Clinical outcomes in pediatric inflammatory bowel disease patients: a systematic review of prospective studies.

BACKGROUND AND AIM: We studied response and remission rates in children and adolescents with inflammatory bowel disease whose real-world data were collected prospectively. METHODS: A systematic literature search was performed in MEDLINE, Embase, and the Improve Care Now registry from inception until March 17, 2022. Inclusion criteria were prospective studies with patients < 18 years at diagnosis (M0) and minimum follow-up of 1 year (M12) mentioning disease phenotype and disease activity. Exclusion criteria were (i) reporting disease activity only at diagnosis, (ii) retrospective studies, and (iii) outcome limited to steroid-free remission. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols guidelines and the Newcastle-Ottawa scale were applied. Proportions between groups were compared using a chi-square test (α = 0.05). RESULTS: The search yielded 394 records and 7 inclusions with a sample size ranging from 33 to 390 patients (total population: 888) and a median follow-up of 1-5 years. Proportions of disease activity differed between M0 and M12 (P < 0.0001) with more inactive (χ2  = 5.5) and less moderate-to-severe disease (χ2  = 23) at M12. Interestingly, disease activity after 1 year did not differ globally (P = 0.53). Proportions of disease activity in Crohn's disease only and limited to Belgium significantly differed from baseline after 5 years (P < 0.0001 for evolution) but not between 1- and 5-year follow-up (P = 0.94). CONCLUSIONS: The few available prospective cohorts reported a significant decrease in disease activity after 1 year, with no global differences. Proportions of disease activity did not differ between 1- and 5-year follow-up in the Belgian Crohn's disease cohort, suggesting stable disease activity.

Proton Pump Inhibitors Reduce Duodenal Eosinophilia, Mast Cells, and Permeability in Patients With Functional Dyspepsia.

BACKGROUND & AIMS: Despite the growing recognition of duodenal alterations in the pathophysiology of functional dyspepsia (FD), the effect and mechanism of proton pump inhibitors (PPIs) or first-line therapy remain unclear. We studied duodenal and systemic alterations in relation to PPI therapy in patients with FD and healthy volunteers (HVs). METHODS: We performed a prospective interventional study assessing symptoms (Patient Assessment of Gastrointestinal Symptom Severity Index), duodenal alterations, and systemic factors in patients with FD ("FD-starters") and HVs before and after PPI therapy (pantoprazole 40 mg once daily for 4 weeks). Duodenal mucosal eosinophils, mast cells and permeability were quantified. Luminal pH and bile salts were determined in duodenal aspirates. Procedures were also performed in PPI-refractory patients with FD ("FD-stoppers") before and 8 weeks after PPI withdrawal. Between- and within-group changes from baseline and associations with duodenal or systemic factors were analyzed using linear mixed models. RESULTS: The study was completed by 30 HV, 27 FD-starters, and 18 FD-stoppers. Symptoms and duodenal eosinophils, mast cells (all, P < .0001), and paracellular passage (P = .02) were significantly higher in FD-starters vs HVs and reduced with PPI therapy. Symptoms and duodenal immune cells also decreased in FD-stoppers off PPIs. In contrast, immune cells and permeability increased in HVs on PPIs. Dyspeptic symptoms correlated with eosinophils before and during PPI therapy, and increased eosinophils and permeability in HVs on PPIs were associated with changes in bile salts. CONCLUSIONS: We provide the first prospective evidence for eosinophil-reducing effects as a therapeutic mechanism of PPIs in FD, with differential effects in HVs pointing to a role of luminal changes. ClinicalTrials.gov, Number: NCT03545243.

Native species exhibit physiological habituation to invaders: a reason for hope.

Animals cope with environmental perturbations through the stress response, a set of behavioural and physiological responses aimed to maintain and/or return to homeostasis and enhance fitness. Vertebrate neuroendocrine axis activation in response to environmental stressors can result in the secretion of glucocorticoids (GCs), whose acute increases may be adaptive, while chronic elevation may be detrimental. Invasive grey squirrels (Sciurus carolinensis) act as a stressor eliciting elevation of GCs in native red squirrels (Sciurus vulgaris). Here we used 6-year data of variation in faecal glucocorticoid metabolite (FGM) concentrations following invasion by grey squirrels in three red squirrel populations, to identify if red squirrels showed physiological habituation to this stressor. The decrease in FGMs over time was more pronounced shortly after invasion and at high densities of grey squirrels while it decreased less strongly and was no longer influenced by the invader density as time since invasion elapsed. At the individual level, FGMs also decreased more markedly as each red squirrel experienced prolonged contact with the invader. Our study provides compelling new data suggesting that native species in the wild can habituate to prolonged contact with invasive species, showing that they may avoid the potentially harmful effects of chronic elevations in GCs.

