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Abstract Introduction: A multi-cancer early detection (MCED) test as a complement to existing screening tests could increase the number of cancer cases detected in a population, potentially improving patient outcomes and survival as well as decreasing harmful and aggressive treatments. The Circulating Cell-free Genome Atlas study (CCGA; NCT02889978) was designed to develop and validate a blood-based MCED test analyzing plasma cell-free DNA (cfDNA) to detect cancer signals across multiple cancer types and simultaneously predict their signal origin. Here, the results of the third and final pre-specified CCGA validation sub-study for a refined MCED test in a large cohort in preparation for clinical use are reported. Methods: CCGA is a prospective, multicenter, case-control, observational study with longitudinal follow-up (overall population N=15,254). In this sub-study (n=5309), key primary objectives were to evaluate test performance for cancer signal detection (specificity, overall sensitivity, sensitivity by clinical stage) and signal origin prediction (accuracy). cfDNA from evaluable samples was analyzed using a targeted methylation bisulfite sequencing assay and a machine learning algorithm. The classifier was trained to target a specificity of 99.4% and locked before analysis of the independent validation set. Overall, 4077 participants comprised the independent validation set with confirmed status (cancer: n=2823; non-cancer: n=1254 with non-cancer status confirmed at year-one follow-up). MCED test results are reported for this confirmed status set. Results: Mean (SD) age in the cancer and non-cancer groups was 62.6 (11.76) and 56.2 (12.63) years, respectively. Specificity for cancer signal detection was 99.5% (1248/1254; 95% confidence interval: 99.0-99.8%). Overall sensitivity for cancer signal detection was 51.5% (1453/2823; 49.6-53.3%); sensitivity increased with stage (Stage I: 16.8% [14.5-19.5%], Stage II: 40.4% [36.8-44.1%], Stage III: 77.0% [73.4-80.3%], Stage IV: 90.1% [87.5-92.2%]). Stage I-III sensitivity was 67.6% (593/877; 64.4-70.6%) in a pre-specified set of 12 high-signal cancers accounting for ~63% of annual US cancer deaths [1] and was 40.7% (863/2118; 38.7-42.9%) in all cancers. Cancer signals were detected across >50 cancer types [2]. Overall accuracy of signal origin prediction in true positives was 88.7% (87.0-90.2%). Conclusions: In this pre-specified, large-scale, clinical validation sub-study of CCGA, the MCED test detected cancer signals across >50 cancer types, which is critical to maximize the number of cancer cases detected in a population. This MCED test performed with high specificity and high accuracy of signal origin prediction. These data lay the foundation for population-scale clinical implementation of this test. 1.US Mortality Data 1969-2016 (www.seer.cancer.gov); based on 2015-2016. 2.Amin et al. CA Cancer J Clin. 2017;67:93e99. Citation Format: Eric A. Klein, Donald Richards, Allen Cohn, Mohan Tummala, Rosanna Lapham, David Cosgrove, Gina Chung, Jessica Clement, Jingjing Gao, Nathan Hunkapiller, Arash Jamshidi, Kathryn Kurtzman, Michael V. Seiden, Charles Swanton, Minetta C. Liu. Clinical validation of a targeted methylation-based multi-cancer early detection test [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB013.

Aims The outcomes of patients presenting with acute myocarditis and life‐threatening ventricular arrhythmias (LT‐VA) are unclear. The aim of this study was to assess the incidence and predictors of recurrent major arrhythmic events (MAEs) after hospital discharge in this patient population. Methods and results We retrospectively analysed 156 patients (median age 44 years; 77% male) discharged with a diagnosis of acute myocarditis and LT‐VA from 16 hospitals worldwide. Diagnosis of myocarditis was based on histology or the combination of increased markers of cardiac injury and cardiac magnetic resonance (CMR) Lake Louise criteria. MAEs were defined as the relapse, after discharge, of sudden cardiac death or successfully defibrillated ventricular fibrillation, or sustained ventricular tachycardia (sVT) requiring implantable cardioverter‐defibrillator therapy or synchronized external cardioversion. Median follow‐up was 23 months [first to third quartile (Q1–Q3) 7–60]. Fifty‐eight (37.2%) patients experienced MAEs after discharge, at a median of 8 months (Q1–Q3 2.5–24.0 months; 60.3% of MAEs within the first year). At multivariable Cox analysis, variables independently associated with MAEs were presentation with sVT [hazard ratio (HR) 2.90, 95% confidence interval (CI) 1.38–6.11]; late gadolinium enhancement involving ≥2 myocardial segments (HR 4.51, 95% CI 2.39–8.53), and absence of positive short‐tau inversion recovery (STIR) (HR 2.59, 95% CI 1.40–4.79) at first CMR. Conclusions Among patients discharged with a diagnosis of myocarditis and LT‐VA, 37.2% had recurrences of MAEs during follow‐up. Initial CMR pattern and sVT at presentation stratify the risk of arrhythmia recurrence.

