Psychometric properties of the Positive Thinking Skills Scale among undergraduate nursing students.

Increasing the resilience of undergraduate nursing students is essential for the individual student's well-being and the healthcare system dealing with a looming nursing shortage. Undergraduate nursing students have reported that positive thinking and positive reframing are ways of coping with exposure to suffering, but measurement of these skills remains limited in this population. This is the first study to examine the psychometric properties of the Positive Thinking Skills Scale specifically in undergraduate nursing students and in a sample that includes students from both public and private universities. Internal consistency was demonstrated with a Cronbach's alpha of 0.824, convergent validity was demonstrated with correlations with measures of views of suffering and professional quality of life, and the one-factor structure was supported in a sample of 157 undergraduate nursing students. The Positive Thinking Skills Scale can be a useful tool to both assess and measure the development of positive thinking skills in undergraduate nursing students.

Family engagement in paediatric acute care settings: A realist review.

AIM: To create a programme theory of family engagement in paediatric acute care to explicate the relationships between contexts and mechanisms of family engagement that align with family, direct care providers and healthcare organization outcomes. DESIGN: Realist review and synthesis. DATA SOURCES: PubMed, CINAHL, PsycINFO and Web of Science searches for the 2.5-year period (July 2019-December 2021) following our 2021 scoping review. REVIEW METHODS: Following methods described by Pawson and Rycroft-Malone, we defined the scope of the review, searched for and appraised the evidence, extracted and synthesized study findings and developed a supporting narrative of our results. RESULTS: Of 316 initial citations, 101 were included in our synthesis of the final programme theory. Contexts included family and direct care provider individualism, and the organizational care philosophy and environment. Mechanisms were family presence, family enactment of a role in the child's care, direct care providers facilitating a family role in the child's care, unit/organizational promotion of a family role, relationship building and mutually beneficial partnerships. Outcomes were largely family-focussed, with a paucity of organizational outcomes studied. We identified four context-mechanism-outcome configurations. CONCLUSION: This realist review uncovered underlying contexts and mechanisms between patients, direct care providers and organizations in the family engagement process and key components of a mutually beneficial partnership. Given that successful family engagement requires direct care provider and organizational support, future research should expand beyond family outcomes to include direct care providers, particularly nurses and healthcare organization outcomes. IMPACT: The final programme theory of family engagement in paediatric acute care provides a roadmap for clinicians to develop complex interventions to engage families and evaluate their impact. The components of our final programme theory reflect family engagement concepts that have been evolving for decades. PATIENT OR PUBLIC CONTRIBUTION: The team conducting this review included members from the practice setting (JT & KG). In the future, as we and others use this model in practice, we will seek input for refinement from clinicians, patients and caregivers.

Building a community-academic partnership to improve screening for intimate partner violence: Integrating advocates in healthcare clinic settings.

AIMS: To develop an innovative community-academic partnership to advance, test and promote intimate partner violence screening and referral protocols by comparing the effect of integrating intimate partner violence advocates versus enhancing medical training in medical clinic settings serving women from vulnerable populations. Detecting intimate partner violence in healthcare settings allows for survivors to connect to safety and referral resources prior to violence escalating. Screening for intimate partner violence and connecting patients to referral resources requires creating a safe and trusting relationship between healthcare providers and patients. Developing screening and referral protocols responsive to survivors' needs requires involvement of clinic staff, survivors and community agencies that support survivors. DESIGN: Three phases of the project include Discovery, Implementation and Dissemination. Mixed-methodology will help in understanding current practices and effects of interventions. METHODS: Actions included in each phase: Discovery: 1) nurse-led focus groups of clinic staff, providers and survivors to understand current clinic practices; 2) retrospective chart review of the number of screens performed, positive screens detected and interventions performed. IMPLEMENTATION: 1) randomization of patients to be interviewed by a trained advocate or by healthcare provider with enhanced training; and 2) assess the number of screenings and referrals performed in each arm and 3) evaluate outcomes of intervention. Dissemination through: presentations, manuscripts and policy recommendations at the institutional and regional level. This IRB-approved proposal was funded in July 2021 by an Advancing a Healthier Wisconsin grant. DISCUSSION: The partnership has improved channels of communication and understanding between diverse clinical care providers, survivors and community agency staff as they navigate the complex challenges to the development and integration of screening and referral protocols. IMPACT: This project will provide evidence of the most effective intimate partner violence screening and referral methodology that can be utilized in a wide variety of medical settings.

