Implications for sequencing of biologic therapy and choice of second anti-TNF in patients with inflammatory bowel disease: results from the IMmunogenicity to Second Anti-TNF therapy (IMSAT) therapeutic drug monitoring study.

BACKGROUND: Anti-drug antibodies are associated with treatment failure to anti-TNF agents in patients with inflammatory bowel disease (IBD). AIM: To assess whether immunogenicity to a patient's first anti-TNF agent would be associated with immunogenicity to the second, irrespective of drug sequence METHODS: We conducted a UK-wide, multicentre, retrospective cohort study to report rates of immunogenicity and treatment failure of second anti-TNF therapies in 1058 patients with IBD who underwent therapeutic drug monitoring for both infliximab and adalimumab. The primary outcome was immunogenicity to the second anti-TNF agent, defined at any timepoint as an anti-TNF antibody concentration ≥9 AU/ml for infliximab and ≥6 AU/ml for adalimumab. RESULTS: In patients treated with infliximab and then adalimumab, those who developed antibodies to infliximab were more likely to develop antibodies to adalimumab, than patients who did not develop antibodies to infliximab (OR 1.99, 95%CI 1.27-3.20, p = 0.002). Similarly, in patients treated with adalimumab and then infliximab, immunogenicity to adalimumab was associated with subsequent immunogenicity to infliximab (OR 2.63, 95%CI 1.46-4.80, p < 0.001). For each 10-fold increase in anti-infliximab and anti-adalimumab antibody concentration, the odds of subsequently developing antibodies to adalimumab and infliximab increased by 1.73 (95% CI 1.38-2.17, p < 0.001) and 1.99 (95%CI 1.34-2.99, p < 0.001), respectively. Patients who developed immunogenicity with undetectable drug levels to infliximab were more likely to develop immunogenicity with undetectable drug levels to adalimumab (OR 2.37, 95% CI 1.39-4.19, p < 0.001). Commencing an immunomodulator at the time of switching to the second anti-TNF was associated with improved drug persistence in patients with immunogenic, but not pharmacodynamic failure. CONCLUSION: Irrespective of drug sequence, immunogenicity to the first anti-TNF agent was associated with immunogenicity to the second, which was mitigated by the introduction of an immunomodulator in patients with immunogenic, but not pharmacodynamic treatment failure.

Camera-traps are a cost-effective method for surveying terrestrial squamates: A comparison with artificial refuges and pitfall traps.

INTRODUCTION: Fundamental data on the distributions, diversity, and threat status of terrestrial snakes and lizards (hereafter squamates) is limited. This is due to the cryptic nature of species in this faunal group, and to limitations in the effectiveness of the survey methods used to detect these species. Camera-traps are a useful tool for detecting numerous vertebrate species, yet their use for detecting squamates has been limited. Here, we apply recent methodological advancements in camera-trapping and assessed the utility of camera-traps for inventorying a squamate assemblage by comparing camera-trapping survey results with two widely used labour-intensive methods: artificial refuges and pitfall traps. METHODS: We conducted a 74-day survey using camera-traps and, concurrently, four by four-day surveys using labour-intensive methods. Given the duration and three detection methods, we compared seven variants of survey protocol, including using each method alone or all methods simultaneously. We compared both the effectiveness and cost-effectiveness of each survey protocol by estimating the number of species detected at the transect level, and by calculating the costs of conducting those surveys. RESULTS: We found the camera-trapping survey was most cost-effective, costing 687 AUD (CI 534-912) per squamate species detected, compared with the 2975 AUD (CI 2103-4486) per squamate species detected with the labour-intensive methods. Using all methods together was less cost-effective than using camera-traps alone. Additionally, there was a 99% probability that camera-traps would detect more species per transect than the labour-intensive methods examined. DISCUSSION & CONCLUSION: By focusing the analysis at the level of the survey, rather than the level of the device, camera-traps are both a more effective and cost-effective technique for surveying terrestrial squamates. Where circumstances are appropriate, those wildlife researchers and managers currently using camera-traps for non-squamate surveys, can adopt the methods presented to incorporate squamate surveys with little upfront cost. Additionally, researchers currently using traditional techniques can be confident that switching to camera-traps will likely yield improved results. Still, camera-traps are not a panacea and careful consideration into the benefits and usefulness of these techniques in individual circumstances is required.

Elucidating Patterns in the Occurrence of Threatened Ground-Dwelling Marsupials Using Camera-Traps.

