Modularity of PGL2(𝔽p)-representations over totally real fields.

We study an analog of Serre's modularity conjecture for projective representations [Formula: see text], where K is a totally real number field. We prove cases of this conjecture when [Formula: see text].

Microscopic colitis in Northern Ireland: an updated clinicopathological audit and assessment of compliance with European guidelines.

AIM: We previously reported the first population-based study of the epidemiology of microscopic colitis in Northern Ireland. The aim of the current study is to provide updated data on incidence, diagnostic methods and clinicopathological associations, following dissemination of the previous report. A further aim was to compare the findings against relevant recommendations from the 2020 European guidelines. METHOD: Study cases were identified via the Belfast Health and Social Care Trust pathology laboratory system for new cases of collagenous colitis or lymphocytic colitis diagnosed from 2017 to 2020 inclusive. Demographic and clinical information was collated from electronic healthcare records. RESULTS: Two hundred and seventeen new diagnoses of microscopic colitis were made between 2017 and 2020, comprising 89 (41%) collagenous colitis and 128 (59%) lymphocytic colitis. The overall incidence of microscopic colitis, expressed per 100,000 adult population, ranged from 7.6 to 11.5 (5.9 to 9.0 per 100,000 total population). The 2019 peak of 11.5 cases per 100,000 adult population represents a 71.6% increase in incidence compared with the mean incidence of 6.7 per 100,000 adult population from previous data for 2008-2016. There has also been a significant increase in number of cases diagnosed on separate sampling from the right and left colon (85% in 2019-2020 compared with 30% in 2008-2016; p < 0.001). Overall compliance with coeliac serology testing has improved, with 89% tested in 2017-2018 compared with 75% in 2008-2016. CONCLUSION: Clinicopathological communication has contributed to an increased incidence of microscopic colitis in Northern Ireland through better endoscopic diagnostic sampling and pathology coding practices. Coeliac serology testing has also improved, although continued clinical awareness is required of the need for coeliac serology testing in all patients diagnosed with microscopic colitis.

Ulcerative colitis.

Ulcerative colitis is a chronic inflammatory disease affecting the colon, and its incidence is rising worldwide. The pathogenesis is multifactorial, involving genetic predisposition, epithelial barrier defects, dysregulated immune responses, and environmental factors. Patients with ulcerative colitis have mucosal inflammation starting in the rectum that can extend continuously to proximal segments of the colon. Ulcerative colitis usually presents with bloody diarrhoea and is diagnosed by colonoscopy and histological findings. The aim of management is to induce and then maintain remission, defined as resolution of symptoms and endoscopic healing. Treatments for ulcerative colitis include 5-aminosalicylic acid drugs, steroids, and immunosuppressants. Some patients can require colectomy for medically refractory disease or to treat colonic neoplasia. The therapeutic armamentarium for ulcerative colitis is expanding, and the number of drugs with new targets will rapidly increase in coming years.

Moving towards disease modification in inflammatory bowel disease therapy.

PURPOSE OF REVIEW: The inflammatory bowel diseases (IBDs) are chronic disabling conditions. Despite the benefits of anti-tumor necrosis factor (TNF)-α agents in improving quality of life and reducing the need for surgeries, overall only one-third of patients are in clinical remission at 1 year and loss of response is frequent. It seems clear that treatment must go beyond alleviation of symptoms in IBD. It is important that treatment targets in IBD will ensure mucosal healing and deep remission. RECENT FINDINGS: The induction of deep remission might be the best way to alter the natural course of these diseases by preventing disability and bowel damage. New disability indices and the new Crohn's disease damage score have recently been developed and they can be used to evaluate the long-term effect on patients and as new endpoints in trials. Early intervention with disease-modifying anti-IBD drugs (DMAIDs) should be considered in patients with poor prognostic factors. SUMMARY: New therapeutic targets in IBD patients who failed anti-TNF-α therapy are urgently required, and tofacitinib, vedolizumab and ustekinumab appear to be the most promising drugs. Herein, we review the new and current trends in IBD therapy, with the final aim of changing disease course and patients' lives by both improving quality of life and avoiding disability.

Spinophilin regulates Ca2+ signalling by binding the N-terminal domain of RGS2 and the third intracellular loop of G-protein-coupled receptors.

