Citations

Abstract A short diagnosis-to-treatment interval independently predicts inferior outcomes in follicular lymphoma. Using international discovery and validation cohorts, we demonstrate its prognostic value beyond established prognostic indices, with implications for risk stratification, clinical trial design, and interpretation.

Abstract Background Central precocious puberty (CPP), which is traditionally defined as the development of secondary sexual characteristics before age 8 years in girls and age 9 years in boys, results from the premature activation of the hypothalamic–pituitary–gonadal (HPG) axis. CPP can be associated with short adult stature, adverse psychosocial outcomes, and increased cardiometabolic and cancer risks in adulthood. Gonadotropin-releasing hormone (GnRH) agonists can effectively suppress premature activation of the HPG axis and have the potential to increase adult height as well as improve psychosocial and long-term health outcomes among patients with CPP. However, as secular trends have continued to shift toward earlier age of pubertal onset, some subpopulations of children with CPP, as it is currently defined, may not require the same extent of diagnostic evaluation and treatment. Objective Develop evidence-based recommendations related to the diagnosis and treatment of CPP. Methods A multidisciplinary panel of clinical experts, along with experts in guideline methodology and systematic literature review, used the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach to address 10 clinical questions related to the diagnosis and treatment of CPP. Systematic reviews of health-related benefits and harms were conducted for each clinical question. The guideline development panel (GDP) also used the GRADE evidence-to-decision (EtD) framework to address stakeholder values and preferences, costs and required resources, cost-effectiveness, acceptability, feasibility, and potential impacts on health equity. Results In girls with thelarche (Tanner stage B2) between ages 7.0 and 8.0 years, the GDP suggests watchful waiting via periodic physical examinations (every 4-6 months) rather than immediately performing evaluation with laboratory testing or radiologic imaging. In addition, the GDP suggests that all girls with breast development (ie, Tanner stage B2) before age 7 years should first be observed for 4 to 6 months to differentiate unsustained or slowly progressive puberty vs rapidly progressive puberty. These recommendations are largely based on evidence that girls with slowly progressive puberty attain a normal adult height without treatment. When hormonal evaluation is performed to confirm central (GnRH-dependent) activation as the cause of precocious puberty, the GDP suggests starting the evaluation with ultrasensitive basal luteinizing hormone (LH) concentration rather than routine GnRH/GnRH agonist (GnRHa) stimulation testing for all patients. While brain magnetic resonance imaging has been a traditional part of CPP evaluation, the GDP suggests that it should not be routinely performed in girls ages 6.0 to 8.0 years and boys ages 8.0 to 9.0 years without central nervous system (eg, neuro-ophthalmologic) symptoms, largely based on a low prevalence of pathologic intracranial findings in these age groups. The GDP suggests against routine genetic testing for patients with CPP, although they judged that genetic testing (eg, MKRN3 sequencing) should be considered for patients with familial CPP through a shared decision-making process. The GDP suggests GnRHa treatment for many children with CPP, although available evidence suggests that some patient subgroups (eg, older girls with slowly progressive CPP) may be less likely to receive a net benefit with this treatment. Rather than always starting GnRHa treatment with a monthly injectable formulation, the GDP suggests that treatment should be initiated with the formulation (such as a longer-acting formulation) that is anticipated to be used long-term. The GDP suggests against routine addition of growth hormone therapy to increase adult height. They also suggest against the routine biochemical testing (eg, LH, sex steroids) to monitor pubertal suppression while receiving GnRHa, instead reserving biochemical testing to confirm clinically suspected treatment failure. Finally, the GDP suggests against routinely continuing GnRHa treatment beyond chronologic age 10.0 to 11.0 years (girls) or 11.0 to 12.0 years (boys) and/or bone age 11.0 to 12.0 years (girls) or 12.0 to 13.0 years (boys). Conclusion These clinical recommendations were developed to address important uncertainties in the diagnosis and treatment of children with CPP. They are based on the best available scientific evidence regarding clinical outcomes judged to be most important to patients and families. The GDP's overarching goal was to suggest diagnostic and therapeutic strategies that will most likely provide net clinical benefits while simultaneously considering important contextual factors such as cost and feasibility. The guideline-development process highlighted important knowledge gaps and the substantial need for additional research.

