Douglas J. Opel

Neuregulins Promote Survival and Growth of Cardiac Myocytes PERSISTENCE OF ErbB2 AND ErbB4 EXPRESSION IN NEONATAL AND ADULT VENTRICULAR MYOCYTES

Neuregulins (i.e. neuregulin-1 (NRG1), also called neu differentiation factor, heregulin, glial growth factor, and acetylcholine receptor-inducing activity) are known to induce growth and differentiation of epithelial, glial, neuronal, and skeletal muscle cells. Unexpectedly, mice with loss of function mutations of NRG1 or of either of two of their cognate receptors, ErbB2 and ErbB4, die during midembryogenesis due to the aborted development of myocardial trabeculae in ventricular muscle. To examine the role of NRG and their receptors in developing and postnatal myocardium, we studied the ability of a soluble NRG1 (recombinant human glial growth factor 2) to promote proliferation, survival, and growth of isolated neonatal and adult rat cardiac myocytes. Both ErbB2 and ErbB4 receptors were found to be expressed by neonatal and adult ventricular myocytes and activated by rhGGF2. rhGGF2 (30 ng/ml) provoked an approximate 2-fold increase in embryonic cardiac myocyte proliferation. rhGGF2 also promoted survival and inhibited apoptosis of subconfluent, serum-deprived myocyte primary cultures and also induced hypertrophic growth in both neonatal and adult ventricular myocytes, which was accompanied by enhanced expression of prepro-atrial natriuretic factor and skeletal α-actin. Moreover, NRG1 mRNA could be detected in coronary microvascular endothelial cell primary cultures prepared from adult rat ventricular muscle. NRG1 expression in these cells was increased by endothelin-1, another locally acting cardiotropic peptide within the heart. The persistent expression of both a neuregulin and its cognate receptors in the postnatal and adult heart suggests a continuing role for neuregulins in the myocardial adaption to physiologic stress or injury.

Modulation of the Endothelial Nitric-oxide Synthase-Caveolin Interaction in Cardiac Myocytes IMPLICATIONS FOR THE AUTONOMIC REGULATION OF HEART RATE

The endothelial isoform of nitric oxide synthase (eNOS) is dually acylated and thereby targeted to signal-transducing microdomains termed caveolae. In endothelial cells, eNOS interacts with caveolin-1, which represses eNOS enzyme activity. In cardiac myocytes, eNOS associates with the muscle-specific caveolin-3 isoform, but whether this interaction affects NO production and regulates myocyte function is unknown. We isolated neonatal cardiac myocytes from mutant mice with targeted disruption of the eNOS gene and transfected them with wild-type (WT) eNOS or myristoylation-deficient (myr−) eNOS mutant cDNA. In myocytes expressing WT eNOS, the muscarinic cholinergic agonist carbachol completely abrogated the spontaneous beating rate and induced a 4-fold elevation of the cGMP level. By contrast, in the myr− eNOS myocytes, carbachol failed to exert its negative chronotropic effect and to increase cGMP levels. We then used a reversible permeabilization protocol to load intact neonatal rat myocytes with an oligopeptide corresponding to the caveolin-3 scaffolding domain. This peptide completely and specifically inhibited the carbachol-induced negative chronotropic effect and the accompanying cGMP elevation. Thus, our results suggest that acylated eNOS may couple muscarinic receptor activation to heart rate control and indicate a key role for eNOS/caveolin interactions in the cholinergic modulation of cardiac myocyte function.

The Architecture of Provider-Parent Vaccine Discussions at Health Supervision Visits

OBJECTIVE: To characterize provider-parent vaccine communication and determine the influence of specific provider communication practices on parent resistance to vaccine recommendations. METHODS: We conducted a cross-sectional observational study in which we videotaped provider-parent vaccine discussions during health supervision visits. Parents of children aged 1 to 19 months old were screened by using the Parent Attitudes about Childhood Vaccines survey. We oversampled vaccine-hesitant parents (VHPs), defined as a score ≥50. We developed a coding scheme of 15 communication practices and applied it to all visits. We used multivariate logistic regression to explore the association between provider communication practices and parent resistance to vaccines, controlling for parental hesitancy status and demographic and visit characteristics. RESULTS: We analyzed 111 vaccine discussions involving 16 providers from 9 practices; 50% included VHPs. Most providers (74%) initiated vaccine recommendations with presumptive (eg, “Well, we have to do some shots”) rather than participatory (eg, “What do you want to do about shots?”) formats. Among parents who voiced resistance to provider initiation (41%), significantly more were VHPs than non-VHPs. Parents had significantly higher odds of resisting vaccine recommendations if the provider used a participatory rather than a presumptive initiation format (adjusted odds ratio: 17.5; 95% confidence interval: 1.2–253.5). When parents resisted, 50% of providers pursued their original recommendations (eg, “He really needs these shots”), and 47% of initially resistant parents subsequently accepted recommendations when they did. CONCLUSIONS: How providers initiate and pursue vaccine recommendations is associated with parental vaccine acceptance.

