Comparison of risk profiles of participants in the Women's IschemiA TRial to reduce events in non-ObstRuctive CAD (WARRIOR) trial, using coronary computed tomography angiography vs invasive coronary angiography.

OBJECTIVE: To compare baseline characteristics of participants in the Women's IschemiA TRial to Reduce Events In Non-ObstRuctive CAD (WARRIOR) trial by qualification by Coronary Computed Tomography Angiography (CCTA) or Invasive Coronary Angiography (ICA). METHODS: The WARRIOR trial (NCT03417388) is an ongoing multicenter, prospective, randomized, blinded outcome evaluation of intensive medical therapy vs. usual care in women with suspected Ischemia and No Obstructive Coronary Artery Disease (INOCA) identified by either CCTA or ICA on the outcome of major adverse cardiovascular events (MACE). No coronary artery disease is defined as <50% luminal stenosis and normal coronary arteries is defined as no evidence of atherosclerosis including calcified and non-calcified plaque. Data presented was extracted on May 27, 2020. No clinical outcomes were assessed. RESULTS: An initial sample cohort of 797 women was included. The majority were younger than 65 years, White participants (73.3%), 159 had diabetes (19.9%), and 676 had angina (84.8%) with the remainder having symptoms of suspected ischemic heart disease. Over 50% of randomized participants had normal coronaries without luminal irregularities by ICA or CCTA. Participants randomized to ICA were more likely to have worse baseline clinical risk profiles with older age, higher burden of cardiac risk factors and poor quality of life with disabling angina. CONCLUSIONS: Among this initial sample of women with suspected INOCA randomized in the WARRIOR trial, there is a differential baseline cardiac risk of participants enrolled after CCTA or ICA. However, the majority had no evidence of atherosclerotic plaque or obstructive stenosis, after evaluation by ICA or CCTA. These results suggest that non-invasive evaluation with CCTA is likely to be associated with lower risk of MACE.

Is size in the eye of the beholder? Visual estimation of penis size among transgender and cisgender people and implications for genital gender-affirming surgery and sexual medicine.

BACKGROUND: Transgender men (TM) seeking gender-affirming phalloplasty and transgender women (TW) seeking vaginoplasty and desiring insertive intercourse must consider penis size. Evidence has shown that, at least among cisgender men (CM), penile dimensions tend to be poorly estimated. In transgender patients desiring gender-affirming surgery, inaccuracy in estimation of penis dimensions may lead to unnecessary morbidity: for TW, trauma to the neovagina; for TM with excess girth, an inability to insert. Studies on the accuracy with which transgender and cisgender patients estimate penis size are limited. AIM: To assess the degree of accuracy with which CM and CW, as well as TM and TW, visually estimate the size of the human penis, including length, width, and girth. METHODS: There were 142 participants included (25 TM, 47 TW, 30 CM, and 40 CW; net mean ± SD age, 36.6 ± 11.2 years). Participants were shown these models and asked to estimate length, width, and midshaft girth by visual inspection of 6 realistic models of a penis and scrotum of varying lengths and widths. We evaluated the accuracy of the visual measurements by comparing mean perceived dimensions with the actual dimensions of each model. OUTCOMES: We used a multivariate model of all 3 bias dimensions to test for differences in average bias among gender groups (CM, CW, TM, and TW). RESULTS: TM significantly overestimated length across the longest models. TW significantly overestimated length in the longer 3 models. All groups except for TM significantly underestimated girth in at least 1 model. No groups significantly underestimated width. CM, CW, and TM significantly overestimated width in all 6 models. CLINICAL IMPLICATIONS: When transgender patients use numbers to express penis size (either in neophallus or vaginal depth based on perceived partner size), the result is likely to be larger than expected. Use of realistic penis models as a decision-making tool may help manage patient expectations and surgery decision making preoperatively and improve postoperative patient satisfaction and safety. STRENGTHS AND LIMITATIONS: To our knowledge, this is the first study to assess visual estimation in penis size in TM and CM, as well as TW and CW. The penile models in our study were shown side by side and in the flaccid state despite having dimensions more consistent with an erect penis, which may have influenced estimations across all dimensions. CONCLUSION: Men and women (cisgender and transgender) tend to significantly overestimate penis length and width.

Single protein encapsulated SN38 for tumor-targeting treatment.

