An Evidence-Based Guideline Improves Outcomes for Patients With Hemophagocytic Lymphohistiocytosis and Macrophage Activation Syndrome.

OBJECTIVE: To compare clinical outcomes in children with hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS) who were managed before and after implementation of an evidence-based guideline (EBG). METHODS: A management algorithm for MAS-HLH was developed at our institution based on literature review, expert opinion, and consensus building across multiple pediatric subspecialties. An electronic medical record search retrospectively identified hospitalized patients with MAS-HLH in the pre-EBG (October 15, 2015, to December 4, 2017) and post-EBG (January 1, 2018, to January 21, 2020) time periods. Predetermined outcome metrics were evaluated in the 2 cohorts. RESULTS: After the EBG launch, 57 children were identified by house staff as potential patients with MAS-HLH, and rheumatology was consulted for management. Ultimately, 17 patients were diagnosed with MAS-HLH by the treating team. Of these, 59% met HLH 2004 criteria, and 94% met 2016 classification criteria for MAS complicating systemic juvenile idiopathic arthritis. There was a statistically significant reduction in mortality from 50% before implementation of the EBG to 6% in the post-EBG cohort (P = 0.02). There was a significant improvement in time to 50% reduction in C-reactive protein level in the post-EBG vs pre-EBG cohorts (log-rank P < 0.01). There were trends toward faster time to MAS-HLH diagnosis, faster initiation of immunosuppressive therapy, shorter length of hospital stay, and more rapid normalization of MAS-HLH-related biomarkers in the patients post-EBG. CONCLUSION: While the observed improvements may be partially attributed to advances in treatment of MAS-HLH that have accumulated over time, this analysis also suggests that a multidisciplinary treatment pathway for MAS-HLH contributed meaningfully to favorable patient outcomes.

Substrate-dependent modulation of the leukotriene A4 hydrolase aminopeptidase activity and effect in a murine model of acute lung inflammation.

The aminopeptidase activity (AP) of the leukotriene A4 hydrolase (LTA4H) enzyme has emerged as a therapeutic target to modulate host immunity. Initial reports focused on the benefits of augmenting the LTA4H AP activity and clearing its putative pro-inflammatory substrate Pro-Gly-Pro (PGP). However, recent reports have introduced substantial complexity disconnecting the LTA4H modulator 4-methoxydiphenylmethane (4MDM) from PGP as follows: (1) 4MDM inhibits PGP hydrolysis and subsequently inhibition of LTA4H AP activity, and (2) 4MDM activates the same enzyme target in the presence of alternative substrates. Differential modulation of LTA4H by 4MDM was probed in a murine model of acute lung inflammation, which showed that 4MDM modulates the host neutrophilic response independent of clearing PGP. X-ray crystallography showed that 4MDM and PGP bind at the zinc binding pocket and no allosteric binding was observed. We then determined that 4MDM modulation is not dependent on the allosteric binding of the ligand, but on the N-terminal side chain of the peptide. In conclusion, our study revealed that a peptidase therapeutic target can interact with its substrate and ligand in complex biochemical mechanisms. This raises an important consideration when ligands are designed to explain some of the unpredictable outcomes observed in therapeutic discovery targeting LTA4H.

Private land conservation decision-making: An integrative social science model.

Owners and managers of private lands make decisions that have implications well beyond the boundaries of their land, influencing species conservation, water quality, wildfire risk, and other environmental outcomes with important societal and ecological consequences. Understanding how these decisions are made is key for informing interventions to support better outcomes. However, explanations of the drivers of decision making are often siloed in social science disciplines that differ in focus, theory, methodology, and terminology, hindering holistic understanding. To address these challenges, we propose a conceptual model of private land conservation decision-making that integrates theoretical perspectives from three dominant disciplines: economics, sociology, and psychology. The model highlights how heterogeneity in behavior across decision-makers is driven by interactions between the decision context, attributes of potential conservation behaviors, and attributes of the decision-maker. These differences in both individual attributes and context shape decision-makers' constraints and the potential and perceived consequences of a behavior. The model also captures how perceived consequences are evaluated and weighted through a decision-making process that may range from systematic to heuristic, ultimately resulting in selection of a behavior. Outcomes of private land behaviors across the landscape feed back to alter the socio-environmental conditions that shape future decisions. The conceptual model is designed to facilitate better communication, collaboration, and integration across disciplines and points to methodological innovations that can expand understanding of private land decision-making. The model also can be used to illuminate how behavior change interventions (e.g., policies, regulations, technical assistance) could be designed to target different drivers to encourage environmentally and socially beneficial behaviors on private lands.

