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Abstract Background Guidelines suggest that the diagnosis of acute myocardial infarction (MI) is likely when high concentrations of high-sensitivity cardiac troponin (hs-cTn) are present in the initial sample. These concentration thresholds are much higher than the 99th percentile and are said to provide a high positive predictive value (PPV) for acute MI1. Purpose Evaluate the PPV of recommended baseline hs-cTnT thresholds (>52 and >100 ng/L) for the diagnosis of acute MI from our multi-center United States (US) experience. Methods Retrospective, multicenter (n=22), observational biomarker study involving consecutive, adult patients presenting to the emergency department (ED) in whom at least 1 hs-cTnT measurement was obtained within 12 hours of presentation (CV DataMart Biomarker cohort). The primary endpoint was also evaluated in an adjudicated cohort of consecutive patients presenting to the ED with at least 1 hs-cTnT >99th percentile (ACTION cohort). These cases were adjudicated based on the Fourth Universal Definition of MI by trained physicians. The primary efficacy endpoint was the PPV of acute MI (type 1 or 2), type 1 MI and type 2 MI during index hospitalization using baseline hs-cTnT thresholds of >52 ng/L and >100 ng/L. Results The CV DataMart Biomarker cohort consisted of 143,709 patients, amongst whom 3,003 (2.1%) were diagnosed with acute MI using ICD codes. In the CV DataMart Biomarker cohort, baseline hs-cTnT concentrations of >52 ng/L and >100 ng/L resulted in PPVs of 12% (95% CI: 11, 12) and 17% (95% CI: 17, 19) for acute MI, respectively. In patients with chest pain and baseline hs-cTnT concentrations >52 ng/L, PPV for acute MI was 17% (95% CI: 15, 18), and in those with hs-cTnT concentrations >100 ng/L, PPV was 22% (95% CI: 19, 25). The adjudicated ACTION cohort consisted of 2,107 patients, amongst whom 155 (7.4%) were diagnosed with acute MI including 64 (41%) with type 1 MI and 91 (59%) with type 2 MI. In the ACTION cohort, baseline hs-cTnT concentrations of >52 ng/L and >100 ng/L resulted in PPVs of 46% (95% CI: 40, 53) and 62% (95% CI: 53, 70) for acute MI, respectively. In patients with chest pain and baseline hs-cTnT concentrations >52 ng/L, PPV was 67% (95% CI: 57, 76) for acute MI, 52% (95% CI: 41, 62) for type 1 MI and 15% (95% CI: 8.4, 24) for type 2 MI. In those with chest pain and baseline hs-cTnT concentrations >100 ng/L, PPV was 77% (95% CI: 65, 87) for acute MI, 64% (95% CI: 51, 75) for type 1 MI and 14% (95% CI 6.4, 24) for type 2 MI (Figure). Conclusion Using previously recommended high-risk hs-cTnT thresholds of 52 and 100 ng/L in US patients provides reasonable performance to rule-in acute MI when used in patients with chest pain. When used more broadly across all-comers, the diagnostic performance is poor.

Abstract Rationale Follow-up of patients with emphysema treated with endobronchial valves is limited to 3–12 months after treatment in prior reports. To date, no comparative data exist between treatment and control subjects with a longer follow-up. Objectives To assess the durability of the Spiration Valve System (SVS) in patients with severe heterogeneous emphysema over a 24-month period. Methods EMPROVE, a multicenter randomized controlled trial, presents a rigorous comparison between treatment and control groups for up to 24 months. Lung function, respiratory symptoms, and quality-of-life (QOL) measures were assessed. Results A significant improvement in forced expiratory volume in 1 second was maintained at 24 months in the SVS treatment group versus the control group. Similarly, significant improvements were maintained in several QOL measures, including the St. George’s Respiratory Questionnaire and the COPD Assessment Test. Patients in the SVS treatment group experienced significantly less dyspnea than those in the control group, as indicated by the modified Medical Research Council dyspnea scale score. Adverse events at 24 months did not significantly differ between the SVS treatment and control groups. Acute chronic obstructive pulmonary disease exacerbation rates in the SVS treatment and control groups were 13.7% (14 of 102) and 15.6% (7 of 45), respectively. Pneumothorax rates in the SVS treatment and control groups were 1.0% (1 of 102) and 0.0% (0 of 45), respectively. Conclusions SVS treatment resulted in statistically significant and clinically meaningful durable improvements in lung function, respiratory symptoms, and QOL, as well as a statistically significant reduction in dyspnea, for at least 24 months while maintaining an acceptable safety profile. Clinical trial registered with www.clinicaltrials.gov (NCT01812447).

