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espanolEn el proceso diagnostico de todo paciente con enfermedad hepatica grasa no alcoholica (EHGNA) se deben realizar tres evaluaciones: establecer el diagnostico de higado graso no alcoholico (HGNA) o de esteatohepatitis no alcoholica (NASH); establecer el grado de fibrosis (principal factor pronostico global) y completar el estudio de los factores de riesgo vascular (que condicionaran el pronostico general a medio y largo plazo en la mayoria de los pacientes). El tratamiento es la perdida de peso, idealmente mediante cambios en el estilo de vida a expensas de una dieta hipocalorica y ejercicio. Si este abordaje fracasa, la cirugia bariatrica es una alternativa. Aun no hay farmacos aprobados especificamente para tratar la enfermedad. El seguimiento debe realizarse acorde a la gravedad de la hepatopatia y a las comorbilidades metabolicas, implicando a especialistas de atencion primaria, digestivo, endocrinologia y cardiologia cuando sea preciso EnglishThe evaluation of the patient in whom non alcoholic fatty liver disease (NAFLD) is suspected consists of three stages: stablishing the diagnosis either non-alcoholic fatty-liver or non-alcoholic steatohepatitis. Determining the severity of the fibrosis (main overall prognostic factor) and and completing the study of vascular risk factors (which are also the main general prognostic factors in most of these patients). The NAFLD treatment is weight loss, ideally achieved through lifestyle modifications that include dietary caloric restriction and physical exercise. Bariatric surgery is an option when all of the above fail. Specific drugs for the disease are not yet approved. Follow-up depends on severity of the liver disease and the metabolic comorbidities, being the involvement of Primary Care Physicians, Hepatologist, Endocrinologists and Cardiologist frequently necessary

Background The management of inflammatory bowel disease (IBD) has substantially changed in the last decades, both in relation to medical and surgical treatments. Aims Principal: To know the rate of surgery in a newly diagnosed IBD cohort within the first year after diagnosis. Secondary: To describe the type of surgeries and indications in this cohort, and to identify predictive factors for surgery (focused on intestinal resection) in these patients. Methods Prospective, population-based nationwide registry. Adult patients diagnosed with IBD -Crohn’s disease (CD) and ulcerative colitis (UC)- during 2017 in Spain were included and were followed-up for 1 year. Kaplan-Meier curves were used to calculate the rate of surgery. In patients with intestinal resections, only medical treatments before surgery were considered. Predictive factors for surgery were identified by Cox-regression analysis. Results 3,454 patients (1,647 CD and 1,807 UC) were included (table 1). The incidence rate for surgery was significantly higher among CD patients (figure 1). A total of 197 patients (6%) underwent surgery within the first 12 months: 126 (64%) intestinal resections, and 71 (36%) perianal surgeries. Fifty-seven percent of intestinal resections were urgent, and 43% elective. The main indications for intestinal resections were: intestinal obstruction in 37%, abscess/fistula in 27%, perforation/acute abdomen in 25%, and refractoriness to medical treatment in 18% of cases. A total of 174 CD patients (10.6%) underwent surgery ¾61% intestinal resections and 39% perianal. Twenty-three UC patients (1.3%) were operated on; the number of surgeries in UC was too low to identify predictive factors. In CD patients, to have been treated with thiopurines [Hazard ratio (HR)=0.2, 95% confidence interval (CI)=0.1–0.3) was associated with lower likelihood of intestinal resection. Disease behaviour at diagnosis [stricturing vs. inflammatory (HR=6.5, 95%CI=4–10) and fistulising vs. inflammatory (HR=13, 95%CI=9–21)] was associated with the risk of intestinal resection. Biologic treatment was not associated with the likelihood of intestinal resection (figure 2). Conclusion Six percent of IBD patients undergo surgery within the first year of diagnosis, being higher in CD (11%) than in UC (1.3%). Sixty percent of intestinal resections are urgent procedures. The risk of surgery is increased in CD patients with fistulising and stricturing behaviour. Thiopurine, but not biologic treatment, is associated with lower risk of surgery.

