CLDN1 knock out keratinocytes as a model to investigate multiple skin disorders.

The transmembrane protein claudin-1 is critical for formation of the epidermal barrier structure called tight junctions (TJ) and has been shown to be important in multiple disease states. These include neonatal ichthyosis and sclerosing cholangitis syndrome, atopic dermatitis and various viral infections. To develop a model to investigate the role of claudin-1 in different disease settings, we used CRISPR/Cas9 to generate human immortalized keratinocyte (KC) lines lacking claudin-1 (CLDN1 KO). We then determined whether loss of claudin-1 expression affects epidermal barrier formation/function and KC differentiation/stratification. The absence of claudin-1 resulted in significantly reduced barrier function in both monolayer and organotypic cultures. CLDN1 KO cells demonstrated decreases in gene transcripts encoding the barrier protein filaggrin and the differentiation marker cytokeratin-10. Marked morphological differences were also observed in CLDN1 KO organotypic cultures including diminished stratification and reduced formation of the stratum granulosum. We also detected increased proliferative KC in the basale layer of CLDN1 KO organotypic cultures. These results further support the role of claudin-1 in epidermal barrier and suggest an additional role of this protein in appropriate stratification of the epidermis.

JAK Signaling Is Critically Important in Cytokine-Induced Viral Susceptibility of Keratinocytes.

Little is known about whether type 1 (IFNγ), 2 (IL-4/IL-13), or 3 (IL-17A/IL-22) cytokines affect the susceptibility of keratinocytes (KC) to viruses. These immune pathways predominate in various skin diseases: lupus, atopic dermatitis (AD), and psoriasis, respectively. Janus kinase inhibitors (JAKi) are approved to treat both AD and psoriasis, and are in clinical development for lupus. We evaluated whether these cytokines alter viral susceptibility of KC and determined if this effect is modulated by treatment with JAKi. Viral susceptibility to vaccinia virus (VV) or herpes simplex virus-1 (HSV-1) ± JAKi was assessed in immortalized and primary human KC pretreated with cytokines. Exposure to type 2 (IL-4 + IL-13) or the type 3 (IL-22) cytokines significantly increased KC viral susceptibility. Specifically, there was a peak increase of 12.2 ± 3.1-fold (IL-4 + IL-13) or 7.7 ± 2.8-fold (IL-22) in VV infection as measured by plaque number. Conversely, IFNγ significantly reduced susceptibility to VV (63.1 ± 64.4-fold). The IL-4 + IL-13-induced viral susceptibility was reduced (44 ± 16%) by JAK1 inhibition, while the IL-22-enhanced viral susceptibility was diminished (76 ± 19%) by TYK2 inhibition. IFNγ-mediated resistance to viral infection was reversed by JAK2 inhibition (366 ± 294% increase in infection). Cytokines expressed in AD skin (IL-4, IL-13, IL-22) increase KC viral susceptibility while IFNγ is protective. JAKi that target JAK1 or TYK2 reversed cytokine-enhanced viral susceptibility, while JAK2 inhibition reduced the protective effects of IFNγ.

Implementation Science and Practice-Oriented Research: Convergence and Complementarity.

Implementation science is the scientific study of methods to promote the uptake of research findings and other evidence-based practices in routine care, with the goal of improving the quality and effectiveness of health services (Bauer et al., 2015). In addition to this common goal, practice-oriented psychotherapy research (and researchers) and implementation science (and scientists) share a common focus on the people and the places where treatment happens. Thus, there exists strong potential for combining these two approaches. In this article, we provide a primer on implementation science for psychotherapy researchers and highlight important areas and examples of convergence and complementarity between implementation science and practice-oriented psychotherapy research. Specifically, we (a) define and describe the core features of implementation science; (b) discuss similarities and areas of complementarity between implementation science and practice-oriented psychotherapy research; (c) discuss a case example that exemplifies the integration of implementation science and practice-oriented research; and (d) propose directions for future research and collaborations that leverage both implementation science and practice-oriented research.

Targeting of Enrollment Assistance Resources in Health Insurance Television Advertising: A Comparison of Spanish- Vs. English-Language Ads.

