Structural Remodeling of the Human Colonic Mesenchyme in Inflammatory Bowel Disease.

Intestinal mesenchymal cells play essential roles in epithelial homeostasis, matrix remodeling, immunity, and inflammation. But the extent of heterogeneity within the colonic mesenchyme in these processes remains unknown. Using unbiased single-cell profiling of over 16,500 colonic mesenchymal cells, we reveal four subsets of fibroblasts expressing divergent transcriptional regulators and functional pathways, in addition to pericytes and myofibroblasts. We identified a niche population located in proximity to epithelial crypts expressing SOX6, F3 (CD142), and WNT genes essential for colonic epithelial stem cell function. In colitis, we observed dysregulation of this niche and emergence of an activated mesenchymal population. This subset expressed TNF superfamily member 14 (TNFSF14), fibroblastic reticular cell-associated genes, IL-33, and Lysyl oxidases. Further, it induced factors that impaired epithelial proliferation and maturation and contributed to oxidative stress and disease severity in vivo. Our work defines how the colonic mesenchyme remodels to fuel inflammation and barrier dysfunction in IBD.

Histone H3K27me3 demethylases regulate human Th17 cell development and effector functions by impacting on metabolism.

T helper (Th) cells are CD4+ effector T cells that play a critical role in immunity by shaping the inflammatory cytokine environment in a variety of physiological and pathological situations. Using a combined chemico-genetic approach, we identify histone H3K27 demethylases KDM6A and KDM6B as central regulators of human Th subsets. The prototypic KDM6 inhibitor GSK-J4 increases genome-wide levels of the repressive H3K27me3 chromatin mark and leads to suppression of the key transcription factor RORγt during Th17 differentiation. In mature Th17 cells, GSK-J4 induces an altered transcriptional program with a profound metabolic reprogramming and concomitant suppression of IL-17 cytokine levels and reduced proliferation. Single-cell analysis reveals a specific shift from highly inflammatory cell subsets toward a resting state upon demethylase inhibition. The root cause of the observed antiinflammatory phenotype in stimulated Th17 cells is reduced expression of key metabolic transcription factors, such as PPRC1. Overall, this leads to reduced mitochondrial biogenesis, resulting in a metabolic switch with concomitant antiinflammatory effects. These data are consistent with an effect of GSK-J4 on Th17 T cell differentiation pathways directly related to proliferation and include regulation of effector cytokine profiles. This suggests that inhibiting KDM6 demethylases may be an effective, even in the short term, therapeutic target for autoimmune diseases, including ankylosing spondylitis.

Designing a Framework for Remote Cancer Care Through Community Co-design: Participatory Development Study.

BACKGROUND: Recent shifts to telemedicine and remote patient monitoring demonstrate the potential for new technology to transform health systems; yet, methods to design for inclusion and resilience are lacking. OBJECTIVE: The aim of this study is to design and implement a participatory framework to produce effective health care solutions through co-design with diverse stakeholders. METHODS: We developed a design framework to cocreate solutions to locally prioritized health and communication problems focused on cancer care. The framework is premised on the framing and discovery of problems through community engagement and lead-user innovation with the hypothesis that diversity and inclusion in the co-design process generate more innovative and resilient solutions. Discovery, design, and development were implemented through structured phases with design studios at various locations in urban and rural Kentucky, including Appalachia, each building from prior work. In the final design studio, working prototypes were developed and tested. Outputs were assessed using the System Usability Scale as well as semistructured user feedback. RESULTS: We co-designed, developed, and tested a mobile app (myPath) and service model for distress surveillance and cancer care coordination following the LAUNCH (Linking and Amplifying User-Centered Networks through Connected Health) framework. The problem of awareness, navigation, and communication through cancer care was selected by the community after framing areas for opportunity based on significant geographic disparities in cancer and health burden resource and broadband access. The codeveloped digital myPath app showed the highest perceived combined usability (mean 81.9, SD 15.2) compared with the current gold standard of distress management for patients with cancer, the paper-based National Comprehensive Cancer Network Distress Thermometer (mean 74.2, SD 15.8). Testing of the System Usability Scale subscales showed that the myPath app had significantly better usability than the paper Distress Thermometer (t63=2.611; P=.01), whereas learnability did not differ between the instruments (t63=-0.311; P=.76). Notable differences by patient and provider scoring and feedback were found. CONCLUSIONS: Participatory problem definition and community-based co-design, design-with methods, may produce more acceptable and effective solutions than traditional design-for approaches.

