Culturally sensitive emergency care for sexual and gender minority youth: A quality improvement initiative.

BACKGROUND: Despite evidence of the impact of provider implicit bias and overt discrimination experienced by sexual and gender minority youth (SGMY), evidence surrounding sexual and gender minority cultural sensitivity training for pediatric emergency health professionals is limited. No targeted training existed to improve the clinical preparedness of healthcare professionals serving SGMY by increasing providers' knowledge and attitudinal awareness in a pediatric emergency department at a large, urban pediatric hospital in the Southeastern United States. METHODS: The Institute for Healthcare Improvement's [15] Model for Improvement informed the project and was completed in four Plan-Do-Study-Act cycles. A cross-sectional, pre-test post-test design was used to gather demographic data, administer the LGBT-DOCSS questionnaire, and collect participant feedback on the training session. The LGBT-DOCSS results were analyzed using an independent samples t-test. INTERVENTIONS: Evidence-based pedagogical strategies were utilized for a 60-minute staff training session. Staff (n = 25) had six opportunities to attend one of the training sessions over a period of 4 months. RESULTS: Self-selection and voluntary participation contributed to recruiting participants who demonstrated high baseline LGBT-DOCSS scores, particularly on the subscales that measure knowledge and attitudinal awareness. After the sessions, participants showed an increase in LGBT-DOCSS scores with a statistically significant increase in the clinical preparedness subscale. CONCLUSIONS: This project was the first at the institution to focus on culturally sensitive emergency care for sexual and gender minority youth. The content was well received by staff, who demonstrated increased clinical preparedness after the training. Implementing the training as a required component of new nurse orientation and onboarding is the next step in creating a safety culture for SGMY in the PED setting.

Molecular basis for integrin adhesion receptor binding to p21-activated kinase 4 (PAK4).

Integrin adhesion receptors provide links between extracellular ligands and cytoplasmic signaling. Multiple kinases have been found to directly engage with integrin ß tails, but the molecular basis for these interactions remain unknown. Here, we assess the interaction between the kinase domain of p21-activated kinase 4 (PAK4) and the cytoplasmic tail of integrin ß5. We determine three crystal structures of PAK4-ß5 integrin complexes and identify the PAK-binding site. This is a region in the membrane-proximal half of the ß5 tail and confirmed by site-directed mutagenesis. The ß5 tail engages the kinase substrate-binding groove and positions the non-phosphorylatable integrin residue Glu767 at the phosphoacceptor site. Consistent with this, integrin ß5 is poorly phosphorylated by PAK4, and in keeping with its ability to occlude the substrate-binding site, weakly inhibits kinase activity. These findings demonstrate the molecular basis for ß5 integrin-PAK4 interactions but suggest modifications in understanding the potential cellular role of this interaction.

Transgenic Drosophila lines for LexA-dependent gene and growth regulation.

Conditional expression of short hairpin RNAs with binary genetic systems is an indispensable tool for studying gene function. Addressing mechanisms underlying cell-cell communication in vivo benefits from simultaneous use of 2 independent gene expression systems. To complement the abundance of existing Gal4/UAS-based resources in Drosophila, we and others have developed LexA/LexAop-based genetic tools. Here, we describe experimental and pedagogical advances that promote the efficient conversion of Drosophila Gal4 lines to LexA lines, and the generation of LexAop-short hairpin RNA lines to suppress gene function. We developed a CRISPR/Cas9-based knock-in system to replace Gal4 coding sequences with LexA, and a LexAop-based short hairpin RNA expression vector to achieve short hairpin RNA-mediated gene silencing. We demonstrate the use of these approaches to achieve targeted genetic loss-of-function in multiple tissues. We also detail our development of secondary school curricula that enable students to create transgenic flies, thereby magnifying the production of well-characterized LexA/LexAop lines for the scientific community. The genetic tools and teaching methods presented here provide LexA/LexAop resources that complement existing resources to study intercellular communication coordinating metazoan physiology and development.

The Relationship Between Critical Care Work Environment and Professional Quality of Life.

