Assessing adherence to objective disease monitoring and outcomes with adalimumab in a real-world IBD cohort.

BACKGROUND: Data suggests that tight objective monitoring may improve clinical outcomes in IBD. AIM: To assess the adherence to serial tight objective monitoring(clinical and biomarkers) and its effect on clinical outcomes. METHODS: We retrospectively reviewed the chart of 428 consecutive IBD patients started on adalimumab between January 1,2015-January 1,2019 [338 Crohn's disease(CD), 90 ulcerative colitis(UC)]. Clinical symptoms(assessed by Harvey-Bradshaw-Index,partial Mayo),C-Reactive Protein(CRP), and fecal calprotectin(FCAL) assessments were captured at treatment initiation and at 3,6,9, and12 months. Dose optimization and drug sustainability curves were plotted by Kaplan-Meier method. RESULTS: Clinical evaluation was available in nearly all patients at 3(CD-UC:95-94%), 6(90-83%), 9(86-85%) and 12(96-89%) months. CRP testing frequency decreased in CD patients over time. Compliance to serial FCAL testing was low. Clinical remission at one-year was higher in patients adherent to early assessment visit at 3 months(p = 0.001 for CD and UC). Adherence to early follow-up resulted in earlier dose optimization in CD and UC patients(pLogrank=0.026 for UC & p = 0.09 for CD). Overall drug sustainability did not differ. CONCLUSION: Clinical & CRP, but not FCAL, were frequently assessed in patients starting adalimumab. Adherence to early objective combined follow-up visits resulted in earlier dose optimization, improved one-year clinical outcomes but did not change drug sustainability.

Signalling of information that is neither cryptic nor private.

It is commonly assumed that in order for animal signals to be advantageous, the information being signalled could not have been obtained otherwise, and is therefore 'cryptic' or 'private'. Here, we suggest a scenario in which individuals can gain an advantage by signalling 'public' information that is neither cryptic nor private. In that scenario, signalling increases the efficiency with which that 'public' information is transmitted. We formalize our idea with a game in which offspring can signal their condition to their parents. Specifically, we consider a resource-strapped parent who can only invest in one of its two offspring, and we allow offspring the chance to influence parental investment through a signal. A parent in the game seeks to invest in the higher-quality offspring, which it could identify either through a publicly available cue, such as body size, or by relying on a signal provided by the offspring. We find that if the signal can convey information about offspring quality more efficiently than cues, then signalling of condition between offspring and parents can be favoured by selection, even though parents could potentially have acquired the same information from the cue. Our results suggest that the biological function of signals may be broader than currently considered, and provide a scenario where low cost signalling can be favoured. More generally, efficiency benefits could explain signalling across a range of biological and economic scenarios.

The association between the emergence of cooperative breeding and clutch size.

Previous theoretical work has suggested that smaller brood sizes helped facilitate the emergence of cooperative breeding in birds. However, recent empirical evidence has found no statistically significant difference between the clutch sizes of cooperative breeders and that of noncooperative breeders. One explanation for this finding is that while small clutch sizes may predispose species to cooperative breeding, the emergence of cooperative breeding itself may influence the evolution of clutch size. Here, we develop a set of models using population dynamics to describe how the emergence of cooperative breeding influences clutch size. We find, in contrast to previous theoretical work, that the emergence of cooperative breeding does not necessarily decrease (and under certain conditions may actually increase) clutch size. In particular, clutch size may increase after the emergence of cooperative breeding if helpers--philopatric individuals that assist their breeding relatives--are able to substantially improve breeder fecundity at low costs to their own survival, and if the association between breeder and helper is brief. In many cases, clutch size increases following the emergence of cooperative breeding not because it is optimal for the breeder, but as the result of breeder-helper conflict over resource allocation.

Subcutaneous ustekinumab for the treatment of anti-TNF resistant Crohn's disease--the McGill experience.