Establishing trends in endangered fauna against management efforts is a key but often challenging enterprise. Camera-traps offer a new and literal window into monitoring many different mammalian species. Getting it right demands seeking baseline information about how often target species interact with these devices, prior to setting a long-term monitoring strategy. We used a camera-trap array to collect detection data on three species of threatened ground-dwelling marsupials in south-eastern mainland Australia. Over a four-year period, occupancy estimates for two species of bandicoot (southern brown bandicoot Isoodon obesulus and long-nosed bandicoot Perameles nasuta) and a single species of rat-kangaroo (long-nosed potoroo Potorous tridatylus) were generated. These estimates were variously robust depending on visitation history, but nevertheless indicated persistence of these rare and otherwise under threat species. Detection probability for each species differed between study areas, type of management and with complexity of ground and shrub vegetation cover. The relationship between detection and vegetation structure dictated that survey effort was only robust where conditions were optimal for a given species. Outside of that further survey effort would be required to have confidence in survey outcome. In the future this would demand a different sampling strategy, be that through lengthening survey time or adding additional camera units at sites.

MicroRNA-31 Targets Thymic Stromal Lymphopoietin in Mucosal Infiltrated CD4+ T Cells: A Role in Achieving Mucosal Healing in Ulcerative Colitis?

Background: Ulcerative colitis (UC) is characterized by disruption of the mucosal intestinal barrier. MicroRNAs, single-stranded noncoding RNAs of approximately 22nt, are dysregulated in UC. MicroRNAs targeting thymic stromal lymphopoietin (TSLP), a cytokine involved in T-cell maturation and polarization, may be involved in regulating UC inflammation and mucosal healing. Methods: Biopsy samples from non-UC (n = 38), inactive UC (n = 18), and active UC (n = 23) patients were analyzed for mRNA (real-time quantitative polymerase chain reaction) or TSLP protein expression (enzyme-linked immunosorbent assay). Flow cytometry was used to isolate CD4+ T cells from biopsies. The functional mechanism was shown using luciferase assays and antago-miR transfections. The TSLP/miR-31 association was analyzed on 196 subjects from a previous clinical trial that tested the anti-IL-13 drug tralokinumab, whereas mucosal healing effects were studied on a subset of patients (n = 13) from this trial. Results: We found that TSLP is reduced at both mRNA and protein levels in inflamed UC patients when compared with healthy subjects, in both whole biopsies and biopsy-isolated CD4+ CD25+ T cells. The expression of miR-31, predicted to target TSLP, inversely co-related to the levels of TSLP mRNA in T cells. Blocking miR-31 in vitro in T cells increased both TSLP mRNA expression and protein secretion. Luciferase assays showed that miR-31 directly targeted TSLP mRNA, suggesting a direct mechanistic link. We also found that TSLP is increased in patients who achieve mucosal healing, comparing biopsies before and after treatment from the tralokinumab trial. Conclusions: Our data suggest a role for TSLP in promoting mucosal healing and regulating inflammation in UC, whereas miR-31 can directly block this effect.

Improving outpatient services: the Southampton IBD virtual clinic.

The follow-up of inflammatory bowel disease (IBD) patients is challenging due to the relapsing remitting nature of the diseases, the wide spectrum of severity and complexity as well as the need for monitoring of long-term complications and drug treatments. Conventional outpatient follow-up lacks flexibility for patients and there are competing pressures for clinic time. Alternative follow-up pathways include telephone clinics, self-management programmes or discharging patients. The IBD virtual clinic (VC) is a further option. Patients with an established diagnosis for >2 years, who have been stable for >1 year, do not have primary sclerosing cholangitis and who give their consent, are entered into the VC system. Two months before their annual follow-up is due patients are sent blood test forms and a simple questionnaire with an information sheet. If they meet any of the criteria on the questionnaire, they are asked to contact the IBD specialist nursing team to discuss their situation. The blood test results and the patient's database entry are reviewed to ensure that they are not due surveillance investigations. The patients and their GPs then receive a letter informing them of their management plan. We currently follow-up 20% of the Southampton IBD cohort using the VC. The VC system is an innovative, efficient and patient-responsive method for following up mild to moderate IBD. It is well liked by patients but is dependent on a well-maintained database with good integration of IT systems and requires both clerical and IBD nurse specialist support.

Nitrogen content, amino acid composition and digestibility of fungi from a nutritional perspective in animal mycophagy.

