Proposal and Rationale for a Cardioethics Curriculum.

The modern practice of cardiovascular medicine involves many ethical controversies in the care of our complex patients. Accordingly, we propose a framework for a practical, clinically based "cardioethics" curriculum that might be incorporated into fellowship training to prepare cardiologists to cope with increasingly complex ethical dilemmas. This work can also be adopted into continuing medical education for cardiologists and other cardiovascular practitioners given the critical importance of collaborative care in cardiology. We discuss heart transplant allocation, futility concerns, withdrawing care, advance care planning, conflicts of interests, and distributive justice. Sound ethical decision-making in cardiology requires a combination of extensive technical knowledge, nuanced appreciation of individual patient goals and values, and thoughtful application of ethical principles and reasoning. Cardiologists have an exceptionally broad toolkit of medications and interventions to address high-stakes disease states. We should maintain a similarly broad ethical toolkit to provide the best care for our patients.

Case report of a breast granular cell tumor in a young transgender man.

INTRODUCTION AND IMPORTANCE: Granular cell tumors (GCTs) can be diagnostically challenging due to their rarity, diverse anatomic locations, and clinical and radiologic similarities to other more common entities. GCTs involving the breast are rare and are most commonly encountered in premenopausal cisgender women. We report an unusual case of a breast GCT in a young transgender man. CASE PRESENTATION: A 20-year-old transgender man who was on testosterone therapy for about 1 year presented with a painless, palpable mass in the right breast which radiologically resembled a lymph node. A fine needle aspiration showed morphology and immunohistochemistry consistent with a GCT. The tumor was excised by a mastectomy for therapeutic and gender-affirming purposes which confirmed the diagnosis of a breast GCT. CLINICAL DISCUSSION: Breast GCTs are most commonly found in cisgender women, however the mechanisms behind this relationship and whether transgender persons have an altered risk profile are not well understood. Breast GCTs are typically benign lesions with a low chance of recurrence following excision. CONCLUSION: GCTs are rare and poorly understood entities which have not been previously documented in transgender patients and can resemble other benign or malignant lesions.

Detecting intratumoral heterogeneity in routine breast-HER2 testing: low yield of testing multiple blocks.

BACKGROUND: Intratumoral heterogeneity can lead to uncertainty in breast carcinoma HER2 testing, both with respect to pathology reporting and clinical significance. The standard practice is to perform breast biomarker testing on a single representative section of tumor; however, concern over heterogeneity often leads to testing on additional tissue blocks. Our objective was to assess the diagnostic yield of testing multiple blocks of a single invasive breast carcinoma. METHODS: We performed a retrospective review of 139 consecutive cases (between 2006 and 2012) in which clinical HER2 testing was performed in multiple blocks. Tumor characteristics and HER2 studies (both immunohistochemistry and data from in situ hybridization) were reviewed. Regional differences in morphology and HER2 immunoreactivity were recorded. In situ hybridization was performed in 25 of 139 of the cases; patterns of genetic heterogeneity were reviewed. We audited discordances in HER2 result between blocks. RESULTS: Testing of multiple blocks yielded no additional HER2 information in 134 (96.4%) of 139 cases. Morphologic differences or heterogeneity in HER2 expression was observed in 22 (15.8%) of 139 of cases. Only 5 of these showed differences in HER2 between blocks, of which 4 were associated with equivocal HER2 immunohistochemistry, and 4 were high-grade. CONCLUSIONS: In the vast majority of cases, even those with heterogeneity, testing of a single block is sufficient for an accurate HER2 determination. High-grade tumors with equivocal HER2 status and observable heterogeneity are more likely to yield a different result on testing of additional blocks.

Implications of the 2013 ACC/AHA cholesterol guidelines for adults in contemporary cardiovascular practice: insights from the NCDR PINNACLE registry.