Locomotor and respiratory muscle feedback via group III/IV afferents influences the blood pressure response during exercise. Specifically, stimulation of the inspiratory and locomotor muscle afferents (via inspiratory loading (IL) and subsystolic circulatory occlusion (CUFF), respectively) increases the blood pressure response during exercise with combined IL and CUFF (IL+CUFF) further augmenting the blood pressure response. Sex differences in blood pressure have been observed in both IL and CUFF when investigated individually, while the influence of sex hormones is unclear. It is unknown if sex and menstrual cycle phase influences the blood pressure response to IL+CUFF during exercise. Purpose To determine if sex and menstrual cycle phase influence the blood pressure response during IL+CUFF in men and premenopausal women. We hypothesized that women will exhibit attenuated increases in blood pressure compared to age‐matched men during IL, CUFF, and IL+CUFF, while no differences would be present across the menstrual cycle. Methods To date, 13 adults (7M/6W; M: 28±6 vs. W: 29±4 yrs, p=0.30; M: 27±5 vs. W: 25±2 kg/m 2 , p=0.85) have participated in this study. Participants performed four 10 min exercise bouts at 40% of their peak oxygen uptake. The participants performed spontaneously breathing (SB) during the first 5 minutes and voluntary hyperventilation (i.e. breathing frequency of 40 breaths/min with 50% duty cycle) during the last 5 minutes. During this last 5 min, IL (30% maximal inspiratory pressure), CUFF (80 mmHg), IL + CUFF, or no intervention (CTL) occurred in a randomized order. Women completed the study protocol twice, once during midluteal (ML) phase and once during early follicular (EF) phase. Blood pressure was measured using manual sphygmomanometry. Changes in systolic blood pressure (ΔSBP), diastolic blood pressure (ΔDBP), and mean arterial pressure (ΔMAP) were determined by subtracting values obtained during IL, CUFF, IL+CUFF, or CTL from SB. Results There were no significant differences in ΔMAP across groups during CTL (M: 5±5; ML 2±2; EF: 2±2 mmHg, all p>0.24), IL (M: 11±4; ML 10±2; EF 12±5 mmHg, all p>0.60), CUFF (M: 19±6; ML 16±4; EF 20±2 mmHg, all p>0.20), or IL + CUFF (M: 24±5; ML 23±6; EF 23±3 mmHg, all p>0.82). There were no significant differences in ΔSBP across groups during CTL (M: 5±4; ML 5±4; EF: 8±13 mmHg, all p>0.49), IL (M: 17±6; ML 17±5; EF 19±8 mmHg, all p>0.63), CUFF (M: 24±12; ML 23±7; EF 28±5 mmHg, all p>0.31), or IL + CUFF (M: 34±8; ML 33±11; EF 33±8 mmHg, all p>0.94). There were no significant differences in ΔDBP across group during CTL (M: 5±8; ML 0±1; EF: −1±4 mmHg, all p>0.05), IL (M: 8±3; ML 7±2; EF 9±4 mmHg, all p>0.71), CUFF (M: 16±4; ML 13±4; EF 16±2 mmHg, all p>0.20), or IL + CUFF (M: 19±6; ML 18±6; EF 18±3 mmHg, all p>0.75). Conclusion With this limited sample size, our data suggest that neither sex nor menstrual cycle phase influences the blood pressure response with IL, CUFF or IL+CUFF. Support or Funding Information NIH HL126638 AHA 18POST3990251 This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .

