Initial Treatment Research Articles

Abstract PR008: Genome-wide analyses of cfDNA fragmentomes for therapeutic monitoring of patients with pancreatic cancer

Abstract Determining response to therapy for patients with pancreatic cancer can be challenging using imaging alone, and there is an unmet need for noninvasive assessment of tumor burden. We developed a method for assessing response to therapy using circulating cell-free DNA (cfDNA) and tested it using 217 plasma samples from 40 patients with metastatic pancreatic cancer treated with immune checkpoint inhibition and radiation as part of the CheckPAC trial (NCT02866383). Samples were evaluated before and after initiation of therapy using a mutation-independent and tumor-independent approach (ARTEMIS-DELFI), combining genome-wide cfDNA fragmentation profiles and repeat landscapes. Patients with below median scores (n=16) at the time of the first follow up CT scan at 8 weeks had a longer median progression free survival (PFS) and longer median overall survival (OS) than patients with above median scores (n=17) (PFS: 153 days versus 50 days; HR=0.26, 95% CI=0.11-0.64, p=0.0013) (OS: 375 days versus 121 days; HR=0.12, 95% CI=0.045-0.30, p<0.0001). Additionally, a “fast fail” analysis of patients with scores above the 75th percentile evaluated at 2 weeks after initiation of therapy (n=9) resulted in shorter median PFS and shorter median OS than patients with lower scores (n=27) (PFS: 46 days versus 110 days; HR=0.29 95% CI=0.13-0.66, p=0.0027), (OS: 88 days versus 230 days; HR=0.35 95% CI=0.16-0.78, p=0.00011). We validated the approach in a separate cohort of 205 samples from 40 patients with pancreatic cancer treated with first line chemotherapy, with and without IL-6 inhibition, as part of the PACTO trial (NCT02767557). Patients with below median scores at the 8-week first follow up CT scan (n=16) had a longer median OS than patients with above median scores (n=16) (OS: 288 days vs 199 days, HR=0.488, 95% CI=0.24–1.01, p=0.048). Similar results were observed at 2 weeks after initiation of therapy when considering patients with scores above the 75th percentile (n=9) compared to patients with lower scores (n=27) (OS: 196 days versus 280 days) (HR=0.17, 95% CI=0.06-0.46, p=0.0074). These analyses suggest that non-invasive fragmentation-based cfDNA approaches can identify individuals with pancreatic cancer who are not responding to therapy as early as two weeks after treatment initiation. Incorporation of these molecular methods to evaluate tumor burden may provide timely information for patient-physician decision making to improve patient care. Citation Format: Carolyn A Hruban, Daniel C. Bruhm, Inna M Chen, Shashikant Koul, Akshaya V Annapragada, Nicholas A Vulpescu, Sarah Short, Susann Theile, Kavya Boyapati, Stephen Cristiano, Vilmos Adleff, Julia S Johannsen, Robert B Scharpf, Zachariah H Foda, Jillian A Phallen, Victor E Velculescu. Genome-wide analyses of cfDNA fragmentomes for therapeutic monitoring of patients with pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr PR008.

Abstract B046: Methylation based circulating tumor DNA serial monitoring correlates with immunotherapy response in non-small cell lung cancer

Abstract Purpose: Circulating tumor DNA (ctDNA) can reflect the genetic and epigenetic composition of malignancies and can serve as a non-invasive biomarker for cancer diagnostics and monitoring. This study aimed to evaluate the utility of a methylation based ctDNA assay as a predictive tool in non-small cell lung cancer (NSCLC) anti-PD1 based immunotherapy monitoring. Methods: We evaluated a cohort of patients with NSCLC treated with anti-PD1 based immunotherapy, from which 108 blood specimens were collected at baseline and during treatment follow-up. Tumor Methylation Scores (TMS) were measured with an amplicon-based, multiplexed cfDNA assay that utilizes quantitative counting templates (QCTs) in conjunction with next-generation sequencing to count the number of methylated molecules at more than 500 genomic locations that are hypermethylated in cancer tissue. The association between TMS and real-world progression-free survival (rwPFS) on therapy was conducted using Cox proportional hazards model and plotted using the Kaplan-Meier method. Results: The change in TMS measured 4-10 weeks post-treatment initiation strongly correlated with immunotherapy response, as measured by rwPFS (p<0.0001), compared to a weaker correlation of imaging RECIST v1.1 measurements with rwPFS (p=0.55). Furthermore, TMS tracked with tumor burden on therapy in real-world cases. Conclusions: In this real-world dataset of NSCLC patients treated with anti- PD1 immunotherapy regimens, TMS scores measured within a 4-10 week window after treatment initiation can be predictive of response to therapy. Beyond this window, the TMS score can be associated with rwPFS and tumor dynamics. Early evidence suggests that changes in the methylation profile may be informative for monitoring occurrence of new somatic mutations. The cases presented demonstrate the applicability of using TMS for serial therapeutic response monitoring. Citation Format: Angela Hsiao, Brian Woodward, Patrick Ye, Matthew Varga, Kevin Lu, Ghaith Altaie, Naomi Searle, Robb Veins, Sydne Langpap, Zeqian Li, Gary Palmer, Hatim Husain. Methylation based circulating tumor DNA serial monitoring correlates with immunotherapy response in non-small cell lung cancer [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr B046.

