Perceived barriers, recommendations, and resources for multistate licensure in the United States: A mixed-methods study of laboratory genetic counselors.

With genetic counselor licensure now available in 32 states, the number of laboratory genetic counselors (LGCs) who are required to be licensed in multiple states has risen substantially. Although previous studies have documented the complexity of the multistate licensing (MSL) process, there has been little research on the experiences of LGCs applying for and maintaining licensure. The purpose of this study was to identify perceived barriers, recommendations, and resources for LGCs pursuing MSL. A 15-item mixed-methods, anonymous questionnaire was used to survey genetic counselors currently or formerly employed by genetic testing laboratories. Responses were analyzed with a combination of descriptive statistics and inductive thematic analysis. Of the 150 eligible participants who completed the survey, the majority worked at a commercial, non-academic laboratory (84%, n = 126), had 1-4 years of laboratory genetic counseling experience (54%, n = 81), held non-patient-facing roles (65%, n = 97), and were required by their employer to hold licensure in at least one state (73%, n = 110). Most participants (86%, n = 129) felt there were barriers to MSL for LGCs, with three emergent themes: (1) resource burden, (2) complexity, and (3) legislative ambiguity. Participants described the current MSL process as tedious, cumbersome, confusing, overwhelming, and redundant. Several shared that the current licensing system undermines the intent to improve the status of the profession and actually negatively impacts patient care. Recommendations to improve MSL included overall process enhancements, like transitioning to online systems and a single central information repository for licensees, increased professional advocacy, and investing in collaborative pathways to licensure such as interstate compacts. Participants found national genetic counseling organizations, state-based genetic counseling organizations, and genetic counseling colleagues to be the most helpful resources for understanding licensure law and where to apply for licensure.

Abandoning the word Caucasian.

Traditionally, the field of genetics has used patient-reported genetic ancestry to assist in risk assessment, calculate detection rates, and understand residual risks for recessive or X-linked genetic diseases. Patient-reported genetic ancestry is useful for variant curation, based on practice guidelines from medical societies. Words used to describe a person's race, ethnicity, and genetic ancestry have changed over the last few centuries, especially in the last few decades. The origin and use of Caucasian to describe people of European ancestry have come into question. With recommendations from the Department of Health and Human Services (HHS) and the American College of Medical Genetics and Genomics (ACMG), among other organizations, the medical and genetics communities are moving away from using this term altogether. The purpose of this article is to review the history of the word Caucasian and to provide evidence that it should be avoided when documenting genetic ancestry in medical records, laboratory forms, and medical research.

Easing the burden of multi-state genetic counseling licensure in the United States: Process, pitfalls, and possible solutions.

State-based genetic counseling licensure creates standardization, ensures high-quality care, and supports the credentialing of genetic counselors (GCs) in the United States. However, it also has the unintended consequence of requiring substantial time and resources from genetic counselors who need to obtain licensure in multiple states. There is a wide range of variability among state licensure applications, required supporting documentation, verification processes, and cost-all of which are barriers for genetic counselors. New licensure laws are being passed on a regular basis, further complicating this process. Resources may be available to some genetic counselors such as employer reimbursement and administrative support; however, access to this support is not universal. This paper reviews the current condition of genetic counseling multi-state licensure, including barriers, unique challenges, and possible solutions for increased efficiencies, based on the authors' experiences and examples found in other healthcare fields.

Knowledge, attitudes, and clinical experience of physicians regarding preimplantation genetic diagnosis for hereditary cancer predisposition syndromes.

Approximately 5-10% of cancers are caused by an inherited predisposition. Individuals affected by hereditary cancer are often concerned about transmitting a predisposition to cancer to their children. Preimplantation genetic diagnosis (PGD) is a technology that allows embryos without a deleterious mutation associated with a hereditary cancer syndrome to be identified and implanted. The aim of this study is to assess the knowledge, attitudes, and clinical experience of physicians regarding PGD for hereditary cancer predisposition syndromes. Hereditary Breast and Ovarian Cancer (HBOC) and Familial Adenomatous Polyposis (FAP) are two hereditary cancer syndromes highlighted in this present study. A survey assessing physicians' attitudes, knowledge, and clinical practice was completed by a total of 373 gynecologic oncologists (GYN ONCs) and obstetrics and gynecologists (OB/GYNs). Physicians had a limited knowledge of PGD for hereditary cancer; however, physicians reported PGD was an appropriate option for patients with either HBOC or FAP. Although GYN ONCs were more likely to care for patients with hereditary cancer (P < 0.001), they were less likely than OB/GYNs to refer their patients to a PGD specialist (P = 0.004). While 80% of GYN ONCs and 91% of OB/GYNs would refer patients to a PGD specialist, clinical experience indicates that only 29% actually referred their patients. Since 68% of physicians had incorrect or limited knowledge of PGD for hereditary cancer, there is a need for additional education.

Interaction between myosin heavy chain and troponin isoforms modulate cardiac myofiber contractile dynamics.

