Society for Birth Defects Research and Prevention 2022-2027 strategic plan.

BACKGROUND: The sixth Strategic Planning Session of the Society for Birth Defects Research and Prevention (BDRP) was held on April 24-25, 2022, in Alexandria, VA. METHODS: This effort built upon previous strategic planning sessions, conducted every 5 years. RESULTS: The overall process was designed to identify BDRP's vision, purpose, culture, and potential, as well as to communicate the value that BDRP brings to its members, volunteers, partners, and the greater community. CONCLUSIONS: The BDRP 2022-2027 Strategic Plan provides the BDRP leadership, members, and staff with a clearly articulated framework and direction to support long-term sustainability and growth of the society.

Shift to Virtual Self-Management Programs During COVID-19: Ensuring Access and Efficacy for Older Adults.

Background: The COVID-19 pandemic resulted in significant uncertainty and disruption to many aspects of daily living, including physical activity, socialization opportunities, and access to healthcare services. Under these conditions, at-risk older adults are even more likely to be inactive and isolated, leading to potential exacerbation of musculoskeletal and chronic conditions and emotional distress. This case study provides an overview of our experience and best practices developed during our shift from onsite programming to virtual. Methodology: HSS utilized varied online approaches, including phone/video conference classes, webinars, on-demand videos and email campaigns to successfully transition programs. Due to this shift, HSS changed its evaluation to an online approach, using a mixed method to adequately assess the impact of programs. Results: Between April and August 2020, our virtual programs reached 428,766 participants, resulting in a 10,807% increase in program reach. Most participants assessed were 60 years or older (72%) and reported knowledge (85%) and self-management skills (83%) gained as well as high program satisfaction (90%). Analyses of program data did not show any statistical significant difference in self-reported health outcomes. However, qualitative results showed virtual programming helped to foster social connectivity during COVID-19, helped to build a daily routine, and positively impacted mental and physical health. Conclusion: Shifting to virtual programming in the face of the pandemic enabled us to deliver effective programs affording our community the opportunity to stay physically active and socially connected despite the quarantine orders.

Thinking about Others' Minds: Mental State Inference in Boys with Conduct Problems and Callous-Unemotional Traits.

Children with conduct problems (CP) and high levels of callous-unemotional traits (CP/HCU) have been found to have an intact ability to represent other minds, however, they behave in ways that indicate a reduced propensity to consider other people's thoughts and feelings. Here we report findings from three tasks assessing different aspects of mentalising in 81 boys aged 11-16 [Typically developing (TD) n = 27; CP/HCU n = 28; CP and low levels of callous-unemotional traits (CP/LCU) n = 26]. Participants completed the Movie Assessment of Social Cognition (MASC), a task assessing ability/propensity to incorporate judgements concerning an individual's mind into mental state inference; provided a written description of a good friend to assess mind-mindedness; and completed the Social Judgement Task (SJT), a new measure assessing mentalising about antisocial actions. Boys with CP/HCU had more difficulty in accurately inferring others' mental states in the MASC than TD and CP/LCU boys. There were no group differences in the number of mind-related comments as assessed by the mind-mindedness protocol or in responses to the SJT task. These findings suggest that although the ability to represent mental states is intact, CP/HCU boys are less likely to update mental state inferences as a function of different minds.

The first 60 years: Honoring Teratology's past, a new perspective on the future.

BACKGROUND: This paper updates the history of the Teratology Society, now known as the Society for Birth Defects Research and Prevention (BDRP), for its first 60 years and describes the current strategy to position the Society to continue to advance its multidisciplinary science in the future. Common threads across our history include the positive impact of the Society's approach to sharing multidisciplinary, cutting-edge science and the collegial nature of the annual meetings. AIM: In recent years, we have tackled challenging issues through periodic strategic planning sessions to improve the impact of the Society and its value to our members. MATERIALS & METHODS: Archived and current resources were reviewed for this historical perspective. RESULTS: In 2019, the Society took steps to rebrand itself to clarify our mission to the broader scientific and governmental communities. DISCUSSION: Although our name has changed, the mission remains to understand and prevent birth defects and disorders of developmental and reproductive origin. CONCLUSION: As BDRP, we continue to promote the exchange of research and ideas, provide educational opportunities, influence policy through advocacy, and evolve our communications to better serve our members and to have a greater impact on the health of future generations.

Identifying Barriers to Access and Utilization of Preventive Health-Care Services by Young Adults in Vermont.

