Suppression of inflammatory arthritis by the parasitic worm product ES-62 is associated with epigenetic changes in synovial fibroblasts.

ES-62 is the major secreted protein of the parasitic filarial nematode, Acanthocheilonema viteae. The molecule exists as a large tetramer (MW, ~240kD), which possesses immunomodulatory properties by virtue of multiple phosphorylcholine (PC) moieties attached to N-type glycans. By suppressing inflammatory immune responses, ES-62 can prevent disease development in certain mouse models of allergic and autoimmune conditions, including joint pathology in collagen-induced arthritis (CIA), a model of rheumatoid arthritis (RA). Such protection is associated with functional suppression of "pathogenic" hyper-responsive synovial fibroblasts (SFs), which exhibit an aggressive inflammatory and bone-damaging phenotype induced by their epigenetic rewiring in response to the inflammatory microenvironment of the arthritic joint. Critically, exposure to ES-62 in vivo induces a stably-imprinted CIA-SF phenotype that exhibits functional responses more typical of healthy, Naïve-SFs. Consistent with this, ES-62 "rewiring" of SFs away from the hyper-responsive phenotype is associated with suppression of ERK activation, STAT3 activation and miR-155 upregulation, signals widely associated with SF pathogenesis. Surprisingly however, DNA methylome analysis of Naïve-, CIA- and ES-62-CIA-SF cohorts reveals that rather than simply preventing pathogenic rewiring of SFs, ES-62 induces further changes in DNA methylation under the inflammatory conditions pertaining in the inflamed joint, including targeting genes associated with ciliogenesis, to programme a novel "resolving" CIA-SF phenotype. In addition to introducing a previously unsuspected aspect of ES-62's mechanism of action, such unique behaviour signposts the potential for developing DNA methylation signatures predictive of pathogenesis and its resolution and hence, candidate mechanisms by which novel therapeutic interventions could prevent SFs from perpetuating joint inflammation and destruction in RA. Pertinent to these translational aspects of ES-62-behavior, small molecule analogues (SMAs) based on ES-62's active PC-moieties mimic the rewiring of SFs as well as the protection against joint disease in CIA afforded by the parasitic worm product.

Integration of Health Coaches in a Whole Health Team Model of Chronic Pain Care: a Qualitative Study.

OBJECTIVE: Health coaching has shown promise in helping patients manage their chronic disease and in improving health outcomes, yet the implementation of health coaching in healthcare systems is understudied. Further, evidence suggests that interdisciplinary care teams may be more effective in treating chronic pain than usual care. As such, we sought to examine the benefits and drawbacks to embedding health coaches within interdisciplinary pain care teams ("Whole Health Teams"). DESIGN: As part of a multisite clinical trial (at five Veterans Health Administration sites) investigating the effectiveness of a Whole Health Team (WHT) approach to care for patients with chronic pain, qualitative interviews gathered data on how the experience of treating patients in the WHT differed from the experience treating patients outside the WHT, as well as provider experiences coordinating patient care within the WHT. PARTICIPANTS: Twenty-two WHT members, study investigators, and study coordinators. APPROACH: Data were analyzed using a rapid analysis approach. RESULTS: Overall, stakeholders perceived considerable synergy within the interdisciplinary pain care team. Each provider brought a different perspective to the patient's health concerns, which stakeholders felt was valuable and increased patient progress towards goals. The team model was also viewed as efficient because everyone was committed to working together and communicating as a team. Logistically, however, stakeholders noted challenges to working as a team, especially regarding patient goal setting. Furthermore, multiple stakeholders believed the care team model required a high degree of dedication to teamwork and communication among its members to be successful. CONCLUSIONS: Embedding health coaches within interdisciplinary pain care teams may improve care processes and accelerate patient progress. Successful implementation would require adequate training, role clarification, and expectation setting to facilitate good communication across all care team members. Additional research is needed to evaluate the clinical outcomes of integrating health coaches on WHTs versus other implementation approaches.

Annexin-A1: The culprit or the solution?

Annexin-A1 has a well-defined anti-inflammatory role in the innate immune system, but its function in adaptive immunity remains controversial. This glucocorticoid-induced protein has been implicated in a range of inflammatory conditions and cancers, as well as being found to be overexpressed on the T cells of patients with autoimmune disease. Moreover, the formyl peptide family of receptors, through which annexin-A1 primarily signals, has also been implicated in these diseases. In contrast, treatment with recombinant annexin-A1 peptides resulted in suppression of inflammatory processes in murine models of inflammation. This review will focus on what is currently known about annexin-A1 in health and disease and discuss the potential of this protein as a biomarker and therapeutic target.