Patient-mediated interventions in hospital: A systematic review.

AIMS: To describe the characteristics of hospital-based, patient-mediated interventions and their impact on patient, clinician and organization outcomes. DESIGN: Systematic review. DATA SOURCES: Health literature databases (MEDLINE, CINAHL and EMBASE) were searched in August 2021. Backward and forward citation searching was conducted. REVIEW METHODS: Studies investigating patient-mediated interventions, targeted at adult hospitalized patients were eligible. Data were extracted related to study and intervention characteristics. Narrative synthesis was used to understand intervention impact on patient, clinician and organization outcomes (as per a framework). Methodological quality was assessed using the Mixed Methods Assessment Tool. RESULTS: Thirty-three studies, reporting 18 interventions, were included. Twelve interventions prompted patients to report health information about their own health/needs/concerns and six interventions encouraged patients to provide feedback about clinical practice. Across all interventions, there was evidence that patients used patient-mediated interventions and that they may improve patient communication. Healthcare professional outcomes were mixed for actual/intended use, acceptability and usefulness of interventions; yet there was some evidence of healthcare professional behaviour change. Interventions that encouraged patients to report health information about their own health/needs/concerns appeared more successful than other types of interventions. CONCLUSIONS: There is some evidence that hospital-based patient-mediated interventions may influence patient communication and healthcare professional behaviour. Patient-mediated interventions that encourage patients to report patient data before a clinical encounter may be more impactful than interventions that encourage patient feedback during or post-encounter. IMPACT: To date, most patient-mediated intervention research has been conducted in primary care settings; we uncovered the types of patient-mediated interventions that have been trialled in hospitals. We found that patient communication and healthcare professional behaviour may be influenced by these patient-mediated interventions. Future researchers could explore the suitability and effectiveness of a wider range of hospital-based patient-mediated interventions. NO PATIENT OR PUBLIC CONTRIBUTION: There was no funding to remunerate a patient/member of the public for this review.

Patient engagement, involvement, or participation - entrapping concepts in nurse-patient interactions: A critical discussion.

The importance of patients taking an active role in their healthcare is recognized internationally, to improve safety and effectiveness in practice. There is still, however, some ambiguity about the conceptualization of that patient role; it is referred to interchangeably in the literature as engagement, involvement, and participation. The aim of this discussion paper is to examine and conceptualize the concepts of patient engagement, involvement, and participation within healthcare, particularly nursing. The concepts were found to have semantic differences and similarities, although, from a nursing perspective, they can be summoned to illustrate the establishment of a mutual partnership between a patient and a nurse. The individualization of such processes requires the joint effort of engagement, involvement, or participation, represented by interactive actions of both the patient (asking questions, telling/speaking up, knowledge acquisition, learning, and decision-making) and the nurse (recognizing, responding, information sharing, teaching, and collaborating). Suggesting that the concepts can be used interchangeably comes with some caution, requiring that nurses embrace patients playing a role in their health and healthcare. Further research and practice development should focus on how patients and nurses receive and respond to each other to establish patient engagement, involvement, and participation.

Small Molecule Inhibitors of Nuclear Export and the Amelioration of Lupus by Modulation of Plasma Cell Generation and Survival.

OBJECTIVE: To investigate the hypothesis that selective inhibitors of nuclear export (SINE compounds), recently approved for treatment of refractory plasma cell (PC) malignancy, may have potential in the treatment of lupus. METHODS: Female NZB/NZW mice were treated with the SINE compound KPT-350 or vehicle control. Tissue specimens were harvested and analyzed by flow cytometry, using standard markers. Nephritis was monitored by determining the proteinuria score and by histologic analysis of kidney specimens. Serum anti-double-stranded DNA (anti-dsDNA) levels were measured by enzyme-linked immunosorbent assay, and total numbers of IgG-secreting and dsDNA-specific antibody-secreting cells were assessed by enzyme-linked immunospot assay. RESULTS: KPT-350 abrogated murine lupus nephritis at both early and late stages of the disease and rapidly impaired generation of autoreactive PCs in germinal centers (GCs). SINE compounds inhibited the production of NF-κB-driven homeostatic chemokines by stromal cells, altering splenic B and T cell strategic positioning and significantly reducing follicular helper T cell, GC B cell, and autoreactive PC counts. KPT-350 also decreased levels of cytokines and chemokines involved in PC survival and recruitment in the kidney of lupus-prone mice. Exportin 1, the target of SINE compounds, was detected in GCs of human tonsils, splenic B cells of lupus patients, and multiple B cell subsets in the kidneys of patients with lupus nephritis. CONCLUSION: Collectively, our results provide support for the therapeutic potential of SINE compounds, via their targeting of several molecular and cellular pathways critical in lupus pathogenesis, including autoantibody production by plasma cells.