BACKGROUND: Ustekinumab is a fully human IgG1κ monoclonal antibody that blocks the biologic activity of interleukin-12/23. Ustekinumab is approved for treatment of plaque psoriasis and has been shown to be effective for induction and maintenance of clinical response in anti-TNF resistant Crohn's disease (CD). The aim of the study was to describe the real-life experience with open-label use of ustekinumab in anti-TNF resistant CD patients. METHODS: A retrospective observational open-label study. Clinical response was defined by physician's global assessment combined with decision to continue therapy. The clinical response was evaluated at 3, 6, 12months and last follow-up. RESULTS: Thirty-eight patients were included in the study. Initial clinical response was achieved in 28/38 (73.7%) of the patients. Among the initial responders, 80% with follow-up data maintained their response for 6months. At 12months of follow-up, 88.9% of patients responding at 6months maintained their response. At the last follow-up (7.9±5.2 mo) 27/38 (71%) of the patients were responding, and 73.3% were able to discontinue corticosteroids. Dose escalation was required in 47.7% of the patients and was successful in 61.1% of them. SUMMARY: In this real-life cohort of severe anti-TNF resistant CD, an initial clinical response to subcutaneous ustekinumab was observed in 73.7% of the patients. The initial response was successfully maintained in the majority of patients for up to 12months. Subcutaneous ustekinumab is an effective therapeutic option in this challenging patient cohort. The optimal dosing and injection schedule remain to be established in future studies.

Serological testing for coeliac disease in Type 1 diabetes mellitus: is immunoglobulin A level measurement necessary?

AIMS: Immunoglobulin A (IgA) measurement is advocated when case finding for coeliac disease in patients with Type 1 diabetes mellitus. Currently, there is a paucity of contemporary studies assessing IgA deficiency in Type 1 diabetes. This study evaluates the prevalence of IgA deficiency in individuals with Type 1 diabetes, compared with patients with coeliac disease and control subjects. In addition, we evaluate whether routine IgA measurement is justifiable when case finding for coeliac disease in patients with Type 1 diabetes. METHODS: All patients were assessed using IgA endomysial antibodies, IgA anti-tissue transglutaminase antibodies and total IgA levels. Altogether, 2434 individuals were tested: 1000 patients with Type 1 diabetes, 234 patients with coeliac disease and 1200 population control subjects. Definitive IgA deficiency was defined as total IgA levels < 0.07 g/l. RESULTS: The prevalence of IgA deficiency was significantly more common in patients with Type 1 diabetes (0.9%, n = 9/1000; P = 0.036) and coeliac disease (1.29%, n = 3/234; P = 0.041) when compared with population control subjects (prevalence of 0.17%, 2/1200). No statistical difference between Type 1 diabetes and coeliac disease for IgA deficiency was identified (P = 0.87). Of patients in the group with Type 1 diabetes, 3.3% (33/1000) had coeliac disease, and of those only one patient had IgA deficiency leading to an antibody-negative presentation. Both IgA-deficient individuals within the population control subjects had normal duodenal biopsies and no relevant symptoms. CONCLUSIONS: IgA deficiency is more common in Type 1 diabetes compared with population control subjects. Despite this, very few individuals with Type 1 diabetes and IgA deficiency appear to have villous atrophy on biopsy. These outcomes question the practice of routine IgA measurement when case finding for coeliac disease in patients with Type 1 diabetes.

Quality not quantity for transglutaminase antibody 2: the performance of an endomysial and tissue transglutaminase test in screening coeliac disease remains stable over time.

National Institute of Clinical Excellence (NICE) and European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) guidance for the diagnosis of coeliac disease has been published. However, there is some controversy regarding the advice on the use of stratifying levels of immunoglobulin (IgA) tissue transglutaminase antibody (TG2) test positivity in the absence of test standardization and the vagueness of the indication to test equivocal samples. Using repeat service audit, we demonstrate that a combination of TG2 followed by IgA endomysial antibodies (EMA) is the best strategy for all degrees of mucosal abnormality using our test combination. Reliance upon immunoassay titre is not as effective, and cannot be applied consistently across populations in the absence of assay standardization. Guidelines advocating the use of tests should involve experts in laboratory diagnostics and external quality assurance to ensure that errors of generalization do not occur and that test performance is achievable in routine diagnostic use.