BACKGROUND: The alkaloid camptothecin analog SN38 is a potent antineoplastic agent, but cannot be used directly for clinical application due to its poor water solubility. Currently, the prodrug approach on SN38 has resulted in 3 FDA-approved cancer therapeutics, irinotecan, ONIVYDE, and Trodelvy. However, only 2-8% of irinotecan can be transformed enzymatically in vivo into the active metabolite SN38, which severely limits the drug's efficacy. While numerous drug delivery systems have been attempted to achieve effective SN38 delivery, none have produced drug products with antitumor efficacy better than irinotecan in clinical trials. Therefore, novel approaches are urgently needed for effectively delivering SN38 to cancer cells with better efficacy and lower toxicity. METHODS: Based on the unique properties of human serum albumin (HSA), we have developed a novel single protein encapsulation (SPE) technology to formulate cancer therapeutics for improving their pharmacokinetics (PK) and antitumor efficacy and reducing their side effects. Previous application of SPE technology to doxorubicin (DOX) formulation has led to a promising drug candidate SPEDOX-6 (FDA IND #, 152154), which will undergo a human phase I clinical trial. Using the same SPE platform on SN38, we have now produced two SPESN38 complexes, SPESN38-5 and SPESN38-8. We conducted their pharmacological evaluations with respect to maximum tolerated dose, PK, and in vivo efficacy against colorectal cancer (CRC) and soft tissue sarcoma (STS) in mouse models. RESULTS: The lyophilized SPESN38 complexes can dissolve in aqueous media to form clear and stable solutions. Maximum tolerated dose (MTD) of SPESN38-5 is 250 mg/kg by oral route (PO) and 55 mg/kg by intravenous route (IV) in CD-1 mice. SPESN38-8 has the MTD of 45 mg/kg by IV in the same mouse model. PK of SPESN38-5 by PO at 250 mg/kg gave mouse plasma AUC0-∞ of 0.05 and 4.5 nmol × h/mL for SN38 and SN38 glucuronidate (SN38G), respectively, with a surprisingly high molar ratio of SN38G:SN38 = 90:1. However, PK of SPESN38-5 by IV at 55 mg/kg yielded much higher mouse plasma AUC0-∞ of 19 and 28 nmol × h/mL for SN38 and SN38G, producing a much lower molar ratio of SN38G:SN38 = 1.5:1. Antitumor efficacy of SPESN38-5 and irinotecan (control) was evaluated against HCT-116 CRC xenograft tumors. The data indicates that SPESN38-5 by IV at 55 mg/kg is more effective in suppressing HCT-116 tumor growth with lower systemic toxicity compared to irinotecan at 50 mg/kg. Additionally, SPESN38-8 and DOX (control) by IV were evaluated in the SK-LMS-1 STS mouse model. The results show that SPESN38-8 at 33 mg/kg is highly effective for inhibiting SK-LMS-1 tumor growth with low toxicity, in contrast to DOX's insensitivity to SK-LMS-1 with high toxicity. CONCLUSION: SPESN38 complexes provide a water soluble SN38 formulation. SPESN38-5 and SPESN38-8 demonstrate better PK values, lower toxicity, and superior antitumor efficacy in mouse models, compared with irinotecan and DOX.

Dietary Composition, Angiographic Coronary Disease, and Cardiovascular Outcomes in the WISE Study (Women's Ischemia Syndrome Evaluation).

BACKGROUND: Studies relating diet to angiographic coronary artery disease (CAD) and subsequent major adverse cardiac events (MACE) in women are limited. Information on diet was collected in the Women's Ischemia Syndrome Evaluation (WISE), a prospective cohort study of symptomatic women referred for coronary angiography to evaluate suspected ischemic heart disease. METHODS: A consecutive subgroup (n = 201 of 936) of enrolled women completed the modified Block food frequency questionnaire (FFQ). Data on outcomes were collected and adjudicated after 8-year follow-up. A set of logistic regression models were fitted for non-obstructive versus obstructive coronary stenosis (<50% versus ≥50%). Cox proportional hazard regression models were fitted for outcomes, with each dietary composition variable adjusted for the degree of coronary stenosis. RESULTS: At baseline, the subgroup cohort was 58 ± 12 years old with a body mass index (BMI) of 30 ± 7 kg/m2. An increased proportion of calories consumed from protein was associated with higher levels of baseline obstructive coronary stenosis. Those individuals who ate a higher amount of protein, carotene, and servings of vegetables and meat, however, were each associated with lower subsequent adverse outcomes, respectively. CONCLUSIONS: Among women undergoing coronary angiography for suspected CAD, a higher percentage of protein intake was associated with higher baseline stenosis severity; however, the amount of protein intake, vegetable, meat, and carotene intake, was conversely associated with subsequent lower adverse cardiovascular outcome risk.

