T cell activation and lowered T regulatory cell numbers are key processes in severe major depressive disorder: Effects of recurrence of illness and adverse childhood experiences.

BACKGROUND: Major depressive disorder (MDD) is characterized by increased T helper (Th)1 polarization, T cell activation (e.g., CD71+ and CD40L+), and cannabinoid receptor type 2 bearing CD20+ B cells; and lower T regulatory (Treg) numbers. AIMS: To delineate the effects of adverse childhood experiences (ACEs) and recurrence of illness (ROI) on activated T and CB2-bearing B populations, and Tregs, including FoxP3 + CD152+, FoxP3 + GARP+, and FoxP3 + CB1+ cells. METHODS: We measured ROI, ACEs, the number of activated T cells, Tregs, and CD20 + CB2+ B cells, in 30 MDD patients and 20 healthy controls. RESULTS: A larger part of the variance in the depression phenome (40.8 %) was explained by increased CD20 + CB2+ and activated T cells, and lowered Tregs. ROI and lifetime suicidal behaviors were significantly and positively associated with CD20 + CB2+, CD3 + CD71+, CD3 + CD40L+, CD4 + CD71+, CD4 + CD40L+, and CD4HLADR+ numbers. ROI was significantly correlated with CD8 + CD40L+ numbers. The sum of ACEs was significantly associated with CD20 + CB2+, CD3 + CD40L+, CD4 + 40 L+ numbers, T cell activation (positively) and Treg (inversely) indices. One replicable latent vector could be extracted from activated T cells, lifetime and current suicidal behaviors, number of depressive episodes, and severity of depression, and 48.8 % of its variance was explained by ACEs. CONCLUSIONS: ACE-induced activation of T effector and cytotoxic cells and B cells with autoimmune potential, coupled with lowered Treg numbers are a key component of depression. The findings indicate that increasing ROI, the phenome of depression and suicidal behaviors, are caused by autoimmune processes, which are the consequence of ACEs and increasing sensitization of immune responses.

Moving toward affective immunology: Legacy and future directions.

The term "affective immunology" has recently been used to denote a field focused on the interplay between affective processes (including mood states, specific emotions, and regulatory processes) and various aspects of immune function. The overarching goals of this commentary are a) to provide historical underpinnings of this field with a focus on the profound impact of the work of Janice Kiecolt-Glaser, who is further honored in this special issue, b) to review important off-shoots of her legacy work in this domain, and c) to highlight important future directions for the field. Kiecolt-Glaser's work laid much of the foundation for affective immunology, with groundbreaking research related to depression, hostility and dyadic interactions, loneliness, and other affective patterns, often in the context of holistic models, novel experimental designs, and interventions. Her former mentees (and many of their mentees) have carried on her legacy in these domains, in ways that continue to advance appreciation of how affective processes relate to immune function. There are numerous remaining questions for the field to pursue, including better understanding of the role of emotion regulation, emotional reactivity and recovery, restorative processes, affective variability, and developmental and dynamic social processes. Such work will require greater use of longitudinal and within-person approaches and/or examination of processes in daily life, as well as models that account for interactive and reciprocal processes and which integrate behavior, social context, sociocultural factors, individual differences, and other aspects of health. As more work in these domains continues, building on Kiecolt-Glaser's rich legacy, we move toward the emergence of affective immunology as an important subfield in the domain of psychoneuroimmunology, one which will offer more nuanced understanding of the role of affective processes in immune health.

Timing matters: A meta-analysis on the dynamic effect of stress on salivary immunoglobulin.

The impact of psychological stress on physiological systems has been a focus of extensive research, particularly in understanding its diverse effects on immune system activity and disease risk. This meta-analysis explores the dynamic effect of acute stress on salivary immunoglobulin-A (S-IgA) levels, a key biomarker for secretory immunity within the oral environment. Analyzing data from 34 samples comprising 87 effect sizes and a total of 1,025 subjects, a multi-level approach is employed to account for the temporal variability in measuring the stress response. The results reveal a significant increase in S-IgA levels peaking around 10 min after stress exposure, followed by a return to baseline levels approximately 30 min later. In addition, the meta-analysis identified several research gaps of the extant literature, such as limitations in the considered time lag after stress. In conclusion, the findings emphasize the temporal nuances of the S-IgA response to stress, which can help to infer potential biological pathways and guide sampling designs in future studies. Further, we highlight the use of a multi-level meta-analysis approach to investigate the temporal dependencies of the interplay between stress and immune functioning.