BACKGROUND: In a significant update, the 2013 American College of Cardiology/American Heart Association (ACC/AHA) cholesterol guidelines recommend fixed-dose statin therapy for those at risk and do not recommend nonstatin therapies or treatment to target low-density lipoprotein cholesterol (LDL-C) levels, limiting the need for repeated LDL-C testing. OBJECTIVES: The goal of this study was to examine the impact of the 2013 ACC/AHA cholesterol guidelines on current U.S. cardiovascular practice. METHODS: Using the NCDR PINNACLE (National Cardiovascular Data Registry Practice Innovation and Clinical Excellence) registry data from 2008 to 2012, we assessed current practice patterns as a function of the 2013 cholesterol guidelines. Lipid-lowering therapies and LDL-C testing patterns by patient risk group (atherosclerotic cardiovascular disease [ASCVD], diabetes, LDL-C ≥190 mg/dl, or an estimated 10-year ASCVD risk ≥7.5%) were described. RESULTS: Among a cohort of 1,174,545 patients, 1,129,205 (96.1%) were statin-eligible (91.2% ASCVD, 6.6% diabetes, 0.3% off-treatment LDL-C ≥190 mg/dl, 1.9% estimated 10-year ASCVD risk ≥7.5%). There were 377,311 patients (32.4%) not receiving statin therapy and 259,143 (22.6%) receiving nonstatin therapies. During the study period, 20.8% of patients had 2 or more LDL-C assessments, and 7.0% had more than 4. CONCLUSIONS: In U.S. cardiovascular practices, 32.4% of statin-eligible patients, as defined by the 2013 ACC/AHA cholesterol guidelines, were not currently receiving statins. In addition, 22.6% were receiving nonstatin lipid-lowering therapies and 20.8% had repeated LDL-C testing. Achieving concordance with the new cholesterol guidelines in patients treated in U.S. cardiovascular practices would result in significant increases in statin use, as well as significant reductions in nonstatin therapies and laboratory testing.

Impact of the 2014 expert panel recommendations for management of high blood pressure on contemporary cardiovascular practice: insights from the NCDR PINNACLE registry.

BACKGROUND: Since 2003, the Seventh Report of the Joint National Committee (JNC-7) has been the predominant guideline for blood pressure management. A 2014 expert panel recommended increasing the blood pressure targets for patients age 60 years and older, as well as those with diabetes or chronic kidney disease. OBJECTIVES: The purpose of this study was to examine the effect of the 2014 expert panel blood pressure management recommendations on patients managed in U.S. ambulatory cardiovascular practices. METHODS: Using the National Cardiovascular Data Registry PINNACLE Registry, we assessed the proportion of patients who met the 2003 and 2014 panel recommendations, highlighting the populations of patients for whom the blood pressure goals changed. RESULTS: Of 1,185,253 patients in the study cohort, 706,859 (59.6%) achieved the 2003 JNC-7 goals. Using the 2014 recommendations, 880,378 (74.3%) patients were at goal. Among the 173,519 (14.6%) for whom goal achievement changed, 40,323 (23.2%) had a prior stroke or transient ischemic attack, and 112,174 (64.6%) had coronary artery disease. In addition, the average Framingham risk score in this group was 8.5 ± 3.2%, and the 10-year ASCVD risk score was 28.0 ± 19.5%. CONCLUSIONS: Among U.S. ambulatory cardiology patients with hypertension, nearly 1 in 7 who did not meet JNC-7 recommendations would now meet the 2014 treatment goals. If the new recommendations are implemented in clinical practice, blood pressure target achievement and cardiovascular events will need careful monitoring, because many patients for whom the target blood pressure is now more permissive are at high cardiovascular risk.

HER2 testing of multifocal invasive breast carcinoma: how many blocks are enough?

OBJECTIVES: To determine the diagnostic yield of testing multiple blocks for HER2 in cases of multifocal breast carcinoma. METHODS: We identified 246 consecutive cases of multifocal invasive breast carcinoma in which HER2 was tested on more than 1 tumor focus. We performed an audit of all cases with respect to tumor size, grade, and histologic type. RESULTS: HER2 status was concordant between multiple foci in 230 (93.5%) of 246 cases, with the largest focus having the most positive HER2 result in 242 (98.4%) of 246 cases. We did not find a single case in which a smaller focus demonstrated a more positive HER2 status unless this focus was either higher grade or different histologically. CONCLUSIONS: Our findings support the evaluation of HER2 on the largest focus, with additional testing on smaller foci having a different histologic type or higher grade.

A comparison of ejaculated and testicular spermatozoa aneuploidy rates in patients with high sperm DNA damage.

