Genetic counselors' and community clinicians' implementation and perceived barriers to informed consent during pre-test counseling for hereditary cancer risk.

As demand for genetic cancer risk assessment (GCRA) continues to increase, so does the sense of urgency to scale up efforts to triage patients, facilitate informed consent, and order genetic testing for cancer risk. The National Society of Genetic Counselors outlines the elements of informed consent that should be addressed in a GCRA session. While this practice resource aims to improve health equity, research on how well the elements of informed consent are implemented in practice is lacking. This retrospective and prospective mixed-methods study assessed how adequately the elements of informed consent are addressed during pre-test GCRA among 307 community clinicians (CC) and 129 cancer genetic counselors (GC), and barriers they face to addressing these elements. Results revealed that more than 90% of both cohorts consistently addressed components of at least 5 of the 10 elements of informed consent during a pre-test consultation. Technical aspects and accuracy of the test and utilization of test results were the most similarly addressed elements. Notably, GCs more often review the purpose of the test and who to test, general information about the gene(s), and economic considerations whereas CCs more often review alternatives to testing. Both cohorts reported psychosocial aspects of the informed consent process as the least adequately addressed element. Time constraints and patient-related concerns were most often cited by both cohorts as barriers to optimal facilitation of informed consent. Additional barriers reported by CCs included provider lack of awareness, experience, or education, and availability of resources and institutional support. Findings from this study may contribute to the development of alternative delivery models that incorporate supplementary educational tools to enhance patient understanding about the utility of genetic testing, while helping to mitigate the barrier of time constraints. Equally important is the use of this information to develop continuing education tools for providers.

Clinical and laboratory genetic counselor attitudes on the reporting of variants of uncertain significance for multigene cancer panels.

Research suggests variants of uncertain significance (VUSs) present a variety of challenges for genetic counselors (GCs), nongenetics clinicians, and patients. Multigene cancer panels reveal more VUSs than single gene testing as a result of the increase in the number of genes being tested. This study surveyed 87 clinical cancer GCs involved with direct patient care and 19 laboratory GCs who provide guidance to clinicians regarding genetic test results about their attitudes on various options for the reporting of VUSs by laboratories for broad multigene cancer panels. Independent samples t-tests were utilized to compare the two groups. Based on a six-point Likert-type scale (1 = Strongly Disagree to 6 = Strongly Agree), clinical cancer GCs (M = 5.4; SD = 0.8) and laboratory GCs (M = 5.2; SD = 0.9) agreed overall that VUSs should be reported (p = 0.44; Cohen's d = 0.21). When asked about specific reporting options, both clinical cancer GCs (M = 1.9; SD = 1.1) and laboratory GCs (M = 2.1; SD = 1.4) disagreed that VUSs should be reported only for genes related to the indication for testing (p = 0.50; Cohen's d = 0.17). Overall, most GCs felt clinicians should not choose whether VUSs should be reported on genetic test results, with clinical cancer GCs (M = 1.9; SD = 1.3) feeling more strongly against it than laboratory GCs (M = 3.1; SD = 1.4; p = 0.002; Cohen's d = 0.88). Generally, GCs were more in favor of VUSs not being reported for population-based screening, with laboratory GCs (M = 4.7; SD = 0.8) agreeing more with that practice than clinical cancer GCs (M = 3.7; SD = 1.4; p = 0.001; Cohen's d = 0.80). Both clinical cancer GCs (M = 4.1; SD = 1.2) and laboratory GCs (M = 3.9; SD = 1.2) agreed additional guidelines on how to approach VUSs in clinical practice should be developed (p = 0.54; Cohen's d = 0.17). While most GCs supported the reporting of VUSs overall, our analyses suggest clinical cancer and laboratory GCs may have different attitudes toward specific VUS-related reporting options. Further research is needed to elucidate GC preferences to help inform best practices for the reporting of VUSs. The development of additional standardized guidelines on how to approach VUSs would further support clinical practice.

Pain Screening in the Older Adult With Delirium.