Olfactory and Neuropsychological Functioning in Olfactory Reference Syndrome.

BACKGROUND: Olfactory reference syndrome (ORS) is an underrecognized, understudied, and often severe psychiatric disorder characterized by a prominent and distressing or impairing preoccupation with a false belief of emitting an offensive body odor. As this condition has only recently been recognized in the International Classification of Diseases (the 11th Edition), no empirical evidence exists about the underlying features and etiology of the disorder. OBJECTIVE: To examine the neuropsychological and olfactory functioning of individuals with ORS and address whether there is central nervous system or sensory dysfunction associated with the condition. METHODS: In this preliminary investigation, 9 consecutive participants with ORS completed a structured clinical interview and neuropsychological and olfaction evaluations. RESULTS: A proportion of individuals with ORS displayed deficits in aspects of cognitive functioning (i.e., processing speed, executive functioning, recognition memory bias for ORS-related words), olfaction functioning (i.e., odor detection and discrimination), and emotional processing. CONCLUSIONS: Based on these preliminary findings of cognitive, olfaction, and emotional processing deficits in individuals with ORS, further neuropsychological and olfaction studies are needed that better characterize this understudied patient group and address this study's limitations.

Cognitive Impairment in Men with Prostate Cancer Treated with Androgen Deprivation Therapy: A Systematic Review and Meta-Analysis.

PURPOSE: Use of androgen deprivation therapy may increase the risk of cognitive impairment in men with prostate cancer. We performed a systematic review of the risk of overall cognitive impairment as an outcome in men receiving androgen deprivation therapy for prostate cancer. MATERIALS AND METHODS: Studies were identified through PubMed®, MEDLINE®, PsycINFO®, Cochrane Library and Web of Knowledge/Science™. Articles were included if they 1) were published in English, 2) had subjects treated for prostate cancer with androgen deprivation therapy, 3) incorporated longitudinal comparisons and 4) used control groups. In addition, prospective studies were required to assess an established cognitive related end point using International Cognition and Cancer Task Force criteria defining impaired cognitive performance as scoring 1.5 or more standard deviations below published norms on 2 or more tests, or scoring 2.0 or more standard deviations below published norms on at least 1 test. The effect of androgen deprivation therapy on cognitive impairment was pooled using a random effects model. RESULTS: Of 221 abstracts 26 were selected for full text review, and 2 prospective and 4 retrospective studies were analyzed. Androgen deprivation therapy was not associated with overall cognitive impairment when the prospective cohort studies were pooled (OR 1.57, 95% CI 0.50 to 4.92, p = 0.44) with significant heterogeneity between estimates (I2 = 83%). In retrospective data the relative risk of any cognitive impairment, including senile dementia and Alzheimer disease, was increased in men receiving androgen deprivation therapy, although the difference was not statistically significant (HR 1.28, 95% CI 0.93 to 1.76, p = 0.13) with moderate heterogeneity between estimates (I2 = 67%). CONCLUSIONS: Analyses between overall cognitive impairment and use of androgen deprivation therapy defined according to International Cognition and Cancer Task Force criteria in a pooled analysis were inconclusive. In retrospective cohort studies the risk of overall cognitive impairment after androgen deprivation therapy was not significant. Better prospective studies need to be designed for the assessment of this end point.

Neuropsychological assessment without upper limb involvement: a systematic review of oral versions of the Trail Making Test and Symbol-Digit Modalities Test.