Coordinated expression of species-specific myosin heavy chain (MHC) and troponin (Tn) isoforms may bring about a dynamic complementarity to match muscle contraction speed with species-specific heart rates. Contractile system function and dynamic force-length measurements were made in muscle fibers from mouse and rat hearts and in muscle fibers after reconstitution with either recombinant homologous Tn or orthologous Tn. The rate constants of length-mediated cross-bridge (XB) recruitment (b) and tension redevelopment (k(tr)) of mouse fibers were significantly faster than those of rat fibers. Both the tension cost (ATPase/tension) and rate constant of length-mediated XB distortion (c) were higher in the mouse than in the rat. Thus the mouse fiber was faster in all dynamic and functional aspects than the rat fiber. Mouse Tn significantly increased b and k(tr) in rat fibers; conversely, rat Tn significantly decreased b and k(tr) in mouse fibers. Thus the length-mediated recruitment of force-bearing XB occurs much more rapidly in the presence of mouse Tn than in the presence of rat Tn, demonstrating that the speed of XB recruitment is regulated by Tn. There was a significant interaction between Tn and MHC such that changes in either Tn or MHC affected the speed of XB recruitment. Our data demonstrate that the dynamics of myocardial contraction are different in the mouse and rat hearts because of sequence heterogeneity in MHC and Tn. At the myofilament level, coordinated expression of complementary regulatory contractile proteins produces a functional dynamic phenotype that allows the cardiovascular systems to function effectively at different heart rates.

Differences in myofilament calcium sensitivity in rat psoas fibers reconstituted with troponin T isoforms containing the alpha- and beta-exons.

The carboxy terminus of fast skeletal muscle troponin T (fsTnT) is highly conserved. However, mutually exclusive splicing of exons 16 and 17 in the fsTnT gene results in the expression of either the alpha- or beta-fsTnT isoform. The alpha-isoform is expressed only in adult fast skeletal muscle, whereas the beta-isoform is expressed in varying quantities throughout muscle development. Reconstitution of detergent-skinned adult rat psoas muscle fibers with rat fast skeletal troponin complexes containing either fsTnT isoform demonstrated that reconstitution with alpha-fsTnT resulted in greater myofilament Ca(2+) sensitivity than reconstitution with beta-fsTnT, without changes to Ca(2+)-activated maximal tension, ATPase activity or tension cost. The observed isoform-specific differences in myofilament Ca(2+) sensitivity may be due to changes in the transition of the thin-filament regulatory unit from the off to the on state, possibly due to altered interactions of the C-terminus of fsTnT with troponins I and/or C.

Functional consequence of mutation in rat cardiac troponin T is affected differently by myosin heavy chain isoforms.

Cardiac troponin T (cTnT) is an essential component of the thin filament regulatory unit (RU) that regulates Ca2+ activation of tension in the heart muscle. Because there is coupling between the RU and myosin crossbridges, the functional outcome of cardiomyopathy-related mutations in cTnT may be modified by the type of myosin heavy chain (MHC) isoform. Ca2+ activation of tension and ATPase activity were measured in muscle fibres from normal rat hearts containing alpha-MHC isoform and propylthiouracil (PTU)-treated rat hearts containing beta-MHC isoform. Muscle fibres from normal and PTU-treated rat hearts were reconstituted with two different mutations in rat cTnT; the deletion of Glu162 (cTnT(E162DEL)) and the deletion of Lys211 (cTnT(K211DEL)). Alpha-MHC and beta-MHC isoforms had contrasting impact on tension-dependent ATP consumption (tension cost) in cTnT(E162DEL) and cTnT(K211DEL) reconstituted muscle fibres. Significant increases in tension cost in alpha-MHC-containing muscle fibres corresponded to 17% (P < 0.01) and 23% (P < 0.001) when reconstituted with cTnT(E162DEL) and cTnT(K211DEL), respectively. In contrast, tension cost decreased when these two cTnT mutants were reconstituted in muscle fibres containing beta-MHC; by approximately 24% (P < 0.05) when reconstituted with cTnT(E162DEL) and by approximately 17% (P = 0.09) when reconstituted with cTnT(K211DEL). Such differences in tension cost were substantiated by the mechano-dynamic analysis of cTnT mutant reconstituted muscle fibres from normal and PTU-treated rat hearts. Our observation demonstrates that qualitative changes in MHC isoform alters the nature of cardiac myofilament dysfunction induced by mutations in cTnT.

Troponin T modulates sarcomere length-dependent recruitment of cross-bridges in cardiac muscle.