Direct fitness for dynamic kin selection.

The direct-fitness approach to modelling the evolution of social traits is an alternative to the classical inclusive-fitness-based approach. Despite both its utility and popularity, the direct-fitness approach has not yet been extended to include the analysis of dynamic traits, i.e. traits whose level of expression may vary over time. In this article, I apply the direct-fitness approach to cope with the evolution of a dynamic resource-allocation behaviour when this behaviour influences the fitness of relatives. I am able to implement the direct-fitness approach using components (reproductive value, fitness changes and measures of relatedness) found in standard, social-evolutionary models. I illustrate the modified direct-fitness model with an example studied by previous authors, and I show how the direct-fitness perspective can aid the validation of analytical results by means of a genetic algorithm.

The genetical theory of kin selection.

Natural selection operates both directly, via the impact of a trait upon the individual's own fitness, and indirectly, via the impact of the trait upon the fitness of the individual's genetically related social partners. These effects are often framed in terms of Hamilton's rule, rb - c > 0, which provides the central result of social-evolution theory. However, a number of studies have questioned the generality of Hamilton's rule, suggesting that it requires restrictive assumptions. Here, we use Fisher's genetical paradigm to demonstrate the generality of Hamilton's rule and to clarify links between different studies. We show that confusion has arisen owing to researchers misidentifying model parameters with the b and c terms in Hamilton's rule, and misidentifying measures of genotypic similarity or genealogical relationship with the coefficient of genetic relatedness, r. More generally, we emphasize the need to distinguish between general kin-selection theory that forms the foundations of social evolution, and streamlined kin-selection methodology that is used to solve specific problems.

Raised tryptase without anaphylaxis or mastocytosis: heterophilic antibody interference in the serum tryptase assay.

Mast cell tryptase (MCT) is a key diagnostic test for mastocytosis and anaphylaxis. High serum tryptase levels are also one of the risk factors for adverse reaction in venom immunotherapy, yet occasional patients are seen with raised levels in the absence of either diagnosis. False positive results can be due to assay interference by heterophilic antibodies such as rheumatoid factor (RF) and human anti-mouse antibodies (HAMA). We therefore investigated heterophilic antibody interference by rheumatoid factor activity and HAMA as a cause of raised MCT results in the Phadia tryptase assay. Serum samples from 83 patients were assayed for MCT and rheumatoid factor before and after the use of heterophilic antibody blocking tubes (HBT). Samples with more than 17% reduction in MCT with detectable RF were then assayed for HAMA. Fourteen (17%) of the 83 samples with positive RF showed a >17% decrease in mast cell tryptase after HBT blocking. Post-HBT, eight of 14 (57%) reverted from elevated to normal range values with falls of up to 98%. RF levels were also decreased significantly (up to 75%). Only one of the 83 tested was apparently affected by HAMA in the absence of detectable IgM RF. In conclusion, any suspicious MCT result should be checked for heterophilic antibodies to evaluate possible interference. False positive MCT levels can be caused by rheumatoid factor. We suggest a strategy for identifying assay interference, and show that it is essential to incorporate this caveat into guidance for interpretation of MCT results.

Investment in the public good through conditional phenotypes of large effect.

We investigate the evolution of an individual's willingness to invest in a public good (what we call, helping) in a patch-structured population with limited natal dispersal. We assume that an individual's decision to invest is informed by its dispersal status: an individual makes one decision given it is native to the patch on which it breeds, and is free to make a different decision given that it is not native to the patch on which it breeds. Unlike previous work, we assume that investment in the public good, and the public good, itself, both have a large effect on individual fecundity. Kin selection analysis reveals that only extreme investment decisions (i.e. 'always invest' or 'never invest') can be evolutionarily stable. Numerical results suggest that the evolutionary instability of the 'never invest' phenotype (what we call, complete nonhelping) implies the evolutionary stability of 'always invest' (what we call, complete helping). In addition, numerical results show that bistability of extreme phenotypes is possible, indicating that the adaptive significance of altruism, in this context, is greater than has been previously recognized. Numerical results are supported by computer simulation, and results, themselves, are briefly discussed in a concluding section.

