A biomarker-stratified comparison of top-down versus accelerated step-up treatment strategies for patients with newly diagnosed Crohn's disease (PROFILE): a multicentre, open-label randomised controlled trial.

BACKGROUND: Management strategies and clinical outcomes vary substantially in patients newly diagnosed with Crohn's disease. We evaluated the use of a putative prognostic biomarker to guide therapy by assessing outcomes in patients randomised to either top-down (ie, early combined immunosuppression with infliximab and immunomodulator) or accelerated step-up (conventional) treatment strategies. METHODS: PROFILE (PRedicting Outcomes For Crohn's disease using a moLecular biomarker) was a multicentre, open-label, biomarker-stratified, randomised controlled trial that enrolled adults with newly diagnosed active Crohn's disease (Harvey-Bradshaw Index ≥7, either elevated C-reactive protein or faecal calprotectin or both, and endoscopic evidence of active inflammation). Potential participants had blood drawn to be tested for a prognostic biomarker derived from T-cell transcriptional signatures (PredictSURE-IBD assay). Following testing, patients were randomly assigned, via a secure online platform, to top-down or accelerated step-up treatment stratified by biomarker subgroup (IBDhi or IBDlo), endoscopic inflammation (mild, moderate, or severe), and extent (colonic or other). Blinding to biomarker status was maintained throughout the trial. The primary endpoint was sustained steroid-free and surgery-free remission to week 48. Remission was defined by a composite of symptoms and inflammatory markers at all visits. Flare required active symptoms (HBI ≥5) plus raised inflammatory markers (CRP >upper limit of normal or faecal calprotectin ≥200 µg/g, or both), while remission was the converse-ie, quiescent symptoms (HBI <5) or resolved inflammatory markers (both CRP ≤ the upper limit of normal and calprotectin <200 µg/g) or both. Analyses were done in the full analysis (intention-to-treat) population. The trial has completed and is registered (ISRCTN11808228). FINDINGS: Between Dec 29, 2017, and Jan 5, 2022, 386 patients (mean age 33·6 years [SD 13·2]; 179 [46%] female, 207 [54%] male) were randomised: 193 to the top-down group and 193 to the accelerated step-up group. Median time from diagnosis to trial enrolment was 12 days (range 0-191). Primary outcome data were available for 379 participants (189 in the top-down group; 190 in the accelerated step-up group). There was no biomarker-treatment interaction effect (absolute difference 1 percentage points, 95% CI -15 to 15; p=0·944). Sustained steroid-free and surgery-free remission was significantly more frequent in the top-down group than in the accelerated step-up group (149 [79%] of 189 patients vs 29 [15%] of 190 patients, absolute difference 64 percentage points, 95% CI 57 to 72; p<0·0001). There were fewer adverse events (including disease flares) and serious adverse events in the top-down group than in the accelerated step-up group (adverse events: 168 vs 315; serious adverse events: 15 vs 42), with fewer complications requiring abdominal surgery (one vs ten) and no difference in serious infections (three vs eight). INTERPRETATION: Top-down treatment with combination infliximab plus immunomodulator achieved substantially better outcomes at 1 year than accelerated step-up treatment. The biomarker did not show clinical utility. Top-down treatment should be considered standard of care for patients with newly diagnosed active Crohn's disease. FUNDING: Wellcome and PredictImmune Ltd.

Opioid use and associated factors in 1676 patients with inflammatory bowel disease: a multicentre quality improvement project.

Objective: Despite its association with poorer outcomes, opioid use in inflammatory bowel disease (IBD) is not well characterised in the UK. We aimed to examine the extent of opioid use, the associated factors and the use of mitigation techniques such as pain-service review and opioid weaning plans among individuals with IBD. Methods: Data were collected from consecutive patients attending IBD outpatient appointments at 12 UK hospitals. A predefined questionnaire was used to collect data including patient demographics, IBD history, opioid use in the past year (>2 weeks) and opioid-use mitigation techniques. Additionally, consecutive IBD-related hospital stays leading up to July 2019 were reviewed with data collected regarding opioid use at admission, discharge and follow-up as well as details of the admission indication. Results: In 1352 outpatients, 12% had used opioids within the past 12 months. Over half of these individuals were taking opioids for non-IBD pain and less than half had undergone an attempted opioid wean.In 324 hospitalised patients, 27% were prescribed opioids at discharge from hospital. At 12 months postdischarge, 11% were using opioids. Factors associated with opioid use in both cohorts included female sex, Crohn's disease and previous surgery. Conclusions: 1 in 10 patients with IBD attending outpatient appointments were opioid exposed in the past year while a quarter of inpatients were discharged with opioids, and 11% continued to use opioids 12 months after discharge. IBD services should aim to identify patients exposed to opioids, reduce exposure where possible and facilitate access to alternative pain management approaches.

