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Background/Objectives: Proton therapy delivers highly conformal doses to the target area without producing an exit dose, minimizing cumulative doses to healthy liver tissue. This study aims to evaluate current practices, challenges, and variations in the implementation of proton stereotactic body radiation therapy (SBRT) and hypofractionated therapy for liver malignancies, with the goal of providing a technical assessment to promote broader adoption and support future clinical trials. Methods and Materials: An extensive survey was conducted by NRG Oncology across North American proton treatment centers to assess the current practices of proton liver SBRT and hypofractionated therapy. The survey focused on key aspects, including patient selection, prescription and normal tissue constraints, simulation and motion management, treatment planning, quality assurance (QA), treatment delivery, and the use of image-guided radiation therapy (IGRT). Results: This survey captures the current practice patterns and status of proton SBRT and hypofractionated therapy in liver cancer treatment. Proton therapy is increasingly preferred for treating inoperable liver malignancies due to its ability to minimize healthy tissue exposure. However, the precision required for proton therapy presents challenges, particularly in managing uncertainties and target motion during high-dose fractions and short treatment courses. Survey findings revealed significant variability in clinical practices across centers, highlighting differences in motion management, dose fractionation schedules, and QA protocols. Conclusion: Proton SBRT and hypofractionated therapy offer significant potential for treating liver malignancies. A comprehensive approach involving precise patient selection, treatment planning, and QA is essential for ensuring safety and effectiveness. This survey provides valuable insights into current practices and challenges, offering a foundation for technical recommendations to optimize the use of proton therapy and guide future clinical trials.

Background: Trochlear dysplasia is important in recurrent patellofemoral instability (PFI); reliable metrics are essential to understand this condition and help define optimal treatment. One such measurement is the entry point to transition point (EP-TP) angle, which describes 2 components of patellar tracking from full knee extension to flexion: (1) mediodistal movement and (2) pure distal movement. Currently, measurement of this metric relies on 3-dimensional (3D) models. Purpose: To further develop the EP-TP angle metric to allow its digital measurement, to establish cohort and interrater reliability values, and to evaluate its appropriateness for clinical use. Study Design: Cohort study (diagnosis); Level of evidence, 3. Methods: A data set composed of 30 recurrent PFI patient knees and 30 control knees was acquired. Each knee came with anterior views of the distal femur and curvature maps, which highlighted relevant structures such as the trochlear groove and the medial and proximal ridge. Three raters measured EP-TP angles utilizing a digital tool with and without the curvature maps. Significance of differences in means, presence of a TP, and interrater reliability with intraclass correlation coefficients were tested and evaluated according to an established guideline (<0.5, poor reliability; >0.5-0.75, moderate; >0.75-0.9, good; >0.9 excellent reliability). A significance level of .05 corrected with the Bonferroni method was assumed. Results: PFI knees had a significantly higher EP-TP angle than the control cohort (48.9° ± 10.8° vs 11.8° ± 14.6°; P < .001). Patients had a greater TP prevalence than controls (96.7% vs 10.0%). Interrater reliability for the EP-TP angle with curvature maps was significantly better than without (0.84 [95% CI, 0.76-0.89] vs 0.67 [95% CI, 0.55-0.78]; P < .001). Conclusion: The EP-TP angle is significantly different between PFI patients and controls. This study presents a digital approach for measuring the EP-TP angle, in contrast with the initially described method, which required 3D prints. This digital approach, when aided with curvature mapping, yields better reliability.

Background: In the emergency setting, many diagnostic pathways incorporate change in high-sensitivity cardiac troponin (hs-cTn) concentrations (i.e., the delta) to classify patients as low-risk (rule-out) or high-risk (rule-in) for possible myocardial infarction (MI). However, the impact of analytical variation on the delta for correct classification is unknown, especially at concentrations below and around the 99th percentile. Our objective was to assess the impact of delta variation for correct risk classification across the European Society of Cardiology (ESC 0/1 h and 0/2 h), the High-STEACS, and the common change criteria (3C) pathways. Methods: A yearlong accuracy study for hs-cTnT was performed where laboratories across Canada tested three patient-based samples (level 1 target value = 6 ng/L, level 2 target value = 9 ng/L, level 3 target value = 12 ng/L) monthly across 41 different analyzers. The assigned low-delta between levels 1 and 2 was 3 ng/L (i.e., 9 − 6 = 3 ng/L) and the assigned high-delta between levels 1 and 3 was 6 ng/L (i.e., 12 − 6 = 6 ng/L). The low- and high-deltas for each analyzer were determined monthly from the measured values, with the difference calculated from the assigned deltas. The obtained deltas were then assessed via the different pathways on correct classification (i.e., percent correct with 95% confidence intervals, CI) and using non-parametric analyses. Results: The median (interquartile range) difference between the measured versus assigned low-delta (n = 436) and high-delta (n = 439) was −1 ng/L (−1 to 0). The correct classification differed among the pathways. The ESC 0/1 h pathway yielded the lowest percentage of correct classification at 35.3% (95% CI: 30.8 to 40.0) for the low-delta and 90.0% (95% CI: 86.8 to 92.6) for the high-delta. The 3C and ESC 0/2 h pathways yielded higher and equivalent estimates on correct classification: 95.2% (95% CI: 92.7 to 97.0) for the low-delta and 98.2% (95% CI: 96.4 to 99.2) for the high-delta. The High-STEACS pathway yielded 99.5% (95% CI: 98.4 to 99.9) of correct classifications for the high-delta but only 36.2% (95% CI: 31.7 to 40.9) for the low-delta. Conclusions: Analytical variation will impact risk classification for MI when using hs-cTn deltas alone per the pathways. The 3C and ESC 0/2 h pathways have <5% misclassification when using deltas for hs-cTnT in this dataset. Additional studies with different hs-cTnI assays at concentrations below and near the 99th percentile are warranted to confirm these findings.

