Summary Background Tioguanine (or thioguanine) is an alternative drug for IBD patients who fail prior conventional immunomodulating therapy. Aim To report effectiveness, safety and therapeutic drug monitoring in a cohort of patients with prolonged tioguanine maintenance therapy. Methods In this nationwide, multicentre study, medical records of tioguanine‐ using IBD patients were retrospectively reviewed. Response to therapy was defined as clinical effectiveness without (re)initiation of corticosteroids, concurrent biological therapy or surgical intervention. All adverse events that occurred during the follow‐up were listed and graded according to the common terminology criteria (CTC). Results Two hundred and seventy‐four patients (female 63%, Crohn's disease in 68%) were included with median treatment duration of 51 months, 1567 patient‐years of follow‐up and median 20 mg/d tioguanine dosage. Tioguanine was tolerated in 79%, clinical effectiveness at 6 months was documented in 66% and sustained clinical effectiveness during 12 months in 51% of patients. Forty‐one per cent of patients developed adverse events: 5% were graded as severe. Adverse events comprised infection requiring hospitalisation in three and skin cancer in eight patients (two melanomas). Asymptomatic nodular regenerative hyperplasia of the liver occurred in two out of 52 patients with liver biopsies (3.8%) and portal hypertension in three whereof one potentially associated with tioguanine (0.4%). Clinical effectiveness was correlated with 6‐thioguanine nucleotide threshold concentrations >682 pmol/8×108 RBC (P < 0.05). Conclusions Long‐term tioguanine therapy for at least 12 months was effective in 51% and well tolerated as a maintenance treatment for IBD in about 70% of patients. Adverse events were common, but mainly mild or moderate. 6‐Thioguanine nucleotide threshold concentration ≥ 700 pmol/8×108 RBC is proposed as target level with higher odds for clinical effectiveness.

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HIV infection and methamphetamine (METH) use are highly comorbid and represent a significant public health problem. Both conditions are known to negatively impact a variety of brain functions. One brain function that may be affected by HIV and METH use is sensorimotor gating, an automatic, pre-conscious filtering of sensory information that is thought to contribute to higher order cognitive processes. Sensorimotor gating is often measured using prepulse inhibition (PPI), a paradigm that can be conducted in both humans and animals, thereby enabling crossspecies translational studies. While previous studies suggest HIV and METH may individually impair PPI, little research has been conducted on the effects of combined HIV and METH on PPI.The goal of this cross-species study was to determine the effects of METH on PPI in the inducible Tat (iTat) mouse model of HIV and in people with HIV. PPI was measured in the iTat mouse model before, during, and after chronic METH treatment and after Tat induction. Chronic METH treatment decreased PPI in male but not female mice. PPI normalized with cessation of METH.Inducing Tat expression decreased PPI in male but not in female mice. No interactions between chronic METH treatment and Tat expression were observed in mice. In humans, HIV was associated with decreased PPI in both men and women. Furthermore, PPI was lowest in people with HIV who also had a history of METH dependence. Overall, these results suggest HIV and METH may additively impair early information processing in humans, potentially affecting downstream cognitive function.

ObjectivesDelirium is an underdiagnosed, severe and costly disorder, and 30%–40% of cases can be prevented. A fully automated model to predict delirium (DEMO) in older people has been developed, and the objective of this study is to validate the model in a hospital setting.SettingSecondary care, one hospital with two locations.DesignObservational study.ParticipantsThe study included 450 randomly selected patients over 60 years of age admitted to Zuyderland Medical Centre. Patients who presented with delirium on admission were excluded.Primary outcome measuresDevelopment of delirium through chart review.ResultsA total of 383 patients were included in this study. The analysis was performed for delirium within 1, 3 and 5 days after a DEMO score was obtained. Sensitivity was 87.1% (95% CI 0.756 to 0.939), 84.2% (95% CI 0.732 to 0.915) and 82.7% (95% CI 0.734 to 0.893) for 1, 3 and 5 days, respectively, after obtaining the DEMO score. Specificity was 77.9% (95% CI 0.729 to 0.882), 81.5% (95% CI 0.766 to 0.856) and 84.5% (95% CI 0.797 to 0.884) for 1, 3 and 5 days, respectively, after obtaining the DEMO score.ConclusionDEMO is a satisfactory prediction model but needs further prospective validation with in-person delirium confirmation. In the future, DEMO will be applied in clinical practice so that physicians will be aware of when a patient is at an increased risk of developing delirium, which will facilitate earlier recognition and diagnosis, and thus will allow the implementation of prevention measures.

Thiopurine derivatives, such as azathioprine and mercaptopurine, are standard conventional treatment options in inflammatory bowel disease (IBD). Unfortunately, approximately half of patients discontinue thiopurine therapy within 2 years. To improve the prediction of clinical effectiveness, thiopurine therapy is currently optimized using therapeutic drug monitoring. Ras-related C3 botulinum toxin substrate 1 (Rac1) has been suggested as a potential pharmacodynamic marker of the thiopurine effect in lymphocytes. The active thiopurine metabolite 6-thioguanine triphosphate (6-Thio-GTP) causes T cell apoptosis via Rac1 and the downstream transcription factor signal transducer and activator of transcription 3 (STAT3). The aim of this study was to develop and validate a functional pharmacodynamic multiparameter flow cytometric assay to determine Rac1/pSTAT3 expression in the various leukocyte subpopulations in peripheral blood in order to predict therapeutic response in IBD patients in the future. Peripheral blood samples of healthy subjects (no fever or clinical complaints of active disease, C-reactive protein < 10 mg/L) were used for immunocytochemical labeling, applying an optimized fixation and permeabilization strategy. A gating procedure was performed to separate all leukocyte subpopulations. Quantitative data were obtained by measuring presence and median fluorescent intensity. In vitro, Rac1 presence and expression were detectable in all leukocyte subpopulations. After IL-6 stimulation, used as proxy for inflammation, a distinct pSTAT3 signal could be detected in T lymphocytes of healthy subjects. In vivo, an upregulated pSTAT3 signal was detected in nearly all IBD patients with active disease and differed substantially from the signal found in IBD patients in remission on thiopurines and healthy subjects. We developed and validated a functional flow cytometric assay to assess Rac1 and pSTAT3 presence and expression. This opens a venue for a pharmacodynamic assay to predict thiopurine effectiveness in IBD patients.