Mechanisms of the Cu(I)-Catalyzed Intermolecular Photocycloaddition Reaction Revealed by Optical and X-ray Transient Absorption Spectroscopies.

The [2 + 2] photocycloaddition provides a simple, single-step route to cyclobutane moieties that would otherwise be disfavored or impossible due to ring strain and/or steric interactions. We have used a combination of optical and X-ray transient absorption spectroscopies to elucidate the mechanism of the Cu(I)-catalyzed intermolecular photocycloaddition reaction using norbornene and cyclohexene as model substrates. We find that for norbornene the reaction proceeds through an initial metal-to-ligand charge transfer (MLCT) state that persists for 18 ns before the metal returns to the monovalent oxidation state. The Cu K-edge spectrum continues to evolve until ∼5 µs and then remains unchanged for the 50 µs duration of the measurement, reflecting product formation and ligand dissociation. We hypothesize that the MLCT transition and reverse electron transfer serve to sensitize the triplet excited state of one of the norbornene ligands, which then dimerizes with the other to give the product. For the case of cyclohexene, however, we do not observe a charge transfer state following photoexcitation and instead find evidence for an increase in the metal-ligand bond strength that persists for several ns before product formation occurs. This is consistent with a mechanism in which ligand photoisomerization is the initial step, which was first proposed by Salomon and Kochi in 1974 to explain the stereoselectivity of the reaction. Our investigation reveals how this photocatalytic reaction may be directed along strikingly disparate trajectories by only very minor changes to the structure of the substrate.

Steroid use and misuse: a key performance indicator in the management of IBD.

Corticosteroids remain an important tool for inducing remission in inflammatory bowel disease (IBD) but they have no role in maintenance of remission. The significant adverse side effect profile of these drugs means their use should be avoided where possible or measures taken to reduce their risk. Despite an expanding array of alternative therapies, corticosteroid dependency and excess remain common. Appropriate steroid use is now regarded a key performance indicator in the management of IBD. This article aims to outline indications for corticosteroid use in IBD, their risks and strategies to reduce their use and misuse.

Inflammatory bowel disease psychological support pilot reduces inflammatory bowel disease symptoms and improves psychological wellbeing.

This prospective service evaluation aimed to determine if integrated psychological support for patients with inflammatory bowel disease (IBD) enhanced outcomes. 75 patients were assessed and treated by a specialist liaison psychiatric service between 2015 and 2017; 43 received psychiatric intervention alone, 32 were referred for psychological intervention by clinical health psychologist; 26 completed this. Pre-post data (n=15 available) included global impression, quality of life, and psychiatric and IBD symptom scores. Referrer/patient satisfaction and cost-effectiveness were retrospectively calculated. Psychological intervention led to reductions in IBD symptoms (ΔSIBD; p=0.003), alongside improvements in depression scores (ΔPHQ-9, p=0.006) and global impression (ΔCGI; p=0.046). Patient/referrer satisfaction was very high. Indicative data comparing service utilisation 1 year before and after engagement found reductions in outpatient appointments and in imaging. This small study suggests consideration of increased access to integrated psychological support services to improve outcomes and gather further evidence of efficacy.

Development of a compact imaging spectrometer form for the solar reflective spectral region.

Current imaging spectrometer forms for terrestrial remote sensing in the visible, near-, and shortwave infrared (VNR/SWIR) spectral range have been implemented in hardware and achieve a high level of performance in terms of both aberration control and signal-to-noise level. These forms are compact, relative to prior art, but more size, weight, and power optimization, while maintaining performance, is desirable for usage on small satellite platforms. Pursuant to that goal, we have developed a compact breadboard prototype VNIR/SWIR imaging spectrometer that maintains the current aberration control and has a large number of spatial samples. The new form utilizes a catadioptric lens and a flat dual-blaze immersion grating yielding a compact design that is relatively easy to manufacture.