Functional Hypothalamic Amenorrhea and Preclinical Cardiovascular Disease.

CONTEXT: Endothelial dysfunction is a preclinical cardiovascular disease (CVD) marker. Due to various neuroendocrine aberrations, functional hypothalamic amenorrhea (FHA) may be a sex-specific risk factor for CVD in young women. OBJECTIVE: To investigate endothelial function in women with FHA, compared with eumenorrheic controls and recently menopausal women. METHODS: We performed a cross-sectional analysis among women with FHA (n = 30), eumenorrheic controls (n = 29), and recently menopausal women (n = 30). FHA was defined as amenorrhea ≥3 consecutive months, estradiol <50 pg/mL, follicle-stimulating hormone (FSH) < 10 mIU/mL, and luteinizing hormone (LH) < 10 mIU/mL, excluding other etiologies. Participants were recruited through obstetrics and gynecology referrals, social media advertising, and review of electronic health records. Preclinical CVD was measured using EndoPAT 2000 to calculate reactive hyperemic index (RHI). RHI ≤1.67 indicates endothelial dysfunction. RESULTS: Mean estradiol levels in women with FHA, as compared with eumenorrheic controls and recently menopausal women, were 29.0 ± 18.1, 46.4 ± 15.7, and 10.9 ± 14.4 pg/mL (P < .0001), respectively. Women with FHA had lower insulin (P = .0095) and higher cortisol (P = .0004) compared with controls. RHI was significantly lower in women with FHA compared with eumenorrheic controls and recently menopausal women (1.8 ± 0.5 vs 2.2 ± 0.5 vs 2.2 ± 0.6, respectively; P = .008), and 35% of women with FHA had RHI ≤1.67, consistent with endothelial dysfunction. CONCLUSION: These results demonstrate endothelial dysfunction in 1 out of 3 young women with FHA. FHA may be a contributor to preclinical CVD, and it is not explained by hypoestrogenemia alone.

Single Protein Encapsulated SN38 for Tumor-Targeting Treatment.

Background: The alkaloid camptothecin analog SN38 is a potent antineoplastic agent, but cannot be used directly for clinical application due to its poor water solubility. Currently, the prodrug approach on SN38 has resulted in 3 FDA-approved cancer therapeutics, irinotecan, ONIVYDE, and Trodelvy. However, only 2-8% of irinotecan can be transformed enzymatically in vivo into the active metabolite SN38, which severely limits the drug's efficacy. While numerous drug delivery systems have been attempted to achieve effective SN38 delivery, none have produced drug products with antitumor efficacy better than irinotecan in clinical trials. Therefore, novel approaches are urgently needed for effectively delivering SN38 to cancer cells with better efficacy and lower toxicity. Methods: Based on the unique properties of human serum albumin (HSA), we have developed a novel single protein encapsulation (SPE) technology to formulate cancer therapeutics for improving their pharmacokinetics (PK) and antitumor efficacy and reducing their side effects. Previous application of SPE technology to doxorubicin (DOX) formulation has led to a promising drug candidate SPEDOX-6 (FDA IND #, 152154), which will undergo a human phase I clinical trial. Using the same SPE platform on SN38, we have now produced two SPESN38 complexes, SPESN38-5 and SPESN38-8. We conducted their pharmacological evaluations with respect to maximum tolerated dose, PK, and in vivo efficacy against colorectal cancer (CRC) and soft tissue sarcoma (STS) in mouse models. Results: The lyophilized SPESN38 complexes can dissolve in aqueous media to form clear and stable solutions. Maximum tolerated dose (MTD) of SPESN38-5 is 250 mg/kg by oral route (PO) and 55 mg/kg by intravenous route (IV) in CD-1 mice. SPESN38-8 has the MTD of 45 mg/kg by IV in the same mouse model. PK of SPESN38-5 by PO at 250 mg/kg gave mouse plasma AUC0-∞ of 0.0548 and 4.5007 (nmol × h/mL) for SN38 and SN38 glucuronidate (SN38G), respectively, with a surprisingly high molar ratio of SN38G:SN38 = 82:1. However, PK of SPESN38-5 by IV at 55 mg/kg yielded much higher mouse plasma AUC0-∞ of 18.80 and 27.78 nmol × h/mL for SN38 and SN38G, producing a much lower molar ratio of SN38G:SN38 = 1.48:1. Antitumor efficacy of SPESN38-5 and irinotecan (control) was evaluated against HCT-116 CRC xenograft tumors. The data indicates that SPESN38-5 by IV at 55 mg/kg is more effective in suppressing HCT-116 tumor growth with lower systemic toxicity compared to irinotecan at 50 mg/kg. Additionally, SPESN38-8 and DOX (control) by IV were evaluated in the SK-LMS-1 STS mouse model. The results show that SPESN38-8 at 33 mg/kg is highly effective for inhibiting SK-LMS-1 tumor growth with low toxicity, in contrast to DOX's insensitivity to SK-LMS-1 with high toxicity. Conclusion: SPESN38 complexes provide a water soluble SN38 formulation. SPESN38-5 and SPESN38-8 demonstrate better PK values, lower toxicity, and superior antitumor efficacy in mouse models, compared with irinotecan and DOX.