Disordered T cell-B cell interactions in autoantibody-positive inflammatory arthritis.

T peripheral helper (Tph) cells, identified in the synovium of adults with seropositive rheumatoid arthritis, drive B cell maturation and antibody production in non-lymphoid tissues. We sought to determine if similarly dysregulated T cell-B cell interactions underlie another form of inflammatory arthritis, juvenile oligoarthritis (oligo JIA). Clonally expanded Tph cells able to promote B cell antibody production preferentially accumulated in the synovial fluid (SF) of oligo JIA patients with antinuclear antibodies (ANA) compared to autoantibody-negative patients. Single-cell transcriptomics enabled further definition of the Tph gene signature in inflamed tissues and showed that Tph cells from ANA-positive patients upregulated genes associated with B cell help to a greater extent than patients without autoantibodies. T cells that co-expressed regulatory T and B cell-help factors were identified. The phenotype of these Tph-like Treg cells suggests an ability to restrain T cell-B cell interactions in tissues. Our findings support the central role of disordered T cell-help to B cells in autoantibody-positive arthritides.

Th1 polarization defines the synovial fluid T cell compartment in oligoarticular juvenile idiopathic arthritis.

Oligoarticular juvenile idiopathic arthritis (oligo JIA) is the most common form of chronic inflammatory arthritis in children, yet the cause of this disease remains unknown. To understand immune responses in oligo JIA, we immunophenotyped synovial fluid T cells with flow cytometry, bulk RNA-Seq, single-cell RNA-Seq (scRNA-Seq), DNA methylation studies, and Treg suppression assays. In synovial fluid, CD4+, CD8+, and γδ T cells expressed Th1-related markers, whereas Th17 cells were not enriched. Th1 skewing was prominent in CD4+ T cells, including Tregs, and was associated with severe disease. Transcriptomic studies confirmed a Th1 signature in CD4+ T cells from synovial fluid. The regulatory gene expression signature was preserved in Tregs, even those exhibiting Th1 polarization. These Th1-like Tregs maintained Treg-specific methylation patterns and suppressive function, supporting the stability of this Treg population in the joint. Although synovial fluid CD4+ T cells displayed an overall Th1 phenotype, scRNA-Seq uncovered heterogeneous effector and regulatory subpopulations, including IFN-induced Tregs, peripheral helper T cells, and cytotoxic CD4+ T cells. In conclusion, oligo JIA is characterized by Th1 polarization that encompasses Tregs but does not compromise their regulatory identity. Targeting Th1-driven inflammation and augmenting Treg function may represent important therapeutic approaches in oligo JIA.

Prosocial responses to COVID-19: Examining the role of gratitude, fairness and legacy motives.

The COVID-19 pandemic has produced an unprecedented collective action problem. Individuals must make a variety of decisions that influence both their own well-being and the health of those around them. Achieving the collective best-interest depends on most individuals responding in socially optimal ways, which includes remaining familiar with the current status of the pandemic, adhering to health guidelines relevant to the pandemic, and having a constructive emotional response to the pandemic. We sought to examine how individual differences in core moral motivators of collective action (i.e., fairness and gratitude) relate to individuals' COVID-19 responses. In a two-wave study (T1: N = 254; T2: N = 135) conducted in May and June 2020, we find that individual differences in fairness and gratitude were associated with more adaptive (i.e. positive emotions) and prosocial (i.e. remaining familiar with the pandemic, adhering to public health guidelines, prioritizing saving lives) responses to the pandemic. These effects are mediated through differences in impact legacy motives (i.e. being concerned about the impact one leaves behind once they have passed). Understanding the links between gratitude, fairness and legacy motives, and their impact on prosociality, could promote both current and intergenerational prosocial decision making.

Factors Associated with Adjustment Disorder - the Different Contribution of Daily Stressors and Traumatic Events and the Mediating Role of Psychological Well-Being.

The definition of adjustment disorder (AjD) was recently revised by the 11th version of the International Classification of Diseases. Thus far, only two studies explored stressors associated with symptoms of AjD according to the new definition, revealing that there might be a difference in associations with daily stressors compared to traumatic events. The present study aims at examining the associations of AjD with both types of stressors as well as the mediating role of psychological well-being that was previously suggested as a buffer against mental illness. Four hundred and 19 participants completed questionnaires assessing the prevalence of daily stressors and traumatic events experienced in the last 2 years, psychological well-being and the diagnostic criteria of AjD. Results revealed a direct effect of the prevalence of daily stressors on the diagnosis of AjD as well as the mediating effect of psychological well-being of this association. However, no effect was found for traumatic events on AjD or psychological well-being. Given these findings, psychological well-being should be regarded as a means to reduce the prevalence of AjD among individuals coping with multiple and continuous daily stressors.