BACKGROUND: Professional quality of life is the quality a person feels in relation to work. For critical care nurses, it is composed of compassion satisfaction and compassion fatigue. Professional quality of life is affected by work environment. The American Association of Critical-Care Nurses (AACN) has identified 6 standards for a healthy work environment. OBJECTIVE: To explore which of the AACN healthy work environment standards have the strongest impact on professional quality of life in critical care nurses. METHODS: In an exploratory, cross-sectional survey of nurses working in 4 adult critical care units of a single health care facility, professional quality of life was assessed using the Professional Quality of Life Scale (ProQOL), and work environment was evaluated using the AACN Healthy Work Environment Assessment Tool. RESULTS: Participants reported compassion satisfaction and burnout levels as average and secondary traumatic stress levels as high. The composite average for all 6 AACN healthy work environment standards was good. A multiple regression analysis revealed true collaboration, effective decision-making, and authentic leadership as significant predictors of compassion satisfaction. Authentic leadership was the only predictor of burnout. Appropriate staffing, meaningful recognition, and authentic leadership were predictors of secondary traumatic stress. CONCLUSION: Authentic leadership is the strongest predictor of compassion satisfaction, burnout, and secondary traumatic stress. Therefore, improving leadership should be a priority in intensive care units seeking to improve nurses' professional quality of life.

Barriers to Reproductive Healthcare for Women With Opioid Use Disorder.

The health impact of opioid use disorder on women and infant health alongside persistent rates of unintended pregnancy calls for better targeted reproductive healthcare for all women, especially those receiving treatment for opioid treatment disorder and decreasing barriers to care. This cross-sectional mixed-methods study explored the reproductive intentions and contraceptive practices of women (N = 50) in medication-assisted treatment of opioid use disorder with a focus on knowledge and use of long-acting reversible contraception (LARC), specifically intrauterine devices and implants. Eighty-four percent of the 50 women interviewed had experienced at least 1 unintended pregnancy, and 30% were using contraceptive methods with high failure rates. Although approximately 75% of women indicated awareness of both forms of LARCs, only 6% reported current or past use of either device. Qualitative results found the greatest barriers to the uptake of LARC were women's expressed fears of complications and inaccurate information from family, friends, and acquaintances. Increasing awareness of the benefits of LARC as ideal contraception for women who may desire a future pregnancy is important for improving reproductive health for women receiving treatment of opioid use disorder.

Barriers and Facilitators of Breastfeeding Reported by Postpartum Women in Methadone Maintenance Therapy.

INTRODUCTION: This study utilized a cross-sectional qualitative and quantitative interview-based survey to capture the infant feeding practices and barriers to exclusive breastfeeding for women in methadone maintenance therapy. Participants were recruited from an opioid dependence treatment center in an urban setting in the Southeastern United States. MATERIALS AND METHODS: A convenience sample of women in treatment (n = 30) were interviewed using an adapted instrument designed to capture decisions and intentions to formula feed or breastfeed; support from friends and family; hospital experience; support from healthcare personnel; and maternal knowledge of breastfeeding while taking methadone. RESULTS: The majority of women in the sample initiated breastfeeding, but only 10% continued for >1 month. Challenges related to infant hospital stay posed a significant barrier. Two-thirds of infants remained hospitalized after the mother was discharged. Out of the 24 women who initiated breastfeeding, 11 reported that they discontinued because of issues related to infant's neonatal intensive care unit (NICU) stay. Eleven women reported that their healthcare providers did not discuss breastfeeding with them. Women who were encouraged to breastfeed by healthcare staff were more likely to breastfeed for longer durations. CONCLUSIONS: Women in treatment for opioid dependence both desire and attempt to establish breastfeeding, but encounter significant challenges, including long NICU stays and lack of support and education, that compromise their success. These findings should inform the development of future programs or interventions geared toward increasing breastfeeding initiation, support, and duration among women who give birth to babies while in treatment for opioid addiction.

Safety of Rolled and Folded Cotton Blankets Warmed in 130°F and 200°F Cabinets.

