Investigating the role of faecal calprotectin in luminal gastroenterology

Providing a sensitive, non-invasive, cheap marker of disease activity inflammatory bowel disease (IBD) comprises an area of ongoing interest and unmet clinical need. In previous years, options included only serum CRP (poorly sensitive and specific), colonoscopy (invasive, costly, perforation risk, inability to view proximal small bowel), CT (costly, ionising radiation risk) and radiolabelled white cell scanning (costly, poor sensitivity). My thesis describes a series of trials performed to establish the role of faecal calprotectin to define current disease activity in IBD patients. Prompted by studies demonstrating the potential role for a novel faecal marker of clinical utility in the context of NSAID enteropathy, we chose to investigate the role of this biomarker, faecal calprotectin (FC), in Crohn’s disease. To facilitate this I used existing cohorts and then generated new cohorts in which to address fundamental and clinically relevant questions of importance. We compared FC to radiolabelled white cell scanning in our first study which initiated and established a mutually beneficial collaboration between luminal gastroenterology and clinical biochemistry. Thereafter we recruited a rigorously phenotyped cohort of Crohn’s disease patients in remission to answer two separate research questions. First, was there a significant intra-individual variability of FC and secondly, would FC sampling in remission predict future relapse over the ensuing 12 months? Thereafter, in a new cohort, we investigated whether we were over-investigating new GP referrals to the GI clinic with only mildly elevated FC values. Finally, and most recently, we sought to investigate whether or not there was any correlation between serum calprotectin and FC in a new unselected GI cohort of patients, thereby potentially obviating the need for our patients to collect stool samples. Our data demonstrated that FC correlated well with radiolabelled white cell scanning in assessment of Crohn’s disease activity, thereby potentially avoiding this costly test as part of disease monitoring. In addition, we defined an acceptable intra-individual variability of FC in Crohn’s disease to support the clinical utility of one off testing using FC. Our prospective dataset revealed that an FC in remission can indeed stratify Crohn’s disease patients to estimate future relapse risk thereby allowing us to personalise medical therapies with more aggressive therapeutics employed in those with Crohn’s disease in remission but with residual high FC. The work we undertook in our primary care dataset revealed an extremely low yield of investigating mildly elevated FC and thus we developed a new shared protocol with our GP colleagues in which serial FC testing is recommended rather than referral to secondary care for such patients. Lastly, our most recent work demonstrated that there was no significant correlation between serum and FC in an unselected GI cohort meaning the search for a GI-specific serum biomarker of inflammation goes on – this is in accord with a variety of other chronic inflammatory diseases in which circulating biomarkers have proven challenging to find and especially to validate. This body of work has been presented nationally and internationally at meetings, and has been published in discipline relevant, peer reviewed medical journals. Moreover, it has supported the adoption of FC into everyday NHS GI practice. We were the first UK hospital to establish an NHS service for this biomarker in 2007 when we performed around 50 assays per month. Currently, the test is in widespread use and the Glasgow Royal Infirmary biochemistry lab now analyses 1400 samples per month. This has become an established non-invasive, cheap, sensitive marker of IBD activity in clinical practice, often avoiding the need for colonoscopy for the purposes of disease activity monitoring. This biomarker is also being used to gauge the success or failure of medical therapies in IBD and is a useful tool to differentiate irritable bowel syndrome from IBD. The clinical utility of the test has allowed GPs to triage referrals and often avoid referrals completely and has engaged patients in the self-monitoring of their IBD

Urinary proteomics can define distinct diagnostic inflammatory arthritis subgroups

