Citations

ImportanceThe advanced ambulatory heart failure (HF) population comprises patients who have progressed beyond the pillars of recommended stage C HF therapies but can still find meaningful life-years ahead. Although these patients are commonly encountered in practice, national databases selectively capture the small groups accepted for heart transplant listing or left ventricular assist devices. The epidemiology, trajectories, and therapies for other ambulatory patients with advanced HF are poorly understood.ObservationsIn December 2022, the National Heart, Lung and Blood Institute convened a team of experts to identify knowledge gaps and research priorities for the ambulatory population with limiting daily symptoms and transition toward refractory end-stage D HF, designated as stage C2D. This article summarizes the findings from that 3-day workshop. Workshop participants surveyed the initial challenges and knowledge gaps for (1) recognition of ambulatory C2D HF, (2) estimation of the magnitude of the affected population and identifiable subpopulations, and (3) physiologic phenotypes, such as low cardiac output, right HF, cardiorenal syndromes, congestive hepatopathy and frailty, which offer distinct targets for existing and emerging therapies. Social drivers of HF and patient preferences for quality/length of survival were highlighted as essential modifiers for personalization of therapies.Conclusions and RelevanceTen key points summarized workshop findings, with target cohorts for study proposed as a crucial next step. This workshop summary is intended as a call for action to address knowledge gaps and develop new strategies to improve outcomes in the large ambulatory population with C2D HF.

Abstract Background Incorporating image guidance into ion beam therapy is critical for minimizing beam range uncertainties and realizing the modality's potential. One promising avenue for image guidance is to capture transmission ion radiographs (iRads) before and/or during treatment. iRad image quality is typically maximized using a single‐event imaging system, which involves tracking individual ions, albeit the approach is generally not suited to clinical beam settings. An alternative faster and clinically compatible method is integrated mode imaging, where individual pencil beam data is acquired, rather than single ion data. To evaluate the usefulness of transmission ion imaging for image guidance, it is crucial to evaluate the image quality of integrated mode iRad systems. Purpose We report extensive image quality metrics of integrated mode carbon ion radiographs (cRads) and compare them with proton radiographs (pRads). Methods iRads were obtained at the Marburg Ion Beam Therapy Center using a plastic volumetric scintillator equipped with CCD cameras. The detector captures orthogonal views of the 3D energy deposition in the scintillator from individual pencil beams. Four phantoms were scanned using a field of view and a beam spacing of 1 mm. First, 9 tissue‐substitute inserts were used to evaluate water equivalent thickness (WET) accuracy. Radiographs of those inserts were reconstructed for beam spacings ranging from 1 to 7 mm to evaluate the impact of spacing on quantitative accuracy. For spatial resolution, custom 3D printed line pair (lp) modules ranging from 0.5 to 10 lp/cm were scanned. To evaluate low contrast detectability, a custom 3D printed low contrast module consisting of 20 holes with depths ranging from 1 to 8 mm and diameters from 1 to 10 mm was scanned. iRads of an anthropomorphic head phantom were also obtained. Results Spatial resolution and low contrast detection are systematically improved for cRads compared to pRads. Image resolution was 3.7 lp/cm for cRads and 1.7 lp/cm for pRads in the center of the field of view. Spatial resolution was found to vary with the object's location in the field of view. While pRads could mostly resolve low contrast holes of 10 mm in diameter, cRads could resolve holes of up in 4 mm diameter. WET accuracy is similar for both ion species, with a root mean squared error of approximately 1 mm. WET accuracy was stable (maximum of 0.1 mm increase) across beam spacings, although important under‐sampling artifacts were observed for iRads reconstructed using large beam spacings, especially for cRads. iRads of the anthropomorphic head phantom showed improved apparent contrast using cRads, especially to identify bony structures. Conclusions This work is the first investigation of image quality metrics such as spatial resolution and low contrast detectability for integrated mode cRads, with a full comparison with pRads. Enhanced image quality is obtained with cRads compared to pRads, although pRads still maintain high WET accuracy and deliver image quality within acceptable bounds.