Fungi comprise a major part of the diet of many animals. Even so, the nutritional value of fungi has been much debated, with some arguing that fungi are nutritionally poor. However, the chemical composition of fungi and of the biology of the animals that eat them are not well understood, particularly in reference to amino acid (AA) composition of fungi and digestibility of fungal protein. We analysed fibre, total nitrogen (N), available N, and AA contents and measured in vitro digestibility of a wide range of epigeous and hypogeous fungi collected in Australia and the USA to test three hypotheses: (i) fungi are nutritionally poor because they contain few nutrients or are otherwise of low digestibility, (ii) fungi vary substantially in their nutritional composition; and (iii) animals can counter this variable quality by eating diverse taxa. Resultant data indicate many fungi are a reasonable source of AAs and digestible nitrogen. However, they vary highly between species in AA content, and the protein has a poor balance of digestible AAs. This helps explain why many mycophagous animals eat a wide array of fungi and often have digestive strategies to cope with fungi, such as foregut fermentation. Another common strategy is to supplement the diet with high quality protein, such as insect protein. Accordingly, evaluating nutritional value of fungi requires consideration of physiology of the animal species and their whole diet.

Improving outpatient services: the Southampton IBD virtual clinic.

The follow-up of inflammatory bowel disease (IBD) patients is challenging due to the relapsing remitting nature of the diseases, the wide spectrum of severity and complexity as well as the need for monitoring of long-term complications and drug treatments. Conventional outpatient follow-up lacks flexibility for patients and there are competing pressures for clinic time. Alternative follow-up pathways include telephone clinics, self-management programmes or discharging patients. The IBD virtual clinic (VC) is a further option. Patients with an established diagnosis for >2 years, who have been stable for >1 year, do not have primary sclerosing cholangitis and who give their consent, are entered into the VC system. Two months before their annual follow-up is due patients are sent blood test forms and a simple questionnaire with an information sheet. If they meet any of the criteria on the questionnaire, they are asked to contact the IBD specialist nursing team to discuss their situation. The blood test results and the patient's database entry are reviewed to ensure that they are not due surveillance investigations. The patients and their GPs then receive a letter informing them of their management plan. We currently follow-up 20% of the Southampton IBD cohort using the VC. The VC system is an innovative, efficient and patient-responsive method for following up mild to moderate IBD. It is well liked by patients but is dependent on a well-maintained database with good integration of IT systems and requires both clerical and IBD nurse specialist support.

What is the educational value of ward rounds? A learner and teacher perspective.

Ward rounds (WRs) have been a valuable resource in medical education for both learners and teachers since first recorded in 1660. Previous studies have shown that over 50% of junior doctor learning occurs on WRs. However, postgraduate medical education in the UK has changed significantly over recent years with the adoption of the foundation programme and the application of the European Working Time Directive (EWTD). Using an anonymous questionnaire and small group discussions, foundation year doctors were surveyed regarding their perceptions of the educational value of WRs. Eighteen per cent of foundation year doctor learning occurs on WRs. Hindrances to learning and teaching include lack of time, increasing patient numbers and an absence of team consistency. The current study is the first to investigate the impact on the educational value of WRs following the introduction of the EWTD and the foundation programme. WRs continue to play a crucial role in postgraduate medical education but increasing pressure of service commitment and lack of teacher training continue to threaten this learning opportunity.

Diversity and habitat relationships of hypogeous fungi. III. Factors influencing the occurrence of fire-adapted species.

Among the huge array of hypogeous ectomycorrhizal fungi so far documented from Australia, six genera and more than 30 species occur within the family Mesophelliaceae, all of which show various adaptations for surviving in fire-prone landscapes. These mostly endemic fungi are critical to postfire reestablishment of regenerating vegetation, and their fruit-bodies provide essential food resources for diverse ground-dwelling fauna. We developed habitat models for five common representatives of the Mesophelliaceae based on repeat collections of their fruit-bodies from 136 study plots situated along a series of environmental gradients across the south-eastern mainland of Australia. At a meso- or landscape scale, temperature influenced the occurrence of Castoreum radicatum, Mesophellia clelandii and Nothocastoreum cretaceum, with the type of response varying. Below a threshold, C. radicatum preferred sites with cooler mean annual temperatures. In contrast, M. clelandii and N. cretaceum had optimal ranges of temperature, above and below which the probability of detecting them dropped. Also at a landscape scale, C. radicatum was more likely to be detected at sites with lower levels of precipitation during the driest quarter of the year. At a micro-site scale, M. clelandii and N. cretaceum were more likely to occur in stands with an intermediate number of host eucalypt stems, likely relating to successional age of the stand. Sites with a higher number of large fallen trees were more likely to have N. cretaceum, while sites with intermediate litter depths were more likely to have C. radicatum and M. clelandii. Mesophellia glauca and M. trabalis showed no consistent patterns. They are apparently the most broadly adaptable in terms of the independent variables tested. Although fire has been previously suggested to be heavily implicated in the life cycle of several members of the Mesophelliaceae, we found no relationship between time since disturbance by fire and other factors and likelihood of occurrence. Instead, other habitat attributes appeared to be more important in explaining their distribution. The complex and differing responses of the species of Mesophelliaceae studied here, to features of their environment, reinforce the need to manage multiple-use forest landscapes across the region for a diversity of attributes.