A close-up on the expanding landscape of CD21-/low B cells in humans.

Memory B cells (MBCs) are an essential part of our immunological memory. They respond fast upon re-encountering pathogens and can differentiate into plasma cells that secrete protective antibodies. The focus of this review is on MBCs that lack, or express low levels of, CD21, hereafter referred to as CD21-/low. These cells are expanded in peripheral blood with age and during chronic inflammatory conditions such as viral infections, malaria, common variable immunodeficiency, and autoimmune diseases. CD21-/low MBCs have gained significant attention; they produce disease-specific antibodies/autoantibodies and associate with key disease manifestations in some conditions. These cells can be divided into subsets based on classical B-cell and other markers, e.g. CD11c, FcRL4, and Tbet which, over the years, have become hallmarks to identify these cells. This has resulted in different names including age-associated, autoimmune-associated, atypical, tissue-like, tissue-resident, tissue-restricted, exhausted, or simply CD21-/low B cells. It is however unclear whether the expanded 'CD21-/low' cells in one condition are equivalent to those in another, whether they express an identical gene signature and whether they have a similar function. Here, we will discuss these issues with the goal to understand whether the CD21-/low B cells are comparable in different conditions.

Tailored to Fit: How an Implementation Framework Can Support Pragmatic Pain Care Trial Adaptation for Diverse Veterans Affairs Clinical Settings.

BACKGROUND: Veterans Affairs (VA) has rolled out a holistic, multicomponent Whole Health care model nationwide, yet no pragmatic trials have been conducted in real-world clinical settings to compare its effectiveness against other evidence-based approaches for chronic pain management in veterans. OBJECTIVES: We describe the adaptation of the first large pragmatic randomized controlled trial of the Whole Health model for chronic pain care for diverse VA clinical settings. RESEARCH DESIGN: Informed by the Promoting Action on Research Implementation in Health Systems implementation framework, we conducted qualitative semistructured interviews to obtain feedback on trial design from VA leadership, frontline clinicians, and veterans with chronic pain at 5 VA enrollment sites. Next, we convened in-person evidence-based quality improvement (EBQI) meetings with study stakeholders (including frontline clinicians and administrators) at each site to discuss study design; review interview themes; and identify site-specific barriers, facilitators, and approaches to implementation. Ethnographic observations from EBQI meetings provided additional insight into implementation strategies. SUBJECTS: Seventy-four veteran and VA staff stakeholders were interviewed; 71 stakeholders participated in EBQI meetings. RESULTS: At each site, unique clinical contexts and varying resources for Whole Health and pain care delivery affected plans for trial implementation. We present examples of local adaptations that emerged through the formative evaluation process to facilitate implementation and yield a more pragmatic trial design. CONCLUSIONS: A systematic formative evaluation can facilitate engagement and buy-in of study stakeholders. Locally tailored pragmatic implementation strategies may improve the likelihood of successful trial execution as well as future implementation of evidence-based pain care approaches in real-world clinical settings.

Spin States of Homochiral and Heterochiral Isomers of [Fe(PyBox)2 ]2+ Derivatives.