Systematic review of family engagement interventions in neonatal, paediatric, and adult ICUs.

AIMS AND OBJECTIVES: The purpose of this systematic review was to evaluate interventions that have been used to engage families in direct care activities (active family engagement) in adult, paediatric, and neonatal intensive care unit (ICU) settings. BACKGROUND: Family engagement is universally advocated across ICU populations and practice settings; however, appraisal of the active family engagement intervention literature remains limited. SEARCH STRATEGY: Ovid Medline, PsycArticles & PsycInfo, Scopus, and CINAHL were searched for family interventions that involved direct care of the patient to enhance the psychological, physical, or emotional well-being of the patient or family in neonatal, paediatric, or adult ICUs. INCLUSION/EXCLUSION CRITERIA: Studies were included if an active family engagement intervention was evaluated. Studies were excluded if they were not published in English or reported non-interventional research. RESULTS: A total of 6210 abstracts were screened and 19 studies were included. Most studies were of low to moderate quality and were conducted in neonatal ICUs within the United States. Intervention dosage and frequency varied widely across studies. The interventions focused on developmental care (neonatal ICU) and involved families in basic patient care. Family member outcomes measured included satisfaction, stress, family-centred care, confidence, anxiety, and depression. Most studies found improvements in one or more outcomes. CONCLUSIONS: There is a paucity of literature about active family engagement interventions, especially in adult and paediatric populations. The optimal dosage and frequency of family engagement interventions remains unknown. Our systematic review found that data are limited on the relationship between family engagement and patient outcomes, and provides a timely appraisal to guide future research. RELEVANCE TO CLINICAL PRACTICE: Further research on the efficacy of family engagement interventions is warranted. The translation of active family engagement interventions into clinical practice should also be supported.

Engagement of Families in the Care of Hospitalized Pediatric Patients: A Scoping Review.

This scoping review was conducted to examine the range, nature, and extent of the published family engagement literature specific to the pediatric acute care setting to highlight future research and practice development opportunities. Included studies (N = 247) revealed global relevance. Engagement strategies ranged from more passive such as allowing/encouraging families to be present at the bedside to more active strategies aimed at promoting mutual and reciprocal nurse-patient interactions. Family engagement is distinguished by a mutually beneficial partnership of families with health care team members and care organizations. Future research in the area of family engagement in pediatric nursing should focus on determining the core engaging health professional behaviors and engaged parent outcomes; extending the knowledge base related to mutually beneficial partnerships between families and health care teams; developing effectiveness studies to determine the optimal engaging actions by teams to achieve parent engagement; and measuring the influence of engagement on parent and infant/child outcomes.

Mixed Methods Study of Nurse Assessment of Patient Preferences for Engagement During Hospitalization.

BACKGROUND: Global healthcare initiatives emphasize the importance of engaging patients in their healthcare to improve patients' experience and outcomes. Assessing patient preferences for engagement is critical, as there are many ways patients can engage in their care and preferences vary across individuals. OBJECTIVE: The primary purpose of this study was to evaluate the effect of implementation of the Patient Preferences for Engagement Tool 13-Item Short Form (PPET13) during hospitalization on patient and nurse experience of engagement. Readmissions and emergency department (ED) usage within 30 days postdischarge were also examined. METHODS: The mixed methods study was conducted within two medical units in the United States between December 2018 and May 2019. Preimplementation group patients completed a demographic survey and the Patient Experience of Engagement Survey (PEES) on discharge. Implementation group patients completed the PPET13 within 24 hours of admission with their nurse and the demographic survey and PEES on discharge. A focus group with nurses who implemented the PPET13 was conducted following the implementation period. Data analysis included confirmatory factor analysis, multiple and logistic regression, and qualitative content analysis. RESULTS: There was significant improvement in PEES scores during the implementation phase. The PEES score was a significant predictor of ED visits, but not 30-day readmissions. Nurses were not always certain how to best integrate patient preferences for engagement into their care delivery and suggested integrating the PPET13 into the electronic health record to assist with streamlining the assessment and communicating preferences across the care team. DISCUSSION: Assessing patients' preferences for engagement using the PPET13 was associated with an improved experience of engagement, which was found to mediate the relationship between utilization of PPET13 and ED usage within 30 days postdischarge. Use of a patient engagement preference tool, such as the PPET13, can help inform the delivery of individualized engagement strategies to improve patient and family engagement and outcomes; however, nurses need formalized education on how to tailor their care to meet the individual engagement preferences of their patients.

