Favourable Tolerability and Drug Survival of Tioguanine Versus Methotrexate After Failure of Conventional Thiopurines in Crohn's Disease.

BACKGROUND AND AIMS: Both methotrexate and tioguanine can be considered as treatment options in patients with Crohn's disease after failure of conventional thiopurines. This study aimed to compare tolerability and drug survival of methotrexate and tioguanine therapy after failure of conventional thiopurines in patients with Crohn's disease. METHODS: We conducted a retrospective, multicentre study, including patients with Crohn's disease initiating monotherapy methotrexate or tioguanine after failure [all causes] of conventional thiopurines. Follow-up duration was 104 weeks or until treatment discontinuation. The primary outcome was cumulative therapy discontinuation incidence due to adverse events. Secondary outcomes included total number of [serious] adverse events, and ongoing monotherapy. RESULTS: In total, 219 patients starting either methotrexate [n = 105] or tioguanine [n = 114] were included. In all 65 [29.7%] patients (methotrexate 43.8% [46/105 people], tioguanine 16.7% [19/114 people], p <0.001) discontinued their treatment due to adverse events during follow-up. Median time until discontinuation due to adverse events was 16 weeks (interquartile range [IQR] 7-38, p = 0.812). Serious adverse events were not significantly different. Patients treated with methotrexate experienced adverse events more often [methotrexate 83%, tioguanine 46%, p <0.001]. Total monotherapy drug survival after 104 weeks was 22% for methotrexate and 46% for tioguanine [p <0.001]. CONCLUSIONS: We observed a higher cumulative discontinuation incidence due to adverse events for methotrexate [44%] compared with tioguanine [17%] in Crohn's disease patients after failure of conventional thiopurines. The total adverse events incidence during methotrexate use was higher, whereas serious adverse events incidence was similar. These favourable results for tioguanine treatment may guide the selection of immunosuppressive therapy after failure of conventional thiopurines.

Early detection and follow-up of colorectal neoplasia based on faecal volatile organic compounds.

AIM: Early detection and removal of colorectal cancer (CRC) and advanced adenomas (AAs) decreases the incidence of and mortality from the disease. We aimed to evaluate the potential of faecal volatile organic compounds (VOCs) for detection and follow-up of colorectal adenoma using advanced electronic nose technology. METHOD: This was a prospective multi-centre case-control cohort including two district hospitals and one tertiary referral hospital. Patients undergoing colonoscopy were instructed to collect a faecal sample prior to bowel cleansing and were included in the study when CRC, AAs, large adenomas (LAs; 0.5-1.0 cm), small adenomas (SAs; 0.1-0.5 cm) or no endoscopic abnormalities (controls) were observed. Patients undergoing polypectomy and controls were asked for a second sample after 3 months. Faecal VOCs were measured with gas chromatography-ion mobility spectrometry. Random forest, support vector machine, Gaussian process and neural net classification were used to evaluate accuracy. RESULTS: In total, 14 patients with CRC, 64 with AAs, 69 with LAs, 127 with SAs and 227 controls were included. A second sample was collected from 32 polypectomy patients and 32 controls. Faecal VOCs discriminated CRC and adenomas from control [AUC (95% CI): CRC vs control 0.96 (0.89-1); AA vs control 0.96 (0.93-1); LA vs control 0.96 (0.92-0.99); SA vs control 0.96 (0.94-0.99)]. There were no significant differences between CRC and adenoma groups. Patients with adenomas and controls were discriminated prior to polypectomy, whereas 3 months after polypectomy VOC profiles were similar [T0 adenoma vs control 0.98 (0.95-1); T1 adenoma vs control 0.55 (0.40-0.69)]. CONCLUSIONS: Faecal VOC profiles may be useful for early detection of CRC and adenomas and the timing of polyp surveillance as polypectomy led to a normalization of the VOC profile.

Comparison of types and antimicrobial susceptibility of Staphylococcus from conventional and organic dairies in west-central Minnesota, USA.

AIMS: To assess whether conventional and organic dairy management practices are associated with differences in the susceptibility of Staphylococcus to antimicrobial agents. METHODS AND RESULTS: Staphylococcus was isolated from milk samples collected from conventional and organic dairies in west-central Minnesota. Isolates were categorized as (1) coagulase-positive, (2) novobiocin-sensitive coagulase-negative or (3) novobiocin-resistant coagulase-negative. Novobiocin-resistant coagulase-negative Staphylococcus (CNS) was more common on conventional farms and novobiocin-sensitive CNS predominated the isolates from organic farms. Overall, a larger proportion of isolates from organic rather than conventional farms were susceptible to erythromycin, pirlimycin and tetracycline. However, for pirlimycin and tetracycline, different patterns of susceptibility were observed among Staphylococcus categories. CONCLUSION: In this study, organic dairy management was associated with more overall antimicrobial susceptibility among Staphylococcus than was conventional management. However, different patterns of susceptibility among Staphylococcus categories suggest that multiple management practices, including some unrelated to antimicrobial use, may contribute to the observed differences in susceptibility. SIGNIFICANCE AND IMPACT OF THE STUDY: This study adds to our understanding of the implications of dairy management choices.

Bloodmeal digestion by strains of Anopheles stephensi liston (Diptera: Culicidae) of differing susceptibility to Plasmodium falciparum.

Blood digestion was studied in strains of Anopheles stephensi which had been genetically selected for either refractoriness or susceptibility to infection by Plasmodium falciparum. Females of the refractory Pb3-9a strain ingested more blood than selected (Sda-500) and unselected (Punjab) susceptible females and began to degrade the haemoglobin soon after feeding. In susceptible females, haemoglobin degradation started only after a significant post-feeding lag period. Total protein content of the midgut after the bloodmeal was correspondingly higher for refractory than for susceptible females, but absolute and relative rates of protein degradation were not significantly different between the different mosquito strains. Bloodmeal induction of midgut trypsin activity and the maximal trypsin activity were the same for the different strains. The residual aminopeptidase activity and its relative post-feeding activity (enzyme units per midgut) were significantly higher in refractory females. However, when converting to specific aminopeptidase activity, no differences between strains were evident. The results indicate that both the early initiation of haemoglobin degradation and higher aminopeptidase activity in the Pb3-9a refractory strain are important in the limitation of parasite development within the mosquito midgut, whereas trypsin plays no role in this process.