Coping with climate change: Three insights for research, intervention, and communication to promote adaptive coping to climate change.

Climate change poses a major threat to human well-being and will be the root cause of a variety of stressors in coming decades. Psychologists have an important role to play in developing interventions and communication strategies to help people understand and cope with climate change impacts. Through a review of the literature, we identify three guiding insights for strategies to promote adaptive coping and resilience to climate change stress. First, it is unlikely that one single "correct" or "best" way of communicating about adaptive coping with climate change exists, but there are established best practices communicators can follow. Second, in implementing these best practices, practitioners must attend to the impact of variability in the nature of different kinds of stress caused by climate change, as well as individual differences in how people chronically respond to stressors. Third, because individuals, communities, and ecosystems are interconnected, work on adaptive coping to climate change must address individual coping in the context of community and ecosystem resilience. These insights from psychological science can be leveraged to promote human flourishing despite increasing stressors posed by climate change.

Targeting Glycosylated PD-1 Induces Potent Antitumor Immunity.

Immunotherapies targeting programmed cell death protein 1 (PD-1) and programmed cell death 1 ligand 1 (PD-L1) immune checkpoints represent a major breakthrough in cancer treatment. PD-1 is an inhibitory receptor expressed on the surface of activated T cells that dampens T-cell receptor (TCR)/CD28 signaling by engaging with its ligand PD-L1 expressed on cancer cells. Despite the clinical success of PD-1 blockade using mAbs, most patients do not respond to the treatment, and the underlying regulatory mechanisms of PD-1 remain incompletely defined. Here we show that PD-1 is extensively N-glycosylated in T cells and the intensities of its specific glycoforms are altered upon TCR activation. Glycosylation was critical for maintaining PD-1 protein stability and cell surface localization. Glycosylation of PD-1, especially at the N58 site, was essential for mediating its interaction with PD-L1. The mAb STM418 specifically targeted glycosylated PD-1, exhibiting higher binding affinity to PD-1 than FDA-approved PD-1 antibodies, potently inhibiting PD-L1/PD-1 binding, and enhancing antitumor immunity. Together, these findings provide novel insights into the functional significance of PD-1 glycosylation and offer a rationale for targeting glycosylated PD-1 as a potential strategy for immunotherapy. SIGNIFICANCE: These findings demonstrate that glycosylation of PD-1 is functionally significant and targeting glycosylated PD-1 may serve as a means to improve immunotherapy response.

Th17 reprogramming of T cells in systemic juvenile idiopathic arthritis.

Systemic juvenile idiopathic arthritis (sJIA) begins with fever, rash, and high-grade systemic inflammation but commonly progresses to a persistent afebrile arthritis. The basis for this transition is unknown. To evaluate a role for lymphocyte polarization, we characterized T cells from patients with acute and chronic sJIA using flow cytometry, mass cytometry, and RNA sequencing. Acute and chronic sJIA each featured an expanded population of activated Tregs uncommon in healthy controls or in children with nonsystemic JIA. In acute sJIA, Tregs expressed IL-17A and a gene expression signature reflecting Th17 polarization. In chronic sJIA, the Th17 transcriptional signature was identified in T effector cells (Teffs), although expression of IL-17A at the protein level remained rare. Th17 polarization was abrogated in patients responding to IL-1 blockade. These findings identify evolving Th17 polarization in sJIA that begins in Tregs and progresses to Teffs, likely reflecting the impact of the cytokine milieu and consistent with a biphasic model of disease pathogenesis. The results support T cells as a potential treatment target in sJIA.

Scientists' incentives and attitudes toward public communication.

In an era of large-scale science-related challenges and rapid advancements in groundbreaking science with major societal implications, communicating about science is critical. The profile of science communication has increased over the last few decades, with multiple sectors calling for such activities. As scientists respond to calls for public-facing communication, we need to evaluate where the scientific community stands. We conducted a unique census of science faculty at land-grant universities across the United States intended to spur the next generation of science communicators and research. Despite scientists' strong approval of science communication efforts, potential areas of tension, attributable to lack of institutional support and confidence in communication skills, constrain these efforts.

Measuring ICD-11 adjustment disorder: the development and initial validation of the International Adjustment Disorder Questionnaire.

