Evaluation of Genetic Variants Associated with the Risk of Thiopurine-Related Pancreatitis: A Case Control Study from ENEIDA Registry.

INTRODUCTION: Risk factors for developing pancreatitis due to thiopurines in patients with inflammatory bowel disease (IBD) are not clearly identified. Our aim was to evaluate the predictive pharmacogenetic risk of pancreatitis in IBD patients treated with thiopurines. METHODS: We conducted an observational pharmacogenetic study of acute pancreatitis events in a cohort study of IBD patients treated with thiopurines from the prospectively maintained ENEIDA registry biobank of GETECCU. Samples were obtained and the CASR, CEL, CFTR, CDLN2, CTRC, SPINK1, CPA1, and PRSS1 genes, selected based on their known association with pancreatitis, were fully sequenced. RESULTS: Ninety-five cases and 105 controls were enrolled; a total of 57% were women. Median age at pancreatitis diagnosis was 39 years. We identified 81 benign variants (50 in cases and 67 in controls) and a total of 35 distinct rare pathogenic and unknown significance variants (10 in CEL, 21 in CFTR, 1 in CDLN2, and 3 in CPA1). None of the cases or controls carried pancreatitis-predisposing variants within the CASR, CPA1, PRSS1, and SPINK1 genes, nor a pathogenic CFTR mutation. Four different variants of unknown significance were detected in the CDLN and CPA1 genes; one of them was in the CDLN gene in a single patient with pancreatitis and 3 in the CPA1 gene in 5 controls. After the analysis of the variants detected, no significant differences were observed between cases and controls. CONCLUSION: In patients with IBD, genes known to cause pancreatitis seem not to be involved in thiopurine-related pancreatitis onset.

Search for small-bowel capsule diagnostic yield optimization conducted through observational analysis. / Búsqueda de optimización de la cápsula endoscópica mediante análisis observacional.

OBJECTIVES: To search for parameters susceptible to optimization when performing capsule endoscopy (CE) in a third level hospital with high volume and experience in this test. PATIENTS AND METHODS: Retrospective observational study, including 1325 CEs performed between 2017 and 2022. Overall diagnostic yield, effective diagnostic yield, by indication, place of request and waiting list, as well as complete examination rate and cleansing degree were analyzed. RESULTS: The overall diagnostic yield was 70.99%, while the effective diagnostic yield was 72.7%. Diagnostic yields varied between 60.2% and 77.9% depending on the indication and between 64.7% and 74.3% depending on the requesting center. The mean waiting list was 101.15 days, with a tendency to worse results when the waiting list was longer. A total of 77.8% of the examinations were complete. Completion rates were lower in patients >70 years of age (p=0.001), as well as in those with gastric transit >60minutes (p=0.000). A total of 77.3% were clean, with debris that did not impede diagnosis being found in 16.9% and debris that did impede diagnosis in 5.8%. There was a relationship, although not significant, between cleansing degree and age. CONCLUSIONS: The diagnostic yields of CE in our center are in line with those previously reported. Differences were found according to the place of request. Waiting list could also influence diagnostic yield. Completion rates are lower in >70 years of age and when gastric transit is >60minutes. Cleansing degree achieved is acceptable.

Comparative study of overweight and obese patients with nonalcoholic fatty liver disease.

BACKGROUND AND AIMS: non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disorder in the western world. Although NAFLD prevalence is higher in patients with a BMI > 25 kg /m2, it is unclear if there are differences between overweight and obese patients. The associated biochemical, dietary and genetic parameters were compared between overweight and obese patients with NAFLD. METHODS: patients with biopsy-proven NAFLD (n = 203) were enrolled in a cross-sectional study. The MEDAS questionnaire was used to assess adherence to the Mediterranean diet. Biochemical, anthropometrical parameters and the I148M variant (rs738409) of the PNPLA3 gene and rs180069 of the TNF-α gene were evaluated. RESULTS: overweight patients had higher serum adiponectin levels (22.5 ± 21.9 vs 11.2 ± 18.1 ng/ml; p < 0.05) and lower resistin (3.3 ± 1.7 vs 8.1 ± 8 ng/ml; p < 0.001) and leptin concentrations (22.9 ± 21.9 vs 55.8 ± 45 ng/ml; p < 0.001) than obese patients. Non-alcoholic steatohepatitis (NASH) was more frequent in the obese group (59.3% vs 41.3%; p = 0.02). The multivariate analysis showed adherence to the Mediterranean diet to be an independent protective factor for NASH and liver fibrosis in overweight patients (OR 0.7, 95% CI 0.5-0.8). CONCLUSIONS: NASH was more prevalent in obese patients than in overweight subjects. HOMA-IR and adherence to the Mediterranean diet provided protection against fibrosis in overweight patients. Adherence to the Mediterranean diet was the only independent factor associated with NASH in these patients.