Behaviorally Conditioned Immune Responses: "To Learn New Things, Read Old Books and Papers".

BACKGROUND: More than a century ago, experimental work and clinical observations revealed the functional communication between the brain and the peripheral immune system. This is documented on the one hand by studies first demonstrating the effects of catecholamines on the circulation of leukocytes in experimental animals and humans, and on the other hand via the work of Russian physiologist Ivan Petrovic Pavlov and his coworkers, reporting observations that associative learning can modify peripheral immune functions. This work later fell into oblivion since little was known about the endocrine and immune system's function and even less about the underlying mechanisms of how learning, a central nervous system activity, could affect peripheral immune responses. SUMMARY: In this article, we embark on a fascinating exploration of the historical trajectory of behaviorally conditioned immune responses. KEY MESSAGE: We will pay homage to the visionary scientists who laid the groundwork for this field of research, tracing its evolution from early theories of how associative learning can affect immunity to the modern-day insights that behavioral conditioning of pharmacological responses can be exploited to improve the efficacy of medical interventions for patients.

Exploring the Relationship between Psychoneuroimmunology and Oral Diseases: A Comprehensive Review and Analysis.

The relationship between psychoneuroimmunology (PNI) and oral health has recently garnered increasing attention due to the intricate interaction among psychological factors, the nervous system, immune responses, and oral diseases. This comprehensive review aims to elucidate the multifaceted connections between PNI and various oral conditions and conduct an in-depth analysis. Psychological factors, such as stress, anxiety, and depression, have been linked to oral microbiome alterations and immune function and the development and progression of oral diseases, such as periodontal disorders, oral ulcers, and temporomandibular disorders. Conversely, oral health conditions, particularly chronic periodontitis, have been associated with systemic inflammation, affecting mental health and overall well-being through neuroendocrine-immune pathways. Moreover, neural mechanisms, including the brain-gut axis and the autonomic nervous system, significantly influenced oral health through immune modulation and inflammatory responses. Understanding these complex interactions has implications for therapeutic interventions that target both psychological well-being and oral health outcomes. This review synthesizes current research findings from various disciplines, including immunology, neuroscience, dentistry, and psychology, to offer a comprehensive understanding of the bidirectional relationship between PNI and oral diseases. The implications of these interactions on treatment strategies, preventive measures, and interdisciplinary approaches underscore the need for integrated healthcare models that address psychological and oral health aspects to improve outcomes and quality of life in patients.

A Psychoneuroimmunological Reading of Jane Austen's Persuasion in the Context of Bodily Aging.

Jane Austen normally avoids discussing appearance throughout her works. Persuasion constitutes the exception to the rule, as the story focuses on the premature aging experienced by her protagonist, Anne Elliot, seemingly due to disappointed love. Much has been written about Anne's "loss of bloom," but never from the perspective of psychoneuroimmunology, the field that researches the interrelation between psychological processes and the nervous and immune systems. In this paper, we adopt a perspective of psychoneuroimmunology to argue that Austen established a connection between psychological distress, specifically lovesickness, and the development of early senescence signs, and vice versa, since the recovery of love is associated with happiness and physical glow. From a gender perspective, we discuss how Austen brightly reflected these interrelationships through the story of Anne, when the latest psychoneuroimmunological research has actually shown that women age earlier than men as a consequence of psychological turmoil.

The Role of Innate and Adaptive Immune System in the Pathogenesis of Schizophrenia.

Schizophrenia is one of the most severely debilitating mental disorders that affects 1.1% of the world's population. The exact cause of the disease is not known, but genetics, environmental factors (such as infectious agents, season and region of birth, exposure to viruses, low birth weight, advanced paternal age, and tobacco), and immune system dysfunction can all contribute to the development of schizophrenia. Recently, the role of the immune system in schizophrenia has received much attention. Both acquired and innate immune systems are involved in the pathogenesis of schizophrenia and facilitate the disease's progression. Almost all cells of the immune system including microglia, B cells, and T cells play an important role in the blood-brain barrier damage, inflammation, and in the progression of this disease. In schizophrenia, the integrity of the blood-brain barrier is reduced and then the immune cells are recruited into the endothelium following an increase in the expression of cell adhesion molecules. The entry of immune cells and cytokines leads to inflammation and antibody production in the brain. Accordingly, the results of this study strengthen the hypothesis that the innate and acquired immune systems are involved in the pathogenesis of schizophrenia.

