Crohn's disease (CD) is a chronic inflammatory bowel disease associated with psychological distress and intestinal microbial changes. Here, we examined whether a 3-month period of Cognitive Behavioral and Mindfulness with Daily Exercise (COBMINDEX) intervention, which improves the wellbeing and inflammatory state of CD patients, may also affect their gut microbiome. Gut microbiota, circulating inflammatory markers and hormones were analyzed in 24 CD patients before (T1) and after 3 months of COBMINDEX (T2), and in 25 age- and sex-matched wait-list control patients at the corresponding time-points. Microbiota analysis examined relative taxonomical abundance, alpha and beta diversity, and microbiome correlations with inflammatory and psychological parameters. At T1, CD patients exhibited a characteristic microbial profile mainly constituted of Proteobacteria (17.71%), Firmicutes (65.56%), Actinobacteria (8.46%) and Bacteroidetes (6.24%). Baseline bacterial abundances showed significant correlations with psychological markers of distress and with IFN$\gamma $gamma. Following COBMINDEX, no significant changes in alpha and beta diversity were observed between both study groups, though a trend change in beta diversity was noted. Significant changes occurred in the abundance of phyla, families and genera only among the COBMINDEX group. Furthermore, abundance of phyla, families and genera that were altered following COBMNIDEX, significantly correlated with levels of cytokines and psychological parameters. Our results demonstrated that a short-term intervention of COBMINDEX was associated with changes in microbial indices, some of which are linked to psychological manifestations and systemic inflammation in CD patients. Psychological interventions to reduce chronic stress, such as COBMINDEX, appear to be beneficial in mitigating the pathobiology of CD patients, and may thus provide a useful adjunct to pharmacological therapy.

Lesion detectability in PET/CT is often challenging in clinical scenarios that includes high attenuation, scatter and randoms. We studied the impact of sensitivity on small lesion detectability and image quality in Omni Legend 32 system (GE HealthCare), compared to Discovery MI 25 cm (GE HealthCare), with TOF performance of 385 psec and NEMA sensitivity of 21 cps/kBq. Omni Legend 32 cm is based on 4×4×30 mm 3 bismuth germanate crystals coupled to silicon photomultipliers (digital-BGO). This scanner features ultra-high NEMA sensitivity of 46 cps/kBq, as well as high spatial resolution of 3.6 mm (2.5 mm for BSREM reconstruction), and energy resolution on 9.8%.For small lesion detectability evaluation, uniformly filled IEC phantom was scanned; then synthetic spherical lesions with a diameter as small as 4 mm and lesion to background ratio of 3:1 were digitally inserted. Independent and identically distributed noise realizations were replayed at activity concentrations of 5.2-3.4 kBq/ml and reconstructed using OSEM, OSEM-PSF and BSREM. Reconstructed images were analyzed using channelized Hotelling model observer. [1] It was found that Omni Legend 32 cm increases small lesion detectability by 16% on average and up to 20%, compared to the Discovery MI 25 cm TOF PET/CT with matched scan time/injected dose.For clinically-relevant image quality assessment, and the enhancement gained by the deep learning-based TOF reconstruction (Precision DL), [2] a phantom study was performed using Oval PET phantom with small spheres [3] ranging from 8 mm to 13 mm. The phantom was filled with FDG, maintaining a sphere to background ratio of 4:1. To reach high count rates, the background activity at scan start was 14.2 kBq/ml, and decayed to clinically relevant activities ~4 kBq/ml. The impact on image enhancement was evaluated using contrast recovery, background variability and contrast to noise ratio calculated for various activities, noise equivalent count and scan times.