Introduction Heart failure (HF) patients demonstrate augmented ventilation for a given metabolic demand which results in increased respiratory muscle work and subsequent competition for blood flow between the respiratory and locomotor muscle beds. Unloading the respiratory muscles during submaximal exercise has been shown to increase leg oxygen uptake (VO 2 ) in HF patients due increased leg blood flow via increased cardiac output and redistribution of cardiac output from the respiratory to locomotor muscles. It has been suggested that increased leg VO 2 following respiratory muscle unloading in HF during submaximal exercise is due to augmented convective O 2 transport in HF; however, it is unclear if diffusive O 2 transport also increases with respiratory muscle unloading. We hypothesized that respiratory muscle unloading during submaximal exercise will lead to increased leg VO 2 due to combined increases in convective and diffusive O 2 transport. Methods Ten HF patients with reduced systolic function (6M/4W; 53±15 yrs; BMI: 29±6 kg/m 2 ) were recruited. Patients performed two submaximal exercise bouts (i.e. with and without respiratory muscle unloading (via mechanical ventilator) (RM unloading and control (CTL), respectively)). During exercise, leg blood flow (Q L ) was measured via thermodilution. Intrathoracic pressure was measured via esophageal balloon. Radial arterial and femoral venous blood gases were measured. Blood gases were used to calculate arterial and venous oxygen content (CaO 2 and CvO 2 , respectively). Leg VO 2 was calculated as Q L multiplied by the difference between CaO 2 ‐CvO 2 . Leg O 2 delivery was calculated as Q L multiplied by CaO 2 . Leg diffusion capacity (DO 2 ) was calculated as leg VO 2 divided by femoral venous partial pressure of O 2 . Results From CTL to RM unloading, leg VO 2 increased during submaximal exercise (0.7±0.3 vs. 1.0±0.4 L/min, p<0.01, respectively). From CTL to RM unloading, leg O 2 delivery increased during submaximal exercise (0.9±0.4 vs. 1.4±0.5 L/min, p<0.01, respectively), whereas CaO 2 ‐CvO 2 was not different (14.1±3.0 vs. 14.2±3.2 mL/dL, p=0.57, respectively). From CTL to RM unloading, leg DO 2 increased during submaximal exercise (30.4±10.8 vs. 49.7±18.6 mL/mmHg, p<0.01, respectively). There was a negative relationship between the degree of RM unloading (i.e. percent decrease in mean inspiratory esophageal pressure) and percent increase in leg DO 2 with RM unloading (r= −0.77, p<0.01). Conclusion Our results demonstrate that unloading the respiratory muscles leads to increased leg VO 2 due to convective and diffusive O 2 transport during submaximal exercise in HF patients. These findings suggest that the naturally occurring respiratory muscle work in HF compromises convective and diffusive O 2 transport and thus constrains leg VO 2 during submaximal exercise in HF. Support or Funding Information NIH HL126638 AHA 18POST3990251 This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .

Local warming in human skin elicits a biphasic vasodilation with a local sensory nerve component (initial peak) and nitric oxide mediated plateau. Though microvascular dysfunction in type 2 diabetes mellitus (T2DM) is well known, effects at the neural level of control in individuals with well managed T2DM are less understood. We tested the hypothesis that local sensory nerve contributions to vasodilation are less in T2DM compared to healthy controls (C). We measured skin blood flow using laser‐Doppler flowmetry (LDF) and arterial pressure using Finometer in T2DM and C subjects at baseline and during 35 minutes of local warming (LW) of the skin to 42 °C. Two LDF sites received Ringers via microdialysis throughout LW; one site was pretreated with local lidocaine (LIDO) to block local sensory innervation. Maximum cutaneous vascular conductance (CVC) was evaluated using microdialysis of nitroprusside. In preliminary studies (N = 4 T2DM, 6 C), CVC during the initial peak at the untreated site was decreased in T2DM (73 ± 4 vs. C: 85 ± 5 % max; P = 0.05), but was not different at the LIDO site (T2DM: 54 ± 9 vs. C: 66 ± 6 % max; P > 0.05). The difference between sites (sensory nerve contribution) was similar between groups (T2DM: 19 ± 7 vs. C: 18 ± 7 % max; P > 0.05), and was lower with LIDO than was previously shown with local EMLA. Our results suggest a non‐neural component which is decreased in T2DM. Supported by NIH HL73884 and CTSA UL1 RR024150.

Thermoregulatory increases in skin blood flow in humans are brought about by a combination of cutaneous vasodilation and increased cardiac output. As such, whole body heating (WBH) in humans is associated with increased heart rate and decreased blood pressure compared to normothermic baseline conditions. We hypothesized that the tachycardia and hypotension associated with WBH in resting humans would be diminished in individuals with type 2 diabetes mellitus (T2DM) compared to controls (C) of similar age due to altered autonomic control of cardiac function in T2DM. We measured heart rate (HR; ECG) and beat‐to‐beat blood pressure (Finometer) in 6 individuals with T2DM and 6 control subjects at baseline and during WBH with a water‐perfused suit. Resting HR and blood pressure were similar in C vs. T2DM (HR: C: 59 ± 2; T2DM: 62 ± 4, P > 0.05; MAP: C: 93 ± 7; T2DM: 95 ± 7, P > 0.05). During body heating, heart rate increased significantly in both groups; at peak of WBH, HR was 91 ± 4 in C and 92 ± 1 in T2DM. This represented a change of 32 ± 3 in C and 27 ± 3 in T2DM (P > 0.05). Our preliminary data suggest a similar increase in HR and decrease in BP during body heating in T2DM when compared with C. This may have implications for clinical applications in the treatment and management of T2DM, particularly with regard to heat exposure and/or exercise.