Objectives: New methods are needed to detect pancreatic ductal adenocarcinoma (PDAC) earlier to improve outcomes. We previously reported that a panel of protein N-glycosylation traits (NGTs) discriminated PDAC from healthy controls with an area under the curve (AUC) of 0.81–0.88. However, it remained unclear whether this panel accurately differentiates PDAC from other benign pancreatic disorders. Our study aims to evaluate the performance of the NGT panel in combination with CA19-9 in a diverse cohort, including PDAC cases, healthy controls, and controls with benign pancreatic disorders. Methods: Protein N-glycosylation profiles were determined in plasma samples using an in-house developed mass spectrometry assay. CA19-9 levels were measured using a routine immunoassay test. Results of total plasma NGTs and CA19-9 were evaluated separately as well as in combination. Logistic regression was performed to calculate odds ratios (ORs), AUC, sensitivity, and specificity to determine the performance of NGTs and CA19-9 in distinguishing PDAC from controls. Results: In total, 221 individuals were included: 45 (20.4%) with PDAC, and 176 (79.6%) controls (53 healthy and 123 with benign pancreatic disease). The AUC for differentiating PDAC from the total control cohort based on the combination of the NGT panel and CA19-9 was 0.94 (95% CI, 0.90–0.97), with a sensitivity of 0.89 (95% CI, 0.78–0.98) and specificity of 0.86 (95% CI, 0.81–0.91). Comparison of PDAC cases with healthy controls only resulted in an AUC of 0.96 (95% CI, 0.93–0.99), with a sensitivity of 0.84 (95% CI, 0.73–0.93) and specificity of 0.98 (95% CI, 0.94–1.00). Conclusions: Both plasma NGTs and CA19-9 distinguish PDAC from a diverse control cohort. The accuracy further improves when these readouts are combined, showing promise for future early detection methods.

Abstract Background Doxycycline is a frequently used alternative treatment for community-acquired pneumonia (CAP) in hospitalized patients; however, the evidence base is limited. We aimed to compare outcomes in CAP patients treated with doxycycline or azithromycin in combination with beta-lactams. Methods We evaluated patients with CAP admitted to Mayo Clinic hospitals from May 2018 to September 2022 and treated with either azithromycin or doxycycline in combination with a beta-lactam. Patients who received both antibiotics or were on either antibiotic as chronic therapy prior to admission were excluded. The primary outcome was mortality. Patients were 1-to-1 matched according to the presence of congestive heart failure, coronary artery disease, chronic obstructive pulmonary disease, human immunodeficiency virus infection, recent immunosuppressant use, and pneumonia severity index class. Results Among 8492 patients (5810 for azithromycin, 2682 for doxycycline), 2671 doxycycline-treated patients were matched with azithromycin-treated patients. In-hospital mortality was significantly lower in the azithromycin group than in the doxycycline group (odds ratio, 0.71; 95% confidence interval [CI], .56–.9), as was 90-day mortality (hazard ratio, 0.83; 95% CI, .73–.95). Patients on azithromycin also had significantly more hospital-free days (HFDs) than those on doxycycline (estimate, 1.37; 95% CI, .99–1.74). Conclusions Among hospitalized patients with CAP, azithromycin was associated with lower mortality and more HFDs compared with doxycycline in combination with beta-lactams. Randomized, controlled trials are needed to assess the effectiveness of each regimen and to compare their potential side effects.

