Citations

Background and Aims: Cholangiocarcinoma (CCA) is a rare but aggressive malignancy with poorly understood genetic susceptibility. To date, genome-wide association studies (GWAS) investigating germline variants associated with CCA risk remain limited. We aimed to identify genetic risk loci for CCA and its clinical subtypes through comprehensive GWAS and post-GWAS analyses. Approach and Results: We conducted a GWAS of 2366 CCA cases and 11,750 controls of European ancestry. Genome-wide significant loci ( p <5×10 −8 ) were identified and further examined through fine-mapping, functional annotation, and HLA imputation. Subgroup analyses were conducted by CCA subtypes and primary sclerosing cholangitis (PSC) status. Cross-trait linkage disequilibrium score regression and Mendelian randomization were employed to investigate the shared genetic architecture and potential causal relationships with a diverse range of traits. We identified 1 new genome-wide significant variant, rs535777 (OR=1.44), near HLA-DRB1/DQA1 associated with CCA, and 2 variants associated with extrahepatic CCA: rs116224263 (OR=0.17) in LINC02506 at 4p15.1 and rs6914950 (OR=1.63) near HLA-DRB1/DQB1 . Stratified analyses revealed rs2395184 (OR=3.51) near HLA-DRA/DRB5 associated with PSC-related CCA, and rs142674434 (OR=2.98) in THSD7A at 7p21.3 associated with non-PSC-related CCA. HLA imputation uncovered new amino acid residues associated with disease risk. Cross-trait analyses identified shared genetic signals between CCA and anthropometric, lipidemic, lifestyle, and medical traits. Mendelian randomization supported putative causal associations for 12 traits with CCA or its subtypes. Conclusions: Our large-scale GWAS highlights new genetic variants and HLA-linked mechanisms underlying CCA susceptibility. Integrating multi-step post-GWAS approaches enhances understanding of CCA pathogenesis and may facilitate the development of risk biomarkers for early detection and precision prevention strategies.

Introduction: Nasal analysis is a challenging skill that otolaryngology trainees must demonstrate competency in on-board examinations. Study objective: To compare where experts and trainees focus their gaze when completing nasal analysis of a patient, as measured by eye tracking software. Methods: Participants of various training levels ( n = 27) were shown photographs of six faces from all standard angles for photographic nasal analysis. Eye-tracking data were collected. Heat and gaze maps, the time to first fixation on areas of interest, duration, and number of fixations were extracted. These metrics were compared between experts and trainees using t -tests and one-way ANOVA. Results: Qualitative comparisons of gaze patterns reveal a more comprehensive and organized approach among experts than trainees. However, quantitative measures of eye-tracking metrics, including the time to first fixations, duration, and number of fixations made by experts and trainees, were similar. Conclusions: Gaze tracking reveals more thorough and efficient eye movements among experts than trainees during nasal analysis. Further study may be useful in the development of learning tools to guide effective nasal analyses.

Abstract Background While type 2 diabetes (T2DM) is a known risk factor for aortic valve calcification (AVC) and aortic stenosis (AS), the specific mechanisms remain unclear. The aim of this study was to determine early factors associated with AVC in patients with T2DM. Methods This cross-sectional study is a pre-specified substudy of an ongoing multicenter randomized controlled trial, the STENO INTEN-CT trial (Screening and Intervention for Subclinical Coronary Artery Disease in Patients With Type 2 Diabetes). Eligibility criteria are patients with diagnosed T2DM without prior ischemic heart disease, and age between 55-69 years (male) and 60-74 years (female). All patients underwent a non-contrast cardiac computed tomography scan and AVC was measured in Agatston units. Results Of the 3635 patients included in this study, nearly half (n = 1694) demonstrated an AVC &gt; 0 (n=1502 with 0 &lt; AVC &lt; 300 and n = 192 with AVC ≥ 300). With increasing AVC, patients were elder, predominantly males, and had significantly more comorbidities (obesity, hypertension, chronic obstructive pulmonary disease, and kidney dysfunction). Patients with higher AVC were more likely to be treated with statins (AVC = 0: n = 1509 (78%), 0 &lt; AVC &lt; 300: n = 1217 (81%), AVC ≥ 300: n = 163 (85%), p = 0.009). Higher body mass index (OR: 1.03 (1.02-1.04), p &lt; 0.001), statin use (OR: 1.49 (1.24-1.80), p &lt;0.001), low-density lipoprotein (OR: 1.24 (1.12 - 1.37), p &lt; 0.001), and kidney dysfunction, measured as urine albumine-creatinine ratio (OR: 1.00 (1.00-1.00), p &lt;0.001), were independently associated with increasing AVC (Figure 1). However, T2DM severity, measured as the duration of T2DM, HbA1c levels, and the number of antidiabetic drugs used, was not associated with increasing AVC severity (Figure 1+2). Conclusion AVC is highly prevalent, affecting nearly half of patients with T2DM. However, early factors driving AVC are not associated with T2DM severity, but rather to diabetes-related comorbidities and complications.