Importance of knowledge in the behavioural treatment of panic disorder.

BACKGROUND: Cognitive behavioural therapy (CBT) for panic disorder encourages patients to learn about and make changes to thoughts and behaviour patterns that maintain symptoms of the disorder. Instruments to assess whether or not patients understand therapy content do not currently exist. AIMS: The aim of this study was to examine if increases within specific knowledge domains of panic disorder were related to improvement in panic symptoms following an intensive 2-day panic treatment. METHOD: Thirty-nine Veterans enrolled in an intensive weekend panic disorder treatment completed knowledge measures immediately before the first session of therapy and at the end of the last day of therapy. Four panic disorder experts evaluated items and reached consensus on subscales. Subscales were reduced further to create psychometrically sound subscales of catastrophic misinterpretation (CM), behaviours (BE), and self-efficacy (SE). A simple regression analysis was conducted to determine whether increased knowledge predicted symptom change at a 3-month follow-up assessment. RESULTS: The overall knowledge scale was reduced to three subscales BE (n = 7), CM (n = 13) and SE (n = 8) with good internal consistency. Veterans' knowledge of panic disorder improved from pre- to post-treatment. Greater increase in scores on the knowledge assessment predicted lower panic severity scores at a 3-month follow-up. A follow-up analysis using the three subscales as predictors showed that only changes in CM significantly contributed to the prediction. CONCLUSIONS: In an intensive therapy format, reduction in panic severity was related to improved knowledge overall, but particularly as a result of fewer catastrophic misinterpretations.

Cyclodextrin-Promoted Fluorescence Detection of Aromatic Toxicants and Toxicant Metabolites in Commercial Milk Products.

The detection of polycyclic aromatic hydrocarbons (PAHs) and their metabolites in food and in agricultural sources is an important research objective due to the PAHs' known persistence, carcinogenicity, and toxicity. PAHs have been found in the milk of lactating cows, and in the leaves and stems of plants grown in PAH-contaminated areas, thereby making their way into both cow milk and plant milk alternatives. Reported herein is the rapid, sensitive, and selective detection of 10 PAHs and PAH metabolites in a variety of cow milks and plant milk alternatives using fluorescence energy transfer from the PAH to a high quantum yield fluorophore, combined with subsequent array-based statistical analyses of the fluorescence emission signals. This system operates with high sensitivity (low micromolar detection limits), selectivity (100% differentiation even between structurally similar analytes), and general applicability (for both unmodified lipophilic PAHs and highly polar oxidized PAH metabolites, as well as for different cow and plant milk samples). These promising results show significant potential to be translated into solid-state devices for the rapid, sensitive, and selective detection of PAHs and their metabolites in complex, commercial food products.

Combination GITR targeting/PD-1 blockade with vaccination drives robust antigen-specific antitumor immunity.

Tumor progression is facilitated immunologically by mechanisms that include low antigen expression, an absence of coimmunostimulatory signals, and the presence of regulatory T cells (Tregs), all of which act to suppress and restrict effector T cells in the tumor. It may be possible to overcome these conditions by a combination of modulatory immunotherapy agents and tumor-antigen targeting to activate and drive effective antitumor T cell responses. Here, we demonstrated that co-administration of aGITR and aPD-1 monoclonal antibodies (mAb) in combination with a peptide vaccine (Vax) in mice bearing established tumors significantly delayed tumor growth and induced complete regression in 50% of the mice. This response was associated with increased expansion and functionality of potent Ag-specific polyfunctional CD8+ T cells, reduced Tregs, and the generation of memory T cells. Tumor regression correlated with the expansion of tumor-infiltrating antigen-specific CD8+ effector memory T cells, as depletion of this cell population significantly reduced the effectiveness of the triple combination Vax/aGITR/aPD-1 therapy. These findings support the concept that dual aGITR/aPD-1 combination with cancer vaccines may be a novel strategy against poorly immunogenic tumors.

Targeting of CD122 enhances antitumor immunity by altering the tumor immune environment.