Signalling by G proteins is controlled by the regulator of G-protein signalling (RGS) proteins that accelerate the GTPase activity of Galpha subunits and act in a G-protein-coupled receptor (GPCR)-specific manner. The conserved RGS domain accelerates the G subunit GTPase activity, whereas the variable amino-terminal domain participates in GPCR recognition. How receptor recognition is achieved is not known. Here, we show that the scaffold protein spinophilin (SPL), which binds the third intracellular loop (3iL) of several GPCRs, binds the N-terminal domain of RGS2. SPL also binds RGS1, RGS4, RGS16 and GAIP. When expressed in Xenopus laevis oocytes, SPL markedly increased inhibition of alpha-adrenergic receptor (alphaAR) Ca2+ signalling by RGS2. Notably, the constitutively active mutant alphaAR(A293E) (the mutation being in the 3iL) did not bind SPL and was relatively resistant to inhibition by RGS2. Use of betaAR-alphaAR chimaeras identified the 288REKKAA293 sequence as essential for the binding of SPL and inhibition of Ca2+ signalling by RGS2. Furthermore, alphaAR-evoked Ca2+ signalling is less sensitive to inhibition by SPL in rgs2-/- cells and less sensitive to inhibition by RGS2 in spl-/- cells. These findings provide a general mechanism by which RGS proteins recognize GPCRs to confer signalling specificity.

Artificial intelligence and inflammatory bowel disease: practicalities and future prospects.

Artificial intelligence (AI) is an emerging technology predicted to have significant applications in healthcare. This review highlights AI applications that impact the patient journey in inflammatory bowel disease (IBD), from genomics to endoscopic applications in disease classification, stratification and self-monitoring to risk stratification for personalised management. We discuss the practical AI applications currently in use while giving a balanced view of concerns and pitfalls and look to the future with the potential of where AI can provide significant value to the care of the patient with IBD.

Nicorandil associated colonic ulceration: case series of an increasingly recognized complication.

BACKGROUND: Nicorandil is widely accepted in the therapeutic armamentarium of ischemic heart disease and, although nicorandil-induced oral and anal ulcerations have been established in the literature, only five cases have reported the possibility of nicorandil-induced ulceration elsewhere in the gastrointestinal tract. There have been recent case reports which have suggested the possible causative association between nicorandil and colonic ulceration, either in isolation or in combination with anal ulceration. METHODS: We report a case series of eight patients prescribed with nicorandil therapy presenting with gastrointestinal symptoms and subsequently diagnosed with colonic ulceration on colonoscopy. RESULTS: Eight patients were identified (five female, three male). Colonoscopic findings varied from solitary to multiple colonic ulcers. No concomitant oral or anal ulcerations were noted in these patients. Biopsies from the ulcers showed only non-specific inflammation. Cessation of nicorandil therapy resulted in resolution of symptoms and complete healing of colonic ulcers. CONCLUSION: Nicorandil therapy appears to be an emerging etiology in the development of idiopathic colonic ulceration and therefore should be considered as a differential diagnosis in a selected group of patients.

How do patients with inflammatory bowel disease want their biological therapy administered?

BACKGROUND: Infliximab is usually administered by two monthly intravenous (iv) infusions, therefore requiring visits to hospital. Adalimumab is administered by self subcutaneous (sc) injections every other week. Both of these anti-TNF drugs appear to be equally efficacious in the treatment of Crohn's Disease and therefore the decision regarding which drug to choose will depend to some extent on patient choice, which may be based on the mode of administration.The aims of this study were to compare preferences in Inflammatory Bowel Disease (IBD) patients for two currently available anti-TNF agents and the reasons for their choices. METHODS: An anonymous questionnaire was distributed to IBD patients who had attended the Gastroenterology service (Ulster Hospital, Dundonald, Belfast, N. Ireland. UK) between January 2007 and December 2007. The patients were asked in a hypothetical situation if the following administering methods of anti-TNF drugs (intravenous or subcutaneous) were available, which drug route of administration would they choose. RESULTS: One hundred and twenty-five patients fulfilled the inclusion criteria and were issued questionnaires, of these 78 questionnaires were returned (62 percent response). The mean age of respondent was 44 years. Of the total number of respondents, 33 patients (42 percent) preferred infliximab and 19 patients (24 percent) preferred adalimumab (p = 0.07). Twenty-six patients (33 percent) did not indicate a preference for either biological therapy and were not included in the final analysis. The commonest reason cited for those who chose infliximab (iv) was: "I do not like the idea of self-injecting," (67 percent). For those patients who preferred adalimumab (sc) the commonest reason cited was: "I prefer the convenience of injecting at home," (79 percent). Of those patients who had previously been treated with an anti-TNF therapy (n = 10, all infliximab) six patients stated that they would prefer infliximab if given the choice in the future (p = 0.75). CONCLUSIONS: There was a trend towards patient preference for infliximab (iv) treatment as opposed to adalimumab (sc) in patients with IBD. This difference may be due to the frequency of administration, mode of administration or differing 'times in the market-place', as infliximab had been approved for a longer period of time in Crohn's disease. Further studies are required in IBD patients to investigate whether patient choice will affect compliance, patient satisfaction and efficacy of treatment with anti-TNF therapies.