PURPOSE Hepatocellular carcinoma (HCC), the fourth most common cancer in Africa, has a dismal overall survival of only 3 months like in sub-Saharan Africa. This is affected by the low gross domestic product and human development index, absence of coherent guidelines, and other factors. METHODS An open forum for HCC-experienced health care workers from Africa and the rest of the world was held in October 2021. Participants completed a survey to help assess the real-life access to screening, diagnoses, and treatment in the North and Southern Africa (NS), East and West Africa (EW), Central Africa (C), and the rest of the world. RESULTS Of 461 participants from all relevant subspecialties, 372 were from Africa. Most African participants provided hepatitis B vaccination and treatment for hepatitis B and C. More than half of the participants use serum alpha-fetoprotein and ultrasound for surveillance. Only 20% reported using image-guided diagnostic liver biopsy. The Barcelona Clinic Liver Cancer is the most used staging system (52%). Liver transplant is available for only 28% of NS and 3% EW. C reported a significantly lower availability of resection. Availability of local therapy ranged from 94% in NS to 62% in C. Sorafenib is the most commonly used systemic therapy (66%). Only 12.9% reported access to other medications including immune checkpoint inhibitors. Besides 42% access to regorafenib in NS, second-line treatments were not provided. CONCLUSION Similarities and differences in the care for patients with HCC in Africa are reported. This reconfirms the major gaps in access and availability especially in C and marginally less so in EW. This is a call for concerted multidisciplinary efforts to achieve and sustain a reduction in incidence and mortality from HCC in Africa.

201 Background: Cancer-related mortality is disproportionately higher in marginalized populations, necessitating adequate representation in cancer clinical trials. Historically, this goal has been challenging, despite recognition of the importance for clinical practice. Moreover, minority recruitment has decreased in oncology clinical trials published from 2003-2016, indicating an urgent need for effective interventions for this issue. Methods: We conducted a systematic review of interventions focused on increasing minority recruitment/retention in cancer clinical trials between 2012-2023, or on improving attitudes of minority groups towards enrollment. We queried Embase and Scopus databases for articles/abstracts that focused on underrepresented ethnic minority enrollment in cancer clinical trials, in English language, were conducted in the US, Canada, Australia, New Zealand, or Western Europe, and were investigating effectiveness of interventions to improve minority enrollment in adult populations. Results: 261 unique articles/abstracts met our search criteria, with an additional 55 duplicates. 117 were removed for being irrelevant or too old, 31 for being reviews, 85 due to not containing an intervention, 5 for not reporting minority data, and 6 for not adequately comparing the strength of interventions. 17 met all inclusion criteria. Several interventions were identified, including targeted patient education (n=7), assigning patient navigators (n=6), community organization engagement (n=3), nested family/community approaches (n=2), and financial assistance (n=1). Targeted education involved video, audio, or interactive mediums. Most studies involved Black (n=12) and Hispanic (n=5) populations, with a smaller number focusing on Asian/Asian Pacific Islanders (n=2), Arabs (n=1), and Indian/South Asians (n=1). Geographically, these studies were notably concentrated in the American South (n=7). The Midwest and Mid-Atlantic regions contributed equally (n=3 each), and fewer studies were from the Northeast and West (n=2 each). Conclusions: Racial minorities continue to be underrepresented in cancer clinical trials, underscoring the need for concerted efforts to promote healthcare equity and enhance these trials’ generalizability. In our systematic review, targeted education, patient navigators, and active community engagement emerged as efficacious strategies, and were the most frequently utilized to bolster minority enrollment. Future studies should prioritize investigating and implementing these interventions, to ensure diverse, representative, and applicable clinical trial participation.

191 Background: ANC is used to determine the dosing of chemotherapy and eligibility in clinical trials. Duffy-null phenotype is associated with a lower ANC and present in 2/3 of the Black population. Therefore, ANC reference intervals from hospitals serving a larger percentage (%) of Black population are expected to be lower. Ideally, reference intervals should represent the normal values of the population served. The objective of this study is to determine if the ANC reference intervals of hospitals in the US are representative of the population served based on racial diversity. Methods: We obtained hospital ANC reference intervals from the Mayo Clinic EPIC electronic medical records Care Everywhere health information exchange. Reference intervals from 2020-2023 were included. For each hospital, we determined the city where it is located. For each city, the % of Black population was obtained from the 2020 US Census. We studied the correlation (Pearson) between reference ANC values and % of Black population. To determine the expected ANC reference intervals, we obtained ANC data from the 2021-2022 National Health and Nutrition Examination Survey (NHANES) and performed a reference interval simulation study. Individuals with cancer and cirrhosis were excluded. Random samples of 120 individuals were selected, consisting of n samples from Black individuals and 120-n samples from non-Black individuals. This was performed for n from 0 to 120, and repeated 1000 times per n. Results: We collected data from 107 hospitals across 40 states and 81 cities. Fifty-three (49.5%) hospitals were academic. The % of Black populations in the cities served by the hospitals was a mean of 23.4% (range, 0.7%-82.8%). There was no correlation between ANC upper (r = -0.17, p=0.07) and lower (r = 0.01, p=0.88) limits based on the % Black population. This finding was similar in both academic and non-academic hospitals. Assessment of the ANC distribution in the US population based on race by using the NHANES database showed a clear association with race at the 2.5th (p<0.001) and 97.5th (p=0.009) percentiles with an overall estimated mid-95% reference range of 2.0-8.3 for non-Black individuals and 1.3-7.7 for Black individuals. Conclusions: Hospitals serving a higher % of Black population have similar upper and lower ANC reference intervals compared to those serving a lower % of Black population. This contrasts with the findings from NHANES data which showed significant variations in the normal ANC values between Black and non-Black individuals. Therefore, current hospital ANC reference intervals may not represent the diversity of the population served. Potential clinical implications include misdiagnosis of neutropenia, delay or underdosing of chemotherapy, and inappropriate exclusion in clinical trials, especially in areas with a high % of Black population.