Abstract Background Medical and psychological factors contribute to the heightened psychological distress and reduced health-related quality of life in patients with Crohn’s disease. Whether Social Support plays a role in this scenario is unknown. We used the Multidimensional Scale of Perceived Social Support (MSPSS) to investigate whether Social Support associates with psychological distress and quality of life in Crohn’s disease. Methods Consecutive adult patients with Crohn’s disease, presenting at specialist gastroenterology services or recruited by advertising, with mild to moderate disease activity by the Harvey-Bradshaw Index (HBI), were enrolled into the study. Patients completed the 12-item MSPSS questionnaire that measures psychological support in three categories: Family, Friends and Significant Other, and provides individual category scores and a total score (range of all scores 1–7; a higher score indicates more social support). Patients also completed the following questionnaires: psychological distress (Brief Symptom Inventory, with Global Severity Index, GSI), quality of life (Short Inflammatory Bowel Disease Questionnaire, SIBDQ), satisfaction with life (SWLS), family stress (Family Assessment Device, FAD), coping strategies (Brief-COPE), and presenteeism and work activity (WPAI). Statistics: Spearman rho. *p<0.05, **p<0.01. Results The cohort comprised 126 patients, mean (SD) age 33.7 (10.6) years, females 79%, HBI 8.4 (2.5), CRP 1.2 (2.3), calprotectin 394 (674). MSPSS scores were as follows: Total score 5.72 (1.14), Friends 5.36 (1.34), Family 5.73 (1.14), and Significant Other 6.07 (1.15); Cronbach’s α ≥ .877. MSPSS scores correlated negatively with family stress measure FAD: Friends -.258**, Family -.732**, Significant Other -.401**; and with GSI psychological stress measure: Friends -305**, Family -.352**, Significant Other -.245**. MSPSS correlated positively with SIBDQ quality of life: Friends .300**, Family .188*, Significant Other .200*; and with satisfaction with life SWLS: Friends .379**, Family .333**, Significant Other .245**. MSPSS correlations with emotion-focused coping were: Friends -.337**, Family -.263**, Significant Other -.329**. MSPSS Family score correlated negatively with WPAI presenteeism -.270*, and WPAI work activity -.294**. Conclusion In mild to moderate Crohn’s disease, strong social support was associated with better quality of life, more satisfaction with life, and better performance in the work arena. Social support was associated with reduced psychological distress, reduced family stress, and less use of emotion-focused coping. This research shows the importance of social support in improving the psychological condition of patients with Crohn’s disease.

Abstract Background Crohn’s disease (CD) is associated with psychological stress and alteration of gut microbiota as compared to healthy individuals. Previous work has reported imbalances in CD patients across four major bacterial phyla including Firmicutes, Bacteroidetes, Proteobacteria and Actinobacteria. We aimed to determine the effect on gut microbiota of a 3-month period of Cognitive Behavioral and Mindfulness-Based Stress Reduction (COBMINDEX), a psychological intervention shown to improve the wellbeing and inflammatory state of CD patients. Methods Microbial analysis of stool samples, circulating inflammatory markers and a wide range of psychological parameters related to stress, well-being and daily activities were measured and compared among 25 CD patients before (T1) and after (T2) COBMINDEX, and 25 matched CD wait-list controls at the corresponding time-points T1 and T2. Stool DNA extracts were subjected to 16S amplicon sequencing (Illumina) and analysed for taxonomical abundance, alpha and beta diversity using the QIIME2 pipeline and correlated with inflammatory and clinical parameters. Results Microbial alpha diversity among all CD patients at T1 significantly correlated to the 3 key cytokines: IL-10 (p=0.04, correlation=0.48), INFg (p=0.02, correlation=0.53), and INFa (p=0.02, correlation=0.51). At T2, while beta diversity was significantly increased in the COBMINDEX group (p=0.03), it was significantly decreased (p=0.0001) among the wait-list controls (Figure 1). Furthermore, compared with the wait-list controls, changes in inflammatory and clinical markers such as INFg, TNFa, IL-6, calprotectin and CRP, occurring following COBMINDEX, were accompanied by changes in the 4 main phyla including Firmicutes, Bacteroidetes, Proteobacteria and Actinobacteria (Figure 2). Lastly, changes in a variety of unique taxa, not previously implicated in CD, were also associated with changes in inflammatory and clinical markers such as INFg, TNFa, IL-6, calprotectin and CRP in the COBMINDEX but not in wait-list controls (Figure 2). Conclusion Our results show that microbial diversity is connected to the inflammatory profile of CD patients, and is significantly altered by COBMINDEX. Moreover, changes in the 4 main phyla that are known to be different among CD patients are linked to changes in various inflammatory markers, demonstrating the microbial-inflammatory relationship among CD patients. Lastly, we found that changes in the abundancies of 7 taxa, hitherto untied to CD in the literature, correlate with inflammatory markers, hinting at new microbial targets in CD.