Invasive alien species as an environmental stressor and its effects on coping style in a native competitor, the Eurasian red squirrel.

Free-living animals cope with environmental stressors through physiological and behavioural responses. According to the unidimensional model, these responses are integrated within a coping style: proactive individuals (bold, active-explorative and social) have a lower hypothalamic-pituitary-adrenal (HPA) axis reactivity than reactive ones (shy, less active-explorative, less social). These associations may change when individuals are exposed to human-induced rapid environmental change (HIREC), such as the introduction of invasive alien species (IAS). Here, we studied Eurasian red squirrels to investigate the relationship between personality traits and one integrated measure of HPA axis activity, both in areas uncolonized (natural populations) and colonized by an IAS, the Eastern grey squirrel (invaded populations). We expected an association between physiological and behavioural responses, and that activity, exploration and social tendency would covary, forming a behavioural syndrome in natural populations, while competition with the IAS was predicted to disrupt these associations. We used faecal glucocorticoid metabolites (FGMs) as an integrated measure of adrenocortical activity, and measured the levels of four personality traits (exploration, activity, activity-exploration and social tendency) with an open field test and a mirror image stimulation test. We found no correlation between FGMs and personality traits, neither in natural nor invaded populations. However, we found correlations among personality traits in areas without interspecific competition, indicating a behavioural syndrome, which was disrupted in invaded populations. This is one of the few studies showing that an IAS, acting as an environmental stressor, alters a native species' behavioural syndrome, but does not influence its coping style.

Personality traits, sex and food abundance shape space use in an arboreal mammal.

Animal space use is affected by spatio-temporal variation in food availability and/or population density and varies among individuals. This inter-individual variation in spacing behaviour can be further influenced by sex, body condition, social dominance, and by the animal's personality. We used capture-mark-recapture and radio-tracking to examine the relationship between space use and personality in Eurasian red squirrels (Sciurus vulgaris) in three conifer forests in the Italian Alps. We further explored to what extent this was influenced by changes in food abundance and/or population density. Measures of an individual's trappability and trap diversity had high repeatability and were used in a Principal Component Analysis to obtain a single personality score representing a boldness-exploration tendency. Males increased home-range size with low food abundance and low female density, independent of their personality. However, bolder males used larger core-areas that overlapped less with other males than shy ones, suggesting different resource (food, partners) utilization strategies among personality types. For females, space use-personality relationships varied with food abundance, and bolder females used larger home ranges than shy ones at low female density, but the trend was opposite at high female density. Females' intrasexual core-area overlap was negatively related to body mass, with no effect of personality. We conclude that relationships between personality traits and space use in free-ranging squirrels varied with sex, and were further influenced by spatio-temporal fluctuations in food availability. Moreover, different personality types (bold-explorative vs. shy) seemed to adopt different space-use strategies to increase access to food and/or partners.

Duodenal Dysbiosis and Relation to the Efficacy of Proton Pump Inhibitors in Functional Dyspepsia.

Proton pump inhibitors (PPI) may improve symptoms in functional dyspepsia (FD) through duodenal eosinophil-reducing effects. However, the contribution of the microbiome to FD symptoms and its interaction with PPI remains elusive. Aseptic duodenal brushings and biopsies were performed before and after PPI intake (4 weeks Pantoprazole 40 mg daily, FD-starters and controls) or withdrawal (2 months, FD-stoppers) for 16S-rRNA sequencing. Between- and within-group changes in genera or diversity and associations with symptoms or duodenal factors were analyzed. In total, 30 controls, 28 FD-starters and 19 FD-stoppers were followed. Mucus-associated Porphyromonas was lower in FD-starters vs. controls and correlated with symptoms in FD and duodenal eosinophils in both groups, while Streptococcus correlated with eosinophils in controls. Although clinical and eosinophil-reducing effects of PPI therapy were unrelated to microbiota changes in FD-starters, increased Streptococcus was associated with duodenal PPI effects in controls and remained higher despite withdrawal of long-term PPI therapy in FD-stoppers. Thus, duodenal microbiome analysis demonstrated differential mucus-associated genera, with a potential role of Porphyromonas in FD pathophysiology. While beneficial effects of short-term PPI therapy were not associated with microbial changes in FD-starters, increased Streptococcus and its association with PPIeffects in controls suggest a role for duodenal dysbiosis after long-term PPI therapy.

Novel concepts in the pathophysiology and treatment of functional dyspepsia.