The Trail Making Test (TMT) and written version of the Symbol Digit Modalities Test (SDMT) assess attention, processing speed, and executive functions but their utility is limited in populations with upper limb dysfunction. Oral versions of the TMT and SDMT exist, but a systematic review of their psychometric properties and clinical utility has not been conducted, which was the goal of this study. Searches were conducted in PubMed and PsycINFO, test manuals, and the reference lists of included articles. Four measures were identified: the SDMT-oral, oral TMT-A, oral TMT-B, and the Mental Alternation Test (MAT). Two investigators independently reviewed abstracts to identify peer-reviewed articles that reported on these measures in adult populations. From each article, one investigator extracted information on reliability, validity, responsiveness, minimum detectable change, normative data, and demographic influences. A second investigator verified the accuracy of the data in a random selection of 10% of papers. The quality of the evidence for each psychometric property was rated on a 4-point scale (unknown, poor, adequate, excellent). Results showed excellent evidence for the SDMT-oral, adequate evidence for the oral TMT-B and MAT, and adequate to poor evidence for the oral TMT-A. These findings inform the clinical assessment of attention, processing speed, and executive functions in individuals with upper limb disability.

Behavior change interventions: the potential of ontologies for advancing science and practice.

A central goal of behavioral medicine is the creation of evidence-based interventions for promoting behavior change. Scientific knowledge about behavior change could be more effectively accumulated using "ontologies." In information science, an ontology is a systematic method for articulating a "controlled vocabulary" of agreed-upon terms and their inter-relationships. It involves three core elements: (1) a controlled vocabulary specifying and defining existing classes; (2) specification of the inter-relationships between classes; and (3) codification in a computer-readable format to enable knowledge generation, organization, reuse, integration, and analysis. This paper introduces ontologies, provides a review of current efforts to create ontologies related to behavior change interventions and suggests future work. This paper was written by behavioral medicine and information science experts and was developed in partnership between the Society of Behavioral Medicine's Technology Special Interest Group (SIG) and the Theories and Techniques of Behavior Change Interventions SIG. In recent years significant progress has been made in the foundational work needed to develop ontologies of behavior change. Ontologies of behavior change could facilitate a transformation of behavioral science from a field in which data from different experiments are siloed into one in which data across experiments could be compared and/or integrated. This could facilitate new approaches to hypothesis generation and knowledge discovery in behavioral science.

The Relationship of Hypochondriasis to Anxiety, Depressive, and Somatoform Disorders.

BACKGROUND: Though the phenotype of anxiety about medical illness has long been recognized, there continues to be debate as to whether it is a distinct psychiatric disorder and, if so, to which diagnostic category it belongs. OBJECTIVE: Our objective was to investigate the pattern of psychiatric comorbidity in hypochondriasis (HC) and to assess the relationship of health anxiety to anxiety, depressive, and somatoform disorders. METHODS: Data were collected as part of a clinical trial on treatment methods for HC. In all, 194 participants meeting criteria for Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) HC were assessed by sociodemographic variables, results of structured diagnostic interviews, and validated instruments for assessing various symptom dimensions of psychopathology. RESULTS: Most of the individuals with HC had comorbid psychiatric illness; the mean number of comorbid diagnoses was 1.4, and 35.1% had HC as their only diagnosis. Participants were more likely to have only comorbid anxiety disorders than only comorbid depressive or somatoform disorders. Multiple regression analysis of continuous measures of symptoms revealed the strongest correlation of health anxiety with anxiety symptoms, and a weaker correlation with somatoform symptoms; in multiple regression analysis, there was no correlation between health anxiety and depressive symptoms. CONCLUSION: Our findings suggest that the entity of health anxiety (HC in DSM-IV and illness anxiety disorder in DSM-5) is a clinical syndrome distinct from other psychiatric disorders. Analysis of comorbidity patterns and continuous measures of symptoms suggest that its appropriate classification is with anxiety rather than somatoform or mood disorders.