Abstract Background: Specialised knowledge in adult congenital heart disease is crucial but often lacking, particularly in resource-limited settings. The Global Conversations in Adult Congenital Heart Disease webinar series was initiated to provide accessible, global education via virtual platforms. Objective: This study evaluates the attendance patterns, participant demographics, knowledge outcomes, and audience feedback of the Global Conversations in Adult Congenital Heart Disease webinar series , analysing 19 monthly sessions conducted from October 2023 to April 2025. Methods: Registration data, session viewership, and total series reach were recorded. Demographics were collected per session. Pre- and post-session quizzes were used to assess changes in knowledge; scores from these independent groups were compared using the Mann–Whitney U test. Post-webinar surveys collected improvement suggestions. Results: Out of 1,956 registrants from 89 countries, 54.6% attended the sessions, representing 1,068 participants from 64 nations: mainly Colombia (30.9%), Peru (18%), the USA (14.1%), and Mexico (9.9%). Median quiz scores improved from 50% pre-session ( n = 120) to 100% post-session ( n = 108), a statistically significant gain ( p = 0.035). Notably, 29% had no prior adult congenital heart disease education. Most post-webinar survey respondents rated case presentations and discussions as excellent (75.0%) or good (20.1%). Qualitative feedback suggested areas for improvement included audiovisual quality, audience engagement, content delivery, and language accessibility. Conclusion: The Global Conversations in Adult Congenital Heart Disease webinar series successfully engaged a diverse international audience and showed significant differences in quiz scores between pre- and post-session independent groups, demonstrating the potential benefit and feasibility of virtual education in bridging gaps in adult congenital heart disease training, particularly in resource-limited countries.

Abstract Background Approximately 12 000 adolescents and young adults (ages 15-39, AYAs) are diagnosed with a primary central nervous system (CNS) tumor each year. DNA methylation profiling has transformed CNS tumor classification by refining diagnostic accuracy and identifying biologically distinct subtypes, but its application has not been systematically evaluated in the AYA population. In this study, we examined the spectrum of CNS tumor types across age groups, with a focus on the AYA population. Methods We assembled a large dataset of CNS tumor samples with age annotations and methylation profiles matching with high confidence to a CNS tumor type using the NCI/Bethesda classifier. Prevalence of tumor type, methylation class and DNA copy number aberrations were compared across age strata (pediatric, AYA, and adult). Results The cohort of 21 712 CNS tumors included 5351 tumors from AYAs (25%), which showed a mixed pattern, with tumors typical of childhood (eg, medulloblastoma) as well as those common in older adults (eg, glioblastoma). Several tumor types were specifically enriched in the AYA, including IDH-mutant astrocytoma, pleomorphic xanthoastrocytoma, posterior fossa group B ependymoma, and diffuse hemispheric glioma, H3 G34-mutant, among others. Distinct methylation subclasses of multiple tumor types were observed in the AYA, and patterns of genomic aberrations showed age-specific distributions. Conclusion Large-scale methylation profiling revealed unique classification patterns of CNS tumors in AYAs, with specific tumor types, subclasses, and genomic alterations enriched in this population. These data may serve as a valuable reference resource for better understanding the spectrum of CNS tumors affecting AYA patients.