Mounting evidence demonstrates that CD8+CD122+ T cells have suppressive properties with the capacity to inhibit T cell responses. Therefore, these cells are rational targets for cancer immunotherapy. Here, we demonstrate that CD122 monoclonal antibody (mAb; aCD122) therapy significantly suppressed tumor growth and improved long-term survival in tumor-bearing mice. This therapeutic effect correlated with enhanced polyfunctional, cytolytic intratumoral CD8+ T cells and a decrease in granulocytic myeloid-derived suppressor cells (G-MDSCs). In addition, aCD122 treatment synergized with a vaccine to augment vaccine-induced antigen (Ag)-specific CD8+ T cell responses, reject established tumors and generate memory T cells. Furthermore, aCD122 mAb synergized with an anti-GITR (aGITR) mAb to confer significant control of tumor growth. These results suggest CD122 might be a promising target for cancer immunotherapy, either as a single agent or in combination with other forms of immunotherapy.

Almost human: Anthropomorphism increases trust resilience in cognitive agents.

We interact daily with computers that appear and behave like humans. Some researchers propose that people apply the same social norms to computers as they do to humans, suggesting that social psychological knowledge can be applied to our interactions with computers. In contrast, theories of human­automation interaction postulate that humans respond to machines in unique and specific ways. We believe that anthropomorphism­the degree to which an agent exhibits human characteristics­is the critical variable that may resolve this apparent contradiction across the formation, violation, and repair stages of trust. Three experiments were designed to examine these opposing viewpoints by varying the appearance and behavior of automated agents. Participants received advice that deteriorated gradually in reliability from a computer, avatar, or human agent. Our results showed (a) that anthropomorphic agents were associated with greater trust resilience, a higher resistance to breakdowns in trust; (b) that these effects were magnified by greater uncertainty; and c) that incorporating human-like trust repair behavior largely erased differences between the agents. Automation anthropomorphism is therefore a critical variable that should be carefully incorporated into any general theory of human­agent trust as well as novel automation design.

Optimising outcome on thiopurines in inflammatory bowel disease by co-prescription of allopurinol.

BACKGROUND AND AIMS: Azathioprine and mercaptopurine remain first line immunomodulatory treatments for inflammatory bowel disease. Toxicity and non-response are significant issues. Co-prescription of allopurinol with reduced-dose (25-33%) azathioprine or mercaptopurine may overcome these problems. We present the outcome of co-prescription in a large single-centre cohort. METHOD: Patients on thiopurine/allopurinol co-prescription were identified. Indication for and outcome on combination treatment were established. Blood parameters and metabolite results were compared on single agent and combination treatment. Toxicity associated with combination treatment was sought. RESULTS: 110 patients on combination treatment were identified. Clinical remission was achieved in 60/79 (76%) of patients in whom the effect of thiopurine could be studied in isolation. 20/25 patients with hepatotoxicity tolerated combination treatment and normalised their liver function tests. 24/28 patients with atypical side effects tolerated co-therapy. 13/20 non-responders responded to combination treatment. In patients started on combination treatment as first line therapy, 15/23 achieved clinical remission. Thioguanine nucleotides were significantly higher and methylated metabolites significantly lower on combination therapy. Mean cell volume was higher and total white cell and neutrophil counts lower on combination treatment. 13 adverse events occurred, including 6 specific to co-therapy (3 rash, 2 abnormal liver function tests, 1 dosing error). All were minor and self-limiting. CONCLUSION: This is the largest published experience of the use of allopurinol to optimise outcomes on thiopurine treatment. Combination therapy permitted successful treatment of a significant number of patients who would otherwise have been labelled as thiopurine failures. A few self-limiting side effects were encountered.

Nutritional management of adults with inflammatory bowel disease: practical lessons from the available evidence.