PURPOSE: The objective of this study was to examine barriers to accessing and utilizing routine preventive health-care checkups for Vermont young adults. METHODS: A population-based analysis was conducted using aggregated data from the 2011-2014 Behavioral Risk Factor Surveillance System (BRFSS) surveys of Vermont young adults aged 18-25 years (N = 1,329). Predictors analyzed as barriers were classified county of residence, health-care coverage, and annual household income level, as well as covariates, with the outcome of the length of time since the last routine checkup. RESULTS: A total of 81.1% of Vermont young adults reported having a routine checkup in the past 2 years. Health-care coverage was a predictor of undergoing routine checkups within the past 2 years, with 85.2% of insured respondents undergoing checkups compared with 56.3% of uninsured respondents (p < .001). Additionally, 81.9% of respondents from Vermont counties classified as mostly rural reported undergoing a checkup within the past 2 years (p < .05). A total of 80.8% of respondents from the middle level (p < .05) and 89.0% of respondents from the highest level (p < .001) of annual household incomes reported undergoing a checkup in the past 2 years. Finally, age (p < .001) and sex (p < .01) were shown to indicate receipt of routine preventive checkups more often. CONCLUSIONS: For Vermont young adults, health-care coverage, classified county of residence, and household income level were shown to be indicators of undergoing routine preventive health care more often. Further investigation is needed to examine how these barriers may impede preventive screenings, thereby contributing to the ongoing development of health-care guidelines and policies for young adults in rural settings.

Communication Skills Training for Surgical Residents: Learning to Relate to the Needs of Older Adults.

BACKGROUND: It is vital for physicians and surgeons to communicate successfully with older adults, who will constitute one-fifth of the US population by 2030. Older adults often perceive themselves as stigmatized and powerless in healthcare settings. Effective communication leads to better patient compliance and satisfaction, which is now a component of Medicare hospital reimbursement and physician and surgeon compensation from hospitals and networks. OBJECTIVE: To increase orthopaedic surgery resident understanding of the unique needs of older adults in order to maintain effective and sensitive communication with this vulnerable population. DESIGN: A two-part training program (ongoing for 8 years) comprised of: 1) small-group interactive didactic sessions on aging issues; and 2) workshop demonstrations given by the residents to a group of older adults, followed by a Question & Answer session. Residents were assessed using a 22-item pre-post questionnaire covering medical knowledge of aging, attitudes toward older adults, and personal anxiety about aging. Older adult participants were surveyed for perceptions of residents' sensitivity toward them. SETTING: Hospital for Special Surgery in New York City, a specialized urban academic center, with a 5-year Orthopedic Surgery Residency program. PARTICIPANTS: 70 PGY3 residents, for whom the program is a requirement, and 711 older adult participants recruited from a community convenience sample. RESULTS: Older adult participants: Of 711 participants, 672 (95%) responded; 96% strongly agreed/agreed that the residents had demonstrated sensitivity toward them. Residents: Of 70 residents, 35 (50%) were assessed. Mean knowledge scores increased significantly (p ≤ 0.001); five of nine attitude items (p ≤ 0.05) and one of four anxiety items improved significantly (p ≤ 0.001). CONCLUSIONS: Significant change was seen in residents' attitudes and anxiety levels toward older adults, attributes that are usually deep seated and hard to change. Residents moved along the Accreditation Council for Graduate Medical Education Milestones continuum for three core competencies.

The social networks of smokers attempting to quit: An empirically derived and validated classification.

Social relationships play an important role in the uptake, maintenance, and cessation of smoking behavior. However, little is known about the natural co-occurrence of social network features in adult smokers' networks and how multidimensional features of the network may connect to abstinence outcomes. The current investigation examined whether qualitatively distinct subgroups defined by multiple characteristics of the social network could be empirically identified within a sample of smokers initiating a quit attempt. Egocentric social network data were collected from 1571 smokers (58% female, 83% white) engaged in a 3-year smoking cessation clinical trial. Using nine indicator variables reflecting both risk and protective network features, finite mixture models identified five social network subgroups: High Stress/High Contact, Large and Supportive, Socially Disconnected, Risky Friends and Low Contact, and High Contact with Smokers and Light Drinkers. External variables supported the validity of the identified subgroups and the subgroups were meaningfully associated with baseline demographic, psychiatric, and tobacco measures. The Socially Disconnected subgroup was characterized by little social interaction, low levels of stress, and low exposure to social environmental smoking cues, and had the highest probability of successful cessation at 1 week compared with all other social network subgroups. At 6 months posttreatment its members had higher abstinence rates than members of the High Stress/High Contact subgroup and the Risky Friends and Low Contact subgroup. The present study highlights the heterogeneity of smokers' social milieus and suggests that network features, especially those entailing exposure to smoking cues and contexts, heighten risk for smoking cessation failure. (PsycINFO Database Record

Suffering in Advanced Cancer: A Randomized Control Trial of a Narrative Intervention.