PURPOSE: In 2014, ECRI recommended that blanket warming cabinets be set at a maximum temperature of 130°F because of safety concerns with warmed rolled and folded blankets. We could find no research to support this recommendation. The purpose of this study was to measure skin temperatures and thermal comfort in healthy volunteers before and after application of folded and rolled dry cotton blankets warmed in 130°F or 200°F cabinets. DESIGN: Randomized, descriptive, and comparative study. METHODS: Participants (n = 20) received two blankets (one rolled and one folded) from warming cabinets set at 130°F or 200°F. Folded blankets were applied to the back and rolled to the neck. Skin temperatures and thermal comfort were obtained at fixed time intervals. FINDINGS: Skin temperatures from blankets in the 200°F cabinet were greater than those in the 130°F cabinet. No skin temperatures reached temperature and/or duration thresholds for dermal injury. CONCLUSIONS: This study provides supportive evidence that warming cabinets may be set at a maximum of 200°F without compromising patient safety.

Language-Appropriate Appointment Reminders: Assessing the Communication Preferences of Women With Limited English Proficiency.

INTRODUCTION: The purpose of this study was to assess the communication preferences and the telephone, text, and e-mail usage of women with limited English proficiency who attended an outpatient women's health clinic. METHODS: This study surveyed a convenience sample (N = 220) of Spanish- and Arabic-speaking women in an obstetrics and gynecology clinic. The survey instrument was designed to capture the experience of women with limited English proficiency who received automated English-only telephone appointment reminders. We evaluated how these women currently use short message service (SMS) technology and/or access e-mail, the costs they incur for these services, and their preferences for and receptiveness to receiving appointment reminders through a variety of modalities including text, e-mail, phone, or direct mail. RESULTS: More than half of women surveyed reported either not receiving an appointment reminder or reported difficulty understanding the reminder they did receive. Of all women surveyed, 91% preferred appointment reminders in their primary language regardless of their ability to read, write, speak, or understand English. Significant variation in preferences was found within and between the 2 language groups. DISCUSSION: The data suggest that the current appointment-reminder system is both inefficient and linguistically inappropriate for female clients with limited English proficiency. This project offers preliminary data on the preferences of Spanish- and Arabic-speaking women. Creating language-appropriate appointment reminders in both phone and text formats reflects an institutional commitment to the language preferences of all women, not just those who speak the dominant language, in accordance with accreditation guidelines defined by the Centers for Medicare and Medicaid Services and The Joint Commission.

PAK6 targets to cell-cell adhesions through its N-terminus in a Cdc42-dependent manner to drive epithelial colony escape.

The six serine/threonine kinases in the p21-activated kinase (PAK) family are important regulators of cell adhesion, motility and survival. PAK6, which is overexpressed in prostate cancer, was recently reported to localize to cell-cell adhesions and to drive epithelial cell colony escape. Here we report that PAK6 targeting to cell-cell adhesions occurs through its N-terminus, requiring both its Cdc42/Rac interactive binding (CRIB) domain and an adjacent polybasic region for maximal targeting efficiency. We find PAK6 localization to cell-cell adhesions is Cdc42-dependent, as Cdc42 knockdown inhibits PAK6 targeting to cell-cell adhesions. We further find the ability of PAK6 to drive epithelial cell colony escape requires kinase activity and is disrupted by mutations that perturb PAK6 cell-cell adhesion targeting. Finally, we demonstrate that all type II PAKs (PAK4, PAK5 and PAK6) target to cell-cell adhesions, albeit to differing extents, but PAK1 (a type I PAK) does not. Notably, the ability of a PAK isoform to drive epithelial colony escape correlates with its targeting to cell-cell adhesions. We conclude that PAKs have a broader role in the regulation of cell-cell adhesions than previously appreciated.

Signaling, Regulation, and Specificity of the Type II p21-activated Kinases.

The p21-activated kinases (PAKs) are a family of six serine/threonine kinases that act as key effectors of RHO family GTPases in mammalian cells. PAKs are subdivided into two groups: type I PAKs (PAK1, PAK2, and PAK3) and type II PAKs (PAK4, PAK5, and PAK6). Although these groups are involved in common signaling pathways, recent work indicates that the two groups have distinct modes of regulation and have both unique and common substrates. Here, we review recent insights into the molecular level details that govern regulation of type II PAK signaling. We also consider mechanisms by which signal transduction is regulated at the level of substrate specificity. Finally, we discuss the implications of these studies for clinical targeting of these kinases.

Striving for evidence-based practice innovations through a hybrid model journal club: A pilot study.