Abstract RATIONALE: Chronic Obstructive Pulmonary Disease (COPD) is a leading cause of mortality worldwide. We previously published the polygenic transcriptome risk score (PTRS) which uses the cumulative effect of predicted gene expression to construct genetic predictors for complex diseases, and we demonstrated the value of PTRS for COPD built on Genotype-Tissue Expression (GTEx) Lung tissue with significantly improved cross-ancestry portability. However, the postmortem collection and lack of lung disease status on GTEx samples likely affect results. We hypothesized that the performance of PTRS will be improved by using disease-relevant expression quantitative trait loci (eQTLs) to construct the score. Here, we aimed to improve performance of PTRS by leveraging disease-relevant eQTLs. METHODS: We constructed two transcriptome prediction models, Elastic Net (EN) and Prediction Using Models Informed by Chromatin conformation and Epigenomics (PUMICE), using TOPMed lung RNA-seq data from the Lung Tissue Research Consortium (LTRC), which included COPD patients undergoing lung surgery. We compared their performance with two published models built on RNA-seq from GTEx Lung tissue, GTEx-EN and GTEx-PUMICE. We first integrated each of four transcriptome models with multi-ancestry GWAS of FEV1/FVC ratio (Shrine et al. 2023) to generate transcriptome-wide association study (TWAS) results, which produced trait-associated genes. Pathway analysis was then conducted on significant TWAS genes. Finally, the PTRS was computed on TWAS genes that were included in the top 20 significantly enriched pathways. We tested performance of PTRS in race-stratified analysis for moderate-to-severe and severe COPD in COPDGene. RESULTS: Our models produced more significant TWAS genes (FDR&lt;0.05) and had more overlaps with genes identified for FEV1/FVC ratio from Shrine et al. 2023 compared to two GTEx models (Fig. A). Additionally, our models had significantly higher AUC for predicting both moderate-to-severe and severe COPD in race-stratified analysis. The mean AUC from LTRC-EN for predicting severe COPD was 0.57 and 0.55 respectively for EUR and AFA, which was significantly higher than mean AUC of 0.54 and 0.51 from GTEx-EN (Delong p-value=8.15x10-10 for EUR and 1.42x10-3 for AFA) (Fig. B). Similarly, the PTRS derived from our models produced higher Odds Ratios (OR) per standard deviation. The mean OR from LTRC-PUMICE for moderate-to-severe COPD was 1.25 and 1.18 respectively for EUR and AFA, while it was 1.17 and 1.12 from GTEx-PUMICE (Fig. C). CONCLUSIONS: Our study demonstrates the value of leveraging disease-relevant RNA-seq to construct transcriptome prediction models and their improvement on identifying lung function genes and predicting COPD across ancestries.

Objective The pattern and timing of palliative care utilisation and end-of-life characteristics in extracorporeal membrane oxygenation (ECMO)-supported patients remain underused. We wanted to share our centre’s experience. Methods This is an institutional review board-approved retrospective study of 45 patients who underwent ECMO at a large ECMO centre in North America between January 2013 and July 2018. Results Only 28.9% of the ECMO patients received in-hospital palliative care consultation at a median of 18 days (IQR 12–31) after hospitalisation and 10.5 days (IQR 1–28) from ECMO initiation. 1-year mortality was high, with 44% dying during hospitalisation and an additional 13% within the following year. Patients experienced prolonged hospitalisations (median hospital length of stay: 39 days, IQR 19–89) and exhibited high rates of tracheostomy (53%) and renal replacement therapy (60%). Most end-of-life cases involved the withdrawal of life-sustaining therapy during ECMO, yet only 53% had a completed living will. Conclusion Our study underscores the need for early initiation of palliative care consultation to enhance symptom management, advance care planning, caregiver support and quality of life for ECMO patients and their families.

ABSTRACTItraconazole and posaconazole are frequently prescribed following transplantation to prevent and treat fungal infections. Navigating drug interactions is challenging due to these agents’ potent CYP3A4 inhibition, and literature describing concurrent apixaban, a CYP3A4 substrate, is limited. This retrospective study of cardiothoracic transplant recipients evaluates the impact of itraconazole and posaconazole on apixaban exposure and reports clinical outcomes from routine apixaban dose reduction. Institutional practice reduces apixaban to 2.5 mg twice daily with itraconazole or posaconazole and obtains apixaban therapeutic drug monitoring (TDM), expected range 34–230 ng/mL. Eighteen levels collected in 15 patients on itraconazole displayed a median [IQR] apixaban trough of 143 ng/mL [95–195]. Fifteen levels collected in 13 patients on posaconazole displayed a median [IQR] apixaban trough of 124 ng/mL [93–174]. Two major bleed events, three VTE, two stroke, and eight instances of clot resolution were identified. Reduced‐dose apixaban resulted in apixaban exposure similar to normal dosing in the general population. Apixaban TDM is encouraged for individualized dosing when administered with itraconazole and posaconazole.