Testicular spermatozoa are utilized to achieve pregnancy in couples with severe male factor infertility. Several studies suggest that aneuploidy rates in spermatozoa are elevated at the testicular level in infertile patients compared to ejaculates of normal controls. However, essential data regarding aneuploidy rates between ejaculated and testicular spermatozoa in the same individuals is lacking. The purpose of our study was to compare aneuploidy rates at the testicular and post-testicular level from the same patients with persistently high sperm DNA damage. Ejaculates and testicular biopsies were obtained from eight patients with persistently high DNA damage (>30%). Both ejaculated and testicular samples were analyzed for sperm DNA damage and sperm aneuploidy for chromosomes 13, 18, 21, X, and Y. In addition, semen samples from ten normozoospermic men presenting for fertility evaluation served as a control group. A strong correlation between the alteration of spermatogenesis and chromatin deterioration was observed in our study. In the same individuals, testicular samples showed a significantly lower DNA damage compared to ejaculated spermatozoa (14.9% ± 5.0 vs. 40.6% ± 14.8, P<0.05), but significantly higher aneuploidy rates for the five analyzed chromosomes (12.41% ± 3.7 vs. 5.77% ± 1.2, P<0.05). While testicular spermatozoa appear favourable for ICSI in terms of lower DNA damage, this potential advantage could be offset by the higher aneuploidy rates in testicular spermatozoa.

The utility and cost of Chlamydia trachomatis and Neisseria gonorrhoeae screening of a male infertility population.

OBJECTIVE: To determine the utility and cost of Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG) screening in infertile males. DESIGN: Cohort study. SETTING: Canadian tertiary-level male infertility clinic and university-affiliated laboratories. PATIENT(S): 5,588 male infertility patients. INTERVENTION(S): CT and NG testing on 8,972 urine and semen samples. MAIN OUTCOME MEASURE(S): Prevalence of CT and NG infection in infertile males versus general male population in Canada over 8 years (2003-2010) and the reagent cost to detect one case of CT or NG. RESULT(S): In infertile males, the prevalence rate for CT and NG was 0.304% and 0.0537%, which was statistically significantly lower (3.4- and 8.1-fold lower, respectively) than the age-adjusted general population prevalence. With the reagents costing $86.20 per patient tested, the reagent cost alone to diagnose one case of CT or NG was $38,669. CONCLUSION(S): The prevalence of CT and NG in this study are among the lowest reported in the male infertility literature. These findings question the utility of CT/NG screening in this low-risk population and emphasize that decisions about the utility of screening must be based on the prevalence rates of the disease in the studied population.

Diagnosis and treatment of azoospermia resulting from testicular sarcoidosis.

Genitourinary sarcoidosis is uncommon, with only rare documented cases of testicular involvement reported. We detail the case of a 37-year-old male who initially presented for azoospermia and secondary infertility. A testicular biopsy revealed nonnecrotizing granulomas and a chest x-ray identified perihilar lymphadenopathy and granulomatous lung nodules. A corticosteroid regimen was administered, and routine semen analyses were conducted. Significant improvements were noted after prednisone treatments. A successful in vivo fertilization was obtained. This is the first known case of testicular sarcoidosis diagnosed during investigations into azoospermia and secondary infertility which, after treatment with corticosteroids, resulted in natural fertilization.

Pathophysiology of fat embolism: a rabbit model.

OBJECTIVES: The objective of this study was to assess the effects of fat embolism on rabbit physiology. METHODS: After anesthetic administration, both femoral condyles of the right knee only of 23 New Zealand white rabbits were exposed through a medial parapatellar approach to the knee. In the pulmonary fat embolism group (n = 15), the femoral canal was drilled in a retrograde fashion and then reamed and pressurized with a 1- to 1.5-mL cement injection. In the no-pressurization group (n = 4), after reaming, no cement was injected. In the control group (n = 4), the knee incision was immediately closed. Animals were then observed for 5 hours. Hemodynamics and blood gases were recorded at standard intervals. Postmortem, the lungs were removed en bloc and fixed for histologic assessment and quantitative histomorphometry. RESULTS: Four intraoperative deaths occurred in the pulmonary fat embolism group immediately after pressurization and may have been associated with hypotension and cardiac arrest. In the pulmonary fat embolism group, pulmonary artery pressure increased, and both mean arterial pressure and PaO2 decreased after pressurization. Approximately 2% of lung volume was occupied by intravascular fat and there were no signs of perivascular inflammation. Control and no-pressurization animals remained stable throughout the experiment. CONCLUSIONS: This model simulates pulmonary fat embolism after long-bone fractures. Despite cardiorespiratory dysfunction, there was no evidence of fat initiating pulmonary inflammation based on histologic data within the timeframe of the investigation.

Disruption of telomere-telomere interactions associated with DNA damage in human spermatozoa.