Validity and reliability of a survey to identify vaccine-hesitant parents.

OBJECTIVE To assess the construct validity and reliability of the Parent Attitudes about Childhood Vaccines survey. STUDY DESIGN Cross-sectional survey of parents of 19-35 month old children in a closed model HMO. We used factor analysis to confirm survey sub-domains and Cronbachs α to determine the internal consistency reliability of sub-domain scales. Construct validity was assessed by linking parental responses to their childs immunization record. RESULTS Our response rate was 46% (N=230). Factor analysis identified 3 factors that explained 70% of the total variance for the 18 survey items. We deleted 3 items that failed to load highly (>.4) on an identified factor, correlated poorly with other items, or had a hesitant response that was not associated with increased under-immunization. Cronbachs α coefficients for the 3 sub-domain scales created by grouping the remaining 15 items were .74, .84, and .74, respectively. Children of parents with survey scores of 50-79 had 14% more days under-immunized from birth to 19 months (95% CI: 8.0, 20.5) than those with parents who scored <50. Scores of ≥ 80 were associated with 51% more days under-immunized (95% CI: 38.2, 63.4). CONCLUSION The revised survey is a valid and reliable instrument to identify vaccine-hesitant parents.

Development of a survey to identify vaccine-hesitant parents: the parent attitudes about childhood vaccines survey.

Objective: To develop a survey to accurately assess parental vaccine hesitancy. Results: The initial survey contained 17 items in four content domains: (1) immunization behavior; (2) beliefs about vaccine safety and efficacy; (3) attitudes about vaccine mandates and exemptions; and (4) trust. Focus group data yielded an additional 10 survey items. Expert review of the survey resulted in the deletion of nine of 27 items and revisions to 11 of the remaining 18 survey items. Parent pretesting resulted in the deletion of one item, the addition of one item, the revision of four items, and formatting changes to enhance usability. The final survey contains 18 items in the original four content domains. Methods: An iterative process was used to develop the survey. First, we reviewed previous studies and surveys on parental health beliefs regarding vaccination to develop content domains and draft initial survey items. Focus groups of parents and pediatricians generated additional themes and survey items. Six immunization experts reviewed the items in the resulting draft survey and ranked them on a 1–5 scale for significance in identifying vaccine-hesitant parents (5 indicative of a highly significant item). The lowest third of ranked items were dropped. The revised survey was pretested with 25 parents to assess face validity, usability and item understandability. Conclusions: The Parent Attitudes about Childhood Vaccines survey was constructed using qualitative methodology to identify vaccine-hesitant parents and has content and face validity. Further psychometric testing is needed.

Social Marketing as a Strategy to Increase Immunization Rates

Today in the United States, outbreaks of vaccine-preventable disease are often traced to susceptible children whose parents have claimed an exemption from school or child care immunization regulations. The origins of this immunization hesitancy and resistance have roots in the decline of the threat of vaccine-preventable disease coupled with an increase in concerns about the adverse effects of vaccines, the emergence of mass media and the Internet, and the intrinsic limitations of modern medicine. Appeals to emotion have drowned out thoughtful discussion in public forums, and overall, public trust in immunizations has declined. We present an often overlooked behavior change strategy-social marketing-as a way to improve immunization rates by addressing the important roots of immunization hesitancy and effectively engaging emotions. As an example, we provide a synopsis of a social marketing campaign that is currently in development in Washington state and that is aimed at increasing timely immunizations in children from birth to age 24 months.

The Relationship Between Parent Attitudes About Childhood Vaccines Survey Scores and Future Child Immunization Status: A Validation Study

IMPORTANCE Acceptance of childhood vaccinations is waning, amplifying interest in developing and testing interventions that address parental barriers to immunization acceptance. OBJECTIVE To determine the predictive validity and test-retest reliability of the Parent Attitudes About Childhood Vaccines survey (PACV), a recently developed measure of vaccine hesitancy. DESIGN, SETTING, AND PARTICIPANTS Prospective cohort of English-speaking parents of children aged 2 months and born from July 10 through December 10, 2010, who belonged to an integrated health care delivery system based in Seattle and who returned a completed baseline PACV. Parents who completed a follow-up survey 8 weeks later were included in the reliability analysis. Parents who remained continuous members in the delivery system until their child was 19 months old were included in the validity analysis. EXPOSURE The PACV, scored on a scale of 0 to 100 (100 indicates high vaccine hesitancy). MAIN OUTCOMES AND MEASURES Childs immunization status as measured by the percentage of days underimmunized from birth to 19 months of age. RESULTS Four hundred thirty-seven parents completed the baseline PACV (response rate, 50.5%), and 220 (66.5%) completed the follow-up survey. Of the 437 parents who completed a baseline survey, 310 (70.9%) maintained continuous enrollment. Compared with parents who scored less than 50, parents who scored 50 to 69 on the survey had children who were underimmunized for 8.3% (95% CI, 3.6%-12.8%) more days from birth to 19 months of age; those who scored 70 to 100, 46.8% (40.3%-53.3%) more days. Baseline and 8-week follow-up PACV scores were highly concordant (ρ = 0.844). CONCLUSIONS AND RELEVANCE Scores on the PACV predict childhood immunization status and have high reliability. Our results should be validated in different geographic and demographic samples of parents.