Arrestins and spinophilin competitively regulate Na+,K+-ATPase trafficking through association with a large cytoplasmic loop of the Na+,K+-ATPase.

The activity and trafficking of the Na(+),K(+)-ATPase are regulated by several hormones, including dopamine, vasopressin, and adrenergic hormones through the action of G-protein-coupled receptors (GPCRs). Arrestins, GPCR kinases (GRKs), 14-3-3 proteins, and spinophilin interact with GPCRs and modulate the duration and magnitude of receptor signaling. We have found that arrestin 2 and 3, GRK 2 and 3, 14-3-3 epsilon, and spinophilin directly associate with the Na(+),K(+)-ATPase and that the associations with arrestins, GRKs, or 14-3-3 epsilon are blocked in the presence of spinophilin. In COS cells that overexpressed arrestin, the Na(+),K(+)-ATPase was redistributed to intracellular compartments. This effect was not seen in mock-transfected cells or in cells expressing spinophilin. Furthermore, expression of spinophilin appeared to slow, whereas overexpression of beta-arrestins accelerated internalization of the Na(+),K(+)-ATPase endocytosis. We also find that GRKs phosphorylate the Na(+),K(+)-ATPase in vitro on its large cytoplasmic loop. Taken together, it appears that association with arrestins, GRKs, 14-3-3 epsilon, and spinophilin may be important modulators of Na(+),K(+)-ATPase trafficking.

Evolving primary and secondary endpoints in randomized controlled trials leading to approval of biologics and small molecules in IBD: an historical perspective.

Introduction: Therapeutic goals in inflammatory bowel diseases (IBD) have evolved, over the last decades, from clinical response to complete remission (clinical and endoscopic remission).Areas covered: Development of biologics and small molecules has been associated with the development of new endpoints in IBD trials that could not have been achieved in the pre-biologics era. Herein, we focus on evolving endpoints for approved biologics and small molecules. We searched for relevant publications using Medline/PubMed, Embase and the Cochrane Library from their inception to 1 July 2019.Expert opinion: Endpoints differ between induction (clinical and endoscopic response) and maintenance trials (clinical and endoscopic remission) because the goal is to evaluate the anti-inflammatory effect of a given drug during induction, whereas full disease control is the ultimate goal during the maintenance phase in order to change patients' life and disease course. Histological healing has recently emerged as a new co-primary endpoint in ulcerative colitis, and is now part of the definition of mucosal healing in these trials. Whether new endpoints such as transmural and radiologic healing could become an endpoint and replace endoscopy in Crohn's disease trials in the near future requires further investigation.

Practice pattern variability in the management of acute severe colitis: a UK provider survey.

INTRODUCTION: Lack of comparative trial data on dosing regimens of infliximab in patients with acute severe ulcerative colitis (ASUC) failing intravenous corticosteroids has resulted in variability of rescue regimes in ASUC with potential impact on clinical outcomes. We aimed to evaluate practice variability and physician perspectives in decision-making with rescue therapy. METHODOLOGY: An internet-based survey of members of the inflammatory bowel disease (IBD) section of the British Society of Gastroenterology was conducted. The survey evaluated provider characteristics and general practice in the setting of ASUC, followed by a vignette with linked questions. RESULTS: The response rate of the survey was 31% (209/682 IBD section members). 134 (78%) reported they would use standard infliximab dose (5 mg/kg) while 37 (22%) favoured a higher front-loading dose of 10 mg/kg citing low albumin, high C-reactive protein as their reason for their preference. IBD specialists chose the higher front-loading dose more often compared with other gastroenterologists (p=0.01) In the specific case vignette, accelerated induction (AI) was favoured by 51% of the respondents while 25% used the standard induction regime and 19% favoured colectomy. IBD specialists more often favoured AI compared with other gastroenterologists (p=0.03) with the main reason being presence of predictors of low infliximab levels (74%). The reasons cited for favouring standard induction (n=57) included lack of evidence for AI (18), their usual practice (11), unlicensed regime (7), and safety concerns (4). CONCLUSIONS: There are significant variations in practice in the use of infliximab rescue therapies with an urgent need for development of care pathways to standardise practice.

