Repeated Bordetella pertussis Infections Are Required to Reprogram Acellular Pertussis Vaccine-Primed Host Responses in the Baboon Model.

BACKGROUND: The United States has experienced a resurgence of pertussis following the introduction of acellular pertussis (aP) vaccines. This is likely due to the failure of aP vaccines to induce durable immunity and prevent infection, carriage, and transmission. METHODS: To evaluate the impact of aP vaccination on the immune response to infection and test the ability of infection to reprogram aP-imprinted immune responses, we challenged unvaccinated and aP-vaccinated baboons with Bordetella pertussis multiple times and accessed the immune responses and outcomes of infections after each exposure. RESULTS: Multiple infections were required to elicit T-helper 17 responses and protection in aP-vaccinated animals comparable to responses seen in unvaccinated animals after a single challenge. Even after 3 challenges, T-helper 1 responses were not observed in aP-vaccinated animals. Immunoglobulin G responses to vaccine and nonvaccine antigens were not negatively affected in aP-vaccinated animals. CONCLUSIONS: Our results indicate that it is possible to retrain aP-primed immune responses, but it will likely require an optimal booster and multiple doses. Our results in the baboon model suggest that circulation of B. pertussis in aP-vaccinated populations is concentrated in the younger age bands of the population, providing information that can guide improved modeling of B. pertussis epidemiology in aP-vaccinated populations.

Maternal Vaccination With a Monocomponent Pertussis Toxoid Vaccine Is Sufficient to Protect Infants in a Baboon Model of Whooping Cough.

Background: Bordetella pertussis is a human pathogen responsible for serious respiratory illness. The disease is most severe in infants too young to be vaccinated with most hospitalizations and deaths occurring within this age group. The Advisory Committee on Immunization Practices recommended immunization of pregnant women to protect infants from birth until their first vaccination at 6-8 weeks of age. We previously demonstrated that maternal vaccination with licensed acellular pertussis vaccines protected newborn baboons from disease. We hypothesized that protection was due to toxin-neutralizing, maternal anti-pertussis toxin antibodies and predicted that maternal vaccination with a pertussis toxoid (PTx)-only vaccine would protect newborns from disease. Methods: Infant baboons born to unvaccinated mothers or mothers vaccinated with a PTx-only vaccine were challenged with B. pertussis at 5 weeks of age and followed for infection and signs of disease. Results: Although all challenged infants were heavily colonized, the infant baboons born to mothers vaccinated with PTx-only vaccine were free from clinical disease following exposure to B. pertussis. In contrast, disease was observed in infants born to unvaccinated mothers. Conclusions: Our results demonstrated that maternal vaccination with a PTx-only vaccine is sufficient to protect newborn baboons from disease following exposure to pertussis.

Histopathology of Bordetella pertussis in the Baboon Model.

Pertussis is a severe respiratory disease caused by Bordetella pertussis The classic symptoms of pertussis include paroxysmal coughing with an inspiratory whoop, posttussive vomiting, cyanosis, and persistent coryzal symptoms. Infants under 2 months of age experience more severe disease, with most deaths occurring in this age group. Most of what is known about the pathology of pertussis in humans is from the evaluation of fatal human infant cases. The baboon model of pertussis provides the opportunity to evaluate the histopathology of severe but nonfatal pertussis. The baboon model recapitulates the characteristic clinical signs of pertussis observed in humans, including leukocytosis, paroxysmal coughing, mucus production, heavy colonization of the airway, and transmission of the bacteria between hosts. As in humans, baboons demonstrate age-related differences in clinical presentation, with younger animals experiencing more severe disease. We examined the histopathology of 5- to 6-week-old baboons, with the findings being similar to those reported for fatal human infant cases. In juvenile baboons, we found that the disease is highly inflammatory and concentrated to the lungs with signs of disease that would typically be diagnosed as acute respiratory distress syndrome (ARDS) and bronchopneumonia. In contrast, no significant pathology was observed in the trachea. Histopathological changes in the trachea were limited to cellular infiltrates and mucus production. Immunohistostaining revealed that the bacteria were localized to the surface of the ciliated epithelium in the conducting airways. Our observations provide important insights into the pathology of pertussis in typical, severe but nonfatal pertussis cases in a very relevant animal model.