Emerging data increasingly point towards the duodenum as a key region underlying the pathophysiology of functional dyspepsia (FD), one of the most prevalent functional GI disorders. The duodenum plays a major role in the control and coordination of gastroduodenal function. Impaired duodenal mucosal integrity and low-grade inflammation have been associated with altered neuronal signalling and systemic immune activation, and these alterations may ultimately lead to dyspeptic symptoms. Likely luminal candidates inducing the duodenal barrier defect include acid, bile, the microbiota and food antigens although no causal association with symptoms has been convincingly demonstrated. Recognition of duodenal pathology in FD will hopefully lead to the discovery of new biomarkers and therapeutic targets, allowing biologically targeted rather than symptom-based therapy. In this review, we summarise the recent advances in the diagnosis and treatment of FD with a focus on the duodenum.

Spillover of an alien parasite reduces expression of costly behaviour in native host species.

Understanding the effects of invasive alien species (IAS) on native host-parasite relationships is of importance for enhancing ecological theory and IAS management. When IAS and their parasite(s) invade a guild, the effects of interspecific resource competition and/or parasite-mediated competition can alter existing native host-parasite relationships and the dependent biological traits such as native species' behaviour. We used a natural experiment of populations of native red squirrels Sciurus vulgaris that were colonized by the alien grey squirrel Sciurus carolinensis, comparing repeated measurements of red squirrel parasite infection and personality with those taken in sites where only the native species occurred. We explored two alternative hypotheses: (a) individual differences in personality traits (activity and/or sociability) of native red squirrel positively affect the probability of macroparasite spillover and thus the likelihood to acquire the alien's parasitic helminth Strongyloides robustus; (b) the combined effects of grey squirrel presence and parasite infection result in a reduction of costly personality traits (activity and/or exploration). Using data from 323 arena tests across three experimental (native species and IAS) and three control sites (only native species), we found negative correlations between native species' activity and infection with S. robustus in the sites invaded by the alien species. Activity was also negatively correlated with infection by its native helminth Trypanoxyuris sciuri but only when grey squirrels were present, while in the red-only sites there was no relationship of T. sciuri infection with any of the personality traits. Moreover, individuals that acquired S. robustus during the study reduced their activity after infection, while this was not the case for animals that remained uninfected. Our results show that parasite-mediated competition is costly, reducing activity in individuals of the native species, and altering the native host-native parasite relationships.

Stress in biological invasions: Introduced invasive grey squirrels increase physiological stress in native Eurasian red squirrels.

Invasive alien species can cause extinction of native species through processes including predation, interspecific competition for resources or disease-mediated competition. Increases in stress hormones in vertebrates may be associated with these processes and contribute to the decline in survival or reproduction of the native species. Eurasian red squirrels (Sciurus vulgaris) have gone extinct across much of the British Isles and parts of Northern Italy following the introduction of North American invasive grey squirrels (Sciurus carolinensis). We extracted glucocorticoid metabolites from faecal samples to measure whether the presence of the invasive species causes an increase in physiological stress in individuals of the native species. We show that native red squirrels in seven sites where they co-occurred with invasive grey squirrels had glucocorticoid concentrations that were three times higher than those in five sites without the invasive species. Moreover, in a longitudinal study, stress hormones in native red squirrels increased after colonisation by grey squirrels. When we experimentally reduced the abundance of the invasive grey squirrels, the concentration of faecal glucocorticoid metabolites in co-occurring red squirrels decreased significantly between pre- and postremoval periods. Hence, we found that the invasive species acts as a stressor which significantly increases the concentrations of glucocorticoids in the native species. Given that sustained elevations in glucocorticoids could reduce body growth and reproductive rate, our results are consistent with previous studies where the co-occurrence of the invasive grey squirrel was associated with smaller size and lower reproductive output in red squirrels.

Cow's Milk Allergy Prescribing Is Influenced by Regional and National Guidance.

OBJECTIVES: Cow's milk allergy (CMA) is the most common food allergy in children with many clinical manifestations, leading to misdiagnoses such as gastro-oesophageal reflux, infantile colic, and lactose intolerance with inappropriate prescribing. We aimed to determine the impact of infant feeding guidelines on CMA prescribing in UK primary care using a simple and inexpensive training package. METHODS: Prospectively collected data of infant feeding prescriptions in Northern Ireland from June 2012 to March 2014 were analysed with the intervention period between November 2012 and March 2013. A comparison was made between hypoallergenic formulae, appropriate for CMA, versus alternative prescriptions including antiregurgitation and colic products, lactose-free and partially hydrolysed milks, or infant Gaviscon. RESULTS: Comparing pre- and postintervention period, the total quantity of hypoallergenic formulae increased by 63.2% and alternative prescriptions decreased by 44.6% (P < 0.001). The total amount of all prescribed products decreased by 41.0% (P < 0.001). During the study period, the proportion of recommended CMA treatment increased from 3.4% before training to 9.8% in the short- and long-term follow-up (P < 0.001). The overall increase was £33,508 per year or £95.5 per general practitioner's surgery. CONCLUSIONS: We present the first study evaluating the impact of infant feeding guidelines on CMA prescribing in UK primary care. Practical advice and teaching of health professionals allowed for effective implementation of regional and national guidelines, with a significant impact on prescription patterns. This study shows promising results for prospective research on a national scale, including socioeconomical impact and cost-effectiveness.

