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ImportanceThe population prevalence of cardiac transthyretin amyloidosis (ATTR) caused by pathogenic variation in the TTR gene (vATTR) is unknown.ObjectiveTo estimate the population prevalence of disease-causing TTR variants and evaluate associated phenotypes and outcomes.Design, Setting, and ParticipantsThis population-based cohort study analyzed UK Biobank (UKB) participants with whole-exome sequencing, electrocardiogram, and cardiovascular magnetic resonance data. Participants were enrolled from 2006 to 2010, with a median follow-up of 12 (IQR, 11-13) years (cutoff date for the analysis, March 12, 2024). Sixty-two candidate TTR variants were extracted based on rarity (minor allele frequency ≤0.0001) and/or previously described associations with amyloidosis if more frequent.ExposureCarrier status for TTR variants.Main Outcomes and MeasuresAssociations of TTR carrier status with vATTR prevalence and cardiovascular imaging and electrocardiogram traits were explored using descriptive statistics. Associations between TTR carrier status and atrial fibrillation, conduction disease, heart failure, and all-cause mortality were evaluated using adjusted Cox proportional hazards models. Genotypic and diagnostic concordance was examined using International Statistical Classification of Diseases, Tenth Revision codes from the hospital record.ResultsThe overall cohort included 469 789 UKB participants (mean [SD] age, 56.5 [8.1] years; 54.2% female and 45.8% male). A likely pathogenic/pathogenic (LP/P) TTR variant was detected in 473 (0.1%) participants, with Val142Ile being the most prevalent (367 [77.6%]); 91 individuals (0.02%) were carriers of a variant of unknown significance . The overall prevalence of LP/P variants was 0.02% (105 of 444 243) in participants with European ancestry and 4.3% (321 of 7533) in participants with African ancestry. The LP/P variants were associated with higher left ventricular mass indexed to body surface area (β = 4.66; 95% CI, 1.87-7.44), and Val142Ile was associated with a longer PR interval (β = 18.34; 95% CI, 5.41-31.27). The LP/P carrier status was associated with a higher risk of heart failure (hazard ratio [HR], 2.68; 95% CI, 1.75-4.12) and conduction disease (HR, 1.88; 95% CI, 1.25-2.83). Higher all-cause mortality risk was observed for non-Val142Ile LP/P variants (HR, 1.98; 95% CI, 1.06-3.67). Thirteen participants (2.8%) with LP/P variants had diagnostic codes compatible with cardiac or neurologic amyloidosis. Variants of unknown significance were not associated with outcomes.Conclusions and RelevanceThis study found that approximately 1 in 1000 UKB participants were LP/P TTR variant carriers, exceeding previously reported prevalence. The findings emphasize the need for clinical vigilance in identifying individuals at risk of developing vATTR and associated poor outcomes.

Abstract The management of acute myocarditis (AM) is addressed in multiple clinical guidelines. We systematically reviewed current guidelines developed by national and international medical organizations on the management of AM to aid clinical practice. Publications in MEDLINE, EMBASE and Cochrane were identified between 1 January 2013 and 12 April 2024. Additionally, the websites of relevant organizations and the Guidelines International Network, Guideline Central, and NHS knowledge and library hub were reviewed. Two reviewers independently screened titles and abstracts, two reviewers assessed the rigour of guideline development, and one reviewer extracted the recommendations. Two of the three guidelines identified showed good rigour of development. Those rigorously developed agreed on the definition of AM, sampling serum troponin as part of the workflow for AM, testing for B-type natriuretic peptides in heart failure, key diagnostic imaging in the form of cardiovascular magnetic resonance, coronary angiography to exclude significant coronary disease, indications for endomyocardial biopsy (EMB), and indications for immunosuppression and advanced treatment options. Discrepancies exist in sampling creatine kinase-myocardial bound as a marker of myocardial injury, indications for EMB, and indications for immunosuppression and treatment of uncomplicated AM. Evidence is lacking for the use of 18F-Fluorodeoxyglucose Positron Emission Tomography for myocardial imaging, exercise restriction, follow-up measures, and genetic testing, and there are few high-quality randomized trials to support treatment recommendations. Recommendations for management of AM in the guidelines have largely been developed from expert opinion rather than trial data.

