Recruitment of CXCR4+ type 1 innate lymphoid cells distinguishes sarcoidosis from other skin granulomatous diseases.

Sarcoidosis is a multiorgan granulomatous disease that lacks diagnostic biomarkers and targeted treatments. Using blood and skin from patients with sarcoid and non-sarcoid skin granulomas, we discovered that skin granulomas from different diseases exhibit unique immune cell recruitment and molecular signatures. Sarcoid skin granulomas were specifically enriched for type 1 innate lymphoid cells (ILC1s) and B cells and exhibited molecular programs associated with formation of mature tertiary lymphoid structures (TLSs), including increased CXCL12/CXCR4 signaling. Lung sarcoidosis granulomas also displayed similar immune cell recruitment. Thus, granuloma formation was not a generic molecular response. In addition to tissue-specific effects, patients with sarcoidosis exhibited an 8-fold increase in circulating ILC1s, which correlated with treatment status. Multiple immune cell types induced CXCL12/CXCR4 signaling in sarcoidosis, including Th1 T cells, macrophages, and ILCs. Mechanistically, CXCR4 inhibition reduced sarcoidosis-activated immune cell migration, and targeting CXCR4 or total ILCs attenuated granuloma formation in a noninfectious mouse model. Taken together, our results show that ILC1s are a tissue and circulating biomarker that distinguishes sarcoidosis from other skin granulomatous diseases. Repurposing existing CXCR4 inhibitors may offer a new targeted treatment for this devastating disease.

Investigating the translational value of Periprosthetic Joint Infection (PJI) models to determine the risk and severity of Staphylococcal biofilms.

With the advent of antibiotic-eluting polymeric materials for targeting recalcitrant infections, using preclinical models to study biofilm is crucial for improving the treatment efficacy in periprosthetic joint infections. The stratification of risk and severity of infections is needed to develop an effective clinical dosing framework with better outcomes. Here, using in-vivo and in-vitro implant-associated infection models, we demonstrate that methicillin-sensitive and resistant Staphylococcus aureus (MSSA and MRSA) have model-dependent distinct implant and peri-implant tissue colonization patterns. The maturity of biofilms and the location (implant vs tissue) were found to influence the antibiotic susceptibility evolution profiles of MSSA and MRSA and the models could capture the differing host-microbe interactions in vivo. Gene expression studies revealed the molecular heterogeneity of colonizing bacterial populations. The comparison and stratification of the risk and severity of infection across different preclinical models provided in this study can guide clinical dosing to effectively prevent or treat PJI.

Thyroid hormones mediate the impact of early-life stress on ventral tegmental area gene expression and behavior.

Proper thyroid function is essential to the developing brain, including dopamine neuron differentiation, growth, and maintenance. Stress across the lifespan impacts thyroid hormone signaling and anxiety disorders and depression have been associated with thyroid dysfunction (both hypo- and hyper-active). However, less is known about how stress during postnatal development impacts thyroid function and related brain development. Our previous work in mice demonstrated that early-life stress (ELS) transiently impinged on expression of a transcription factor in dopamine neurons, Otx2, shown to be regulated by thyroid hormones. We hypothesized that thyroid hormone signaling may link experience of ELS with transcriptional dysregulation within the dopaminergic midbrain, and ultimately behavior. Here, we find that ELS transiently increases thyroid-stimulating hormone levels (inversely related to thyroid signaling) in both male and female mice at P21, an effect which recovers by adolescence. We next tested whether transient treatment of ELS mice with synthetic thyroid hormone (levothyroxine, LT4) could ameliorate the impact of ELS on sensitivity to future stress, and on expression of genes related to dopamine neuron development and maintenance, thyroid signaling, and plasticity within the ventral tegmental area. Among male mice, but not females, juvenile LT4 treatment prevented hypersensitivity to adult stress. We also found that rescuing developmental deficits in thyroid hormone signaling after ELS restored levels of some genes altered directly by ELS, and prevented alterations in expression of other genes sensitive to the second hit of adult stress. These findings suggest that thyroid signaling mediates the deleterious impact of ELS on VTA development, and that temporary treatment of hypothyroidism after ELS may be sufficient to prevent future stress hypersensitivity.