BACKGROUND: Adjustment disorder (AjD) is one of the most frequently used diagnoses in psychiatry but a diagnostic definition for AjD was only introduced in release of the ICD-11. This study sought to develop and validate a new measure operationalizing the ICD-11's narrative description of AjD, and to determine the current rate of people meeting the symptoms indicative of AjD in the general population of the Republic of Ireland. METHODS: The International Adjustment Disorder Questionnaire (IADQ) was constructed to measure the core diagnostic criteria of ICD-11 AjD: stressor exposure, preoccupations with, and failure to adapt to, the stressor, timing of symptom onset, and functional impairment. A nationally representative sample (N = 1,020) of adults from Ireland completed the IADQ. RESULTS: Confirmatory factor analysis supported construct validity and the reliability estimates were excellent. The IADQ correlated strongly with depression, anxiety, and posttraumatic stress. The criteria were met by 7.0% of the sample, adjusted for other exclusionary disorders. DISCUSSION: The IADQ is a measure based on the ICD-11's description and produces reliable scores, however it should not be used for clinical assessment until validated with clinical interviews.

Risk of Diabetes Mellitus in Patients with Juvenile Idiopathic Arthritis.

OBJECTIVE: To examine the risk of type 1 diabetes (T1D) associated with juvenile idiopathic arthritis (JIA). METHODS: Using the IBM MarketScan database, we compared JIA patients with asthma patients and healthy individuals for the risk of incident T1D. RESULTS: We included patients with 15,210 JIA, 76,050 patients with asthma, and 76,050 healthy individuals matched 1:5 on age, sex, and index date. After adjustment for confounders, the multivariable HR of T1D associated with JIA was 1.48 (95% CI 0.86-2.56) versus asthma and 1.81 (95% CI 1.03-3.17) versus healthy individuals. CONCLUSION: JIA appears to be associated with an increased risk of T1D compared to patients with asthma and healthy children.

A physically cryptographic warhead verification system using neutron induced nuclear resonances.

Arms control treaties are necessary to reduce the large stockpiles of the nuclear weapons that constitute one of the biggest dangers to the world. However, an impactful treaty hinges on effective inspection exercises to verify the participants' compliance to the treaty terms. Such procedures would require verification of the authenticity of a warhead undergoing dismantlement. Previously proposed solutions lacked the combination of isotopic sensitivity and information security. Here we present the experimental feasibility proof of a technique that uses neutron induced nuclear resonances and is sensitive to the combination of isotopics and geometry. The information is physically encrypted to prevent the leakage of sensitive information. Our approach can significantly increase the trustworthiness of future arms control treaties while expanding their scope to include the verified dismantlement of nuclear warheads themselves.

Pain and Catastrophizing in Patients With Rheumatoid Arthritis: An Observational Cohort Study.

BACKGROUND: The aims of this study were to define changes in catastrophizing that occur with initiation of a new disease-modifying antirheumatic drug (DMARD) and to examine the relationship between changes in Clinical Disease Activity Index (CDAI) and changes in catastrophizing. METHODS: Participants in an ongoing multisite, observational study completed the Pain Catastrophizing Scale (PCS) before and 12 weeks after DMARD initiation. We used multivariable linear regression models to examine the association between changes in CDAI as the exposure and change in pain catastrophizing as the outcome. We also assessed the relationship between changes in each component of CDAI and change in PCS, using multivariable linear regression models. RESULTS: Among the 165 rheumatoid arthritis patients with data on CDAI at both time points, CDAI decreased from 22 to 11.5 on a 76-point scale (p < 0.0001) after 12 weeks. Pain intensity decreased from a median of 5 to 3 on a 10-point numeric rating scale (p < 0.0001), and catastrophizing decreased, from 16.0 to 12.0 on the 52-point PCS (p = 0.0005). Among the 163 with complete data for the regression analysis, changes in CDAI were positively correlated with changes in catastrophizing (standardized ß = 0.19, p = 0.01). Of the components of the CDAI, change in assessor global score was most strongly associated with changes in catastrophizing (standardized ß = 0.24, p = 0.003). CONCLUSIONS: Pain catastrophizing decreases, in conjunction with disease activity, after initiation of a new DMARD. These findings provide support for catastrophizing as a dynamic construct that can be altered with treatment directed at decreasing inflammatory disease activity and pain.

Acceptability of the dengue vaccination among parents in urban poor communities of Quezon City, Philippines before and after vaccine suspension.