The Psychoneuroimmunological Model of Moral Distress and Health in Healthcare Workers: Toward Individual and System-Level Solutions.

Healthcare is presently experiencing a global workforce crisis, marked by the inability of hospitals to retain qualified healthcare workers. Indeed, poor working conditions and staff shortages have contributed to structural collapse and placed a heavy toll on healthcare workers' (HCWs) well-being, with many suffering from stress, exhaustion, demoralization, and burnout. An additional factor driving qualified HCWs away is the repeated experience of moral distress, or the inability to act according to internally held moral values and perceived ethical obligations due to internal and external constraints. Despite general awareness of this crisis, we currently lack an organized understanding of how stress leads to poor health, wellbeing, and performance in healthcare workers. To address this critical issue, we first review the literature on moral distress, stress, and health in HCWs. Second, we summarize the biobehavioral pathways linking occupational and interpersonal stressors to health in this population, focusing on neuroendocrine, immune, genetic, and epigenetic processes. Third, we propose a novel Psychoneuroimmunological Model of Moral Distress and Health in HCWs based on this literature. Finally, we discuss evidence-based individual- and system-level interventions for preventing stress and promoting resilience at work. Throughout this review, we underscore that stress levels in HCWs are a major public health concern, and that a combination of system-level and individual-level interventions are necessary to address preventable health care harm and foster resilience in this population, including new health policies, mental health initiatives, and additional translational research.

The influence of everyday emotions on mucosal immunity: An intensive longitudinal modeling approach.

Mucosal immunity is a multifaceted system of immunological responses that provides a barrier against pathogenic invasion and can be regulated by psychosocial and neuroendocrine factors. The present study aims to elucidate the association between everyday emotional states, emotion regulation skills, and mucosal immunity by utilizing an ambulatory assessment approach. 30 healthy subjects (61% male; M = 30.18 years old) completed an emotion questionnaire (PANAS) and collected saliva samples via passive drool to determine salivary immunoglobulin-A (S-IgA) excretion rate three times a day over a period of 1 week. In a multi-level model, the influence of emotions on S-IgA, both on a within-subject and between-subject level, was estimated. We found that most of the variation in S-IgA (74%) was accounted for by within-subject changes rather than stable between-subject differences. On a within-subject level, negative emotions had a significant positive effect on S-IgA levels (b = 1.87, p = .015), while positive emotions had no effect. This effect of negative emotions was moderated by the individual emotion regulation skills, with higher regulation skills corresponding to smaller effects (b = -2.67, p = .046). Furthermore, S-IgA levels decreased over the course of a day, indicating circadian rhythmicity (b = -0.13, p = .034). These results highlight the possibilities of intensive longitudinal data to investigate the covariance between psychological and immunological states over time.

Psychosocial predictors of the innate immune response to influenza vaccination.

Experimental activation of the innate immune system has contributed significantly to both our understanding of how psychological factors influence immune function as well as how immune activity influences the brain and behavior. The annual influenza vaccine can be used to interrogate the effects of mild immune stimulation on day-to-day changes in psychological processes in human subjects that range across the lifespan and in both clinical and non-clinical populations. Yet, the immune response to the influenza vaccine in the days immediately following its administration are not well characterized. The present study describes changes in inflammatory and antiviral gene expression within circulating immune cells, plasma cytokines, and C-reactive protein (CRP) following receipt of the flu vaccine, and further reports the association between several common behavioral health factors and the acute immune response. Participants were 65 adults (mean age 18.81 ± 1.03 years; 66.2% female) who provided a blood sample immediately before and then 24 h after receiving the vaccine. A subsample also provided additional blood samples at 48 and 72 h. Plasma was assayed for CRP, IL-6, IL-10, IL-8, TNF-α, and IFN-γ, and peripheral blood mononuclear cell RNA was sequenced for evidence of change in expression of an a priori set of type 1 interferon (IFN) and inflammatory response genes (INFLAM). Plasma cytokines, CRP, and IFN response genes increased 24 h after vaccination, all ps < .001. The increase in IFN gene expression correlated with the observed increase in plasma cytokines and CRP, p < .0001. The immune response to influenza vaccination at 24-hours was moderated by anxiety symptoms, BMI, being female, sleep, and history of influenza vaccination. These factors and their associations with common immune challenges may be useful in studies interrogating the origins of immune dysregulation. The annual influenza vaccine is an accessible and reliable exogenous activator of both circulating and transcriptional markers of innate immune reactivity, with sensitivity to behavioral health factors relevant for psychoneuroimmunology research.