AbstractINTRODUCTIONWell‐chosen biomarkers have the potential to increase the efficiency of clinical trials and drug discovery and should show good precision as well as clinical validity.METHODSWe suggest measures that operationalize these criteria and describe a general approach that can be used for inference‐based comparisons of biomarker performance. The methods are applied to measures obtained from structural magnetic resonance imaging (MRI) from individuals with mild dementia (n = 70) or mild cognitive impairment (MCI; n = 303) enrolled in the Alzheimer's Disease Neuroimaging Initiative.RESULTSVentricular volume and hippocampal volume showed the best precision in detecting change over time in both individuals with MCI and with dementia. Differences in clinical validity varied by group.DISCUSSIONThe methodology presented provides a standardized framework for comparison of biomarkers across modalities and across different methods used to generate similar measures and will help in the search for the most promising biomarkers.Highlights A framework for comparison of biomarkers on pre‐defined criteria is presented. Criteria for comparison include precision in capturing change and clinical validity. Ventricular volume has high precision in change for both dementia and mild cognitive impairment (MCI) trials. Imaging measures’ performance in clinical validity varies more for dementia than for MCI.

PURPOSE Although cure rates for childhood acute lymphoblastic leukemia (ALL) exceed 90%, ALL remains a leading cause of cancer death in children. Half of relapses arise in children initially classified with standard-risk (SR) disease. MATERIALS AND METHODS To identify genomic determinants of relapse in children with SR ALL, we performed genome and transcriptome sequencing of diagnostic and remission samples of children with SR (n = 1,381) or high-risk B-ALL with favorable cytogenetic features (n = 115) enrolled on Children's Oncology Group trials. We used a case-control study design analyzing 439 patients who relapsed and 1,057 who remained in complete remission for at least 5 years. RESULTS Genomic subtype was associated with relapse, which occurred in approximately 50% of cases of PAX5 -altered ALL (odds ratio [OR], 3.31 [95% CI, 2.17 to 5.03]; P = 3.18 × 10 –8 ). Within high-hyperdiploid ALL, gain of chromosome 10 with disomy of chromosome 7 was associated with favorable outcome (OR, 0.27 [95% CI, 0.17 to 0.42]; P = 8.02 × 10 –10 ; St Jude Children's Research Hospital validation cohort: OR, 0.22 [95% CI, 0.05 to 0.80]; P = .009), and disomy of chromosomes 10 and 17 with gain of chromosome 6 was associated with relapse (OR, 7.16 [95% CI, 2.63 to 21.51]; P = 2.19 × 10 –5 ; validation cohort: OR, 21.32 [95% CI, 3.62 to 119.30]; P = .0004). Genomic alterations were associated with relapse in a subtype-dependent manner, including alterations of INO80 in ETV6::RUNX1 ALL, IKZF1 , and CREBBP in high-hyperdiploid ALL and FHIT in BCR::ABL1 -like ALL. Genomic alterations were also associated with the presence of minimal residual disease, including NRAS and CREBBP in high-hyperdiploid ALL. CONCLUSION Genetic subtype, patterns of aneuploidy, and secondary genomic alterations determine risk of relapse in childhood ALL. Comprehensive genomic analysis is required for optimal risk stratification.

Background: Little is known about the relationship between neighborhood disadvantage and neuromyelitis optica spectrum disorder (NMOSD) outcomes. Objective: The objective is to determine the impact of neighborhood disadvantage on time from symptom onset to diagnosis and annualized relapse rate (ARR). Methods: Neighborhood disadvantage were captured with the Area Deprivation Index (ADI), a validated measure of neighborhood-level disadvantage. Negative binomial regression models assessed the impact of ADI on diagnostic delay (⩾3 months between symptom onset and diagnosis) and ARR. Results: A total of 158 NMOSD patients were identified, a majority of whom were White (56.3%) and female (89.9%) with a mean age of 46 years at diagnosis. The ADI did not significantly affect odds of diagnostic delay (odds ratio (OR) = 0.99, p = 0.26). In univariable models, the ADI was not significantly associated with ARR (OR = 1.004, p = 0.29), but non-White race (OR = 1.541, p = 0.02) and time on immunosuppressive therapies (ISTs; OR = 0.994, p = 0.03) were. White patients used IST for an average of 81% of the follow-up period, compared to an average of 65% for non-White patients ( p < 0.01). Conclusion: No significant relationship between neighborhood-level disadvantage and diagnostic delay or ARR in NMOSD patients was observed. Non-White patients had a higher ARR, which may be related to less IST use.