The following iron(II) complexes of 2,6-bis(oxazolinyl)pyridine (PyBox; LH ) derivatives are reported: [Fe(LH )2 ][ClO4 ]2 (1); [Fe((R)-LMe )2 ][ClO4 ]2 ((R)-2; LMe =2,6-bis{4-methyloxazolinyl}pyridine); [Fe((R)-LPh )2 ][ClO4 ]2 ((R)-3) and [Fe((R)-LPh )((S)-LPh )][ClO4 ]2 ((RS)-3; LPh =2,6-bis{4-phenyloxazolinyl}pyridine); and [Fe((R)-LiPr )2 ][ClO4 ]2 ((R)-4) and [Fe((R)-LiPr )((S)-LiPr )][ClO4 ]2 ((RS)-4; LiPr =2,6-bis{4-isopropyloxazolinyl}pyridine). Solid (R)-3⋅MeNO2 exhibits an unusual very gradual, but discontinuous thermal spin-crossover with an approximate T1/2 of 350 K. The discontinuity around 240 K lies well below T1/2 , and is unconnected to a crystallographic phase change occurring at 170 K. Rather, it can be correlated with a gradual ordering of the ligand conformation as the temperature is raised. The other solid compounds either exhibit spin-crossover above room temperature (1 and (RS)-3), or remain high-spin between 5-300 K [(R)-2, (R)-4 and (RS)-4]. Homochiral (R)-3 and (R)-4 exhibit more twisted ligand conformations and coordination geometries than their heterochiral isomers, which can be attributed to steric clashes between ligand substituents [(R)-3]; or, between the isopropyl substituents of one ligand and the backbone of the other ((R)-4). In solution, (RS)-3 retains its structural integrity but (RS)-4 undergoes significant racemization through ligand redistribution by 1 H NMR. (R)-4 and (RS)-4 remain high-spin in solution, whereas the other compounds all undergo spin-crossover equilibria. Importantly, T1/2 for (R)-3 (244 K) is 34 K lower than for (RS)-3 (278 K) in CD3 CN, which is the first demonstration of chiral discrimination between metal ion spin states in a molecular complex.

High radiative forcing climate scenario relevance analyzed with a ten-million-member ensemble.

Developing future climate projections begins with choosing future emissions scenarios. While scenarios are often based on storylines, here instead we produce a probabilistic multi-million-member ensemble of radiative forcing trajectories to assess the relevance of future forcing thresholds. We coupled a probabilistic database of future greenhouse gas emission scenarios with a probabilistically calibrated reduced complexity climate model. In 2100, we project median forcings of 5.1 watt per square meters (5th to 95th percentiles of 3.3 to 7.1), with roughly 0.5% probability of exceeding 8.5 watt per square meters, and a 1% probability of being lower than 2.6 watt per square meters. Although the probability of 8.5 watt per square meters scenarios is low, our results support their continued utility for calibrating damage functions, characterizing climate in the 22nd century (the probability of exceeding 8.5 watt per square meters increases to about 7% by 2150), and assessing low-probability/high-impact futures.

Evaluation of a New Integrative Health and Wellness Clinic for Veterans at the San Francisco VA Health Care System: A Mixed-Methods Pilot Study.

Objective: The Integrative Health and Wellness Clinic (IHWC), established in 2019 at the San Francisco VA Health Care System, is an interdisciplinary clinic consisting of a medical provider, dietician, physical therapist, and psychologist trained in complementary and integrative health (CIH) following the VA Whole Health model of care. Veterans with complex chronic conditions seeking CIH and nonpharmacologic approaches are referred to the IHWC. This study evaluated the clinic's acceptability and feasibility among veteran patients and its preliminary impact on health and wellbeing, health-related goals, and use of CIH approaches. Methods: Mixed methods were used to assess patient-reported outcomes and experiences with the IHWC. Participants completed surveys administered at baseline and 6-months and a subset completed a qualitative interview. Pre- and post-scores were compared using t-tests and chi-square tests. Results: Thirty-five veterans completed baseline and 6-month follow up surveys. Of these, 13% were women; 24% < 50 years of age, and 44% identified as racial/ethnic minorities. Compared to baseline, at 6 months, there were significant (P < .05) improvements in overall health, physical health, perceived stress, and perceived helpfulness of clinicians in assisting with goal attainment; there was a trend toward improved mental health (P = .057). Interviews (n = 25) indicated satisfaction with the interdisciplinary clinical model, support of IHWC providers in goal attainment, and positive impact on physical and mental health. Areas for improvement included logistics related to scheduling of multiple IHWC providers and referrals to other CIH services. Conclusion: Results revealed significant improvement in important clinical domains and satisfaction with interprofessional IHWC clinic providers, but also opportunities to improve clinic processes and care coordination. An interdisciplinary clinic focused on CIH and Whole Health is a feasible and acceptable model of care for veterans with complex chronic health conditions in the VA healthcare system.

Cartilage destruction in early rheumatoid arthritis patients correlates with CD21-/low double-negative B cells.