Autoimmune rheumatic diseases in women with coronary microvascular dysfunction: a report from the Women's Ischemia Syndrome Evaluation-Coronary Vascular Dysfunction (WISE-CVD) project.

Background: While autoimmune rheumatic diseases (ARDs) have been linked with coronary microvascular dysfunction (CMD), the relationship between ARD and CMD in women with signs and symptoms of ischemia and no obstructive arteries (INOCA) are not well described. We hypothesized that among women with CMD, those with ARD history have greater angina, functional limitations, and myocardial perfusion compromise compared to those without ARD history. Methods: Women with INOCA and confirmed CMD by invasive coronary function testing were included from the Women's Ischemia Syndrome Evaluation-Coronary Vascular Dysfunction (WISE-CVD) project (NCT00832702). Seattle Angina Questionnaire (SAQ), Duke Activity Status Index (DASI), and cardiac magnetic resonance myocardial perfusion reserve index (MPRI) were collected at baseline. Chart review was performed to confirm self-reported ARD diagnosis. Results: Of the 207 women with CMD, 19 (9%) had a confirmed history of ARD. Compared to those without ARD, women with ARD were younger (p = 0.04). In addition, they had lower DASI-estimated metabolic equivalents (p = 0.03) and lower MPRI (p = 0.008) but similar SAQ scores. There was a trend towards increased nocturnal angina and stress-induced angina in those with ARD (p = 0.05 for both). Invasive coronary function variables were not significantly different between groups. Conclusions: Among women with CMD, women with a history of ARD had lower functional status and worse myocardial perfusion reserve compared to women without ARD. Angina-related health status and invasive coronary function were not significantly different between groups. Further studies are warranted to understand mechanisms contributing to CMD among women with ARDs with INOCA.

Fitness attenuates long-term cardiovascular outcomes in women with ischemic heart disease and metabolic syndrome.

Background: The prevalence of metabolic syndrome continues to increase steadily while fitness remains relatively low. The contribution of fitness on longer-term cardiovascular outcomes and mortality in individuals with cardiovascular disease and metabolic syndrome remains unknown. Design: Women's Ischemia Syndrome Evaluation (WISE) prospective cohort (enrolled 1996-2001) of women undergoing invasive coronary angiography with signs/symptoms of ischemic heart disease. Methods: Investigated the association of fitness, defined as >7METs measured by self-reported Duke Activity Status Index (DASI), and both metabolic syndrome (ATPIII criteria) and dysmetabolism (ATPIII criteria and/or treated diabetes) with long-term cardiovascular outcomes and all-cause mortality risk. Results: Among the 492 women followed for a median of 8.6 years (range 0-11 years), 19.5% were fit-metabolically healthy (reference), 14.4% fit-metabolic syndrome, 29.9% unfit-metabolically healthy, and 36.2% unfit-metabolic syndrome. Compared to reference, MACE risk was 1.52-fold higher in fit-metabolic syndrome women (HR 1.52, 95% CI 1.03-2.26) and 2.42-fold higher in unfit-metabolic syndrome women (HR 2.42, 95% CI 1.30-4.48). Compared to reference, mortality risk was 1.96-fold higher in fit-dysmetabolism (HR 1.96, 95% CI 1.29-3.00) and 3-fold higher in unfit-dysmetabolism women (HR 3.0, 95% CI 1.66-5.43). Conclusions: In a high risk cohort of women with signs/symptoms of ischemic heart disease, unfit-metabolically healthy and fit-metabolically unhealthy women were at higher risk of long-term MACE and mortality compared to fit-metabolically healthy women; and women who were unfit and metabolically unhealthy were at the highest risk. Our study demonstrates that metabolic health and fitness play an important role in long term outcomes that warrants further investigation. Registration: https://www.clinicaltrials.gov/ct2/show/NCT00000554 (NCT00000554).