Externalised nurse-led model for hepatitis C virus microelimination and impact of drug use profile.

Direct-acting antivirals have greatly simplified the treatment of hepatitis C virus (HCV), yet circuits that bring diagnosis and treatment closer to people who inject drugs (PWID) are needed to achieve the elimination targets of the WHO. With this purpose we have established an externalised nurse-driven circuit among former and active PWID in an addiction centre (AC) and a harm reduction centre (HRC). The nursing staff offered HCV screening, diagnosis and treatment to the AC and HRC users, administered medication after the hepatologist's remote prescription to those with an active infection who accepted being treated, and implemented educational and harm reduction interventions. Participants and results: Between October 2018 and March 2021, 566 users accepted screening. 134 (24%) had an active infection, with a higher prevalence among HRC users (42% vs 17%; p<0.001), who were more frequently foreigners, homeless and reported active drug use and syringe sharing. Treatment initiation was similar between groups. Overall sustained viral response (SVR) for intention-to-treat (ITT) and per protocol (PP) was 70% and 88% respectively. Overall adherence was good in both groups; however, SVR was higher in AC users compared to HRC users (ITT-SVR 81% vs 55%). All reinfections (6% by ITT) occurred in the HRC group. Overall loss to follow-up rate was 21%. This patient-centred nurse-driven circuit demonstrates that HCV treatment can be successfully delivered to PWID even with active drug use and socio-economic complexity. User-specific characteristics need to be considered when setting up these interventions to maximise success.

HPB O05 - Changing paradigms in the management of severe acute pancreatitis: Focused multi-disciplinary working between surgeons and intensivists to mitigate organ failure in order to reduce mortality

Abstract Background Mortality was classically bimodal in severe acute pancreatitis and organ failure is the single most important factor in predicting outcome in severe acute pancreatitis. Initial interventions are supportive often requiring critical care. Subsequently treatments are required to manage necrosis and any organ recovery remains under threat. The outcomes and interventions from surgery and critical care are reviewed to determine how to balance organ failure and the need for necrosectomy in a modern multi-disciplinary tertiary care centre Method The Royal Liverpool provides a tertiary service to all patients with pancreatitis across Merseyside and North Wales. All patients that were transferred to critical care from 2018 – 2023 were analysed using the intensive care national audit and research centre database which contains information on organ failure. The patients with severe pancreatitis were then reviewed using electronic clinical notes and radiology images to determine clinical course and management. Results Of 134 patients, 48 (36%) were admitted locally, 85 (64%) transferred in, occurring 35% &amp;lt;2weeks, 29% 2-4weeks, 28% 4-6weeks and 8% &amp;gt;8weeks. 76 (57%) required necrosis intervention, 58 (43%) were conservatively managed. Mortality was 38% with 35% &amp;lt;4weeks, 22% 4-8weeks, 22% 8-12weeks, 22% &amp;gt;12weeks. No significant difference in mortality between conservative or interventional management (15 (45%) vs 18 (55%)) nor median age (58 vs 57.5 yrs). Survival related to number of failing organs (dead vs alive): nil organs: 10 patients vs 27 patients (20%vs32%), One: 11 vs 45 (22%vs45%), Two: 21 vs 9 (42%vs11%), Three: 8 vs 3 (16%vs4%), p&amp;lt;0.005. Conclusion Of patients deemed fit for ITU admission with necrotising pancreatitis, the classic paradigms of biphasic mortality no longer occur. Differences in mortality from intervention and age of patient has been negated by optimal ITU management for organ failure. For the initial phases and the intervention phases of management, ensuring degree of organ failure is key to survival. There is a significant change when two organs fail in mortality and this stresses the importance of holistic management. Our ITU promotes pancreas specific organ preservation measures of early enteral feeding, cessation/tailoring of antibiotics, early extubation/tracheostomy and most importantly multidisciplinary working

Early Diagnostic Prediction of Infective Endocarditis: Development and Validation of EndoPredict-Dx

Background: Infective endocarditis is a life-threatening disease with diverse clinical presentations, making diagnosis challenging and requiring a range of complementary tests. The level of suspicion, based on clinical judgment, guides decisions regarding the initiation of empirical treatment and the selection of appropriate diagnostic tools. This study aimed to develop and validate the EndoPredict-Dx score for early prediction of infective endocarditis diagnosis. Methods: Patients admitted to a specialized cardiovascular hospital emergency department with suspected infective endocarditis between January 2011 and January 2020 were included. The primary outcome was left-sided infective endocarditis according to the Duke criteria. Logistic regression was used to derive the scoring system, with internal validation performed through bootstrapping. Candidate variables were obtained from the admission medical history, physical examination, and laboratory parameters. Results: Of the 805 individuals with suspected infective endocarditis (median age 56 years (40–73); 58.6% men), 530 confirmed the diagnosis based on the Duke criteria. The EndoPredict-Dx assigned points for male sex, previous endocarditis, petechiae, heart murmur, suspected embolism, symptoms lasting 14 or more days at the time of admission, hemoglobin level ≤ 12 g/dL, leukocyte level ≥ 10 × 109/L, C-reactive protein level ≥ 20 mg/L, and urine red blood cells ≥ 20,000 cells/mL. Patients were divided into three risk groups. The AUROC was 0.78 (95% CI 0.75–0.81) for the derivation cohort and 0.77 for the internal validation. Conclusions: The EndoPredict-Dx score accurately predicted the likelihood of infective endocarditis using clinical and laboratory data collected at admission.