BACKGROUND: In patients with cognitive impairments who are unable to self-report pain, nurses must rely on behavioral observation tools to assess and manage pain. Although frequently employed in medical-surgical units, evidence supporting the psychometric efficacy of the Pain in Advanced Dementia (PAINAD) for pain screening in older adults with delirium is lacking. AIM: To examine the psychometrics of the PAINAD for older adults with delirium in medical-surgical settings. DESIGN: A descriptive repeated measures design. SETTING: Medical-surgical units in an urban tertiary care hospital. PARTICIPANTS: Sixty-eight older adults with delirium. METHODS: Patients with delirium unable to self-report pain were screened by two data collectors with the PAINAD and the Critical Care Pain Observation Tool (CPOT). Patients with a PAINAD score ≥3 or a CPOT score ≥2 received a pain intervention. Pain assessments were repeated 30 minutes post baseline or pain intervention. RESULTS: Patients were predominately female (58.8%) with dementia (71%). Thirty-nine patients screened positive for pain and received a pain intervention. PAINAD reliability was strong (Cronbach's α = 0.81-0.87; interrater intraclass coefficients [ICC] = 0.91-0.94; test-retest ICC = 0.76-0.77). Construct validity was supported by a statistically significant interaction effect between time (baseline versus follow-up) and condition (pain intervention versus no pain group; Rater 1: F(1,66) = 8.31, p = 0.005, ηp2 = 0.11; Rater 2: F(1,66) = 8.22, p = 0.006, ηp2 = 0.11. CONCLUSIONS: The PAINAD is a reliable and valid tool for pain screening for older adults with delirium in medical-surgical settings. CLINICAL IMPLICATIONS: Pain and delirium frequently co-occur in the older adult population. Best practices require a holistic assessment for contributing pain and non-pain factors in patients exhibiting distress.

Does Moral Distress Differ Between California Certified Registered Nurse Anesthetists in Independent Versus Medically Supervised Practice: An Exploratory Study.

The purpose of this exploratory, descriptive study was to determine if moral distress levels differed between certified registered nurse anesthetists (CRNAs) working in medically supervised versus independent practice in California. A 63-question survey was administered to 1,190 California CRNAs. Moral distress was measured by the included Ethics Stress Scale. The response rate was 14.7%, yielding demographic and Ethics Stress scores for 175 respondents. Sixty-five participants answered an open-ended question about moral distress yielding qualitative data. Medically supervised CRNAs had a lower mean moral distress scores (176.8) versus independent practice CRNAs (187.8) (p = .002). Lower scores on the ESS indicate higher moral distress. Qualitative data demonstrated that CRNAs experienced moral distress in the following situations: when pressured to give anesthesia to unoptimized patients, when differences of opinion regarding anesthetic plans occurred, in dealing with end-of-life issues, when working with incompetent providers, and during interprofessional struggles between CRNAs and anesthesiologists. In order to reduce moral distress among CRNAs, implications for practice include increased administrative support, increased communication and reciprocated collegial respect between anesthesiologists and CRNAs, and CRNA representation on ethics committees.

Safety of Intravenous Administration of an AAV8 Vector Coding for an Oxidation-Resistant Human α1-Antitrypsin for the Treatment of α1-Antitrypsin Deficiency.

α1-antitrypsin (AAT) deficiency is a common autosomal recessive hereditary disorder, with a high risk for the development of early-onset panacinar emphysema. AAT, produced primarily in the liver, functions to protect the lung from neutrophil protease; with AAT deficiency, unimpeded neutrophil proteases destroy the lung parenchyma. AAT is susceptible to oxidative damage resulting in an inability to inhibit its target proteases, neutrophil elastase, and cathepsin G. The major sites of oxidative modification on the AAT molecule are methionine residues 351 and 358. We have previously demonstrated that an engineered variant of AAT that resists oxidation by modifying both protein surface methionines (M351V and M358L) provides antiprotease protection, despite oxidative stress. In mice, intravenous delivery of the modified AAT(AVL) variant by AAV serotype 8, AAV8hAAT(AVL), primarily to the liver resulted in long-term expression of an AAT that resists oxidative inactivation. In this study, we evaluated the safety of intravenous administration of AAV8hAAT(AVL) in a dose-escalating, blinded, placebo-controlled toxicology study in wild-type mice. The study assessed organ histology and clinical pathology findings of mice, intravenously administered AAV8hAAT(AVL) at three doses (5.0 × 1011, 5.0 × 1012, and 5.0 × 1013 genome copies [gc]/kg), compared to control mice injected intravenously with phosphate-buffered saline. As previously demonstrated, administration of AAV8hAAT(AVL) resulted in dose-dependent expression of high, potentially therapeutic, levels of serum human AAT protein that persist for at least 6 months. Antibodies against the AAV8 capsid were elicited as expected, but there was no antibody detected against the AAT(AVL) protein generated by the AAV8hAAT(AVL) vector. There was no morbidity or mortality observed in the study. The data demonstrate that intravenous administration of AAV8hAAT(AVL) is safe with no significant adverse effect attributed to AAV8hAAT(AVL) vector at any dose. This study demonstrates that AAV8hAAT(AVL) has a safety profile consistent with the requirements for proceeding to a clinical study.

