Citations

Abstract. Introduction: Preterm birth drives adverse perinatal maternal and infant health outcomes through heterogeneous symptoms, severity, and etiologies. Delivery prior to reaching 37 weeks of gestation may result from medically indicated intervention for pregnancy complications or spontaneously in the absence of prior symptoms. Placental tissue collected following preterm birth exhibits differential DNA methylation compared to full-term placentas and may indicate pregnancy health during gestation. Placental DNA currently has limited utility for assessing health of ongoing pregnancy, as sampling placental tissue during gestation increases the risk of infection and miscarriage. Risks associated with placental sampling during pregnancy limit the use of DNA methylation in clinical preterm birth prediction. Assessing preterm birth risk during gestation requires non-invasive methods for characterizing placental DNA methylation. Results: We quantified genome-wide DNA methylation patterns of hypermethylated cell-free DNA in pregnant (n = 99) and non-pregnant (n = 93) plasma using cell-free methylated DNA immunoprecipitation sequencing (cfMeDIP-seq). In each sample, we assessed DNA methylation status in 300-bp genomic windows, examining both sequencing read counts and calculated absolute molar DNA amount. Known hypermethylated placental regions, including RASSF1, STAT5A, and ERG promoters showed significantly increased odds of detection in pregnant samples, suggesting enrichment of cell-free placental DNA. Of the 536,444 300-bp windows examined, 173,071 (32%) showed significant enrichment in pregnant plasma. Linear modeling identified 107,505 differentially methylated regions (DMRs) associated with pregnancies later diagnosed with intrauterine growth restriction (IUGR) (n = 22). Alu elements showed increased representation in these DMRs than expected, while other repetitive elements exhibited underrepresentation. Discussion: These results demonstrate cfMeDIP-seq's ability to enrich for cell-free placental DNA and characterize cell-free DNA methylation signatures of pregnancies complicated by IUGR. Enrichment of cell-free placental DNA enables non-invasive profiling of placental DNA methylation from maternal plasma. Detectable epigenetic signatures in maternal plasma may identify pregnancies at elevated risk for preterm birth before clinical symptoms appear. Our findings further highlight the potential of cell-free placental DNA for monitoring pregnancy health.

Objectives: Rates of locoregional recurrence and distant metastases are high following curative-intent resection for patients with localized pancreatic adenocarcinoma. Adjuvant therapies have been investigated with the intent to reduce the risk of recurrence and improve OS. The objective of this study is to update and summarize the current evidence for adjuvant therapy following surgical resection for nonmetastatic PDAC with a focus on high-level evidence and randomized controlled trials is provided. Methods: This multispecialty-led committee included gastrointestinal radiation and medical oncology, gastroenterology, radiology, and surgical oncology. Using the population, intervention, comparator, outcome, timing and study design framework, evidence regarding treatment outcomes was assessed using Cochrane and PRISMA methodology. Eligible studies included prospective and retrospective (n≥25) studies published between January 1, 2013 and February 13, 2026, from Ovid MEDLINE, Ovid EMBASE, Ovid Cochrane Database of Systematic Review, and Scopus databases. Study type and quality were assessed. Well-established RAND/UCLA consensus methodology (modified Delphi) was used to rate the appropriateness of the treatment options. Results: Of the 74 references used as evidence, 74 are categorized as therapeutic references. Study type and quality for the references were assessed, and included 31 well-designed studies (phase II randomized and phase III), 14 moderately well-designed studies that account for most common biases (matched cohort and phase II studies), 28 studies with design limitations (retrospective reviews), and 1 reference meta-analysis. Conclusions: This systematic review and guidelines provide up-to-date recommendations focusing on recent advancements for adjuvant treatment of resected PDAC using modern systemic therapy regimens and selective use of radiotherapy using modern techniques.

Cardiac allograft vasculopathy (CAV) remains a leading cause of graft failure after heart transplantation, yet an early, non-invasive risk stratification tool is not available. Artificial intelligence electrocardiography (AI-ECG) can estimate biological heart age, and it has been associated with cardiovascular risk. Its deviation with chronological age, called delta age, and its utility in the prediction of CAV has never been explored. We conducted a retrospective single-center study for heart transplant recipients bridged with Impella 5.5 (Abiomed, Danvers, MA, USA) at Mayo Clinic Florida (2020–2023). ΔAge was calculated at discharge and 1-year post-transplant. The primary outcome was confirmed CAV at 1 year. Univariate and multivariable logistic regression models were used to assess the independent association between the ΔAge and the development of CAV, with discrimination evaluated by AUC and internally validated via bootstrap resampling (2000 iterations). Fifty patients were reviewed. CAV developed in 13 (26%) patients in 3 years. CAV+ patients had a significantly higher ΔAge at discharge compared to CAV- patients (median −1.0 vs. −11.0 years, p = 0.0023) and at 1 year (median +7.0 vs. −4.0 years, p = 0.0080). On univariate analysis, ΔAge at discharge was a significant predictor of the development of CAV (OR 1.084 per year, AUC 0.788). On multivariable adjustment, ΔAge at discharge remained an independent predictor (adjusted OR 1.138, 95% CI 1.023–1.265, p = 0.018, and model AUC 0.859). ΔAge at discharge is a novel and potential predictor of the development of CAV within 3 years. These findings support the integration of AI-ECG into post-transplant surveillance as a scalable, low-cost tool.

