Metabolic Phenotypes of Response to Vaccination in Humans.

Herpes zoster (shingles) causes significant morbidity in immune compromised hosts and older adults. Whereas a vaccine is available for prevention of shingles, its efficacy declines with age. To help to understand the mechanisms driving vaccinal responses, we constructed a multiscale, multifactorial response network (MMRN) of immunity in healthy young and older adults immunized with the live attenuated shingles vaccine Zostavax. Vaccination induces robust antigen-specific antibody, plasmablasts, and CD4+ T cells yet limited CD8+ T cell and antiviral responses. The MMRN reveals striking associations between orthogonal datasets, such as transcriptomic and metabolomics signatures, cell populations, and cytokine levels, and identifies immune and metabolic correlates of vaccine immunity. Networks associated with inositol phosphate, glycerophospholipids, and sterol metabolism are tightly coupled with immunity. Critically, the sterol regulatory binding protein 1 and its targets are key integrators of antibody and T follicular cell responses. Our approach is broadly applicable to study human immunity and can help to identify predictors of efficacy as well as mechanisms controlling immunity to vaccination.

Veteran Beliefs About the Causes of Gulf War Illness and Expectations for Improvement.

BACKGROUND: Individuals' beliefs about the etiology of persistent physical symptoms (PPS) are linked to differences in coping style. However, it is unclear which attributions are related to greater expectations for improvement. METHOD AND RESULTS: A cross-sectional regression analysis (N = 262) indicated that Veterans with Gulf War Illness (GWI) who attributed their GWI to behavior, (e.g., diet and exercise), had greater expectations for improvement (p = .001) than those who attributed their GWI to deployment, physical, or psychological causes (p values > .05). CONCLUSIONS: Findings support the possible clinical utility of exploring perceived contributing factors of PPS, which may increase perceptions that improvement of PPS is possible. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02161133.

Motherhood and DREADD manipulation of the nucleus accumbens weaken established pair bonds in female prairie voles.

Monogamous pair bonding has evolved to enhance reproductive success and ensure offspring survival. Although the behavioral and neural mechanisms regulating the formation of pair bonds have been relatively well outlined, how these relationships are regulated and maintained across the lifetime of an individual remains relatively unexplored. One way to explore this is to study the maintenance of a social bond across a major life-history transition. The transition to motherhood is among the most poignant moments in the life history of a female, and is associated with significant neural and behavioral changes and shifting priorities. The nucleus accumbens (NAc) is known to modulate social valence and is central to mammalian pair bonding. In this study, we investigated two mechanisms driving variation in bond strength in the socially monogamous prairie vole (Microtus ochrogaster). We manipulated neural activity of the NAc at two distinct stages of life-history, before and after the birth of offspring, to assess how neural activity and social contexts modulate female pair bond strength. Our results showed DREADD (Designer Receptor Exclusively Activated by Designer Drugs) inhibition of the NAc decreases affiliative behavior towards the mating partner, whereas DREADD activation of the NAc increases affiliative behavior of strangers, thereby decreasing social selectivity. We also found a robust "birth effect" on pair bond strength, such that bonds with partners were weakened after the birth of offspring, an effect not attributable to the amount of cohabitation time with a partner. Overall, our data support the hypotheses that NAc activity modulates reward/saliency within the social brain in different ways, and that motherhood comes with a cost for the bond strength between mating partners.

Understanding Veterans' Causal Attributions of Physical Symptoms.

BACKGROUND: Illness beliefs are significant contributors to health outcomes. Beliefs about the cause of physical symptoms are considered particularly important among those with medically unexplained symptoms and illnesses (MUS); yet little is known about causal beliefs among those with the most severe MUS (i.e., Veterans). The goal of the current study was to examine Veteran's causal attributions of their physical symptoms. METHOD: A total of 91 combat Veterans with MUS were surveyed using a mixed-methods design about the cause of their physical symptoms, physical symptom severity, and PTSD symptoms. Causal attributions of physical symptoms were analyzed through thematic response analysis and grouped into categories. Chi-square analysis was used to assess the distribution of causal attribution types across Veterans with varying physical symptom severity and PTSD symptom severity. RESULTS: Veterans with MUS reported an average of 7.9 physical symptoms, and attributed the cause of their symptoms to seven different categories ("Do not Know," "Stress/Mental Health," "Deployment/Environment," "Functional/Symptom," "Medically Explained," "Medically Unexplained Syndrome," and "Lifestyle"). Exploratory chi-square analysis revealed significant differences in causal attributions across physical symptom severity and severity of PTSD symptoms. Veterans with more severe PTSD and Veterans with more severe physical symptoms were more likely to attribute their MUS to stress/mental health or to a medically unexplained syndrome compared with those with low/no PTSD symptoms and physical symptom severity. Veterans with minimal PTSD and Veterans with minimal physical symptom severity were more likely to attribute the cause of their MUS to lifestyle choices (e.g., exercise/diet) compared with those with high PTSD and physical symptom severity. CONCLUSION: Veterans with MUS endorse multiple, varied causal attributions for their physical symptoms, suggesting more complex causal beliefs than typically assumed. This has important implications for patient-provider communication and development of concordance around MUS treatment.

