Citations

Background Right ventricular (RV) maladaptation to elevated pulmonary afterload is the primary determinant of outcomes in pulmonary artery (PA) hypertension; however, the pathobiological mechanisms underlying RV decompensation remain poorly understood. Methods We performed global untargeted metabolomics on plasma from 55 patients who underwent gold‐standard RV‐PA coupling measurements using multibeat pressure volume loop assessment in a single‐center cohort and from 1027 patients with coupling surrogate measurements in a larger multicenter cohort, the PVDOMICS (Pulmonary Vascular Disease Phenomics) study. Age and sex‐adjusted linear regression was performed to identify associations between metabolites and coupling metrics. Additionally, we performed a metabolic flux analysis using gene expression data from RV tissue in an independent cohort of 32 patients. Partial least squares–discriminant analysis was used to identify metabolites and reactions characteristic of the decompensated RV. Results RV‐PA coupling was negatively associated with tricarboxylic acid (TCA) cycle intermediate levels. Specifically, plasma α‐ketoglutarate and fumarate were significantly associated with all coupling metrics in both cohorts. Metabolic flux analysis indicated that decompensated RVs exhibited aberrant TCA cycle activity, including reduced acetyl coenzyme A entry and increased lactate elimination, suggesting a shift from the TCA cycle toward glycolysis at the RV tissue level. Conclusions We identify an association between circulating TCA cycle intermediate levels and RV‐PA uncoupling in 2 independent cohorts, and dysregulated TCA cycle metabolism in decompensated PA hypertension RVs, suggesting that aberrant TCA cycle metabolism could represent a hallmark of RV maladaptation in PA hypertension. Further study of this pathway is warranted to develop novel biomarkers of RV function or RV‐targeted therapies.

AbstractPersons Living with Dementia (PLWD), diagnosed or undiagnosed, have high Emergency Department (ED) use. Identification of such patients poses significant challenges for emergency clinicians with considerable downstream implications on patients, care partners, and healthcare systems. With the advent of Geriatric Emergency Departments (GEDs) there is an opportunity to understand and improve care of PLWDs in EDs with effective allocation of resources and the development of novel techniques to better support detecting those at risk, communicating findings, and coordinating care for such patients. Advances have been made leveraging Electronic Health Record (EHR) data to risk stratify patients for dementia in the hope that those at high‐risk may benefit from further evaluation. The promise of multiple blood‐base biomarkers (BBM) as a future modality to improve detection of those at risk of dementias, will also have the potential to advance the delivery of care of PLWD and their care partners in EDs.Highlights EDs have an integral role in delivering care for Person Living with Dementia and their care partners. High acuity and fast paced ED environment and other barriers makes it difficult to identify Person Living with Dementia. EHR‐based risk stratification algorithms can identify patients at risk for Dementia in ED and outpatient settings. Use of Blood‐Based Biomarkers in the ED setting is novel and considerations of its use and implications need to be studied. EHR based risk stratification algorithm and Blood Based Biomarkers when used judiciously have the potential to overcome some of the known barriers to identify and improve care for Person Living with Dementia as they transition through EDs.

Background Complications of endoscopic mucosal resection (EMR) of large colorectal polyps remain a concern. Objective We aimed to compare safety and efficacy of cold EMR (without electrocautery) to hot EMR (with electrocautery) of large colorectal polyps. Design In this multicentre randomised trial, patients with any large (≥20 mm) non-pedunculated colon polyp were assigned to cold or hot EMR (primary intervention), and to submucosal injection with a viscous or non-viscous solution (secondary intervention) following a 2×2 design. The primary outcome was the rate of severe adverse events (SAEs). The secondary outcome was polyp recurrence. In this study, we report results of the primary intervention. Results 660 patients were randomised and analysed. An SAE was observed in 2.1% of patients in the cold EMR group and in 4.3% in the hot EMR group (p=0.10) (per protocol analysis 1.4 vs 5.0%, p=0.017) with fewer perforations following cold EMR (0%) compared with hot EMR (1.6%, p=0.028). Postprocedure bleeding did not differ (1.5% vs 2.2%, p=0.57). The effect of cold resection was independent of the type of submucosal injection solution, polyp size or antithrombotic medications. Recurrence was detected in 27.6% and 13.6% in the cold and hot EMR groups, respectively (p<0.001). Recurrence was not significantly different for 20–29 mm polyps (18.6% vs 13.4%, p=0.24) and for sessile serrated polyps (14.1% vs 8.5%, p=0.33). Conclusion Universal application of cold EMR did not significantly lower SAEs (unless cold EMR could be completed) and doubled the recurrence rate compared with hot EMR. Trial registration details ClinicalTrials.gov, number: NCT03865537 .