Balance between activating NKG2D, DNAM-1, NKp44 and NKp46 and inhibitory CD94/NKG2A receptors determine natural killer degranulation towards rheumatoid arthritis synovial fibroblasts.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation and synovial hyperplasia leading to progressive joint destruction. Fibroblast-like synoviocytes (FLS) are central components of the aggressive, tumour-like synovial structure termed pannus, which invades the joint space and cartilage. A distinct natural killer (NK) cell subset expressing the inhibitory CD94/NKG2A receptor is present in RA synovial fluid. Little is known about possible cellular interactions between RA-FLS and NK cells. We used cultured RA-FLS and the human NK cell line Nishi, of which the latter expresses an NK receptor repertoire similar to that of NK cells in RA synovial fluid, as an in vitro model system of RA-FLS/NK cell cross-talk. We show that RA-FLS express numerous ligands for both activating and inhibitory NK cell receptors, and stimulate degranulation of Nishi cells. We found that NKG2D, DNAM-1, NKp46 and NKp44 are the key activating receptors involved in Nishi cell degranulation towards RA-FLS. Moreover, blockade of the interaction between CD94/NKG2A and its ligand HLA-E expressed on RA-FLS further enhanced Nishi cell degranulation in co-culture with RA-FLS. Using cultured RA-FLS and the human NK cell line Nishi as an in vitro model system of RA-FLS/NK cell cross-talk, our results suggest that cell-mediated cytotoxicity of RA-FLS may be one mechanism by which NK cells influence local joint inflammation in RA.

Enhancing patient engagement and blood pressure management for renal transplant recipients via home electronic monitoring and web-enabled collaborative care.

BACKGROUND: Effective management of hypertension in chronic kidney disease and renal transplantation is a clinical priority and has societal implications in terms of preserving and optimizing the value of scarce organs. However, hypertension is optimally managed in only 37% of people with chronic kidney disease, and poor control can contribute to premature graft loss in renal transplant recipients. This article describes a telehealth system that incorporates home electronic blood pressure (BP) monitoring and uploading to a patient portal coupled with a Web-based dashboard that enables clinical pharmacist collaborative care in a renal transplant clinic. MATERIALS AND METHODS: The telehealth system was developed and implemented as a quality improvement initiative in a renal transplant clinic in a large, 700-bed, urban hospital with the aim of improving BP in posttransplant patients. A convenience sample of 66 posttransplant patients was recruited by the clinical pharmacist from consecutive referrals to the Transplant Clinic. RESULTS: Preliminary results show statistically significant reductions in average systolic and diastolic BP of 6.0 mm Hg and 3.0 mm Hg, respectively, at 30 days after enrollment. Two case reports describe the instrumental role of home BP monitoring in the context of medication therapy management. CONCLUSIONS: Optimizing BP control for both pre- and post-renal transplant patients is likely to benefit society in terms of preserving scarce resources and reducing healthcare costs due to premature graft failure. Connected health systems hold great promise for supporting team-based care and improved health outcomes.

A randomized trial of treatments for high-utilizing somatizing patients.