BACKGROUND: Advanced cancer can erode patients' wellbeing. Narrative interventions have improved patients' wellbeing, but might not be feasible for widespread implementation. OBJECTIVES: (1) Test the effects of miLivingStory, a telephone-based life review and illness narrative intervention with online resources and social networking, on community-dwelling advanced cancer patients' wellbeing. (2) Explore intervention use and satisfaction. PATIENTS AND SETTING: Stage III or IV cancer patients having completed initial therapy were randomized to miLivingStory or to an active control group, miOwnResources. Data and Analysis: Primary outcomes measured at baseline, two and four months included subscales for the FACIT-Sp peace and meaning and the POMS-SF depressed, anxious, and angry mood, scored on 0-4-point Likert scales. Linear mixed modeling, controlling for baseline primary outcome scores, tested for group comparisons of repeated outcome measures. Pairwise comparisons tested for within- and between-group differences. Intervention use and satisfaction data were collected automatically and by survey. RESULTS: Eighty-six primarily white, female patients with high baseline wellbeing completed the study. There were no between-group differences at baseline or at two months. At four months, miLivingStory had a direct and positive effect for peace (2.86 vs. 2.57, p = 0.029), a trend effect for lower depressed mood (0.55 vs. 0.77, p = 0.097), and appeared to protect against the control group's declining wellbeing between two and four months. miLivingStory use was low and assessed as helpful to quite helpful. CONCLUSIONS: Telephone-based narrative interventions hold promise in improving advanced cancer patients' wellbeing. Further testing of delivery and implementation strategies is warranted.

Toxicological and ecotoxicological properties of gas-to-liquid (GTL) products. 1. Mammalian toxicology.

Gas-to-liquid (GTL) products are synthetic hydrocarbons produced from natural gas using a Fischer-Tropsch process. This process yields a synthetic crude oil that consists of saturated hydrocarbons, primarily linear alkanes, with increasing amounts of branched (methyl-groups) alkanes as the chains get longer. In addition, small amounts of cycloalkanes (branched cyclopentanes and cyclohexanes) may be formed as the polymerization reaction prolongs. This synthetic crude can subsequently be refined to a range of products very similar to petroleum refining. However, in contrast to their petroleum-derived analogs, GTL products are essentially free of unsaturated or aromatic constituents and also no sulfur-, oxygen-, or nitrogen-containing constituents are present. From a regulatory perspective, GTL products are new substances which require extensive testing to assess their hazardous properties. As a consequence, a wide range of GTL products, covering the entire portfolio of GTL products, have been tested over the past few years in a wide variety of toxicological studies, including reproductive and prenatal development toxicity studies. This review provides an overview of the hazardous properties of the various GTL products. In general, the data collected on GTL products provide strong proof that they exert minimal health effects. In addition, these data provide supporting evidence for what is known on the mechanisms of mammalian toxicology of their petroleum-derived analogs. In the few cases where adverse effects were found for the GTL substances, these were usually less severe than the adverse effects observed with their petroleum-derived analogs.

Transitions in Smokers' Social Networks After Quit Attempts: A Latent Transition Analysis.

INTRODUCTION: Smokers' social networks vary in size, composition, and amount of exposure to smoking. The extent to which smokers' social networks change after a quit attempt is unknown, as is the relation between quitting success and later network changes. METHODS: Unique types of social networks for 691 smokers enrolled in a smoking-cessation trial were identified based on network size, new network members, members' smoking habits, within network smoking, smoking buddies, and romantic partners' smoking. Latent transition analysis was used to identify the network classes and to predict transitions in class membership across 3 years from biochemically assessed smoking abstinence. RESULTS: Five network classes were identified: Immersed (large network, extensive smoking exposure including smoking buddies), Low Smoking Exposure (large network, minimal smoking exposure), Smoking Partner (small network, smoking exposure primarily from partner), Isolated (small network, minimal smoking exposure), and Distant Smoking Exposure (small network, considerable nonpartner smoking exposure). Abstinence at years 1 and 2 was associated with shifts in participants' social networks to less contact with smokers and larger networks in years 2 and 3. CONCLUSIONS: In the years following a smoking-cessation attempt, smokers' social networks changed, and abstinence status predicted these changes. Networks defined by high levels of exposure to smokers were especially associated with continued smoking. Abstinence, however, predicted transitions to larger social networks comprising less smoking exposure. These results support treatments that aim to reduce exposure to smoking cues and smokers, including partners who smoke. IMPLICATIONS: Prior research has shown that social network features predict the likelihood of subsequent smoking cessation. The current research illustrates how successful quitting predicts social network change over 3 years following a quit attempt. Specifically, abstinence predicts transitions to networks that are larger and afford less exposure to smokers. This suggests that quitting smoking may expand a person's social milieu rather than narrow it. This effect, plus reduced exposure to smokers, may help sustain abstinence.