Latinx adults, especially immigrants, face higher uninsurance and lower awareness of the Affordable Care Act's (ACA) provisions and resources compared to other racial/ethnic groups. Television advertising of ACA health plans has directed many consumers to application assistance and enrollment, but little is known about how ads targeted Latinx consumers. We used Kantar Media/CMAG data from the Wesleyan Media Project to assess Spanish- vs. English-language ad targeting strategies and to assess which enrollment assistance resources (in person/telephone vs. online) were emphasized across three Open Enrollment Periods (OEP) (2013-14, 2014-15, 2015-16). We examined differences in advertisement sponsorship and volume of Spanish- versus English-language ads across the three OEPs. State-based Marketplaces sponsored 47% of Spanish-language airings; insurance companies sponsored 55% of English-language airings. The proportion of Spanish-language airings increased over time (8.8% in OEP1, 11.1% in OEP2, 12.0% in OEP3, p <.001). Spanish-language airings had 49% lower (95%CI: 0.50,0.53) and 2.20 times higher odds (95%CI: 2.17,2.24) of mentioning online and telephone/in-person enrollment assistance resources, respectively. While there was a significant decrease in mention of telephone/in-person assistance over time for English-language airings, these mentions increased significantly in Spanish-language airings. Future research should examine the impact of the drastic federal cuts to ACA outreach and marketing.

Factors that Influenced Adoption of a School-Based Trauma-Informed Universal Mental Health Intervention.

We know little about why school administrators choose to adopt preventive mental health interventions within the context of school-based prevention trials. This study used a qualitative multiple-case study design to identify factors that influenced the adoption of a trauma-informed universal intervention by urban public school administrators during an efficacy trial. Semi-structured interviews were conducted with 15 school administrators who adopted a trauma-informed mindfulness intervention called RAP (Relax, be Aware, and do a Personal Rating) Club as part of their participation in a school-based trial with eighth graders. Findings indicated that administrators adopted RAP Club to provide support for students affected by trauma and prevent students from engaging in unhealthy coping behaviors. Examples of contextual factors that contributed to adoption included a lack of trauma-informed mental health programs within schools, inadequate district funding for preventive school mental health services, and the perceived benefits of engaging in a university-community partnership. The study's findings suggest strategies to increase school program adoption in the context of research and, more broadly, for implementation science.

Come together, play, be active: Physical activity engagement of school-age children at Play Streets in four diverse rural communities in the U.S.

Across the U.S., Play Streets - temporary street closures creating safe places for play for a few hours- are being implemented in urban areas during summer. Play Streets have never been implemented or evaluated in rural communities but have the potential to address challenges residents face accessing safe physical activity opportunities in these areas. Community organizations in four diverse low-income rural communities (selected to represent African American, American Indian, Latino, or White, non-Hispanic populations) received mini-grants in 2017 to implement four, three-hour Play Streets during the summer focusing on school-aged children in elementary-to-middle school. Physical activity was measured using Digi-walker (Yamax-SW200) pedometers and the System for Observing Play and Recreation in Communities (SOPARC/iSOPARC). Sixteen Play Streets were implemented in rural Maryland, North Carolina, Oklahoma, and Texas communities during June-September 2017. A total of 370 children (mean age = 8.81 years [SD = 2.75]; 55.0% female) wore pedometers across all 16 Play Streets (µâ€¯= 23.13 [SD = 8.59] children/Play Street). School-aged children with complete data (n = 353) wore pedometers for an average of 92.97 min (SD = 60.12) and accrued a mean of 42.08 steps/min (SD = 17.27), with no significant differences between boys (µâ€¯= 43.82, SD = 15.76) and girls (µâ€¯= 40.66, SD = 18.34). iSOPARC observations revealed no significant differences in child activity by sex; however, male teens were more active than female teens. Most adults were sedentary during Play Streets according to pedometer and iSOPARC data. Children in diverse rural communities are physically active at Play Streets. Play Streets are a promising intervention for promoting active play among children that lack safe opportunities to be active.

A Strategy toward Icetexane Natural Products.

Icetexane diterpenoids are richly complex polycyclic natural products that have been described with a variety of biological activities. We report here a general synthetic approach toward the 6-7-6 tricyclic core structure of these interesting synthetic targets based on a two-step enolate alkylation and ring-closing metathesis reaction sequence.