Crohn’s disease (CD) is a chronic inflammatory bowel disease associated with psychological stress that is regulated primarily by the pituitary-hypophysis-adrenal (HPA) axis. Here, we determined whether the psychological characteristics of CD patients associate with their inflammatory state, and whether a 3-month period of Cognitive Behavioral and Mindfulness-Based Stress Reduction (COBMINDEX) impacts their inflammatory process. Circulating inflammatory markers (IFN-α, IFN-γ, TNF-α, MCP-1, IL-6, IL-8, IL-10, IL-12p70, IL-18, IL-23, and IL-33) and a wide range of psychological parameters were measured before (T1) and after (T2) COBMINDEX in CD patients. Inflammatory parameters were also compared to age- and sex-matched healthy controls (HCs) at T1, and to wait-list CD patients (at T1 and T2) who were followed for 3 months but did not receive COMBINDEX. Psychological symptoms were assessed by two questionnaires: the Perceived Stress Scale PSS4, and the Brief Symptom Inventory of psychological distress with Global Severity Index GSI. Statistical significance was assessed using Spearman correlation. CD patients (N=100, mean age 33.6 ± 13 years, 69% female, Harvey-Bradshaw Index mean 31± 55) exhibited increased peripheral low-grade inflammation compared with HCs, demonstrated by higher serum levels of interleukin (IL)-6 (mean 4.084± 8.4) and IL-18 (mean 302.09± 286) shown in Figure 1. Notably, IL-18 levels correlated with a higher stress score and a lower wellbeing score in CD patients (Figure 2). COBMINDEX was accompanied by changes in inflammatory markers that coincided with changes in cortisol: changes in serum levels of cortisol correlated positively with those of IL-10 (0.32, p<0.05) and INFα (0.36, p<0.05) and correlated negatively with those of MCP-1 (-0.34, p<0.05). Finally, baseline inflammatory markers of CD patients predicted COBMINDEX efficacy, as changes in HBI were negatively correlated with cytokines levels of IFNa (p=0.046), IFNg (p=0.03), IL-10 (p=0.002), IL-23 (p=0.025), IL33 (p=0.009) and IL12p70 (p=0.037) at T1 in the COBMINDEX group, but not in the wait-list group. In addition, basal levels of circulating cortisol at T1 negatively correlated with changes in GSI (-0.33, p<0.05) between T1 and T2 in the COBMINDEX group, but not in the wait-list group. Our results show that CD patients have a characteristic immunological profile that correlates with psychological stress and disease activity, and predicts COBMINDEX outcomes. We suggest that COBMINDEX induces stress resilience in CD patients, which not only impacts their well-being, but also their disease-associated inflammatory process.