Impact of integrating traditional care with the modern healthcare system in reducing tuberculosis diagnosis delays in Ethiopia: a clustered randomized controlled study.

Diagnosis and treatment initiation delays for tuberculosis (TB) are significant challenges in resource-limited settings. These delays can result in poor treatment outcomes, disease transmission, and increased costs. This study aimed to assess the effect of integrating traditional care with modern healthcare systems on reducing TB diagnosis delay. A cluster randomized controlled trial was conducted among TB patients, with 510 participants, 255 individuals were assigned to the intervention group and 255 to the control group. Training in the intervention group was provided for both traditional and modern healthcare providers in three rounds to enhance their knowledge, attitudes, and skills in TB screening and referral. A non-parametric independent sample test was used to compare the baseline and end-line data. The effect size was determined using Cohen's d. To account for individual and cluster-level variations, a mixed-effect parametric survival model was employed. Furthermore, conditional (fixed only) and marginal (random effects) graphs were used to compare between the intervention and control groups. A total of 510 participants were included in the baseline study, with a similar number of participants included in the endline study. In the intervention group, the delay in diagnosis was 4.185 per 1000 person-days post-intervention, compared to 4.608 per 1000 person-days pre-intervention. In the control group, the delay for diagnosis was 4.759 per 1000 person-days pre-intervention and 5.031 per 1000 person-days post-intervention. The median time to diagnosis was 135days. The non-parametric comparison showed that the intervention significantly reduced patient delays in the intervention group compared to the control group (p = 0.006), with a Cohen's d effect size of 0.246. The intervention also significantly reduced diagnosis delay in the intervention group compared to the control group (p = 0.036), with a Cohen's d effect size of 0.187. The diagnosis of TB was accelerated by 1.076 times due to the integration of traditional care with the modern healthcare system in the intervention group compared to the control group (δ: 1.076; 95% CI 1.021, 1.134). The involvement of traditional care providers in TB control programs significantly reduced diagnosis delays in Ethiopia. These findings suggest the need for integrating traditional care with modern healthcare systems for the effective prevention of TB in high-burden countries. Clinical trial registration ClinicalTrials.gov ID: NCT05236452.

Protocol for a mixed methods process evaluation for a randomised controlled trial to improve shared decision-making about, and uptake of, osteoporosis medicines: the iFraP study

Background High quality shared decision-making (SDM) conversations involve people with or at risk of osteoporosis and clinicians working together to decide, where appropriate, which evidence-based medicines best fit the person’s life, beliefs, and values. The improving uptake of Fracture Prevention drug treatments (iFraP) intervention comprises a computerised Decision Support Tool (DST), clinician training package and information resources, designed for use in UK Fracture Liaison Service (FLS) consultations. The iFraP intervention will be tested in a pragmatic, parallel-group, individual randomised controlled trial in patients referred to four FLSs in England. This mixed methods process evaluation aims to assess which components of iFraP were delivered and how (fidelity), whether iFraP results in a change in osteoporosis drug treatment initiation rates and how, and how context affects implementation of iFraP and outcomes. Methods We will collect quantitative data using (1) Case Report Forms completed by FLS clinicians; (2) self-reported questionnaires completed by patient participants; and (3) DST analytic data. We will collect qualitative data using (1) semi-structured interviews with patients who receive the iFraP intervention in their FLS appointment, FLS clinicians delivering iFraP appointments, and primary care clinicians that have consulted with a patient following their iFraP FLS appointment; and (2) FLS consultation recordings. A triangulation protocol will be used to integrate the quantitative and qualitative findings to generate novel insights about the intervention under evaluation. Discussion The process evaluation, alongside the trial, will help to understand what elements of the iFraP intervention were delivered and how, the mechanisms of impact and how context affected implementation and outcomes, and intervention acceptability. Mixed methods interpretation will lead to further insights about the implementation of SDM and DSTs in-practice. Trial registration ISRCTN: 10606407, 21/11/2022 https://doi.org/10.1186/ISRCTN10606407

HPB SO37 - GTN Patch for Medical Relaxation of the Sphincter of Oddi: “A Safe and Effective Pre-ERCP Treatment for Controlled Bile Leak Post-Cholecystectomy"

