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.

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.

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.

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.

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.

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.

Association of coronary microvascular dysfunction and cardiac bridge integrator 1, a cardiomyocyte dysfunction biomarker.

BACKGROUND: Coronary microvascular dysfunction (CMD) is associated with heart failure with preserved ejection fraction (HFpEF); however, pathophysiology is not well described. HYPOTHESIS: We hypothesized that CMD in women with suspected ischemia with no obstructive coronary artery disease (INOCA) is associated with cardiomyocyte dysfunction reflected by plasma levels of a cardiomyocyte calcium handling protein, cardiac bridge integrator 1 (cBIN1). METHODS: Women with suspected INOCA undergoing coronary function testing were included. Coronary flow reserve, vasodilation to nitroglycerin, change in coronary blood flow (ΔCBF), and vasodilation to acetylcholine (ΔAch) were evaluated. cBIN1 score (CS) levels in these women (n = 39) were compared to women with HFpEF (n = 20), heart failure with reduced ejection fraction (HFrEF) (n = 36), and reference controls (RC) (n = 50). Higher CS indicates cardiomyocyte tubule dysfunction. RESULTS: INOCA, HFpEF, and HFrEF women were older than RC (p < .05). Higher CS was associated with vasoconstriction to acetylcholine (r = -0.43, p = .011) with a trend towards lower ΔCBF (r = 0.30, p = .086). Higher CS was specific for ΔAch and ΔCBF but had limited sensitivity. INOCA women had higher CS than RC, but lower CS than HFpEF/HFrEF groups (p < .001). CONCLUSIONS: CS, a plasma biomarker indicating poor cardiomyocyte health, was higher in women with suspected INOCA as compared to RC, but lower than in women with HFpEF. Elevated CS in suspected INOCA patients represents an intermediate group between health and disease, supporting the hypothesis that CMD may progress to HFpEF. Larger prospective cohort studies are needed to confirm the pathophysiological relationship between cBIN1, CMD, and HFpEF.

Perceptions of a Health Care Notebook from Female Breast Cancer Survivors with Cognitive Impairment.

Strengthening communication between providers and patients, especially those with cognitive impairment, is required given care complexity and fragmentation across the care continuum. Therefore, determining patient perceptions about the Siebens Health Care Notebook (SHCN), a tool to support self-management and strengthen communication and care continuity, is fundamental to understanding SHCN usability. Participants were breast cancer survivors in a study evaluating a 6-week cognitive rehabilitation program, who reported cancer-related cognitive impairment (Functional Assessment of Cancer Therapy-Cognitive Function-Perceived Cognitive Impairment (PCI) subscale < 59). Participant groups were alternately assigned to receive the SHCN (intervention) or not (control). SHCN recipients completed a 3-item qualitative perception survey at program completion. Both groups were surveyed at baseline, program completion, and 4 weeks later about communication with physicians. Scores were compared using Wilcoxon rank-sum tests. No baseline demographic or PCI score differences occurred between intervention (n = 29) and control (n = 16) groups. Of 22 (76%) who completed the SHCN perception survey, 100% endorsed it as useful in tracking health information, as helpful, and would recommend it to others. No group differences in communication activities with physicians were demonstrated. Women reporting cognitive impairment after breast cancer treatment perceived the SHCN as a beneficial self-care tool and would suggest it to others. Communication activities with physicians did not change during the study's short duration. Future research is needed to evaluate SHCN features contributing to helpfulness and details on use, including two-way communication activities between patients and physicians, across the care continuum.

Phytoestrogen blood levels and adverse outcomes in women with suspected ischemic heart disease.