Retinal pathological features and proteome signatures of Alzheimer's disease.

Alzheimer's disease (AD) pathologies were discovered in the accessible neurosensory retina. However, their exact nature and topographical distribution, particularly in the early stages of functional impairment, and how they relate to disease progression in the brain remain largely unknown. To better understand the pathological features of AD in the retina, we conducted an extensive histopathological and biochemical investigation of postmortem retina and brain tissues from 86 human donors. Quantitative examination of superior and inferior temporal retinas from mild cognitive impairment (MCI) and AD patients compared to those with normal cognition (NC) revealed significant increases in amyloid ß-protein (Aß42) forms and novel intraneuronal Aß oligomers (AßOi), which were closely associated with exacerbated retinal macrogliosis, microgliosis, and tissue atrophy. These pathologies were unevenly distributed across retinal layers and geometrical areas, with the inner layers and peripheral subregions exhibiting most pronounced accumulations in the MCI and AD versus NC retinas. While microgliosis was increased in the retina of these patients, the proportion of microglial cells engaging in Aß uptake was reduced. Female AD patients exhibited higher levels of retinal microgliosis than males. Notably, retinal Aß42, S100 calcium-binding protein B+ macrogliosis, and atrophy correlated with severity of brain Aß pathology, tauopathy, and atrophy, and most retinal pathologies reflected Braak staging. All retinal biomarkers correlated with the cognitive scores, with retinal Aß42, far-peripheral AßOi and microgliosis displaying the strongest correlations. Proteomic analysis of AD retinas revealed activation of specific inflammatory and neurodegenerative processes and inhibition of oxidative phosphorylation/mitochondrial, and photoreceptor-related pathways. This study identifies and maps retinopathy in MCI and AD patients, demonstrating the quantitative relationship with brain pathology and cognition, and may lead to reliable retinal biomarkers for noninvasive retinal screening and monitoring of AD.

Loneliness as a risk factor for cancer-related cognitive impairment: a secondary data analysis from the Haze study.

PURPOSE: The purpose of this study was to investigate the association between loneliness and cancer-related cognitive impairment (CRCI) in a cohort of breast cancer survivors. METHODS: Female breast cancer survivors (stage I-III) reporting cognitive impairments 2 months to 5 years after chemotherapy (n = 61) participated in a prospective, nonblinded, waitlist-controlled pilot study. The intervention was a tailored cognitive rehabilitation program. Data were collected pre-/post-intervention. Loneliness was measured using the UCLA Loneliness Scale. Perceived cognitive function was measured using two subscales of the FACT-Cog and two PROMIS - Applied Cognition short forms. Spearman correlation coefficients were calculated to determine the relationship between loneliness and perceived cognitive function (PCF). RESULTS: Participants' loneliness severity was correlated with diminished PCF across all cognitive measures (Spearman r= -0.63 FACT-Cog Perceived Cognitive Impairment, p < 0.0001; r= -0.6 FACT-Cog Perceived Cognitive Abilities, p < 0.0001; r= -0.49 PROMIS Cognitive Ability, p = 0.0002; r = 0.50 PROMIS General Concerns, p = 0.0002). Loneliness scores significantly decreased following participation in the cognitive rehabilitation program in intervention participants as compared to wait-list controls [-5.0 ± 7.24, 95% CI (-8.06, -1.94), p = 0.0025]. CONCLUSIONS: Perceived loneliness was significantly and consistently correlated with PCF. The intervention may have served a dual purpose in both addressing cognitive deficits and loneliness. Additional research dedicated to understanding the association between loneliness and cognitive function, as well as screening for and addressing loneliness in clinical oncology settings, may be warranted. IMPLICATIONS FOR REHABILITATIONScreening for and addressing loneliness in oncology rehabilitation settings is warranted.Rehabilitation professionals are well-positioned to screen for and address loneliness during clinic visits as part of routine cancer rehabilitation care.Group settings may be appropriate for addressing cancer-related cognitive impairment in rehabilitation, as these groups may serve the dual purpose of addressing cognitive impairment and loneliness simultaneously.