Occupational Therapy for Functional Impairments Resulting From COVID-19 Infection: A Case Report.

This case report examines the role of occupational therapy in the recovery of a client who became critically ill with severe acute respiratory syndrome coronavirus 2. In it, we describe evaluation and treatment methods, functional impairments, and special considerations when working with a client with severe coronavirus disease 2019 infection. The client was a 43-yr-old Hispanic man treated in a long-term acute-care hospital. Client-centered treatment sessions focused on activities of daily living (ADLs), self-feeding, medication management, and leisure and were implemented in 30- to 45-min sessions 3 times per week for 5 wk. The Activity Measure for Post Acute Care Daily Activities Short Form was used to measure basic mobility, daily activities, and applied cognition in the acute setting. A manual dynamometer was used to measure grip strength, and the Nine-Hole Peg Test was used to measure digit dexterity. Both were used in the context of occupational engagement. Data were collected at evaluation, every 2 wk, and at discharge. The client achieved his goals and demonstrated marked improvement in independence with basic ADLs, leisure activities, bilateral grip strength, and manual dexterity.

Characterization of Virus-specific Immune Response During Varicella Zoster Virus Encephalitis in a Young Adult.

An immunocompetent adult received corticosteroids for chest pain, which later was clinically found to be herpes zoster (HZ). She developed severe disease and rapid viral dissemination that elicited an exceptionally strong varicella zoster virus-specific B-cell and CD8 T-cell response. Clinicians should consider atypical HZ presentation prior to corticosteroid administration.

Breadth and Functionality of Varicella-Zoster Virus Glycoprotein-Specific Antibodies Identified after Zostavax Vaccination in Humans.

Herpes zoster (HZ) (shingles) is the clinical manifestation of varicella-zoster virus (VZV) reactivation. HZ typically develops as people age, due to decreased cell-mediated immunity. However, the importance of antibodies for immunity against HZ prevention remains to be understood. The goal of this study was to examine the breadth and functionality of VZV-specific antibodies after vaccination with a live attenuated HZ vaccine (Zostavax). Direct enumeration of VZV-specific antibody-secreting cells (ASCs) via enzyme-linked immunosorbent spot assay (ELISPOT assay) showed that Zostavax can induce both IgG and IgA ASCs 7 days after vaccination but not IgM ASCs. The VZV-specific ASCs range from 33 to 55% of the total IgG ASCs. Twenty-five human VZV-specific monoclonal antibodies (MAbs) were cloned and characterized from single-cell-sorted ASCs of five subjects (>60 years old) who received Zostavax. These MAbs had an average of ∼20 somatic hypermutations per VH gene, similar to those seen after seasonal influenza vaccination. Fifteen of the 25 MAbs were gE specific, whereas the remaining MAbs were gB, gH, or gI specific. The most potent neutralizing antibodies were gH specific and were also able to inhibit cell-to-cell spread of the virus in vitro Most gE-specific MAbs were able to neutralize VZV, but they required the presence of complement and were unable to block cell-to-cell spread. These data indicate that Zostavax induces a memory B cell recall response characterized by anti-gE > anti-gI > anti-gB > anti-gH antibodies. While antibodies to gH could be involved in limiting the spread of VZV upon reactivation, the contribution of anti-gE antibodies toward protective immunity after Zostavax needs further evaluation.IMPORTANCE Varicella-zoster virus (VZV) is the causative agent of chickenpox and shingles. Following infection with VZV, the virus becomes latent and resides in nerve cells. Age-related declines in immunity/immunosuppression can result in reactivation of this latent virus, causing shingles. It has been shown that waning T cell immunity correlates with an increased incidence of VZV reactivation. Interestingly, serum with high levels of VZV-specific antibodies (VariZIG; IV immunoglobulin) has been administered to high-risk populations, e.g., immunocompromised children, newborns, and pregnant women, after exposure to VZV and has shown some protection against chickenpox. However, the relative contribution of antibodies against individual surface glycoproteins toward protection from shingles in elderly/immunocompromised individuals has not been established. Here, we examined the breadth and functionality of VZV-specific antibodies after vaccination with the live attenuated VZV vaccine Zostavax in humans. This study will add to our understanding of the role of antibodies in protection against shingles.