Severe insulin resistance secondary to insulin antibodies: successful treatment with the immunosuppressant MMF.

We have evaluated the use of the immunosuppressant mycophenolate mofetil (MMF) in the treatment of severe insulin resistance caused by neutralising anti-insulin antibodies in type 1 diabetes mellitus (T1DM). A 12-yr-old boy with a 5-month history of T1DM developed severe immunological insulin resistance secondary to human insulin antibodies. Various different treatment modalities, including lispro insulin, intravenous insulin, prednisolone and immunoabsorption, were tried, all without a sustained response to treatment. Although the introduction of the immunosuppressant MMF only resulted in a small reduction in haemoglobin A1c (from 10.9 to 9.8%), it did result in a significant reduction in insulin requirements from 6000 to 250 U/d (75 to 3.1 U/kg/d), disappearance of the severe nocturnal hypoglycaemia associated with high titres of insulin antibodies and a reduction in the level of these antibodies from 34.6 to 2.7 mg/dL. MMF may be considered as a means of immunosuppression in patients with markedly raised insulin antibodies whose diabetes cannot be controlled with insulin alone.

Predicting relapse in Crohn's disease: a biopsychosocial model.

BACKGROUND: Crohn's disease (CD) is a chronic relapsing inflammatory bowel disorder. Both biological and psychosocial factors may modulate the illness experience. AIM: The aim of this study was to identify clinical, biological and psychosocial parameters as predictors of clinical relapse in quiescent CD. METHODS: Patients in medically induced remission were followed prospectively for 1 year, or less if they relapsed. Disease characteristics were determined at baseline. Serum cytokines, anti-Saccharomyces cerevisiae antibodies, C-reactive protein (CRP), erythrocyte sedimentation rate and intestinal permeability were measured every 3 months. Psychological distress, perceived stress, minor life stressors and coping strategies were measured monthly. A time-dependent multivariate Cox regression model determined predictors of time to relapse. RESULTS: 101 patients (60 females, 41 males) were recruited. Fourteen withdrew and 37 relapsed. CRP (HR = 1.5 per 10 mg/l, 95% CI 1.1 to 1.9, p = 0.007), fistulising disease (HR = 3.2, 95% CI, 1.1 to 9.4, p = 0.04), colitis (HR = 3.5 95% CI 1.2 to 9.9, p = 0.02) and the interaction between perceived stress and avoidance coping (HR = 7.0 per 5 unit increase for both scales, 95% CI 2.3 to 21.8, p = 0.003) were predictors of earlier relapse. CONCLUSIONS: In quiescent CD, a higher CRP, fistulising disease behaviour and disease confined to the colon were independent predictors of relapse. Moreover, patients under conditions of low stress and who scored low on avoidance coping (ie, did not engage in social diversion or distraction) were least likely to relapse. This study supports a biopsychosocial model of CD exacerbation.

Dietary lipids alter the effect of steroids on the transport of fructose following intestinal resection in rats.

BACKGROUND: Glucocorticosteroids alter intestinal morphology and transport. We tested the hypothesis that the desired intestinal adaptive response following intestinal resection may be enhanced further by the locally active steroid budesonide, and by feeding a saturated as compared with a polyunsaturated fatty acid diet. METHODS: An in-vitro uptake method was used to assess intestinal fructose uptake by rats of semisynthetic diets enriched in saturated or polyunsaturated fatty acids, and injected with budesonide or control solution. RESULTS: Budesonide increased ileal fructose uptake in chow and PUFA-fed animals, but reduced jejunal fructose uptake in rats fed SFA. GLUT5 and GLUT2 protein and mRNA did not correlate with changes in fructose uptake. Steroids reduced jejunal proglucagon expression in animals fed chow. Animals fed SFA and given budesonide had a reduction in jejunal ODC mRNA compared with those fed PUFA or chow. CONCLUSIONS: (1) budesonide increases ileal fructose uptake following intestinal resection, and this beneficial effect is prevented by feeding SFA rather than PUFA; (2) fructose uptake does not correlate with GLUT5 and GLUT2 protein and mRNA; (3) ODC and proglucagon may be involved in this adaptive response.