BACKGROUND: Somatization and hypochondriacal health anxiety are common sources of distress, impairment, and costly medical utilization in primary care practice. A range of interventions is needed to improve the care of these patients. OBJECTIVE: To determine the effectiveness of two cognitive behavioral interventions for high-utilizing, somatizing patients, using the resources found in a routine care setting. DESIGN: Patients were randomly assigned to a two-step cognitive behavioral treatment program accompanied by a training seminar for their primary care physicians, or to relaxation training. Providers routinely working in these patients' primary care practices delivered the cognitive behavior therapy and relaxation training. A follow-up assessment was completed immediately prior to treatment and 6 and 12 months later. SUBJECTS: Eighty-nine medical outpatients with elevated levels of somatization, hypochondriacal health anxiety, and medical care utilization. MEASUREMENTS: Somatization and hypochondriasis, overall psychiatric distress, and role impairment were assessed with well-validated, self-report questionnaires. Outpatient visits and medical care costs before and after the intervention were obtained from the encounter claims database. RESULTS: At 6 month and 12 month follow-up, both intervention groups showed significant improvements in somatization (p < 0.01), hypochondriacal symptoms (p < 0.01), overall psychiatric distress (p < 0.01), and role impairment (p < 0.01). Outcomes did not differ significantly between the two groups. When both groups were combined, ambulatory visits declined from 10.3 to 8.8 (p = 0.036), and mean ambulatory costs decreased from $3,574 to $2,991 (pp = 0.028) in the year preceding versus the year following the interventions. Psychiatric visits and costs were unchanged. CONCLUSIONS: Two similar cognitive behavioral interventions, delivered with the resources available in routine primary care, improved somatization, hypochondriacal symptoms, overall psychiatric distress, and role function. They also reduced the ambulatory visits and costs of these high utilizing outpatients.

CXCR4 and vascular cell adhesion molecule 1 are key chemokine/adhesion receptors in the migration of cytokine-activated T cells.

OBJECTIVE: To examine the migratory properties of cytokine-activated T (Tck) cells. METHODS: Tck cells were generated by culture of peripheral blood T cells in the presence of interleukin-6 (IL-6), tumor necrosis factor α, and IL-2. Changes in cell surface phenotype were analyzed by flow cytometry. Chemotactic responsiveness was measured using in vitro chemotaxis assays and transendothelial migration through human umbilical vein endothelial cell monolayers. Levels of vascular cell adhesion molecule 1 (VCAM-1) were measured by sandwich enzyme-linked immunosorbent assay. RESULTS: Cytokine stimulation up-regulated the expression of chemokine receptors and integrins on Tck cells, including CXCR4, very late activation antigen 4 (VLA-4), and lymphocyte function-associated antigen 1. Increased expression of CXCR4 and VLA-4 integrin resulted in concentration-dependent chemotaxis to their ligands, stromal cell-derived factor 1 (SDF-1) and VCAM-1, which could be selectively blocked using a specific CXCR4 inhibitor and antibodies against VLA-4. Increased expression of VLA-4 also resulted in increased transendothelial migration of Tck cells, which could be abrogated using blocking antibodies against VLA-4. Tck cells also showed an increased chemotactic response to rheumatoid arthritis (RA) fibroblast-like synoviocytes cultured in vitro, which could be blocked using inhibitors against VLA-4 and CXCR4. CONCLUSION: The activated phenotype of Tck cells results in increased migratory responsiveness to SDF-1 and soluble VCAM-1, which are among the chemokines and proteins found elevated in the RA synovial joint environment. Cytokine-dependent activation may contribute to RA pathogenicity by promoting T cell recruitment to and retention in the joint, perpetuating the inflammatory cascade in RA.

The study design and rationale of the randomized controlled trial: translating COPD guidelines into primary care practice.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a progressive, debilitating disease associated with significant clinical burden and is estimated to affect 15 million individuals in the US. Although a large number of individuals are diagnosed with COPD, many individuals still remain undiagnosed due to the slow progression of the disorder and lack of recognition of early symptoms. Not only is there under-diagnosis but there is also evidence of sub-optimal evidence-based treatment of those who have COPD. Despite the development of international COPD guidelines, many primary care physicians who care for the majority of patients with COPD are not translating this evidence into effective clinical practice. METHOD/DESIGN: This paper describes the design and rationale for a randomized, cluster design trial (RCT) aimed at translating the COPD evidence-based guidelines into clinical care in primary care practices. During Phase 1, a needs assessment evaluated barriers and facilitators to implementation of COPD guidelines into clinical practice through focus groups of primary care patients and providers. Using formative evaluation and feedback from focus groups, three tools were developed. These include a computerized patient activation tool (an interactive iPad with wireless data transfer to the spirometer); a web-based COPD guideline tool to be used by primary care providers as a decision support tool; and a COPD patient education toolkit to be used by the practice team. During phase II, an RCT will be performed with one year of intervention within 30 primary care practices. The effectiveness of the materials developed in Phase I are being tested in Phase II regarding physician performance of COPD guideline implementation and the improvement in the clinically relevant outcomes (appropriate diagnosis and management of COPD) compared to usual care. We will also examine the use of a patient activation tool - 'MyLungAge' - to prompt patients at risk for or who have COPD to request spirometry confirmation and to request support for smoking cessation if a smoker. DISCUSSION: Using a multi-modal intervention of patient activation and a technology-supported health care provider team, we are testing the effectiveness of this intervention in activating patients and improving physician performance around COPD guideline implementation. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01237561.