Current diagnostic tests applied to inflammatory arthritis lack the necessary specificity to appropriately categorise patients. There is a need for novel approaches to classify patients with these conditions. Herein we explored whether urinary proteomic biomarkers specific for different forms of arthritis (rheumatoid arthritis (RA), psoriatic arthritis (PsA), osteoarthritis (OA)) or chronic inflammatory conditions (inflammatory bowel disease (IBD)) can be identified. Fifty subjects per group with RA, PsA, OA or IBD and 50 healthy controls were included in the study. Two-thirds of these populations were randomly selected to serve as a training set, while the remaining one-third was reserved for validation. Sequential comparison of one group to the other four enabled identification of multiple urinary peptides significantly associated with discrete pathological conditions. Classifiers for the five groups were developed and subsequently tested blind in the validation test set. Upon unblinding, the classifiers demonstrated excellent performance, with an area under the curve between 0.90 and 0.97 per group. Identification of the peptide markers pointed to dysregulation of collagen synthesis and inflammation, but also novel inflammatory markers. We conclude that urinary peptide signatures can reliably differentiate between chronic arthropathies and inflammatory conditions with discrete pathogenesis

Dietary treatment of Crohn’s disease: perceptions of families with children treated by exclusive enteral nutrition, a questionnaire survey

Background: Diet is strongly associated with the aetiology of Crohn’s Disease (CD) and exclusive enteral nutrition (EEN) is the primary induction treatment in paediatric CD. This study explored opinions around the use of EEN and alternative novel, solid food-based diets (SFDs) expressed by paediatric patients with CD, previously treated with EEN and their parents. Methods: This anonymous questionnaire surveyed families of CD patients treated with EEN over 1 year. Two questionnaire forms were completed; one asking the patients’ opinions and another referring to their main carer. This questionnaire explored participants’ demographic characteristics; acceptability of a repeat EEN course to treat a future flare (EEN repeat); their opinion on how difficult EEN would be compared to an example SFD; and their intention to participate in a future clinical trial assessing the therapeutic efficacy of an SFD in CD. Results: Forty-one families of CD patients were approached with 29 sending replies (71%). Most of our participants were positive on completing another EEN course, however the majority would choose an SFD alternative (Patients: 66, Parents:72%). Both patients and their parents rated EEN to be more difficult to adhere to compared to an example SFD (p < 0.05), and their ratings were strongly correlated (EEN:r = 0.83, SFD:r = 0.75, p < 0.001). The majority of our respondents would agree to participate in a clinical trial assessing an SFD’s effectiveness (Patients:79, Parents:72%) for the management of active CD. Conclusions: While patients with CD and their families would accept an EEN repeat, the majority would prefer an SFD alternative. CD families surveyed are supportive of the development of solid food-based dietary treatments

The distinct features of microbial 'dysbiosis' of Crohn's disease do not occur to the same extent in their unaffected, genetically linked kindred

Background/Aims: Studying the gut microbiota in unaffected relatives of people with Crohn’s disease (CD) may advance our understanding of the role of bacteria in disease aetiology. Methods: Faecal microbiota composition (16S rRNA gene sequencing), genetic functional capacity (shotgun metagenomics) and faecal short chain fatty acids (SCFA) were compared in unaffected adult relatives of CD children (CDR, n = 17) and adult healthy controls, unrelated to CD patients (HUC, n = 14). The microbiota characteristics of 19 CD children were used as a benchmark of CD ‘dysbiosis’. Results: The CDR microbiota was less diverse (p = 0.044) than that of the HUC group. Local contribution of β-diversity analysis showed no difference in community structure between the CDR and HUC groups. Twenty one of 1,243 (1.8%) operational taxonomic units discriminated CDR from HUC. The metagenomic functional capacity (p = 0.207) and SCFA concentration or pattern were similar between CDR and HUC (p>0.05 for all SCFA). None of the KEGG metabolic pathways were different between these two groups. Both of these groups (HUC and CDR) had a higher microbiota α-diversity (CDR, p = 0.026 and HUC, p<0.001) with a community structure (β-diversity) distinct from that of children with CD. Conclusions: While some alterations were observed, a distinct microbial ‘dysbiosis’, characteristic of CD patients, was not observed in their unaffected, genetically linked kindred

Metabolic Profiling in Maturity-Onset Diabetes of the Young (MODY) and Young Onset Type 2 Diabetes Fails to Detect Robust Urinary Biomarkers