AbstractStandard of care first‐line systemic treatment for advanced biliary tract cancer includes chemo‐immunotherapy with gemcitabine, cisplatin, and durvalumab, followed by maintenance durvalumab monotherapy. The present work aims to investigate the differences in baseline clinical and molecular characteristics between patients with early progression during chemo‐immunotherapy and those who reach durvalumab maintenance therapy. The study population included patients with unresectable, locally advanced, or metastatic BTC who received treatment at 38 clinical Institutions in 12 countries from July 2021 to December 2023. The primary objective of the study was to investigate whether baseline clinical and molecular characteristics differed between patients with early progression during chemo‐immunotherapy versus those reaching durvalumab maintenance therapy. Four hundred forty‐eight patients were included in this study. Two hundred twenty‐seven patients (50.7%) received maintenance with durvalumab monotherapy, whereas 221 (49.3%) did not receive maintenance therapy due to PD during first‐line chemo‐immunotherapy before completing 8 cycles. Results show that patients who received maintenance were more likely to be older (≥70 years), have an ECOG = 0, locally advanced disease, and a neutrophil‐to‐lymphocyte ratio (NLR) <3. A higher proportion of patients with BAP1 mutations received maintenance, while TP53 mutations were more common in those who progressed early. According to the present analysis, a substantial proportion of patients (50.7%) with advanced BTC who were treated with chemotherapy plus durvalumab proceeded to receive maintenance therapy with durvalumab monotherapy, with a median treatment duration of 4.4 cycles. Patients ≥70 years, with ECOG PS 0, with locally advanced disease, and with NLR <3 had a higher likelihood of receiving maintenance therapy.

ABSTRACT Background Advancements in organ transplant technology are pushing global transplant capabilities to new heights. However, challenges persist in pediatric surgical and medical transplant fellowship training, primarily due to a limited number of adequate training programs and gaps in education. Addressing these gaps is essential for improving patient outcomes and advancing the field of pediatric transplantation. Methods An international survey was distributed to 416 pediatric transplant fellows via multiple global transplant associations. The 29‐question survey, available in English and Spanish, assessed current clinical knowledge, training satisfaction, and preferred learning formats. The survey received responses from 237 pediatric transplant fellows. Results One of the key findings was that respondents felt most confident in their pre‐transplantation clinical knowledge. About 75.5% of fellows reported being extremely or very aware of pre‐transplant workups and assessments. However, significant gaps were identified in other areas of training. Notably, 24% of respondents felt extremely knowledgeable about the side effects of immunosuppression, and only 22.8% were very confident in managing acute rejection. Fellows expressed strong interest in dynamic educational formats, particularly clinical case discussions (88.8%). Preferred methods to enhance training included continuing medical education (64.6%), hands‐on workshops, and support for transition protocols and psychosocial counseling. Conclusion This global survey highlights critical educational gaps in pediatric transplant fellowship training and identifies preferred learning methods among fellows. Targeted improvements such as standardized curricula, case‐based learning, interdisciplinary collaboration, and accessible continuing education are essential to enhance training. These strategies will ensure that future transplant professionals are well‐equipped to deliver high‐quality care across diverse healthcare settings.