Telomeres play a fundamental role in the organization of the sperm nucleus resulting in the looped chromosome configuration and non-random positioning of chromosomes. Telomeres localize in the nuclear periphery and interact dynamically by forming dimers and tetramers. The purpose of this study was to evaluate the relationship of telomere interactions to DNA damage, a factor known to adversely influence male fertility. Telomeres were localized by fluorescence in situ hybridization (FISH) using human chromosome pan-telomeric probe in ten samples with low and ten samples with high sperm DNA damage. The samples with a low DNA fragmentation index (DFI) had a mean number of telomere signals of 21.7±1.9 compared to a mean of 26.5±3.4 signals in the samples with a high DFI (p<.005). The percentage of cells with a typical telomere distribution of ≤23 telomere-telomere dimers was observed in 70.8%±15.6 samples with a low DFI compared to 44.2%±22.4 in samples with a high DFI (p<.05). These results suggest that sperm DNA damage is associated with disruption of the normal telomere-telomere interactions leading to possible loss of the looped chromosome configuration. Improperly packed and organized sperm chromatin might have a high probability of disrupting the extremely structured sequence of sperm chromosome deposition, activation, and processing by the oocyte at the time of fertilization. These results might provide additional information on the nature of sperm DNA damage and the role of such damage on fertilization and development of the zygote.

Frequency and severity of sperm DNA damage in patients with confirmed cases of male infertility of different aetiologies.

Men with high sperm DNA damage have a reduced fertility potential. Correlation of specific clinical factors to the degree of sperm DNA damage remains unclear. This retrospective study evaluated the frequency and severity of sperm DNA damage in men with different aetiologies of male factor infertility. Patients with male factor infertility (n=288) underwent flow cytometry-based sperm DNA damage assessment and results were correlated with the major aetiologies of male infertility: varicocele, bacteriospermia and idiopathic infertility. Sperm DNA damage was significantly correlated to the patient's age, sperm motility, normal morphology and vitality (P < 0.001). High sperm DNA damage (30%) was most frequently found in the group with bacteriospermia (48%), compared with 30% of the men with varicoceles and 22% of the men with idiopathic infertility (P < 0.02). While some tendency was observed for a correlation of increasing sperm DNA damage in patients with grade III and bilateral varicoceles, this difference did not reach statistical significance. The data support the importance of proper physical and laboratory investigations of the fertility status in men to correctly diagnose and treat male infertility.

Testicular spermatozoa have statistically significantly lower DNA damage compared with ejaculated spermatozoa in patients with unsuccessful oral antioxidant treatment.

OBJECTIVE: To compare DNA damage in ejaculated and testicular spermatozoa in patients with previously unsuccessful oral antioxidant treatment. DESIGN: Prospective clinical study. SETTING: University-affiliated teaching hospital. PATIENT(S): Twelve men with persistently high sperm DNA damage. INTERVENTION(S): Evaluation of DNA damage of ejaculated and testicular spermatozoa by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling (TUNEL) assay. MAIN OUTCOME MEASURE(S): The DNA damage of ejaculated spermatozoa compared with that of testicular spermatozoa, both samples collected on the day of intracytoplasmic sperm injection. RESULT(S): Ejaculated spermatozoa showed a threefold higher DNA damage when compared with testicular samples (39.7% +/- 14.8 vs. 13.3% +/- 7.3). CONCLUSION(S): Our results indicated that in patients with previously unsuccessful oral antioxidant treatment the retrieved testicular spermatozoa had a lower degree of DNA damage compared with ejaculated sperm collected on the same day.

Sperm DNA damage: correlation to severity of semen abnormalities.

OBJECTIVES: To analyze the relationship between DNA damage and standard semen parameters (SSP) in patients who present for fertility evaluation. Evaluation of male fertility includes assessment of the SSP and increasingly sperm DNA damage. However, the relationship between DNA damage and SSP remains controversial. METHODS: Following Institutional Research Ethics Board approval, semen samples from 2586 unselected nonazoospermic patients were subjected to computer-assisted semen analysis and flow cytometry-based sperm DNA damage assessment expressed as the DNA fragmentation index. RESULTS: Sperm DNA damage was significantly negatively correlated to sperm SSP (concentration, motility, and normal morphology) and positively correlated to patient's age. DNA damage increased in association with the number of abnormalities in SSP. Patients with oligoasthenoteratozoospermia had significantly higher DNA damage and more frequent DNA damage over 30% compared with normozoospermic patients and patients with abnormalities in 1 or 2 SSP. CONCLUSIONS: Our results indicate that DNA damage is significantly correlated to SSP as well as age. In addition, the degree of DNA damage increases with the number of abnormal parameters in a sample and is most severe in patients with oligoasthenoteratozoospermia. Complex and possibly age-related mechanisms of DNA damage in human spermatozoa may be responsible for the strong relationship between SSP and DNA fragmentation index.