The relevance of the contribution of psychoneuroendocrinoimmunology and psychology of reasoning and decision making to nursing science: A discursive paper.

AIM: Patients' death or adverse events appear to be associated with poor healthcare decision-making. This might be due to an inability to have an adequate representation of the problem or of the connections among problem-related elements. Changing how a problem is formulated can reduce biases in clinical reasoning. The purpose of this article is to explore the possible contributions of psychoneuroendocrinoimmunology (PNEI) and psychology of reasoning and decision-making (PRDM) to support a new nursing theoretical frame. DESIGN: Discursive paper. METHOD: This article discusses the main assumptions about nursing and nurses' ability to face patient's problems, suggesting a new approach that integrates knowledge from PNEI and PRDM. While PNEI explains the complexity of systems, highlighting the importance of systems connections in affecting health, PRDM underlines the importance of the informative context in creating a mental representation of the problem. Furthermore, PRDM suggests the need to pay attention to information that is not immediately explicit and its connections. CONCLUSION: Nursing recognizes the patient-nurse relationship as the axiom that governs care. The integration of PNEI and PRDM in nursing theoretics allows the expansion of the axiom by providing essential elements to read a new type of relationship: the relationship among information. PNEI explains the relationships between biological systems and the psyche and between the whole individual and the environment; PRDM provides tools for the nurse's analytical thinking system to correctly process information and its connections. IMPACT ON NURSING PRACTICE: A theoretical renewal is mandatory to improve nursing reasoning and nursing priority identification. Integrating PNEI and PRDM into nursing theoretics will modify the way professionals approach patients, reducing cognitive biases and medical errors. NO PATIENT OR PUBLIC CONTRIBUTION: There was no patient or public involvement in the design or writing of this discursive article.

Toward a dynamic immunopsychiatry.

In this article, we briefly clarify several points regarding immunopsychiatry. In particular, we argue that higher density data and a greater focus on temporal dynamics are both important, and that studies incorporating these features have the potential to greatly advance the field. We also respond to recent comments made on our original article on this topic (Moriarity and Slavich, 2023), including the contention that our perspective on immunopsychiatry is reductionistic. To the contrary, we believe that strong immunopsychiatry studies are highly integrative and include data from multiple major levels of analysis to form a more complete picture of how processes that are relevant for mental health and behavior emerge and dynamically change over time in relation to one another.

Childhood Maltreatment and Immune Cell Gene Regulation during Adolescence: Transcriptomics Highlight Non-Classical Monocytes.

Childhood maltreatment has been repeatedly linked to a higher incidence of health conditions with an underlying proinflammatory component, such as asthma, chronic obstructive pulmonary disease, stroke, and cardiovascular disease. Childhood maltreatment has also been linked to elevated systemic inflammation prior to the onset of disease. However, childhood maltreatment is highly comorbid with other risk factors which have also been linked to inflammation, namely major depression. The present analysis addresses this issue by assessing the association of maltreatment with genome-wide transcriptional profiling of immune cells collected from four orthogonal groups of adolescents (aged 13-17): maltreated and not maltreated in childhood, with and without major depressive disorder. Maltreatment and psychiatric history were determined using semi-structured clinical interviews and cross-validated using self-report questionnaires. Dried whole blood spots were collected from each participant (n = 133) and assayed to determine the extent to which maltreatment in childhood was associated with a higher prevalence of transcriptional activity among differentially expressed genes, specific immune cell subtypes, and up- or down-regulation of genes involved in immune function after accounting for current major depression. Maltreatment was associated with increased interferon regulatory factor (IRF) transcriptional activity (p = 0.03), as well as nuclear factor erythroid-2 related factor 1 (NRF1; p = 0.002) and MAF (p = 0.01) among up-regulated genes, and increased activity of nuclear factor kappa beta (NF-κB) among down-regulated genes (p = 0.01). Non-classical CD16+ monocytes were implicated in both the up- and down-regulated genes among maltreated adolescents. These data provide convergent evidence supporting the role of maltreatment in altering intracellular and molecular markers of immune function, as well as implicate monocyte/macrophage functions as mechanisms through which childhood maltreatment may shape lifelong immune development and function.