Promoting patient engagement: a scoping review of actions that align with the interactive care model.

BACKGROUND: Conceptual clarity for the term patient engagement is growing. However, there is variability in patient engagement in healthcare, which could be due to the absence of models to guide practice or a myriad of organisational, nurse and patient factors. The recently developed 'Interactive Care Model' provides guidance on how to genuinely promote individualised patient engagement. An understanding of how to action this model in nursing is required. AIMS: The aim of this scoping review was to examine actions in the published scientific literature that align with the Interactive Care Model, in the context of nursing care of hospitalised patients. DATA SOURCES: In 2018, searches of CINAHL, Cochrane Library, MEDLINE and PsycInfo were undertaken, for literature published between 2008 and 2018. This was followed by citation tracking. REVIEW METHODS: Two researchers screened and selected studies using prespecified criteria. Data were charted into a pre-established tool and collated and summarised using numerical summaries and deductive content analysis. For content analysis, categories were generated from the 'Interactive Care Model'. FINDINGS: Forty-three studies were included in the review, 33 noninterventional and 10 interventional studies. Publications on the topic are increasing in number over time, with most conducted in Europe with patient or nurse participants. Forty-two actions were found in the literature that aligned with the 'Interactive Care Model'. The actions uncovered differed between intervention and noninterventional studies; in interventional studies actions were formalised. CONCLUSIONS: This review provides an overview of actions that promote patient engagement and could inform implementation of the Interactive Care Model and the design and testing of patient engagement interventions to support the model. There are opportunities to explore latter phases of the Interactive Care Model to foster patient engagement in self-management and to motivate patients' management of healthcare beyond hospitalisation. Further, there is a need to rigorously evaluate patient engagement interventions.

Systematic review of psychometric properties of instruments measuring patient preferences for engagement in health care.

AIM: To identify, critically appraise, and summarize instruments that measure patients' preferences for engagement in health care. DESIGN: Psychometric systematic literature review. DATA SOURCES: PubMed, Embase, CINAHL, and PsycINFO were searched from inception to March 2019. REVIEW METHODS: Three reviewers independently evaluated the 'methodological quality' and the 'measurement properties' of the included instruments using the Consensus-based Standards for the Selection of Health Measurement Instruments (COSMIN) checklist and Terwee's quality criteria. Each instrument was given a Grading of Recommendations Assessment, Development and Evaluation (GRADE) score. The review was registered at PROSPERO (registry number CRD42018109253). RESULTS: A total of 16 studies evaluating 8 instruments measuring patients' preferences for engagement in health care were included. All instruments were downgraded for their 'methodological quality' or 'measurement properties', or a combination of both. Common concerns were lack of theoretical basis, absence of patient input during development, incorrect usage and reporting of validity measures and absence of a priori hypotheses to test validity. CONCLUSIONS: There were no identified instruments that demonstrated adequate evidence for all measurement properties. The Patient Preferences for Patient Participation Scale (4Ps) and 10-item Decisional Engagement Scale (DES-10) had the highest overall GRADE scores; however, each had some underlying developmental or methodological issues. IMPACT: Assessing how patients prefer to engage in their care is a critical first step to truly individualize engagement interventions to meet patient expectations. Systematic reviews of measures of patient experience with engagement in health care have been undertaken but none are available on measures of patient preferences for engagement. The results highlight the need to further develop and test instruments that measure patients' preferences for engagement in health care within a framework for consumerism. Involving the consumer in the instrument development process will ensure that engagement strategies used by healthcare providers are relevant and individualized to consumer preferences.

Validity and Reliability of the Antepartum Gastrointestinal Symptom Assessment Instrument.

