deaths with venetoclax-dexamethasone versus 8 (6%) with pomalidomide-dexamethasone. CONCLUSION The primary end point of PFS was not met. PFS and OS were numerically longer with venetoclax-dexamethasone versus pomalidomide-dexamethasone in t(11;14)-positive RRMM. Consistent with previous studies, infections were associated with venetoclax-dexamethasone; no new safety signals were observed.

Abstract Using the US National Inpatient Sample, we analyzed 424,540 adult hospitalizations for sickle cell crisis (SCC) from 2016–2020 to quantify cardiovascular comorbidities and their associations with in-hospital mortality. The cohort (mean age 32.4 years; 55.4% female) was predominantly Black (93.0%) and socioeconomically disadvantaged (51.1% lowest income quartile); most admissions occurred at urban teaching hospitals (82.1%). Age showed a monotonic relation with mortality (multivariable HR per year 1.04, 95% CI 1.03–1.05). In adjusted models, six cardiovascular factors independently predicted higher mortality: systolic heart failure (HR: 2.0; 1.35–2.96), atrial fibrillation/flutter (HR: 1.58; 1.08–2.30), ischemic stroke (HR: 3.25; 1.85–5.71), right ventricular failure (HR: 3.14; 1.46–6.75), pulmonary embolism (HR: 5.61; 3.78–8.33) and acute coronary syndrome (HR: 3.70; 2.30–5.95) (All p<0.01). By contrast, chronic coronary artery disease was inversely associated with mortality (adjusted OR 0.41, 0.23–0.74, p<0.01), a paradoxical pattern that likely reflects index-event (collider) bias, treatment confounding, or differential specialty follow-up and warrants prospective adjudication. Compared with White patients, Black patients had lower adjusted in-hospital mortality (HR 0.44, 0.21–0.94, p = 0.03). Our findings prioritize thrombo-ischemic and rhythm/pump failure phenotypes as high-yield targets for risk stratification and crisis-time management, and they motivate integrated cardio-hematologic strategies and prospective validation.