Assessing genetic counselors' graduate school education and training in congenital heart defects.

Genetic counselors are one of the many providers involved in caring for patients with congenital heart defects (CHDs); however, little is known about the cardiovascular genetics training they receive by their graduate programs. To explore the recalled education experiences regarding CHDs by practicing genetic counselors, we surveyed graduates of programs primarily accredited by the American Council on Genetic Counseling (ACGC) about their graduate training in this area, the depth of CHD-specific education they received, and whether CHDs are a substantial referral indication in their current practice. Genetic counselors were recruited from the National Society of Genetic Counselors and Twitter (n = 112), and participants reflecting multiple specialties and 35 graduate programs completed an online survey which included questions about fieldwork placements and lectures in cardiovascular genetics, exposure to classification schemes regarding cardiac embryology, and education in counseling strategies for CHDs and CHD-related topics during their graduate training. When asked whether CHDs are a substantial referral indication seen in their current practice, 55% (62/112) responded yes. Most participants (79%, 88/112) recalled receiving some education about CHDs, but 91% (80/88) reported receiving little to no education regarding embryologic classification of CHDs and how to apply classification schemes to their counseling. Both participating prenatal and pediatric GCs reported that CHDs can be a common referral indication, yet they reported receiving limited education on teratogens associated with CHDs, family screening recommendations, and recurrence risk counseling for CHDs. Based on participant responses, the majority of respondents reported receiving sufficient education on syndromes with CHDs which can be beneficial in specialties such as pediatrics. This exploratory study provides insight into opportunities to further support genetic counseling educational opportunities for CHDs. These findings suggest genetic counseling graduate programs could consider implementing education on CHD counseling strategies as a standardized component of the curriculum and that practicing genetic counselors could benefit from educational opportunities and resources with updated information on this topic.

Adolescents with congenital heart defects: a patient and parental perspective of genetic information and genetic risk.

Congenital heart defects (CHDs) occur in 8 of 1000 live-born children, making them common birth defects in the adolescent population. CHDs may have single gene, chromosomal, or multifactorial causes. Despite evidence that patients with CHD want information on heritability and genetics, no studies have investigated the interest or knowledge base in the adolescent population. This information is necessary as patients in adolescence take greater ownership of their health care and discuss reproductive risks with their physicians. The objectives of this survey-based study were to determine adolescents' recall of their own heart condition, to assess patient and parent perception of the genetic contribution to the adolescent's CHD, and to obtain information about the preferred method(s) for education. The results show that adolescent patients had good recall of their type of CHD. Less than half of adolescents and parents believed their CHD had a genetic basis or was heritable; however, adolescents with a positive family history of CHD were more likely to believe that their condition was genetic (p = 0.0005). The majority of patients were interested in receiving additional genetics education and preferred education in-person and in consultation with both parents and a physician. The adolescents who felt most competent to have discussions with their doctors regarding potential causes of their heart defect previously had a school science course which covered topics in genetics. These results provide insight into adolescents' perceptions and understanding about their CHD and genetic risk and may inform the creation and provision of additional genetic education.

The impact of cardiovascular genetic counseling on patient empowerment.

Cardiovascular genetic counseling (CVGC) is recommended for a variety of inherited heart conditions; however, its impact on patient empowerment has not been assessed. The Genetic Counseling Outcome Scale (GCOS) is a validated patient reported outcome tool which measures empowerment to capture the impact of clinical genetics services. As a routine clinical practice at our center, adult patients attending a CVGC appointment complete the 24-item GCOS survey and a 5-item survey on knowledge of cardiac surveillance recommendations for relatives prior to the clinic visit. To investigate the effect of CVGC, we contacted participants after the appointment to repeat these surveys prior to genetic test result disclosure. Forty-two participants completed pre- and post-GC surveys. The mean difference between pre- and post-GC empowerment scores was 17.5 points (mean pre-GC score = 118.5, mean post-GC score = 136, p < 0.0001; effect size, d = 0.94). Forty percent of individuals (17/42) were aware of surveillance recommendations for at-risk family members prior to GC; this increased to 76% of individuals (32/42) post-GC (p < 0.01). This is the first study to explore patient empowerment before and after GC in a cardiology setting. The results demonstrate a significant increase in empowerment and awareness of recommendations for at-risk relatives as a result of CVGC. This study demonstrates the utility of CVGC in patient care.

Prognostic biomarkers for acute graft-versus-host disease risk after cyclophosphamide-fludarabine nonmyeloablative allotransplantation.