Abstract Background Bile leak is a frequent complication following laparoscopic total, subtotal cholecystectomy, and bile duct exploration (BDE) with an incidence up to 2.8%. It can contributing significantly to postoperative morbidity and mortality. GTN has demonstrated efficacy in reducing papillary muscle contraction and Sphincter of Oddi pressure. Similarly GTN might promote healing and closure of bile leaks post total or subtotal cholecystectomy. This study aims to assess the safety and effectiveness of GTN in treating bile leaks post total, subtotal cholecystectomy or bile duct exploration. Method Data was prospectively collected from patients who developed bile leaks after total or subtotal cholecystectomy between June 2020 and June 2024. Inclusion criteria were patients with a bile leak post-surgery during this period. Exclusion criteria included unstable patients, uncontrolled bile leaks, the presence of biliary obstruction, or major bile duct injuries. Suitable patients were treated with a GTN patch as first line management before potential ERCP. A 5 mg GTN skin patch was applied every 24 hours, starting at least 48 hours post-surgery if drain output exceeded 100 ml/hour. Patients were consented about side effects including hypotension and headache. Results Seven patients were treated with GTN, with mean age of 51 years, four were females. Four cases were emergencies and four had subtotal cholecystectomies, one in the elective group. Bile leaks occurred after biloma drainage and one after removal of trans-cystic drain post trans-cystic BDE. All patients experienced significant drain output reduction the day after starting GTN. There were no complications during or after treatment. One required ERCP two months later for persistent low-volume bile leak of 5-10 ml per day. Headaches occurred in two cases, treatment was discontinued in one. The average time to GTN treatment was 3.4 days. Conclusion This study demonstrates GTN treatment's safety and effectiveness for managing bile leaks following total, subtotal cholecystectomy or BDE. We recommend GTN as the primary therapy for controlled bile leaks, barring biliary obstruction or major injury. Response can be evaluated within 24-48 hours through significant output reduction. Implementing local protocols can minimize variations in GTN treatment initiation times. GTN should be prioritized over ERCP to prevent complications like perforation, pancreatitis, and bleeding. We aim for this study to underscore GTN's efficacy to surgeons and promote multicentre research initiatives.

Hematological changes in women with cervical cancer before and after cancer treatment: retrospective cohort study.

Hematological changes is one of the most common complications occurred in cancer patients. Therefore, the current study aimed to assess the hematological toxicity of cervical cancer patients before and after the initiation of treatment. The retrospective cohort study was conducted from 2015 to 2022 at the University of Gondar Comprehensive Specialized Hospital. The hematological profile and sociodemographic and clinical data of the cervical cancer patients were collected using data extraction sheets. The Epidata version 3.1 and SPSS version 25 were used for data entry and analysis, respectively. Descriptive statistics were employed to summarize the data. To compare the median differences in hematological parameters before and after treatment, the Wilcoxon rank test was used. In addition, to assess the presence of an independent association between hematological abnormalities and the independent variables, logistic regression models were used. A p value less than 0.05 was considered to indicate statistical significance for all tests. In current study, the median (Interquartile range) of hemoglobin levels, white blood cell counts, and platelet counts, before treatment were 13.2 (12.1, 15) g/dl, 7.5 (5.8, 11.8) *109/L, and 330 (252, 383) *109/L, respectively. However, after treatment the median (Interquartile range) value of hemoglobin levels, white blood cell counts, and platelet counts were significantly lowered. On the other hand, red cell distribution width was significantly greater after treatment. At baseline, the magnitude of leucocytosis, anemia, and thrombocytosis were 27.9%, 24.6%, and 18.7%, respectively. After the treatment, anemia increased to 44.3%, but leucocytosis and thrombocytosis were replaced by leucopenia 18.3% and thrombocytopenia 17.8%, respectively. Hematological abnormalities such as anemia, leucopenia and thrombocytopenia were high after chemo-radiotherapy, and surgery. As the stage of cancer advances, the risk of developing anemia, leucocytosis, and thrombocytosis increased in 7.6, 6.9 and 9 times, respectively. Furthermore, being HIV patients and rural resident increased the risk of developing anemia about twofold. In conclusion hematological abnormalities were observed before and after cervical cancer treatment, with significance increment after chemo-radiotherapy and surgery. As the stage of cancer advances, the risk of developing hematological abnormalities increases. Therefore, routine monitoring of hematological changes before and after treatment and screening for major risk factors are important for improved patients' management.

Hepatitis C Infection Confirmation and Fewer Visits Contribute to Improving Treatment Rates in a Predominantly African American Health Center

Background/Objectives: The approval of direct-acting antiviral (DAA) therapy for hepatitis C (HCV) resulted in a highly effective oral treatment for patients. The primary objective of this study was to identify reasons that patients were not treated versus why patients were treated. Identifying potential reasons for the failure to treat can provide a pathway to interventions using evidence-based data. Methods: The electronic medical records in an urban predominately African American (AA) population were searched for all patients with HCV seen at least once in a Gastroenterology or Infectious Disease clinic in 2019. Data collected included demographics, treatment visits, laboratory data, insurance and ZIP codes for median income. Results: Of the 441 patients who were not yet treated at the first 2019 visit, only 43% were treated by July 2020. Insurance and median income were not factors in failure to treat. Patients with an average of four visits were more likely to be treated than those with two or less, suggesting that failure to follow up was a significant factor for patient treatment (42% vs. 8% p &lt; 0.0001). Confirmation of viral infection at first visit was an important factor with respect to treatment (treated 38% vs. not treated 25% p &lt; 0.02). Conclusions: Significant numbers of our patients (57%) failed to be treated after at least one clinic visit. The two critical factors were PCR confirmation prior to the initial visit and the requirement for multiple visits before the initiation of treatment. Since the degree of fibrosis had no impact on treatment, initiating treatment immediately after confirming infection with HCV should improve patient treatment rates and outcomes.

