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ObjectivesWomen with Turner syndrome (TS) are frequently counselled against pregnancy due to lack of data and unclear aortic dissection risk. However, with advances in fertility therapy, more women with TS are contemplating pregnancy. This study compared rates of adverse cardiovascular (CV) outcomes among: (1) pregnant and non-pregnant women with TS and (2) pregnant women with TS with/without structural heart disease.MethodsRetrospective analysis of pregnant and age-matched non-pregnant controls with TS (2005–2017) across 10 CV centres was done. Data were collected at initial evaluation in pregnancy and outcomes were assessed to 6 months postpartum. Adverse CV events were defined as CV death, aortic dissection/rupture and/or aortic intervention. Non-pregnant age-matched controls were followed over the same time period.ResultsSixty-eight pregnancies were included (60 women, mean age 33 years, 48% primigravid, 49% fertility therapy, 80% structurally normal heart, 25% XO karyotype). Based on American Society of Reproductive Medicine criteria, 10 pregnancies occurred in women stratified to high-risk category. There were no CV events in the pregnant women or in the non-pregnant women with TS. Obstetric events complicated 12 (18%) pregnancies with 9 (13%) attributed to hypertensive disorder of pregnancy. Fetal events included small for gestational age neonates (18%), preterm delivery (15%) and fetal death (3%).ConclusionsThis study helps to refine the approach to pregnancy in women with TS. Among women with TS without structural heart disease, pregnancy does not impose an increased risk of CV outcomes. Among women with TS with structural heart disease, the risk of pregnancy is not as prohibitive as previously described but does require ongoing evaluation.

Bleeding is the most common complication of anticoagulant use. The evaluation and management of the bleeding patient is a core competency of emergency medicine. As the prevalence of patients receiving anticoagulant agents and variety of anticoagulants with different mechanisms of action, pharmacokinetics, indications, and corresponding reversal agents increase, physicians and other clinicians working in the emergency department require a current and nuanced understanding of how best to assess, treat, and reverse anticoagulated patients. In this project, we convened an expert panel to create a consensus decision tree and framework for assessment of the bleeding patient receiving an anticoagulant, as well as use of anticoagulant reversal or coagulation factor replacement, and to address controversies and gaps relevant to this topic. To support decision tree interpretation, the panel also reached agreement on key definitions of life-threatening bleeding, bleeding at a critical site, and emergency surgery or urgent invasive procedure. To reach consensus recommendations, we used a structured literature review and a modified Delphi technique by an expert panel of academic and community physicians with training in emergency medicine, cardiology, hematology, internal medicine/thrombology, pharmacology, toxicology, transfusion medicine and hemostasis, neurology, and surgery, and by other key stakeholder groups.

Surveillance and management guidelines for Fontan patients are lacking due to the paucity of evidence in the literature of screening efficacy on outcome measures. The Fontan Working Group within the New England Congenital Cardiology Association designed an electronic survey to assess surveillance practices for patients with Fontan procedures among New England congenital cardiologists and to explore variability in screening low‐risk vs high‐risk Fontan patients across regional programs. Fifty‐six cardiologists representing 12 regional programs responded to the survey, comprising ~40% of the total New England congenital cardiac physicians. The majority of desired testing and consultation was available within 50 miles of the patient's home institution with some limitations of cardiac catheterization and cardiac magnetic resonance imaging availability. Surveillance and screening were less frequent in low‐risk Fontan patients compared to high‐risk Fontan patients. Counseling practices were similar for both low‐risk and high‐risk Fontan patients. Aspirin monotherapy was recommended by 82% of providers for low‐risk Fontan patients, while anticoagulation regimens were more varied for the high‐risk population. Practitioners with ≤15 years of experience were more likely to provide quality of life testing in both low‐risk and high‐risk Fontan patients. There were no other major differences in testing frequencies by years of practice, quaternary vs nonquaternary care facility, or the number of Fontan patients in a practice. This survey provides insight into regional practices of screening and surveillance of Fontan patients. These data may be used to design future research studies and evidence‐based guidelines to streamline the approach to manage these complex patients.