Abstract Background Synthetic control arms (SCAs) derived from historical trial data can complement randomized controlled trials (RCTs), particularly in oncology where feasibility, ethical, and cost constraints may limit conventional trial designs. However, their validity for overall survival (OS) remains uncertain. We evaluated the feasibility and limitations of constructing SCAs from the ARCAD metastatic colorectal cancer (mCRC) database across multiple treatment lines. Methods Seven landmark RCTs representing first-, second-, and third-line settings were selected. External control arms were constructed from ARCAD individual patient-level data using propensity score matching based on key clinical and biological variables from a validated ARCAD prognostic score, with adjustment for geographic region and time era when needed. A prespecified two-step benchmarking framework assessed: (1) control-arm OS reproducibility and (2) virtual trial comparisons between matched synthetic controls and original RCT experimental arms. Agreement was evaluated using hazard ratios (HRs) and Z-tests. Results A total of 28,022 patients met the inclusion criteria. ARCAD-derived SCAs were successfully constructed for all selected RCTs and closely reproduced control-arm OS. After matching, baseline characteristics were well balanced, with minimal differences between included and excluded patients. Virtual trials showed concordant treatment-effect estimates with the original RCTs, with a median absolute HR deviation of 0.05 and no significant differences by Z-tests (P>.05). Survival outcomes were consistently reproduced across treatment lines. Conclusion ARCAD-derived SCAs reliably reproduced control-arm OS and benchmark treatment-effect estimates from landmark RCTs in mCRC. Despite limitations related to residual confounding and missing data, this framework supports benchmarking, trial design, and exploratory analyses when conventional control arms are impractical.

Background We examined the relationship between infection‐related hospitalization (IRH) and heart failure (HF) in a large clinical health system and assessed whether IRH improved prediction beyond HF risk equations. Methods We studied 80 880 adults (14 150 with IRH and 66 730 age‐ and sex‐matched comparators) aged ≥18 years without HF in the Rochester Epidemiology Project from 1/1/2005–12/31/2019. IRH was identified using International Classification of Diseases ( ICD ) codes. HF incidence was defined as ≥1 HF‐related ICD code. Multivariable Cox models assessed the association between IRH and incident HF. Among 29 219 adults aged 30 to 79 years without baseline cardiovascular disease in the Rochester Epidemiology Project, Harrell's concordance statistic assessed whether IRH improved discrimination of the Predicting Risk of Cardiovascular Disease EVENTs–Heart Failure (PREVENT‐HF) equations. Results Participants were 53.3% women, 85.6% White individuals, and 95.1% non‐Hispanic individuals, with a mean age of 56.0±20.0 years. Median follow‐up time was 6.2 years. Among the IRH group, 2729 developed incident HF (2.75/100 person‐years) versus 4854 (1.00/100 person‐years) in the comparator. The multivariable adjusted hazard ratio for incident HF among participants with versus without an IRH was 1.85 (95% CI, 1.76, 1.94). In a separate cohort, incorporating IRH into PREVENT‐HF increased the concordance statistic from 0.776 to 0.779 (change, 0.003 [95% CI, 0.001–0.004]). The PREVENT‐HF risk score underestimated the 10‐year risk of HF by up to 9% among participants with an IRH. Conclusions IRH was associated with incident HF but provided negligible change to 10‐year HF risk discrimination. However, among individuals with an IRH, incorporating this information meaningfully improved 10‐year HF risk prediction. Severe infections may serve as a risk‐enhancing factor warranting enhanced preventive measures, particularly in populations where IRH is more common.