Coping with Medically Unexplained Physical Symptoms: the Role of Illness Beliefs and Behaviors.

BACKGROUND: Medically unexplained syndromes (MUS) are both prevalent and disabling. While illness beliefs and behaviors are thought to maintain MUS-related disability, little is known about which specific behavioral responses to MUS are related to disability or the way in which beliefs and behaviors interact to impact functioning. The purpose of the present study was to examine the relationship between illness beliefs and disability among patients with MUS, and assess the extent to which behaviors mediate this relationship. METHODS: The study examined data from the baseline assessment of a multi-site randomized controlled trial (RCT). Participants were 248 veterans with MUS. Illness beliefs, behavioral responses to illness, and disability were assessed through self-report questionnaire. Data were analyzed using mediation analysis. RESULTS: Threat-related beliefs predicted greater disability through decreased activity and increased practical support seeking. Protective beliefs predicted less disability through reductions in all-or-nothing behavior and limiting behavior. CONCLUSIONS: These outcomes suggest that all-or-nothing behavior, limiting behavior, and practical support seeking are important in the perpetuation of disability among those with MUS. This has implications for improving MUS treatment by highlighting potential treatment targets. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02161133.

Helpful ways providers can communicate about persistent medically unexplained physical symptoms.

BACKGROUND: Communication between patients and providers about persistent "medically unexplained" physical symptoms (MUS) is characterized by discordance. While the difficulties are well documented, few studies have examined effective communication. We sought to determine what veterans with Gulf War Illness (GWI) perceive as the most helpful communication from their providers. Veterans with GWI, a type of MUS, have historically had complex relationships with medical providers. Determining effective communication for patients with particularly complex relationships may help identify the most critical communication elements for all patients with MUS. METHODS: Two hundred and-ten veterans with GWI were asked, in a written questionnaire, what was the most useful thing a medical provider had told them about their GWI. Responses were coded into three categories with 10 codes. RESULTS: The most prevalent helpful communication reported by patients was when the provider offered acknowledgement and validation (N = 70). Specific recommendations for managing GWI or its symptoms (N = 48) were also commonly reported to be helpful. In contrast, about a third of the responses indicated that nothing about the communication was helpful (N = 63). There were not differences in severity of symptoms, disability or healthcare utilization between patients who found acknowledgement and validation, specific recommendations or nothing helpful. CONCLUSIONS: Previous research has documented the discord between patients and providers regarding MUS. This study suggests that most patients are able to identify something helpful a provider has said, particularly acknowledgement and validation and specific treatment recommendations. The findings also highlight missed communication opportunities with a third of patients not finding anything helpful.

Costimulatory Effects of an Immunodominant Parasite Antigen Paradoxically Prevent Induction of Optimal CD8 T Cell Protective Immunity.

Trypanosoma cruzi infection is controlled but not eliminated by host immunity. The T. cruzi trans-sialidase (TS) gene superfamily encodes immunodominant protective antigens, but expression of altered peptide ligands by different TS genes has been hypothesized to promote immunoevasion. We molecularly defined TS epitopes to determine their importance for protection versus parasite persistence. Peptide-pulsed dendritic cell vaccination experiments demonstrated that one pair of immunodominant CD4+ and CD8+ TS peptides alone can induce protective immunity (100% survival post-lethal parasite challenge). TS DNA vaccines have been shown by us (and others) to protect BALB/c mice against T. cruzi challenge. We generated a new TS vaccine in which the immunodominant TS CD8+ epitope MHC anchoring positions were mutated, rendering the mutant TS vaccine incapable of inducing immunity to the immunodominant CD8 epitope. Immunization of mice with wild type (WT) and mutant TS vaccines demonstrated that vaccines encoding enzymatically active protein and the immunodominant CD8+ T cell epitope enhance subdominant pathogen-specific CD8+ T cell responses. More specifically, CD8+ T cells from WT TS DNA vaccinated mice were responsive to 14 predicted CD8+ TS epitopes, while T cells from mutant TS DNA vaccinated mice were responsive to just one of these 14 predicted TS epitopes. Molecular and structural biology studies revealed that this novel costimulatory mechanism involves CD45 signaling triggered by enzymatically active TS. This enhancing effect on subdominant T cells negatively regulates protective immunity. Using peptide-pulsed DC vaccination experiments, we have shown that vaccines inducing both immunodominant and subdominant epitope responses were significantly less protective than vaccines inducing only immunodominant-specific responses. These results have important implications for T. cruzi vaccine development. Of broader significance, we demonstrate that increasing breadth of T cell epitope responses induced by vaccination is not always advantageous for host immunity.