It is important to identify patients with Maturity-onset diabetes of the young (MODY) as a molecular diagnosis determines both treatment and prognosis. Genetic testing is currently expensive and many patients are therefore not assessed and are misclassified as having either type 1 or type 2 diabetes. Biomarkers could facilitate the prioritisation of patients for genetic testing. We hypothesised that patients with different underlying genetic aetiologies for their diabetes could have distinct metabolic profiles which may uncover novel biomarkers. The aim of this study was to perform metabolic profiling in urine from patients with MODY due to mutations in the genes encoding glucokinase (GCK) or hepatocyte nuclear factor 1 alpha (HNF1A), type 2 diabetes (T2D) and normoglycaemic control subjects. Urinary metabolic profiling by Nuclear Magnetic Resonance (NMR) and ultra performance liquid chromatography hyphenated to Q-TOF mass spectrometry (UPLC-MS) was performed in a Discovery set of subjects with HNF1A-MODY (n = 14), GCK-MODY (n = 17), T2D (n = 14) and normoglycaemic controls (n = 34). Data were used to build a valid partial least squares discriminate analysis (PLS-DA) model where HNF1A-MODY subjects could be separated from the other diabetes subtypes. No single metabolite contributed significantly to the separation of the patient groups. However, betaine, valine, glycine and glucose were elevated in the urine of HNF1A-MODY subjects compared to the other subgroups. Direct measurements of urinary amino acids and betaine in an extended dataset did not support differences between patients groups. Elevated urinary glucose in HNF1A-MODY is consistent with the previously reported low renal threshold for glucose in this genetic subtype. In conclusion, we report the first metabolic profiling study in monogenic diabetes and show that, despite the distinct biochemical pathways affected, there are unlikely to be robust urinary biomarkers which distinguish monogenic subtypes from T2D. Our results have implications for studies investigating metabolic profiles in complex traits including T2D.publishedVersio

Diminishing benefits of urban living for children and adolescents’ growth and development

Optimal growth and development in childhood and adolescence is crucial for lifelong health and well-being1–6 . Here we used data from 2,325 population-based studies, with measurements of height and weight from 71 million participants, to report the height and body-mass index (BMI) of children and adolescents aged 5–19 years on the basis of rural and urban place of residence in 200 countries and territories from 1990 to 2020. In 1990, children and adolescents residing in cities were taller than their rural counterparts in all but a few high-income countries. By 2020, the urban height advantage became smaller in most countries, and in many high-income western countries it reversed into a small urban-based disadvantage. The exception was for boys in most countries in sub-Saharan Africa and in some countries in Oceania, south Asia and the region of central Asia, Middle East and north Africa. In these countries, successive cohorts of boys from rural places either did not gain height or possibly became shorter, and hence fell further behind their urban peers. The difference between the age-standardized mean BMI of children in urban and rural areas was <1.1 kg m–2 in the vast majority of countries. Within this small range, BMI increased slightly more in cities than in rural areas, except in south Asia, sub-Saharan Africa and some countries in central and eastern Europe. Our results show that in much of the world, the growth and developmental advantages of living in cities have diminished in the twenty-first century, whereas in much of sub-Saharan Africa they have amplified

A multicentre study of nutrition risk assessment in adult patients with inflammatory bowel disease attending outpatient clinics