OBJECTIVE: To examine the psychometric properties of the nine-item Antepartum Gastrointestinal Symptom Assessment (AP-GI-SA) instrument. DESIGN: Single-group prospective design. SETTING: Urban prenatal clinic serving a diverse population. PARTICIPANTS: Convenience sample of 45 pregnant women. METHODS: Participants completed the AP-GI-SA before a scheduled prenatal care appointment. We used Bayesian structural equation modeling to evaluate the construct validity of the scale and assessed known-groups validity. We assessed reliability through maximal reliability coefficient estimate and measured internal consistency with Cronbach's alpha coefficient. RESULTS: Participants completed the instrument in 2 minutes or less. Construct validity was supported by confirmatory factor analysis (posterior predictive p value = 0.49, gamma-hat = 0.970, and root mean square error of approximation = 0.065), which indicated that the single-factor model is a plausible data-generative model for GI symptoms. The maximal reliability coefficient of 0.75 and Cronbach's alpha coefficient of 0.67 supported reliability. Average AP-GI-SA scores were the highest for women in the third trimester. Of all nine GI symptoms, heartburn in the third trimester received the highest score. CONCLUSION: Our findings provide preliminary support for the validity and reliability of the AP-GI-SA. The instrument may be used as a measure in intervention studies where GI symptoms of pregnancy are an outcome. The AP-GI-SA could also be useful in clinical settings to quickly evaluate GI symptoms.

Development and Psychometric Analysis of the Patient Preferences for Engagement Tool.

BACKGROUND: Assessing patients' preferences for engaging in healthcare is needed to inform the planning and delivery of individualized healthcare. Unfortunately, patients are often not engaged in their care to the extent that they would like, leading to patient feelings of disempowerment and frustration. OBJECTIVES: The purpose of this study was to (a) develop and (b) psychometrically test the Patient Preferences for Engagement Tool (PPET), a clinical assessment tool that can be used by nursing staff to identify patient preferences for engagement in healthcare. The usability of the PPET was also examined for both nurses and patients participating in the study. METHODS: The psychometric evaluation design used content and construct validity testing (exploratory and confirmatory factor analysis, known groups comparisons) and reliability estimation using Cronbach's alpha coefficient. The sample consisted of 308 adult patients aged 18-101 years from a Midwestern U.S. Magnet-designated academic medical center. RESULTS: Content validity index was at least 0.8 for all but one item. Using a split sample, a six-factor solution was first identified using exploratory factor analysis and then confirmed using confirmatory factor analysis. Demographic and illness factors were not significant predictors of factor scores. Cronbach's alpha coefficients of all six factors were >0.7. Both patients and nurses gave high ratings to the tool on effectiveness, efficiency, and satisfaction with use. DISCUSSION: The PPET demonstrated acceptable validity and reliability estimates. Assessing patient preferences for engagement gives value to the patient voice and provides an opportunity to have discussions with patients about various ways they can engage in their healthcare. Future research will focus on reducing the number of items on the PPET to construct a clinically useful resource for providers to use to assess patient preferences for healthcare engagement, leading to the development of more personalized care delivery methods.

Patients' perspectives on engaging in their healthcare while hospitalised.

AIMS AND OBJECTIVES: To examine patients' experiences and preferences for engaging in their healthcare while hospitalised. BACKGROUND: Promoting patient engagement or involvement in healthcare has become an important component of contemporary, consumer-oriented approaches to quality care. Previous research on patient engagement highlights that preferences for engagement are not assessed while hospitalised, leading to patient role confusion and frustration. METHODS: Semistructured interviews were conducted with patients from January-March 2017 to examine their experiences and preferences for engaging in their care while hospitalised on medical-surgical units in the United States. Inductive thematic analysis was used to uncover the themes from the interview transcriptions. The reporting of research findings followed the COREQ checklist. RESULTS: Seventeen patients, eight male and nine female, aged between 19-83 years old were interviewed. Patients had a difficult time articulating how they participated in their care while hospitalised, with the majority stating there were few decisions to be made. Many patients felt that decisions were made prior to or during hospitalisation for them. Patients described their engagement through the following themes: sharing the subjective, involvement of family, information-gathering, constraints, "I let them take care of me," and variability. CONCLUSIONS: Engagement is a dual responsibility of both nurses and patients. Patients' experiences highlight that engagement preferences and experiences are not universal between patients, speaking to the importance of assessing patient preferences for engagement in health care upon hospital admission. RELEVANCE TO CLINICAL PRACTICE: The articulation of what patients actually experience in the hospital setting contributes to improve nursing practice by offering insight into what is important to the patient and how best to engage with them in their care. The constraints that patients reported facing related to their healthcare engagement should be used to inform the delivery of future engagement interventions in the acute care setting.

