Citations

Abstract Purpose To assess if PSA density (PSAD) velocity is a predictor of clinically significant prostate cancer (csPCa). Methods Patients undergoing prostate MR for suspected csPCa between 2017 and 2023 were included. Of these, patients who underwent two or more MR exams within 0.3 to 2 years to each other and pathological confirmation within 1 year after the last MR were identified. PI-RADS score, patient age, screening or active surveillance (AS), PSA, PSAD, PSA-velocity and PSAD-velocity were assessed if they were predictor of csPCa. For univariate analysis, all variables were assessed using student t or chi-square tests. When variables were considered significant, variables were entered into multivariate logistic regression model. Results 23,244 MRs were performed (17,703 screening, 5,541AS). 1,174 patients (mean age: 65.9) met the inclusion criteria, and 550 patients (47%) were diagnosed with csPCa. On univariate analysis, PI-RADS score (p<.0001), age (67.0 vs 64.9, p<.0001), AS exam (67% vs 59%, p = 0.004), PSA (7.5 vs 6.6, p<.001 ), PSAD (0.16 vs 0.12, p<.0001) and PSAD-velocity (0.023 vs 0.012, p = 0.005 ) were predictors of csPCa but PSA-velocity (1.4 vs 1.2, p=.4) was not. On multivariate analysis, PI-RADS score (p<.0001), age (p<.0001), AS exam (p<.0001), PSA (p<.0001) and PSAD (p<.0001) remained significant predictors, but PSAD-velocity was not (p=.1). Conclusions Higher PSAD-velocity was associated with presence of csPCa on univariate analysis but not on multivariate analysis when combined with other predictors such PI-RADS score, age, and PSAD.

Krabbe disease is an autosomal recessive leukodystrophy caused by a deficiency of the lysosomal enzyme galactosylceramidase (GALC), responsible for the degradation of galactolipids, resulting in toxic psychosine accumulation and progressive demyelination of the central and peripheral nervous systems. Newborn screening (NBS) has increased recognition of later-onset Krabbe disease, although interpretation of complex GALC genotypes remains challenging, particularly in the presence of “pseudodeficiency” and modifier alleles. In this case report, we describe a child with late-infantile Krabbe disease identified through NBS with markedly reduced GALC activity and a homozygous GALC haplotype containing c.956A>G (p.Tyr319Cys; Y319C) and c.1685T>C (p.Ile562Thr; I562T), in addition to other benign variants. Retrospective analysis of the newborn screening specimen demonstrated mild psychosine elevation. Despite preserved neurodevelopment, longitudinal surveillance demonstrated progressive cerebral white matter abnormalities by 3 years and 9 months of age and psychosine elevation in erythrocytes (14 pmol/g Hb; controls < 5), prompting umbilical cord blood transplantation (UCBT). Following transplantation, GALC enzyme activity normalized, psychosine levels decreased, and serial neuroimaging demonstrated radiographic stability without neurologic regression at last follow-up (9 years old). This case expands the phenotypic spectrum associated with homozygosity for the p.Tyr319Cys variant and highlights the role of p.Ile562Thr in amplifying the pathogenic potential when in cis with p.Tyr319Cys. This GALC haplotype illustrates how “pseudodeficiency” and modifier alleles may collectively influence biochemical, radiologic, and clinical disease expression. These findings emphasize the importance of integrating genotype, psychosine, enzyme activity, and longitudinal neuroimaging when evaluating infants with NBS results positive for Krabbe disease.

Objective: Standardized training and education are priorities for improving system-level quality and outcomes for pediatric trauma patients. The objective of this study is to identify common educational needs of pediatric trauma clinicians in the United States and the gaps in currently available education courses, to inform future curriculum development. Methods: An anonymous, IRB-approved, 30-item cross-sectional survey was developed and distributed to pediatric trauma clinicians via e-mail. Demographic and quantitative data were analyzed with descriptive statistics. Open-ended responses were analyzed using reflexive thematic analysis. Results: Two hundred four surveys were analyzed. Respondents were faculty physicians (40.7%), nurses (23.5%), trauma program managers (18.6%), advanced practice providers (11.3%), EMS (4.4%), and trainee physicians (1.5%) representing thirty-seven states. 70% worked at a pediatric trauma center. 65% had taken the ATLS course, but only 50% felt that the course prepared them to care for pediatric trauma patients. 97% had taken PALS, but only 45% felt the course prepared them for pediatric trauma care. Respondents ranked comfort with specific pediatric trauma skills. Confidence was lowest for chest tube placement (mean=5.7/10) and dosing intubation medications (6.1/10). Confidence was highest for tourniquet placement (8.2/10) and assigning a GCS to a school-aged child or teen (8.1/10). Qualitative themes included: (1) Neither ATLS nor PALS provide comprehensive pediatric trauma education; (2) Comfort with pediatric trauma comes from experience rather than course completion; (3) There is a desire for additional pediatric-specific education, and (4) Multiple specific topics were identified as educational needs. Conclusion: ATLS and PALS alone do not meet the need for comprehensive pediatric trauma education in the United States. Experience is most helpful for proficiency, putting low-volume centers at a disadvantage. Pediatric-specific trauma education is desired, including simulation-based courses and app-based reference materials. Pediatric procedural skills, age-specific assessment and physiology, and evidence-based best practices should be targeted.