Thyroid hormones mediate the impact of early-life stress on ventral tegmental area gene expression and behavior.

Proper thyroid function is essential to the developing brain, including dopamine neuron differentiation, growth, and maintenance. Stress across the lifespan impacts thyroid hormone signaling and anxiety disorders and depression have been associated with thyroid dysfunction (both hypo- and hyper-active). However, less is known about how stress during postnatal development impacts thyroid function and related brain development. Our previous work in mice demonstrated that early-life stress (ELS) transiently impinged on expression of a transcription factor in dopamine neurons shown to be regulated by thyroid hormones. We hypothesized that thyroid hormone signaling may link experience of ELS with transcriptional dysregulation within the dopaminergic midbrain, and ultimately behavior. Here, we find that ELS transiently increases thyroid-stimulating hormone levels (inversely related to thyroid signaling) in both male and female mice at P21, an effect which recovers by adolescence. We next tested whether transient treatment of ELS mice with synthetic thyroid hormone (levothyroxine, LT4) could ameliorate the impact of ELS on sensitivity to future stress, and on expression of genes related to dopamine neuron development and maintenance, thyroid signaling, and plasticity within the ventral tegmental area. Among male mice, but not females, juvenile LT4 treatment prevented hypersensitivity to adult stress. We also found that rescuing developmental deficits in thyroid hormone signaling after ELS restored levels of some genes altered directly by ELS, and prevented alterations in expression of other genes sensitive to the second hit of adult stress. These findings suggest that thyroid signaling mediates the deleterious impact of ELS on VTA development, and that temporary treatment of hypothyroidism after ELS may be sufficient to prevent future stress hypersensitivity.

HiCuT: An efficient and low input method to identify protein-directed chromatin interactions.

3D genome organization regulates gene expression, and disruption of these long-range (>20kB) DNA-protein interactions results in pathogenic phenotypes. Chromosome conformation methods in conjunction with chromatin immunoprecipitation were used to decipher protein-directed chromatin interactions. However, these methods required abundant starting material (>500,000 cells), sizable number of sequencing reads (>100 million reads), and elaborate data processing methods to reduce background noise, which limited their use in primary cells. Hi-C Coupled chromatin cleavage and Tagmentation (HiCuT) is a new transposase-assisted tagmentation method that generates high-resolution protein directed long-range chromatin interactions as efficiently as existing methods, HiChIP and ChIA-PET, despite using 100,000 cells (5-fold less) and 12 million sequencing reads (8-fold fewer). Moreover, HiCuT generates high resolution fragment libraries with low background signal that are easily interpreted with minimal computational processing. We used HiCuT in human primary skin cells to link previously identified single nucleotide polymorphisms (SNPs) in skin disease to candidate genes and to identify functionally relevant transcription factors in an unbiased manner. HiCuT broadens the capacity for genomic profiling in systems previously unmeasurable, including primary cells, human tissue samples, and rare cell populations, and may be a useful tool for all investigators studying human genetics and personalized epigenomics.

Integration of TeamSTEPPS Framework and Escape Room to Improve Teamwork and Collaboration.