Mechanisms of copper and zinc bioremoval by microalgae and bacteria grown in nutrient rich wastewaters.

Swine farming produces large quantities of nutrient-rich wastewater, which often contains metals such as Cu and Zn, used as feed additives for pigs. These metals must be removed from the wastewater before discharge but their retention in the biomass can limit its subsequent utilization. Photobioreactors are a very promising alternative for swine wastewater treatment, as the consortium of microalgae and bacteria growing symbiotically in these reactors allows high nutrient and metal removal efficiency at moderate costs. This work studies the mechanisms of removal of Cu(II) and Zn(II) by the two types of microorganisms growing in these photobioreactors. A microalga commonly used in wastewater treatment (Scenedesmus almeriensis) and an activated sludge were kept in contact with synthetic wastewater containing 100 mg/L of Cu and Zn. After 72 h, Scenedesmus almeriensis removed 43% of Cu and 45% of Zn, while activated sludge removed 78% of Cu and 96% of Zn. Single and sequential extractions of the biomasses using different extracting reagents revealed that biosorption on protonable groups is the dominant removal mechanisms. Mild reagents solubilized 69% of Cu and 94% of Zn from the microalgae and 76% of Cu and 93% of Zn from the activated sludge. Low metal concentrations in the oxidizable and residual fractions evidenced minimal bioaccumulation inside the cells. FTIR and ESEM-EDX analysis confirmed biosorption by ion exchange and complexation as the main metal remediation mechanisms. The weak bonds of the biosorbed Cu and Zn ions are beneficial for the valorization of biomass and the obtaining of safe bioproducts.

[Trend in medicines use for attention deficit hyperactivity disorder in children and adolescents (2010-2019).] / Tendencia del consumo de fárma-cos en el trastorno por déficit de atención e hiperactividad en niños y adolescentes (2010-2019).

OBJECTIVE: Attention deficit hyperactivity disorder (ADHD) is a common childhood neurodevelopmental disorder characterised primarily by three core symptoms: inattention, hyperactivity and impulsivity. It is one of the most commonly diagnosed childhood psychiatric disorders, with a worldwide prevalence of between 3% and 5%, and between 6% and 7% in the Spanish population. The aim of the study is to analyse the trend in the consumption of drugs used for the treatment of ADHD between 2010-2019 in Castilla y León. METHODS: Epidemiological registry study of all dispensing in pharmacies in Castilla y León between 2010 and 2019 to patients under 19 years of age, of active substance N06BA04 (methylphenidate), N06BA09 (atomoxetine), N06BA12 (lisdexamfetamine), N06BA07 (modafinil) and C02AC02 (guanfacine). Data on drug use were obtained from the information system for the pharmaceutical provision of Castilla y León, CONCYLIA. Frequencies in absolute values and the corresponding percentages were calculated. Student's t-test was used to estimate differences between continuous variables and Pearson's Chi-square test for categorical variables, while the trend in consumption was analysed using the Cochran-Armitage test. RESULTS: ADHD medication was dispensed annually to 1.77% of the population, with consumption being more than three times higher in boys than in girls (2.69% vs 0.81%; p=0.001). The age group with the highest peak use was 10-14 years with 3.42%. Methylphenidate was the drug used by the highest percentage of the population (2.44%) followed by lisdexamfetamine (0.37%). CONCLUSIONS: Approximately 2 out of every 100 people aged 0-19 years were treated with some ADHD medication, mainly methylphenidate, in Castilla y León between 2010 and 2019.