Communication competence, psychological well-being, and the mediating role of coping efforts among women with breast cancer: cross-sectional and longitudinal evidence.

Despite existing research identifying psychological benefits of patients' interpersonal competence in various contexts, little longitudinal research has addressed underlying mechanism(s). To address this limitation, we examined both the cross-sectional and longitudinal associations between cancer patients' communication competence in close relationships and psychological well-being, as well as the mediating role of coping efforts. Data came from a larger project with women with breast cancer (N = 661), recruited from April 2005 to May 2007 at three large university-affiliated cancer centers in the U.S. to study the effects of an Internet-based system providing patients and families with a range of services. The present study focused on survey data at baseline, 6 weeks, and 12 weeks after the intervention (controlling for the possible effects of the intervention). Results from both cross-sectional and longitudinal analyses indicated that competence in open communication between patients and their close support persons had a positive association with patients' psychological well-being and that approach coping efforts partially mediated this association. We discussed the implications and limitations of the study.

Feasibility of articulated arm mounted Oculus Rift Virtual Reality goggles for adjunctive pain control during occupational therapy in pediatric burn patients.

For daily burn wound care and therapeutic physical therapy skin stretching procedures, powerful pain medications alone are often inadequate. This feasibility study provides the first evidence that entering an immersive virtual environment using very inexpensive (∼$400) wide field of view Oculus Rift Virtual Reality (VR) goggles can elicit a strong illusion of presence and reduce pain during VR. The patient was an 11-year-old male with severe electrical and flash burns on his head, shoulders, arms, and feet (36 percent total body surface area (TBSA), 27 percent TBSA were third-degree burns). He spent one 20-minute occupational therapy session with no VR, one with VR on day 2, and a final session with no VR on day 3. His rating of pain intensity during therapy dropped from severely painful during no VR to moderately painful during VR. Pain unpleasantness dropped from moderately unpleasant during no VR to mildly unpleasant during VR. He reported going "completely inside the computer generated world", and had more fun during VR. Results are consistent with a growing literature showing reductions in pain during VR. Although case studies are scientifically inconclusive by nature, these preliminary results suggest that the Oculus Rift VR goggles merit more attention as a potential treatment for acute procedural pain of burn patients. Availability of inexpensive but highly immersive VR goggles would significantly improve cost effectiveness and increase dissemination of VR pain distraction, making VR available to many more patients, potentially even at home, for pain control as well as a wide range of other VR therapy applications. This is the first clinical data on PubMed to show the use of Oculus Rift for any medical application.

Health assessment of gasoline and fuel oxygenate vapors: reproductive toxicity assessment.

Vapor condensates of baseline gasoline (BGVC), or gasoline-blended with methyl tertiary butyl ether (G/MTBE), ethyl t-butyl ether (G/ETBE), t-amyl methyl ether (G/TAME), diisopropyl ether (G/DIPE), ethanol (G/EtOH), or t-butyl alcohol (G/TBA) were evaluated for reproductive toxicity in rats at target concentrations of 2000, 10,000, or 20,000mg/m(3), 6h/day, 7days/week. BGVC and G/MTBE were assessed over two generations, the others for one generation. BGVC and G/MTBE F1 offspring were evaluated for neuropathology and changes in regional brain glial fibrillary acidic protein content. No neurotoxicity was observed. Male kidney weight was increased consistent with light hydrocarbon nephropathy. In adult rats, decreased body weight gain and increased liver weight were seen. Spleen weight decreased in adults and pups exposed to G/TBA. No pathological changes to reproductive organs occurred in any study. Decreased food consumption was seen in G/TAME lactating females. Transient decreases in G/TAME offspring weights were observed during lactation. Except for a minor increase in time to mating in G/TBA which did not affect other reproductive parameters, there were no adverse reproductive findings. The NOAEL for reproductive and offspring parameters was 20,000mg/m(3) for all vapor condensates except for lower offspring NOAELs of 10,000mg/m(3) for G/TBA and 2000mg/m(3) for G/TAME.