Abstract 4119426: Enhancing early detection of ICI myocarditis cases during hospitalization: A role for large language models

Background: Immune-checkpoint inhibitor (ICI)-induced myocarditis is the most fatal immune-related adverse event (irAE). Early recognition and treatment of ICI myocarditis is associated with improved outcomes. However, current approaches to the diagnosis of ICI myocarditis have limitations. Open-source large language models (LLMs) are an accessible and scalable method of answering queries from human-generated text, and therefore may assist in the real-time early detection of ICI myocarditis among at-risk patients. Research Question: Can a free, open-source LLM detect cases of ICI myocarditis early in admission? Aims: We investigated the ability of a LLM pipeline to screen for ICI myocarditis within one day of admission using hospital medical records. Methods: Hospital admissions of patients on ICI therapy from November 4th, 2021, to September 5th, 2023 were retrospectively reviewed by a multidisciplinary immunotoxicity team using established, published definitions for the presence of ICI myocarditis. Progress notes written the day before, day of, and day after admission were fed into an open-source LLM pipeline built using Mistral 7B OpenOrca with retrieval augmentation generation (RAG). Performance of the LLM was measured via sensitivity and specificity in comparison to the gold standard of manual adjudication. Results: Of the 1874 hospital admissions of patients on ICI therapy, there were 22 (1.2%) cases of myocarditis. The average time to initiation of treatment was 2.45 days. Using notes written within one day after admission, the LLM detected ICI myocarditis with 95.5±8.7% sensitivity and 95.4±1.0% specificity, spending 2.13 seconds per chart. Conclusion: LLMs serve as a useful tool to screen for ICI myocarditis, detecting 95.5% of cases within one day of admission with 95.4% specificity. Future studies will investigate if integrating this tool into the real-time management of irAEs could lead to earlier diagnosis, faster initiation of treatment, and improved patient outcomes.

Thibang Diphatlha: a sequential multiple assignment randomized trial designed to increase timely adoption of cervical cancer treatment in Botswana.

Delays and missed opportunities for timely treatment contribute significantly to stark inequities in cervical cancer mortality in low- and middle-income countries (LMICs) compared to high-income countries. The vast majority (approximately 90%) of new cases and deaths occur in LMICs, particularly those with high rates of HIV such as Botswana. To date, most of the implementation and cancer control research in Botswana and other LMICs has focused on cancer prevention and screening, with limited focus on cancer treatment. As such, there is a critical need to identify effective strategies to ensure timely care, and to understand contextual factors that shape the response to strategies. Without this fundamental knowledge, cervical cancer will remain a public health crisis in Botswana and other LMICs. To help fill this known gap, this study tests the effectiveness of adaptive strategies on timely treatment adoption using a hybrid (type III) Sequential Multiple Assignment Randomized Trial (SMART) design and evaluate contextual mechanisms contributing to the success or failure of each adaptive strategy. The adaptive strategies are designed to target contextual determinants identified in our prior work, including delayed communication of results to patients, individual and structural barriers to accessing treatment, and suboptimal care coordination between referring and cancer treatment clinics, and are supported by systematic evidence of the effectiveness of nudge strategies in clinical care. The primary implementation outcome is adoption, defined as the initiation of treatment within 90days. Secondary outcomes include fidelity, reach, acceptability, implementation costs, and cancer and HIV-related clinical outcomes. The rationale for the study is that enhancing coordination, communication, and navigation through centralized outreach will both increase timely treatment adoption and be scalable and sustainable after the project is completed. This innovative study seeks to decrease cervical cancer mortality in LMICs by developing and implementing effective and sustainable strategies that can be sustained and adapted to other contexts. Additionally, this study seeks to advance the long-term impact of global implementation science through strong and sustained partnerships in Botswana and other LMICs. ClinicalTrials.govNCT05952141. Registered on July 11, 2023. https://clinicaltrials.gov/study/NCT05952141 PROTOCOL VERSION AND DATE: Version 1 (September 28, 2024).

Abstract 4136169: Phenotypic clustering of right heart dilatation in pulmonary arterial hypertension