Abstract Background Health-related quality-of-life by the self-report, disease-specific Short Inflammatory Bowel Disease Questionnaire (SIBDQ) is increasingly used as an outcome measure in Crohn`s disease (CD) patients in clinical trials. Higher SIBDQ scores indicate better quality-of-life; the range is 10 to 70. However, the construct validity of SIBDQ and its responsiveness to change of disease status require validation. Methods Adult (≥18 years) CD patients (n = 108) with Harvey–Bradshaw Index (HBI) >4 and <16 prospectively filled in the SIBDQ at two time-points (T1, T2) 3 months apart. Medical data at T1 and T2 were collected, and recorded by their physicians in the HBI. Biomarkers of disease activity included Calprotectin and C-reaction protein (CRP), measured at T1 and T2. The construct validity of SIBDQ in relation to biomarkers and HBI was determined by Pearson correlations and group comparisons using Student`s t-test. Statistical significance was taken as p < 0.05. Patients’ medications were prescribed without regard to the study protocol. Results Demographic and medical characteristics (median, %) of the cohort were: age 30 years; females 65%, married/partner 48%; higher education 83%; BMI 22; non-smokers/past-smokers 92%; disease duration 5 years; past Crohn’s disease-related surgery 17%; Montreal classification A2 89%, L2+L3 89%, B1+B2 89%, perianal disease 18%; medications: corticosteroids 4%, 5-ASA 5%, immunomodulators 21%, biologicals 43%. HBI and SIBDQ median scores at T1 and T2 were: HBI: 9 and 4 (p < 0.001); SIBDQ: 43 and 49 (p < 0.001). SIBDQ scores correlated inversely with Calprotectin (r = −0.395, p = .002), CRP (r = −0.208, p = .046), and HBI (r = −0.345, p < 0.001). Baseline HBI scores were used to divide the cohort into two groups for comparison: mild disease (5–7) vs. moderate disease (8–16). Mild disease patients reported higher SIBDQ scores than those with moderate disease (42.7 vs. 39.7, t = 1.96, p = 0.05). Regarding sensitivity of SIBDQ to clinical changes between T1 and T2, we found that change in SIBDQ correlated significantly with change in CRP across these two administrations (r = −0.232, p = 0.042). Finally, defining clinical response in CD as a decrease from baseline HBI score by ≥3 points, SIBDQ change scores were significantly larger in treatment responders (n = 51, M = 6.25) than non-responders (n = 30, M = 1.13, t = −3.042, p = 0.003). Conclusion The SIBDQ measure is a valid assessment of quality-of-life in CD, correlating with biomarkers and sensitive to change of disease activity, with potential for use as a patient-reported outcome in both clinical practice and as a primary end-point in clinical trials.

Abstract Background Crohn’s disease (CD) patients have reduced quality-of-life (QoL) in physical, emotional and social domains, and diminished work and leisure activities. We examined whether Mindfulness-Based Stress Reduction and Cognitive Intervention (‘Intervention’) can improve QoL and ability to work. Methods Patients (≥18 years), Harvey–Bradshaw Index (HBI) >4 and <16, were randomised to Intervention or Control groups. Intervention was taught in 8 weekly sessions by social workers via SKYPETM with twice-daily practice and back-report required. Medications were not controlled. HBI was completed at entry (T1) and 12 weeks (T2), and these questionnaires: (1) Short inflammatory bowel disease questionnaire (SIBDQ), disease-specific HRQoL measure. (2) Short-Form 12 (SF-12) questionnaire, generic HRQoL measure of physical health (PH) and mental health (MH). (3) EQ-5D-3L HRQoL questionnaire. (4) Work Productivity and Activity Impairment (WPAI) questionnaire, measuring absenteeism, presenteeism (reduced productivity), work impairment (composite of absenteeism and presenteeism), and leisure activity impairment. Statistics: Pearson Chi-squared, Wilcoxon signed-rank test. Results There were 39 Intervention and 43 Control patients. Demographic and medical characteristics (median, %) were: age 30 y; women 65%, married/partner 48%; higher education 83%; BMI 22; non- or past-smokers 92%; disease duration 5 y; HBI 8 (range 5–15); past surgery 17%; Montreal A2 89%, L2+L3 89%, B1+B2 89%, perianal disease 18%; drugs: corticosteroids 4%, 5-ASA 5%, immunomodulators 21%, biologics 43%; (p = ns between groups). Socio-economic status was higher in Intervention (87% = good/very good) than Control (58%, p = 0.016). HBI, SIBDQ and SF PH improved in both groups, but SF MH, EQ-5D-3L and all WPAI measures improved only in Intervention group (Table). Non-significance of WPAI indices between groups resulted from small sample size. Conclusion Mindfulness-Based Stress Reduction and Cognitive Intervention led to increased QoL and less work and activity impairment. If confirmed in a large cohort the intervention may be offered to all CD patients.