ABSTRACT Background and Aims Primary sclerosing cholangitis (PSC) is a progressive cholestatic liver disease with a high risk of malignancy and limited therapeutic options. Both the American Association for the Study of Liver Diseases (AASLD) and the European Association for the Study of the Liver (EASL) recommend structured baseline evaluation, fibrosis staging and longitudinal surveillance. However, real‐world adherence to these practices in North America remains unclear. Methods We conducted a retrospective cohort study of 1300 patients with PSC enrolled in the Consortium for Autoimmune Liver Diseases (CALiD) registry between 2018 and 2024 across 19 centres in North America. Guideline adherence was assessed for diagnostic measures at baseline (colonoscopy to establish IBD status and noninvasive fibrosis staging) and longitudinal surveillance (colonoscopy in PSC‐IBD, abdominal imaging for hepatobiliary cancer surveillance and CA 19‐9 testing). Prescribing patterns for ursodeoxycholic acid (UDCA) were also characterised. Multivariable logistic regression was used to evaluate demographic, clinical and socioeconomic predictors of adherence. Results At diagnosis, 78.8% of eligible patients with available data underwent colonoscopy to establish IBD status, and 45% underwent noninvasive fibrosis staging. During follow‐up, only 30%–35% of patients with PSC‐IBD underwent colonoscopy annually, while abdominal imaging for hepatobiliary cancer surveillance declined from 74% at Year 1 to 51% by Year 4. CA 19‐9 testing was documented in 47% over 5‐year period. UDCA was prescribed in 51% at baseline, with median dose of 12.5 mg/kg/day. Socioeconomic factors, including lower education and household income, were associated with reduced adherence, while cirrhosis strongly predicted completion of surveillance imaging. Conclusions Adherence to guideline‐based care in PSC remains suboptimal in North America Suboptimal adherence was observed for strongly recommended practices with longstanding guideline support (colonoscopy to establish IBD status; annual CRC surveillance in PSC‐IBD) as well as practices where guideline consensus has evolved more recently or where societies differ (baseline fibrosis assessment; hepatobiliary cancer imaging). Efforts to standardise care and address socioeconomic barriers are urgently needed to improve outcomes.

Abstract Objective: To define the incidence of donor-derived infection (DDI) in recipients of solid organ transplant (SOT) from donors with positive blood cultures and to assess the impact of shorter versus longer duration of targeted preemptive antibiotic therapy (PAT). Design: Retrospective, single-center, cohort study. Setting: Mayo Clinic Arizona. Patients: Recipients transplanted between 1/1/2019 and 7/1/2024 who received an organ from a donor with positive blood cultures. Methods: The primary outcome was incidence of DDI. Secondary outcomes included duration of PAT and incidence of donor blood culture contamination. Results: Among 199 SOT recipients from 167 unique donors with positive blood cultures, two recipients developed confirmed DDI within 30 days of SOT. Both cases were gram negative bacillary bacteremia not treated in donors and occurred immediately posttransplant prior to adequate recipient PAT. Six-month graft survival and recipient survival were 96.5% and 97.5% respectively. 139 recipients (69.8%) received PAT for a median duration of 7 days. There was no difference in rate of infections between recipients provided with ≤7 days versus 8–14 days of PAT for donor blood cultures; however, recipients who received 8–14 days had more Clostridioides difficile infections (CDIs) within 60 days of SOT (7.7% vs 1.5% ≤ 7 days, P = .040) and were more often discharged on intravenous antibiotics (32.3% vs 11.3%, P < .001). Conclusion: We observed a low rate of DDI following receipt of organs from donors with positive blood cultures. DDI occurred in cases without adequate donor/recipient treatment. Longer durations of targeted PAT resulted in more CDI and intravenous antibiotics on discharge.

ABSTRACT Background Delirium predicts adverse outcomes in older emergency department (ED) patients, but many acutely ill patients without delirium have underlying cognitive impairment that goes unrecognized. Whether cognitive impairment screening improves risk prediction beyond delirium remains uncertain. We compared practical bedside screening strategies for delirium, cognitive impairment, or both for predicting 90‐day functional decline and mortality in older adults admitted from the ED. Methods A prospective cohort comprising patients aged ≥ 65 years admitted from the ED of a large hospital in São Paulo, Brazil. Trained professionals screened for delirium using the brief Confusion Assessment Method (bCAM) and for cognitive impairment using the 10‐point Cognitive Screener (10‐CS). Patients were classified as having normal cognition (bCAM negative, 10‐CS > 5), delirium (bCAM positive), or cognitive impairment without delirium (bCAM negative, 10‐CS ≤ 5). Blinded investigators assessed decline in basic activities of daily living (ADL) and mortality within 90 days of admission. Fine‐Gray models (death as a competing risk) and Cox models estimated associations with outcomes, adjusting for sociodemographic and clinical factors. Results Among 830 patients (mean age = 80 ± 9 years; women = 47%), 427 (51.5%) had normal cognition, 171 (20.6%) had delirium, and 232 (27.9%) had cognitive impairment without delirium. Among delirium‐negative patients with cognitive impairment, 52% had no documented dementia diagnosis or reported memory problems. Compared with normal cognition, cognitive impairment without delirium was associated with 90‐day functional ADL decline (sub‐HR = 1.60; 95% CI = 1.03–2.49) and mortality (HR = 2.31; 95% CI = 1.18–4.51), with risks similar to those observed in delirium. A staged strategy (bCAM first, then 10‐CS if bCAM negative) showed higher discrimination than delirium‐only or 10‐CS‐only screening. Conclusions Cognitive impairment without delirium is common, often unrecognized, and predicts 90‐day adverse outcomes in older patients admitted from the ED. A brief staged screening strategy integrating delirium assessment with cognitive impairment testing among delirium‐negative patients may enhance early detection of cognitive vulnerability and support care planning.