BACKGROUND: Involvement of B cells in the pathogenesis of rheumatoid arthritis (RA) is supported by the presence of disease-specific autoantibodies and the efficacy of treatment directed against B cells. B cells that express low levels of or lack the B cell receptor (BCR) co-receptor CD21, CD21-/low B cells, have been linked to autoimmune diseases, including RA. In this study, we characterized the CD21+ and CD21-/low B cell subsets in newly diagnosed, early RA (eRA) patients and investigated whether any of the B cell subsets were associated with autoantibody status, disease activity and/or joint destruction. METHODS: Seventy-six eRA patients and 28 age- and sex-matched healthy donors were recruited. Multiple clinical parameters were assessed, including disease activity and radiographic joint destruction. B cell subsets were analysed in peripheral blood (PB) and synovial fluid (SF) using flow cytometry. RESULTS: Compared to healthy donors, the eRA patients displayed an elevated frequency of naïve CD21+ B cells in PB. Amongst memory B cells, eRA patients had lower frequencies of the CD21+CD27+ subsets and CD21-/low CD27+IgD+ subset. The only B cell subset found to associate with clinical factors was the CD21-/low double-negative (DN, CD27-IgD-) cell population, linked with the joint space narrowing score, i.e. cartilage destruction. Moreover, in SF from patients with established RA, the CD21-/low DN B cells were expanded and these cells expressed receptor activator of the nuclear factor κB ligand (RANKL). CONCLUSIONS: Cartilage destruction in eRA patients was associated with an expanded proportion of CD21-/low DN B cells in PB. The subset was also expanded in SF from established RA patients and expressed RANKL. Taken together, our results suggest a role for CD21-/low DN in RA pathogenesis.

Correlation of Professional Antigen-Presenting Tbet+CD11c+ B Cells With Bone Destruction in Untreated Rheumatoid Arthritis.

OBJECTIVE: Subsets of CD21-/low memory B cells (MBCs), including double-negative (DN, CD27-IgD-) and Tbet+CD11c+ cells, are expanded in chronic inflammatory diseases. In rheumatoid arthritis (RA), CD21-/low MBCs correlate with joint destruction. However, whether this is due to the Tbet+CD11c+ subset, its function and pathogenic contribution to RA are unknown. This study aims to investigate the association between CD21-/lowTbet+CD11c+ MBCs and joint destruction as well as other clinical parameters and to elucidate their functional properties in patients with untreated RA (uRA). METHODS: Clinical observations were combined with flow cytometry (n = 36) and single-cell RNA sequencing (scRNA-seq) and V(D)J sequencing (n = 4) of peripheral blood (PB) MBCs from patients with uRA. The transcriptome of circulating Tbet+CD11c+ MBCs was compared with scRNA-seq data of synovial B cells. In vitro coculture of Tbet+CD11c+ B cells with T cells was used to assess costimulatory capacity. RESULTS: CD21-/lowTbet+CD11c+ MBCs in PB correlated with bone destruction but no other clinical parameters analyzed. The Tbet+CD11c+ MBCs have undergone clonal expansion and express somatically mutated V genes. Gene expression analysis of these cells identified a unique signature of more than 150 up-regulated genes associated with antigen presentation functions, including B cell receptor activation and clathrin-mediated antigen internalization; regulation of actin filaments, endosomes, and lysosomes; antigen processing, loading, presentation, and costimulation; a transcriptome mirrored in their synovial tissue counterparts. In vitro, Tbet+CD11c+ B cells induced retinoic acid receptor-related orphan nuclear receptor γT expression in CD4+ T cells, thereby polarizing to Th17 cells, a T cell subset critical for osteoclastogenesis and associated with bone destruction. CONCLUSION: This study suggests that Tbet+CD11c+ MBCs contribute to the pathogenesis of RA by promoting bone destruction through antigen presentation, T cell activation, and Th17 polarization.

Targeting CD38 with monoclonal antibodies disrupts key survival pathways in paediatric Burkitt's lymphoma malignant B cells.

Objectives: Paediatric Burkitt's lymphoma (pBL) is the most common childhood non-Hodgkin B-cell lymphoma. Despite the encouraging survival rates for most children, treating cases with relapse/resistance to current therapies remains challenging. CD38 is a transmembrane protein highly expressed in pBL. This study investigates the effectiveness of CD38-targeting monoclonal antibodies (mAbs), daratumumab and isatuximab, in impairing crucial cellular processes and survival pathways in pBL malignant cells. Methods: In silico analyses of patient samples, combined with in vitro experiments using the Ramos cell line, were conducted to assess the impact of daratumumab and isatuximab on cellular proliferation, apoptosis and the phosphoinositide 3-kinase (PI3K) pathway. Results: Isatuximab was found to be more effective than daratumumab in disrupting B-cell receptor signalling, reducing cellular proliferation and inducing apoptosis. Additionally, isatuximab caused a significant impairment of the PI3K pathway and induced metabolic reprogramming in pBL cells. The study also revealed a correlation between CD38 and MYC expression levels in pBL patient samples, suggesting CD38 involvement in key oncogenic processes. Conclusion: The study emphasises the therapeutic potential of CD38-targeting mAbs, particularly isatuximab, in pBL.