Life expectancy and quality of life for those born with congenital heart disease (CHD) have greatly improved over the past 3 decades. While representing a great advance for these patients, who have been able to move from childhood to successful adult lives in increasing numbers, this development has resulted in an epidemiological shift and a generation of patients who are at risk of developing chronic multisystem disease in adulthood. Noncardiac complications significantly contribute to the morbidity and mortality of adults with CHD. Reduced survival has been documented in patients with CHD with renal dysfunction, restrictive lung disease, anemia, and cirrhosis. Furthermore, as this population ages, atherosclerotic cardiovascular disease and its risk factors are becoming increasingly prevalent. Disorders of psychosocial and cognitive development are key factors affecting the quality of life of these individuals. It is incumbent on physicians who care for patients with CHD to be mindful of the effects that disease of organs other than the heart may have on the well-being of adults with CHD. Further research is needed to understand how these noncardiac complications may affect the long-term outcome in these patients and what modifiable factors can be targeted for preventive intervention.

Recurrent ascites is a common manifestation of failing Fontan circulation. We present the hemodynamic response to large-volume paracentesis in a patient with Fontan circulation and Fontan-associated liver disease, documenting an immediate and substantial decline in systemic venous pressure and increase in cardiac output. These preliminary observations may have implications for the management of ascites in adults with Fontan circulation.

Introduction:Fifteen-year survival after Fontan operation approaches 95%, but morbidities are increasingly prevalent. It is unknown how well cardiologists can predict which pts are at risk for major adverse events (MAE), but awareness is critical to enable appropriate counseling. We asked cardiologists the “surprise” question: would you be surprised if your patient has a MAE in the next year?Methods:We performed a prospective, multi-center study across New England. The attending cardiologist was asked the yes/no “surprise” question. Inclusion criteria included lateral tunnel or extracardiac Fontan and age >10 yrs; individuals were excluded for current transplant evaluation, history of Fontan conversion, or pregnancy. Baseline clinical data were collected. After 12 months, cardiologists were surveyed to assess for MAE (see Table) and multivariate analysis (MVA) was performed for those deemed to be at risk and those with MAE.Results:From 2018-19, 146 pts and 40 cardiologists were enrolled at 9 sites. 99/146 pts (68%) were predicted to be a “Good Fontan.” After 1 yr, 17 (12%) patients experienced a MAE (Table). The simple kappa coefficient of ability to predict MAE was 0.17 (95% CI 0.02-0.32), suggesting ability to predict MAE was only 17% better than random chance. In MVA of those at risk (47/146), diuretic/beta blocker use (p=<0.0001) and systolic dysfunction (p=0.0046) were associated with identified risk. MVA of pts who experienced MAE (n=17) found prior unplanned cardiac admission (p=0.0062), diuretic/beta blocker use (p=0.028) and significant AV valve regurgitation (p=0.049) to be associated with MAE.Conclusions:Cardiologists are only marginally able to identify which Fontan pts are at risk for MAE in the next year. There was overlap between factors associated with prediction of “at risk” group and MAE, namely use of diuretic/blocker and the linked systolic dysfunction/AV valve regurgitation, which merits close attention in follow-up and further study.

Exercise oscillatory ventilation (EOV) refers to regular oscillations in minute ventilation (VE) during exercise. Its presence correlates with heart failure severity and worse prognosis in adults with acquired heart failure. We evaluated the prevalence and predictive value of EOV in patients with single ventricle Fontan physiology.

Biomarkers are increasingly part of assessing and managing heart failure (HF) in adults with congenital heart disease (CHD).

The Fontan procedure has undergone many modifications since first being performed on a patient with tricuspid valve atresia in 1968. It is now the procedure of choice for individuals born with single‐ventricle physiology or for those in whom a biventricular repair is not feasible. Forty years of experience with the Fontan procedure have gradually revealed the shortfalls of such a circulatory arrangement. Sequelae related to the underlying congenital anomaly or to the altered physiology of passive, nonpulsatile flow through the pulmonary arterial bed can result in failure of the Fontan circulation over time. Liver abnormalities including abnormalities in the clotting cascade have been well documented in Fontan patients. The clinical significance of these findings, however, has remained poorly understood. As Fontan survivors have increased in age and number, we have begun to better recognize subclinical hepatic dysfunction and the contribution of liver disease to adverse outcomes in this population. The purpose of this review is to summarize the existing data pertaining to liver disease in the Fontan population and to identify some questions that have yet to be answered.