Five candidate plasma biomarkers (suppression of tumorogenesis 2 [ST2], regenerating islet-derived-3α [REG3α], elafin, tumor necrosis factor receptor 1 [TNFR1], and soluble IL-2 receptor-alpha [sIL2Rα]) were measured at specific time points after cyclophosphamide/fludarabine-based nonmyeloablative allotransplantation (NMAT) in patients who did or did not develop acute graft-versus-host disease (aGVHD). Plasma samples from 34 patients were analyzed at days +7, +14, +21, and +30. At a median follow-up of 358 days, 17 patients had experienced aGVHD with a median time to onset at day +36. Risk of aGVHD was associated with elevated plasma ST2 concentrations at day +7 (c-statistic = .72, P = .03), day +14 (c-statistic = .74, P = .02), and day +21 (c-statistic = .75, P = .02); elevated plasma REG3α concentrations at day +14 (c-statistic = .73, P = .03), day +21 (c-statistic = .76, P = .01), and day +30 (c-statistic = .73, P = .03); and elevated elafin at day +14 (c-statistic = .71, P = .04). Plasma concentrations of TNFR1 and sIL2Rα were not associated with aGVHD risk at any of the time points studied. This study identified ST2, REG3α, and elafin as prognostic biomarkers to evaluate risk of aGVHD after cyclophosphamide/fludarabine-based NMAT. These results need to be confirmed in an independent validation cohort.

Dolutegravir: An Integrase Strand Transfer Inhibitor for the Treatment of Human Immunodeficiency Virus 1 in Adults.

Objective: To review the efficacy, safety, pharmacokinetics, pharmacodynamics, administration, drug interactions, and cost of dolutegravir (Tivicay), a third in class integrase strand transfer inhibitor (INSTI), for the treatment of human immunodeficiency virus (HIV-1) in adults. Data Sources: MEDLINE, International Pharmaceutical Abstracts, ClinicalTrials.gov, and Google Scholar searches (January 2000 to May 2014) were conducted for articles published in English and limited to human subjects, using the key words antiretroviral drugs, HIV integrase strand transfer inhibitors, dolutegravir, DTG, and S/GSK1349572. Study Selection and Data Extraction: Following MEDLINE, International Pharmaceutical Abstracts, ClinicalTrials.gov, and Google Scholar searches, 6 clinical trials were identified and included in this review. Phase III/IV studies evaluating the safety and efficacy of dolutegravir in humans were selected and evaluated. Data Synthesis: In treatment naïve and experienced patients dolutegravir was noninferior to raltegravir at suppressing viral load when added to background therapy. Abacavir/lamivudine/dolutegravir was noninferior to efavirenz/emtricitabine/tenofovir disoproxil fumarate and darunavir/ritonavir plus background therapy at suppressing viral load. In patients with multiple-class antiretroviral resistance at baseline, dolutegravir decreased HIV RNA by 1.4 log10 copies/mL at day 8, 63% of patients had achieved virologic suppression at week 8, and retained potency in treatment-experienced INSTI-resistant patients up to week 48 or 96 of follow-up. Conclusion: Dolutegravir is a safe, effective, and well-tolerated treatment option for adults with HIV-1, even in the setting of resistance to other antiretrovirals.

Teplizumab for treatment of type 1 diabetes mellitus.

OBJECTIVE: To review the pharmacology, pharmacokinetics, safety, and efficacy of teplizumab and evaluate relevant clinical trial data. DATA SOURCES: Searches of MEDLINE, International Pharmaceutical Abstracts, ClinicalTrials.gov, American Diabetes Association scientific posters, and Google Scholar (1966-May 2012) were conducted using the key words teplizumab, anti-CD3 monoclonal antibody, MGA031, and hOKT3γ1 (Ala-Ala). Searches were limited to articles published in English. STUDY SELECTION AND DATA EXTRACTION: Clinical trials evaluating teplizumab for type 1 diabetes mellitus (T1DM) published in English were selected from the data sources. All published relevant abstracts were included. References cited in identified articles were used for additional citations. DATA SYNTHESIS: T1DM accounts for up to 10% of all cases of diabetes mellitus. T1DM is characterized as a chronic and progressive autoimmune disease leading to the destruction of insulin-producing ß-cells of the pancreas. Teplizumab is a humanized Fc-mutated anti-CD3 monoclonal antibody that alters the function of the T-lymphocytes that mediate the destruction of the insulin-producing ß-cells. While clinical data are limited, both Phase 2 and Phase 3 studies have demonstrated preserved C-peptide response as a measure of insulin production, decreased exogenous insulin use, and improved glycemic control following a 12- to 14-day teplizumab infusion in patients diagnosed with T1DM within the previous 6 weeks. However, 1 Phase 3 trial failed to find the same benefits in those diagnosed with T1DM within the previous 12 weeks when a lower cumulative teplizumab dose was used. Initial studies indicated that teplizumab is well tolerated, with a self-limiting rash as the most commonly reported adverse effect. CONCLUSIONS: Teplizumab is an anti-CD3 human monoclonal antibody with promising activity in treatment of patients with T1DM. Results from Phase 3 trials are needed to further determine safety, efficacy, and dosing frequency.