Objectives: Modifiable lifestyle factors are associated with morbidity and mortality in hematopoietic stem cell transplant (HSCT) survivors. The aims of the study were to examine: (a) receipt of provider advice to change behaviors, (b) health behavior change, and (c) how modifiable lifestyle factors might cluster together. Methods: Patients within a large HSCT program completed a survey (N =870) of lifestyle factors at pre-HSCT evaluation. The survey assessed self-reported adherence to American Cancer Society and HSCT guidelines for cancer survivorship in the year prior to a pre-HSCT evaluation. Lifestyle factors of interest were physical activity, fruit and vegetable consumption, tobacco use, alcohol use, and height/weight to calculate Body Mass Index (BMI). Results: Among patients not meeting all five guidelines (98%), 31% received provider advice to change. Between 10% and 42% reported healthy behavior change since diagnosis. Physical activity, fruit and vegetable consumption, and BMI were the most commonly clustered lifestyle behaviors. Conclusions: A considerable proportion of patients did not meet national guidelines for lifestyle factors. Results highlight an immediate opportunity to improve health care delivery and transplant outcomes via pre-HSCT lifestyle screening and implementation of effective health behavior change interventions.

Abstract RATIONALE: Susceptibility to severe COVID-19 and long COVID may be influenced by pre-existing lung structure. ECG-gated, non-contrast cardiac CT scans, originally acquired for assessing coronary artery calcium, are available in multiple longitudinal cohort studies and have been previously validated against lung CT scans for densitometry; however, protocol variation across cohorts may hinder direct comparison. To address this, we developed a quality control (QC) rubric to grade cardiac CT scans for standardized quantitative lung measures across cohorts. METHODS: C4R assessed SARS-CoV-2 infection and outcomes in 14 NHLBI cohorts, of which 10 (six community-based and four longitudinal case-control studies) included CT scans (12,459 participants with lung and 13,752 with cardiac CTs). Logic rules were applied to categorize scans (Table): Grade “A-B” scans had 2-3.5mm slice thickness, at least 20 axial slices, no lung cropping in axial view and lung and airway volumes greater than the cohort-specific 1st percentile. “C-D” scans had one lung obscured by cropping around the heart, so quantitative measures were restricted to the lung in complete view. “F-H” scans were deemed unusable, suffering from low slice count (&lt;20), severe image cropping, low lung or airway volumes (&lt; 1st%ile). Visual inspection was performed on a sample from each category to ensure accuracy. Percent of lung voxels in low attenuation areas &lt; -950 HU (LAA950), high attenuation areas (-600 to -250 HU, HAA) and 15th percentile HU value (perc15) were measured. Within-participant variability was quantified using the intraclass correlation coefficient (ICC). RESULTS: We performed QC on cardiac CT scans from an initial sample of 6,275 participants from three C4R cohorts (ARIC, CARDIA, MASALA), imaged with GE or Siemens scanners. Of these, 5,125 (81.7%) were graded “A-B”, 496 (7.9%) were “C-D” and 654 (10.4%) were “F-H”. The percentage of “F-H” scans varied widely across cohorts [&lt;1% to 26%] due to image cropping. Among the 5,621 cardiac CT scans graded A-D, the mean±SD for LAA950, HAA and perc15 respectively were 1.1±2.1%, 7.2±4.7% and -887±33 HU. Repeated imaging was available for 107 participants (time interval 5.1±0.7y). For paired scans in grades A-B (n=101/107), the within-participant correlation for LAA950, HAA and perc15 were 0.91, 0.38 and 0.74 respectively. CONCLUSION: Initial application of QC to cardiac CT scans identified scans with high reproducibility, with the aim to provide valid quantitative lung metrics on over 20,000 highly characterized participants in C4R.