Childhood disability in Aboriginal and Torres Strait Islander peoples: a literature review.

INTRODUCTION: Aboriginal and Torres Strait Islander children have higher rates of disability than non-Indigenous children and are considered doubly disadvantaged, yet there is very little data reflecting prevalence and service access to inform design and delivery of services. Failing to address physical, social, and psychological factors can have life-long consequences and perpetuate longstanding health disparities. METHODS: A narrative literature review was undertaken to identify peer reviewed literature describing factors impacting on the prevention, recognition, and access to support and management of disability in Indigenous Australian children. RESULTS: Twenty-seven peer-reviewed journal articles met inclusion criteria. The majority of articles focused on the hearing loss and learning disabilities consequent of otitis media. Few articles reported data on urban or metropolitan Indigenous populations or described interventions. Individual/community-, provider-, and systems level factors were identified as impacting on recognition and management of disability in young Indigenous children. CONCLUSIONS: Given the burden of childhood disability, the limited literature retrieved is concerning as this is a barometer of activity and investment. Solutions addressing childhood disability will require collaboration between health, social and educational disciplines as well as an increased investment in prevention, identification and promotion of access.

The experience of lung cancer in Aboriginal and Torres Strait Islander peoples and what it means for policy, service planning and delivery.

BACKGROUND: Aboriginal and Torres Strait Islander peoples experience inferior outcomes following diagnosis of lung cancer. AIM: To examine the experience of lung cancer in this population and identify reasons for poorer outcomes and lower levels of treatment compared with non-Aboriginal and Torres Strait Islander peoples, and opportunities for early intervention. METHOD: Literature was sought via electronic database searches and journal hand-searching for the period from January 1995 to July 2010. Databases used included Indigenous HealthInfoNet, SCOPUS, PsycInfo, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Medline, HealthInsite and Google Scholar. FINDINGS: Exposure to risk factors, cultural and spiritual values, remoteness and geographic characteristics, entrenched socioeconomic inequalities and racism contribute to reduced service access and poor outcomes. The review highlighted a complex interplay of individual, social, health system and environmental factors that impact on optimal lung cancer care and lung cancer outcomes. Considering the burden of lung cancer within a framework of social determinants of health is necessary for policy-making and service planning and delivery. CONCLUSIONS: It is imperative that the disproportionate burden of lung cancer in Aboriginal and Torres Strait Islander peoples is addressed immediately. Whilst strategic interventions in lung cancer prevention and care are needed, service providers and policy makers must acknowledge the entrenched inequality that exists and consider the broad range of factors at the patient, provider and system level. Primary care strategies and health promotion activities to reduce risk factors, such as smoking, must also be implemented, with Aboriginal and Torres Strait Islander peoples' engagement and control at the core of any strategy. This review has indicated that multifaceted interventions, supported by enabling policies that target individuals, communities and health professionals, are necessary to improve lung cancer outcomes and disparities.

Pneumococcus in Aboriginal and Torres Strait Islander peoples: the role of Aboriginal health workers and implications for nursing practice.

BACKGROUND: Pneumonia is a common cause of hospitalization in Aboriginal and Torres Strait Islander men and women. AIM: This article seeks to describe the importance of immunizing against pneumonia in Aboriginal Australians and suggest strategies for screening and follow-up. METHOD: An integrative literature review, using both published and gray literature was undertaken to identify methods of screening and surveillance strategies for pneumococcus. RESULTS: The literature was summarized under the following themes: Pneumococcal disease; prevention strategies; access to care; improving access to vaccinations; culturally competent interventions and the role of Aboriginal health professionals. CONCLUSION: Community controlled conditions and the role of the Aboriginal Health Workers are seen as critical to reducing health disparities. Nurses can play a critical role in bridging the gap between mainstream and community controlled organizations. Working to increase the numbers of Aboriginal health professionals is a critical step in improving health outcomes for Aboriginal and Torres Strait Islander peoples.