Introduction: Right ventricular (RV) and right atrial (RA) dilatation are important hallmarks of disease severity in patients with pulmonary arterial hypertension (PAH). To obtain more insights on the clinical significance of RA dilatation, we phenotypically characterized patients with right heart dilatation. Aim: Description of different RV/RA phenotypes in PAH Methods: 203 incident, treatment naïve PAH patients with cardiac magnetic resonance (CMR) imaging were included. Phenotypic clustering was based on RA and RV dilatation. Conform literature, RA dilatation was defined by a RA index maximal area &gt;15 cm 2 /m 2 . RV dilatation was defined by an RVEDV/LVEDV ratio &gt;1.3 and &gt;2.4 for extreme dilatation. Results: Four phenotypic patient clusters were identified: no dilatation (n=48), RV dilatation (n=78), RV+RA dilatation (n=53) and extreme RV dilatation + RA dilatation (n=23), Figure 1A. To unravel the additive clinical value of RA dilatation, we mainly compared patients with RV dilatation and patients with RV+RA dilatation. Intriguingly, patients with RV+RA dilatation demonstrated lower 3- and 5-year survival rates (58% and 43% vs. 75% and 55%) (Figure 1B) and were less likely to reverse RV dilatation after treatment initiation than patients with RV dilatation only. Despite the consequences of RA dilatation, we could not identify an explanation for the difference in RA dilatation between both groups. No difference in afterload was observed, shown by comparable pulmonary vascular resistance (9.9 [6.8-13] WU vs. 10 [7.5-12.3] WU, p&gt;0.05). RV function was similarly impaired (RV ejection fraction: 36±9% vs. 33±9%, p&gt;0.05). End-diastolic elastance (0.73 [0.39-1.11] mmHg/mL vs. 0.58 [0.40-0.94] mmHg/mL, p&gt;0.05) and severity of tricuspid regurgitation did not differ. Finally, diuretic use (40% vs. 40%, p&gt;0.05), age (54±16 vs. 57±19 yrs, p&gt;0.05), female gender (70% vs. 60%, p&gt;0.05) and iPAH diagnoses was similar (69% vs. 59%, p&gt;0.05). Conclusion: PAH-patients with both RA and RV dilatation have a worse clinical profile than patients with only RV dilatation. However, no clear trigger for RA dilatation was found and future mechanistic studies should unravel factors explaining these differences in right heart adaptation.

Abstract 4143250: Individualized Interactomes from Pulmonary Arterial Hypertension Biopsies Predict Therapeutic Response: an In Silico Clinical Study

Introduction: Pulmonary arterial hypertension (PAH) is a highly morbid cardiopulmonary disease characterized by substantial pathobiological and clinical heterogeneity, which is believed to underlie variable treatment-response observed in clinical trials and at point-of-care during real-world practice. Utilizing patient-specific pathogenetic information to inform drug selection for use in clinical practice is expected to improve clinical efficacy of PAH drugs, but such strategies are currently lacking. Methods: We conducted a retrospective analysis of 25 PAH patients (32 samples, receiving PAH therapies) undergoing right heart catheterization (RHC) for the routine clinical assessment of dyspnea at Rhode Island Hospital (Warren Alpert Medical School of Brown University) , along with 3 healthy controls. A minimally invasive "cell biopsy" approach was used to collect Pulmonary Arterial Endothelial Cells (PAECs) from the tips of pulmonary artery catheters. Transcriptomic RNA-seq was performed on mRNA isolated from cell passage 3 or 4 for all samples. We deployed an innovative network medicine method to construct sample-specific interactomes from the transcriptomic data and human protein-protein interactome. The individualized interactomes captured patient-specific molecular features, which could then be used to predict therapeutic response in PAH patients. Results: The individualized interactomes have a range of 5276 [4900, 7263] nodes and 7204 [6606, 12992] edges. We observed that an increase in 6MWD from baseline that was sustained at 12 months following treatment initiation was associated with higher fraction of drug targets in the individualized interactomes. By contrast, such a positive association was not observed in comparator drugs. Similarly, we observed a transition in BNP levels from elevated at baseline to within the normal range at 12 months that corresponded to an absolute decrease of ~250 pg/mL. Higher fraction of drug targets in the individualized interactomes was also associated with a significant improvement in REVEAL 2.0 Risk score at 6 months (p=0.004) and 12 months (p&lt; 0.001). Conclusions: "Cell biopsies" taken at point-of-care for clinically indicated RHCs may be leveraged to predict therapeutic response and inform precision-based initiatives in pulmonary vascular disease through transcriptome-derived sample-specific interactomes and systems pharmacology tools.

Abstract 4140102: Changes in EQ-5D-5L with Aficamten in Obstructive Hypertrophic Cardiomyopathy (oHCM): the SEQUOIA-HCM Trial

Introduction: In patients with obstructive hypertrophic cardiomyopathy (oHCM), the SEQUOIA-HCM trial demonstrated that aficamten, a next-in-class cardiac myosin inhibitor, improved exercise capacity, heart failure symptoms and hemodynamics compared with placebo. Aficamten’s impact on overall quality-of-life (QoL) in oHCM has not been reported. Hypothesis: Aficamten, compared with placebo, improves QoL as assessed by the EQ-5D-5L. Aims: To describe EQ-5D-5L changes in patients enrolled in SEQUOIA-HCM. Methods: SEQUOIA-HCM (NCT05186818) is a phase III, placebo-controlled trial of adults with symptomatic oHCM randomized to aficamten (n=142) or placebo (n=140) on top of standard-of-care medical therapy. Participants underwent blinded dose escalation over 6 weeks and were treated for 24 weeks followed by a 4-week washout. EQ-5D-5L (ranges from 0 to 1) and overall QoL using the Visual Analogue Scale (VAS; from 0 to 100) was measured at baseline through week 28 with higher scores indicating better QoL. Aficamten treatment effect on EQ-5D-5L was estimated using linear regression (study visits) and mixed effects regression (overall treatment effect) using all follow-up data with model adjustments for baseline EQ-5D-5L score and randomization stratification variables. Results: Mean age (n=282) was 59.1±12.9 years (40.8% women; 79.1% white). Aficamten baseline EQ-5D-5L index and VAS scores were 0.8±0.19 and 71.2±17.9 (placebo: 0.78±0.2; 68.9±18.6), respectively. Aficamten improved the EQ-5D-5L by 0.026 (95% CI: -0.001, 0.052; p=0.056) and the VAS by 2.8 points (95% CI: 0.8, 4.8; p=0.006) versus placebo with significant differences as early as 8 weeks after treatment initiation (p=0.005). After treatment withdrawal at 24 weeks, QoL benefits in aficamten-treated patients decreased compared with placebo (Figure: Index, p&lt;0.001; VAS, p=0.003), with hemodynamic parameters returning to baseline. Conclusions: Aficamten yielded early, sustained and significant improvement in overall QoL compared with placebo. Withdrawal of aficamten was associated with the loss of treatment benefits and perhaps an increased perception of pre-treatment symptoms. These data support a role of aficamten in improving QoL among patients with oHCM.