BACKGROUND: As the need for healthcare professionals continues to grow, different learning environments have been assessed to optimize knowledge while keeping the student engaged. Escape rooms, live action, team-based exercises, supplemented with TeamSTEPPS tools can assist in overall team performance, while keeping the participant engaged in a new learning environment. OBJECTIVE: The goal of this quality improvement project was to enhance teamwork and collaboration through the integration of TeamSTEPPS concepts and escape room active learning. This concept was explored through the integration of TeamSTEPPS tools and strategies in an escape room setting. The purpose was to improve team dynamics and cohesiveness in a new dynamic way with a small cohort of nurse leaders in a large urban academic medical center, while exploring the engagement and depth of learning experience for the participant. METHODS: Twelve nurse leaders completed two different escape rooms while observers completed the TeamSTEPPS observation tool assessing team dynamics and performance and participants assessed their perceptions before and after intervention. These nurses also were observed at staff meetings and completed a perceptions tool on teamwork pre- and postintervention. A postescape room survey was completed by participants to assess learning and interest in this interactive learning exercise. RESULTS: There was a significant statistical difference after TeamSTEPPS and escape room intervention (Mean 17.3 and p = 0.004 SD 5.9) when compared to before intervention as well as has a more positive sense of teamwork was noted. In addition, 75% of the nurses strongly agreed that the escape room was engaging and fun with 25% agreeing. Ninety-one percent agreed or strongly agreed that the escape room was an effective team-building exercise with 100% agreeing or strongly agreeing to recommend the escape room experience to others. CONCLUSIONS: This cohort validated the integration of TeamSTEPPS tools and strategies in an escape room setting as an enjoyable and engaging way to learn while providing an effective team-building activity. This small cohort demonstrates that new methods of learning such as an escape room should be explored further for engaging participants and improving communication and teamwork skills. IMPLICATIONS FOR NURSING: Integrating TeamSTEPPS into an escape room offers this institution a way to continue this project while providing valuable team-building skills to its participants. While this was just a small sample in one intercity hospital, new methods for learning should be reviewed for successful teamwork in nursing and in healthcare as a whole, as there was some data to suggest that utilizing an escape room could have a positive impact on team cohesiveness as well as leadership skills for the individual.

Leveraging Community Engagement to Develop a Mobile Health Application for Older Women With HIV Infection.

OBJECTIVE: To develop a mobile health app for older women with HIV infection that will be used in a larger study. DESIGN: A qualitative study design. SETTING: Baltimore-Washington metropolitan area clinics and communities. PARTICIPANTS: Ten women 50 years and older (mean age = 62.8 years, standard deviation = 3.62, range = 58-69 years) who self-identified as Black or African American and were infected with HIV. METHODS: At the start of the study, we used relevant empirical and the self-determination theory to inform the draft Web-based app content that was shared with two focus groups. Data were analyzed with input from a community advisory board (CAB) to inform the development of the mobile health app. RESULTS: We inductively identified eight subthemes within the coding structure of two overall themes: Navigating Content, Functions, and Features and Enhancing Provider Interaction With Patients that represented the perspectives of participants regarding the app. From the eight subthemes, we integrated the contributions from the CAB, which we then used to further optimize the app. CONCLUSION: The app was designed to provide support, tools, and resources for older women with HIV. Engagement of community collaborators could be challenging because of multiple personal and structural barriers. Nonetheless, the potential community member benefits are invaluable. If successful, the Web-based app could be a model to address the needs of older persons with HIV infection.

Primary, secondary, and tertiary prevention of cardiovascular disease in patients with HIV disease: a guide for nurse practitioners.

HIV infection elevates a patient's risk for developing cardiovascular disease (CVD), due in part to direct effects of increased infection-producing inflammation and to drugs used to treat the infection, which can have untoward effects on serum lipid profiles. HIV-infected older adults often present with multiple comorbidities, including CVD, making disease management more challenging. Treatment paradigms are evolving, and nurse practitioners (NPs) are expected to play an ever-larger role in the management of HIV infection. Due to their accessibility and close patient contact, NPs are especially well suited to work with and educate patients to manage multiple risk factors. Appropriate use of primary, secondary, and tertiary CVD prevention strategies, including education to modify lifestyle risks, individualized antiretroviral treatment regimens to achieve serum lipid targets, and use of additional lipid-modifying strategies to minimize a patient's overall CVD risk profile will be important throughout the treatment lifecycle.