Inflammatory bowel disease (IBD) is associated with impairment of nutritional status both anthropometrically and biochemically, which results from both qualitative and quantitative changes in dietary intake alongside disease activity. Dietary intervention to replace deficiency is essential and may also be used to treat active disease and to reduce symptoms. The evidence for dietary interventions in this area is reviewed and the following recommendations made: ■Assessment of nutritional status is an essential part of the investigation of all patients with IBD and deficiency should be actively sought.■Any patient with macro- or micronutrient deficiency should be referred for dietetic assessment.■Micronutrient deficiency (most frequently iron, vitamin B12, folate and magnesium) should be replaced aggressively, parenterally if necessary.■Significant improvement in gastrointestinal symptoms can be achieved by low-residue diets (for stricturing disease) and (always under dietetic supervision) management of lactose and other intolerances.■Irritable bowel syndrome symptoms in patients with IBD can respond to low fermentable oligo-, di-, monosaccharide and polyol (FODMAP) diets, again this must be done under dietetic supervision.■Active Crohn's disease can be treated by exclusive enteral nutrition (elemental/polymeric/altered fat formulations all have equivalent efficacy).■Enteral nutrition can maintain remission in Crohn's disease and in this context can be given alongside normal oral intake.■Nutritional support does not have an established role in the treatment of active ulcerative colitis, other than in the management of malnutrition.■Total parenteral nutrition should not be used unless intestinal failure occurs.■There is insufficient evidence to support the routine use of Ω3 fish oil, prebiotics and glutamine in the treatment of active IBD.

Pharmacogenomics in the treatment of inflammatory bowel disease.

In recent years, the benefits of early aggressive treatment paradigms for inflammatory bowel disease have emerged. Symptomatic improvement is no longer considered adequate; instead, the aim of treatment has become mucosal healing and altered natural history. Nonetheless, we still fail to achieve these end points in a large number of our patients. There are many reasons why patients fail to respond or develop toxicity when exposed to drugs used for inflammatory bowel disease, but genetic variation is likely to account for a significant proportion of this. Some examples, notably thiopurine methyltransferase polymorphism in thiopurine treatment, are already established in clinical practice. We present a review of the expanding literature in this field, highlighting many interesting developments in pharmacogenomics applied to inflammatory bowel disease and, where possible, providing guidance on the translation of these developments into clinical practice.

Enhanced stem cell tracking via electrostatically assembled fluorescent SPION-peptide complexes.

For cellular MRI there is a need to label cells with superparamagnetic iron oxide nanoparticles (SPION) that have multiple imaging moieties that are nontoxic and have increased NMR relaxation properties to improve the detection and tracking of therapeutic cells. Although increases in the relaxation properties of SPION have been accomplished, detection of tagged cells is limited by either poor cell labeling efficiency or low intracellular iron content. A strategy via a complex formation with transfection agents to overcome these obstacles has been reported. In this paper, we report a complex formation between negatively charged fluorescent monodisperse SPION and positively charged peptides and use the complex formation to improve the MR properties of labeled stem cells. As a result, labeled stem cells exhibited a strong fluorescent signal and enhanced T 2*-weighted MR imaging in vitro and in vivo in a flank tumor model.

Muscle unloading-induced metabolic remodeling is associated with acute alterations in PPARdelta and UCP-3 expression.

A number of physiological changes follow prolonged skeletal muscle unloading as occurs in spaceflight, bed rest, and hindlimb suspension (HLS) and also in aging. These include muscle atrophy, fiber type switching, and loss of the ability to switch between lipid and glucose usage, or metabolic inflexibility. The signaling and genomic events that precede these physiological manifestations have not been investigated in detail, particularly in regard to loss of metabolic flexibility. Here we used gene arrays to determine the effects of 24-h HLS on metabolic remodeling in mouse muscle. Acute unloading resulted in differential expression of a number of transcripts in soleus and gastrocnemius muscle, including many involved in lipid and glucose metabolism. These include the peroxisome proliferator-activated receptors (PPARs). In contrast to Ppar-alpha and Ppar-gamma, which were downregulated by acute HLS, Ppar-delta was upregulated concomitant with increased expression of its downstream target, uncoupling protein-3 (Ucp-3). However, differential expression of Ppar-delta was both acute and transient in nature, suggesting that regulation of PPARdelta may represent an adaptive, compensatory response aimed at regulating fuel utilization and maintaining metabolic flexibility.

IFN-gamma does not mimic the catabolic effects of TNF-alpha.