BACKGROUND/OBJECTIVES: Prior studies linked higher blood phytoestrogen (phytoE) levels of daidzein to beneficial lipoprotein profiles, and higher genistein levels related to worse coronary microvascular dysfunction in women with suspected ischemic heart disease (IHD). However, relationships to adverse outcomes remain unclear. We investigated the associations between eight serum phytoE and major adverse cardiac events (MACE) including myocardial infarction, stroke, hospitalization for heart failure and angina, cardiovascular and all-cause mortality, in women undergoing functional coronary angiography (FCA) for suspected ischemia. SUBJECTS/METHODS: We evaluated 143 women enrolled in the Women's Ischemia Syndrome Evaluation (1996-2001) for serum phytoE levels and 10-year outcomes. Median follow-up duration was 6.08 years (range 0.01-8.16) for time to MACE and 9.11 years (range 0.01-11.08 years) for time to death. Kaplan-Meier plots were analyzed and Cox regression models adjusted for age, body mass index, hypertension, diabetes, dyslipidemia and tobacco use. RESULTS: The median age was 54.7 (range 20.6-76.1) years and BMI was 29.3 (range 18.4-57.2). Of the cohort, 80.4% had nonobstructive coronary artery disease, 56% had hypertension, 22.4% had diabetes, 58.1% had dyslipidemia and 59.4% of the women used tobacco. Each unit decrease in log glycitin was associated with increased MACE hazard (HR 1.97, 95% [CI 1.23, 3.14], p = 0.005). Glycitin absence was associated with earlier angina hospitalization (log rank p = 0.05). After 6 years, MACE increased with each unit decrease in log genistein (HR 6.17, 95% [CI 1.81, 20.8], p = 0.0036). Other phytoE did not show statistically significant associations with outcomes. CONCLUSIONS: Among women with suspected IHD undergoing clinically indicated invasive FCA, low serum glycitin was associated with increased MACE and earlier angina hospitalization, while low genistein was associated with increased MACE after 6 years. Future studies are needed regarding phytoE, nutrition, outcomes and possibly supplementation.

Risk factors for heart failure in women with ischemia and no obstructive coronary artery disease.

Study objective: Women with ischemia and no obstructive coronary artery disease (INOCA) are at increased risk for heart failure (HF) hospitalizations, which is predominantly HF with preserved ejection fraction (HFpEF). We aimed to identify predictors for the development of heart failure HF in a deeply phenotyped cohort of women with INOCA and long-term prospective follow-up. Design setting and participants: Women enrolled in the NHLBI-sponsored Women's Ischemia Syndrome Evaluation (WISE) were evaluated for baseline characteristics including clinical history, medications, physical exam, laboratory data and angiographic data. Using a multivariate Cox analysis, we assessed the association between baseline characteristics and the occurrence of HF hospitalizations in 493 women with evidence of ischemia but no obstructive coronary disease, no prior history of HF, and available follow-up data. Results: During a median follow-up of 6-years, 18 (3.7%) women were hospitalized for HF. Diabetes mellitus and tobacco use were associated with HF hospitalization. In a multivariate analysis adjusting for known HFpEF predictors including age, diabetes, hypertension, tobacco use, and statin use, novel predictive variables included higher resting heart rate, parity and IL-6 levels and lower coronary flow reserve (CFR) and poor functional status. Conclusions: There is a considerable incidence of HF hospitalization at longer term follow-up in women with INOCA. In addition to traditional risk factors, novel risk variables that independently predict HF hospitalization include multi-parity, high IL-6, low CFR, and poor functional status. These novel risk factors may be useful to understand mechanistic pathways and future treatment targets for prevention of HFpEF.

Emerging From the Haze: A Multicenter, Controlled Pilot Study of a Multidimensional, Psychoeducation-Based Cognitive Rehabilitation Intervention for Breast Cancer Survivors Delivered With Telehealth Conferencing.