Abstract Introduction Female sexual dysfunctions (FSDs) are prevalent yet underrecognized concerns among menopausal women, particularly those aged 65 and older. Age- and menopause-related sexual health issues often go unaddressed due to societal stigma and misconceptions, leading many women to attribute their symptoms to a normal part of aging. This perception limits diagnosis and treatment of conditions like hypoactive sexual desire disorder and genitourinary syndrome of menopause. Objective This study aims to compare sexual function and distress between women aged 50-64 and those aged 65 and older, with a focus on addressing critical knowledge gaps in sexual function among older women. Methods This cross-sectional study included women aged 50 and above who visited Mayo Clinic Women’s Health Clinics in Rochester, MN; Scottsdale, AZ; and Jacksonville, FL between, May 1, 2015, and August 31, 2022. Participants completed the Female Sexual Function Index (FSFI) and Female Sexual Distress Scale (FSDS-R), along with assessments of chief sexual health complaints, mood (PHQ-9), and anxiety (GAD-7) included in the Data Registry on Experiences of Aging, Menopause, and Sexuality (DREAMS). Results Among 4900 women included in the analysis, the median number of sexual health complaints was 2.0 in midlife (50-64 yrs) and 1.0 in older (65+ yrs) age groups (p = 0.004). Chief complaints of loss of sexual desire (47.6% vs. 33.4%; p &lt; 0.001) and reduced genital sensation (16.9% vs. 13.0%; p = 0.024) were more common in the midlife age group. No significant differences were found in rates of complaints of vaginal dryness (51.2% vs. 52.5%; p = 0.57), painful intercourse (32.6% vs 30.7%; p = 0.38), or of difficulties with arousal or orgasm (24.0% vs 20.8%; p = 0.09). Midlife age women were also more likely to report pelvic pain (6.7% vs. 4.5%; p = 0.050), while older women reported more genital pain (8.1% vs. 5.8%; p = 0.038). FSFI scores indicated age-related differences in desire (2.4 vs. 3.0; p &lt; 0.001), lubrication (3.9 vs. 3.6; p &lt; 0.001), and pain (4.8 vs. 4.0; p &lt; 0.001), aligning with the chief complaints, while arousal (3.6, p = 0.890), orgasm (4.0, p = 0.926), and satisfaction (4.4, p = 0.346) scores were similar between groups. Total FSFI scores showed no significant difference between the age groups (total = 22.2 vs 21.2, p = 0.109). Median FSDS-R scores indicated higher distress in the midlife group (15.0 vs. 13.0; p = 0.015), while overall FSD prevalence (FSFI ≤26.55 and FSDS ≥11) was similar between groups (56.2% vs 51.8%; p = 0.056). Conclusions Midlife and older women were equally likely to experience FSD in women presenting to women’s health clinics, but older women reported less distress. These results are strikingly similar to previous research indicating that while older women have FSD, there is less distress associated with it. Raising awareness and promoting open dialogue can help older women recognize that their sexual health concerns are both valid and treatable, ultimately improving quality of life. Disclosure No.

OBJECTIVE The optimal dose for triazoles in pediatric patients may substantially vary given the dynamic changes in pharmacokinetics and pharmacodynamics, based on disease severity. Therapeutic drug monitoring has been a valuable tool to help guide management and avoid potential toxicities associated with treatment of invasive fungal infections (IFIs). Goal azole serum concentrations are based on specific drug, indication, and minimum inhibitory concentration when known. This study aimed to determine the optimal pediatric azole doses needed to achieve targeted serum concentrations of isavuconazole, itraconazole, posaconazole, and voriconazole. METHODS This is a single center, retrospective chart review of pediatric patients who received isavuconazole, itraconazole, posaconazole, or voriconazole between January 1, 2011, and August 31, 2021. RESULTS A total of 273 pediatric patients received isavuconazole, itraconazole, posaconazole, or voriconazole in the inpatient or outpatient setting during the study period. Of the 273 patients, only 122 met criteria for inclusion in the analysis. Eighty-three percent of patients reached a goal serum concentration. Patients younger than 12 years required a higher dose (mg/kg/day) to achieve goal serum concentrations. Patients who received an azole in the form of an oral tablet or intravenously were more likely to reach a goal concentration than those not receiving these formulations. Median time to goal concentration occurred at 20 days for isavuconazole, 34 days for itraconazole, 11 days for posaconazole, and 10 days for voriconazole. CONCLUSIONS Higher starting azole doses are needed to obtain goal concentrations quickly, especially for children younger than 12 years.