A System-Level Approach to Overweight and Obesity in the Veterans Health Administration.

Healthcare systems are challenged by steady increases in the number of patients who are overweight and obese. Large-scale, evidence-based behavioral approaches for addressing overweight and obesity have been successfully implemented in systems such as the Veterans Health Administration (VHA). These population-based interventions target reduction in risk for obesity-associated conditions through lifestyle change and weight loss, and are associated with modest weight loss. Despite the fact that VHA has increased the overall reach of these behavioral interventions, the number of high-risk overweight and obese patients continues to rise. Recommendations for weight loss medications and bariatric surgery are included in clinical practice guidelines for the management of overweight and obesity, but these interventions are underutilized. During a recent state of the art conference on weight management held by VHA, subject matter experts identified challenges and gaps, as well as potential solutions and overarching policy recommendations, for implementing an integrated system-wide approach for improving population-based weight management.

Acellular pertussis vaccines protect against disease but fail to prevent infection and transmission in a nonhuman primate model.

Pertussis is a highly contagious respiratory illness caused by the bacterial pathogen Bordetella pertussis. Pertussis rates in the United States have been rising and reached a 50-y high of 42,000 cases in 2012. Although pertussis resurgence is not completely understood, we hypothesize that current acellular pertussis (aP) vaccines fail to prevent colonization and transmission. To test our hypothesis, infant baboons were vaccinated at 2, 4, and 6 mo of age with aP or whole-cell pertussis (wP) vaccines and challenged with B. pertussis at 7 mo. Infection was followed by quantifying colonization in nasopharyngeal washes and monitoring leukocytosis and symptoms. Baboons vaccinated with aP were protected from severe pertussis-associated symptoms but not from colonization, did not clear the infection faster than naïve animals, and readily transmitted B. pertussis to unvaccinated contacts. Vaccination with wP induced a more rapid clearance compared with naïve and aP-vaccinated animals. By comparison, previously infected animals were not colonized upon secondary infection. Although all vaccinated and previously infected animals had robust serum antibody responses, we found key differences in T-cell immunity. Previously infected animals and wP-vaccinated animals possess strong B. pertussis-specific T helper 17 (Th17) memory and Th1 memory, whereas aP vaccination induced a Th1/Th2 response instead. The observation that aP, which induces an immune response mismatched to that induced by natural infection, fails to prevent colonization or transmission provides a plausible explanation for the resurgence of pertussis and suggests that optimal control of pertussis will require the development of improved vaccines.

Participatory System Dynamics Modeling: Increasing Stakeholder Engagement and Precision to Improve Implementation Planning in Systems.

Implementation planning typically incorporates stakeholder input. Quality improvement efforts provide data-based feedback regarding progress. Participatory system dynamics modeling (PSD) triangulates stakeholder expertise, data and simulation of implementation plans prior to attempting change. Frontline staff in one VA outpatient mental health system used PSD to examine policy and procedural "mechanisms" they believe underlie local capacity to implement evidence-based psychotherapies (EBPs) for PTSD and depression. We piloted the PSD process, simulating implementation plans to improve EBP reach. Findings indicate PSD is a feasible, useful strategy for building stakeholder consensus, and may save time and effort as compared to trial-and-error EBP implementation planning.

Racial/ethnic differences in identity and mental health outcomes among young sexual minority women.

Previous research suggests that sexual minorities are at greater risk for trauma exposure, mental health problems, and substance use. To date, few studies have examined racial/ethnic differences among sexual minorities in relation to health-related behaviors and outcomes. Furthermore, studies of racial/ethnic differences among young adult sexual minority women (SMW) are virtually nonexistent. The current study adds to the previous literature by exploring differences in trauma exposure, sexual identity, mental health, and substance use in a nonprobability national sample of young adult SMW. A total of 967 self- identified lesbian and bisexual women were recruited via the Internet using social networking sites to participate in a larger longitudinal study on young women's health behaviors. The present study included 730 (76%) White, 108 (10%) African American, 91 (9%) Latina, and 38 (4%) Asian women ages 18 to 25 years. Results revealed differences in socioeconomic variables, degree of outness to family, childhood sexual assault, and forcible rape, but not overall lifetime trauma exposure. Among mental health and health-related behavior variables, few differences between groups emerged. Our findings indicate that both researchers and clinicians should turn their attention to processes of resilience among young SMW, particularly young SMW of color.