OBJECTIVE: To quantify the effect of a psychoeducation-based cognitive rehabilitation intervention on breast cancer survivors' self-report of cognitive function and investigate the feasibility of accrual, adherence, and multisite program delivery using secure telehealth conferencing. DESIGN: Prospective, nonblinded, wait-list controlled pilot study. SETTING: Nonprofit academic medical center and university medical center with associated community practice affiliates. PARTICIPANTS: Adult female survivors of stage I-III breast cancer reporting cognitive complaints 2 months to 5 years after chemotherapy (N=61). Ongoing endocrine and/or anti-HER-2 therapy was allowed. Patients were excluded for history of other conditions involving impaired cognitive function. Combination referred and volunteered sample. In total, 107 women were screened, 61 consented, and 52 analyzed. No attrition due to adverse events. Group allocation was based on consent timing and next scheduled cohort to minimize wait time for wait-list controls. INTERVENTION: Psychoeducation-based cognitive rehabilitation intervention delivered in a group setting during 6 weekly 2.5-hour classes. Included presentation, class exercises, discussion, and homework exercises. Provided in-person and virtually by Health Insurance Portability and Accountability Act compliant and encrypted telehealth conferencing. MAIN OUTCOME MEASURES: Primary: self-report of perceived cognitive function (PCF) was compared between the intervention group (n=27) and wait-list controls (n=28) with the Functional Assessment of Cancer Therapy-Cognition perceived cognitive impairment subscale. Secondary: feasibility for multisite delivery via teleconferencing was measured by total accrual, percent adherence to 4 of the 6 weeks of content, and participant satisfaction ratings. RESULTS: The intervention group demonstrated improvement in PCF both at the conclusion of the intervention and 1 month later (P<.01). Within-group improvement in PCF was maintained at 6 and 12 months (P<.01). CONCLUSION: These study results provide further preliminary evidence of the efficacy of psychoeducation-based cognitive rehabilitation as an intervention for decreased PCF in breast cancer survivors with cognitive complaints after chemotherapy. Feasibility for accrual, adherence, and participant satisfaction with secure telehealth conferencing was demonstrated. These positive pilot study results will inform future work.

Resting coronary velocity and myocardial performance in women with impaired coronary flow reserve: Results from the Women's Ischemia Syndrome Evaluation-Coronary Vascular Dysfunction (WISE-CVD) study.

BACKGROUND: Women with evidence of ischemia and no obstructive coronary arteries (INOCA) often have coronary microvascular dysfunction (CMD) indicated by impaired coronary flow reserve (CFR) to adenosine. Low CFR is associated with an adverse prognosis, including incident heart failure. Because the CFR calculation relies on the baseline intrinsic coronary vasomotor flow velocity, a major determinate of CFR and the degree of variation in baseline flow alone may be an important contributor to risk of adverse outcomes in women with CMD. A better understanding of baseline blood flow in the setting of low CFR and its association with myocardial performance would be helpful. METHODS: We evaluated 74 women who underwent invasive coronary reactivity testing in the Women's Ischemia Syndrome Evaluation-Coronary Vascular Dysfunction (WISE-CVD) study and had impaired CFR (<2.32). We assessed the relationship between coronary artery baseline average peak velocity (bAPV) at rest and cardiac magnetic resonance imaging measures of left ventricular (LV) structure and function. RESULTS: When stratified as low (<22 cm/s) versus high (≥22 cm/s) bAPV, there were no differences in cardiovascular risk factors, coronary plaque burden, or LV structure. However, low bAPV was associated with higher LV end-diastolic filling pressure (P = 0.04), lower LV ejection fraction (P = 0.001), and differences in late systolic and diastolic strain rates (P = 0.01 to 0.05). CONCLUSIONS: In women with impaired CFR, low resting coronary flow velocity is associated with more adverse myocardial performance, which may contribute to risk for adverse outcomes and particularly heart failure in women with CMD.

Impact of the extent of pathologic complete response on outcomes after neoadjuvant chemotherapy.