OBJECTIVE: The purpose of this study was to pilot a "hybrid" style journal club and determine whether measurable effects could be detected over 8-weeks' time on evidence-based practice ability, desire, behaviors, use, and barriers. BACKGROUND: Journal clubs have been suggested as a method to increase nurses' confidence with using research evidence to guide practice. However, it is yet unknown how nurse educators can best implement effective programs for clinicians with varying schedules, education levels, and research skills. SETTING AND PARTICIPANTS: Thirty-six participants from one large urban United States hospital (72% registered nurses) were invited to access bi-weekly interdisciplinary journal club activities. Nurse educators created curriculum focused on clinical problem solving that was offered via in-person sessions or a social media site. METHODS: A pretest-posttest no control group design was used to measure impacts of those engaged in journal club activities. Data were collected using a combination of validated evidence-based practice instruments and program participation records. FINDINGS: A two-tailed paired t test showed significant increases over 8weeks' time in evidence-based practice use (p=.002) and behaviors (p=.007). Slight preference for in-person sessions was reported, although greater participation was reflected in online activities. Mean satisfaction ratings were high; however, attrition rates suggest that more is needed to maximize clinician engagement. CONCLUSION: A hybrid method using online and in-person sessions was feasible and adaptive for varying learning styles and work schedules. Positive changes in measurements were detected among journal club participants. Instruments were identified that may be useful for trialing similar programs intended to increase evidence-based practice self-efficacy, use, behaviors, and ability.

Disruption of CXCR2-mediated MDSC tumor trafficking enhances anti-PD1 efficacy.

Suppression of the host's immune system plays a major role in cancer progression. Tumor signaling of programmed death 1 (PD1) on T cells and expansion of myeloid-derived suppressor cells (MDSCs) are major mechanisms of tumor immune escape. We sought to target these pathways in rhabdomyosarcoma (RMS), the most common soft tissue sarcoma of childhood. Murine RMS showed high surface expression of PD-L1, and anti-PD1 prevented tumor growth if initiated early after tumor inoculation; however, delayed anti-PD1 had limited benefit. RMS induced robust expansion of CXCR2(+)CD11b(+)Ly6G(hi) MDSCs, and CXCR2 deficiency prevented CD11b(+)Ly6G(hi) MDSC trafficking to the tumor. When tumor trafficking of MDSCs was inhibited by CXCR2 deficiency, or after anti-CXCR2 monoclonal antibody therapy, delayed anti-PD1 treatment induced significant antitumor effects. Thus, CXCR2(+)CD11b(+)Ly6G(hi) MDSCs mediate local immunosuppression, which limits the efficacy of checkpoint blockade in murine RMS. Human pediatric sarcomas also produce CXCR2 ligands, including CXCL8. Patients with metastatic pediatric sarcomas display elevated serum CXCR2 ligands, and elevated CXCL8 is associated with diminished survival in this population. We conclude that accumulation of MDSCs in the tumor bed limits the efficacy of checkpoint blockade in cancer. We also identify CXCR2 as a novel target for modulating tumor immune escape and present evidence that CXCR2(+)CD11b(+)Ly6G(hi) MDSCs are an important suppressive myeloid subset in pediatric sarcomas. These findings present a translatable strategy to improve the efficacy of checkpoint blockade by preventing trafficking of MDSCs to the tumor site.

Integrin cytoplasmic tail interactions.

Integrins are heterodimeric cell surface adhesion receptors essential for multicellular life. They connect cells to the extracellular environment and transduce chemical and mechanical signals to and from the cell. Intracellular proteins that bind the integrin cytoplasmic tail regulate integrin engagement of extracellular ligands as well as integrin localization and trafficking. Cytoplasmic integrin-binding proteins also function downstream of integrins, mediating links to the cytoskeleton and to signaling cascades that impact cell motility, growth, and survival. Here, we review key integrin-interacting proteins and their roles in regulating integrin activity, localization, and signaling.

Substrate and inhibitor specificity of the type II p21-activated kinase, PAK6.

