What's in a Name? Terminology Preferences Among Patients Receiving Methadone Treatment.

BACKGROUND: Despite recognition of the importance of substance use disorder (SUD) terminology, few studies examine terminology preferences among patients with SUDs. OBJECTIVE: To examine preferences of patients with opioid use disorder (OUD) concerning the terminology used by addiction counselors. DESIGN: From January 1, 2019, to February 28, 2020, participants were recruited consecutively from 30-day treatment review sessions at outpatient methadone treatment programs in the Northeastern United States to complete a cross-sectional survey. PARTICIPANTS: Participants were English-speaking adult patients with OUD enrolled in methadone treatment. MAIN MEASURES: Participants completed 7-point Likert-type scales from 1 ("Strongly Disagree") to 7 ("Strongly Agree") to rate their preferences for (a) the presenting problem, (b) collective nouns referring to those with the presenting problem, and (c) personal descriptors. We used univariate analysis of covariance (ANCOVA) to examine the associations between demographics (i.e., age, sex, and race) and terminology preferences and ordinal logit regression to explore the association between 12-step program partiality and preference for the term "addict." KEY RESULTS: We surveyed 450 patients with mean age of 38.5 (SD = 11.1) years; 59.6% self-identified as male, 77.6% as White, and 12.7% as Hispanic. The highest-rated preferences for presenting problem were "addiction," "substance use," and "substance abuse." The highest-rated collective noun terms were "client," "patient," and "guest." "Person with an addiction," "person with substance use disorder," and "substance-dependent person" were the highest-rated personal descriptors. There were significant differences in terminological preference based on race and age. Twelve-step program partiality was associated with greater preference for the term "addict" (F = 21.22, p < .001). CONCLUSIONS: Terminology preferences among people receiving methadone treatment aligned with existing guidelines recommending that clinicians use medically accurate and destigmatizing terminology when referring to substance use disorders and the persons who have them. Demographic differences emerged in terminological preferences, warranting further examination.

A Student Walks into Class Vignettes to Identify Substance Use Disorder Models of Illness among College Students.

INTRODUCTION: Illness models, including illness recognition, perceived severity, and perceived nature can affect treatment-seeking behaviors. Vignettes are a leading approach to examine models of illness but are understudied for substance use disorders (SUDs). We created vignettes for multiple common DSM-5 SUDs and assessed SUD illness models among college students. METHODS: Seven vignettes in which the protagonist meets DSM-5 diagnostic criteria for SUDs involving tobacco, alcohol, cannabis, Adderall, cocaine, Vicodin, and heroin were pilot tested and randomly assigned to 216 college students who completed measures related to illness recognition, perceived severity, and perceived nature. MANOVAs with Scheffe post-hoc tests were conducted to examine vignette group differences on models of illness. RESULTS: Vignettes met acceptable levels of clarity and plausibility. Participants characterized the protagonist's substance use as a problem, a SUD, or an addiction most frequently with Vicodin, heroin, and cocaine and least frequently with tobacco and cannabis. Participants assigned to the Vicodin, heroin, and cocaine vignettes were the most likely to view the protagonist's situation as serious and life-threatening, whereas those assigned to the cannabis vignette were the least likely. Numerically more participants characterized the pattern of substance use as a problem (91%) or an addiction (90%) than a SUD (76%), while only 15% characterized it as a chronic medical condition. CONCLUSIONS: Illness recognition and perceived severity varied across substances and were lowest for cannabis. Few participants conceptualized SUDs as chronic medical conditions. College students may benefit from psychoeducation regarding cannabis use disorder and the chronic medical condition model of SUDs.

Genetic variability in exon 1 of the glucocorticoid receptor gene NR3C1 is associated with postoperative complications.