The Influence of Provider Communication Behaviors on Parental Vaccine Acceptance and Visit Experience.

OBJECTIVES We investigated how provider vaccine communication behaviors influence parental vaccination acceptance and visit experience. METHODS In a cross-sectional observational study, we videotaped provider-parent vaccine discussions (n = 111). We coded visits for the format providers used for initiating the vaccine discussion (participatory vs presumptive), parental verbal resistance to vaccines after provider initiation (yes vs no), and provider pursuit of recommendations in the face of parental resistance (pursuit vs mitigated or no pursuit). Main outcomes were parental verbal acceptance of recommended vaccines at visits end (all vs ≥ 1 refusal) and parental visit experience (highly vs lower rated). RESULTS In multivariable models, participatory (vs presumptive) initiation formats were associated with decreased odds of accepting all vaccines at visits end (adjusted odds ratio [AOR] = 0.04; 95% confidence interval [CI] = 0.01, 0.15) and increased odds of a highly rated visit experience (AOR = 17.3; 95% CI = 1.5, 200.3). CONCLUSIONS In the context of 2 general communication formats used by providers to initiate vaccine discussions, there appears to be an inverse relationship between parental acceptance of vaccines and visit experience. Further exploration of this inverse relationship in longitudinal studies is needed.

Physician Communication Training and Parental Vaccine Hesitancy: A Randomized Trial

BACKGROUND AND OBJECTIVES: Physicians have a major influence on parental vaccine decisions. We tested a physician-targeted communication intervention designed to (1) reduce vaccine hesitancy in mothers of infants seen by trained physicians and (2) increase physician confidence in communicating about vaccines. METHODS: We conducted a community-based, clinic-level, 2-arm cluster randomized trial in Washington State. Intervention clinics received physician-targeted communications training. We enrolled mothers of healthy newborns from these clinics at the hospital of birth. Mothers and physicians were surveyed at baseline and 6 months. The primary outcome was maternal vaccine hesitancy measured by Parental Attitudes on Childhood Vaccines score; secondary outcome was physician self-efficacy in communicating with parents by using 3 vaccine communication domains. RESULTS: We enrolled 56 clinics and 347 mothers. We conducted intervention trainings at 30 clinics, reaching 67% of eligible physicians; 26 clinics were randomized to the control group. Maternal vaccine hesitancy at baseline and follow-up changed from 9.8% to 7.5% in the intervention group and 12.6% to 8.0% in the control group. At baseline, groups were similar on all variables except maternal race and ethnicity. The intervention had no detectable effect on maternal vaccine hesitancy (adjusted odds ratio 1.22, 95% confidence interval 0.47–2.68). At follow-up, physician self-efficacy in communicating with parents was not significantly different between intervention and control groups. CONCLUSIONS: This physician-targeted communication intervention did not reduce maternal vaccine hesitancy or improve physician self-efficacy. Research is needed to identify physician communication strategies effective at reducing parental vaccine hesitancy in the primary care setting.

Controversies in Vaccine Mandates

Policies that mandate immunization have always been controversial. The controversies take different forms in different contexts. For routine childhood immunizations, many parents have fears about both short- and long-term side effects. Parental worries change as the rate of vaccination in the community changes. When most children are vaccinated, parents worry more about side effects than they do about disease. Because of these worries, immunization rates go down. As immunization rates go down, disease rates go up, and parents worry less about side effects of vaccination and more about the complications of the diseases. Immunization rates then go up. For teenagers, controversies arise about the criteria that should guide policies that mandate, rather than merely recommend and encourage, certain immunizations. In particular, policy makers have questioned whether immunizations for human papillomavirus, or other diseases that are not contagious, should be required. For healthcare workers, debates have focused on the strength of institutional mandates. For years, experts have recommended that all healthcare workers be immunized against influenza. Immunizations for other infections including pertussis, measles, mumps, and hepatitis are encouraged but few hospitals have mandated such immunizations-instead, they rely on incentives and education. Pandemics present a different set of problems as people demand vaccines that are in short supply. These issues erupt into controversy on a regular basis. Physicians and policy makers must respond both in their individual practices and as advisory experts to national and state agencies. The articles in this volume will discuss the evolution of national immunization programs in these various settings. We will critically examine the role of vaccine mandates. We will discuss ways that practitioners and public health officials should deal with vaccine refusal. We will contrast responses of the population as a whole, within the healthcare setting, and in the setting of pandemic influenza.