ABSTRACT Background and Aims It remains unclear whether different factors influence 30‐ and 90‐day readmission rates. We identified predictors of 90‐day mortality in a global cohort of hospitalised patients with cirrhosis. Methods Variables associated with 30‐ and 90‐day post‐discharge readmission, liver transplantation (LT), and mortality were compared in prospectively enrolled, non‐electively hospitalised adult patients with cirrhosis. Results We enrolled 4208 patients from 125 centres across 37 countries. Alcohol‐related liver disease was the most common aetiology of cirrhosis (40%), followed by hepatitis B virus infection (21%); 47% were readmitted, 8% received liver transplantation (LT), and 23% died within 90 days post‐discharge. In multivariable analysis, country income was significantly associated with both 30‐ and 90‐day readmission rates, the receipt of LT, and mortality within 30 and 90 days post‐discharge (all p ‐values < 0.001). Independent predictors of higher rates of 30‐ and 90‐day readmissions, respectively, were disease severity ( p < 0.001, p = 0.003), prior ascites ( p = 0.025, p = 0.016), prior hospitalisation ( p < 0.001), hyponatremia ( p < 0.001, p = 0.008), and in‐hospital vasopressor use ( p = 0.002, p = 0.011). Prior variceal bleeding independently predicted higher 90‐day readmission rates, whereas age, disease severity, mechanical ventilation, and in‐hospital vasopressor use (all, p < 0.001) increased odds of 30‐ and 90‐day post‐discharge death. Additionally, admission ( p = 0.011) and nosocomial ( p = 0.022) infections increased the odds of 90‐day post‐discharge death. Conclusion In a global cohort of hospitalised patients with cirrhosis, patients in high‐income countries exhibited the highest rates of 30‐ and 90‐day readmission, alongside lower mortality rates and a higher incidence of LT. Variables that predict 30‐day readmission also predicted 90‐day readmission. Understanding these disparities is essential for achieving health equity.

BACKGROUND: Anthracyclines are a widely used and effective class of chemotherapy. However, a major limitation for their use is cardiotoxicity, manifesting as systolic dysfunction, congestive heart failure, and arrhythmias. The objective of this study was to identify genes and genetic risk variants for doxorubicin-induced arrhythmia. METHODS: We performed genome-wide association studies and meta-analysis across 2 independent nonoverlapping, genetically homogenous data sets from the Molecular Epidemiology Resource (cases N=77, controls N=1184) and Tapestry (cases N=13, controls N=172). Doxorubicin-related arrhythmia was the primary cardiac outcome, followed by investigation of a broader phenotype of cardiac events. Effects of doxorubicin on top-associated genes were assessed by quantitative polymerase chain reaction on RNA extracted from human cardiomyocytes following treatment with doxorubicin and by echocardiography in a zebrafish model of doxorubicin-induced cardiomyopathy. RESULTS: In the meta-analysis, rs12151014 at the KCTD15 locus was associated with doxorubicin-related arrhythmia at the genome-wide significance (minor allele frequency in Molecular Epidemiology Resource cases 0.195 versus 0.069 in controls; Tapestry cases 0.192 versus 0.079 in controls) P =9.01×10 −9 ; odds ratio, 3.61. MMP 16 rs1094199 was associated with the broader phenotype of arrhythmia and heart failure (minor allele frequency in Molecular Epidemiology Resource cases 0.079 versus 0.019 in controls; Tapestry cases 0.038 versus 0.015) P =1.98×10 − 8 ; odds ratio=6.15. In human cardiomyocytes, MMP16 and KCTD15 gene expression was significantly downregulated by doxorubicin, and in a zebrafish MMP16 knockout was protective of doxorubicin-induced decline in left ventricular ejection fraction. CONCLUSIONS: Genetic variants at KCTD15 and MMP16 are associated with doxorubicin-related arrhythmia and cardiac events. MMP16 is a potential cardioprotective therapeutic target.