Patients undergoing major surgery experience postoperative inflammation, which may contribute to postoperative morbidity. Endogenous glucocorticoids (GCs) are an essential part of the stress response, but this response varies between individuals, which may in turn affect clinical outcome and specifically postoperative inflammation. Exon 1 of the NR3C1 gene, encoding the GC receptor (GR), contains an established region of differential regulation. DNA methylation patterns in this region have been found to differ between individuals. The present study investigated the methylation status and genotype in the cytosine­phosphate­guanine (CpG) island in exon 1 of NR3C1 in 24 patients [Median age 65.5 (range 42­81) years, 11 male, 13 female] who underwent major abdominal (12 pancreatic, 12 hepatic) surgery and explored its association with postoperative complications. DNA was extracted from peripheral blood leukocytes and underwent targeted bisulfite sequencing of the CpG island. Complications were graded according to the Clavien­Dindo classification and 14 out of 24 patients had postoperative complications. Multifactorial and partial least square analyses were used to analyse the data. A homogenous demethylated pattern was observed in all patients and no single CpG methylation was associated with postoperative complications. Four SNPs were significantly associated with higher Clavien­Dindo scores. Genetic variability in the chromosome 5:143,402,505­143,405,805 region of exon 1 of the GR gene NR3C1, but not DNA methylation, was associated with more severe postoperative complications in patients having major abdominal surgery. These results indicated that the patients' response to GCs may be of clinical importance for inflammatory conditions.

Tumour-associated B cells in urothelial urinary bladder cancer.

Tumour infiltrating B cells and CD38+ plasma cells have been correlated with survival in different malignancies but their role in urinary bladder cancer is unclear. IL-10 is a multifunctional cytokine with both anti-inflammatory and immunostimulatory properties, that can be released by regulatory B cells (Bregs). We have stained paraffin-embedded tumour sections from 31 patients with invasive urothelial urinary bladder cancer with respect to CD20+ B cells, CD38+ cells, IL-10-expressing cells, IgG, C1q and C3a and analysed the impact of these markers on survival. Interestingly, we observe tumour-associated CD20+ B cells forming follicle-like structures in tumours of some patients. We demonstrate that follicle-like structures, tumour-associated CD38+ cells, IL-10 produced by non-B cells, tumour infiltrating IgG and activation of the complement system, may associate to longer survival of urinary bladder cancer patients. IL-10 expression by tumour-associated Bregs may instead negatively affect prognosis. More research is needed to fully understand the role of B cells and IL-10 in urinary bladder cancer.

Increased CD4+ T cell lineage commitment determined by CpG methylation correlates with better prognosis in urinary bladder cancer patients.

BACKGROUND: Urinary bladder cancer is a common malignancy worldwide. Environmental factors and chronic inflammation are correlated with the disease risk. Diagnosis is performed by transurethral resection of the bladder, and patients with muscle invasive disease preferably proceed to radical cystectomy, with or without neoadjuvant chemotherapy. The anti-tumour immune responses, known to be initiated in the tumour and draining lymph nodes, may play a major role in future treatment strategies. Thus, increasing the knowledge of tumour-associated immunological processes is important. Activated CD4+ T cells differentiate into four main separate lineages: Th1, Th2, Th17 and Treg, and they are recognized by their effector molecules IFN-γ, IL-13, IL-17A, and the transcription factor Foxp3, respectively. We have previously demonstrated signature CpG sites predictive for lineage commitment of these four major CD4+ T cell lineages. Here, we investigate the lineage commitment specifically in tumour, lymph nodes and blood and relate them to the disease stage and response to neoadjuvant chemotherapy. RESULTS: Blood, tumour and regional lymph nodes were obtained from patients at time of transurethral resection of the bladder and at radical cystectomy. Tumour-infiltrating CD4+ lymphocytes were significantly hypomethylated in all four investigated lineage loci compared to CD4+ lymphocytes in lymph nodes and blood (lymph nodes vs tumour-infiltrating lymphocytes: IFNG -4229 bp p < 0.0001, IL13 -11 bp p < 0.05, IL17A -122 bp p < 0.01 and FOXP3 -77 bp p > 0.05). Examination of individual lymph nodes displayed different methylation signatures, suggesting possible correlation with future survival. More advanced post-cystectomy tumour stages correlated significantly with increased methylation at the IFNG -4229 bp locus. Patients with complete response to neoadjuvant chemotherapy displayed significant hypomethylation in CD4+ T cells for all four investigated loci, most prominently in IFNG p < 0.0001. Neoadjuvant chemotherapy seemed to result in a relocation of Th1-committed CD4+ T cells from blood, presumably to the tumour, indicated by shifts in the methylation patterns, whereas no such shifts were seen for lineages corresponding to IL13, IL17A and FOXP3. CONCLUSION: Increased lineage commitment in CD4+ T cells, as determined by demethylation in predictive CpG sites, is associated with lower post-cystectomy tumour stage, complete response to neoadjuvant chemotherapy and overall better outcome, suggesting epigenetic profiling of CD4+ T cell lineages as a useful readout for clinical staging.