OBJETIVO: El trastorno por déficit de atención e hiperactividad (TDAH) es un trastorno común del neurodesarrollo infantil que se caracteriza fundamentalmente por tres síntomas a nivel central: falta de atención, hiperactividad e impulsividad. Se trata de uno de los trastornos psiquiátricos infantiles más comúnmente diagnosticados, con una prevalencia a nivel mundial que oscila entre el 3% y el 5%, y entre el 6% y el 7% en la población española. El objetivo del estudio es analizar la tendencia del consumo de los fármacos utilizados para el tratamiento del TDAH entre los años 2010-2019 en Castilla y León. METODOS: Estudio epidemiológico de registro de todas las dispensaciones realizadas en las oficinas de farmacia de Castilla y León entre el año 2010 y 2019 a pacientes menores de 19 años, de los principios activos N06BA04 (metilfenidato), N06BA09 (atomoxetina), N06BA12 (lisdexanfetamina), N06BA07 (modafinilo) y C02AC02 (guanfacina). Los datos de utilización de medicamentos se obtuvieron a partir del sistema de información para la prestación farmacéutica de Castilla y León, CONCYLIA. Se calcularon frecuencias en valores absolutos y los porcentajes correspondientes. Se utilizó el test-t de Student para estimar diferencias entre variables continuas y el test Chi-cuadrado de Pearson para las categóricas, mientras que la tendencia de consumo se analizó mediante el test de Cochran-Armitage. RESULTADOS: Se dispensaron anualmente los medicamentos para el TDAH al 1,77% de la población, siendo el consumo más de tres veces mayor en niños que en niñas (2,69% vs 0,81%; p=0,001). La franja de edad donde se observó el mayor pico de consumo fue de los 10 a 14 años con un 3,42%. El metilfenidato fue el medicamento consumido por un mayor porcentaje de la población (2,44%) seguido de la lisdexanfetamina (0,37%). CONCLUSIONES: Aproximadamente 2 de cada 100 personas entre 0 y 19 años fueron tratadas con algún medicamento para la TDAH, fundamentalmente metilfenidato, en Castilla y León entre 2010 y 2019.

Role of Oxidative Stress and Lipid Peroxidation in the Pathophysiology of NAFLD.

Non-alcoholic fatty liver disease (NAFLD) is characterised by an excess of hepatic fat that can progress to steatohepatitis, fibrosis, cirrhosis and hepatocarcinoma. The imbalance between lipid uptake/lipogenesis and lipid oxidation/secretion in the liver is a major feature of NAFLD. Given the lack of a non-invasive and reliable methods for the diagnosis of non-alcoholic steatohepatitis (NASH), it is important to find serum markers that are capable of discriminating or defining patients with this stage of NASH. Blood samples were obtained from 152 Caucasian subjects with biopsy-proven NAFLD due to persistently elevated liver enzyme levels. Metabolites representative of oxidative stress were assessed. The findings derived from this work revealed that NAFLD patients with a NASH score of ≥ 4 showed significantly higher levels of lipid peroxidation (LPO). Indeed, LPO levels above the optimal operating point (OOP) of 315.39 µM are an independent risk factor for presenting a NASH score of ≥ 4 (OR: 4.71; 95% CI: 1.68−13.19; p = 0.003). The area under the curve (AUC = 0.81, 95% CI = 0.73−0.89, p < 0.001) shows a good discrimination ability of the model. Therefore, understanding the molecular mechanisms underlying the basal inflammation present in these patients is postulated as a possible source of biomarkers and therapeutic targets in NASH.

Effectiveness and safety of methotrexate monotherapy in patients with Crohn's disease refractory to anti-TNF-α: results from the ENEIDA registry.

BACKGROUND: Methotrexate can be used to maintain remission in Crohn's disease patients who are intolerant to thiopurines. Data on its use as monotherapy in other scenarios are limited. AIM: To assess the effectiveness of methotrexate monotherapy in Crohn's disease patients after previous failure to anti-tumour necrosis factor (anti-TNFα) drugs. METHODS: A retrospective, observational multicentre study of data from the Spanish ENEIDA registry. Participants were patients with active Crohn's disease and previous failure to anti-TNFα started on methotrexate monotherapy. Short-term effectiveness was assessed at 12-16 weeks based on Harvey-Bradshaw index (HBI): clinical remission as HBI ≤ 3 points and clinical response as HBI drop of ≥ 3 points over baseline. Long-term effectiveness was defined as steroid-free methotrexate persistence from 12 to 16 weeks until maximum follow up. Adverse events were recorded. RESULTS: Data were compiled for 110 patients treated with methotrexate after a failed response to one (39%) or two (55.6%) anti-TNFα agents. Short-term clinical response and remission rates were 60% and 30.9% respectively. Of 74 patients who continued after week 16, long-term effectiveness was achieved in 82% and 74% at 12 and 24 months respectively. In the multivariate analysis, non-remission at short term (vs remission) was associated with long-term failure (HR 2.58, 95%CI 1.95-3.68, P = 0.028). Adverse events (evaluated in 100 patients) were recorded in 44%, and in 30.4% of these patients, they led to methotrexate discontinuation. CONCLUSIONS: The benefits observed suggest methotrexate monotherapy could be a valid option in Crohn's disease patients with previous failure to anti-TNFα.