Pitfalls and potential: Translating the two-hit model of early life stress from pre-clinical non-human experiments to human samples.

Exposure to early life stress (ELS) has been linked to at least double the risk of psychopathology as well as higher morbidity and earlier mortality across the lifespan. For this reason, the field of developmental psychopathology has spent decades identifying factors that explain which individuals are at risk for negative health outcomes. Preclinical experiments in this field commonly test the "two-hit hypothesis", which explores how ELS potentiates vulnerability to pathogenic physiological and behavioral outcomes when an individual is exposed to a stressor later in development. Yet, translation of the two-hit hypothesis to humans is conceptually and practically challenging, thus impeding progress in the field. This review summarizes the two-hit hypothesis used in preclinical experiments as it pertains to two putative pathways linking ELS to psychopathology: the innate immune and neuroendocrine systems. This review also identifies important considerations when translating this model to humans and provides several recommendations. Specifically, attention to the "biological salience" of different forms of ELA and the concordance of that salience with later probes of the system are needed. Further, the consequences of ELS may be context-specific rather than ubiquitous, at least among young people. Within this conceptualization, "second hits" may be best operationalized using standardized acute challenges to the innate immune and neuroendocrine systems (e.g., psychosocial stress). Third, more explicit reporting of sex differences in the human literature is needed. Finally, preclinical experimental designs that more accurately reflect the natural occurrence of ELS in community samples will more effectively advance the understanding of developmental mechanisms that occur as a consequence of ELS.

Loneliness, immunological recovery patterns, and health-related quality of life (HRQOL) outcomes in patients receiving hematopoietic stem cell transplantation.

PURPOSE: Loneliness may compromise health-related quality of life (HRQOL) outcomes and the immunological impacts of loneliness via neuroendocrinological mechanisms likely have consequences for patients who have undergone a hematopoietic stem cell transplantation (HSCT). RESEARCH APPROACH AND MEASURES: Loneliness (pre-transplant), immunological recovery (Day 30, Day 100, 1-year post-transplant), and HRQOL (Day 100, 1 year) were measured in a sample of 205 patients completing a HSCT (127 autologous, 78 allogenic). RESULTS: Greater levels of pre-transplant loneliness predicted poorer HRQOL at Day 100 and 1-year follow-up. Loneliness also was associated with higher absolute neutrophil to absolute lymphocyte (ANC/ALC) ratios in the entire sample at Day 30, which in turn was associated with Day 100 HRQOL. CONCLUSIONS: Findings demonstrate that pretransplant loneliness predicts HRQOL outcomes and associates with inflammatory immunological recovery patterns in HSCT patients. The balance of innate neutrophils to adaptive lymphocytes at Day 30 present a distinct profile in lonely individuals, with this immunity recovery profile predicting reduced HRQOL 100 days after the transplant. Addressing perceptions of loneliness before HSCT may be an important factor in improving immunological recovery and HRQOL outcomes.

Do interventions for mood improve inflammatory biomarkers in inflammatory bowel disease?: a systematic review and meta-analysis.