Background Studies to evaluate the use of mycophenolate mofetil (MMF) in inflammatory bowel disease (IBD) are limited after the appearance of biological treatments. Aims Our primary objective was to evaluate the effectiveness and safety of MMF in IBD. Methods IBD patients who had received MMF were retrieved from the ENEIDA registry. Clinical activity as per the Harvey‐Bradshaw Index (HBI), partial Mayo score (pMS), physician global assessment (PGA) and C-reactive protein (CRP) were reviewed at baseline, at 3 and 6 months, and at final follow-up. Adverse events and causes of treatment discontinuation were documented. Results A total of 83 patients were included (66 Crohn's disease, 17 ulcerative colitis), 90% of whom had previously received other immunosuppressants. In 61% of patients systemic steroids were used at initiation of MMF, and in 27.3% biological agents were co-administered with MMF. Overall clinical effectiveness was observed in 64.7% of the population. At the end of treatment, 45.6% and 19.1% of subjects showed remission and clinical response, respectively. MMF treatment was maintained for a median of 28.9 months (IQR: 20.4–37.5). Conclusion Our study suggests, in the largest cohort to date, that MMF may be an effective alternative to thiopurines and methotrexate in IBD.

Acute pancreatitis is an entity of notable importance due to its high incidence and its non-negligible morbidity and mortality. Idiopathic acute pancreatitis is that in which the cause of the clinical condition cannot be determined after an initial basic study. Understanding the underlying etiology enables clinicians to propose a targeted treatment to reduce the risk of recurrence. Endoscopic ultrasonography and magnetic resonance cholangiopancreatography are the tests of choice to deepen the aetiological study. The main cause is undiagnosed lithiasic disease in the initial study, whose treatment of choice is cholecystectomy. Moreover, recurrent acute pancreatitis is diagnosed after 2 or more episodes of acute pancreatitis. The objective of this review is to provide an updated approach for these 2 entities, reviewing aspects of their epidemiology, diagnosis and available alternative therapies.

Resumen La pancreatitis aguda es una entidad de notable importancia debido a su elevada incidencia y a su no desdenable morbimortalidad. Se conoce como pancreatitis aguda idiopatica aquella en la que no se consigue determinar la causa del cuadro tras un estudio basico inicial. Conocer la etiologia subyacente permite plantear un tratamiento dirigido para asi disminuir el riesgo de recurrencia. La ecoendoscopia y la colangiografia por resonancia magnetica son las pruebas de eleccion para profundizar en el estudio etiologico. La principal causa es la enfermedad litiasica no diagnosticada en el estudio inicial, cuyo tratamiento de eleccion es la colecistectomia. Por otra parte, la pancreatitis aguda recurrente se diagnostica tras la existencia de 2 o mas episodios de pancreatitis aguda. El objetivo de esta revision es proporcionar una aproximacion actualizada de estas 2 entidades, repasando aspectos de su epidemiologia, diagnostico y alternativas terapeuticas disponibles.

The widely expressed two-pore homodimeric inward rectifier CLC-2 chloride channel regulates transepithelial chloride transport, extracellular chloride homeostasis, and neuronal excitability. Each pore is independently gated at hyperpolarized voltages by a conserved pore glutamate. Presumably, exiting chloride ions push glutamate outwardly while external protonation stabilizes it. To understand the mechanism of mouse CLC-2 opening we used homology modelling-guided structure–function analysis. Structural modelling suggests that glutamate E213 interacts with tyrosine Y561 to close a pore. Accordingly, Y561A and E213D mutants are activated at less hyperpolarized voltages, re-opened at depolarized voltages, and fast and common gating components are reduced. The double mutant cycle analysis showed that E213 and Y561 are energetically coupled to alter CLC-2 gating. In agreement, the anomalous mole fraction behaviour of the voltage dependence, measured by the voltage to induce half-open probability, was strongly altered in these mutants. Finally, cytosolic acidification or high extracellular chloride concentration, conditions that have little or no effect on WT CLC-2, induced reopening of Y561 mutants at positive voltages presumably by the inward opening of E213. We concluded that the CLC-2 gate is formed by Y561-E213 and that outward permeant anions open the gate by electrostatic and steric interactions.