Identification of Safe and Effective Intravenous Dose of AAVrh.10hFXN to Treat the Cardiac Manifestations of Friedreich's Ataxia.

Friedreich's ataxia (FA) is a life-threatening autosomal recessive disorder characterized by neurological and cardiac dysfunction. Arrhythmias and heart failure are the main cause of premature death. From prior studies in murine models of FA, adeno-associated virus encoding the normal human frataxin gene (AAVrh.10hFXN) effectively treated the cardiac manifestations of the disease. However, the therapeutic dose window is limited by high level of human frataxin (hFXN) gene expression associated with toxicity. As a therapeutic goal, since FA heterozygotes have no clinical manifestations of FA, we estimated the level of frataxin (FXN) necessary to convert the heart of a homozygote to that of a heterozygote. In noncardiac cells, FA heterozygotes have 30-80% of normal FXN levels (17.7-47.2 ng/mg, average 32.5 ng/mg) and FA homozygotes 2-30% normal levels (1.2-17.7 ng/mg, average 9.4 ng/mg). Therefore, an AAV vector would need to augment endogenous in an FA homozygote by >8.3 ng/mg. To determine the required dose of AAVrh.10hFXN, we administered 1.8 × 1011, 5.7 × 1011, or 1.8 × 1012 gc/kg of AAVrh.10hFXN intravenously (IV) to muscle creatine kinase (mck)-Cre conditional knockout Fxn mice, a cardiac and skeletal FXN knockout model. The minimally effective dose was 5.7 × 1011 gc/kg, resulting in cardiac hFXN levels of 6.1 ± 4.2 ng/mg and a mild (p < 0.01 compared with phosphate-buffered saline controls) improvement in mortality. A dose of 1.8 × 1012 gc/kg resulted in cardiac hFXN levels of 33.7 ± 6.4 ng/mg, a significant improvement in ejection fraction and fractional shortening (p < 0.05, both comparisons) and a 21.5% improvement in mortality (p < 0.001). To determine if the significantly effective dose of 1.8 × 1012 gc/kg could achieve human FA heterozygote levels in a large animal, this dose was administered IV to nonhuman primates. After 12 weeks, the vector-expressed FXN in the heart was 17.8 ± 4.9 ng/mg, comparable to the target human levels. These data identify both minimally and significantly effective therapeutic doses that are clinically relevant for the treatment of the cardiac manifestations of FA.

Risk-reducing mastectomy decisions among women with mutations in high- and moderate- penetrance breast cancer susceptibility genes.

BACKGROUND: Women harboring mutations in breast cancer susceptibility genes are at increased lifetime risk of developing breast cancer and are faced with decisions about risk management, including whether to undergo high-risk screening or risk-reducing mastectomy (RRM). National guidelines recommend BRCA1 or BRCA2 mutation carriers consider RRM, but that carriers of moderate penetrance mutations (e.g., ATM or CHEK2) should be managed based on family history. We aimed to investigate determinants of decision for RRM, and hypothesized that mutation status, age, family history, partner status, and breast cancer would impact RRM decision making. METHODS: We performed a retrospective study assessing RRM decisions for 279 women. RESULTS: Women with BRCA and moderate penetrance gene mutations, a personal history of breast cancer, or a first degree relative with a history of breast cancer were more likely to undergo RRM. Breast cancer status and age showed an interaction effect such that women with breast cancer were less likely to undergo RRM with increasing age. CONCLUSION: Although national guidelines do not recommend RRM for moderate penetrance carriers, the rates of RRM for this population approached those for BRCA mutation carriers. Further insights are needed to better support RRM decision-making in this population.