Effectiveness of Health Promotion, Management, and Maintenance Interventions Within the Scope of Occupational Therapy for Community-Dwelling Older Adults: A Systematic Review.

OBJECTIVE: This systematic review examined the effectiveness of health promotion, management, and maintenance interventions within the scope of occupational therapy to improve occupational performance and quality of life (QOL) and decrease health care utilization for community-dwelling older adults. METHOD: Thirty-eight articles representing 36 studies were included in the review. Articles were published 2008-2015 and described studies of participants with a mean age of 65 or older who were living in the community. RESULTS: Strong evidence supports the use of group, individual, or a combination of group and individual interventions to improve occupational performance. Group interventions were also effective at improving QOL. The evidence was insufficient that any of these interventions decreased health care utilization. CONCLUSION: Addressing health promotion, management, and maintenance is within the scope of occupational therapy practice and has been shown to improve occupational performance and QOL for older adults. Implications for practice and future research are discussed.

Deficiency of antigen-specific B cells results in decreased Trypanosoma cruzi systemic but not mucosal immunity due to CD8 T cell exhaustion.

Vaccines against mucosally invasive, intracellular pathogens must induce a myriad of immune responses to provide optimal mucosal and systemic protection, including CD4(+) T cells, CD8(+) T cells, and Ab-producing B cells. In general, CD4(+) T cells are known to provide important helper functions for both CD8(+) T cell and B cell responses. However, the relative importance of CD4(+) T cells, CD8(+) T cells, and B cells for mucosal protection is less clearly defined. We have studied these questions in detail using the murine model of Trypanosoma cruzi infection. Despite our initial hypothesis that mucosal Abs would be important, we show that B cells are critical for systemic, but not mucosal, T. cruzi protective immunity. B cell-deficient mice developed normal levels of CD8(+) effector T cell responses early after mucosal T. cruzi infection and T. cruzi trans-sialidase vaccination. However, after highly virulent systemic challenge, T. cruzi immune mice lacking T. cruzi-specific B cells failed to control parasitemia or prevent death. Mechanistically, T. cruzi-specific CD8(+) T cells generated in the absence of B cells expressed increased PD-1 and Lag-3 and became functionally exhausted after high-level T. cruzi systemic challenge. T. cruzi immune serum prevented CD8(+) T cell functional exhaustion and reduced mortality in mice lacking B cells. Overall, these results demonstrate that T. cruzi-specific B cells are necessary during systemic, but not mucosal, parasite challenge.

Broadly reactive human CD8 T cells that recognize an epitope conserved between VZV, HSV and EBV.

Human herpesviruses are important causes of potentially severe chronic infections for which T cells are believed to be necessary for control. In order to examine the role of virus-specific CD8 T cells against Varicella Zoster Virus (VZV), we generated a comprehensive panel of potential epitopes predicted in silico and screened for T cell responses in healthy VZV seropositive donors. We identified a dominant HLA-A*0201-restricted epitope in the VZV ribonucleotide reductase subunit 2 and used a tetramer to analyze the phenotype and function of epitope-specific CD8 T cells. Interestingly, CD8 T cells responding to this VZV epitope also recognized homologous epitopes, not only in the other α-herpesviruses, HSV-1 and HSV-2, but also the γ-herpesvirus, EBV. Responses against these epitopes did not depend on previous infection with the originating virus, thus indicating the cross-reactive nature of this T cell population. Between individuals, the cells demonstrated marked phenotypic heterogeneity. This was associated with differences in functional capacity related to increased inhibitory receptor expression (including PD-1) along with decreased expression of co-stimulatory molecules that potentially reflected their stimulation history. Vaccination with the live attenuated Zostavax vaccine did not efficiently stimulate a proliferative response in this epitope-specific population. Thus, we identified a human CD8 T cell epitope that is conserved in four clinically important herpesviruses but that was poorly boosted by the current adult VZV vaccine. We discuss the concept of a "pan-herpesvirus" vaccine that this discovery raises and the hurdles that may need to be overcome in order to achieve this.