Cachexia is common in chronic inflammatory diseases and is attributed, in part, to an elevation of circulating proinflammatory cytokines. TNF-alpha is the prototype in this category. IFN-gamma is also thought to play a role, but the evidence supporting this model is primarily indirect. To determine the direct effects of IFN-gamma stimulation on muscle cells, we selected key components of the procatabolic signaling pathways by which TNF-alpha stimulates protein loss. We tested two hypotheses: 1) IFN-gamma mimics TNF-alpha signaling by increasing intracellular oxidant activity and activating MAPKs and NF-kappaB and 2) IFN-gamma increases the expression of the ubiquitin ligases atrogin1/MAFbx and muscle-specific ring finger protein 1 (MuRF1). Results showed that treatment with IFN-gamma at 60 ng/ml increased Stat1 phosphorylation after 15 min, indicating receptor activation. IFN-gamma had no effect on cytosolic oxidant activity, as measured by 2',7'-dichlorofluorescein oxidation. Nor did IFN-gamma activate JNK, ERK1/2, or p38 MAPK, as assessed by Western blot. Treatment for up to 60 min did not decrease IkappaB-alpha protein levels, as measured by Western blot analysis, or the DNA binding activity of NF-kappaB, as measured by EMSA. After 6 h, IFN-gamma decreased Akt phosphorylation and increased atrogin1/MAFbx and MuRF1 mRNA. Daily treatment for up to 72 h did not alter adult fast-type myosin heavy chain content or the total protein-to-DNA ratio. These data show that responses of myotubes to IFN-gamma and TNF-alpha differ markedly and provide little evidence for a direct catabolic effect of IFN-gamma on muscle.

Discovery of [4-Amino-2-(1-methanesulfonylpiperidin-4-ylamino)pyrimidin-5-yl](2,3-difluoro-6- methoxyphenyl)methanone (R547), a potent and selective cyclin-dependent kinase inhibitor with significant in vivo antitumor activity.

The cyclin-dependent kinases (CDKs) and their cyclin partners are key regulators of the cell cycle. Since deregulation of CDKs is found with high frequency in many human cancer cells, pharmacological inhibition of CDKs with small molecules has the potential to provide an effective strategy for the treatment of cancer. The 2,4-diamino-5-ketopyrimidines 6 reported here represent a novel class of potent and ATP-competitive inhibitors that selectively target the cyclin-dependent kinase family. This diaminopyrimidine core with a substituted 4-piperidine moiety on the C2-amino position and 2-methoxybenzoyl at the C5 position has been identified as the critical structure responsible for the CDK inhibitory activity. Further optimization has led to a good number of analogues that show potent inhibitory activities against CDK1, CDK2, and CDK4 but are inactive against a large panel of serine/threonine and tyrosine kinases (K(i) > 10 microM). As one of these representative analogues, compound 39 (R547) has the best CDK inhibitory activities (K(i) = 0.001, 0.003, and 0.001 microM for CDK1, CDK2, and CDK4, respectively) and excellent in vitro cellular potency, inhibiting the growth of various human tumor cell lines including an HCT116 cell line (IC(50) = 0.08 microM). An X-ray crystal structure of 39 bound to CDK2 has been determined in this study, revealing a binding mode that is consistent with our SAR. Compound 39 demonstrates significant in vivo efficacy in the HCT116 human colorectal tumor xenograft model in nude mice with up to 95% tumor growth inhibition. On the basis of its superior overall profile, 39 was chosen for further evaluation and has progressed into Phase I clinical trial for the treatment of cancer.

Redox modulation of contractile function in respiratory and limb skeletal muscle.

For the last half century, scientists have studied the biological importance of free radicals in respiratory and limb muscles. We now know that muscle fibers continually produce both reactive oxygen species (ROS) and nitric oxide (NO) and that both cascades play critical roles in contractile regulation. Under basal conditions, muscle-derived ROS and NO exert opposing effects. Low-level ROS activity is an essential part of the homeostatic milieu and is required for normal force production whereas NO derivatives function as a brake on the system, limiting force. The modulatory effects of ROS and NO are disrupted by conditions that exaggerate production including mechanical unloading, inflammatory disease, and strenuous exercise. Marked increases in ROS or NO levels cause contractile dysfunction, resulting in muscle weakness and fatigue. These principles provide a foundation for ongoing research to identify the mechanisms of ROS and NO action and develop interventions that protect muscle function.