We previously identified a +ACA polymorphism at ‐600 bp in the BRCA1 promoter that creates a FAC1 transcriptional repressor binding site. Subsequently, we performed a genotyping study to determine the prevalence of this BRCA1 promoter polymorphism among unaffected individuals and patients with breast disease. The genotypic distribution of the BRCA1 promoter was determined for 997 unaffected individuals and 763 patients with breast disease from the Mayo Clinic, UNC Hospitals, and the Carolina Breast Cancer Study. The BRCA1 promoter genotypic frequency among unaffected individuals was 481/997 (48%) WT/WT, 432/997 (43%) WT/ACA, and 91/997 (9%) ACA/ACA. The BRCA1 promoter genotypic frequency among patients with breast disease was 348/763 (46%) WT/WT, 343/763 (45%) WT/ACA, and 72/763 (9%) ACA/ACA. No differences were noted in the genotypic distribution of the BRCA1 promoter among patients with DCIS, BRCA1 mutation, suspected BRCA1‐related cancer (BRCAx), or sporadic breast cancer. The allelic frequency of the +ACA BRCA1 promoter polymorphism among breast disease groups [343/415 (83%) WT/ACA and 72/415 (17%) ACA/ACA] were not different than the allelic frequency of the controls [432/523 (83%) WT/ACA and 91/523 (17%) ACA/ACA]. Our results suggest that the +ACA BRCA1 promoter polymorphism occurs commonly, and may contribute to breast cancer upon activation of the FAC1 repressor protein. Support: NIH CA78343.

Importance: The increasing prevalence and clinical and clinical impact of chronic conditions (CCs) have been recognized as an important public health concern. Objectives: To evaluate trends in co-existing CCs and their association 30-day mortality and readmission rates in hospitalized patients with first-ever stroke and transient ischemic attack (TIA). Design: Retrospective study of patient hospitalized for first stroke or TIA. Results: Study cohort of 6,771 patients, hospitalized for first-ever stroke (n = 4,068 60.1%) and first-ever TIA (n = 2,703, 39.9%) with mean age 68.2 (standard deviation, ± 15.6) years, 51.4 % men, mean number of CCs 2.9 (± 1.7), 30-day mortality 8.6% and 30-day readmission rate 8.2%. The prevalence of multiple CCs was increased from 73.7% in 2005-2006 to 81.9% in 2013-2015, which was driven by a dramatic rise in the proportion of patient with ≥4 CCs from 27.4% to 46.4% during the study interval. In multivariable models, significant predictors of a) 30-day mortality were co-existing heart failure (HF) (odds ratio [OR] 1.45, 95% confidence interval [CI] 1.09-1.92), cardiac arrhythmia (OR 1.74, 95% CI 1.40-2.17), coronary artery disease(CAD) (OR 1.64, 95% CI 1.29-2.08), cancer (OR 1.67, 95% CI 1.31-2.14), and diabetes (HR 1.28, 95% CI 1.01-1.62) and b) 30-day readmission were co-existing HF (OR 1.45, 95% CI 1.06-1.99), chronic kidney disease (OR 1.55, 95% CI 1.17-2.04), CAD (OR 1.36, 95% CI 1.09-1.70), and cancer (OR 1.58, 95% CI 1.25-2.00), and patients with ≥4 co-existing CCs (OR 1.83, 95% CI 1.37-2.45). Conclusions and Relevance: In this large patient-population, we demonstrated a recent trend of continued increase in several CCs among hospitalized patients with acute stroke and TIA over 10-year period. Several CCs were associated with increased risk of 30-day all-cause mortality and readmission after initial hospitalization. Thus, interventions targeted to patients with CCs may improve these outcomes for patients with stroke and TIA.

Drug interactions are common and can affect patient outcomes. Drugs that undergo emergency approval have less preapproval drug testing to identify potential interactions. Tramadol is an effective pain medication prodrug with a complex mechanism of action that requires extensive metabolism. Remdesivir is an antiviral medication given emergency approval to treat hospitalized patients with COVID-19 infections. Remdesivir is also a nucleotide analogue prodrug that undergoes intracellular metabolic conversions to its active metabolite. We discuss the case of a hospitalized patient in the United States diagnosed with COVID-19 pneumonia who developed acute pain crisis secondary to a drug–drug interaction between tramadol and remdesivir, and we propose a possible mechanism of interaction.