Human Trafficking in Correctional Institutions: A Survey of Correctional and Anti-Trafficking Leaders.

Growing awareness of the overlap between justice involvement and human trafficking victimization has led to calls for correctional institutions to prevent, identify, and respond to trafficking. However, it is unclear how correctional facilities (i.e., jails and prisons) are responding to such calls to action. To examine current efforts to address human trafficking in U.S. correctional facilities, this study surveyed correctional and anti-trafficking leaders (n = 46) about their perceptions and experiences with human trafficking screening, response, and training in correctional facilities. Although the majority of leaders (89%) agreed individuals in their state's correctional facilities have experienced human trafficking, they generally did not perceive that correctional staff were prepared to respond. Bivariate tests revealed that correctional and anti-trafficking leaders differed on their perceptions regarding correctional staffs' knowledge about human trafficking risk factors (p = .014), identification ability (p = .006), and response knowledge (p = .036), with anti-trafficking leaders perceiving correctional staff to be less prepared in these areas. Approximately 16% of leaders reported strategies to identify and respond to trafficking in correctional facilities, and about 27% reported human trafficking training for corrections staff. To promote a just society, study findings offer preliminary guidance for anti-trafficking correctional initiatives and future research.

Antigen-specific TGF-ß-induced regulatory T cells secrete chemokines, regulate T cell trafficking, and suppress ongoing autoimmunity.

The ability to regulate ongoing inflammation using regulatory T cells (Tregs) is under intense investigation. Strategies to induce and expand Ag-specific Tregs are being developed, and whether various types of Tregs are suppressive in the inflammatory conditions associated with ongoing disease needs to be determined. In this study, we report that TGF-ß-induced Tregs (iTregs) and expanded Tregs specific for a major self-Ag in autoimmune gastritis suppress inflammation and associated pathology when administered late in the process of ongoing disease. Transferred iTregs localized to the stomach, maintained Foxp3 and suppressor functions, and engaged several distinct mechanisms to alleviate disease progression. In addition to suppressing the production of inflammatory cytokines in the stomach and preventing the destruction of parietal cells, we show that iTregs secrete numerous chemokines and regulate both iTreg and effector T cell trafficking into the stomach. These data support efforts to use iTregs in therapies to treat autoimmunity and inflammatory diseases and provide novel insight into the biological mechanisms of iTreg-mediated immune suppression.

Importance of the CCR5-CCL5 axis for mucosal Trypanosoma cruzi protection and B cell activation.

Trypanosoma cruzi is an intracellular parasite and the causative agent of Chagas disease. Previous work has shown that the chemokine receptor CCR5 plays a role in systemic T. cruzi protection. We evaluated the importance of CCR5 and CCL5 for mucosal protection against natural oral and conjunctival T. cruzi challenges. T. cruzi-immune CCR5(-/-) and wild-type C57BL/6 mice were generated by repeated infectious challenges with T. cruzi. CCR5(-/-) and wild-type mice developed equivalent levels of cellular, humoral, and protective mucosal responses. However, CCR5(-/-)-immune mice produced increased levels of CCL5 in protected gastric tissues, suggesting compensatory signaling through additional receptors. Neutralization of CCL5 in CCR5(-/-)-immune mice resulted in decreased mucosal inflammatory responses, reduced T. cruzi-specific Ab-secreting cells, and significantly less mucosal T. cruzi protection, confirming an important role for CCL5 in optimal immune control of T. cruzi replication at the point of initial mucosal invasion. To investigate further the mechanism responsible for mucosal protection mediated by CCL5-CCR5 signaling, we evaluated the effects of CCL5 on B cells. CCL5 enhanced proliferation and IgM secretion in highly purified B cells triggered by suboptimal doses of LPS. In addition, neutralization of endogenous CCL5 inhibited B cell proliferation and IgM secretion during stimulation of highly purified B cells, indicating that B cell production of CCL5 has important autocrine effects. These findings demonstrate direct effects of CCL5 on B cells, with significant implications for the development of mucosal adjuvants, and further suggest that CCL5 may be important as a general B cell coactivator.