Gastrointestinal emergencies.

Gastrointestinal Emergencies describes itself as "the definitive reference guide for the management of gastrointestinal emergencies and endoscopic complications", The book covers the huge topic of acute gastroenterology in a succinct and easy to read format. At just over 200 pages it covers a lot more than what you might expect and makes for easy and enjoyable reading.

Ocurrence of ectomycorrhizal, hypogeous fungi in plantations of exotic tree species in central Argentina.

Eleven hypogeous, ectomycorrhizal species of Basidiomycota, including two new species, and one of the Zygomycota were collected in exotic tree plantations in C6rdoba Province, Argentina. Descomyces fusisporus sp. nov., D. varians sp. nov., Hydnangium archeri (Berk.) Rodway, H. carneum Wallr., Hysterangium gardneri E. Fisch. and Setchelliogaster tenuipes (Setch.) Pouzar were associated with Eucalyptus spp. Endogone lactiflua Berk., Hymenogaster lycoperdineus Vittad., H. griseus Vittad., H. rehsteineri Bucholtz, Rhizopogon couchii A.H. Sm. and R. roseolus (Corda) Th. Fr., were associated with various northern hemisphere tree species. Descriptions are provided to aid identification of the hypogeous fungi in exotic plantations of Argentina.

Prescribed burning in a Eucalyptus woodland suppresses fruiting of hypogeous fungi, an important food source for mammals.

Fruit bodies of hypogeous fungi are an important food source for many small mammals and are consumed by larger mammals as well. A controversial hypothesis that prescribed burning increases fruiting of certain hypogeous fungi based on observations in Tasmania was tested in the Australian Capital Territory to determine if it applied in a quite different habitat. Ten pairs of plots, burnt and nonburnt, were established at each of two sites prescribe-burnt in May 1999. When sampled in early July, after autumn rains had initiated the fungal fruiting season, species richness and numbers of fruit bodies on the burnt plots were extremely low: most plots produced none at all. Both species richness and fruit body numbers were simultaneously high on nonburnt plots. One of the sites was resampled a year after the initial sampling. At that time species richness and fruit body abundance were still significantly less on burnt plots than on nonburnt, but a strong trend towards fungal recovery on the burnt plots was evident. This was particularly so when numbers of fruit bodies of one species, the hypogeous agaric Dermocybe globuliformis, were removed from the analysis. This species strongly dominated the nonburnt plots but was absent from burnt plots in both years. The trend towards recovery of fruit body abundance in the burnt plots one year after the burn was much more pronounced with exclusion of the Dermocybe data. The Tasmanian-based hypothesis was based mostly on the fruiting of two fire-adapted species in the Mesophelliaceae. Neither species occurred on our plots. Accordingly, the results and conclusions of the Tasmanian study cannot be extrapolated to other habitats without extensive additional study. Implications for management of habitat for fungi and the animals that rely on the fungi as a food source are discussed.

The octreotide test dose is not a reliable predictor of the subsequent response to somatostatin analogue therapy in patients with acromegaly.

In many centres, a test dose (TD) of octreotide is administered before commencing somatostatin analogue therapy (SAT), although the merits of this procedure are uncertain. We have analysed the value of the GH response to a TD in predicting the efficacy of subsequent SAT in 47 patients with acromegaly (25 male, median age 51 years, range 20-82). The primary goal of SAT was a mean GH of < 5 mU/l. Median baseline GH was 19.3 mU/l (2.2-233 mU/l) and with the TD fell by 78% (35-98%) to a nadir of 4.2 mU/l (< 0.3-85 mU/l). Optimal predictive power was observed when GH fell to < 5 mU/l after the TD. With this criterion, the TD had a positive predictive value (PPV) of achieving the primary goal on SAT of 82% and a negative predictive value (NPV) of 50%. However, baseline GH was also highly predictive of the likelihood of successful SAT (GH < 5 mU/l). The GH response to the TD had PPV of 83% and NPV of 61% of normalising IGF-I on SAT. In summary, baseline GH and nadir after a TD are highly predictive of a good response to SAT; however, a poor response to a TD does not exclude an optimal response to SAT. Furthermore, failure to achieve biochemical control does not equate to no benefit, as biochemical improvement was seen in every patient; therefore, no patient should be deprived of octreotide therapy because of the result of a TD. In conclusion, our data indicate that the octreotide TD has no place in selecting patients for SAT.