The heterogenic nature of troponin T (TnT) isoforms in fast skeletal and cardiac muscle suggests important functional differences. Dynamic features of rat cardiac TnT (cTnT) and rat fast skeletal TnT (fsTnT) reconstituted cardiac muscle preparations were captured by fitting the force response of small amplitude (0.5%) muscle length changes to the recruitment-distortion model. The recruitment of force-bearing cross-bridges (XBs) by increases in muscle length was favored by cTnT. The recruitment magnitude was approximately 1.5 times greater for cTnT- than for fsTnT-reconstituted muscle fibers. The speed of length-mediated XB recruitment (b) in cTnT-reconstituted muscle fiber was 0.50-0.57 times as fast as fsTnT-reconstituted muscle fibers (3.05 vs. 5.32 s(-1) at sarcomere length, SL, of 1.9 microm and 4.16 vs. 8.36 s(-1) at SL of 2.2 microm). Due to slowing of b in cTnT-reconstituted muscle fibers, the frequency of minimum stiffness (f(min)) was shifted to lower frequencies of muscle length changes (at SL of 1.9 microm, 0.64 Hz, and 1.16 Hz for cTnT- and fsTnT-reconstituted muscle fibers, respectively; at SL of 2.2 microm, 0.79 Hz, and 1.11 Hz for cTnT- and fsTnT-reconstituted muscle fibers, respectively). Our model simulation of the data implicates TnT as a participant in the process by which SL- and XB-regulatory unit cooperative interactions activate thin filaments. Our data suggest that the amino-acid sequence differences in cTnT may confer a heart-specific regulatory role. cTnT may participate in tuning the heart muscle by decreasing the speed of XB recruitment so that the heart beats at a rate commensurate with f(min).

Increase in tension-dependent ATP consumption induced by cardiac troponin T mutation.

How different mutations in cardiac troponin T (cTnT) lead to distinct secondary downstream cellular remodeling in familial hypertrophic cardiomyopathy (FHC) remains elusive. To explore the molecular basis for the distinct impact of different mutations in cTnT on cardiac myocytes, we studied mechanical activity of detergent-skinned muscle fiber bundles from different lines of transgenic (TG) mouse hearts that express wild-type cTnT (WTTG), R92W cTnT, R92L cTnT, and Delta-160 cTnT (deletion of amino acid 160). The amount of mutant cTnT is approximately 50% of the total myocellular cTnT in both R92W and R92L TG mouse hearts and approximately 35% in Delta-160 TG mouse hearts. Myofilament Ca2+ sensitivity was enhanced in all mutant cTnT TG cardiac muscle fibers. Compared with the WTTG fibers, Ca2+ sensitivity increased significantly at short sarcomere length (SL) of 1.9 microm (P < 0.001) in R92W TG fibers by 2.2-fold, in R92L by 2.0-fold, and in Delta-160 by 1.3-fold. At long SL of 2.3 microm, Ca2+ sensitivity increased significantly (P < 0.01) in a similar manner (R92W, 2.5-fold; R92L, 1.9-fold; Delta-160, 1.3-fold). Ca2+-activated maximal tension remained unaltered in all TG muscle fibers. However, tension-dependent ATP consumption increased significantly in Delta-160 TG muscle fibers at both short SL (23%, P < 0.005) and long SL (37%, P < 0.0001), suggesting a mutation-induced change in cross-bridge detachment rate constant. Chronic stresses on relative cellular ATP level in cardiac myocytes may cause a strain on energy-dependent Ca2+ homeostatic mechanisms. This may result in pathological remodeling that we observed in Delta-160 TG cardiac myocytes where the ratio of sarco(endo)plasmic reticulum Ca2+-ATPase 2/phospholamban decreased significantly. Our results suggest that different types of stresses imposed on cardiac myocytes would trigger distinct cellular signaling, which leads to remodeling that may be unique to some mutants.

Repeated low level formaldehyde exposure produces enhanced fear conditioning to odor in male, but not female, rats.

Multiple chemical sensitivity (MCS) is an ill-defined disorder in humans attributed to exposure to volatile organic compounds. This study draws on apparent parallels between individuals with posttraumatic stress disorder (PTSD) and panic disorder and a subset of those reporting MCS, using a conditioned fear task in rats. Male and female Sprague-Dawley rats were given repeated exposure to 2 ppm formaldehyde (Form) (1 h/day x 5 days/week x 4 week) or air, and after 2-3 weeks, rats were trained on the conditioned fear task. One half of Air and Form rats were given odor (orange oil, the conditioned stimulus, CS) paired with footshock (PRD) and the other half was given the same stimuli in an unpaired manner (UNP). After 24 h, rats were placed into the same context without the CS or footshock. Male and female PRD groups demonstrated contextual freezing 5-15% of the time, while the UNP groups showed freezing 30-50% of the time, with no effect of Air or Form pretreatment. For the next 5 days, rats were placed into a novel context and tested for freezing in the absence or presence of the CS. In male rats, Form pretreatment produced a significantly greater freezing response in both UNP and PRD groups in the presence of the CS, with no differences in freezing in the absence of the CS. In female rats, no significant differences between Form pretreated rats and Air controls were observed in either the PRD or UNP groups. The increase in conditioned fear responding to the CS after Form exposure in males suggests that repeated low-level Form may act as a stressor to produce sensitized responding within olfactory/limbic pathways, and may help explain the panic-like responses observed in a subset of individuals reporting MCS. Furthermore, the male/female differences suggest a gonadal hormonal contribution to this behavior.