B cells inhibit bone formation in rheumatoid arthritis by suppressing osteoblast differentiation.

The function of B cells in osteoblast (OB) dysfunction in rheumatoid arthritis (RA) has not been well-studied. Here we show that B cells are enriched in the subchondral and endosteal bone marrow (BM) areas adjacent to osteocalcin+ OBs in two murine RA models: collagen-induced arthritis and the TNF-transgenic mice. Subchondral BM B cells in RA mice express high levels of OB inhibitors, CCL3 and TNF, and inhibit OB differentiation by activating ERK and NF-κB signaling pathways. The inhibitory effect of RA B cells on OB differentiation is blocked by CCL3 and TNF neutralization, and deletion of CCL3 and TNF in RA B cells completely rescues OB function in vivo, while B cell depletion attenuates bone erosion and OB inhibition in RA mice. Lastly, B cells from RA patients express CCL3 and TNF and inhibit OB differentiation, with these effects ameliorated by CCL3 and TNF neutralization. Thus, B cells inhibit bone formation in RA by producing multiple OB inhibitors.

Nurses' Experiences Empowering Hospitalized Patients.

Four focus groups were conducted to explore acute care nurses' experiences empowering patients and the facilitators and barriers they encountered during the process. Thirty-four nurses employed at four hospitals in the Midwestern United States participated in the study between February and April 2015. Facilitators of empowerment included establishing a therapeutic relationship, fostering communication, providing education, respecting patient autonomy, engaging support systems, and lifting spirit/giving hope. Barriers included conflicting information about plans of care, lack of time, fear and anxiety over unfamiliar environments and routines, ineffective or inadequate support systems, lack of/low accountability, and killing the soul. Nurses also described innovative strategies they used to overcome the barriers. The development of future inpatient empowerment interventions needs to focus on the innovative strategies nurses used to overcome barriers in addition to considering the facilitators and barriers to empowerment that nurses identified.

Inhibition of G Protein ßγ Subunit Signaling Abrogates Nephritis in Lupus-Prone Mice.

OBJECTIVE: Despite considerable advances in the understanding of systemic lupus erythematosus (SLE), there is still an urgent need for new and more targeted treatment approaches. We previously demonstrated that small-molecule blockade of G protein ßγ subunit (Gßγ) signaling inhibits acute inflammation through inhibition of chemokine receptor signal transduction. We undertook this study to determine whether inhibition of Gßγ signaling ameliorates disease in a mouse model of SLE. METHODS: Lupus-prone (NZB × NZW)F1 female mice were prophylactically or therapeutically treated with the small-molecule Gßγ inhibitor gallein. Tissue samples were analyzed by flow cytometry and immunohistochemistry. The development and extent of nephritis were assessed by monitoring proteinuria and by immunohistochemical analysis. Serum immunoglobulin levels were measured by enzyme-linked immunosorbent assay, and total IgG and anti-double-stranded DNA (anti-dsDNA) antibody-secreting cells were measured by enzyme-linked immunospot assay. RESULTS: Gallein inhibited accumulation of T cells and germinal center (GC) B cells in the spleen. Both prophylactic and therapeutic treatment reduced GC size, decreased antibody-secreting cell production in the spleen, and markedly decreased accumulation of autoreactive anti-dsDNA antibody-secreting cells in kidneys. Gallein also reduced immune complex deposition in kidneys. Finally, gallein treatment dramatically inhibited kidney inflammation, prevented glomerular damage, and decreased proteinuria. Mechanistically, gallein inhibited immune cell migration and signaling in response to chemokines in vitro, which suggests that its mechanisms of action in vivo are inhibition of migration of immune cells to sites of inflammation and inhibition of immune cell maturation. CONCLUSION: Overall, these data demonstrate the potential use of gallein or novel inhibitors of Gßγ signaling in SLE treatment.

Production of RANKL by Memory B Cells: A Link Between B Cells and Bone Erosion in Rheumatoid Arthritis.

