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Back in the early 1990's mathematics support was small-scale and loosely organised. Now, in 2021, it is to be found in the full range of university mission groups including those with the highest entry requirements. Today it is undoubtedly true that support centres are part of the landscape of higher education. They have evolved from offering local, drop-in support to first-year engineers to university-wide centres offering help to students in all disciplines and at all levels including postgraduates and sometimes staff. They contribute to university-wide priorities including recruitment, progression, retention, satisfaction, quality enhancement and employability. They have succeeded in raising issues such as the mathematics support of students with additional needs higher up institutional agendas and have firmly put the activities of those who work in this field on the radar of senior management of universities. This paper charts key milestones and events from the trajectory of mathematics support from 1990 to 2020 which have resulted in the thriving support services and community of practitioners that are evident today. It is based on a keynote presentation given by the author at CETL MSOR 2021.

Background and Aims Excluding superimposed enteric infection is critical in the management of acute severe ulcerative colitis [ASUC]. Whilst infection with Clostridium difficile and cytomegalovirus have been shown to increase colectomy and mortality rates, no data exist regarding the impact of common viral enteropathogens in ASUC. Our aim was to determine if viral enteric infection in ASUC alters the severity or outcomes of these episodes. Methods This was a retrospective review of cases presenting to a large tertiary centre. Data were obtained from an in-house, prospectively maintained inflammatory bowel disease database. We identified all ASUC cases treated between October 2015 and January 2021 and compared those testing positive for adenovirus 40/41, human rotavirus or norovirus GI by faecal multiplex polymerase chain reaction [PCR] to those testing negative. Results We identified 147 patients with ASUC and faecal multiplex PCR testing for viral pathogens. In total, 22/147 patients [14.9%] tested positive, two of whom tested positive for two viruses. The infected and non-infected cohorts did not differ significantly with regard to admission C-reactive protein [81.7 vs 76.6, p = 0.77], Mayo endoscopic subscore [2.4 vs 2.3, p = 0.43], length of hospital admission [7.9 vs 7.9 p = 0.99], requirement for rescue therapy [59% vs 56%, p = 0.75] or colectomy rate [4.5% vs 4.1%, p = 0.69]. Conclusions Infection with viral enteropathogens was common in our ASUC cohort, but did not appear to affect disease severity at presentation, the need for rescue therapy or the success rate of rescue therapy.

The dietary management of active ulcerative colitis (UC) is currently poorly understood. Due to the lack of clinical guidelines for this population, diet choice may be based on the personal judgement of the clinician, and without sound evidence. The aim of this systematic review was to appraise the current literature on the dietary management of individuals with active UC, in both inpatient and outpatient settings, to determine if clinical outcomes differ by diet prescription.PUBMED, CINAHL, EMBASE, Web of Science and SCOPUS were comprehensively searched during March and April 2020. Eligible trials recruited adults with active UC comparing different methods of dietary management, including enteral nutrition (EN), total parenteral nutrition (TPN), elimination diets and standard oral diets, in both the inpatient and outpatient settings.10 studies met inclusion criteria of this qualitative synthesis. No difference was found between EN, TPN and bowel rest in terms of disease activity measures when compared to a standard oral diet. The results of this study also showed promising potential for the use of elimination diets in the outpatient setting with four studies finding a significant difference in disease activity measures between the intervention diet and control.There is no strong evidence to support the use of any specific dietary prescription to improve clinical outcomes for individuals with active UC. A number of low quality studies suggest benefit of following an elimination diet, however, additional high quality studies are required before any more specific recommendations can be made.