Crohn’s disease patients suffer from a host of mental symptoms, particularly when the disease is active (Schwartz D et al. United European Gastroenterol J 2018; 6: Supplement 1). We postulated that psychological distress can be diminished by teaching Mindfulness-Based Stress Reduction (MBSR) to patients using an internet-based format. Randomly selected adult patients with active Crohn’s disease, attending for routine follow-up in a teaching hospital, were enlisted in a program where MBSR is taught by specially trained social workers in a series of 1-h sessions delivered once a week, using Skype™ and a standardised protocol. Home practice twice daily with feedback to an application was required. Disease activity (Harvey–Bradshaw Index) was monitored. The Subjective Units of Distress Scale (SUDS, Wolpe J, 1969) was administered before and after each teaching session. The SUDS scale range is 0–10; a higher score indicates more stress. Data analysis using the Wilcoxon signed-ranks test was conducted on SUDS scores of patients with five completed MBSR sessions each. The analysis included sessions 2 through 5 (session 1 was regarded as entry into the protocol). The SUDS scores are labelled as ‘begin-score’ (at beginning of each treatment session) and ‘end-score’ (at end of session). Data are given as median (range). The cohort comprised 13 patients, all with good compliance. Patients' characteristics were: age 29 (22–63) years, females 85%, non-smokers 92%, illness duration 3 (1–25) years, past surgery in 3 patients. All patients had active disease: The Harvey–Bradshaw Index was 8 (6–15). Seven patients were receiving long-term biological medication. The median SUDS begin-score was highest in session 2 and less in subsequent sessions (Table 1). SUDS end-scores were significantly reduced compared with begin-scores in all sessions. The end-score at session 5 was significantly lower than the begin-score at session 2 (p = .011). SUDS scores at beginning and end of sessions, median (range). SUDS scores at beginning and end of sessions, median (range). These preliminary findings, albeit in a small uncontrolled cohort, suggest that MBSR taught weekly, and accompanied by twice-daily home practice, reduces the level of subjective psychological distress in Crohn’s disease patients. Teaching by Skype™ was effective (and could be a cost-saving measure) and daily report to an app ensured compliance. A randomised trial in a large cohort employing several psychological scales is in progress to determine the precise efficacy and long-term effect of MBSR in the armamentarium of therapies available to Crohn’s disease patients.

Active amyloid β-peptide (Aβ) immunization of patients with Alzheimer’s disease (AD) caused meningoencephalitis in ∼6% of immunized patients in a clinical trial. In addition, long-term studies of AD patients show varying degrees of Aβ Ab responses, which correlate with the extent of Aβ clearance from the brain. In this study, we examined the contribution of various HLA-DR alleles to these immune-response variations by assessing Aβ T cell reactivity, epitope specificity, and immunogenicity. Analysis of blood samples from 133 individuals disclosed that the abundant DR haplotypes DR15 (found in 36% of subjects), DR3 (in 18%), DR4 (12.5%), DR1 (11%), and DR13 (8%) were associated with Aβ-specific T cell responses elicited via distinct T cell epitopes within residues 15–42 of Aβ. Because the HLA-DRB1*1501 occurred most frequently, we examined the effect of Aβ challenge in humanized mice bearing this allele. The observed T cell response was remarkably strong, dominated by secretion of IFN-γ and IL-17, and specific to the same T cell epitope as that observed in the HLA-DR15-bearing humans. Furthermore, following long-term therapeutic immunization of an AD mouse model bearing the DRB1*1501 allele, Aβ was effectively cleared from the brain parenchyma and brain microglial activation was reduced. The present study thus characterizes HLA-DR alleles directly associated with specific Aβ T cell epitopes and demonstrates the highly immunogenic properties of the abundant allele DRB1*1501 in a mouse model of AD. This new knowledge enables us to explore the basis for understanding the variations in naturally occurring Aβ-reactive T cells and Aβ immunogenicity among humans.