ABSTRACT The rapid pace of name changes of medically important fungi is creating challenges for clinical laboratories and clinicians involved in patient care. We describe two sources of name change which have different drivers, at the species versus the genus level. Some suggestions are made here to reduce the number of name changes. We urge taxonomists to provide diagnostic markers of taxonomic novelties. Given the instability of phylogenetic trees due to variable taxon sampling, we advocate to maintain genera at the largest possible size. Reporting of identified species in complexes or series should where possible comprise both the name of the overarching species and that of the molecular sibling, often cryptic species. Because the use of different names for the same species will be unavoidable for many years to come, an open access online database of the names of all medically important fungi, with proper nomenclatural designation and synonymy, is essential. We further recommend that while taxonomic discovery continues, the adaptation of new name changes by clinical laboratories and clinicians be reviewed routinely by a standing committee for validation and stability over time, with reference to an open access database, wherein reasons for changes are listed in a transparent way.

Mendelian randomization has become a popular tool to assess causal relationships using existing observational data. While randomized controlled trials are considered the gold standard for establishing causality between exposures and outcomes, it is not always feasible to conduct a trial. Mendelian randomization is a causal inference method that uses observational data to infer causal relationships by using genetic variation as a surrogate for the exposure of interest. Publications using the approach have increased dramatically in recent years, including in the field of hepatology. In this concise review, we describe the concepts, assumptions, and interpretation of Mendelian randomization as related to studies in hepatology. We focus on the strengths and weaknesses of the approach for a non-statistical audience, using an illustrative example to assess the causal relationship between body mass index and NAFLD.

BACKGROUND: Heart failure with preserved ejection fraction is associated with significant functional limitations, yet treatments for improving exercise performance have been elusive. We sought to explore the association between prespecified patient characteristics and changes in 6-minute walk distance that constitute a clinically significant response to dapagliflozin. METHODS: We performed a responder analysis to understand patient characteristics associated with clinically meaningful improvement in 6-minute walk test (6MWT) distance ≥15 m among patients randomized to 12 weeks of dapagliflozin versus placebo in the double-blind PRESERVED-HF trial (Effects of Dapagliflozin on Biomarkers, Symptoms and Functional Status in Patients With Preserved Ejection Fraction Heart Failure). RESULTS: A total of 289 randomized patients had 6MWT distance completed at baseline and 12 weeks. Patients randomized to dapagliflozin improved walking distance by ≥15 m more frequently than those on placebo (n=64, 44% versus n=48, 34%). After adjusting for baseline covariates, patients randomized to dapagliflozin were more likely to experience a clinically meaningful improvement in 6MWT distance compared with those that received placebo (adjusted odds ratio, 1.66 [95% CI, 1.00–2.75]; P =0.05). Dapagliflozin-treated patients were also less likely to have a ≥15 m reduction in 6MWT distance compared with placebo-treated patients (adjusted odds ratio, 0.56 [95% CI, 0.33–0.94]; P =0.03). These results were consistent across all prespecified subgroups (all P values for interaction were not significant). CONCLUSIONS: Compared with those on placebo, patients with heart failure with preserved ejection fraction randomized to dapagliflozin were more likely to experience a clinically meaningful improvement and less likely to experience a deterioration in physical function over 12 weeks as measured by 6MWT distance. Beneficial response to dapagliflozin was consistent across prespecified subgroups. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03030235.

Abstract The Human Phenotype Ontology (HPO) is a widely used resource that comprehensively organizes and defines the phenotypic features of human disease, enabling computational inference and supporting genomic and phenotypic analyses through semantic similarity and machine learning algorithms. The HPO has widespread applications in clinical diagnostics and translational research, including genomic diagnostics, gene-disease discovery, and cohort analytics. In recent years, groups around the world have developed translations of the HPO from English to other languages, and the HPO browser has been internationalized, allowing users to view HPO term labels and in many cases synonyms and definitions in ten languages in addition to English. Since our last report, a total of 2239 new HPO terms and 49235 new HPO annotations were developed, many in collaboration with external groups in the fields of psychiatry, arthrogryposis, immunology and cardiology. The Medical Action Ontology (MAxO) is a new effort to model treatments and other measures taken for clinical management. Finally, the HPO consortium is contributing to efforts to integrate the HPO and the GA4GH Phenopacket Schema into electronic health records (EHRs) with the goal of more standardized and computable integration of rare disease data in EHRs.