Assessing the Content of Television Health Insurance Advertising during Three Open Enrollment Periods of the ACA.

Television advertising has been a primary method for marketing new health plans available under the Affordable Care Act (ACA) to consumers. Data from Kantar Media's Campaign Media Analysis Group were used to analyze advertising content during three ACA open enrollment periods (fall 2013 to spring 2016). Few advertisement airings featured people who were elderly, disabled, or receiving care in a medical setting, and over time airings increasingly featured children, young adults, and people exercising. The most common informational messages focused on plan choice and availability of low-cost plans, but messages shifted over open enrollment cycles to emphasize avoidance of tax penalties and availability of financial assistance. Over the three open enrollment periods, there was a sharp decline in explicit mentions of the ACA or Obamacare in advertisements. Overall, television advertisements have increasingly targeted young, healthy consumers, and informational appeals have shifted toward a focus on financial factors in persuading individuals to enroll in marketplace plans. These advertising approaches make sense in the context of pressures to market plans to appeal to a sufficiently large, diverse group. Importantly, dramatic declines over time in explicit mention of the law mean that citizens may fail to understand the connection between the actions of government and the benefits they are receiving.

Taxane-induced hedgehog signaling is linked to expansion of breast cancer stem-like populations after chemotherapy.

Recurrence of breast cancer after chemotherapy is thought to arise from resistant breast cancer stem cells which are eventually able to repopulate the tumor. The Hedgehog (HH) signaling pathway has been shown to regulate the proliferation and survival of breast cancer stem cells, and has been shown to promote resistance to chemotherapy through the activation of multi-drug resistance and pro survival pathways. Here we report that exposure of heterogenous breast cancer cell lines to docetaxel (DOC) resulted in release of Sonic Hedgehog ligand (SHH) and activation of the HH pathway as evidenced by increased expression and nuclear translocation of the downstream effector Gli-1 at 4-24 h after DOC treatment. This activation had little effect on the bulk of the tumor cell population as inhibition of HH signaling failed to increase apoptosis in response to DOC. However, HH pathway activation was required for clonogenic growth of cell lines after DOC. Increases in stemness markers as well as mammosphere formation were observed after treatment with DOC suggesting an increase in the breast cancer stem cell populations. These increases were similar to that of cell lines cultured in the presence of recombinant SHH and could be eliminated by co-treatment with HH inhibitors. These results suggest that HH pathway activation induced by DOC treatment does not have a chemosensitizing effect on the heterogeneous tumor population, but may be required for survival and expansion of breast cancer stem cells after chemotherapy.

The relationship between childhood adversity and food insecurity: 'It's like a bird nesting in your head'.

OBJECTIVE: Adverse childhood experiences, including abuse, neglect and household instability, affect lifelong health and economic potential. The present study investigates how adverse childhood experiences are associated with food insecurity by exploring caregivers' perceptions of the impact of their childhood adversity on educational attainment, employment and mental health. DESIGN: Semi-structured audio-recorded in-person interviews that included (i) quantitative measures of maternal and child health, adverse childhood experiences (range: 0-10) and food security using the US Household Food Security Survey Module; and (ii) qualitative audio-recorded investigations of experiences with abuse, neglect, violence and hunger over participants' lifetimes. SETTING: Households in Philadelphia, PA, USA. SUBJECTS: Thirty-one mothers of children <4 years old who reported low or very low household food security. RESULTS: Twenty-one caregivers (68 %) reported four or more adverse childhood experiences, and this severity was significantly associated with reports of very low food security (Fisher's exact P=0·021). Mothers reporting emotional and physical abuse were more likely to report very low food security (Fisher's exact P=0·032). Qualitatively, participants described the impact of childhood adverse experiences with emotional and physical abuse/neglect, and household substance abuse, on their emotional health, school performance and ability to maintain employment. In turn, these experiences negatively affected their ability to protect their children from food insecurity. CONCLUSIONS: The associations between mothers' adverse experiences in childhood and reports of current household food security should inspire researchers, advocates and policy makers to comprehensively address family hardship through greater attention to the emotional health of caregivers. Programmes meant to address nutritional deprivation and financial hardship should include trauma-informed approaches that integrate behavioural interventions.