The Rho-specific GEF Lfc interacts with neurabin and spinophilin to regulate dendritic spine morphology.

Neurabin and spinophilin are homologous protein phosphatase 1 and actin binding proteins that regulate dendritic spine function. A yeast two-hybrid analysis using the coiled-coil domain of neurabin revealed an interaction with Lfc, a Rho GEF. Lfc was highly expressed in brain, where it interacted with either neurabin or spinophilin. In neurons, Lfc was largely found in the shaft of dendrites in association with microtubules but translocated to spines upon neuronal stimulation. Moreover, expression of Lfc resulted in reduction in spine length and size. Both the translocation and the effect on spine morphology depended on the coiled-coil domain of Lfc. Coexpression of neurabin or spinophilin with Lfc resulted in their clustering together with F-actin, a process that depended on Rho activity. Thus, interaction between Lfc and neurabin/spinophilin selectively regulates Rho-dependent organization of F-actin in spines and is a link between the microtubule and F-actin cytoskeletons in dendrites.

Oesophageal Stents for Potentially Curable Oesophageal Cancer - A Bridge to Surgery?

For oesophageal cancer patients with potentially curative disease, treatment usually comprises neoadjuvant chemoradiotherapy followed by surgery. Several methods are currently used for nutritional support while patients are undergoing neoadjuvant treatment but these do not relieve dysphagia. Stenting as a bridge to curative surgery has been explored in several case series and a case control study. This is a review of the current literature on the topic. Some small series have shown it to be safe and effective in relieving dysphagia and malnutrition without adverse effect on surgical outcomes, perioperative complications or delay in surgical resection post neoadjuvant therapy. However, there are sufficient concerns about its adverse impact on oncological outcomes such as a reduction in the R0 resection rates, median time to recurrence and 2 - 3 year overall survival, to not currently recommend its routine use in resectable cancers.

Infliximab induction regimens in steroid-refractory acute severe colitis: a multicentre retrospective cohort study with propensity score analysis.

BACKGROUND: Accelerated induction regimens of infliximab have been proposed to improve response rates in patients with steroid-refractory acute severe colitis. AIM: To determine the differences in outcome for acute severe ulcerative colitis between accelerated and standard-dose infliximab METHODS: We collected data on hospitalised patients receiving differing regimens of rescue therapy for steroid-refractory acute severe ulcerative colitis. Our primary outcome was 30-day colectomy rate. Secondary outcomes were colectomy within index admission, and at 90 days and 12 months. We used propensity score analysis with optimal calliper matching using high risk covariates defined a priori to reduce potential provider selection bias. RESULTS: We included 131 patients receiving infliximab rescue therapy; 102 received standard induction and 29 received accelerated induction. In the unmatched cohort, there was no difference by type of induction in the 30-day colectomy rates (18% vs 20%, P = .45), colectomy during index admission (13% vs 20%, P = .26) or overall colectomy (20% vs 24%, P = .38). In the propensity score-matched cohort of 52 patients, 30-day colectomy (57% vs 27%, P = .048) and index admission colectomy (53% vs 23%, P = .045) rates were higher in those receiving standard induction compared to accelerated induction but there was no difference in overall colectomy rates (57% vs 31%, P = .09). There was no significant difference in length of stay or in complication and infection rates. CONCLUSION: In a propensity score-matched cohort, steroid-refractory acute severe ulcerative colitis patients, short-term, but not long-term, colectomy rates appear to be lower in those receiving an accelerated induction regimen.

UK clinical experience up to 52 weeks with linaclotide for irritable bowel syndrome with constipation.