Resilience in community: a social ecological development model for young adult sexual minority women.

Family support and rejection are associated with health outcomes among sexual minority women (SMW). We examined a social ecological development model among young adult SMW, testing whether identity risk factors or outness to family interacted with family rejection to predict community connectedness and collective self-esteem. Lesbian and bisexual women (N = 843; 57% bisexual) between the ages of 18-25 (M = 21.4; SD = 2.1) completed baseline and 12-month online surveys. The sample identified as White (54.2%), multiple racial backgrounds (16.6%), African American (9.6%) and Asian/Asian American (3.1%); 10.2% endorsed a Hispanic/Latina ethnicity. Rejection ranged from 18 to 41% across family relationships. Longitudinal regression indicated that when outness to family increased, SMW in highly rejecting families demonstrated resilience by finding connections and esteem in sexual minority communities to a greater extent than did non-rejected peers. But, when stigma concerns, concealment motivation, and other identity risk factors increased over the year, high family rejection did not impact community connectedness and SMW reported lower collective self-esteem. Racial minority SMW reported lower community connectedness, but not lower collective self-esteem. Families likely buffer or exacerbate societal risks for ill health. Findings highlight the protective role of LGBTQ communities and normative resilience among SMW and their families.

Maternal and neonatal vaccination protects newborn baboons from pertussis infection.

BACKGROUND: The United States is experiencing a pertussis resurgence that resulted in a 60-year high of 48 000 cases in 2012. The majority of hospitalizations and deaths occur in infants too young to be vaccinated. Neonatal and maternal vaccination have been proposed to protect newborns until the first vaccination, currently recommended at 2 months of age. These interventions result in elevated anti-Bordetella pertussis titers, but there have been no studies demonstrating that these measures confer protection. METHODS: Baboons were vaccinated with acellular pertussis vaccine at 2 days of age or at 2 and 28 days of age. To model maternal vaccination, adult female baboons primed with acellular pertussis vaccine were boosted in the third trimester of pregnancy. Neonatally vaccinated infants, infants born to vaccinated mothers, and naive infants born to unvaccinated mothers were infected with B. pertussis at 5 weeks of age. RESULTS: Naive infant baboons developed severe disease when challenged with B. pertussis at 5 weeks of age. Baboons receiving acellular pertussis vaccine and infants born to mothers vaccinated at the beginning of their third trimester were protected. CONCLUSIONS: Our results demonstrate that neonatal vaccination and maternal vaccination confer protection in the baboon model and support further study of these strategies for protection of newborns from pertussis.

Associations of past-year overall trauma, sexual assault and PTSD with social support for young adult sexual minority women.

Background: Young adult sexual minority women (SMW) are at elevated risk for sexual assault (SA), posttraumatic stress disorder (PTSD), and inadequate social support. While SA and PTSD can lead to reductions in social support from close significant others, the impact of SA and PTSD on SMWs' social support has not previously been assessed.Objective: This study examined the associations of past year SA and PTSD with SMW's social support from intimate partners, family, and friends. It was hypothesized that SA and PTSD would be negatively associated with support from partners, family and friends, and that PTSD would moderate the effect of SA on support in early adulthood.Method: Young adult SMW in the United States (N = 235) who were M = 23.93 (SD = 2.15) years old, primarily lesbian or bisexual (n = 186, 79.1%) and White (n = 176, 74.9%) completed measures on past year exposure to SA and non-SA trauma, PTSD, and social support from intimate partners, family and friends.Results: PTSD was associated with less social support from partners, (b = -0.06, SE = 0.02, p = .010, R2change = .02), family, (b = -0.06, SE = 0.03, p = .025, R2change = .02), and friends, (b = -0.07, SE = 0.02, p = .008, R2change = .02). There was a significant interaction between PTSD and SA on social support from partners (b = -0.01, SE = 0.01, p = .047, R2change = .01). Neither non-SA nor SA trauma was associated with support from family or friends.Conclusions: Results underscore the potential impact of recent SA on intimate partnerships for young adult SMW with more severe PTSD. Future work should explore how addressing PTSD and improving social support quality may help SMW recover from traumatic experiences and ameliorate the effects of SA on intimate partnerships.