Density and population size estimates of the endangered northern yellow-cheeked crested gibbon Nomascus annamensis in selectively logged Veun Sai-Siem Pang National Park in Cambodia using acoustic spatial capture-recapture methods.

Many gibbon species are threatened with extinction, including the endangered northern yellow-cheeked crested gibbon, Nomascus annamensis. Assessing gibbon populations and understanding how human disturbances and environmental factors impact these populations is vital for effective conservation planning. In 2010, auditory surveys revealed that Veun Sai-Siem Pang National Park (VSSP) in Cambodia contains one of the largest known N. annamensis populations in the world, with an estimated 456 (95% CI 421-490) gibbon groups. Illegal selective logging is common in the park, but the impact of continued logging on the gibbon population has not been investigated. To determine any change in the N. annamensis population since 2010, between January and April 2019 we conducted auditory surveys at 13 sites that were at least 4 km apart. We surveyed each site for three days, each day recording the gibbon calls heard over 3.25 hours from three listening posts located 500 m apart. At the same sites, we assessed the logging intensity using transects and ecological plots. Gibbon densities can be influenced by various environmental factors such as canopy height and forest type. Therefore, in addition to investigating the relationship between the density of N. annamensis groups and logging, we included five additional environmental variables in our acoustic spatial capture-recapture models. Our best fit model with the lowest AIC value included canopy height, forest type, distance to villages, and logging. We estimate that there are 389 (95% CI 284-542) N. annamensis groups currently in VSSP. Selective logging is widespread in the park, primarily targeting four tree species. The estimated felling time of these logged trees, together with previous reports, indicate that the species most targeted in VSSP varies over time. To conserve the N. annamensis population in VSSP, it is crucial that action is taken to reduce illegal logging.

Virtual Worlds Technology to Enhance Training for Primary Care Providers in Assessment and Management of Posttraumatic Stress Disorder Using Motivational Interviewing: Pilot Randomized Controlled Trial.

BACKGROUND: Many individuals with posttraumatic stress disorder (PTSD) first present to primary care rather than specialty mental health care. Primary care providers often lack the training required to assess and treat patients with PTSD. Virtual trainings have emerged as a convenient and effective way of training primary care providers in PTSD assessment and communication methods (ie, motivational interviewing [MI]). OBJECTIVE: The aim of this study was to conduct a pilot randomized controlled trial of a synchronous Virtual Worlds (VW; a virtual world where learners were immersed as avatars) training versus an asynchronous web-based training on PTSD and MI, comparing the feasibility, acceptability, usability, and preliminary efficacy of 2 different training platforms among primary care providers. METHODS: Participating primary care providers were randomized to a VW and a web-based PTSD training. Outcomes were collected at baseline, posttraining, and 90-days follow-up. Standardized patient interviews measured participants' communication skills in assessing and managing patients with PTSD symptoms. RESULTS: Compared to the web-based training, the VW training platform achieved larger learning gains in MI (ie, partnership and empathy) and in discussing pharmacotherapy and psychotherapy for PTSD. Both VW and web-based trainings led to increases in PTSD knowledge and primary care providers' self-confidence. CONCLUSIONS: The asynchronous web-based PTSD training improved PTSD-related knowledge and self-confidence but was not as effective as the VW immersive experience in teaching MI or clinical management. Because VW training is synchronous and new for many learners, it required more time, facilitation, and technical support. As computer technology improves, VW educational interventions may become more feasible, particularly in teaching clinical skills. TRIAL REGISTRATION: ClinicalTrials.gov NCT03898271; https://tinyurl.com/mu479es5.

Early Increase of Circulating Transitional B Cells and Autoantibodies to Joint-Related Proteins in Patients With Metastatic Melanoma Developing Checkpoint Inhibitor-Induced Inflammatory Arthritis.