BACKGROUND AND OBJECTIVE: With advances in systemic therapies for breast cancer, responses to neoadjuvant chemotherapy (NAC) have increased. Pathologic complete response (pCR) after NAC is an independent prognostic factor. We examined the impact of breast and/or lymph node (LN) pCR on survival. METHODS: From a prospectively maintained database, 202 women were identified with LN-positive breast cancer who underwent NAC then surgery. Clinicopathologic factors and survival were compared between four groups: breast/LNs pCR, node-only pCR, breast-only pCR, and residual disease (RD). RESULTS: Forty-eight (23.8%) patients had breast/LNs pCR, 43 (21.3%) node-only pCR, 5 (2.5%) breast-only pCR, and 106 (52.5%) had RD. There was no difference in age, stage, or breast operation between groups. With a median follow-up of 48.2 months, patients with any pCR had improved disease-free survival (DFS) (HR, 0.3; 95% CI, 0.157-0.572) and OS (HR, 0.192; 95% CI, 0.057-0.652) compared with RD patients. There were no significant differences in DFS (log-rank P = .18) and OS (log-rank P = 0.12) between patients with node-only pCR, breast-only pCR, and breast/LNs pCR. CONCLUSION: In node-positive breast cancer patients receiving NAC, any pCR was associated with improved survival vs RD. The anatomic site of pCR did not impact survival. This suggests that any favorable response to NAC has prognostic value.

Single Protein Encapsulated Doxorubicin as an Efficacious Anticancer Therapeutic.

Small-molecule chemotherapeutics are potent and effective against a variety of malignancies, but common and severe side effects restrict their clinical applications. Nanomedicine approaches represent a major focus for improving chemotherapy, but have met limited success. To overcome the limitations of chemotherapy drugs, we have developed a novel Single Protein Encapsulation (SPE)-based drug formulation and delivery platform and tested its utility in improving doxorubicin (DOX) treatment. Using this methodology, a series of SPEDOX complexes were generated by encapsulating various numbers of DOX molecules into a single human serum albumin (HSA) molecule. UV/fluorescence spectroscopy, membrane dialysis, and dynamic light scattering techniques showed that SPEDOXs are stable and uniform as monomeric HSA and display unique properties distinct from those of DOX and DOX-HSA mixture. Furthermore, detailed procedures to precisely monitor and control both DOX payload and binding strength to HSA were established. Breast cancer xenograft tumor studies revealed that SPEDOX-6 treatment displays improved pharmacokinetic profiles, higher antitumor efficacy, and lower DOX accumulation in the heart tissue compared with unformulated DOX. This SPE technology, which does not involve nanoparticle assembly and modifications to either small-molecule drugs or HSA, may open up a new avenue for developing new drug delivery systems to improve anticancer therapeutics.

Vascular Aging Is Accelerated in Flight Attendants With Occupational Secondhand Smoke Exposure.

OBJECTIVE: To determine whether early vascular aging may be present in flight attendants with remote in-cabin secondhand smoke (SHS) exposure. METHODS: Twenty-six flight attendants with a history of in-cabin SHS exposure prior to the airline smoking bans were recruited. Pulse wave analysis, peripheral arterial tonometry, and brachial artery reactivity testing evaluated their arterial compliance and endothelial function. RESULTS: Flight attendants with remote in-cabin SHS exposure have normal blood pressure, pulse wave velocity, and reactive hyperemia index, but abnormal pulse pressure, augmentation index, flow-mediated dilation, and hyperemic mean flow ratio. CONCLUSION: These preliminary findings suggest that flight attendants with remote in-cabin SHS exposure have preclinical signs of accelerated vascular aging and raise new questions about the relationship between remote SHS exposure and vascular health.

Inter-scan Reproducibility of Cardiovascular Magnetic Resonance Imaging-Derived Myocardial Perfusion Reserve Index in Women with no Obstructive Coronary Artery Disease.