Correlates of Delayed Initial Contact to Emergency Services among Patients with Suspected ST-Elevation Myocardial Infarction.

BACKGROUND: Early diagnosis and treatment of a patient displaying symptoms of myocardial ischemia is paramount in preventing detrimental tissue damage, arrhythmias, and death. Patient-related hospital delay is the greatest considerable cause of total delay in treatment for acute myocardial infarction. OBJECTIVE: To identify patient characteristics contributing to prehospital delay and ultimately developing health interventions to prevent future delay and improve health outcomes. METHODS: A retrospective chart review of 287 patients diagnosed with ST-elevation myocardial infarction (STEMI) was evaluated to examine correlates of patient-related delays to care. RESULTS: Stepwise logistic regression modeling with forward selection (likelihood ratio) was performed to identify predictors of first medical contact (FMC) within 120 minutes of symptom onset and door-to-balloon (DTB) time within 90 minutes. Distance from the hospital, being unmarried, self-medicating, disability, and hemodynamic stability emerged as variables that were found to be predictive of FMC within the first 120 minutes after symptom onset. Similarly, patient characteristics of gender and disability and having an initial nondiagnostic electrocardiogram emerged as significant predictors of DTB within 90 minutes. CONCLUSIONS: Individual attention to high-risk patients and public education campaigns using printed materials, public lectures, and entertainment mediums are likely needed to disseminate information to improve prevention strategies. Future research should focus on identifying the strengths of prehospital predictors and finding other variables that can be established as forecasters of delay. Interventions to enhance survival in acute STEMI should continue as to provide substantial advances in overall health outcomes.

Measurement of macular pigment: Raman spectroscopy versus heterochromatic flicker photometry.

PURPOSE: There are several techniques for measuring macular pigment (MP) in vivo, of which Raman spectroscopy (RS) is a recently developed objective METHOD: This study reports the reproducibility, test-retest variability, and validity of RS MP readings, by comparing them with heterochromatic flicker photometry (HFP). METHODS: MP was measured with HFP and RS in 120 healthy subjects, and the latter technique was also used on two separate occasions in a sample of 20 subjects to investigate the intersessional variability of readings. Intrasessional reproducibility of RS MP measurements was also calculated. In addition, serum concentrations of lutein (L) and zeaxanthin (Z) were measured and correlated with both RS and HFP MP readings. RESULTS: Mean (+/-SD) MP in the right eye was 0.279 +/- 0.145 and 0.319 +/- 0.155 with RS and HFP, respectively. The differences between corresponding MP readings taken on RS and HFP lay within the Bland-Altman 95% limits of agreement for the two instruments in 93.6% and 94.4% of cases in the right and left eyes, respectively. Intrasessional reproducibility of RS readings, expressed as the coefficient of variation, was 8.42% +/- 7.12%. Ninety-five percent of MP readings taken with RS on two separate occasions lay within the 95% limits of agreement for the two sessions. A positive, but insignificant, relationship was observed between RS and HFP MP readings and serum concentrations of L and Z (RS, P = 0.356; HFP, P = 0.540). CONCLUSIONS: RS, an objective method of measuring MP levels in vivo, exhibits acceptable reproducibility and test-retest variability. The results demonstrated good correlation between RS and HFP measurements of MP, thus authenticating RS against a validated psychophysical technique of measuring MP. However, investigators should use only one of these instruments for the duration of any given study because of differences in the scientific rationale, and the factors that influence RS and HFP measurements of MP.

Designer schools: the role of school space and architecture in obesity prevention.

Spatial features of obesogenic environments studied on a broad community level have been associated with childhood overweight and obesity, but little research has focused on the effects of the design of micro spaces, such as schools, on individual health behaviors. This article aims to generate thinking and research on the link between school space and architecture and obesity prevention by reviewing and synthesizing available literature in architecture, environmental psychology, and obesity research, in an effort to propose promising ideas for school space design and redesign. The school environment is defined through 5 dimensions: physical, legal, policy, social, and cultural domains. Theories underlying environmental interventions and documented associations between the environment and health behaviors and outcomes are reviewed to illustrate how existing environmental research could translate to obesity prevention. Design strategies aimed at promoting physical activity and healthful eating are proposed, with particular emphasis on the design of cafeterias, activity spaces, connectivity with the larger community, and student health centers.