Health assessment of gasoline and fuel oxygenate vapors: developmental toxicity in rats.

Gasoline-vapor condensate (BGVC) or condensed vapors from gasoline blended with methyl t-butyl ether (G/MTBE), ethyl t-butyl ether (G/ETBE), t-amyl methyl ether (G/TAME) diisopropyl ether (G/DIPE), ethanol (G/EtOH), or t-butyl alcohol (G/TBA) were evaluated for developmental toxicity in Sprague-Dawley rats exposed via inhalation on gestation days (GD) 5-20 for 6h/day at levels of 0 (control filtered air), 2000, 10,000, and 20,000mg/m(3). These exposure durations and levels substantially exceed typical consumer exposure during refueling (<1-7mg/m(3), 5min). Dose responsive maternal effects were reduced maternal body weight and/or weight change, and/or reduced food consumption. No significant malformations were seen in any study. Developmental effects occurred at 20,000mg/m(3) of G/TAME (reduced fetal body weight, increased incidence of stunted fetuses), G/TBA (reduced fetal body weight, increased skeletal variants) and G/DIPE (reduced fetal weight) resulting in developmental NOAEL of 10,000mg/m(3) for these materials. Developmental NOAELs for other materials were 20,000mg/m(3) as no developmental toxicity was induced in those studies. Developmental NOAELs were equal to or greater than the concurrent maternal NOAELs which ranged from 2000 to 20,000mg/m(3). There were no clear cut differences in developmental toxicity between vapors of gasoline and gasoline blended with the ether or alcohol oxygenates.

The role of the family environment and computer-mediated social support on breast cancer patients' coping strategies.

Despite the importance of family environment and computer-mediated social support (CMSS) for women with breast cancer, little is known about the interplay of these sources of care and assistance on patients' coping strategies. To understand this relation, the authors examined the effect of family environment as a predictor of the use of CMSS groups as well as a moderator of the relation between group participation and forms of coping. Data were collected from 111 patients in CMSS groups in the Comprehensive Health Enhancement Support System "Living with Breast Cancer" intervention. Results indicate that family environment plays a crucial role in (a) predicting breast cancer patient's participation in CMSS groups and (b) moderating the effects of use of CMSS groups on breast cancer patients' coping strategies such as problem-focused coping and emotion-focused coping.

The toxicological properties of petroleum gases.

To characterize the toxicological hazards of petroleum gases, 90-day inhalation toxicity (Organization for Economic Cooperation and Development [OECD] 413) and developmental toxicity (OECD 414) tests were conducted with liquefied propane gas (LPG) at concentrations of 1000, 5000, or 10,000 ppm. A micronucleus test (OECD 474) of LPG was also conducted. No systemic or developmental effects were observed; the overall no observed adverse effect concentration (NOAEC) was 10,000 ppm. Further, there was no effect of LPG exposure at levels up to 10,000 ppm on micronucleus induction and no evidence of bone marrow toxicity. Other alkane gases (ethane, propane, n-butane, and isobutane) were then evaluated in combined repeated exposure studies with reproduction/development toxicity screening tests (OECD 422). There were no toxicologically important changes in parameters relating to systemic toxicity or neurotoxicity for any of these gases at concentrations ranging from 9000 to 16,000 ppm. There was no evidence of effects on developmental or reproductive toxicity in the studies of ethane, propane, or n-butane at the highest concentrations tested. However, there was a reduction in mating in the high-exposure group (9000 ppm) of the isobutane study, which although not significantly different was outside the range previously observed in the testing laboratory. Assuming the reduction in mating to have been toxicologically significant, the NOAEC for the isobutane reproductive toxicity screening test was 3000 ppm (7125 mg/m(3)). A method is proposed by which the toxicity of any of the 106 complex petroleum gas streams can be estimated from its composition.

Toxicological assessment of heavy straight run naphtha in a repeated dose/reproductive toxicity screening test.