Phytophotodermatitis after gardening.

Phytophotodermatitis, otherwise known as 'Strimmer's Rash' is an unusual cause of a widespread rash. We present a case of phytophotodermatitis, which was initially misdiagnosed as chickenpox; the correct diagnosis was made after further careful history taking and illustrates the importance of taking a thorough history when presented with what appears to be a spot diagnosis.

Vertebral wedge fracture after speedboat 'splash down'.

A case is presented of a soldier with wedge fracture of T12 sustained after an axial compression (+/- flexion) injury in a Rigid-Hull Inflatable Boat (RIB). Very powerful boats, such as RIBs, are used on a daily basis in the Royal Navy (RN). Despite this, fractures of the spine are unusual (1). This study explores the mechanism of injury and illustrates that a wedge fracture should be considered in anyone presenting with back pain after a 'splash down' injury.

Oral polyamine administration modifies the ontogeny of hexose transporter gene expression in the postnatal rat intestine.

Gastrointestinal mucosal polyamines influence enterocyte proliferation and differentiation during small intestinal maturation in the rat. Studies in postnatal rats have shown that ornithine decarboxylase (ODC) protein and mRNA peak before the maximal expression of brush-border membrane (BBM) sucrase-isomaltase (SI) and the sugar transporters sodium-dependent glucose transporter 1 (SGLT1) and glucose transporter 2 (GLUT2). This study was undertaken to test the hypothesis that the oral administration of spermidine in postnatal rats upregulates the expression of ODC, thereby enhancing the expression of SI and SGLT1 in the brush-border membrane as well as basolateral membrane-facilitative GLUT2 and Na(+)-K(+)-ATPase. Northern and Western blot analyses were performed with antibodies and cDNA probes specific for SI, SGLT1, GLUT2, alpha(1)- and beta(1)-subunits of Na(+)-K(+)-ATPase, and ODC. Postnatal rats fed 6 mumol spermidine daily for 3 days from days 7 to 9 were killed either on postnatal day 10 (Sp10) or day 13 following a 3-day washout period (Sp13). Sp10 rats showed a precocious increase in the abundance of mRNAs for SI, SGLT1, and GLUT2 and Na(+)-K(+)-ATPase activity and alpha(1)- and beta(1)-isoform gene expression compared with controls. ODC activity and protein and mRNA abundance were also increased in Sp10 animals. The increased expression of these genes was not sustained in Sp13 rats, suggesting that these effects were transient. Thus, 3 days of oral polyamine administration induces the precocious maturation of glucose transporters in the postnatal rat small intestine, which may be mediated by alterations in ODC expression.

Fixation probabilities when generation times are variable: the burst death model.

Estimating the fixation probability of a beneficial mutation has a rich history in theoretical population genetics. Typically, to attain mathematical tractability, we assume that generation times are fixed, while the number of offspring per individual is stochastic. However, fixation probabilities are extremely sensitive to these assumptions regarding life history. In this article, we compute the fixation probability for a "burst-death" life-history model. The model assumes that generation times are exponentially distributed, but the number of offspring per individual is constant. We estimate the fixation probability for populations of constant size and for populations that grow exponentially between periodic population bottlenecks. We find that the fixation probability is, in general, substantially lower in the burst-death model than in classical models. We also note striking qualitative differences between the fates of beneficial mutations that increase burst size and mutations that increase the burst rate. In particular, once the burst size is sufficiently large relative to the wild type, the burst-death model predicts that fixation probability depends only on burst rate.