Strategies to bring clinical trials closer to patients gained momentum during the COVID-19 pandemic, enabling more participants to receive treatment and/or testing in their local communities. Incorporation of decentralized trial elements presents both opportunities and challenges, spanning regulatory, technical, and operational aspects. This ASCO research statement includes timely consensus-driven recommendations and a call for engagement of all research stakeholders. ASCO held multistakeholder meetings with leaders in oncology research and concluded that research-related regulatory and administrative requirements and burdens present critical barriers to decentralizing trials. One example is sponsor and contract research organization (CRO) use of US Food and Drug Administration (FDA)'s Statement of Investigator (Form 1572), which was found to exceed FDA's stated intent and used in conservative ways disproportionate to potential risks to participants and scientific integrity. As a result, research sites experience an avalanche of downstream administrative and regulatory activities that consume considerable resources. This statement recommends four key solutions to address such barriers and recalibrate regulatory and administrative expectations for decentralizing trials: (1) FDA should engage the research community in a public-private partnership to modernize standards and enable local access to trials; (2) sponsors and CROs should develop standards and protocols that accommodate flexible approaches, enable local participation, provide clarity around roles and requirements, and promote consistency; (3) research centers, networks, and sites should update policies and procedures to implement decentralized trial elements; and (4) research community should develop a streamlined, uniform mechanism to simplify regulatory data collection and documentation and use it consistently across trials. We can and must prioritize a concerted commitment to simplify and streamline regulatory requirements and practices to broaden access to and participation in cancer clinical trials.

AbstractThe present study investigated the impact of central α2‐adrenergic mechanisms on sympathetic action potential (AP) discharge, recruitment and latency strategies. We used the microneurographic technique to record muscle sympathetic nerve activity and a continuous wavelet transform to investigate postganglionic sympathetic AP firing during a baseline condition and an infusion of a α2‐adrenergic receptor agonist, dexmedetomidine (10 min loading infusion of 0.225 µg kg−1; maintenance infusion of 0.1–0.5 µg kg h−1) in eight healthy individuals (28 ± 7 years, five females). Dexmedetomidine reduced mean pressure (92 ± 7 to 80 ± 8 mmHg, P < 0.001) but did not alter heart rate (61 ± 13 to 60 ± 14 bpm; P = 0.748). Dexmedetomidine reduced sympathetic AP discharge (126 ± 73 to 27 ± 24 AP 100 beats−1, P = 0.003) most strongly for medium‐sized APs (normalized cluster 2: 21 ± 10 to 5 ± 5 AP 100 beats−1; P < 0.001). Dexmedetomidine progressively de‐recruited sympathetic APs beginning with the largest AP clusters (12 ± 3 to 7 ± 2 clusters, P = 0.002). Despite de‐recruiting large AP clusters with shorter latencies, dexmedetomidine reduced AP latency across remaining clusters (1.18 ± 0.12 to 1.13 ± 0.13 s, P = 0.002). A subset of six participants performed a Valsalva manoeuvre (20 s, 40 mmHg) during baseline and the dexmedetomidine infusion. Compared to baseline, AP discharge (Δ 361 ± 292 to Δ 113 ± 155 AP 100 beats−1, P = 0.011) and AP cluster recruitment elicited by the Valsalva manoeuvre were lower during dexmedetomidine (Δ 2 ± 1 to Δ 0 ± 2 AP clusters, P = 0.041). The reduction in sympathetic AP latency elicited by the Valsalva manoeuvre was not affected by dexmedetomidine (Δ –0.09 ± 0.07 to Δ –0.07 ± 0.14 s, P = 0.606). Dexmedetomidine reduced baroreflex gain, most strongly for medium‐sized APs (normalized cluster 2: –6.0 ± 5 to –1.6 ± 2 % mmHg−1; P = 0.008). These data suggest that α2‐adrenergic mechanisms within the central nervous system modulate sympathetic postganglionic neuronal discharge, recruitment and latency strategies in humans. imageKey points Sympathetic postganglionic neuronal subpopulations innervating the human circulation exhibit complex patterns of discharge, recruitment and latency. However, the central neural mechanisms governing sympathetic postganglionic discharge remain unclear. This microneurographic study investigated the impact of a dexmedetomidine infusion (α2‐adrenergic receptor agonist) on muscle sympathetic postganglionic action potential (AP) discharge, recruitment and latency patterns. Dexmedetomidine infusion inhibited the recruitment of large and fast conducting sympathetic APs and attenuated the discharge of medium sized sympathetic APs that fired during resting conditions and the Valsalva manoeuvre. Dexmedetomidine infusion elicited shorter sympathetic AP latencies during resting conditions but did not affect the reductions in latency that occurred during the Valsalva manoeuvre. These data suggest that α2‐adrenergic mechanisms within the central nervous system modulate sympathetic postganglionic neuronal discharge, recruitment and latency strategies in humans.

Abstract Multiple guidelines exist for the diagnosis and management of heart failure with preserved ejection fraction (HFpEF). We systematically reviewed current guidelines and recommendations, developed by national and international medical organizations, on the management of HFpEF in adults to aid clinical decision-making. We searched MEDLINE and EMBASE on 28 February 2024 for publications over the last 10 years as well as websites of organizations relevant to guideline development. Of the 10 guidelines and recommendations retrieved, 7 showed considerable rigour of development and were subsequently retained for analysis. There was consensus on the definition of HFpEF and the diagnostic role of serum natriuretic peptides and resting transthoracic echocardiography. Discrepancies were identified in the thresholds of serum natriuretic peptides and transthoracic echocardiography parameters used to diagnose HFpEF. There was agreement on the general pharmacological and supportive management of acute and chronic HFpEF. However, differences exist in strategies to identify and address specific phenotypes. Contemporary guidelines for HFpEF management agree on measures to avoid its development and the consideration of cardiac transplantation in advanced diseases. There were discrepancies in recommended frequency of surveillance for patients with HFpEF and sparse recommendations on screening for HFpEF in the general population, use of diagnostic scoring systems, and the role of newly emerging therapies.