Background Homozygous familial hypercholesterolemia (HoFH), characterized by extremely elevated low‐density lipoprotein cholesterol (LDL‐C) due to severely impaired LDL‐C clearance from circulation, remains challenging to treat. Here, we investigated clinical benefits of monoclonal antibody, evinacumab, inhibiting angiopoietin‐like 3, recently approved in children with homozygous familial hypercholesterolemia. Methods This retrospective, observational study included 13 children with homozygous familial hypercholesterolemia on oral lipid‐lowering therapy and assessed their attainment of LDL‐C goal, need for lipoprotein apheresis (LA), and cardiac plaque formation at initiation of evinacumab and at follow‐up of 2.0 (1.3–3.0) years. Results Evinacumab, initiated at age 11 (8.5–13.5) years, increased number of patients reaching LDL‐C goal from none before initiation to 9 of 13 (69%; P =0.004) at follow‐up. Mean±SD LDL‐C at follow‐up was 111 (44) mg/dL, compared with 206 (61) mg/dL before evinacumab (mean difference, −95 mg/dL [95% CI, −142 to −47]; P <0.001). Before initiation of evinacumab, 11 of 13 children received LA with average interval of 7.8 days. At follow‐up, LA frequency decreased in 7 of 11 children with average interval of 18.9 days; increase between LA sessions was 11.0 days (3.5–18.5; P =0.008), 42% longer session interval. For 3 (15%) children, due to evinacumab initiation, LA remained dispensable over the course of treatment. Coronary computed tomography angiography showed plaque stabilization (n=5), regression (n=3), and no formation (n=2), in 10 of 13 (77%) children, and plaque progression in 3 (23%) children. Conclusions Add‐on evinacumab increased number of children with homozygous familial hypercholesterolemia reaching and maintaining LDL‐C goal, concomitant reduction in LA frequency, and in most patients, stabilization or improvement in coronary computed tomography angiography findings.

Abstract Background Chronic Q fever, caused by Coxiella burnetii, presents significant diagnostic and management challenges due to its variable presentation and high morbidity, especially among patients with underlying cardiac or vascular disease. In the United States, cases are rising, often without identifiable exposures, and diagnostic delays remain common. Methods We conducted a retrospective cohort study of chronic Q fever cases at the Mayo Clinic from 2007 to 2023. Patients with clinical evidence and a phase I IgG titer ≥1:1024 and/or positive PCR for C. burnetii were included. Data were abstracted from electronic health records, including demographics, exposures, clinical manifestations, diagnostics, treatments, and outcomes. Statistical analyses assessed factors influencing diagnostic delay and treatment response. Results We identified 33 patients with chronic Q fever (median age 56; 88% male). Median time to diagnosis was 99 days with 11.4 days between Infectious Diseases (ID) evaluation and diagnosis. Animal exposure was reported in 17 patients (52%), while eight (24%) had no identifiable exposure. Patients primarily presented with prosthetic valve endocarditis (n=14, 42%), or vascular graft infection (n=9, 27%). The majority were treated with doxycycline and hydroxychloroquine (n=25, 75%) and 14 patients (42%) required surgical intervention. Mortality attributable to chronic Q fever was 6% (n=2). Conclusions Chronic Q fever remains under-recognized, with substantial diagnostic delays prior to treatment. Cardiovascular infection predominates, and surgical intervention is often required despite prolonged antimicrobial therapy. Early specialist evaluation and standardized diagnostic pathways may improve outcomes.

Abstract Purpose Traditional adverse event (AE) reporting in oncology trials focuses on the single worst CTCAE grade, which may underrepresent chronic or recurrent toxicity burden. We applied a longitudinal toxicity framework to compare toxicity profiles of chemotherapy with or without cetuximab in metastatic colorectal cancer. Patients and Methods We pooled two randomized first-line trials in the ARCAD database. AEs examined were diarrhea, rash, hand-foot syndrome (HFS), fatigue, anorexia, and mucositis. Outcomes included grade ≥3 AE, time to first occurrence of maximum grade, early onset (≤6 weeks), and AEL, a normalized measure of cumulative toxicity burden over treatment. Analyses were adjusted for chemotherapy backbone, ECOG performance status, sex, primary tumor location, dose reduction, and treatment duration. Results Compared with Chemotherapy alone (n = 564), Chemotherapy plus cetuximab (n = 738) was associated with higher grade ≥3 rash (21% vs 0.5%; adjusted odds ratio [OR] 49.89, 95% CI 15.8–157.4), higher rash AEL (0.257 vs 0.069; adjusted mean difference 0.22, 95% CI 0.21–0.23), and more frequent early-onset maximum rash (67% vs 34%; adjusted OR 4.28, 95% CI 2.72–6.74). Rash AEL remained higher with cetuximab within maximum-grade strata. HFS showed higher grade ≥3 risk and overall AEL with cetuximab, but no within-grade AEL difference, indicating higher overall HFS burden reflected grade distribution rather than within-grade chronicity. No consistent differences were observed for other AEs. Conclusions Incorporating onset timing and AEL distinguished persistent toxicity burden from isolated peak events. This framework may support comparative tolerability assessment when chronic toxicity burden is central to decision-making.