Background and Aims The erythrocyte sedimentation rate [ESR] as a component of the Truelove and Witts Criteria [TWC] is the traditional inflammatory marker used for the assessment of ulcerative colitis [UC] activity. However, the C-reactive protein [CRP] is preferentially used in contemporary clinical practice. We aimed to determine the equivalent CRP cut-off for an ESR of >30 mm/h in patients presenting with acute severe UC. Methods Clinical and pathological data were prospectively collected from 163 presentations of severe UC. A CRP cut-off corresponding to an ESR of >30 mm/h was determined using confusion matrices. A validation cohort of 128 presentations was prospectively collected and analysed. Results A CRP cut-off of ≥12 mg/L generated an 85% positive predictive value [PPV] with a sensitivity of 95% and an accuracy of 82% for having a paired ESR of >30 mm/h. There were no statistically significant differences between groups determined by the traditional ESR versus the new CRP-based criterion in the presenting faecal calprotectin, Mayo endoscopic subscore, or the rates of intravenous corticosteroid therapy failure and colectomy-by-discharge. Applying the CRP ≥12 mg/L criterion to a validation cohort of 128 presentations generated a PPV of 83% and a sensitivity of 94%. Conclusions The proposed CRP ≥12 mg/L cut-off is an inclusive, sensitive, and very practical alternative to ESR as part of the TWC for defining UC presentation severity. It demonstrated similar performance characteristics to the classical ESR criterion when used for the assessment of acute UC disease activity. These findings were confirmed in a validation cohort.

An episode of acute severe ulcerative colitis (UC) represents an important watershed moment during the course of the disease with a heightened risk of colectomy during and following these episodes. As such, the prompt identification and early implementation of the appropriate treatment is paramount to obtaining the best clinical outcomes for these unwell patients.A prospective database of 349 consecutive presentations of Truelove and Witts criteria qualifying moderate and severe UC was collated at a single referral centre.This resource was interrogated to identify the C-reactive protein (CRP) level that corresponds with the erythrocyte sedimentation rate (ESR) that is widely accepted as a marker of severe disease activity. A CRP threshold of ≥12mg/L was found to be an inclusive and sensitive cut off that when incorporated into the Truelove and Witts criteria, replacing the traditional ESR >30mm/h criterion, had similar performance characteristics when applied to the assessment of UC disease activity. On the level of the individual patient, the serial CRP concentration is one of the few informative and objective measures of disease acuity and treatment response that will alter management during the hospital admission. This study provides the previously lacking reassurance that baseline immunomodulator usage status need not be taken into account when interpreting the ESR or CRP levels on presentation in established UC patients not on biologic therapy.As many published IBD severity and prognostic indices in contemporary use incorporate either the ESR or CRP as objective markers of disease acuity, this study has high translatability to patients with a secure diagnosis of UC not in their initial flare.Seventeen clinical, laboratory and endoscopic variables present at the time of hospital presentation were assessed for their ability to differentiate intravenous corticosteroid therapy responders from non-responders.A risk score based on a logistic model including the admission indices of oral corticosteroid failure, bowel frequency, CRP, albumin and either disease duration or Mayo endoscopic subscore (MES) was trained on a set of 349 presentations of acute UC. This individualised risk score has the potential to inform clinicians as to the timing of treatment escalation in acute UC.

Background Gastroenterology Departments at hospitals within Australia receive thousands of General Practitioner (GP)-referral letters for gastrointestinal investigations every month. Many of these requests are for colonoscopy. This study aims to evaluate the performance of the current symptoms-based triage system compared to a novel risk score using objective markers. Methods Patients with lower abdominal symptoms referred by their GPs and triaged by a Gastroenterology consultant to a colonoscopy consent clinic were recruited into the study. A risk assessment tool (RAT) was developed using objective data (clinical, demographic, pathology (stool test, FIT), standard blood tests and colonoscopy outcome). Colonoscopy and histology results were scored and then stratified as either significant bowel disease (SBD) or non-significant bowel disease (non-SBD). Results Of the 467 patients in our study, 45.1% were male, the mean age was 54.3 ± 13.8 years and mean BMI was 27.8 ± 6.2. Overall, 26% had SBD compared to 74% with non-SBD (42% of the cohort had a normal colonoscopy). Increasing severity of referral symptoms was related to a higher triage category, (rectal bleeding, P = 2.86*10-9; diarrhoea, P = 0.026; abdominal pain, P = 5.67*10-4). However, there was no significant difference in the prevalence of rectal bleeding (P = 0.991) or diarrhoea (P = 0.843) for SBD. Abdominal pain significantly reduced the risk of SBD (P = 0.0344, OR = 0.52, CI = 0.27-0.95). Conversely, the RAT had a very high specificity of 98% with PPV and NPV of SBD prediction, 74% and 77%, respectively. The RAT provided an odds ratio (OR) of 9.0, 95%CI 4.29-18.75, p = 2.32*10-11), higher than the FIT test (OR = 5.3, 95%CI 2.44-11.69, p = 4.88*10-6), blood score (OR = 2.8, 95%CI 1.72- 4.38, p = 1.47*10-5) or age (OR = 2.5, 95%CI 1.61-4.00, 5.12*10-5) independently. Notably, the ORs of these individual objective measures were higher than the current practice of symptoms-based triaging (OR = 1.4, 95%CI 0.88-2.11, p = 0.153). Conclusions It is critical that individuals with high risk of having SBD are triaged to the appropriate category with the shortest wait time. Here we provide evidence that a combination of blood markers, demographic markers and the FIT test have a higher diagnostic accuracy for SBD than FIT alone.