Abstract Rationale: The 7th World Symposium on Pulmonary Hypertension highlighted the importance of patient-reported outcomes in clinical assessment of pulmonary arterial hypertension (PAH). Patient-reported outcomes, such as health-related quality of life (HRQOL), have been associated with morbidity and mortality in PAH, but the added value of HRQOL measures to validated risk prediction models remains unknown. Methods: Adults with RHC-proven PAH from the Redefining Pulmonary Hypertension through Pulmonary Vascular Disease Phenomics (PVDOMICS) Study, a multi-center observational study, were included in this study. The Pulmonary Hypertension Association Registry (PHAR) was used as a validation cohort. HRQOL was measured using the emPHasis-10 score, where higher scores reflect worse HRQOL. Noninvasive risk assessment was measured by REVEAL Lite 2 risk score, categorized into 3-strata. Cox proportional hazard models were used to model survival evaluating the interaction between risk strata and HRQOL scores, adjusting for age, sex, and incident diagnosis. Harrell's C-statistics were calculated to compare discriminative performance. Results: From the PVDOMICS and PHAR cohorts, 265 and 2671 individuals with PAH and complete emPHasis-10 and REVEAL Lite 2 scores were included. Both cohorts had similar demographics, with an average age of 52±13 and 56±16 years, 75% and 72% female, 81% and 75% White, in the PVDOMICS and PHAR cohorts respectively. Over 87% of PVDOMICS were prevalent cases of PAH, while in the PHAR half were incident. Most individuals (62%) in PVDOMICS were REVEAL Lite 2 low risk, with 16% intermediate and 22% high risk; by contrast, in PHAR 33% were low, 29% intermediate, and 38% high risk. REVEAL Lite 2 scores demonstrated weak to moderate correlation with emPHasis-10 scores in both cohorts (PVDOMICS r=0.48 p&lt;0.001; PHAR r=0.33 p&lt;0.001). Notably, the full range of emPHasis-10 scores were observed in the low-risk individuals across both cohorts. In the PVDOMICS adjusted Cox models, higher emPHasis-10 scores predicted poorer survival (p=0.047) particularly among low-risk individuals (interaction versus high-risk group p=0.08). Similar adjusted models in PHAR demonstrated emPHasis-10 to be a confounder (p=0.001) without significant interaction by risk strata (low vs high-risk interaction p=0.94), but the greatest change in median survival time was observed in the low-risk group (Figure 1). Addition of emPHasis-10 to REVEAL Lite 2 scores improved discrimination in predicting survival (PVDOMICS: C-statistic 0.71 vs 0.73; PHAR: C-statistic 0.67 vs 0.69). Conclusions: Across two multicenter cohorts of incident and prevalent PAH, HRQOL as measured by the emPHasis-10 score improved discrimination for survival, particularly among individuals with lower risk scores.

Abstract Introduction Sex-based differences in morbidity and mortality for pulmonary hypertension (PH) are insufficiently addressed in current research. However, recognizing these differences is crucial for optimal clinical management and improving outcomes. This study assesses the effect of sex on survival among PH patients, while accounting for disease severity, comorbidities, treatment, and race. Methods We analyzed data from the PVRI GoDeep meta-registry, including all incident patients with complete hemodynamic profiles. Survival was evaluated using Kaplan-Meier and Cox proportional hazards models, adjusted for various confounders. Analyses included both PAH and non-PAH groups and risk assessment by the ESC/ERS 2022, REVEAL lite 2, and COMPERA 4-strata scores. All analyses were performed using R (The R Foundation). Results A total of 19,663 incident PH patients were included in the analysis, with 5,581 patients (28%) diagnosed with Group 1 PH and a median age of 64 years [IQR: 52-73]. Among these, male patients (8,704, 44%) had a significantly higher mortality risk than female patients across the entire cohort and within all PH subtypes. The adjusted hazard ratio for mortality in male versus female patients was 1.391 [95% CI: 1.260-1.536] in the overall population and 1.404 [95% CI: 1.264-1.561] for those with PAH. This survival difference was consistent across various severity levels, age groups, and in the presence of comorbidities such as obesity and cardiovascular diseases, as well as among those receiving PAH-specific therapies as well as patients who remained without treatment during the observation period. Notably, male disadvantage in survival was observed in low, intermediate, and high-risk categories for ESC/ERS 2022, REVEAL lite 2, and COMPERA scores but not within REVEAL 2.0, which includes male sex as a non-modifiable risk factor. Racial analysis revealed a greater mortality risk for males among White patients, with no significant differences noted in Black or Asian populations. Conclusion Our PVRI GoDeep meta-registry analysis demonstrates that male PH patients face higher mortality risk across both PAH and non-PAH groups, independent of disease etiology, age, severity, comorbidities, and treatment factors, with this risk amplified in White patients. These findings suggest that male sex should be further considered as a risk factor to refine predictive models for survival in PH.