Learning to Crawl: Determining the Role of Genetic Abnormalities on Postoperative Outcomes in Congenital Heart Disease.

Background Our cardiac center established a systematic approach for inpatient cardiovascular genetics evaluations of infants with congenital heart disease, including routine chromosomal microarray (CMA) testing. This provides a new opportunity to investigate correlation between genetic abnormalities and postoperative course. Methods and Results Infants who underwent congenital heart disease surgery as neonates (aged ≤28 days) from 2015 to 2020 were identified. Cases with trisomy 21 or 18 were excluded. Diagnostic genetic results or CMA with variant of uncertain significance were considered abnormal. We compared postoperative outcomes following initial congenital heart disease surgery in patients found to have genetic abnormality to those who had negative CMA. Among 355 eligible patients, genetics consultations or CMA were completed in 88%. A genetic abnormality was identified in 73 patients (21%), whereas 221 had negative CMA results. Genetic abnormality was associated with prematurity, extracardiac anomaly, and lower weight at surgery. Operative mortality rate was 9.6% in patients with a genetic abnormality versus 4.1% in patients without an identified genetic abnormality (P=0.080). Mortality was similar when genetic evaluations were diagnostic (9.3%) or identified a variant of uncertain significance on CMA (10.0%). Among 14 patients with 22q11.2 deletion, the 2 mortality cases had additional CMA findings. In patients without extracardiac anomaly, genetic abnormality was independently associated with increased mortality (P=0.019). CMA abnormality was not associated with postoperative length of hospitalization, extracorporeal membrane oxygenation, or >7 days to initial extubation. Conclusions Routine genetic evaluations and CMA may help to stratify mortality risk in severe congenital heart disease with syndromic or nonsyndromic presentations.

Psychological distress in response to physical activity restrictions in patients with non-syndromic thoracic aortic aneurysm/dissection.

Individuals diagnosed with thoracic aortic aneurysm/dissection (TAAD) are given activity restrictions in an attempt to mitigate serious health complications and sudden death. The psychological distress resulting from activity restrictions has been established for other diseases or patient populations; however, individuals with non-syndromic TAAD have not been previously evaluated. Seventy-nine participants completed a questionnaire utilizing the Patient Health Questionnaire (PHQ-9) and Generalized Anxiety Disorder (GAD-7) questionnaires, which assess levels of depression and anxiety respectively. Additionally, quantitative and qualitative questions explored self-reported psychological distress in response to activity restrictions. Individuals who reported higher PHQ + GAD scores had been living with a diagnosis longer than two years (p = 0.0004), were between 35 and 65 years old (p = 0.05), reported not coping well (p = 0.0035), and reported physical activity was "very important" (p = 0.04). Results from individual questions showed that individuals who reported their diagnosis affected them financially were 3.5 times more likely to report "feeling nervous, anxious, or on edge" (CI = [0.81, 15.6], p = 0.094). Qualitative analysis revealed themes that identified participant beliefs regarding distress, ability to cope, hindrances to coping ability, and resources. These results show psychological distress can result from physical activity restrictions in non-syndromic TAAD individuals. Additionally, certain subpopulations may be more susceptible to distress. This is the first study to examine the psychological distress individuals with non-syndromic TAAD experience as a result of prescribed activity restrictions. Genetic counselors and other healthcare professionals can utilize this information to provide more tailored cardiovascular genetic counseling and increase its therapeutic potential for patients.

An Emergent Nexus between Striae and Thoracic Aortic Dissection.

Current approaches to stratify the risk for disease progression in thoracic aortic aneurysm (TAA) lack precision, which hinders clinical decision making. Connective tissue phenotyping of children with TAA previously identified the association between skin striae and increased rate of aortic dilation. The objective of this study was to analyze associations between connective tissue abnormalities and clinical endpoints in adults with aortopathy. Participants with TAA or aortic dissection (TAD) and trileaflet aortic valve were enrolled from 2016 to 2019 in the setting of cardiothoracic surgical care. Data were ascertained by structured interviews with participants. The mean age among 241 cases was 61 ± 13 years. Eighty (33%) had history of TAD. While most participants lacked a formal syndromic diagnosis clinically, connective tissue abnormalities were identified in 113 (47%). This included 20% with abdominal hernia and 13% with skin striae in atypical location. In multivariate analysis, striae and hypertension were significantly associated with TAD. Striae were associated with younger age of TAD or prophylactic aortic surgery. Striae were more frequent in TAD cases than age- and sex-matched controls. Thus, systemic features of connective tissue dysfunction were prevalent in adults with aortopathy. The emerging nexus between striae and aortopathy severity creates opportunities for clinical stratification and basic research.

A review of the efficacy and safety of canagliflozin in elderly patients with type 2 diabetes.