BACKGROUND: Psychoneuroimmunological mechanisms and the gut-brain axis appear relevant to disease activity and progression in Inflammatory Bowel Disease (IBD). A recent review showed no effect of psychological therapies on self-reported disease activity in IBD. This meta-analysis aims to establish whether interventions targeting mood outcomes (e.g., depression, anxiety and stress) impact inflammation levels in IBD and possible moderators of these effects. METHODS: The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines were followed. We searched five electronic databases and included randomised controlled trials where interventions targeted mood and assessed inflammatory outcomes pre- and post-intervention in adults with IBD. Independent reviewers screened studies, extracted data, and assessed methodological quality. Data were pooled to estimate standardised mean differences (SMDs) with 95% Confidence Intervals (CIs). A random-effects robust variance estimation accounted for studies measuring multiple biomarkers. Intervention type, mood as a primary or secondary outcome, effect on mood outcomes and IBD subtype were investigated as treatment effect moderators. Where there were sufficient biomarkers, individual meta-analyses were run (Pre-registration PROSPERO: CRD42023389401). FINDINGS: 28 RCTs involving 1789 participants met inclusion criteria. Interventions demonstrated small, statistically significant effects on biomarkers (-0.35, 95% CI: -0.48, -0.22, p < 0.001) and medium effects on mood outcomes (-0.50, 95% CI: -0.73, -0.27, p < 0.001), without evidence of substantive heterogeneity or publication bias. Individual analyses showed small effects for improved faecal calprotectin (-0.19, 95% CI: -0.34, -0.03, p = 0.018) and C-Reactive Protein (-0.29, 95% CI: -0.47, -0.10, p = 0.002). Effect sizes were larger for psychological therapy interventions (compared with exercise or antidepressants) and when there was an effect (SMD ≥0.2) on mood. INTERPRETATION: Treatments which address mood outcomes have beneficial effects on generic inflammation as well as disease-specific biomarkers (faecal calprotectin and C-Reactive Protein). Psychological interventions and interventions with larger treatment effects on mood accentuated the effect on biomarkers. More research is required to understand the biological or behavioural mechanisms underlying this effect. FUNDING: The Medical Research Council and the National Institute for Health and Care Research (NIHR) Maudsley Biomedical Research Centre.

The moderating role of circadian gene polymorphisms in the relationship between sleep disturbance and circulating lymphocyte subsets in colorectal cancer patients.

AIM: We investigated the impact of sleep disturbance on immune status in colorectal cancer (CRC) patients with consideration of the moderating role of circadian clock gene polymorphisms. METHODS: A prospective longitudinal study design was used to collect information regarding sleep disturbance. Blood samples for immunologic assays were obtained the day before the first (baseline) and last cycles of 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) chemotherapy. Clinical sleep disturbance was compared between the two-time points using the Pittsburgh Sleep Quality Index (PSQI) global score. We analysed single-nucleotide polymorphisms in rs2278749, rs3749474, rs2291738, rs17031614, and rs2287161. The dependent variables included changes in the percentages of CD4+, CD8+, CD19+, and CD16/56+ lymphocytes between the two-time points. The results were analysed using moderated regression analysis; the p-values were adjusted using the false discovery rate. RESULTS: Among the 104 patients, no significant dyadic associations were observed between changes in lymphocyte percentages and the PSQI global score. However, the moderated regression analysis revealed five significant associations (rs2287161 with CD8+, rs2278749 and rs2291738 with CD19+, and rs17031614 with CD4+ and CD16/56+ lymphocytes). The inclusion of each interaction resulted in a significant increase (5.7-10.7%) in the variance explained by changes in lymphocyte percentage. CONCLUSION: Patients with specific circadian gene allele types may be more susceptible to immune dysregulation when experiencing sleep disturbances. Considering that sleep disturbance is a modifiable factor that can impact immune regulation, it is essential to prioritise the management of sleep disturbances in CRC patients receiving FOLFOX chemotherapy.

Emotional Stress and Immune Response in Surgery: A Psychoneuroimmunological Perspective.

Psychoneuroimmunology (PNI) offers a deep dive into the nexus between emotional stress, immunity, and surgical outcomes. In this narrative review, we first trace PNI's historical roots, providing a foundational understanding of its evolution. We then dissect its significance across the surgical journey, from the preoperative phase through to postoperative recovery. It becomes evident through our exploration that emotional stress has profound implications for surgery, notably influencing wound healing rates, susceptibility to infections, and overall postoperative well-being. Among the arsenal to combat these challenges, interventions such as cognitive-behavioral therapy, mindfulness, and complementary practices such as meditation and yoga have emerged as potent tools. They not only mitigate stress but also play a pivotal role in enhancing immune function. However, the journey to optimizing surgical outcomes is not just about identifying effective interventions. A resounding theme is the importance of holistic care, ensuring that all patients have equitable access to these tools. As PNI continues to evolve, we stand at the precipice of a healthcare revolution, one that promises a blend of personalized care, anchored in a deep understanding of the mind-body connection in surgical contexts.