Urothelial bladder cancer may suppress perforin expression in CD8+ T cells by an ICAM-1/TGFß2 mediated pathway.

The immune system plays a significant role in urothelial bladder cancer (UBC) progression, with CD8+ T cells being capable to directly kill tumor cells using perforin and granzymes. However, tumors avoid immune recognition by escape mechanisms. In this study, we aim to demonstrate tumor immune escape mechanisms that suppress CD8+ T cells cytotoxicity. 42 patients diagnosed with UBC were recruited. CD8+ T cells from peripheral blood (PB), sentinel nodes (SN), and tumor were analyzed in steady state and in vitro-stimulated conditions by flow cytometry, RT-qPCR, and ELISA. Mass spectrometry (MS) was used for identification of proteins from UBC cell line culture supernatants. Perforin was surprisingly found to be low in CD8+ T cells from SN, marked by 1.8-fold decrease of PRF1 expression, with maintained expression of granzyme B. The majority of perforin-deficient CD8+ T cells are effector memory T (TEM) cells with exhausted Tc2 cell phenotype, judged by the presence of PD-1 and GATA-3. Consequently, perforin-deficient CD8+ T cells from SN are low in T-bet expression. Supernatant from muscle invasive UBC induces perforin deficiency, a mechanism identified by MS where ICAM-1 and TGFß2 signaling were causatively validated to decrease perforin expression in vitro. Thus, we demonstrate a novel tumor escape suppressing perforin expression in CD8+ T cells mediated by ICAM-1 and TGFß2, which can be targeted in combination for cancer immunotherapy.

Urinary Bladder Cancer Tregs Suppress MMP2 and Potentially Regulate Invasiveness.

Regulatory T cells (Treg) have long been considered one-sided suppressors of antitumor immune responses and hence associated with poor patient outcome in cancer. However, evidence is mounting of a paradoxical positive prognostic effect of Tregs on certain malignancies, including urinary bladder cancer (UBC). This discrepancy has partly been attributed to the shear misidentification of Tregs, but also to the inflammatory profile of the tumor. Our aim was to determine whether tumor-infiltrating Forkhead box P3+ (FOXP3+) cells confer a stable Treg phenotype and to investigate putative beneficial Treg functions, focusing on tumor-promoting inflammatory pathways in UBC. Patients (n = 52) with suspected UBC were prospectively included. We show, by using a broad range of analytical approaches, that tumor-infiltrating CD4+FOXP3+ T cells in UBC phenotypically, functionally, and epigenetically represent a true Treg population. At the invasive front of UBC tumors, we found an inverse relationship between Treg frequency and expression of matrix metalloproteinase 2 (MMP2), a key proinvasive factor induced by tumor-promoting inflammation. Correspondingly, a significant, dose-dependent Treg-mediated downregulation of MMP2 protein and mRNA expression was observed in both macrophages and UBC cells. Also, we found that Treg frequency specifically at the invasive front positively correlated with survival. Thus, we identify Treg-mediated suppression of MMP2 in the tumor microenvironment as a mechanism explaining the paradoxical positive prognostic impact of tumor-infiltrating Tregs in UBC. Cancer Immunol Res; 6(5); 528-38. ©2018 AACR.

Levels of physical activity in people with chronic pain.