Gasoline blending stocks (naphthas) are comprised of normal, iso- and cycloparaffins and aromatic hydrocarbons with carbon numbers ranging from C4 to C12. Heavy straight run naphtha (HSRN, CAS number 64741-41-9) was selected for toxicity screening because substances of this type contain relatively high levels (28%) of cycloparaffins by comparison to other naphtha streams and the data complement toxicity information on other gasoline blending streams. Rats were exposed by inhalation to wholly vaporized material at levels of approximately 100, 500, or 3000 parts per million (ppm) daily to screen the potential for systemic toxicity, neurotoxicity, reproductive toxicity, and developmental effects to postnatal day 4. All animals survived the treatment period. Principal effects of repeated exposure included increased liver weights in males and females, increased kidney weights in males, and histological changes in the thyroid, secondary to liver enzyme induction. These changes were not considered to be toxicologically meaningful and are not relevant to humans. There were no treatment-related effects in functional observation tests or motor activity; no significant reductions in fertility or changes in other reproductive parameters; and no evidence of developmental toxicity in offspring. The overall no observed adverse effect concentration was 3000 ppm (approximately 13, 600 mg/m(3)). In conclusion the HSRN effects on liver and kidney are consistent with the results of other studies of volatile fractions or other naphthas or formulated gasoline, and there were no HSRN effects on neurological developmental or reproductive parameters.

A GHS-consistent approach to health hazard classification of petroleum substances, a class of UVCB substances.

The process streams refined from petroleum crude oil for use in petroleum products are among those designated by USEPA as UVCB substances (unknown or variable composition, complex reaction products and biological materials). They are identified on global chemical inventories with unique Chemical Abstract Services (CAS) numbers and names. The chemical complexity of most petroleum substances presents challenges when evaluating their hazards and can result in differing evaluations due to the varying level of hazardous constituents and differences in national chemical control regulations. Global efforts to harmonize the identification of chemical hazards are aimed at promoting the use of consistent hazard evaluation criteria. This paper discusses a systematic approach for the health hazard evaluation of petroleum substances using chemical categories and the United Nations (UN) Globally Harmonized System (GHS) of classification and labeling. Also described are historical efforts to characterize the hazard of these substances and how they led to the development of categories, the identification of potentially hazardous constituents which should be considered, and a summary of the toxicology of the major petroleum product groups. The use of these categories can increase the utility of existing data, provide better informed hazard evaluations, and reduce the amount of animal testing required.

Evaluating the male and female reproductive toxicity of high-boiling petroleum substances.

To meet the EPA HPV Chemical Challenge Program requirement for reproductive toxicity data on sponsored high-boiling petroleum substances (HBPS), an analysis was conducted using the results of 39 repeat-dose and 59 developmental rat dermal toxicity studies on HBPS samples spanning the boiling range of the sponsored substances, and the results of three one-generation reproductive toxicity studies on two samples spanning the concentration range of polycyclic aromatic compounds of sponsored substances. The analysis found little evidence of male or female reproductive tract toxicity based on histopathology, reproductive organ weight, and sperm parameters, and no evidence of effects on fertility, while significant developmental toxicity and/or systemic repeat-dose toxicity were frequently observed. Among 14 samples of HBPS tested in both repeat-dose toxicity and developmental toxicity studies, there were no studies in which an adverse reproductive tract finding occurred at a dose lower than that producing developmental toxicity or other adverse effects in repeat-dose toxicity studies. The current analysis supports the hypothesis that effects in developmental and/or repeat-dose toxicity studies of HBPS occur at doses lower than those that might affect fertility in rat one-generation reproductive studies. When adequate developmental and repeat-dose toxicity studies are available, a reproductive toxicity study of HBPS appears unnecessary.

The fibrillogenic L178H variant of apolipoprotein A-I forms helical fibrils.

A number of amyloidogenic variants of apoA-I have been discovered but most have not been analyzed. Previously, we showed that the G26R mutation of apoA-I leads to increased ß-strand structure, increased N-terminal protease susceptibility, and increased fibril formation after several days of incubation. In vivo, this and other variants mutated in the N-terminal domain (residues 26 to ∼90) lead to renal and hepatic accumulation. In contrast, several mutations identified within residues 170 to 178 lead to cardiac, laryngeal, and cutaneous protein deposition. Here, we describe the structural changes in the fibrillogenic variant L178H. Like G26R, the initial structure of the protein exhibits altered tertiary conformation relative to wild-type protein along with decreased stability and an altered lipid binding profile. However, in contrast to G26R, L178H undergoes an increase in helical structure upon incubation at 37°C with a half time (t(1/2)) of about 12 days. Upon prolonged incubation, the L178H mutant forms fibrils of a diameter of 10 nm that ranges in length from 30 to 120 nm. These results show that apoA-I, known for its dynamic properties, has the ability to form multiple fibrillar conformations, which may play a role in the tissue-specific deposition of the individual variants.