Tumor hyaluronan as a novel biomarker in non-small cell lung cancer: A retrospective study.

INTRODUCTION: Hyaluronan (HA) accumulation is associated with tumorigenesis and aggressive tumor behavior. AIMS: We investigated the biomarker potential of HA in non-small cell lung cancer (NSCLC). METHODS: HA levels were scored using affinity histochemistry in 137 NSCLC samples stratified by HA score ≤10, 11-20, 21-30, and >30 with HA-high defined as ≥25% expression in the extracellular matrix (ECM) of the tumor surface area. Overall survival (OS) and time to progression from initiation of taxane therapy (TTP) were compared using log-rank tests based on HA score. RESULTS: Of 122 patients with recurrent/metastatic NSCLC, 93 had mean HA scores that were not significantly different across clinicopathologic variables. Frequency of HA-high tumors did not differ by histology (34/68 adenocarcinomas vs. 12/25 squamous tumors, Fisher's p = 1.0000). Median OS for recurrent/metastatic adenocarcinoma was 35.5 months (95%, 23.6-50.3) vs. 17.9 months for squamous (95%, 12.7-37.0, log-rank test, p = 0.0165). OS was not significantly different by HA quartiles, high or low (<25) HA score and tumor histology, and HA biopsy site (all p > 0.05). Median TTP (n = 98) significantly differed by HA quartile (2.8 months for HA score ≤10; 5.0 months for 11-20; 7.9 months for 21-30; 3.9 months for >30, p = 0.0265). Improved TTP trended in HA-high over HA-low tumors (n = 98, p = 0.0911). CONCLUSION: In this NSCLC cohort, tumor HA level represents a potential biomarker for TTP, which remains a cornerstone of NSCLC therapy. Further validation is warranted to identify the HA accumulation threshold associated with clinical benefit.

Reduced myocardial perfusion is common among subjects with ischemia and no obstructive coronary artery disease and heart failure with preserved ejection fraction: a report from the WISE-CVD continuation study.

Aim: Women with evidence of ischemia and no obstructive coronary artery disease (INOCA) have an increased risk of major adverse cardiac events, including heart failure with preserved ejection fraction (HFpEF). To investigate potential links between INOCA and HFpEF, we examined pathophysiological findings present in both INOCA and HFpEF. Methods: We performed adenosine stress cardiac magnetic resonance imaging (CMRI) in 56 participants, including 35 women with suspected INOCA, 13 women with HFpEF, and 8 reference control women. Myocardial perfusion imaging was performed at rest and with vasodilator stress with intravenous adenosine. Myocardial perfusion reserve index was quantified as the ratio of the upslope of increase in myocardial contrast at stress vs. rest. All CMRI measures were quantified using CVI42 software (Circle Cardiovascular Imaging Inc). Statistical analysis was performed using linear regression models, Fisher's exact tests, ANOVA, or Kruskal-Wallis tests. Results: Age (P = 0.007), Body surface area (0.05) were higher in the HFpEF group. Left ventricular ejection fraction (P = 0.02) was lower among the INOCA and HFpEF groups than reference controls after age adjustment. In addition, there was a graded reduction in myocardial perfusion reserve index in HFpEF vs. INOCA vs. reference controls (1.5 ± 0.3, 1.8 ± 0.3, 1.9 ± 0.3, P = 0.02), which was attenuated with age-adjustment. Conclusion: Reduced myocardial perfusion reserve appears to be a common pathophysiologic feature in INOCA and HFpEF patients.

Ultra-high sensitivity cardiac troponin-I concentration and left ventricular structure and function in women with ischemia and no obstructive coronary artery disease.