Differentiation of keratinocytes or exposure to type 2 cytokines diminishes S. aureus internalization.

Staphylococcus aureus is a leading cause of skin and soft tissue infections. Colonization by this bacterium is increased in individuals with chronic cutaneous diseases such as atopic dermatitis, psoriasis, and bullous pemphigoid. The greater abundance of S. aureus on the skin of subjects with atopic dermatitis in particular has been linked to recurrent cutaneous infections. The primary cell type of the epidermal layer of the skin is the keratinocyte, and it is thought that S. aureus internalized in keratinocytes associates with an increased incidence of skin infections. This study addresses whether keratinocyte differentiation and/or inflammation, two important characteristics altered in cutaneous diseases, influence bacterial internalization. To do this, S. aureus internalization was measured in immortalized and primary keratinocytes that were differentiated using high Ca2+-containing media and/or exposed to cytokines characteristic of atopic dermatitis (IL-4 and IL-13) or psoriasis (IL-17A and IL-22) skin. Our results indicate that S. aureus internalization is uniquely decreased upon keratinocyte differentiation, since this was not observed with another skin-resident bacterium, S. epidermidis. Additionally, treatment with IL-4 + IL-13 diminished bacterial internalization. We interpret this decrease as a mechanism of keratinocyte-based bacterial killing since a similar number of bacterial genomes were detected in cytokine-treated cells, but less viable internalized S. aureus was recovered. Finally, of the receptors reported for S. aureus binding/internalizing into keratinocytes, expression of the α5 component of the α5ß1 integrin was in greatest accordance with the number of internalized bacteria in the context of keratinocyte differentiation.IMPORTANCEIndividuals with chronic cutaneous diseases demonstrate heightened susceptibility for severe and recurrent infections from Staphylococcus aureus. What drives this altered susceptibility remains poorly understood. Previous publications have detected S. aureus as deep as the dermal layer of skin in subjects with atopic dermatitis, suggesting that the cutaneous environment of this disease enables deeper bacterial infiltration than occurs in healthy individuals. This observation indicates that S. aureus has greater opportunity to interact with multiple skin cell types in individuals with chronic inflammatory skin diseases. Identifying the characteristics of the skin that influence bacterial internalization, a common method to establish reservoirs and evade the immune response, is critical for our understanding of S. aureus pathogenesis. The significance of this research is the novel identification of epidermal characteristics that influence S. aureus internalization. With this knowledge, methods can be developed to identify patient populations at greater risk for cutaneous infections.

The relationship between school mental health service use in high school and educational outcomes of adolescents with psychiatric disorders.

This study aimed to examine the relationship between school mental health service use in high school and educational outcomes of adolescents with psychiatric disorders. The sample included 2617 adolescents who were enrolled in eighth grade in a large urban school district in the United States, were enrolled in Medicaid during eighth grade, and had a mental health diagnosis. Psychiatric hospitalization, school enrollment, school absences, out-of-school suspensions, school dropouts, and school exits for negative reasons were examined as mental health and educational outcomes. Compared with adolescents who used school mental health services for 2 years following eighth grade, adolescents who did not use school mental health service during the high school years had a significantly lower annual number of days enrolled in school and higher rates of exiting school for negative reasons such as school dropout and long-term hospitalization. Our findings support the positive role of school mental health care delivery in high schools in preventing negative educational outcomes for adolescents with psychiatric disorder.

A comprehensive pediatric cardio-oncology program: a single institution approach to cardiovascular care for pediatric patients with cancer and childhood cancer survivors.

Cardiovascular complications related to cancer therapies are broad and variable in onset. These complications are the leading cause of non-cancer related morbidity and mortality in childhood cancer survivors and can also impact ongoing cancer treatment. Despite this understanding, dedicated cardio-oncology programs are lacking in pediatric cardiology. In an attempt to respond to these concerns, a risk-stratified, comprehensive cardio-oncology program was established to address the cardiovascular needs including prevention, early diagnosis, and management of patients with and at risk for cardiovascular complications of cancer therapy. This manuscript describes a single institution's experience of building and managing a multidisciplinary pediatric cardio-oncology program with close collaboration among cardiologists, oncologists, advanced cardiology and oncology practice providers, and allied health providers such as a dietitian and psychologist to provide comprehensive cardiovascular care for childhood cancer patients and survivors. In developing this program, emphasis was on the childhood cancer survivor population, as various cardiovascular complications can present many years after cancer treatment.