Type I diabetes is characterized by destruction of insulin-producing β-islet cells in the pancreas resulting in hyperglycemia and associated morbidity. The successful treatment of diabetes by transplanted islets has resulted in renewed efforts to identify methods to augment islet availability. One approach is to identify and expand islet precursor cells able to later differentiate into functional endocrine cells. A population of cytokeratin 19–negative, vimentin-positive, insulin-negative, glucagon-negative, and nestin-positive cells was cultured from human fetal pancreas and passaged for over 20 population doublings. These cells were stimulated to form cell aggregates when grown on poly-D-lysine (PDL)–coated surfaces and then evaluated for differentiation potential using in vivo function as a surrogate marker for the presence of differentiated precursor cells. Streptozotocin-induced diabetic SCID mice implanted with PDL-induced cell aggregates were able to maintain glucose concentrations below 200 mg/dL for over 70 days (n 5). In addition, human C-peptide was detectable in implanted animals but not in control animals. These findings show that a population of human fetal pancreas–derived cells (1) can be cultured and expanded in vitro, (2) can maintain the ability to differentiate into β-islet-like cells, and (3) can correct hyperglycemia in a mouse model of diabetes. Further improvements in isolation, culture, and differentiation of human pancreas–derived β-cell precursors may one day help to provide a novel source of islets for use in transplantation therapy to treat type I diabetes.

The Model for End-stage Liver Disease excluding INR (MELD-XI) is commonly used to identify patients with a Fontan circulation at increased risk of adverse events, However, this approach has not been evaluated in unselected ambulatory adults.

Programmed cell death is an important regulatory event in spermatogenesis. However, the molecular events governing apoptosis have not been characterized. Using the Leydig cell-specific toxin ethane dimethanesulfonate (EDS) to withdraw androgen support, we have investigated the relationship between apoptosis and apoptosis-related genes. Adult male Sprague-Dawley rats were injected (i.p.) with 100 mg/kg EDS and killed at times of androgen depletion 2, 5, and 8 days postinjection. A 24-fold increase in the apoptotic index 8 days after EDS administration was demonstrated in tissue sections by in situ end-labeling of fragmented DNA. Leydig cell death and androgen withdrawal were confirmed by the absence of 3β-hydroxysteroid dehydrogenase in testes from animals treated with EDS for 2 days. After androgen withdrawal, there were no significant changes in the levels of clusterin, Bcl-xl, Bak, and Bad. However, the expression of Bcl-2 and Bax was up-regulated at 8 days after EDS administration. The induction of Bax at this time suggests that it may play a role in germ cell apoptosis following androgen withdrawal. The concomitant elevation in Bcl-2 expression may represent a survival mechanism for the remaining germ cells. There was also a decline in the expression of Fas-L and Fas-R in the pachytene spermatocytes and spermatids. Fas-R was also present in Sertoli cells, although Fas-L staining was minimal. As the colocalization of Fas-L and Fas-R correlates with the germ cell types that die in response to androgen withdrawal, the potential exists for apoptosis in the rat spermatogenic epithelium to be regulated by the Fas pathway.