Diploid human cells contain two non-identical genomes, and differences in their regulation underlie human development and disease. We present Fiber-seq Inferred Regulatory Elements (FIRE) and show that FIRE provides a more comprehensive and quantitative snapshot of the accessible chromatin landscape across the 6 Gbp diploid human genome, overcoming previously unrecognized biases in existing regulatory element catalogs. FIRE enables comprehensive detection of haplotype-selective chromatin accessibility (HSCA), exposing novel imprinted elements lacking underlying parent-of-origin CpG methylation differences, and gene regulatory modules that permit genes to escape X chromosome inactivation. We uncover that the human leukocyte antigen (HLA) locus harbors the most HSCA in immune cells, where we resolve specific transcription factor (TF) binding events disrupted by disease-associated variants. Finally, we demonstrate that the regulatory landscape of a cell is littered with autosomal somatic chromatin epimutations that are propagated by clonal expansions to create mitotically stable and non-genetically deterministic chromatin alterations.

3053 Background: Recently, early studies have identified circulating stromal cells (CStCs), i.e. Cancer Associated Macrophage-Like cells (CAMLs), in patients (pts) with newly diagnosed invasive cancers, which are phagocytic myeloid immune cells emanating from primary tumors. However, no study has evaluated CAMLs as a pan solid tumor screening tool nor their clinical impact on pt outcomes. We analyzed the blood of untreated newly diagnosed cancer pts (n=441), or in non-malignant conditions (i.e. pancreatic cysts, n=77), or healthy controls (n=100). We found that CAMLs are prevalent (82%) in cancer pt blood, absent in healthy controls (0%) and less common in non-malignant conditions (36%), with correlations to worse clinical outcomes. Methods: Anonymized peripheral blood was taken from n=441 pts before or after confirmation of invasive malignancy [stage I (n=105), stage II (n=125), stage III (n=114), stage IV (n=97) with pathologically confirmed lung (n=84), pancreas (n=61), breast (n=73), prostate (n=65), esophageal (n=34), Renal Cell (n=29), Sarcoma (n=27), or Other (n=68). In addition, anonymized blood was taken from pts with untreated non-malignant conditions including benign breast masses (n=19), Lupus (n=11), liver Cirrhosis (n=6), rising PSA (n=24), or other benign mass (n=17); and from healthy control volunteers (n=100). CAMLs were isolated by CellSieve microfiltration, defined as enlarged polyploid cells with cytokeratin+ and/or CD45/CD14+. Pts were monitored for 0-8 years (median=2.6) for progression free survival (PFS) and overall survival (OS). Results: CAMLs were found in 82% of all cancer pts averaging 5.4 CAMLs, specifically, in 66% of Stage I, 85% Stage II, 84% Stage III, and 92% Stage IV. No CAMLs were found in any healthy controls, but were in 36% of non-malignant pts. CAML sensitivity in cancer vs healthy was 82% (CI95% 78-85%), specificity=100% (CI95% 96-100%), PPV=100% (CI95% 99-100%), NPV=55% (CI95% 50-60%). CAML sensitivity in cancer vs benign was 82% (CI95% 78-85%), specificity=64% (CI95% 32-44%), PPV=93% (CI95% 90-95%), NPV=38% (CI95% 32-44%). CAML presence was significantly associated with worse PFS (HR=2.0, 95%CI 1.4-2.9, p<0.0001) & OS (HR=2.2, 95%CI 1.4-3.3, p=0.0004), with engorged phagocytic CAMLs (>50um), highly significant for worse PFS (HR=3.3, 95%CI 2.5-4.5, p<0.0001) & OS (HR=3.0, 95%CI 2.1-4.3, p<0.0001). Further, in benign pts positive for CAMLs, 2 pts were in situ, 16 had histologies with increased cancer risk (i.e. IPMN, atypical hyperplasia), and 5 pts died within 3 years. Conclusions: CAMLs appear to be a highly sensitive blood based biomarker that can identify invasive carcinoma in all stages of cancer regardless of subtype, but are not found in healthy controls & rare in non-malignant conditions. Further, enlarged phagocytic CAMLs appeared to correlate with shorter PFS and OS prior to treatment induction.