Loss of focal adhesion kinase enhances endothelial barrier function and increases focal adhesions.

OBJECTIVE: To determine the role of FAK in the regulation of endothelial barrier function. METHODS: Stable FAK knockdown HLEC were generated by lentiviral infection of FAK shRNA. Measurements of isometric tension and transendothelial electrical resistance were performed. RESULTS: A FAK knockdown human pulmonary endothelial cell line was generated by lentiviral infection with FAK shRNA and resulted in greater than 90% reduction in FAK protein with no change in Pyk2 protein. Loss of FAK altered cell morphology and actin distribution in both pre- and post-confluent endothelial cells. Large, polygonal shaped endothelial cells with randomly organized stress fibers were identified in pre-confluent cultures, while in confluent monolayers, endothelial cells were irregularly shaped with actin bundles present at cell margins. An increase in the number and size of vinculin plaques was detected in FAK-depleted cells. FAK knockdown monolayers generated a greater transendothelial electrical resistance than controls. Thrombin treatment induced similar changes in TER in both FAK knockdown and control cell lines. FAK-depleted endothelial cells developed a higher stable basal isometric tension compared to control monolayers, but the increase in tension stimulated by thrombin does not differ between the cell lines. Basal myosin II regulatory light chain phosphorylation was unaltered in FAK-depleted cells. In addition, loss of FAK enhanced VE-cadherin localization to the cell membrane without altering VE-cadherin protein levels. CONCLUSIONS: The loss of FAK in endothelial cells enhanced cell attachment and strengthened cell-cell contacts resulting in greater basal tension leading to formation of a tighter endothelial monolayer.

Public service providers' perspectives on and responses to the health and social consequences of gentrification in Atlanta, Georgia.

Service providers' perspectives on, and responses to the health and social impacts of gentrification have been underexplored. This study's objectives were to assess health and social service providers' perspectives on the causes and impacts of gentrification and their responses to gentrification's impacts. Qualitative in-depth interviews were conducted with 15 service providers sampled using maximum variation and snowball sampling, in Atlanta, Georgia, U.S.A. Inductive thematic analysis was used. Providers characterized gentrification as increases in community-level social and economic advantage and displacement of Black and Brown people. Neighborhood divestment and speculative development were reported determinants of gentrification. Revitalization and economic growth were reported positive effects of gentrification; negative ramifications included inflated housing costs, residential displacement, and reduced access to health and social services. Providers enacted multiple solutions to mitigate the negative consequences they observed, including educating residents on housing rights and collaborating with other organizations to expand outreach to displaced residents. Service providers are integral to contributing to knowledge on the causes and impacts of gentrification, and absolving problems resulting from gentrification. . Additional research documenting service provider's responses to the impacts of gentrification are needed to inform how future community development strategies are developed to create more benefits than harms.

Implementing evidence-based practices in nonspecialty mental health settings.

OBJECTIVE: Mental health services are often implemented in settings in which mental health is not the primary mission. Schools, primary care clinics, criminal justice and child welfare institutions, and senior centers have been increasingly adding mental health care to their compendium of services owing to the high rates of mental health needs in these settings. Despite numerous challenges to implementing mental health practices in settings where mental health care has not traditionally been a part of the service model, the demand for mental health services in these settings is growing. Implementation science offers a lens through which to understand unique challenges and potential solutions to implementing mental health services in these settings, with the ultimate goal of ensuring the implementation of evidence-based services. METHOD AND RESULTS: In this conceptual article, we discuss common overarching barriers to implementing evidence-based mental health interventions in nonspecialty mental health settings, such as workforce challenges, competing priorities, and financial considerations. Then, using examples from schools and primary care, we elucidate unique contextual considerations and implementation challenges in these settings. Finally, we articulate a research agenda for advancing implementation of evidence-based practices in nonspecialty mental health including highlighting promising implementation strategies (e.g., task shifting, adaptation) and the most relevant implementation outcomes to assess in these contexts (e.g., appropriateness, feasibility). CONCLUSIONS: Given that nonspecialty mental health settings deliver a large proportion of mental health care to traditionally underserved populations, there are important public health implications to advancing research in this area and ensuring implemented services are evidence-based. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Increasing access to mental health supports for healthcare workers during the COVID-19 pandemic and beyond through a novel coaching program.