Insulin resistance is related with liver fibrosis in type 2 diabetic patients with non-alcoholic fatty liver disease proven biopsy and Mediterranean diet pattern as a protective factor.

BACKGROUND AND AIMS: The prevalence of the non-alcoholic fatty liver disease (NAFLD) in developed countries is up to 30% of the general population, and 50% of patients present type 2 diabetes mellitus (DM2). Fibrosis is the most important prognostic factor in NAFLD. The aim of this study was to search evidence for an early diagnosis of liver fibrosis in subjects with DM2 and to evaluate potential risk and protective factors. METHODS: This study was conducted among 160 diabetic patients with NAFLD proven biopsy. Anthropometric assessments, laboratory test, liver histological features and follow-up of a Mediterranean diet were evaluated. RESULTS: Diabetic patients with liver fibrosis showed a greater number of positive metabolic criteria than diabetic patients without liver fibrosis. Patients with hepatic fibrosis have a lower score on the PREDIMED test (9.0 (2.4) vs. 6.2 (2.3); p < 0.05). Diabetic patients with liver fibrosis showed higher glucose levels (delta: 10.1 (4.5) mg/dl), fasting insulin levels (delta: 3.1 (1.5) UI/L), HOMA-IR (delta: 2.1 (0.3) units) and HbA1c (delta: 0.6 (0.2)%). Non-invasive tests showed a higher score (non-alcoholic fatty liver disease fibrosis score and fibrosis-4) in liver fibrosis subjects than no liver fibrosis subjects. A logistic regression analysis adjusted by age, gender, HbA1c and body mass index showed independent significant direct association between liver fibrosis and homeostatic model assessment of insulin resistance as indicator of insulin resistance (odds ratio (OR) = 1.53: 95% confidence interval (CI): 1.1-2.2; p = 0.026) and inverse association with PREDIMED score as an indicator of adherence to Mediterranean diet (OR = 0.6; 95% CI: 0.4-0.8; p = 0.01). CONCLUSION: In patients with DM2, insulin resistance is an independent risk factor associated with liver fibrosis, and the adherence of a Mediterranean diet is a protective factor associated with absence of liver fibrosis.

Real-world long-term effectiveness of ustekinumab in Crohn's disease: results from the ENEIDA registry.

BACKGROUND: Data on the long-term administration of ustekinumab in recommended doses are limited. AIM: To assess the real-world, long-term effectiveness of ustekinumab in refractory Crohn's disease (CD). METHODS: Multi-centre study of CD patients starting ustekinumab at the recommended dose, followed for 1 year. Values for the Harvey-Bradshaw Index (HBI), endoscopic activity, C-reactive protein (CRP), and faecal calprotectin (FC) were recorded at baseline and at weeks 26 and 52. Demographic and clinical data, previous treatments, adverse events (AEs) and hospitalisations were documented. Potential predictors of remission were examined. RESULTS: A total of 407 patients were analysed. The initial maintenance dose of 90 mg SC was administered every 12, 8 and 4 weeks in 56 (14%), 347 (85%) and 4 (1%) patients, respectively. After 52 weeks, treatment was discontinued in 112 patients (27.5%). At baseline, 295 (72%) had an HBI >4 points. Of these, 169 (57%) and 190 (64%) achieved clinical remission at weeks 26 and 52, respectively. FC levels returned to normal in 44% and 54% of patients at weeks 26 and 52, and CRP returned to normal in 36% and 37% of patients at weeks 26 and 52, respectively. AEs were recorded in 60 patients. The use of fewer previous anti-TNFα agents and ileal localisation were associated with clinical remission, and endoscopic severity was associated with poor response. No factors correlated with endoscopic remission. CONCLUSION: After 52 weeks, ustekinumab demonstrated effectiveness in inducing clinical and endoscopic remission in patients with refractory CD.