OBJECTIVE: Rheumatoid arthritis (RA) is a systemic autoimmune disease that often leads to joint damage. The mechanisms of bone damage in RA are complex, involving activation of bone-resorbing osteoclasts (OCs) by synoviocytes and Th17 cells. This study was undertaken to investigate whether B cells play a direct role in osteoclastogenesis through the production of RANKL, the essential cytokine for OC development. METHODS: RANKL production by total B cells or sorted B cell subpopulations in the peripheral blood and synovial tissue from healthy donors or anti-cyclic citrullinated peptide-positive patients with RA was examined by flow cytometry, real-time polymerase chain reaction, enzyme-linked immunosorbent assay, and immunohistochemical analysis. To define direct effects on osteoclastogenesis, B cells were cocultured with CD14+ monocytes, and OCs were enumerated by tartrate-resistant acid phosphatase staining. RESULTS: Healthy donor peripheral blood B cells were capable of expressing RANKL upon stimulation, with switched memory B cells (CD27+IgD-) having the highest propensity for RANKL production. Notably, switched memory B cells in the peripheral blood from RA patients expressed significantly more RANKL compared to healthy controls. In RA synovial fluid and tissue, memory B cells were enriched and spontaneously expressed RANKL, with some of these cells visualized adjacent to RANK+ OC precursors. Critically, B cells supported OC differentiation in vitro in a RANKL-dependent manner, and the number of OCs was higher in cultures with RA B cells than in those derived from healthy controls. CONCLUSION: These findings reveal the critical importance of B cells in bone homeostasis and their likely contribution to joint destruction in RA.

Expansion of Activated Peripheral Blood Memory B Cells in Rheumatoid Arthritis, Impact of B Cell Depletion Therapy, and Biomarkers of Response.

Although B cell depletion therapy (BCDT) is effective in a subset of rheumatoid arthritis (RA) patients, both mechanisms and biomarkers of response are poorly defined. Here we characterized abnormalities in B cell populations in RA and the impact of BCDT in order to elucidate B cell roles in the disease and response biomarkers. In active RA patients both CD27+IgD- switched memory (SM) and CD27-IgD- double negative memory (DN) peripheral blood B cells contained significantly higher fractions of CD95+ and CD21- activated cells compared to healthy controls. After BCD the predominant B cell populations were memory, and residual memory B cells displayed a high fraction of CD21- and CD95+ compared to pre-depletion indicating some resistance of these activated populations to anti-CD20. The residual memory populations also expressed more Ki-67 compared to pre-treatment, suggesting homeostatic proliferation in the B cell depleted state. Biomarkers of clinical response included lower CD95+ activated memory B cells at depletion time points and a higher ratio of transitional B cells to memory at reconstitution. B cell function in terms of cytokine secretion was dependent on B cell subset and changed with BCD. Thus, SM B cells produced pro-inflammatory (TNF) over regulatory (IL10) cytokines as compared to naïve/transitional. Notably, B cell TNF production decreased after BCDT and reconstitution compared to untreated RA. Our results support the hypothesis that the clinical and immunological outcome of BCDT depends on the relative balance of protective and pathogenic B cell subsets established after B cell depletion and repopulation.

Long-term B cell depletion in murine lupus eliminates autoantibody-secreting cells and is associated with alterations in the kidney plasma cell niche.

Autoantibodies to dsDNA, produced by autoreactive plasma cells (PCs), are a hallmark of systemic lupus erythematosus and play a key role in disease pathogenesis. Recent data suggest that autoreactive PCs accumulate not only in lymphoid tissues, but also in the inflamed kidney in lupus nephritis. We hypothesized that the variable efficacy of anti-CD20 (rituximab)-mediated B cell depletion in systemic lupus erythematosus may be related to the absence of an effect on autoreactive PCs in the kidney. In this article, we report that an enrichment of autoreactive dsDNA Ab-secreting cells (ASCs) in the kidney of lupus-prone mice (up to 40% of the ASCs) coincided with a progressive increase in splenic germinal centers and PCs, and an increase in renal expression for PC survival factors (BAFF, a proliferation-inducing ligand, and IL-6) and PC attracting chemokines (CXCL12). Short-term treatment with anti-CD20 (4 wk) neither decreased anti-dsDNA nor IgG ASCs in different anatomical locations. However, long-term treatment (12 wk) significantly reduced both IgG- and dsDNA-specific ASCs. In addition, long-term treatment substantially decreased splenic germinal center and PC generation, and unexpectedly reduced the expression for PC survival factors in the kidney. These results suggest that prolonged B cell depletion may alter the PC survival niche in the kidney, regulating the accumulation and maintenance of autoreactive PCs.