The COVID-19 pandemic led to heightened anxiety, distress, and burnout among healthcare workers and faculty in academic medicine. Penn Medicine launched Coping First Aid (CFA) in March 2020 in response to the pandemic. Informed by Psychological First Aid principles and therapeutic micro skills, CFA was designed as a tele-mental healthcare service for health system employees and their families delivered by trained lay volunteer coaches under the supervision of licensed mental health clinicians. We present an overview of the model, feasibility and utilization data, and preliminary implementation and effectiveness outcomes based on cross sectional coach (n = 22) and client (n = 57) self-report surveys with a subset of program users in the first year. A total of 44 individuals completed training and were certified to coach. Over the first 24 months of the program, 513 sessions occurred with 273 clients (119 sessions were no-shows or canceled). Follow-up appointments were recommended in 52.6% (n = 270) of sessions and 21.2% (n = 109) of clients were referred for professional mental health care. Client survey respondents reported CFA was helpful; 60% were very or extremely satisfied, and 74% indicated they would recommend the program. Our preliminary findings suggest that CFA was feasible to implement and most clients found the service beneficial. CFA provides a model for rapidly developing and scaling mental health supports during and beyond the pandemic.

The Intergenerational Impact of Structural Racism and Cumulative Trauma on Depression.

Depression among individuals who have been racially and ethnically minoritized in the United States can be vastly different from that of non-Hispanic White Americans. For example, African American adults who have depression rate their symptoms as more severe, have a longer course of illness, and experience more depression-associated disability. The purpose of this review was to conceptualize how structural racism and cumulative trauma can be fundamental drivers of the intergenerational transmission of depression. The authors propose that understanding risk factors for depression, particularly its intergenerational reach, requires accounting for structural racism. In light of the profoundly different experiences of African Americans who experience depression (i.e., a more persistent course of illness and greater disability), it is critical to examine whether an emerging explanation for some of these differences is the intergenerational transmission of this disorder due to structural racism.

Specifying and Reporting Implementation Strategies Used in a School-Based Prevention Efficacy Trial.

BACKGROUND: Implementation strategies used to enhance the implementation of interventions during efficacy and effectiveness studies are rarely reported. Tracking and reporting implementation strategies during these phases has potential to improve future research studies and real-world implementation. We present an exemplar of how this might be executed by specifying and reporting the implementation strategies that were used during a school-based efficacy trial, Project POWER, which tested a trauma-informed prevention program delivered by a university research team, community members, and school staff facilitators in 29 schools. METHODS: Following the conclusion of the 4-year trial, core Project POWER research team members identified the implementation strategies that supported intervention delivery during the trial using an established taxonomy of school-based implementation strategies. The actors, actions, action targets, temporality, dose, and implementation outcomes were specified using established implementation strategies reporting guidelines. RESULTS: The research team identified 37 implementation strategies that were used during the Project POWER trial. Most strategies fell within the categories of Train and Educate Stakeholders, Use Evaluative and Iterative Strategies, and Develop Stakeholder Interrelationships. Actors included members of the research team and partner schools. Strategies were used multiple times during the preparation and implementation phases. Action targets were most often characteristics of individuals, implementation process, and characteristics of the inner setting. Strategies predominantly targeted the implementation outcomes of fidelity, acceptability, feasibility, and adoption. CONCLUSIONS: This study provided evidence that implementation strategies are used and can be identified in efficacy research using a retrospective approach. Identifying and specifying implementation strategies used during the initial phases of the translational research pipeline can inform the implementation strategies that are carried forward, adapted, or discontinued in future trials and routine practice to improve implementation and effectiveness outcomes.