ABSTRACT HLA‐DPA1*01:49 is characterised by a single nucleotide substitution in codon 119 in exon 3.

Introduction Immigrants of African Descent (IAD) are a subset of the population in the United States with unique healthcare needs and experiences driving health disparities, including inadequate access to healthcare for cancer prevention and control. This study reports the impact of a Cancer advocacy program in IAD communities, using the training of trainers approach. Methods IAD from different organizations were invited to undergo cancer advocacy training organized by Inclusive Cancer Care Research Equity and Mayo Clinic Comprehensive Cancer Center as Master trainers on colorectal, breast, and prostate cancers. Participation was through in-person training and Zoom sessions. Our team communicated with participants frequently via email to provide support and updates. The Master trainers led cancer awareness programs within their communities during the second phase of the program. Results Participants included two breast cancer survivors, three prostate cancer survivors, six cancer caregivers, and 19 community advocates. There were 19 advocate-led cancer risk reduction and research participation events, reaching 2045 community members, and 875 were navigated to research. Community responses showed that 96% found the information given at the Master Trainer-led event was very useful, 46% promised to seek more cancer information, and 17% agreed to volunteer to become a cancer advocate. The insights from this study suggested that the train-the-trainers’ approach was efficient in ensuring community ownership of cancer advocacy. Conclusion IAD can be trained to effectively lead advocacy programs in immigrant communities, using the train-the-trainer approach. Future studies should establish the feasibility of sustaining community outreach and research navigation in IAD communities to improve cancer prevention and cancer care outcomes in this population.

Abstract Effector gene expression in CD8+ T cells is tightly controlled at the epigenetic and transcriptional levels; however, crucial regulatory signals remain incompletely understood. In this study, we identify dual specificity phosphatase 2 (DUSP2) as a key epigenetic modulator of effector CD8+ T-cell state, by elucidating inhibition of BAF-mediated chromatin opening by DUSP2. Induced downregulation of DUSP2 in human CD8+ T cells enhances cytotoxicity and effector phenotypes by increasing chromatin accessibility through upregulation of BAF subunits, such as SMARCA4, and permitting binding of ETS1 to BAF subunit gene loci and those essential for effector programs. These findings uncover a previously unrecognized role of DUSP2 in the management of the chromatin landscape in effector CD8+ T cells and the epigenetic fine-tuning of their functionality, highlighting DUSP2 as a promising therapeutic target for T cell–based immunotherapy.

Aim: Despite advances with immune checkpoint inhibitor (ICI)-based regimens in the past decade, patients with metastatic urothelial cancer (mUC) face a poor prognosis with few approved options. Platinum-based chemotherapy with paclitaxel and carboplatin (TC) +/– ICI may be a feasible choice. Methods: We generated an IRB-approved, HIPAA-compliant retrospective database of patients at Mayo Clinic Cancer Center with mUC who started TC +/– ICI after disease progression on ICI from January 2018 through December 2024. Baseline demographics, clinicopathologic features, and treatment outcomes were extracted from the electronic health record. Kaplan-Meier method was used to calculate median duration of response (DOR), progression-free survival (PFS) and overall survival (OS). Results: There were 32 patients who fit inclusion criteria, including 31 patients who had disease progression on ICI in the metastatic setting and 1 patient who developed metastatic disease on adjuvant nivolumab. Patients received a median of 4 cycles (range 1–14) of TC over median 12 weeks (range 3–53). Overall, 81% of patients received TC concurrently with an ICI, and 28% continued maintenance ICI after TC discontinuation (at the treating oncologist’s discretion due to adequate response or toxicity). The best objective response rate was 41% and disease control rate was 75%, with median DOR of 4.8 months (IQR 2.7–10.4), median PFS of 4.6 months (IQR 3.3–10.2), and median OS of 9.4 months (IQR 6.3–15.9). Some patients in this series had very durable responses with PFS > 12 months and OS > 24 months. TC +/– ICI was overall well tolerated with expected type and severity of adverse events. Conclusions: Strategies to overcome ICI resistance are needed, and TC +/– ICI after disease progression on an ICI shows promising tolerability and efficacy in this setting for patients with mUC. Our series was notable for some patients having a durable response. Validation in larger cohorts is warranted.