Clinical Characteristics, Associated Malignancies and Management of Primary Sclerosing Cholangitis in Inflammatory Bowel Disease Patients: A Multicentre Retrospective Cohort Study.

BACKGROUND AND AIMS: Primary sclerosing cholangitis [PSC] is usually associated with inflammatory bowel disease [IBD]. An increased risk of malignancies, mainly colorectal cancer [CRC] and cholangiocarcinoma [CCA], has been reported in PSC-IBD patients. Our aim was to determine the clinical characteristics and management of PSC in IBD patients, and the factors associated with malignancies. METHODS: PSC-IBD patients were identified from the Spanish ENEIDA registry of GETECCU. Additional data were collected using the AEG-REDCap electronic data capture tool. RESULTS: In total, 277 PSC-IBD patients were included, with an incidence rate of 61 PSC cases per 100 000 IBD patient-years, 69.7% men, 67.5% ulcerative colitis and mean age at PSC diagnosis of 40 ± 16 years. Most patients [85.2%] were treated with ursodeoxycholic acid. Liver transplantation was required in 35 patients [12.6%] after 79 months (interquartile range [IQR] 50-139). It was more common in intra- and extrahepatic PSC compared with small-duct PSC (16.3% vs 3.3%; odds ratio [OR] 5.7: 95% confidence interval [CI] = 1.7-19.3). The incidence rate of CRC since PSC diagnosis was 3.3 cases per 1000 patient-years [95% CI = 1.9-5.6]. Having symptoms of PSC at PSC diagnosis was the only factor related to an increased risk of CRC after IBD diagnosis [hazard ratio= 3.3: 95% CI = 1.1-9.9]. CCA was detected in seven patients [2.5%] with intra- and extrahepatic PSC, with median age of 42 years [IQR 39-53], and presented a lower life expectancy compared with patients without CCA and patients with or without CRC. CONCLUSIONS: PSC-IBD patients with symptoms of PSC at PSC diagnosis have an increased risk of CRC. CCA was only diagnosed in patients with intra- and extrahepatic PSC and was associated with poor survival.

Analysis of volatile compounds in gluten-free bread crusts with an optimised and validated SPME-GC/QTOF methodology.

The aroma of bread crust, as one of the first characteristics perceived, is essential for bread acceptance. However, gluten-free bread crusts exhibit weak aroma. A SPME-GC/QTOF methodology was optimised with PCA and RSM and validated for the quantification of 44 volatile compounds in bread crust, extracting 0.75 g of crust at 60 °C for 51 min. LODs ranged between 3.60 and 1760 µg Kg-1, all the R2 were higher than 0.99 and %RSD for precision and %Er for accuracy were lower than 9% and 12%, respectively. A commercial wheat bread crust was quantified, and furfural was the most abundant compound. Bread crusts of wheat starch and of japonica rice, basmati rice and teff flours were also quantified. Teff flour and wheat starch crusts were very suitable for improving gluten-free bread crust aroma, due to their similar content in 2-acetyl-1-pyrroline and 4-hydroxy-2,5-dimethyl-3(2H)-furanone compared to wheat flour crust and also for their high content in pyrazines.

Extruded flour improves batter pick-up, coating crispness and aroma profile.

Fried battered foods are widely consumed worldwide. In this study, the influence of the replacement of native wheat flour by extruded flours (7.5 and 15%) subjected to different extrusion severities on chicken nuggets was assessed. Microstructure, pick-up, moisture and fat content, texture, colour, volatile profile, and consumer acceptability were evaluated. Extruded flour replacement resulted in batters with improved pick-up with increasing percentage and severity of extrusion treatment. Extruded flour also contributed to a moisture increase, while oil remained practically unchanged. Textural properties highlighted a higher crispness of batters made with high-severity treatment extruded flours. Volatile compounds analyses revealed lower amount of lipid oxidation (lower rancidity notes) and higher furfuryl alcohol content (pleasant aroma and darker crust) in fried batters containing extruded flour. Consumers testing showed that batters made with intermediate-severity treatment extruded flour presented the best acceptability. These results confirm that extruded flour inclusion improves the quality of deep-fried batters.