Abstract Background Cardiac dysfunction is a common complication in septic population. Though traditionally considered an acute and reversible phenomenon, the true prevalence of reversible cardiac dysfunction and its long-term prognostic implications remain unclear. Purpose Using serial echocardiographic assessments, this study aimed to investigate the prevalence and reversibility of cardiac dysfunction in septic patients, and to determine whether the recovery of cardiac function is associated with improved 5-year mortality. Methods We retrospectively screened 16,041 septic patients who underwent transthoracic echocardiography during their ICU stay. After excluding patients with a history of heart failure, pre-existing cardiac dysfunction, or lacking follow-up echocardiographic assessments post-ICU discharge, 3,112 patients were enrolled for analysis. To assess the reversibility of cardiac dysfunction, paired-sample t-tests were used to evaluate changes in echocardiographic parameters between in-ICU and post-ICU measurements. Furthermore, 5-year mortality were compared among controls and patients with or without recovery of echocardiographic abnormalities. Results Totally 1,604 patients (51.5%) were found to have newly recognized cardiac dysfunction during ICU stay. The mean interval between ICU admission and follow-up echocardiography was 425 days. Most in-ICU echocardiographic abnormalities demonstrated partial recovery over time, with the exception of left atrial volume index (LAVi) and right ventricular fractional area change (RV FAC) (Figure 1). Recovery of left ventricular ejection fraction (LVEF), average E/e', and tricuspid regurgitation (TR) velocity was significantly associated with reduced 5-year mortality (Figure 2). Older age [adjusted hazard ratio (aHR) 0.99, p=0.034], male gender (aHR 0.54, p=0.003), and elevated troponins (aHR 0.87, p=0.006) were negative predictors for LVEF recovery; while older age (aHR 0.099, p=0.043), higher APACHE III scores (aHR 0.99, p=0.018), atrial fibrillation (aHR 0.59, p=0.046), and chronic pulmonary disease (aHR 0.68, p=0.042) were negative predictors for TR velocity recovery. Conclusions Both the presence and recovery of newly recognized echocardiographic abnormalities during ICU stay were significantly associated with long-term mortality. Certain abnormalities, such as increased LAVi, persisted despite resolution of sepsis.Figure 1 Figure 2

Abstract Purpose: Pancreatic ductal adenocarcinoma (PDAC) is typically detected too late for useful therapeutic interventions; hence, we sought blood biomarkers to detect early-stage disease. Experimental Design: Using mass spectrometry and ELISA on plasma pools from the University of Pennsylvania (Penn) and the Mayo Clinic (Mayo), we identified aminopeptidase N (ANPEP) and polymeric immunoglobulin receptor (PIGR) as increased in early-stage (stage I/II) PDAC plasma compared with controls. We tested ANPEP and PIGR, along with prior data for thrombospondin 2 (THBS2) and carbohydrate antigen 19-9 (CA19-9), in retrospective phase II studies using separate cohorts of PDAC plasmas at different stages versus healthy or nonmalignant disease controls (DC) from Penn (n = 135) and Mayo (n = 537). Results: Comparing healthy controls with stage I/II PDAC, we obtained area under the receiver-operating characteristic curves (AUC) of 0.78 [95% confidence interval (CI), 0.68–0.86]/0.80 (95% CI, 0.74–0.85; ANPEP) and 0.81 (95% CI, 0.70–0.88)/0.86 (95% CI, 0.82–0.90; PIGR) for the Penn/Mayo phase II studies, respectively. In multivariable models, CA19-9/THBS2/ANPEP, CA19-9/THBS2/PIGR, and CA19-9/THBS2/ANPEP/PIGR elicited AUC of 0.94 to 0.96 for Penn and 0.97 for Mayo. Notably, the four-marker panel elicited AUC of 0.87 for the Mayo stage I/II versus DC and 0.91 for stages I to IV versus DC. At a specificity of 95%, a plasma biomarker panel composed of CA19-9 (≥35 U/mL), THBS2 (≥42 ng/mL), ANPEP (≥2,995 ng/mL), and PIGR (≥1,800 ng/mL) yielded a sensitivity of 91.9% for PDAC stages I to IV and 87.5% for PDAC stage I/II. Conclusions: Adding ANPEP and PIGR to a plasma biomarker panel of CA19-9 and THBS2 enhances the detection of early-stage PDAC when comparing cancer versus healthy or nonmalignant DC. Given the concordance of our data in two retrospective phase II studies, assessments in prediagnostic cases are warranted.