A Pilot Randomised Controlled Trial Involving Financial Incentives to Facilitate Hepatitis C Treatment Uptake Among People Who Inject Drugs: ETHOS Engage Study

The primary aim of this study was to establish the feasibility of implementing a larger RCT designed to evaluate the effect of financial incentives on HCV treatment initiation among persons receiving opioid agonist therapy and/or who have injected drugs in the prior six months. ETHOS Engage is an observational cohort of participants recruited from drug treatment and needle and syringe programs in Australia. Among 11 drug and alcohol clinics, participants who were HCV RNA-positive were randomized (1:1) to receive standard of care or a AUD $60 gift card at treatment initiation. Regarding feasibility, 100% (57/57) of eligible participants enrolled to take part. Twenty-eight participants were randomised to the financial incentive arm (AUD $60 gift card) plus standard of care and 29 participants to the standard of care arm. In this pilot RCT (n = 57), median age was 42 years (IQR 37–49), 63% were male (n = 36), 35% Indigenous (n = 20) and 36% (n = 21) reported injecting drugs daily in the past month. Twelve weeks post-study enrolment, 11 (39%) participants in the financial incentive arm and 17 (59%) participants in the standard of care arm initiated HCV treatment. Findings indicate high feasibility among people who inject drugs to be randomised to receive financial incentives to initiate HCV treatment.

Abstract 4135712: Mortality and Cardiovascular Complications Associated with Weight Loss Drugs among Breast Cancer Females Under Cardiotoxic Therapies: A Real-World Populational Study in the United States

Background: Obesity is an adverse prognostic factor for breast cancer (BC). While liraglutide and semaglutide, derived from antidiabetic glucagon-like peptide-1 receptor agonists (GLP1RA), are established weight loss drugs known for their cardiovascular safety in the general obese population, their safety in BC patients undergoing cardiotoxic antineoplastic therapies remains less understood. Objective: To investigate the mortality and cardiovascular outcomes related to GLP1RA used for weight loss among the highly susceptible BC females. Methods: This retrospective cohort study was based on the TrinetX network, comprising real-time health records from over 60 US healthcare organizations. The study population included obese females (≥18 years old) who received at least three prescriptions of either exclusive GLP1RA (liraglutide or semaglutide) or non-GLP1RA weight loss drugs (phentermine, bupropion-naltrexone, orlistat) upon BC diagnosis between 01/01/2015 and 01/01/2022. The index date was the initiation of systemic anti-cancer treatment, including chemotherapy (anthracycline, taxane, or cyclophosphamide), and/or anti-HER2 agents (trastuzumab, pertuzumab, or lapatinib). We used 1:1 propensity score-matching (PSM) to balance demographics, BMI, comorbidities, concurrent medications for cardiovascular diseases and metabolic disorders, BC receptor status and prior treatment, and levels of serum cholesterol (LDL, HDL) and hemoglobin A1c. Cox regression models were applied to compute hazard ratios (HR) and 95% confidence intervals (CIs). Follow-up continued until 05/24/2024, or until adverse cardiovascular events or death occurred. Results: Among 380 PSM-balanced pairs, the GLP1RA group (mean age: 57.6±11) showed significantly lower risks of all-cause mortality (HR 0.593, 95% CI 0.457-0.77), acute heart failure (HR 0.496, 95% CI 0.286-0.859), angina pectoris (HR 0.566, 95% CI 0.343-0.936), and acute stroke (HR 0.661, 95% CI 0.46-0.951) than the non-GLP1RA group (mean age: 57.5±12). Otherwise, no significant difference was shown in acute myocardial infarction (HR 0.787, 95% CI 0.495-1.251), pulmonary hypertension (HR 0.777, 95% CI 0.55-1.099), or arrhythmias (HR 0.829, 95% CI 0.566-1.215). Conclusion: Compared to non-GLP1RA weight loss agents, GLP1RA offers better survival and cardiovascular protection for BC patients undergoing cardiotoxic therapies. Future studies are warranted to validate the safety of these weight loss drugs during the BC treatment continuum.