Abstract We present a comprehensive global analysis of genetic variants associated with autosomal-dominant Alzheimer’s disease (ADAD). A total of 550 variants in the APP, PSEN1 and PSEN2 genes were identified, of which 279 were classified as pathogenic or likely pathogenic based on American College of Medical Genetics and Genomics and the Association for Molecular Pathology criteria, utilizing data from the Dominantly Inherited Alzheimer Network (DIAN), literature and public databases. Symptomatic age at onset (AAO) data were estimated for 227 of these variants, allowing detailed characterization of their frequency, pathogenicity and AAO. Importantly, 226 variants met eligibility criteria for inclusion in disease-modifying clinical trials. Furthermore, we demonstrated the predictive value of mean variant AAO and parental AAO in predicting symptomatic AAO, validated against converters who became symptomatic during follow-up in the DIAN Observational Study. This dataset provides critical insights into the global landscape of ADAD and reveals the genetic and AAO heterogeneity of ADAD variants while refining variant trial eligibility criteria.

Abstract Background and Aims Patients with inflammatory bowel disease (IBD) face increased risk of colorectal cancer (CRC). While the natural history of conventional dysplastic precursor lesions has been well-studied, the neoplastic potential of recently described nonconventional (NC) IBD-associated colonic mucosal lesions is unclear. We aimed to assess the incidence of antecedent NC lesions in patients with IBD who developed CRC. Methods A case-cohort study was performed to include patients with a diagnosis of IBD with or without CRC who underwent at least 2 surveillance endoscopic procedures at our institution between 1/1/2007 and 5/31/2023. NC lesions included serrated change and indefinite for dysplasia. Detection rates pre- and post-introduction of high-definition (HD) surveillance colonoscopy were compared. Results In total, 87 patients with IBD and CRC and 200 patients with IBD without CRC were identified. Of the cases, a majority had ulcerative colitis (n = 52, 60%), most commonly with extensive involvement (n = 46, 89%). Conventional (hazard ratio [HR] 2.18, 95% confidence interval [CI] 1.34-3.52) and NC (HR 2.28, 95% CI 1.59-3.26) lesions were associated with increased risk of CRC. Conventional lesions in the post-HD era appeared to have a stronger association with CRC (HR 2.79, 95% CI 1.62-4.77) than NC lesions (HR 1.62, 95% CI 0.86-3.06). Conclusions Both conventional and NC lesions seem to be associated with increased risk of CRC. Conventional lesions are more strongly associated with CRC than NC lesions in the post-HD era, but misclassifications in the pre-HD era may have resulted in a biased increased risk estimate for NC lesions.

Background The immune response to infections may become dysregulated and promote myocardial damage contributing to heart failure (HF). We examined the relationship between infection‐related hospitalization (IRH) and HF, HF with preserved ejection fraction, and HF with reduced ejection fraction. Methods and Results We studied 14 468 adults aged 45 to 64 years in the ARIC (Atherosclerosis Risk in Communities) Study who were HF free at visit 1 (1987–1989). IRH was identified using select International Classification of Diseases ( ICD ) codes in hospital discharge records and was treated as a time‐varying exposure. HF incidence was defined as the first occurrence of either a hospitalization that included an ICD, Ninth Revision ( ICD‐9 ) discharge code of 428 (428.0–428.9) among the primary or secondary diagnoses or a death certificate with an ICD‐9 code of 428 or an ICD, Tenth Revision ( ICD‐10 ) code of I50 among any of the listed diagnoses or underlying causes of death. We used multivariable‐adjusted Cox proportional hazards models to assess the association between IRH and incident HF, HF with reduced ejection fraction, and HF with preserved ejection fraction. Median follow‐up time was 27 years, 55% were women, 26% were Black, mean age at baseline was 54±6 years, 46% had an IRH, and 3565 had incident HF. Hazard ratio (HR) for incident HF events among participants who had an IRH compared with those who did not was 2.35 (95% CI, 2.19–2.52). This relationship was consistent across different types of infections. Additionally, IRH was associated with both HF with reduced ejection fraction and HF with preserved ejection fraction: 1.77 (95% CI, 1.35–2.32) and 2.97 (95% CI, 2.36–3.75), respectively. Conclusions IRH was associated with incident HF, HF with reduced ejection fraction, and HF with preserved ejection fraction. IRH might represent a modifiable risk factor for HF pathophysiology.