OBJECTIVE: The study aims to illustrate the acceptability of the dengue vaccine before and after the dengue vaccination suspension in urban poor communities in Quezon City, Philippines. RESULTS: There were 12 interviews conducted in November 2017 and 5 focus group discussions in January 2018, a month after vaccine program suspension with 41 participants. All participants were selected through purposive criterion sampling. Thematic analysis showed acceptability of the dengue vaccine was associated with parental experience with vaccination and dengue, trust in public health institutions and communication received by parents. Post-dengue vaccination suspension triangulation indicated that the parents regretted the experience, trust to public institutions was eroded and the communication strategy was deemed inadequate. This led to low vaccine acceptability post-vaccine suspension.

Peer pressure on the riverbank: Assessing catch-and-release anglers' willingness to sanction others' (bad) behavior.

Given the well-documented impacts of angler behavior on the biological fitness of angled and released fish, optimizing the conservation value of catch-and-release angling hinges on the extent to which anglers are willing to adopt recommended best practices and refrain from harmful ones. One potentially powerful mechanism underlying adoption of best practices is the social pressure anglers can apply to one another to enforce community norms and values. Past work in other domains demonstrates that forms of interpersonal communication-including social sanctioning-can foster context-appropriate social norms and increase cooperative behavior; yet to date, little research has examined these dynamics in the context of species conservation. We conducted in-person and online surveys to explore the role of social sanctioning in the context of an internationally renowned wild steelhead (Oncorhynchus mykiss) fishery in British Columbia, Canada. We investigated how diverse social-psychological and demographic factors influence anglers' past and future sanctioning propensity. Results highlight that perceived capacity to influence the angling practices of others and professed concerns about one's own reputation were strongly predictive of both past and future sanctioning. Furthermore, while anglers reported relatively low-levels of past sanctioning behavior, most anglers simultaneously expressed a strong desire to sanction others in the future. Identifying ways to increase the social desirability and visibility of sanctioning actions could assist resource managers in promoting adoption and maintenance of best practices. More broadly, our findings underscore a significant yet underappreciated role for wildlife users and enthusiasts in cultivating a shared conservation ethic to help ensure biological conservation.

Factors associated with insomnia and complementary medicine use in children: results of a national survey.

OBJECTIVES: Sleep difficulties are a serious health problem in children, and interest in using complementary and alternative medicine (CAM) therapies to treat sleep is growing. In this study, we aimed to identify: the prevalence of sleep difficulties in children, and the prevalence and patterns of CAM use among children with trouble sleeping. METHODS: We used the 2012 National Health Interview Survey (NHIS) dataset to estimate the prevalence of sleep difficulties and CAM use in children ages 6-17 years. Prevalence estimates were weighted to reflect the survey's sampling design. We used logistic regression to explore associations between sleep difficulties, psychosocial factors, comorbidities and CAM use. RESULTS: 6.4% of children in the 2012 NHIS dataset reported regular difficulty sleeping in the last year, corresponding to an estimated 1.5 million children in the US. Older age, poorer health status, more missed school days, and multiple comorbidities were all associated with sleep difficulties (p ≤ 0.001). Among children with sleep difficulties, 29% used at least one CAM therapy. Of the CAM therapies surveyed, non-vitamin, non-mineral supplements were the most commonly used (14.6%), followed by manipulation therapies (9.2%) and mind-body techniques (8.8%). Parental education and CAM use were most strongly associated with child CAM use (p ≤ 0.001). CONCLUSIONS: CAM therapies, particularly non-vitamin, non-mineral supplements, are commonly used among children with sleeping problems. More research is needed to characterize the safety and efficacy of CAM therapies for sleep in this population.

Eradication of Triple-Negative Breast Cancer Cells by Targeting Glycosylated PD-L1.

Protein glycosylation provides proteomic diversity in regulating protein localization, stability, and activity; it remains largely unknown whether the sugar moiety contributes to immunosuppression. In the study of immune receptor glycosylation, we showed that EGF induces programmed death ligand 1 (PD-L1) and receptor programmed cell death protein 1 (PD-1) interaction, requiring ß-1,3-N-acetylglucosaminyl transferase (B3GNT3) expression in triple-negative breast cancer. Downregulation of B3GNT3 enhances cytotoxic T cell-mediated anti-tumor immunity. A monoclonal antibody targeting glycosylated PD-L1 (gPD-L1) blocks PD-L1/PD-1 interaction and promotes PD-L1 internalization and degradation. In addition to immune reactivation, drug-conjugated gPD-L1 antibody induces a potent cell-killing effect as well as a bystander-killing effect on adjacent cancer cells lacking PD-L1 expression without any detectable toxicity. Our work suggests targeting protein glycosylation as a potential strategy to enhance immune checkpoint therapy.