Background Anti-tumor necrosis factor-α (anti-TNFa) therapy have been established as an effective maintenance treatment for complicated Crohn’s Disease (CD). However, the efficacy of Infliximab (IFX) and Adalimumab (ADM) may be affected by low serum levels and/or the presence of anti-drug antibodies (ADA). This reinforces the importance of therapeutic drug monitoring (TDM). We aim to assess the clinical benefit of proactive vs. reactive TDM. Secondly, to assess the impact of TDM on clinical management. Thirdly, to identify risk factors for low serum drug levels and the development of ADA in CD patients. Methods This was a single-centred observational cohort study performed at a tertiary hospital, comprising of total 229 CD patients: 142 received IFX and 87 received ADM, who have had a trough drug level, tested using enzyme-linked immunosorbent assay. Demographic and clinical data were retrospectively collected from electronic medical records. Fisher’s Exact Test was used to determine if there are nonrandom associations between variables. A p-value of less than 0.05 was considered statistically significant. Results One hundred and fourteen patients (49%) receiving a standard anti-TNFa regimen had subtherapeutic drug levels (67 had IFX < 3 μg/ml and 47 had ADM < 5 μg/ml). Interestingly, almost half of this cohort were asymptomatic. Reactive TDM completed among symptomatic patients have shown to have a statistically significant benefit in detecting subtherapeutic drug level (p = 0.0001). Following these results, only fifty-two patients (46%) had a change of therapy (29 IFX, 25 ADM); while the remaining sixty-two patients (54%) continued the same dosing regimen with only one documented admission within 90-days following the drug level being taken. Eight patients (4%) were found to have positive ADA, all in the presence of subtherapeutic drug levels. Two of these had a subsequent flare of their disease. They were all switched to another class of biologic therapy. Non-smoking status at diagnosis and the concomitant use of immunomodulator were found to have statistically significant associations with a therapeutic drug level (p = 0.0176 and p = 0.0001, respectively). Similarly, both of these risk factors were associated with lower risk of ADA formation (p = 0.0057 and p = 0.0165, respectively). Conclusion This study suggests that a large proportion of patients have subtherapeutic drug levels at standard dosing schedules. However, low drug levels do not correlate with a higher risk of complications if patients are in clinical remission. The results of this study also indicate that non-smoking status at diagnosis and the concomitant use of immunomodulator are associated with higher serum drug levels and lower risk of developing anti-drug antibodies.

A. Palotie on työryhmän Int IBD Genetics Consortium jäsen. One goal of human genetics is to understand the genetic basis of disease, a challenge for diseases of complex inheritance because risk alleles are few relative to the vast set of benign variants. Risk variants are often sought by association studies in which allele frequencies in case subjects are contrasted with those from population-based samples used as control subjects. In an ideal world we would know population-level allele frequencies, releasing researchers to focus on case subjects. We argue this ideal is possible, at least theoretically, and we outline a path to achieving it in reality. If such a resource were to exist, it would yield ample savings and would facilitate the effective use of data repositories by removing administrative and technical barriers. We call this concept the Universal Control Repository Network (UNICORN), a means to perform association analyses without necessitating direct access to individual-level control data. Our approach to UNICORN uses existing genetic resources and various statistical tools to analyze these data, including hierarchical clustering with spectral analysis of ancestry; and empirical Bayesian analysis along with Gaussian spatial processes to estimate ancestry-specific allele frequencies. We demonstrate our approach using tens of thousands of control subjects from studies of Crohn disease, showing how it controls false positives, provides power similar to that achieved when all control data are directly accessible, and enhances power when control data are limiting or even imperfectly matched ancestrally. These results highlight how UNICORN can enable reliable, powerful, and convenient genetic association analyses without access to the individual-level data.