Immunotherapy has been effective in many cancer types but has failed in multiple clinical trials in prostate cancers, with the underlying mechanisms remaining largely unclear. Here, we demonstrate that androgen receptor pathway inhibitor (ARPI) plus irradiation (IR) triggered robust anticancer immunity in prostate cancers in both patients and mice. We show that androgen-activated AR suppressed innate immune signaling by inducing inhibitor of nuclear factor kappa-B kinase subunit epsilon ( IKBKE ) gene repression through HDAC2 interaction with an IKBKE enhancer RNA ( IKBKE eRNA, or IKBKE-e ). ARPI treatment caused IKBKE derepression and enhanced an IR-induced innate immune response via action of RIG-I and MDA5 dsRNA sensors. IKBKE-e ablation largely enhanced innate immunity in prostate cancer cells in culture and anticancer immunity in mice. Our results revealed AR, HDAC2, and IKBKE eRNA as critical intrinsic immune suppressors in prostate cancer cells, suggesting that rejuvenating inhibitor of nuclear factor kappa-B kinase subunit epsilon (IKKε) signaling by targeting IKBKE-e is an actionable strategy to elicit synthetic anticancer immunity in immunologically “cold” cancers such as prostate cancer.

64 Background: The incidence of eoCRC (diagnosed at age <50) is increasing. We have previously shown higher rates of severe anxiety and depression in this group compared to adults diagnosed at age ≥50 (average-onset CRC, aoCRC). We assessed the impact of ePROM collection coupled with a CC-based supportive care intervention on symptom burden in patients with eoCRC. Methods: The Enhanced, EHR-facilitated Cancer Symptom Control (E2C2) trial was a cluster-randomized, pragmatic trial conducted at Mayo Clinic Rochester and within the Mayo Clinic Health System (in Minnesota and Wisconsin) between 2019 and 2023. Enrolled patients serially reported the severity of six SPPADE symptoms (Sleep deficit, Pain, Physical function impairment, Anxiety, Depression, and Energy deficit/fatigue) on 11-point numerical rating scales. Symptom scores were interpreted as none to mild (0-3), moderate (4-6), or severe (7-10). Those with moderate symptoms were offered symptom management education and self-management materials, while those with severe symptoms were offered the option to work with a symptom care manager. In this post hoc analysis we examined the effects of the intervention on change in symptom scores among those with eoCRC, and using the Kaplan-Meier method, the median time to improvement to a mild/moderate level in those with a severe symptom, comparing eoCRC with aoCRC. Results: Among 4,422 patients with CRC, 887 had eoCRC. Forty-six percent of patients were female ( p =0.61), and a greater proportion of eoCRC patients were of a non-white race (11.6% vs 4.7%), lived in an urban setting (65.6% vs 50.5%), had a Bachelor’s degree or higher (36.8% vs 24.4%), were employed (78.5% vs 36.7%), on a non-government insurance plan (83.4% vs 35.3%), single (19.7% vs 11.2%) or married (74.2% vs 67.9%), and had metastatic disease (54.8% vs 46.1%, p <0.0001 for all). Compared to a pre-intervention baseline, the mean change in symptom scores for eoCRC patients following the intervention demonstrated improvements in anxiety (-0.238), depression (-0.134), and fatigue (-0.146, p <0.05 for all). Time to symptom improvement from severe to mild/moderate was longer for anxiety and depression in eoCRC patients compared to aoCRC patients (Table 1). Conclusions: Collection of ePROMs coupled with a CC-based intervention led to improvements in anxiety, depression, and fatigue among eoCRC patients, although time to symptom improvement was longer among eoCRC patients compared to aoCRC patients. Time to improvement of severe symptom (months), median (95% CI). eoCRC aoCRC p -value Sleep 4.2 (3.1-5.8) 3.8 (2.7-5.4) 0.4 Pain 4.1 (3.0-7.5) 3.2 (2.3-5.0) 0.5 Physical function impairment 3.1 (1.9-6.3) 2.8 (2.2-4.2) 0.5 Anxiety 4.3 (3.4-9.1) 2.6 (2.0-3.5) 0.009 Depression 4.3 (2.6-7.5) 2.6 (2.1-3.5) 0.04 Fatigue 4.3 (3.7-9.5) 3.4 (2.7-4.2) 0.06