BACKGROUND: Linaclotide, a guanylate cyclase C agonist, has been shown in clinical trials to improve symptoms of irritable bowel syndrome with constipation (IBS-C). Here we report data from a real-world study of linaclotide in the UK. METHODS: This 1-year, multicentre, prospective, observational study in the UK enrolled patients aged 18 years and over initiating linaclotide for IBS-C. The primary assessment was change from baseline in IBS Symptom Severity Scale (IBS-SSS) score at 12 weeks, assessed in patients with paired baseline and 12-week data. Change from baseline in IBS-SSS score at 52 weeks was a secondary assessment. Adverse events were recorded. RESULTS: In total, 202 patients were enrolled: 185 (91.6%) were female, median age was 44.9 years (range 18.1-77.2) and 84 (41.6%) reported baseline laxative use. Mean (standard deviation) baseline IBS-SSS score was 339 (92), with most patients (n = 129; 66.8%) classified as having severe disease (score ⩾300). In patients with paired data, there was a significant mean (95% confidence interval) decrease in IBS-SSS score from baseline to 12 weeks [-77.0 (-96.3, -57.7); p < 0.001; n = 124] and baseline to 52 weeks [-70.7 (-95.0, -46.5); p < 0.001; n = 76]. Overall, 174 adverse events were reported in 77 (38.1%) patients, most commonly diarrhoea (n = 54; 26.7%), abdominal pain (n = 21; 10.4%) and abdominal distension (n = 13; 6.4%). CONCLUSION: Linaclotide significantly improved IBS-SSS score at 12 and 52 weeks. These results provide insights into outcomes with linaclotide treatment over 1 year in patients with IBS-C in real-world clinical practice.

Type 1 phosphatase, a negative regulator of cardiac function.

Increases in type 1 phosphatase (PP1) activity have been observed in end stage human heart failure, but the role of this enzyme in cardiac function is unknown. To elucidate the functional significance of increased PP1 activity, we generated models with (i) overexpression of the catalytic subunit of PP1 in murine hearts and (ii) ablation of the PP1-specific inhibitor. Overexpression of PP1 (threefold) was associated with depressed cardiac function, dilated cardiomyopathy, and premature mortality, consistent with heart failure. Ablation of the inhibitor was associated with moderate increases in PP1 activity (23%) and impaired beta-adrenergic contractile responses. Extension of these findings to human heart failure indicated that the increased PP1 activity may be partially due to dephosphorylation or inactivation of its inhibitor. Indeed, expression of a constitutively active inhibitor was associated with rescue of beta-adrenergic responsiveness in failing human myocytes. Thus, PP1 is an important regulator of cardiac function, and inhibition of its activity may represent a novel therapeutic target in heart failure.

The role of smoking and alcohol behaviour in the management of inflammatory bowel disease.

In the era of increasing use of immunosuppressive and biologic therapy for inflammatory bowel disease, environmental influences remain important independent risk factors to modify the course of the disease, affect the need for surgery and recurrence rates post-surgical resection. The effect of smoking on inflammatory bowel disease has been established over the decades, however the exact mechanism of how smoking affects remains as area of research. Alcohol is also among the socio-environmental factors which has been recognised to cause a flare of symptoms in inflammatory bowel disease patients. Nonetheless, the exact relation to date is not fully understood, and various paradoxical results from different studies are still a point of controversy.

Communication of alcohol and smoking lifestyle advice to the gastroenterological patient.

Effective communication between healthcare staff and patients is central to development of the patient-professional relationship. Many barriers influence this communication, often resulting in patients' lack of understanding and retention of information, particularly affecting advice regarding lifestyle habits, such as alcohol consumption and smoking. Alcohol and smoking misuse are potentially modifiable risk factors known to adversely affect a variety of gastroenterological conditions and improvements in communication with patients regarding this is an important management component. This review discusses the clinical impact of these factors and how healthcare professionals can improve communication. We discuss how enhancing verbal communication skills through medical training leads to greater outcomes in patient satisfaction and adherence to treatment and advice. In addition, with the rapid digitalisation of society, platforms such as social media and smartphone applications may be considered as adjuncts to traditional forms of communication.

Preventing disability in inflammatory bowel disease.

Disability is a common worldwide health challenge and it has been increasing over the past 3 decades. The treatment paradigm has changed dramatically in inflammatory bowel diseases (IBDs) from control of symptoms towards full control of disease (clinical and endoscopic remission) with the goal of preventing organ damage and disability. These aims are broadly similar to rheumatoid arthritis and multiple sclerosis. Since the 1990s, our attention has focused on quality of life in IBD, which is a subjective measure. However, as an objective end-point in clinical trials and population studies, measures of disability in IBD have been proposed. Disability is defined as '…any restriction or lack (resulting from an impairment) of ability to perform an activity in the manner or within the range considered normal for a human being.' Recently, after 10 years of an international collaborative effort with the World Health Organization (WHO), a disability index was developed and validated. This index ideally would assist with the assessment of disease progression in IBD. In this review, we will provide the evidence to support the use of disability in IBD patients, including experience from rheumatoid arthritis and multiple sclerosis. New treatment strategies, and validation studies that have underpinned the interest and quantification of disability in IBD, will be discussed.