Background An episode of acute severe ulcerative colitis (UC) is a watershed event during the disease course with a heightened risk of colectomy during and following these episodes.1 The prompt identification of these events followed by the early implementation of appropriate treatment is essential to obtaining the best clinical outcomes for these unwell patients. The majority of published risk scores predicting the important clinical outcomes of intravenous corticosteroid therapy failure and colectomy-by-discharge rely on clinical data from days 1–3 of therapy.2 There is a paucity of tools that allow for a simple and individualised prediction of risk of corticosteroid therapy failure during the earliest stages of admission. Methods Data were prospectively obtained from 349 presentations of moderate–severe UC requiring hospital admission to a tertiary referral hospital. The failure of intravenous corticosteroid therapy was strictly defined by the (Oxford) Day 3 and Day 7 criteria.3 Seventeen clinical, laboratory and endoscopic variables all available within 24 h of hospital presentation were assessed for their ability to differentiate intravenous corticosteroid therapy responders from non-responders. A stepwise generalised linear model was formulated based on the results of the initial univariate analyses. Results Intravenous corticosteroid therapy failure occurred in 208/349 (60%) of presentations. The formulated risk score included the variables of oral corticosteroid therapy failure, bowel frequency and serum albumin concentration with or without the Mayo endoscopic subscore (MES). With the addition of the MES, the area under the curve (AUC) of the risk score was 0.758. When the positive predictive value of the score (threshold) for correctly predicting intravenous corticosteroid therapy failure was set at 85%, 105/275 (38%) of presentations with available data were identified as high risk for corticosteroid therapy failure (Figure 1). Conclusion This practical risk assessment tool provides clinicians with a personalised prediction of the likelihood of success of a course of intravenous corticosteroid therapy in moderate–severe UC. It enables the identification of individuals at high risk of treatment failure who may be suitable for consideration of early treatment escalation or screening for appropriate clinical trials. References

Background and Aim The etiology of Crohn's disease (CD) implicates both genetic and environmental factors. Smoking behavior is one environmental risk factor to play a role in the development of CD. The study aimed to assess the contribution of the interleukin 23 receptor (IL23R) in determining disease susceptibility in two independent cohorts of CD, and to investigate the interactions between IL23R variants, smoking behavior, and CD-associated genes, NOD2 and ATG16L1. Methods Ten IL23R single-nucleotide polymorphisms (SNPs) were genotyped in 675 CD cases, and 1255 controls from Brisbane, Australia (dataset 1). Six of these SNPs were genotyped in 318 CD cases and 533 controls from Canterbury, New Zealand (dataset 2). Case–control analysis of genotype and allele frequencies, and haplotype analysis for all SNPs was conducted. Results We demonstrate a strong increased CD risk for smokers in both datasets (odds ratio 3.77, 95% confidence interval 2.88–4.94), and an additive interaction between IL23R SNPs and cigarette smoking. Ileal involvement was a consistent marker of strong SNP–CD association (P ≤ 0.001), while the lowest minor allele frequencies for location were found in those with colonic CD (L2). Three haplotype blocks were identified across the 10 IL23R SNPs conferring different risk of CD. Haplotypes conferred no further risk of CD when compared with single SNP analyses. Conclusion IL23R gene variants determine CD susceptibility in the Australian and New Zealand population, particularly ileal CD. A strong additive interaction exists between IL23R SNPs and smoking behavior resulting in a dramatic increase in disease risk depending upon specific genetic background.