OBJECTIVE: To review the efficacy and safety of canagliflozin (CAN) in elderly patients with type 2 diabetes mellitus (T2DM). DATA SOURCES: Studies were identified using PubMed, International Pharmaceutical Abstracts, MEDLINE, Academic Search Premier, SCOPUS, and Google Scholar from 2011 to August 2013. The following key words were reviewed: canagliflozin, canagliflozin elderly, canagliflozin geriatrics, dapagliflozin, sodium glucose cotransporter 2 (SGLT2) inhibitors, and SGLT2 receptor inhibitors. DATA EXTRACTION: Articles evaluating CAN for diabetes that were published in English and used human subjects were selected. Fifteen clinical trials were identified and evaluated. STUDY SELECTION: Of 15 identified articles, 2 articles, 2 published posters, and unpublished information from the manufacturer were chosen based on the mean age of the study subjects. DATA SYNTHESIS: Evidence that elderly patients with T2DM have less A1C reduction with CAN is presented; the benefit on A1C is significant. Systolic blood pressure (SBP) and body weight reduction in the elderly were consistent with younger patients. Adverse effects such as increased urinary frequency, genital mycotic infections, and urinary tract infections may discourage the use of CAN in the elderly patient. CONCLUSION: Treatment with CAN improves A1C levels, reduces SBP and body weight, and is overall well tolerated in older subjects with T2DM. Risks and benefits of treatment with CAN should be assessed in geriatric patients on a case-by-case basis. Safety in elderly patients was consistent with that of other phase 3 trials in the general population. Additional longterm cardiovascular studies are needed.

Aclidinium bromide for the treatment of chronic obstructive pulmonary disease.

PURPOSE: The safety and efficacy of the second U.S.-approved long-acting inhaled anticholinergic for controlling bronchospasm in patients with chronic obstructive pulmonary disease (COPD) are reviewed. SUMMARY: Aclidinium bromide (Tudorza, Forest Pharmaceuticals) is indicated for long-term maintenance therapy for COPD-associated bronchospasm. It is marketed as a 60-dose metered-dose inhaler to be used twice daily. In Phase II and III clinical trials involving a total of more than 3000 patients, daily use of aclidinium bromide was found to significantly improve selected key indicators of lung function (trough values for forced expiratory volume at one second [FEV1] and other FEV1 outcome measures) compared with placebo use. Other benefits of aclidinium bromide therapy, including a significant reduction in nighttime COPD symptoms, were demonstrated for up to one year. However, aclidinium bromide has not been consistently demonstrated to be more effective than the other currently available long-acting inhaled anticholinergic, tiotropium bromide. Furthermore, the clinical trials indicated no significant difference between aclidinium bromide and tiotropium bromide with regard to rates of systemic adverse effects. For some patients, aclidinium bromide may offer advantages over tiotropium bromide (e.g., a faster time to peak FEV1, lower cost of therapy). CONCLUSION: Aclidinium bromide is an inhaled anticholinergic that improves lung function measures in patients with COPD. The most common adverse effects during clinical trials of the drug were headache, nasopharyngitis, and cough, none of which occurred at significantly higher rates than were seen with placebo use.

Combination exenatide-sitagliptin therapy used with glipizide in a patient with type 2 diabetes mellitus.

PURPOSE: The case of a patient with type 2 diabetes mellitus who received combination exenatide-sitagliptin with glipizide is reported. SUMMARY: A 55-year-old, 204-lb Caucasian woman arrived at a clinic with polydipsia. Her blood glucose concentration was 450 mg/dL and her glycosylated hemoglobin (HbA(1c)) value was 13.4%. She was diagnosed with type 2 diabetes mellitus and started on metformin hydrochloride 500 mg orally twice daily. Metformin was later discontinued due to elevated liver function test values. Sitagliptin 100 mg daily was substituted, and glipizide was later added and its dosage adjusted over the next several months. After six months, her HbA(1c) value had decreased to 9.3% and she had gained 14 lb. Exenatide was then added to her regimen, and the dosage was adjusted to 10 µg subcutaneously twice daily. Two months after the initiation of sitagliptin, glipizide, and exenatide, the patient had lost 10 lb, reported significant improvements in self-monitored blood glucose readings, and required a reduction in glipizide dosage despite no reported therapeutic lifestyle changes. Seven months after the initiation of exenatide, sitagliptin, and glipizide, her HbA(1c) value was 7.4%. Triple therapy resulted in a total HbA(1c) value reduction of 1.9%, a weight loss of 11 lb, and normalized liver function test values. The patient's high blood pressure was treated with losartan and remained at goal throughout the duration of this report. CONCLUSION: In a patient with type 2 diabetes mellitus, the addition of the incretin mimetic exenatide and the dipeptidyl peptidase-4 inhibitor sitagliptin to glipizide therapy appeared effective and safe.