BACKGROUND: People who suffer from chronic pain are thought to have lower levels of physical activity compared to healthy individuals. However, there is a lack of evidence concerning levels of physical activity in South Africans with chronic pain. OBJECTIVES: To compare levels of physical activity in a South African sample of people with chronic pain compared to matched controls. METHODS: A cross-sectional study was conducted with 24 participants (12 with chronic pain and 12 in the control group matched for age, gender and residential area). Convenience sampling was used. The participants with chronic pain (12) were identified from the Groote Schuur Hospital, Chronic Pain Management Clinic (CPMC) waiting list and had not yet received any chronic pain management intervention. Healthy matched controls were selected from volunteers in the community. With the desired alpha level set at 0.05 and the power at 0.9, 45 participants were required to detect a minimum of a 50 per cent difference between groups in levels of physical activity as measured in steps per day using pedometers. The international physical activity questionnaire (IPAQ) and the brief pain inventory (BPI) were used as measures of physical activity and pain. Objective indicators of physical activity that were used included the 6-minute walk test (6MWT), repeated sit-to-stand test (RSST), 7 days of pedometry and body mass index (BMI). RESULTS: The chronic pain group performed significantly worse on the 6MWT (335 m [30-430] vs 680 m [430-795]; U = 0.5; p < 0.01) and on the RSST (17.9 s [11.83-105] vs 7.85 s [5.5-11.5]; U = 0; p < 0.01). The chronic pain group also had significantly lower scores on pedometry (mean daily: 2985.1 [32.8-13785.4] vs 6409.4 [4207.1-15313.6]; U = 35; p < 0.03). The BMI for the chronic pain group was significantly higher than matched controls (29.36 kg/m2 [18.94-34.63] vs 22.16 kg/m2 [17.1-30.86]; U = 34; p < 0.03). CONCLUSION: Participants with chronic pain had a reduced capacity for physical activity. The pedometry results illustrate a range of maladaptive strategies adopted by those with chronic pain. The majority of people with chronic pain appear to avoid physical activity leading to greater disability as a result of immobility and muscle atrophy. However, a small subgroup appears to ignore their pain and push themselves physically despite their pain. This perseverance behaviour leads to further pain as a consequence of muscle and joint overuse. Both maladaptive behavioural responses result in further sensitisation of the central nervous system. The method used to target physical activity in these patients should be considered in treatment planning, specifically for physiotherapy.

Doxorubicin enhances the capacity of B cells to activate T cells in urothelial urinary bladder cancer.

Cancer is currently treated by a combination of therapies, including chemotherapy which is believed to suppress the immune system. Combination of immunotherapy and chemotherapy correlates with improved survival but needs careful planning in order to achieve a synergistic effect. In this study, we have demonstrated that doxorubicin treatment of B cells resulted in increased expression of CD86 and concordantly increased CD4+ T cell activation in the presence of superantigen, an effect that was inhibited by the addition of a CD86 blocking antibody. Furthermore, doxorubicin resulted in decreased expression of the anti-inflammatory cytokines IL-10 and TNF-α. Finally, B cells from urinary bladder cancer patients, treated with a neoadjuvant regiment containing doxorubicin, displayed increased CD86-expression. We conclude that doxorubicin induces CD86 expression on B cells and hence enhances their antigen-presenting ability in vitro, a finding verified in patients. Development of tailored time and dose schedules may increase the effectiveness of combining chemotherapy and immunotherapy.

Profiling of CD4+ T cells with epigenetic immune lineage analysis.

Proper transcriptional control of pro- and anti-inflammatory responses of the immune system is important for a fine-tuned balance between protection and tolerance. Emerging evidence suggests a key role for epigenetic regulation in governing the Th cell differentiation, where effector cytokines direct the overall immune response. In this study, we describe a method to pinpoint the location of isolated human CD4(+) T cells on any T cell effector axis based on specific CpG methylation of cytokine and transcription factor loci. We apply the method on CD4(+) cells obtained from rheumatoid arthritis and multiple sclerosis patients and show that synovial fluid infiltrating CD4(+) T cells are committed toward both Th1 and regulatory T cell phenotype, whereas the Th2 response is suppressed. Furthermore, we show that the IL-17A gene is regulated by promoter methylation and that Th17 commitment is not a common feature in the inflamed joints of rheumatoid arthritis patients. We conclude that the method described in this paper allows for accurate profiling of Th lineage commitment in ex vivo-isolated CD4(+) T cells.