We examined the associations of past-year sexual and non-sexual assault trauma and PTSD with sexual minority women's social support from close significant others.Higher PTSD was associated with lower social support from partners, family and friends.In intimate partnerships, sexual assault was only associated with less social support when PTSD symptoms were more severe.

Construction and characterization of a derivative of Neisseria gonorrhoeae strain MS11 devoid of all opa genes.

To better understand the role of Opa in gonococcal infections, we created and characterized a derivative of MS11 (MS11Δopa) that had the coding sequence for all 11 Opa proteins deleted. The MS11Δopa bacterium lost the ability to bind to purified lipooligosaccharide (LOS). While nonpiliated MS11Δopa and nonpiliated Opa-expressing MS11 cells grew at the same rate, nonpiliated MS11Δopa cells rarely formed clumps of more than four bacteria when grown in broth with vigorous shaking. Using flow cytometry analysis, we demonstrated that MS11Δopa produced a homogeneous population of bacteria that failed to bind monoclonal antibody (MAb) 4B12, a MAb specific for Opa. Opa-expressing MS11 cells consisted of two predominant populations, where ∼85% bound MAb 4B12 to a significant level and the other population bound little if any MAb. Approximately 90% of bacteria isolated from a phenotypically Opa-negative colony (a colony that does not refract light) failed to bind MAb 4B12; the remaining 10% bound MAb to various degrees. Piliated MS11Δopa cells formed dispersed microcolonies on ME180 cells which were visually distinct from those of piliated Opa-expressing MS11 cells. When Opa expression was reintroduced into MS11Δopa, the adherence ability of the strain recovered to wild-type levels. These data indicate that Opa contributes to both bacterium-bacterium and bacterium-host cell interactions.

Lack of lipid A pyrophosphorylation and functional lptA reduces inflammation by Neisseria commensals.

The interaction of the immune system with Neisseria commensals remains poorly understood. We have previously shown that phosphoethanolamine on the lipid A portion of lipooligosaccharide (LOS) plays an important role in Toll-like receptor 4 (TLR4) signaling. For pathogenic Neisseria, phosphoethanolamine is added to lipid A by the phosphoethanolamine transferase specific for lipid A, which is encoded by lptA. Here, we report that Southern hybridizations and bioinformatics analyses of genomic sequences from all eight commensal Neisseria species confirmed that lptA was absent in 15 of 17 strains examined but was present in N. lactamica. Mass spectrometry of lipid A and intact LOS revealed the lack of both pyrophosphorylation and phosphoethanolaminylation in lipid A of commensal species lacking lptA. Inflammatory signaling in human THP-1 monocytic cells was much greater with pathogenic than with commensal Neisseria strains that lacked lptA, and greater sensitivity to polymyxin B was consistent with the absence of phosphoethanolamine. Unlike the other commensals, whole bacteria of two N. lactamica commensal strains had low inflammatory potential, whereas their lipid A had high-level pyrophosphorylation and phosphoethanolaminylation and induced high-level inflammatory signaling, supporting previous studies indicating that this species uses mechanisms other than altering lipid A to support commensalism. A meningococcal lptA deletion mutant had reduced inflammatory potential, further illustrating the importance of lipid A pyrophosphorylation and phosphoethanolaminylation in the bioactivity of LOS. Overall, our results indicate that lack of pyrophosphorylation and phosphoethanolaminylation of lipid A contributes to the immune privilege of most commensal Neisseria strains by reducing the inflammatory potential of LOS.

Hospital In Home: Evaluating Need and Readiness for Implementation (HENRI) in the Department of Veterans Affairs: protocol for a mixed-methods evaluation and participatory implementation planning study.