Digitally Assisted Peer Recovery Coach to Facilitate Linkage to Outpatient Treatment Following Inpatient Alcohol Withdrawal Treatment: Proof-of-Concept Pilot Study.

BACKGROUND: Alcohol use disorder (AUD), associated with significant morbidity and mortality, continues to be a major public health problem. The COVID-19 pandemic exacerbated the impact of AUD, with a 25% increase in alcohol-related mortality from 2019 to 2020. Thus, innovative treatments for AUD are urgently needed. While inpatient alcohol withdrawal management (detoxification) is often an entry point for recovery, most do not successfully link to ongoing treatment. Transitions between inpatient and outpatient treatment pose many challenges to successful treatment continuation. Peer recovery coaches-individuals with the lived experience of recovery who obtain training to be coaches-are increasingly used to assist individuals with AUD and may provide a degree of continuity during this transition. OBJECTIVE: We aimed to evaluate the feasibility of using an existing care coordination app (Lifeguard) to assist peer recovery coaches in supporting patients after discharge and facilitating linkage to care. METHODS: This study was conducted on an American Society of Addiction Medicine-Level IV inpatient withdrawal management unit within an academic medical center in Boston, MA. After providing informed consent, participants were contacted by the coach through the app, and after discharge, received daily prompts to complete a modified version of the brief addiction monitor (BAM). The BAM inquired about alcohol use, risky, and protective factors. The coach sent daily motivational texts and appointment reminders and checked in if BAM responses were concerning. Postdischarge follow-up continued for 30 days. The following feasibility outcomes were evaluated: (1) proportion of participants engaging with the coach before discharge, (2) proportion of participants and the number of days engaging with the coach after discharge, (3) proportion of participants and the number of days responding to BAM prompts, and (4) proportion of participants successfully linking with addiction treatment by 30-day follow-up. RESULTS: All 10 participants were men, averaged 50.5 years old, and were mostly White (n=6), non-Hispanic (n=9), and single (n=8). Overall, 8 participants successfully engaged with the coach prior to discharge. Following discharge, 6 participants continued to engage with the coach, doing so on an average of 5.3 days (SD 7.3, range 0-20 days); 5 participants responded to the BAM prompts during the follow-up, doing so on an average of 4.6 days (SD 6.9, range 0-21 days). Half (n=5) successfully linked with ongoing addiction treatment during the follow-up. The participants who engaged with the coach post discharge, compared to those who did not, were significantly more likely to link with treatment (83% vs 0%, χ2=6.67, P=.01). CONCLUSIONS: The results demonstrated that a digitally assisted peer recovery coach may be feasible in facilitating linkage to care following discharge from inpatient withdrawal management treatment. Further research is warranted to evaluate the potential role for peer recovery coaches in improving postdischarge outcomes. TRIAL REGISTRATION: ClinicalTrials.gov NCT05393544; https://www.clinicaltrials.gov/ct2/show/NCT05393544.

Mass cytometry as a tool in target validation and drug discovery.