Personalized therapy in rheumatoid arthritis (PETRA): a protocol for a randomized controlled trial to test the effect of a psychological intervention in rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic autoimmune disease that primarily affects cartilage and bone. Psychological stress can both trigger disease exacerbation and result from disease activity. As standard pharmacological interventions alone have limited success in treating RA, a more comprehensive biopsychosocial approach to treatment has been recommended. In this prospective randomized controlled trial (RCT), a psychotherapeutically guided, group-based intervention program will be conducted with RA patients over a period of 9 months. This program combines a dynamic-interactional model with disorder-specific coping-oriented perspectives to improve patients' social, emotional, and problem-solving competencies as well as stress system functional status. The enrolment of 440 patients, randomly allocated to either an intervention (n = 220) or control group (n = 220), is planned. To evaluate the intervention effect, various indicators of RA disease activity, stress system activity, and psychological condition will be assessed through sets of standardized questionnaires and biochemical analyses of blood and saliva samples. Moreover, healthcare-related costs for each patient will be obtained using routine health insurance data. Outcome variables will be measured in all patients at regular intervals prior to intervention (baseline), during the 9-month intervention (five time points), and during a 9-month follow-up phase (three time points), allowing the comprehensive analysis of within- and between-subject effects, i.e. trajectories of the target variables in the intervention and control groups. In addition, to investigate the intervention effects on real-life stress system functioning in RA, 10 integrative single-case studies (n = 5 from the intervention group, n = 5 from the control group) will be conducted. In each study, once before and after the 9-month intervention, urine samples will be collected, and patients will fill out questionnaires for approximately 1 month at 12-h intervals. Moreover, weekly in-depth interviews will be conducted with patients to determine their previous week's emotionally positive and negative incidents. Using time series analysis, it is then possible to investigate whether and how stress system function in these RA patients has improved from the applied intervention. By using both an investigational macro- and microperspective, this project aims to evaluate a psychological intervention in the routine care of individuals with RA.Trial registration German Clinical Trials Register DRKS00028144. Registered on 1 March 2022.

T helper-1 activation via interleukin-16 is a key phenomenon in the acute phase of severe, first-episode major depressive disorder and suicidal behaviors.

BACKGROUND: Immune-inflammatory pathways in major depressive disorder are confined to the major dysmood disorder (MDMD) phenotype (Maes et al., 2022). No studies have addressed the immune profile of first episode MDMD (FE-MDMD). METHODS: This study investigated the immune profiles of 71 patients with the acute phase of first-episode major depressive disorder (FE-MDMD) and 40 healthy controls. We measured 48 cytokines/chemokines/growth factors, classical M1, alternative M2, T helper (Th)-1, Th-2, and Th-17 phenotypes, immune-inflammatory response system (IRS), compensatory immunoregulatory system (CIRS), and neuro-immunotoxicity profiles. RESULTS: FE-MDMD patients show significantly activated M1, M2, Th-1, IRS, CIRS, and neurotoxicity, but not Th-2 or Th-17, profiles compared to controls. FE-MDMD is accompanied by Th-1 polarization, while there are no changes in M1/M2 or IRS/CIRS ratios. The top single indicator of FE-MDMD was by far interleukin (IL)-16, followed at a distance by TRAIL, IL-2R, tumor necrosis factor (TNF)-ß. The severity of depression and anxiety was strongly associated with IRS (positively) and Th-2 (inversely) profiles, whereas suicidal behavior was associated with M1 activation. Around 56-60% of the variance in depression, anxiety, and suicidal behavior scores was explained by IL-16, platelet-derived growth factor (PDGF) (both positively), and IL-1 receptor antagonist (inversely). Increased neurotoxicity is mainly driven by IL-16, TNF-α, TRAIL, IL-6, and chemokine (CCL2, CCL11, CXCL1, CXCL10) signaling. Antidepressant-treated patients show an increased IRS/CIRS ratio as compared with drug-naïve FE-MDMD patients. CONCLUSIONS: FE-MDMD is accompanied by positive regulation of the IRS mainly driven by Th-1 polarization and T cell activation (via binding of IL-16 to CD4), and TNF, chemokine, and growth factor signaling.