BACKGROUND AND OBJECTIVES: The Department of Veterans Affairs (VA) Hospital-In-Home (HIH) program delivers patient-centered, acute-level hospital care at home. Compared to inpatient care, HIH has demonstrated improved patient safety, effectiveness, and patient and caregiver satisfaction. The VA Office of Geriatrics & Extended Care (GEC) has supported the development of 12 HIH program sites nationally, yet adoption in VA remains modest, and questions remain regarding optimal implementation practices to extend reach and adaptability of this innovation. Guided by theoretical and procedural implementation science frameworks, this study aims to systematically gather evidence from the 12 HIH programs and to develop a participatory approach to engage stakeholders, assess readiness, and develop/adapt implementation strategies and evaluation metrics. RESEARCH DESIGN AND METHODS: We propose a multi-phase concurrent triangulation design comprising of (1) qualitative interviews with key informants and document review, (2) quantitative evaluation of effectiveness outcomes, and (3) mixed-methods synthesis and adaptation of a Reach Effectiveness Adoption Implementation Maintenance (RE-AIM)-guided conceptual framework. RESULTS: The prospective phase will involve a participatory process of identifying stakeholders (leadership, HIH staff, veterans, and caregivers), engaging in planning meetings informed by implementation mapping, and developing implementation logic models and blueprints. The process will be assessed using a mixed-methods approach through participant observation and document review. DISCUSSION AND IMPLICATION: This study will support the continued spread of HIH programs, generate a catalog of HIH implementation evidence, and create implementation tools and infrastructure for future HIH development. The multi-phase nature of informing prospective planning with retrospective analysis is consistent with the Learning Health System framework.

Addressing the mental health impact of COVID-19 through population health.

The COVID-19 pandemic has and will continue to result in negative mental health outcomes such as depression, anxiety and traumatic stress in people and populations throughout the world. A population mental health perspective informed by clinical psychology, psychiatry and dissemination and implementation science is ideally suited to address the broad, multi-faceted and long-lasting mental health impact of the pandemic. Informed by a systematic review of the burgeoning empirical research on the COVID-19 pandemic and research on prior coronavirus pandemics, we link pandemic risk factors, negative mental health outcomes and appropriate intervention strategies. We describe how social risk factors and pandemic stressors will contribute to negative mental health outcomes, especially among vulnerable populations. We evaluate the scalability of primary, secondary and tertiary interventions according to mental health target, population, modality, intensity and provider type to provide a unified strategy for meeting population mental health needs. Traditional models, in which evidence-based therapies delivered are delivered in-person, by a trained expert, at a specialty care location have proved difficult to scale. The use of non-traditional models, tailoring preventive interventions to populations based on their needs, and ongoing coordinated evaluation of intervention implementation and effectiveness will be critical to refining our efforts to increase reach.

Stressors and Drinking in Sexual Minority Women: The Mediating Role of Emotion Dysregulation.

Sexual minority women are at elevated risk for exposure to stressors (both traumatic and discriminatory) and have higher rates of alcohol consumption and problems. The psychological mediation framework (Hatzenbuehler, 2009) suggests that both general (e.g., traumatic events to which minorities and nonminorities may be exposed) and minority-group-specific (e.g., discrimination) stressors contribute to psychopathology through mediators such as emotion dysregulation. Guided by this framework, the present study longitudinally examined the relationship between stressors and problematic drinking outcomes (i.e., binge drinking and alcohol-related problems), as mediated by emotion dysregulation, in sexual minority women (SMW). It addressed two research questions: (1) whether stressors longitudinally predict problematic drinking outcomes in SMW, as mediated by emotion dysregulation, and (2) for which specific forms of stressor (i.e., traumatic events and/or discrimination) this mediational relationship is present. Young adult women (N = 1057) who identified as lesbian or bisexual completed annual measures of daily heterosexism, traumas, and drinking outcomes for four years, and completed a measure of emotion dysregulation during the third year of data collection. We found an indirect relationship between discrimination and problematic drinking outcomes via emotion dysregulation. These findings are consistent with the psychological mediation framework (Hatzenbuehler, 2009) and suggest that SMW group-specific processes such as discrimination may be especially important in conferring risk for problem drinking via emotion dysregulation. Clinicians are advised to assess unique stressors faced by SMW and their potential contribution to problematic drinking outcomes, and to target emotion dysregulation in alcohol treatments.

Does it work and does it last? Effects of social and drinking behavior on same- and next-day mood.