Mass cytometry provides highly multiparametric data at a single cell level, coupling the specificity and sensitivity of time-of-flight mass spectrometry with the single-cell throughput of flow cytometry. It offers great value in interrogating the potentially heterogenous impact that a drug may have on a biological system, allowing an investigator to capture not just changes in cell behavior, but how these changes may differ between cell subtypes. In this chapter, we review the technical details of the platform as well as its limitations, before describing our approach to planning and running a mass cytometry experiment. A series of method modules, spanning the staining process through to data cleaning, are described that are then combined to create three separate experiments. The first experiment illustrates a core process in mass cytometry: the validation and titration of a metal-conjugated antibody reporter. The second experiment explores the impact of a kinase inhibitor on cell cycle and apoptosis pathways of a human myeloma cell line. And the third experiment exploits the multiparametric capability of mass cytometry, by exploring the differential expression changes in a transcription factor upon drug treatment across the cellular compartments of a peripheral blood mononuclear cell sample.

Myeloid CD40 deficiency reduces atherosclerosis by impairing macrophages' transition into a pro-inflammatory state.

AIMS: CD40 and its ligand, CD40L, play a critical role in driving atherosclerotic plaque development. Disrupted CD40-signalling reduces experimental atherosclerosis and induces a favourable stable plaque phenotype. We recently showed that small molecule-based inhibition of CD40-tumour necrosis factor receptor associated factor-6 interactions attenuates atherosclerosis in hyperlipidaemic mice via macrophage-driven mechanisms. The present study aims to detail the function of myeloid CD40 in atherosclerosis using myeloid-specific CD40-deficient mice. METHOD AND RESULTS: Cd40flox/flox and LysM-cre Cd40flox/flox mice on an Apoe-/- background were generated (CD40wt and CD40mac-/-, respectively). Atherosclerotic lesion size, as well as plaque macrophage content, was reduced in CD40mac-/- compared to CD40wt mice, and their plaques displayed a reduction in necrotic core size. Transcriptomics analysis of the CD40mac-/- atherosclerotic aorta revealed downregulated pathways of immune pathways and inflammatory responses. Loss of CD40 in macrophages changed the representation of aortic macrophage subsets. Mass cytometry analysis revealed a higher content of a subset of alternative or resident-like CD206+CD209b- macrophages in the atherosclerotic aorta of CD40mac-/- compared to CD40wt mice. RNA-sequencing of bone marrow-derived macrophages of CD40mac-/- mice demonstrated upregulation of genes associated with alternatively activated macrophages (including Folr2, Thbs1, Sdc1, and Tns1). CONCLUSIONS: We here show that absence of CD40 signalling in myeloid cells reduces atherosclerosis and limits systemic inflammation by preventing a shift in macrophage polarization towards pro-inflammatory states. Our study confirms the merit of macrophage-targeted inhibition of CD40 as a valuable therapeutic strategy to combat atherosclerosis.

Single cell spatial analysis reveals inflammatory foci of immature neutrophil and CD8 T cells in COVID-19 lungs.

Single cell spatial interrogation of the immune-structural interactions in COVID -19 lungs is challenging, mainly because of the marked cellular infiltrate and architecturally distorted microstructure. To address this, we develop a suite of mathematical tools to search for statistically significant co-locations amongst immune and structural cells identified using 37-plex imaging mass cytometry. This unbiased method reveals a cellular map interleaved with an inflammatory network of immature neutrophils, cytotoxic CD8 T cells, megakaryocytes and monocytes co-located with regenerating alveolar progenitors and endothelium. Of note, a highly active cluster of immature neutrophils and CD8 T cells, is found spatially linked with alveolar progenitor cells, and temporally with the diffuse alveolar damage stage. These findings offer further insights into how immune cells interact in the lungs of severe COVID-19 disease. We provide our pipeline [Spatial Omics Oxford Pipeline (SpOOx)] and visual-analytical tool, Multi-Dimensional Viewer (MDV) software, as a resource for spatial analysis.

Blockade of NKG2D ameliorates disease in mice with collagen-induced arthritis: a potential pathogenic role in chronic inflammatory arthritis.