Characterization of Disease Patterns in Children with Intracranial Abscesses for Enhanced Clinical Decision-Making

Background: Intracranial suppurative infections in pediatric patients, while rare, pose a significant risk to patient mortality. Early recognition and fast initiation of diagnosis and treatment are crucial to prevent fatal outcomes. Between December 2022 and May 2023, a significant cluster of nine cases emerged, each necessitating neurosurgical intervention. This series highlights an important trend in clinical outcomes and raises questions about underlying factors contributing to this pattern. The need for surgical procedures in all instances suggests a commonality in severity, warranting further investigation into potential causes and preventative measures. This retrospective monocentric study aims to explore the clinical features associated with these cases to identify specific disease patterns that can expedite management in clinical practice. Methods: Cramer’s V effect size was employed to evaluate combinations of clinical features, followed by Fisher’s exact test applied to a constructed contingency table. A p-value was assessed for significance analysis, with combinations achieving a Cramer’s V value of 0.7 or higher being classified as exhibiting very strong correlations. Results: The analysis revealed distinct patterns of clinical features among children diagnosed with intracranial abscesses. Significant associations were identified, including correlations between sinusitis and Streptococcus pyogenes, and fever accompanied by affected temporal, frontal, and frontobasal lobe regions. Conclusions: Despite the generally limited statistical analysis of pediatric intracranial abscesses in the existing literature, this study provides meaningful significant associations between clinical features, delineating specific disease patterns for children with intracranial abscesses. By addressing this gap, the findings contribute valuable insights and offer a framework that could enhance clinical decision-making and support timely disease management in pediatric cases.

Abstract 4136701: A combined approach of cardiac magnetic resonance and CardioMEMS to assess right ventricular dysfunction during exercise in HFpEF-PH

Background: Right ventricular dysfunction (RVD) is common in patients with heart failure with preserved ejection fraction (HFpEF) and is associated with shortened life expectancy. Early identification of these at-risk patients could facilitate the initiation of future treatments. Evaluating the RV during exercise has proven to enhance the diagnostic accuracy in revealing RVD that is not detectable at rest. The CardioMEMS device has emerged as a non-invasive tool to remotely monitor pulmonary artery pressures (PAP) and enable early identification of clinical worsening. Research Questions: Using a hybrid approach of combined real-time CMR-derived volume measurements with CardioMEMS-derived PAP measurements, we aimed to identify RVD during exercise which is not detectible at rest in a population of patients with HFpEF and pulmonary hypertension (PH). Methods: In this prospective cohort study, we used a hybrid approach of two consecutive exercise tests in HFpEF patients ( Figure 1 ). First, PAP were measured using the CardioMEMS signal on a supine bike at rest, and 25%, 50%, and 75% of peak power output determined previously on an upright cycle ergometer. Subsequently, volumes were derived by CMR at rest and during exercise at 25% and 50% of peak power output. The RV end-systolic pressure-volume relationship (RVESPVR), a surrogate of RV contractility, was calculated as mean PAP divided by RV end-systolic volume. RV contractile reserve, as a marker of RVD during exercise, was calculated as the ratio of peak exercise to resting RVESPVR, with values &lt; 2.0 indicating impairment. Results: Fourteen patients with HFpEF-PH were included (age 76.6±6.9 years, 57% women). Eleven (79%) had impaired RV contractile reserve during exercise ( Table 1 ). Although not significant, RVESPVR at rest tended to be better in the group with RVD during exercise (0.47±0.17 vs 0.27±0.03; P=0.070). Peak VO 2 was significantly reduced in patients with RVD during exercise (13.1±2.0 vs. 18.6±6.4%; P&lt;0.021). Conclusion: A new hybrid approach combining cardiac MRI and CardioMEMS is feasible during exercise in HFpEF patients and identifies RVD in approximately eighty percent of patients with HFpEF and elevated mPAP at inclusion. Evaluation of RV contractility at rest showed a discordant trend, pointing out the need to test the RV during exercise. Further research is needed to determine if this approach can predict progression of RVD over time and serve as a risk stratification tool for these patients.

Sustainability of knotworking as a teacher professional development strategy

Teachers are faced with emerging and often complex constraints that can impact their ability to be pedagogically responsive to learners' different needs. These constraints or challenges were compounded by the COVID-19 pandemic. Thus, I extend scholarship in the field of teacher professional development by exploring the potential of implementing a nuanced form of collaborative intervention strategy called knotworking. There is a growing literature, some of which is discussed in this paper, on the utilisation of cultural historical activity theory-based constructs, which include Engeström's (2000a, 2001) knotworking heuristic, to manage the complex, value-based problems that teachers and school leaders are confronted with daily. This paper is a follow-up study that reported on a year-long knotworking intervention at a primary school in Johannesburg. The findings from the initial project (Andrews, 2024) showed that teachers were able to identify complex problems constraining their teaching and, through collaboration, generate new knowledge and teaching methods and deepen their understanding of how to be pedagogically responsive to the different learning needs of their children. In this follow-up paper, the participants in the initial knotworking intervention were interviewed to explore whether the new knowledge or practices they identified and implemented in the classroom had been sustained a year later. Findings from the qualitative data generated from the semi-structured interviews with the teachers show that much of the new knowledge, which included teaching practices, classroom management plans, or learner interventions that emanated from the knotworking interventions were still in use a year later and, in some instances, were integrated into internal operational policies.