Abstract Aims Cardiogenic shock (CS) is often treated with catecholamines titrated to an adequate target mean arterial pressure (MAP) while minimizing adverse effects. We aim to assess the optimal catecholamine dose/MAP balance in heart failure-associated CS (HF-CS). Methods Patients with HF-CS were retrospectively enrolled from 16 tertiary centres in 5 European countries (2016–2021; NCT03313687). Dosage was quantified by inotropic scores (epinephrine, norepinephrine, and dobutamine). Associations of baseline and seven-day summarized dosage with intensive care unit (ICU) discharge (mixed-effects logistic regression) and 30-day mortality (Cox regression) were analysed. Potential catecholamine/MAP target ratios for optimized outcomes were assessed in models adjusted for age, sex, pH, lactate and prior resuscitation, stratified by centre. Results N = 704 patients: median age 63 years, 74% male, 34% post-resuscitation, median lactate 5.2 mmol/l. Of these, 53% were discharged from ICU, 48% died within 30 days. Higher inotropic scores independently predicted a lower probability of ICU discharge (baseline score: OR 0.78 [95%-CI 0.69–0.88]; summarized score: OR 0.46 [0.38–0.56]; both P &lt; .001) and higher risk of 30-day mortality (baseline score: HR 1.27 [1.15–1.40], summarized score HR 1.83 [1.60–2.09]; both P &lt; .001). A score/MAP ratio &lt;0.403 µg/kg/min/mmHg was associated with higher ICU discharge odds (ceiling effect); a &lt; 0.426 µg/kg/min/mmHg with lower 30-day mortality hazards (no ceiling effect). Lowering catecholamine doses by accepting reduced MAP targets was linked to better outcomes. Conclusion In HF-CS, higher catecholamine support independently associates with worse outcomes. Accepting lower blood pressure targets to reduce catecholamine dosage may improve outcomes. Validation in randomized controlled trials is urgently needed.

Abstract Background Tau‐PET tracers are essential for visualizing pathology in Alzheimer's (AD). High detectability to tau is crucial for early detection and monitoring of tau deposition. This study compares the noise to dynamic range ratio (NRR) of [ 18 F]FTP, [ 18 F]MK6240, [ 18 F]PI2620, and [ 18 F]RO948, cross‐sectionally and longitudinally. Methods 460 individuals from the HEAD study (23 cognitively unimpaired (CU) young, 249 CU old and 188 cognitively impaired) underwent [ 18 F]FTP and [ 18 F]MK6240 tau‐PET scans; 94 additionally received [ 18 F]PI2620 and [ 18 F]RO948. A subset of 28 individuals (15 CU and 13 CI) underwent [ 18 F]FTP and [ 18 F]MK6240 follow‐up scans (1.5 ± 0.1 years later). Annual change was measured as [(followup‐baseline)/time between scans]. Noise was calculated as the standard deviation (SD) of CU Aβ‐ participants aged ≤65 (SD CUAβ‐≤65 ). The dynamic range was calculated as the SD across all subjects (SD range ). A lower the NRR (=SD CUAβ‐≤65 /SD range ) indicates more detectability. Analyses were performed at both region‐of‐interest and voxel‐wise levels. Results Across the whole cohort, [ 18 F]MK6240 exhibited lower NRR than [ 18 F]FTP in all regions. Voxel‐wise, differences were most pronounced in the frontal medial temporal regions (Figure 1). Within the four‐tracers subset, [ 18 F]PI2620 and [ 18 F]FTP showed the highest NRR in Braak II, followed by [ 18 F]RO948 and [ 18 F]MK6240. In Braak IV‐VI, [ 18 F]MK6240 consistently demonstrated the lowest values, followed by [ 18 F]PI2620, [ 18 F]FTP and [ 18 F]RO948. Similarly, in metatemporal‐ROI and Braak III, [ 18 F]MK6240 remained the lowest, however followed by [ 18 F]FTP, [ 18 F]PI2620 and [ 18 F]RO948 (Figure 2). Lower [ 18 F]MK6240 NRR was due to larger SD range , while [ 18 F]FTP's lower values stemmed from smaller SD CUAβ‐≤65 . Conversely, high [ 18 F]PI2620 and [ 18 F]RO948 values are driven by larger SD CUAβ‐≤65 . Longitudinal analyses further confirmed that [ 18 F]MK6240 exhibited the lowest NRR across the entire brain, including AD‐related regions, with voxel‐wise differences mainly in the temporal and parietal lobes. Conclusion Tau‐PET tracers exhibit significant variability in detectability. [ 18 F]MK6240 consistently demonstrated lower NRR, implying better detectability across all regions, cross‐sectionally and longitudinally. Despite differences in NRR, [ 18 F]FTP, [ 18 F]RO948 and [ 18 F]PI2620 followed similar pattern. These results provide insights into the differential tracer detectability, helping guide their optimal use in detecting and tracking tau pathology. Ongoing follow‐up scans will further clarify longitudinal tracer detectability and its implications for tau progression in AD.