OBJECTIVE: To assess the role of the activating receptor NKG2D in arthritis. METHODS: Levels of NKG2D and its ligands were determined by fluorescence-activated cell sorting, real-time polymerase chain reaction, and immunohistochemistry in rheumatoid arthritis (RA) synovial membrane tissue and in paw tissue from arthritic mice. Arthritis was induced in DBA/1 mice by immunization with type II collagen, and mice were treated intraperitoneally with a blocking anti-NKG2D antibody (CX5) on days 1, 5, and 8 after clinical onset and were monitored for 10 days. RESULTS: We demonstrated expression of NKG2D and its ligands on human RA synovial cells and extended this finding to the paws of arthritic mice. Expression of messenger RNA for the NKG2D ligand Rae-1 was up-regulated, and NKG2D was present predominantly on natural killer (NK) and CD4+ T cells, in arthritic paw cell isolates. NKG2D was down-modulated during the progression of collagen-induced arthritis (CIA). NKG2D expression in arthritic paws was demonstrated by immunohistochemistry. Blockade of NKG2D ameliorated established CIA, with significant reductions in clinical scores and paw swelling. Histologic analysis of arthritic joints from anti-NKG2D-treated mice demonstrated significant joint protection, compared with control mice. Moreover, anti-NKG2D treatment significantly reduced both interleukin-17 production from CD4+ T cells in arthritic paws and splenic NK cell cytotoxic effector functions in vivo and in vitro. CONCLUSION: Our findings indicate that blockade of NKG2D in a murine model and in human explants has beneficial therapeutic potential that merits further investigation in RA.

Responsiveness of hypochondriacal patients with chronic low-back pain to cognitive-behavioral therapy.

BACKGROUND: Evidence has suggested that cognitive-behavioral therapy (CBT) is effective in reducing hypochondriacal symptoms, and another line of evidence has suggested that CBT is also effective in reducing pain and the psychological conditions associated with chronic low-back pain (CLBP). The purpose of this study was to examine the effectiveness of CBT among hypochondriacal patients with and without CLBP. METHODS: A total of 182 hypochondriacal patients were randomly assigned to a CBT or control group. The Somatic Symptom Inventory was used to define CLBP, and the Symptom Checklist 90R (SCL90R) was used to assess psychological symptoms. The outcome measures for hypochondriasis, the Whiteley Index (WI) and the Health Anxiety Inventory (HAI) were administered before the intervention and at 6 and 12 months after completion of the intervention. RESULTS: In the total sample, both WI and HAI scores were significantly decreased after treatment in the CBT group compared with the control group. Ninety-three (51%) patients had CLBP; the SCL90R scores for somatization, depression, phobic anxiety, paranoid ideation, and general severity were significantly higher in CLBP(+) group than in the CLBP(-) group at baseline. Although the WI and HAI scores were significantly decreased after treatment in the CLBP(-) group, such significant pre- to post-changes were not found in the CLBP(+) group. CONCLUSIONS: CBT was certainly effective among hypochondriacal patients without CLBP, but it appeared to be insufficient for hypochondriacal patients with CLBP. The core psychopathology of hypochondriacal CLBP should be clarified to contribute to the adequate management of hypochondriacal symptoms in CLBP patients.

E-health blood pressure control program.

Both technological and human factors design requirements for integration of home blood pressure monitoring (HBPM) into a patient centered medical home (PCMH) model primary care practice are described. Patients with uncontrolled hypertension were given home blood pressure (BP) monitors, and after a three-month run-in period introduced to either a high-tech only (HBPM connectivity to personal health record and tailored Web portal access) or a high-tech/"high-touch" (high-tech solution plus patient navigator [PN]) solution. Features of the Web portal included: BP graphing function, traffic-light feedback system of BP goal attainment, economic incentives for self-monitoring, and dual patient-facing and care-team-facing dashboard functions. The e-health BP control system with PN support was well received by patients, providers, and the healthcare team. Current e-health technology and limited technological literacy of many patients suggest that a PN or some other personnel resource may be required for the adoption of patient-facing technology in primary care.