OBJECTIVE: To investigate potential associations between B cell-related immunologic changes and development of inflammatory arthritis (IA) after treatment with immune checkpoint inhibitors (ICIs). METHODS: Patients who developed ICI-induced IA (ICI-IA) and patients who did not develop immune-related adverse events (non-IRAE) after receiving ICIs to treat metastatic melanoma were consecutively recruited. Blood samples were collected at the time of ICI-IA occurrence and at different time points during treatment. Peripheral blood B cell subsets during ICI treatment were analyzed by flow cytometry. Rheumatoid factor, anti-citrullinated protein antibodies, and antibodies against joint-related proteins were measured. RESULTS: Proportions of CD19+ B cells were higher in patients with ICI-IA (n = 7) compared to patients with non-IRAE (n = 15) (median 11.7% [interquartile range (IQR) 9.7-16.2%] versus 8.1% [IQR 5.7-11.0%]; P = 0.03). The proportion and absolute numbers of transitional CD19+CD10+CD24high CD38high B cells were increased in patients with ICI-IA compared to non-IRAE patients (median 8.1% [IQR 4.9-12.1%] versus 3.6% [IQR 1.9-4.9%]; median 10.7 cells/µl [IQR 8.9-19.6] versus 4.4 cells/µl [IQR 2.3-6.6]; P < 0.01 for both). In addition, higher levels of transitional B cells were associated with development of ICI-IA (odds ratio 2.25 [95% confidence interval 1.03-4.9], P = 0.04). Transitional B cells increased before the onset of overt ICI-IA and decreased between the active and quiescent stages of ICI-IA (P = 0.02). Autoantibodies to type II collagen epitopes were detected in up to 43% of ICI-IA patients compared to none of the non-IRAE patients (P = 0.02). CONCLUSION: Development of ICI-IA is accompanied by an increase in transitional B cells and by production of autoantibodies to joint-related proteins. Monitoring of B cell-driven abnormalities upon ICI treatment may help earlier recognition of ICI-IA.

Improving women's cardiovascular health: a position statement from the International Council on Women's Health Issues.

Cardiovascular disease (CVD) is the number one killer of women worldwide, and it remains the primary cause of death and disability in both developed and developing countries. The International Council on Women's Health Issues is an international nonprofit association dedicated to the goals of promoting the health, health care, and the well-being of women. Based on the outcomes of a facilitated discussion at its 18th biannual meeting, delegates aim to raise awareness about the potent influence of gender-specific factors on the development, progression, and outcomes of CVD. Key recommendations for decreasing the burden of CVD are also discussed.

Herb-drug Interactions in Neuropsychiatric Pharmacotherapy - A Review of Clinically Relevant Findings.

The management of neuropsychiatric disorders relies heavily on pharmacotherapy. The use of herbal products as complimentary medicine, often concomitantly, is common among patients taking prescription neuropsychiatric drugs. Herb-drug interaction, a clinical consequence of this practice, may jeopardize the success of pharmacotherapy in neuropsychiatry. Besides the wellknown ability of phytochemicals to inhibit and/or induce drug-metabolizing enzymes and transport proteins, several phytoconstituents are capable of exerting pharmacological effects on the central nervous system. This study reviewed the relevant literature and identified 13 commonly used herbal products - celery, echinacea, ginkgo, ginseng, hydroxycut, kava, kratom, moringa, piperine, rhodiola, St. John's wort, terminalia/commiphora ayurvedic mixture and valerian - which have shown clinically relevant interactions with prescription drugs used in the management of neuropsychiatric disorders. The consequent pharmacokinetic and pharmacodynamic interactions with orthodox medications often result in deleterious clinical consequences. This underscores the importance of caution in herb-drug co-medication.

Decisions for lung cancer chemotherapy: the influence of physician and patient factors.

PURPOSE: The purpose of this study is to review the literature examining how the beliefs and behaviours of physicians and patients influence clinical communication, doctor-patient interaction and treatment decisions for lung cancer treatment. METHODS: Literature was obtained via electronic database searches and hand searching of journals from 1990 to 2011. RESULTS: Wide variability in perceptions of the value of chemotherapy in lung cancer is present among both physicians and patients. There is a mismatch in the degree patients and physicians weigh survival, such that patients value survival benefits highly whilst physicians strongly emphasize toxicity and associated symptoms. This lack of congruence between patients and clinicians is influenced by a range of factors and has implications for treatment decisions, long-term survival and quality of life in people affected by lung cancer. CONCLUSION: The divergence of treatment priorities indicates a need for improved communication strategies addressing the needs and concerns of both patients and clinicians. Patients should understand the benefits and risks of treatment options, while clinicians can gain a greater awareness of factors influencing patients' decisions on treatments. Reflecting these perspectives and patient preferences for lung cancer treatment in clinical guidelines may improve clinician awareness.