The p21-activated kinases (PAKs) are important effectors of Rho-family small GTPases. The PAK family consists of two groups, type I and type II, which have different modes of regulation and signaling. PAK6, a type II PAK, influences behavior and locomotor function in mice and has an ascribed role in androgen receptor signaling. Here we show that PAK6 has a peptide substrate specificity very similar to the other type II PAKs, PAK4 and PAK5 (PAK7). We find that PAK6 catalytic activity is inhibited by a peptide corresponding to its N-terminal pseudosubstrate. Introduction of a melanoma-associated mutation, P52L, into this peptide reduces pseudosubstrate autoinhibition of PAK6, and increases phosphorylation of its substrate PACSIN1 (Syndapin I) in cells. Finally we determine two co-crystal structures of PAK6 catalytic domain in complex with ATP-competitive inhibitors. We determined the 1.4 Å co-crystal structure of PAK6 with the type II PAK inhibitor PF-3758309, and the 1.95 Å co-crystal structure of PAK6 with sunitinib. These findings provide new insights into the structure-function relationships of PAK6 and may facilitate development of PAK6 targeted therapies.

Thermal comfort and safety of cotton blankets warmed at 130°F and 200°F.

BACKGROUND: In 2009, the ECRI Institute recommended warming cotton blankets in cabinets set at 130°F or less. However, there is limited research to support the use of this cabinet temperature. PURPOSE: To measure skin temperatures and thermal comfort in healthy volunteers before and after application of blankets warmed in cabinets set at 130 and 200°F, respectively, and to determine the time-dependent cooling of cotton blankets after removal from warming cabinets set at the two temperatures. DESIGN: Prospective, comparative, descriptive. METHODS: Participants (n = 20) received one or two blankets warmed in 130 or 200°F cabinets. First, skin temperatures were measured, and thermal comfort reports were obtained at fixed timed intervals. Second, blanket temperatures (n = 10) were measured at fixed intervals after removal from the cabinets. FINDING: No skin temperatures approached levels reported in the literature that cause epidermal damage. Thermal comfort reports supported using blankets from the 200°F cabinet, and blankets lost heat quickly over time. CONCLUSIONS: We recommend warming cotton blankets in cabinets set at 200°F or less to improve thermal comfort without compromising patient safety.

Soluble IL7Rα potentiates IL-7 bioactivity and promotes autoimmunity.

Human soluble interleukin-7 receptor (sIL7R)α circulates in high molar excess compared with IL-7, but its biology remains unclear. We demonstrate that sIL7Rα has moderate affinity for IL-7 but does not bind thymic stromal lymphopoietin. Functionally, sIL7Rα competes with cell-associated IL-7 receptor to diminish excessive IL-7 consumption and, thus, enhances the bioactivity of IL-7 when the cytokine is limited, as it is presumed to be in vivo. IL-7 signaling in the presence of sIL7Rα also diminishes expression of CD95 and suppressor of cytokine signaling 1, both regulatory molecules. Murine models confirm diminished consumption of IL-7 in the presence of sIL7Rα and also demonstrate a potentiating effect of sIL7Rα on IL-7-mediated homeostatic expansion and experimental autoimmune encephalomyelitis exacerbation. In multiple sclerosis and several other autoimmune diseases, IL7R genotype influences susceptibility. We measured increased sIL7Rα levels, as well as increased IL-7 levels, in multiple sclerosis patients with the predisposing IL7R genotype, consistent with diminished IL-7 consumption in vivo. This work demonstrates that sIL7Rα potentiates IL-7 bioactivity and provides a basis to explain the increased risk of autoimmunity observed in individuals with genotype-induced elevations of sIL7Rα.

Zasp regulates integrin activation.

Integrins are heterodimeric adhesion receptors that link the extracellular matrix (ECM) to the cytoskeleton. Binding of the scaffold protein, talin, to the cytoplasmic tail of ß-integrin causes a conformational change of the extracellular domains of the integrin heterodimer, thus allowing high-affinity binding of ECM ligands. This essential process is called integrin activation. Here we report that the Z-band alternatively spliced PDZ-motif-containing protein (Zasp) cooperates with talin to activate α5ß1 integrins in mammalian tissue culture and αPS2ßPS integrins in Drosophila. Zasp is a PDZ-LIM-domain-containing protein mutated in human cardiomyopathies previously thought to function primarily in assembly and maintenance of the muscle contractile machinery. Notably, Zasp is the first protein shown to co-activate α5ß1 integrins with talin and appears to do so in a manner distinct from known αIIbß3 integrin co-activators.