Aims: Women are disproportionally impacted by ischemia and no obstructive coronary artery disease (INOCA), and such women are at increased risk of developing heart failure with preserved ejection fraction (HFpEF), however the mechanisms linking these conditions remain poorly understood. The aim of this study was to determine whether ultra-high sensitivity cardiac troponin I (u-hscTnI), an indicator of cardiomyocyte injury, is associated with abnormalities in myocardial perfusion and left ventricular (LV) structure and function in women with INOCA. Methods: 327 women with INOCA enrolled in the Women's Ischemia Syndrome Evaluation-Coronary Vascular Dysfunction (WISE-CVD) study underwent vasodilator stress cardiac magnetic resonance imaging (CMRI) and u-hscTnI measurements (Simoa HD-1 Analyzer, Quanterix Corporation). Multivariable linear regression was used to evaluate associations between u-hscTnI concentrations and myocardial perfusion (MPRI), LV mass index and feature-tracking derived strain measures of LV function. Results: u-hscTnI concentrations were quantifiable in 100% of the cohort and ranged from 0.004 to 79.6 pg/mL. In adjusted models, u-hscTnI was associated with LV mass index (+2.03; 95% CI 1.17, 2.89; p < 0.01) and early diastolic radial strain rate (SR) (+0.13; 95% CI 0.01, 0.25; p = 0.03), early diastolic circumferential SR (-0.04; 95% CI -0.08, 0.002; p = 0.06) and early diastolic longitudinal SR (-0.03; 95% CI -0.07, 0.002; p = 0.06). u-hscTnI was not associated with MPRI (p = 0.39) in adjusted models. Conclusion: Together, these findings support cardiomyocyte injury as a putative pathway towards adverse LV remodeling and dysfunction; however, further research is needed to define the specific mechanism(s) driving myocellular injury in INOCA.

Nonalcoholic fatty liver disease prevalence and severity in Asian Americans from the national health and nutrition examination surveys 2017-2018.

Studies have examined nonalcoholic fatty liver disease (NAFLD) prevalence and severity in Asians; however, this is not well understood in Asian Americans (both East and South Asian Americans) as few studies have analyzed this population. We aimed to describe characteristics, prevalence of NAFLD, and its severity in Asian Americans in the National Health and Nutrition Examination Surveys (NHANES) from 2017 to 2018. Respondents 18 years and older with interview, laboratory testing, and transient elastography data were included. Other causes of liver disease were excluded. Controlled attenuation parameter (CAP) cutoff ≥ 274 dB/m, as published in the literature, defined NAFLD. Sensitivity analysis for CAP cutoffs ≥ 248 and ≥302 dB/m were performed. We found that 450 out of 3639 respondents were Asian Americans, and prevalence using CAP ≥ 274 dB/m was 43.23%. Using sensitivity analysis cutoffs of CAP ≥ 248 dB/m and CAP ≥ 302 dB/m, the prevalence was 57.38% and 28.03%, respectively. Compared with non-Asian Americans with NAFLD, Asian Americans with NAFLD had significantly lower body mass index (BMI) and less prevalent smoking history. Comorbidities, such as prediabetes, diabetes, and hypertension, were not significantly different between Asian and non-Asian Americans with NAFLD. Compared to non-Asian Americans with NAFLD, Asian Americans with NAFLD exhibited higher aminotransferases and triglycerides. Fibrosis assessed by transient elastography was not significantly different between Asian and non-Asian Americans with NAFLD. Despite decreased prevalence of BMI ≥ 30 kg/m2 , Asian Americans experienced similar NAFLD prevalence with increased hepatocellular injury and triglyceridemia compared to non-Asian Americans. Fibrosis stages were similar to non-Asian Americans.

Will Apple devices' passive atrial fibrillation detection prevent strokes? Estimating the proportion of high-risk actionable patients with real-world user data.

OBJECTIVE: Utilizing integrated electronic health record (EHR) and consumer-grade wearable device data, we sought to provide real-world estimates for the proportion of wearers that would likely benefit from anticoagulation if an atrial fibrillation (AFib) diagnosis was made based on wearable device data. MATERIALS AND METHODS: This study utilized EHR and Apple Watch data from an observational cohort of 1802 patients at Cedars-Sinai Medical Center who linked devices to the EHR between April 25, 2015 and November 16, 2018. Using these data, we estimated the number of high-risk patients who would be actionable for anticoagulation based on (1) medical history, (2) Apple Watch wear patterns, and (3) AFib risk, as determined by an existing validated model. RESULTS: Based on the characteristics of this cohort, a mean of 0.25% (n = 4.58, 95% CI, 2.0-8.0) of patients would be candidates for new anticoagulation based on AFib identified by their Apple Watch. Using EHR data alone, we find that only approximately 36% of the 1802 patients (n = 665.93, 95% CI, 626.0-706.0) would have anticoagulation recommended even after a new AFib diagnosis. DISCUSSION AND CONCLUSION: These data suggest that there is limited benefit to detect and treat AFib with anticoagulation among this cohort, but that accessing clinical and demographic data from the EHR could help target devices to the patients with the highest potential for benefit. Future research may analyze this relationship at other sites and among other wearable users, including among those who have not linked devices to their EHR.