BACKGROUND: Cardiovascular magnetic resonance imaging (CMRI) derived myocardial perfusion reserve index (MPRI) has recently been shown to detect coronary microvascular dysfunction (CMD) in women with signs and symptoms of ischemia and no obstructive coronary artery disease (CAD). The aim of this study was to determine the inter-scan reproducibility of MPRI in this patient group in order to assess its diagnostic robustness in serial scans and assess its utility as a marker of potential therapies for CMD. METHODS: Rest/stress perfusion CMR was performed at 1.5T using a standardized protocol in 17 women with signs and symptoms of ischemia and no obstructive CAD on two separate days (within 90 days of each other). The same pharmacological stress agent (adenosine/regadenoson) was used for both scans. MPRI was calculated from time-intensity curves of the whole myocardium and blood pool at stress and rest. One experienced observer, blinded to clinical data, performed all measurements. Intra-class correlation coefficients (ICC), coefficient of variation (CoV), and Bland-Altman plots were determined. RESULTS: Mean age was 53±10 years old and BMI 28±7 kg/m2; 47% had hypertension, 4% diabetes, 9% hyperlipidemia and 10% family history of CAD. Mean MPRI for the 17 women was higher for scan 2 compared to scan 1 (1.98±0.3 vs. 1.65±0.78, respectively, p<0.001); and this relationship persisted even when corrected for resting rate pressure product (RPP) (2.42±0.81 vs. 1.97±0.92, respectively, 0.002), The mean bias for MPRI between sequential scans was 0.34 (95% CI: 0.18 to 0.49, limits of agreement: -0.31, 0.98 and when corrected for resting RPP it was 0.45 (95% CI: 0.21 to 0.68, limits of agreement: -0.52, 1.41), ICC and CoV also indicated modest inter-scan reproducibility (ICC 0.57; CoV 20.3%), but both measures were comparable to values seen in prior studies in CAD populations and healthy volunteers. CONCLUSION: Inter-scan reproducibility of CMRI-derived MPRI in women with suspected CMD is modest, with relatively wide limits of agreement. This variability is similar to that seen in other populations, suggesting that some caution must be exercised when using absolute MPRI cut-offs in isolation for the diagnosis of CMD or repeated measures of MPRI to track response to therapy. Additional work is ongoing to improve reproducibility from both biological and technological standpoints.

Improving admission medication reconciliation with pharmacists or pharmacy technicians in the emergency department: a randomised controlled trial.

BACKGROUND: Admission medication history (AMH) errors frequently cause medication order errors and patient harm. OBJECTIVE: To quantify AMH error reduction achieved when pharmacy staff obtain AMHs before admission medication orders (AMO) are placed. METHODS: This was a three-arm randomised controlled trial of 306 inpatients. In one intervention arm, pharmacists, and in the second intervention arm, pharmacy technicians, obtained initial AMHs prior to admission. They obtained and reconciled medication information from multiple sources. All arms, including the control arm, received usual AMH care, which included variation in several common processes. The primary outcome was severity-weighted mean AMH error score. To detect AMH errors, all patients received reference standard AMHs, which were compared with intervention and control group AMHs. AMH errors and resultant AMO errors were independently identified and rated by ≥2 investigators as significant, serious or life threatening. Each error was assigned 1, 4 or 9 points, respectively, to calculate severity-weighted AMH and AMO error scores for each patient. RESULTS: Patient characteristics were similar across arms (mean±SD age 72±16 years, number of medications 15±7). Analysis was limited to 278 patients (91%) with reference standard AMHs. Mean±SD AMH errors per patient in the usual care, pharmacist and technician arms were 8.0±5.6, 1.4±1.9 and 1.5±2.1, respectively (p<0.0001). Mean±SD severity-weighted AMH error scores were 23.0±16.1, 4.1±6.8 and 4.1±7.0 per patient, respectively (p<0.0001). These AMH errors led to a mean±SD of 3.2±2.9, 0.6±1.1 and 0.6±1.1 AMO errors per patient, and mean severity-weighted AMO error scores of 6.9±7.2, 1.5±2.9 and 1.2±2.5 per patient, respectively (both p<0.0001). CONCLUSIONS: Pharmacists and technicians reduced AMH errors and resultant AMO errors by over 80%. Future research should examine other sites and patient-centred outcomes. TRIAL REGISTRATION NUMBER: NCT02026453.