Comparison of the infectivity of Trypanosoma cruzi insect-derived metacyclic trypomastigotes after mucosal and cutaneous contaminative challenges.

Trypanosoma cruzi infects humans when infected triatomine vector excreta contaminate breaks in skin or mucosal surfaces. T. cruzi insect-derived metacyclic trypomastigotes (IMT) invade through gastric mucosa after oral challenges without any visible inflammatory changes, while cutaneous and conjunctival infections result in obvious local physical signs. In this study we compared the infectivity of T. cruzi IMT in mice after cutaneous and oral contaminative challenges simulating natural infections. The 50% infective dose (ID50) for oral challenge was 100 fold lower than the ID50 for cutaneous challenge, indicating that oral mucosal transmission is more efficient than cutaneous transmission.

Treatment and life goals among veterans with Gulf War illness.

Medically unexplained syndromes (MUS), also termed persistent physical symptoms, are both prevalent and disabling. Yet treatments for MUS are marked by high rates of patient dissatisfaction, as well as disagreement between patients and providers on the management of persistent physical symptoms. A better understanding of patient-generated goals could increase collaborative goal setting and promote person-centered care, a critical component of MUS treatment; yet research in this area is lacking. This paper aimed to develop a typology of treatment and life goals among Gulf War veterans with a medically unexplained syndrome (Gulf War Illness). We examined participants' responses to open-ended questions about treatment and life goals using Braun and Clarke's thematic analysis methodology. Results showed that treatment goals could be categorized into four overarching themes: 1) Get better/healthier, 2) Improve quality of life, 3) Improve or seek additional treatment, and 4) Don't know/Don't have any. Life goals were categorized into six overarching themes: 1) Live a fulfilling life, 2) Live a happy life, 3) Live a healthy life, 4) Be productive/financially successful, 5) Manage GWI, and 6) Don't know/Don't have any. Treatment goals were largely focused on getting better/healthier (e.g., improving symptoms), whereas life goals focused on living a fulfilling life. Implications for the treatment of Gulf War Illness and patient-provider communication are discussed. ClinicalTrials.gov Identifier: NCT02161133.

Phage-derived anti-idiotype and anti-YTE antibodies in development of MK-1654 pharmacokinetic and immune response assays.

Background: MK-1654 is a fully human monoclonal antibody with YTE mutations currently in phase III clinical trials for prophylactic use in protecting infants from human respiratory syncytial virus infection. Materials & methods: We generated anti-idiotype (anti-ID) and anti-YTE antibodies against MK-1654 by panning with MorphoSys HuCal phage libraries, and used the antibodies in the development of MK-1654 pharmacokinetic (PK) and immune response (IR) assays. Results: Detection of MK-1654 in nonhuman primate and human nasal wash samples showed combined use of anti-ID and anti-YTE antibodies can deliver desired sensitivity and accuracy in PK studies. IR studies showed anti-ID can serve as suitable positive control in neutralizing antibody assays. Conclusion: Phage-derived anti-IDs and anti-YTEs are suitable for PK and IR assays.

Randomized controlled trial protocol of health coaching for veterans with complex chronic pain.

BACKGROUND: Pain predominant multisymptom illness (pain-CMI) refers to symptom-based conditions where pain is a primary symptom. There is initial evidence that health coaching may be efficacious in treating pain-CMI because it can be tailored to the veteran's goals and emphasizes long-term behavior change, which may indirectly impact the maintaining factors of pain-CMI (e.g., catastrophizing, poor pain control, and limited activity). This paper describes the study protocol and rationale of a randomized controlled trial that will compare the efficacy of remote-delivered health coaching in reducing disability and pain impairment for veterans with pain-CMI to remote-delivered supportive psychotherapy. METHODS: This randomized controlled trial will consist of two treatment arms: remote-delivered health coaching and remote-delivered supportive psychotherapy, the active control. Each treatment condition will consist of twelve, weekly one-on-one meetings with a study provider. In addition to the baseline assessment, participants will also complete 6-week (mid-treatment), 12-week (post-treatment), and 24-week (follow-up) assessments that consist of questionnaires that can be completed remotely. The primary aims for this study are to determine whether health coaching reduces disability and pain impairment as compared to supportive psychotherapy. We will also examine whether health coaching reduces physical symptoms, catastrophizing, limiting activity, and increasing pain control as compared to supportive psychotherapy. DISCUSSION: This study will contribute to the existing literature on pain-CMI and report the effectiveness of a novel, remote-delivered behavioral intervention.