Vaccination against amyloid beta-peptide (Abeta) has been shown to be successful in reducing Abeta burden and neurotoxicity in mouse models of Alzheimer's disease (AD). However, although Abeta immunization did not show T cell infiltrates in the brain of these mice, an Abeta vaccination trial resulted in meningoencephalitis in 6% of patients with AD. Here, we explore the characteristics and specificity of Abeta-induced, T cell-mediated encephalitis in a mouse model of the disease. We demonstrate that a strong Abeta-specific T cell response is critically dependent on the immunizing T cell epitope and that epitopes differ depending on MHC genetic background. Moreover, we show that a single immunization with the dominant T cell epitope Abeta10-24 induced transient meningoencephalitis only in amyloid precursor protein (APP)-transgenic (Tg) mice expressing limited amounts of IFN-gamma under an myelin basic protein (MBP) promoter. Furthermore, immune infiltrates were targeted primarily to sites of Abeta plaques in the brain and were associated with clearance of Abeta. Immune infiltrates were not targeted to the spinal cord, consistent with what was observed in AD patients vaccinated with Abeta. Using primary cultures of microglia, we show that IFN-gamma enhanced clearance of Abeta, microglia, and T cell motility, and microglia-T cell immunological synapse formation. Our study demonstrates that limited expression of IFN-gamma in the brain, as observed during normal brain aging, is essential to promote T cell-mediated immune infiltrates after Abeta immunization and provides a model to investigate both the beneficial and detrimental effects of Abeta-specific T cells.

We sought to analyze the mode of interaction of spinal morphine with systemic morphine or buprenorphine, administered in a wide range of antinociceptive doses. The study was performed on Sprague-Dawley rats by using a plantar stimulation test and isobolographic and fractional analyses of drug interaction. The isobolographic and fractional analyses demonstrated that intrathecal morphine interacted with subcutaneous morphine in a synergistic manner while producing a 50% or 75% antinociceptive effect. The sum of D75 fractions was more than that for 50% antinociception, suggesting a less dramatic interaction. The combination with a maximal relative dose of systemic morphine (0.66:1) showed a maximal degree of supraadditivity. The interaction between spinal morphine and systemic buprenorphine was similar to that of morphine/morphine, although the supra-additivity was not as pronounced. For the doses that produced a 50% antinociceptive effect, a synergistic interaction was observed only for the combination with a morphine/buprenorphine ratio of 1.33:1. When the relative amount of intrathecal morphine was decreased or increased, the effect became additive. At the doses that produced 75% antinociception, both combinations of morphine and buprenorphine demonstrated supraadditive interaction.

Laboratory studies have identified numerous potential therapeutic interventions that might have clinical application for the treatment of human traumatic brain injury. Many of these therapies have progressed into human clinical trials in severe traumatic brain injury. Numerous trials have been completed, and many others have been prematurely terminated or are currently in various phases of testing. The results of the completed Phase III trials have been generally disappointing, compared with the expectations produced by the successes of these interventions in animal laboratory studies. In this review, we summarize the current status of human traumatic brain injury clinical trials, as well as the animal laboratory studies that led to some of these trials. We summarize criteria for conducting clinical trials in severe traumatic brain injury, with suggestions for future improvements. We also attempt to identify factors that might contribute to the discrepancies between animal and human trials, and we propose recommendations that could help investigators avoid certain pitfalls in future clinical trials in traumatic brain injury.

We evaluated the antinociceptive effect of combined spinal administration of morphine and systemic administration of buprenorphine.Experiments were performed on male Wistar rats. Nociception was measured using the tail immersion test. Buprenorphine was injected intraperitoneally (IP) and morphine was injected intrathecally (IT) via a catheter implanted in the subarachnoid space. Interaction of drugs was analyzed using a dose addition model. Both IT (1-5 [micro sign]g) morphine and IP (50-500 [micro sign]g/kg) buprenorphine increased the latencies of nociceptive responses in a dose-dependent manner. IT morphine (4 [micro sign]g) and IP buprenorphine (100 [micro sign]g/kg) produced 62.9 +/- 6.3 and 48.8 +/- 6.6 percent of the maximal possible effect (%MPE), respectively. The combined administration of 2 [micro sign]g of IT morphine and 50 [micro sign]g/kg IP buprenorphine produced a %MPE of 97.1 +/- 3.4. The analysis of drug interaction revealed that IT morphine interacted with IP buprenorphine in a supraadditive manner while producing a potent antinociceptive effect. Implications: The concurrent administration of spinal morphine and systemic buprenorphine produces an antinociceptive effect that is greater than what could have been predicted from individual dose-response curves. This mode of interaction allows maintenance at a significant level of analgesia with reduced doses of opioids, which minimizes the incidence of undesirable side effects. (Anesth Analg 1998;87:583-6)