A nonparametric Bayesian method for dose finding in drug combinations cancer trials.

We propose an adaptive design for early-phase drug-combination cancer trials with the goal of estimating the maximum tolerated dose (MTD). A nonparametric Bayesian model, using beta priors truncated to the set of partially ordered dose combinations, is used to describe the probability of dose limiting toxicity (DLT). Dose allocation between successive cohorts of patients is estimated using a modified continual reassessment scheme. The updated probabilities of DLT are calculated with a Gibbs sampler that employs a weighting mechanism to calibrate the influence of data vs the prior. At the end of the trial, we recommend one or more dose combinations as the MTD based on our proposed algorithm. We apply our method to a Phase I clinical trial of CB-839 and Gemcitabine that motivated this nonparametric design. The design operating characteristics indicate that our method is comparable with existing methods.

Incidence of interruptive penicillin allergy alerts in patients with previously documented beta-lactam exposure: Potential for leveraging the electronic health record to identify erroneous allergies.

BACKGROUND: Approximately 10% of patients report allergies to penicillin, yet >90% of these allergies are not clinically significant. Patients reporting penicillin allergies are often treated with second-line, non-ß-lactam antibiotics that are typically broader spectrum and more toxic. Orders for ß-lactam antibiotics for these patients trigger interruptive alerts, even when there is electronic health record (EHR) data indicating prior ß-lactam exposure. OBJECTIVE: To describe the rate that interruptive penicillin allergy alerts display for patients who have previously had a ß-lactam exposure. DESIGN: Retrospective EHR review from January 2013 through June 2018. SETTING: A nonprofit health system including 1 large tertiary-care medical center, a smaller associated hospital, 2 emergency departments, and ˜250 outpatient clinics. PARTICIPANTS: All patients with EHR-documented of penicillin allergies. METHODS: We examined interruptive penicillin allergy alerts and identified the number and percentage of alerts that display for patients with a prior administration of a penicillin class or other ß-lactam antibiotic. RESULTS: Of 115,081 allergy alerts that displayed during the study period, 8% were displayed for patients who had an inpatient administration of a penicillin antibiotic after the allergy was noted, and 49% were displayed for patients with a prior inpatient administration of any ß-lactam. CONCLUSIONS: Many interruptive penicillin allergy alerts display for patients who would likely tolerate a penicillin, and half of all alerts display for patients who would likely tolerate another ß-lactam.

Ultra-highly sensitive cardiac troponin I: Age and sex differences in healthy individuals.

Background: Associations between elevated circulating cardiac troponin I (cTnI) levels and adverse cardiac outcomes were established prior to the ability to measure extremely low levels of cTnI. Immunoassays that achieve precise ultra-highly sensitive quantification of cTnI (u-hs-cTnI) will allow accurate measurement in healthy subjects. We aimed to evaluate the distribution of u-hs-cTnI values measured by (Simoa HD-1 Analyzer, Quanterix Corporation, Lexington, MA) in healthy subjects and characterize relations to sex and age. Methods: Two independent, healthy cohorts (total of 200 women, 200 men) aged 18-86 years were analyzed in duplicate using the u-hs-cTnI Immunoassay. The u-hs-cTnI 99th percentiles were calculated as the upper limits considering a robust estimation against outliers with 90% confidence intervals. The Quanterix immunoassay analytical performance was established and compared to an existing clinical assay (ARCHITECT STAT High Sensitivity Troponin I, Abbott Laboratories, Wiesbaden, Germany). Results: The lower limit of detection of the u-hs-cTnI assay was calculated to be 0.005 ng/L; we accurately quantified u-hs-cTnI in 95% of healthy individuals. The Quanterix immunoassay within overlapping concentrations correlated with the Abbott assay (R2 = 0.932). The calculated combined 99th percentile was 7.94 ng/L (90% Confidence Interval [CI], 5.47-10.52). Women had lower mean u-hs-cTnI concentrations than men under the age of 40 years. The sex-specific 99th percentile for female vs. male individuals was 4.89 ng/L (90%CI, 3.71-6.25) and 10.49 ng/L (90%CI, 5.19-15.06), respectively. Conclusion: The Quanterix immunoassay provides precise quantification in 95% of healthy individuals. Women under the age of 40 years have significantly lower levels of u-hs-cTnI than men.