Biodiversity threats from outside to inside: effects of alien grey squirrel (Sciurus carolinensis) on helminth community of native red squirrel (Sciurus vulgaris).

Biological invasions are among the major causes of biodiversity loss worldwide, and parasites carried or acquired by invaders may represent an added threat to native species. We compared gastrointestinal helminth communities of native Eurasian red squirrels (Sciurus vulgaris) in the presence and absence of introduced Eastern grey squirrels (Sciurus carolinensis) to detect alterations induced by the alien species. In particular, we investigated whether spillover of a North American nematode Strongyloides robustus occurs and whether prevalence of a local parasite Trypanoxyuris sciuri in red squirrels is affected by grey squirrel presence. The probability of being infected by both parasites was significantly higher in areas co-inhabited by the alien species, where 61 % of examined red squirrels (n = 49) were infected by S. robustus and 90 % by T. sciuri. Conversely, in red-only areas, the two parasites infected only 5 and 70 % of individuals (n = 60). Overall, our findings support the hypothesis that red squirrels acquire S. robustus via spillover from the alien congener and suggest that invaders' presence may also indirectly affect infection by local parasites through mechanisms diverse than spill-back and linked to the increased competitive pressure to which red squirrels are subjected. These results indicate that the impact of grey squirrel on red squirrels may have been underestimated and highlight the importance of investigating variation in macroparasite communities of native species threatened by alien competitors.

Celiac disease: Hope for new treatments beyond a gluten-free diet.

BACKGROUND & AIMS: Celiac disease (CD) is a chronic inflammatory disease of the small intestine induced and maintained by gluten ingestion in susceptible individuals. Current treatment consists of strict adherence to a lifelong gluten-free diet (GFD) which is considered safe and effective in the large majority of patients. However, since adherence to a GFD is difficult and has a negative impact on quality of life, an increasing interest in other treatment options has emerged. Moreover, in some individuals a GFD is not sufficiently effective, necessitating alternative treatments. METHODS: By performing a systematic search, we constructed a detailed narrative review. Only treatment options considered relevant and conducted in a phase I, II or III clinical trial were included. RESULTS: Based on the pathophysiology of CD, four major therapeutic approaches can be distinguished: firstly, by focusing on intraluminal gluten detoxification before absorption occurs, secondly, by modulating intestinal permeability and preventing paracellular uptake, thirdly, by enhancing immunological tolerance to gluten and finally, by regulating gluten auto-immunity. CONCLUSIONS: Despite significant efforts, no treatment has yet completed a phase III clinical trial. Future studies will likely focus on the use of supplemental drugs in conjunction to a GFD, with ALV003 and ZED-1227 currently being the most promising therapeutic options.

Use of infrared thermography to detect reactions to stressful events: does animal personality matter?

The study of the relationship between animal stress and personality for free-ranging animals is limited and provides contrasting results. The perception of stressors by an individual may vary due to its personality, and certain personality traits may help individuals to better cope with them. Using non-invasive infrared thermography (IRT), we investigated the link between physiological and behavioral components expressed during an acute stress event by free-ranging Fremont's squirrels (Tamiasciurus fremonti). We expected that, during the acute stress event of being approached by the researcher, individuals that showed a fast pace-of-life syndrome (bolder, more active, and less social/more aggressive) based on an arena test would exhibit stronger sympathetic-adrenal-medullary system reactivity showing a more intense stress-induced hyperthermia (high core body temperature and low peripheral temperature) than individuals with a slow pace of life (shy, less active, and more social). We successfully employed IRT technology to images of Fremont's squirrels with identification of the individuals' body parts (eye, nose, ear, hind foot). However, we found no support for our hypothesis. Squirrels' body surface temperatures told us more about a squirrel's external environment and less about the thermal state of the body in that environment following a stressful event. Further studies need to assess how to make IRT effective and efficient in the field and improve its performance in studying the relationships between physiology and personality in wildlife.