Abstract INTRODUCTION Anti—amyloid‐β (Aβ) therapies are reshaping Alzheimer's disease (AD) management. Understanding changes in real‐world patterns of diagnostic testing and infusion chair usage is essential for optimizing access to care. METHODS Retrospective analysis of Mayo Clinic enterprise electronic health records (Jan 2019–Mar 2025) assessed trends in AD‐relevant brain imaging, fluid biomarkers, apolipoprotein E (APOE) testing, and lecanemab infusions. Rates of amyloid‐beta (Aβ) positivity by sex and age, APOE genotype frequencies, and lecanemab treatment initiation and discontinuation were evaluated. RESULTS Following national insurance coverage changes, lecanemab infusions grew by 110 infusions per quarter to 605 in Q1 2025. Aβ positron emission tomography scans increased (+22/quarter), cerebrospinal fluid biomarker orders declined (−25/quarter), and plasma p‐tau 217 orders rapidly increased (+238/quarter). Females were more likely to be Aβ positive ( p < 0.006). APOE ‐ε4 homozygotes were less likely to initiate lecanemab (HR = 0.11, p < 0.001). DISCUSSION The adoption of anti‐Aβ therapies coincided with a rapid shift in diagnostic workflows.

Abstract Different MRI image contrasts are designed to highlight various tissue properties and combining them allows extension of probabilistic segmentation beyond the commonly used “gray-white-CSF” models. This work describes a fully automated method that combines T1-weighted, T2-FLAIR, and conventional T2-weighted images to provide internal consistency across prediction of tissue segmentations including segmentation of superficial and deep gray matter, white matter hyperintensities, and MR-visible perivascular spaces. Results from 773 imaging datasets from 403 participants in the Mayo Clinic Study of Aging and Mayo Clinic Alzheimer’s Disease Research Center (ADRC) are presented.

Abstract Modern radiation therapy (RT) technologies allow for improved sparing of normal tissues, decreasing the risk of both acute and long-term toxicities. Existing RT dose constraints for prospective trials within the National Clinical Trials Network (NCTN) were formulated in the context of solid malignancies. As patients with hematologic malignancies are often treated with lower RT doses and are usually younger with more favorable prognoses, customized dose constraints are needed. The NRG Oncology Hematologic Malignancies Working Group (NRG HEME) commissioned a review of existing organ-at-risk (OAR) constraints from published primary literature, the NRG Center for Innovation in Radiation Oncology (CIRO), and national guidelines. Customized constraints were developed by iterative review by NRG HEME. Final recommendations were approved by radiation oncology representatives from all the lymphoma NCTN groups (NRG Oncology, Children’s Oncology Group, Alliance, ECOG-ACRIN, SWOG, Canadian Cancer Trials Group). For 49 OARs, a strict recommended constraint was determined, of which 20 were not present in CIRO. Of the remaining 29 constraints, 20 were lower, 2 were the same, and 5 used different metrics; 2 were higher than at least 1 CIRO trial constraint. Acceptable variations were determined and unacceptable variations were added for select critical OARs for plan scoring. While doses to OARs without explicit unacceptable variations should not exceed acceptable variations, violations should not be considered for plan quality assessment on trials. This consensus list of standard OAR constraints should be incorporated for all future NCTN trials in hematologic malignancies. Strict dose constraints will minimize long-term toxicities in this patient population.