Diabetes is due to loss of appropriate insulin production by pancreatic islet cells, resulting in hyperglycemia and significant morbidity. We have developed cell cultures of pancreas-derived precursor cells that can be maintained for more than 20 population doublings in culture, growing as monolayers of undifferentiated cells. These monolayer cells can then be induced to differentiate into cellular aggregates that resemble islets when grown on different extracellular matrix components, including matrigel, or poly-d-lysine. The induced cellular aggregates, but not monolayer cells, correct hyperglycemia in diabetic (streptozotocin) SCID (severe combined immunodeficiency) mice after implantation under the kidney capsule. This animal model can be used to follow the process of differentiation from undifferentiated precursor cell to fully functional insulin producing beta cells, and to identify key proteins and genes involved in differentiation of pancreatic islet cells. Here we report that in the mice, after implantation of cellular aggregates, human c-peptide concentrations are controlled physiologically appropriately in response to glucose tolerance testing (challenged with 2 grams of glucose injected intraperitoneally) in the treated diabetic SCID mice (n = 6) as well as in normal mice that received implanted cellular aggregates (n = 6). Human c peptide is not detected in any of the control animals, nor in animals implanted with monolayer cells. Comparative RNA microarray data analyses, using U133 arrays (Affymetrix), were compared between the monolayer cells in culture and the cellular aggregates 48 hours after induction with poly-d-lysine. We consider of particular interest the up-regulation of BMP, CXCR4, and HGF in the cell aggregates, and the down-regulation of VCAM-1. We believe that these genes are necessary for either aggregation or for physiologically functional insulin secretion. When examined for greater than two-fold gene expression differences between monolayer and aggregated cells, 424 gene sequences were upregulated and 690 genes down regulated. In addition, RAGE display analysis for tyrosine kinases also showed that the kinases Erb-B2 and PDGFR-B were upregulated at 48 hours in the aggregating process. In contrast, DDR2, a collagen I receptor tyrosine kinase, was expressed equally in both monolayer and aggregated cells. In summary, the results suggest: 1) that a population of pancreatic stem cells can be isolated and cultured in vitro, 2) that these cells can be induced to form functional islet cells that correct hyperglycemia in diabetic mice, 3) that human c-peptide is physiologically regulated in aggregate implanted mice in response to glucose challenge, and 4) HGF, along with other genes of potential interest, is upregulated in the process of differentiation from monolayer to aggregated cell phenotype.

Diabetes is due to loss of appropriate insulin production by pancreatic islet cells, resulting in hyperglycemia and significant morbidity. We have developed cell cultures of pancreas-derived precursor cells that can be maintained for more than 20 population doublings in culture, growing as monolayers of undifferentiated cells. These monolayer cells can then be induced to differentiate into cellular aggregates that resemble islets when grown on different extracellular matrix components, including matrigel, or poly-d-lysine. The induced cellular aggregates, but not monolayer cells, correct hyperglycemia in diabetic (streptozotocin) SCID (severe combined immunodeficiency) mice after implantation under the kidney capsule. This animal model can be used to follow the process of differentiation from undifferentiated precursor cell to fully functional insulin producing beta cells, and to identify key proteins and genes involved in differentiation of pancreatic islet cells. Here we report that in the mice, after implantation of cellular aggregates, human c-peptide concentrations are controlled physiologically appropriately in response to glucose tolerance testing (challenged with 2 grams of glucose injected intraperitoneally) in the treated diabetic SCID mice (n = 6) as well as in normal mice that received implanted cellular aggregates (n = 6). Human c peptide is not detected in any of the control animals, nor in animals implanted with monolayer cells. Comparative RNA microarray data analyses, using U133 arrays (Affymetrix), were compared between the monolayer cells in culture and the cellular aggregates 48 hours after induction with poly-d-lysine. We consider of particular interest the up-regulation of BMP, CXCR4, and HGF in the cell aggregates, and the down-regulation of VCAM-1. We believe that these genes are necessary for either aggregation or for physiologically functional insulin secretion. When examined for greater than two-fold gene expression differences between monolayer and aggregated cells, 424 gene sequences were upregulated and 690 genes down regulated. In addition, RAGE display analysis for tyrosine kinases also showed that the kinases Erb-B2 and PDGFR-B were upregulated at 48 hours in the aggregating process. In contrast, DDR2, a collagen I receptor tyrosine kinase, was expressed equally in both monolayer and aggregated cells. In summary, the results suggest: 1) that a population of pancreatic stem cells can be isolated and cultured in vitro, 2) that these cells can be induced to form functional islet cells that correct hyperglycemia in diabetic mice, 3) that human c-peptide is physiologically regulated in aggregate implanted mice in response to glucose challenge, and 4) HGF, along with other genes of potential interest, is upregulated in the process of differentiation from monolayer to aggregated cell phenotype.

The telomeric repeat amplification protocol (TRAP) assay has been used to test telomerase activity in numerous cancer specimens. We describe primers, controls and quantification methods for the TRAP assay to accurately measure the level of telomerase activity in clinical samples. The assay is reliable and reproducible in routine analyses and can be used to estimate the processivity of telomerase activity.