Both social and drinking behavior have the potential to modify mood. However, if social drinking enhances positive mood and reduces negative mood, as compared to non-drinking social behavior, then interventions to reinforce non-drinking via sober social activity are undermined. Using multilevel modeling analyses, we compared end-of-day mood on drinking days versus non-drinking days, and on days spent with other people as compared to days spent primarily alone. We evaluated the interaction between drinking/non-drinking and social/solitary behavior and assessed whether the effects of social and drinking behavior extended to mood the next day. Participants were 352 college students (53% female; 55% fraternity/sorority membership; mean age 19.7 years) who completed three automated telephone surveys each day during four 14-day intervals over 1 year. Drinking and being social were associated with higher end-of-day positive mood and significantly lower end-of-day negative mood. However, no positive enhancement or negative attenuation effects of alcohol were observed in interaction analyses. Alcohol provided no improvement in mood over-and-above being social at the end of the day or on the following day. However, drinking the previous day significantly reduced next-day positive mood, whereas being social significantly reduced next-day negative mood. These findings provide support for the reinforcing potential of interventions that increase rewarding social activity in the place of alcohol use.

Tracheal colonization factor A (TcfA) is a biomarker for rapid and specific detection of Bordetella pertussis.

Pertussis is a highly contagious disease for which prompt, point-of-care diagnosis remains an unmet clinical need. Results from conventional test modalities (nucleic acid detection, serology, and culture) take hours to days. To overcome this challenge, we identified a new biomarker (tracheal colonization factor A, TcfA) for detection of Bordetella pertussis infection by lateral flow immunoassay (LFIA). We developed a library of 28 epitope-mapped monoclonal antibodies against TcfA and incorporated three antibodies into a LFIA. The LFIA did not cross-react with common bacterial or fungal organisms, but did react with nine distinct B. pertussis strains. The minimal linear epitope sequences targeted by the LFIA were conserved in 98% of 954 B. pertussis isolates collected across 12 countries from 1949-2017. The LFIA's limit of detection was 3.0 × 105 CFU/mL with B. pertussis cells in buffer, 6.2 × 105 CFU/mL with nasopharyngeal washes from a non-human primate model, and 2.3 ng/mL with recombinant TcfA. The LFIA reacted with patient nasopharyngeal swab specimens containing as few as 1.8 × 106 B. pertussis genomes/mL and showed no false-positives. Rapid (< 20 min) LFIA detection of TcfA as a biomarker for B. pertussis infection is feasible and may facilitate early detection of pertussis.

Creating a Practice-Based Implementation Network: Facilitating Practice Change Across Health Care Systems.

A proof-of-concept practice-based implementation network was developed in the US Departments of Veteran Affairs (VA) and Defense to increase the speed of implementation of mental health practices, derive lessons learned prior to larger-scale implementation, and facilitate organizational learning. One hundred thirty-four clinicians in 18 VA clinics received brief training in the use of the PTSD checklist (PCL) in clinical care. Two implementation strategies, external facilitation and technical assistance, were used to encourage the use of outcomes data to inform treatment decisions and increase discussion of results with patients. There were mixed results for changes in the frequency of PCL administration, but consistent increases in clinician use of data and incorporation into the treatment process via discussion. Programs and clinicians were successfully recruited to participate in a 2-year initiative, suggesting the feasibility of using this organizational structure to facilitate the implementation of new practices in treatment systems.

Alcohol and binge eating as mediators between posttraumatic stress disorder symptom severity and body mass index.

OBJECTIVE: Sexual-minority women are at elevated risk for obesity, as well as exposure to traumatic events. Rates of obesity are elevated in individuals with posttraumatic stress disorder (PTSD), but little is known about why this relationship exists. Behavioral mechanisms, such as eating patterns and alcohol use, are possible explanations that would be clinically useful to identify. METHODS: Binge eating and alcohol use were longitudinally investigated as mediators of the relationship between PTSD symptom severity and body mass index (BMI) in a large sample of young-adult, sexual-minority women (N = 425). PTSD symptom severity was assessed at baseline, binge eating and alcohol use were assessed 12 months later, and BMI was assessed 24 months after baseline. RESULTS: Using a multiple mediator model, higher baseline PTSD symptom severity was found to be significantly associated with higher BMI 2 years later, operating through binge-eating behavior but not through alcohol use. Exploratory moderator analyses found that this effect was higher for those with lower baseline BMI. CONCLUSIONS: Results suggest that higher PTSD symptoms are longitudinally associated with increased BMI and that binge eating behavior is one factor that explains this relationship.