Background: Overnutrition and undernutrition can affect patients with inflammatory bowel disease (IBD). Although all IBD outpatients should be screened for nutrition risk, screening is not routinely performed, potentially leading to reduced identification and treatment. This study aimed to estimate the prevalence of nutrition risk in adult IBD outpatients and the proportion of cases who discussed diet and/or nutrition during their routine clinical appointment. Methods: Adults with IBD attending outpatient clinics at four hospitals in Greece and in UK were recruited. Demographic and anthropometric data were collected using face-to-face patient interviews and clinical records. Patients were classified as high (i.e. BMI &lt;18.5kg/m2 or 18.5-54 20kg/m2 and weight loss &gt;5%), moderate (i.e. BMI 20-25 kg/m2 and weight loss &gt;5%) or low risk of undernutrition and high risk of obesity (i.e. BMI 25-30% and weight gain &gt;5%). The proportion of patients who discussed diet and/or nutrition during their clinical appointment was calculated. Results: In total, 390 IBD patients participated. Sixteen (4%) patients were underweight, 113 (29%) were overweight and 71 (18%) were obese. Twenty-one (5%) patients were at high risk of undernutrition; of these four (19%) were under dietetic care. Of those at high risk of undernutrition, 11 (52%) had discussed diet and/or nutrition during their routine clinical appointment. Fifty-six (14%) patients had gained more than 5% weight since their last recorded/reported weight and 19 (5%) were at high risk of obesity. Conclusions: Few patients were identified to be at high risk of undernutrition and less than a fifth of these were under dietetic care. Overnutrition is a growing problem in IBD with almost half of adult patients being overweight or obese. Diet and/or nutrition were not routinely discussed in this group of IBD outpatients

Perfil de crescimento e nutricional dos alunos da Escola Agrotécnica Federal de Rio do Sul: um estudo longitudinal

O presente trabalho de caráter longitudinal objetiva traçar o perfil do crescimento e estado nutricional dos alunos da Escola Agrotécnica Federal de Rio do Sul, entre 1 4 e 1 ó anos no período entre 1 996 e 1 998 e comparar os resultados com os critérios do NCHS/USA. A amostra é composta por 25 alunos do sexo masculino. Para avaliar a estatura utilizou-se estadiômetro e para o peso uma balança da marca Filizola. O estado nutricional foi determinado, segundo os critérios de Waterlow et al. (1977), pelo Software PED. Os resultados demonstraram que os alunos apresentam estatura superior ao percentil 50, e peso próximo ao percentil 7 5, do NCHS. Quanto ao estado nutricional verificamos que os alunos nas três primeiras avaliações apresentam índices altos de normalidade (eutrofia), sendo que na quarta avaliação os índices de sobrepeso quase se igualam aos índices de cutróficos.The present work of longitudinal character objectifics to trace thc growth profile and the nutritional status of the students' from the School Agrotécnica Federal de Rio do Sul, among 1 4 and 1 6 years in the period among 1 996 till 1 998 and to compare the results with the approaches of NCHS/USA. The sample is composed by 2 5 male students. To evaluate the height an stadiometer was used and for the weight a scale of the mark Filizola. The nutritional status was determined, according to thc approaches of Waterlow et al. (1977), for the Software PED. The results demonstrated that the students present superior height to the percentil 50, and weigh elose to the percentil 7 5, of NCHS. With relationship to the nutritional status verified that the students in the first threc evaluations present high indexes of normality (eutroph), and in the fourth evaluation the overweight indexes almost equaled to the eutrophics indexes

DIMORFISMO SEXUAL EM VARIÁVEIS DO CRESCIMENTO SOMÁTICO E DA APTIDÃO FÍSICA DE CRIANÇAS E JOVENS BRASILEIROS

Os conhecimentos referentes ao dimorfismo sexual no domínio somato-motor em crianças e jovens são de fundamental importância. Nessa perspectiva, o presente estudo tem como objetivo descrever a presençade diferenças sexuais na aptidão física de crianças e jovens. O estudo foi desenvolvido pelo método ex post facto com amostra do tipo aleatória por conglomerados. Os procedimentos estatísticos utilizados foram a ANOVA para identificação das diferenças entre os sexos e da ANCOVA para identificação dos efeitos do peso e estatura nos testes motores. Os principais resultados demonstram um claro dimorfismo sexual em praticamente todas as idades, tanto nos testes referenciados à saúde como em testes referenciados à performance desportiva.ABSTRACTThe knowledge concerning sexual dimorphism in domain somatic-motor in children and youth are importance fundamental. In that perspective, the present study aims at the describe the presence of sexual differences in physical fitness of children and youth. The study wasdeveloped at the ex post facto method with aleatory sampling for conglomerate. The statistics procedures went the ANOVA for Identification of the differences between sexes and the ANCOVA for identification of the effects of the weight and stature in motor tests.