Two-pore voltage-gated CLC chloride channels control neuronal and muscle excitability. They share a dimeric structure but their activation mechanism remains unresolved. Here we determine the step-by-step activation mechanism of the broadly expressed CLC-2 channel using homology modelling, molecular dynamic simulations and functional studies. We establish that a two-leaf gate formed by Tyr561-H2O-Glu213 flanked by Lys568/Glu174 and Lys212 closes the canonical pore. Activation begins when a hyperpolarization-propelled intracellular chloride occupies the pore and splits Tyr561-H2O-Glu213 by electrostatic/steric repulsion. Unrestrained Glu213 rotates outwardly to bind Lys212 but the pore remains closed. Protonation breaks the Glu213-Lys212 interaction while another chloride occupies the pore thus catalysing chloride exit via Lys212. Also, we found that the canonical pore is uncoupled from a cytosolic cavity by a Tyr561-containing hydrophobic gate that prevents Glu213 protonation by intracellular protons. Our data provide atomistic details about CLC-2 activation but this mechanism might be common to other CLC channels.

Resumen Objetivos Estimar el nivel de conocimientos de los radiologos y su implicacion en el uso de medidas de radioproteccion. Metodos Se realizo una encuesta anonima y supervisada durante una reunion de trabajo. Resultados De los 65 cuestionarios facilitados, se devolvieron 63. En lineas generales, los radiologos consideraron su nivel de conocimientos como bajo, y quedo estadisticamente demostrado (p = 0,018) que el nivel de conocimientos que creian tener guardaba relacion con el numero de respuestas correctas. Tambien guardaba relacion (p Conclusiones Hay un importante margen de mejora en el nivel de conocimientos en materia de radioproteccion.

OBJECTIVES To estimate radiologistś level of knowledge of and their implication in radioprotection. METHODS An anonymous and supervised survey was conducted during a work meeting. RESULTS Of the 65 questionnaires handed out, 63 were returned. In general, the radiologists surveyed considered their level of knowledge to be low, and it was statistically demonstrated (P = 0.018) that the level of knowledge they believed they had was related to the number of correct answers. The level of knowledge that radiologists believed they had was also related (p < 0.05) with the years of experience, and it was higher in the more experienced radiologists. CONCLUSIONS There is an important margin of improvement in knowledge about radiation protection.

Background Previous studies comparing inflammatory bowel disease(IBD) features between migrant and native patients have shown clinical phenotype differences. To date, no study has focused on IBD immigrants(MP) in Spain. The aim of this study was to explore the features of MP in Spain and to compare age of disease onset, IBD phenotype and therapeutic requirements with native-born IBD patients(NP). Methods This was an observational, multicentric and case-control study of the nationwide ENEIDA registry. We selected all IBD patients who were born outside of Spain and compared with a control cohort of NP. All included patients were diagnosed with IBD before 2015. Results A total of 13,524 patients were included(1864 MP and 11660 NP).The most prevalent ethnic migrant group was Caucasian(771, 41%), followed by Latin American(572, 31%) and Arabian(341,18%), whereas Asian represented only 6%. Table 1 summarizes the demographic and phenotypic features. 71% of MP were diagnosed with IBD in Spain. There was not a gender predisposition to IBD in the overall migrant group, however more female UC MP were detected compared to UC NP(52 % vs 45%, p Conclusion In the largest cohort of migrant IBD patients in Spain, immigrants were younger, had a shorter disease duration and required a higher use of biologics than natives, pointing phenotypic differences in this population and a universal access to the healthcare system all over the country.

Background Crohn’s disease (CD) can develop fistulizing complications at any time during the disease course. Enterocutaneous fistulas (ECF) are disabling lesions with a significant impact on quality of life. The aim of this study was to describe the characteristics and natural history of ECF complicating CD, and to analyze its medical and/or surgical management. Methods A retrospective analysis of all adult patients with fistulizing CD with at least one episode of ECF from the ENEIDA registry (over 68,000 patients) was performed. ECF were defined as a communication between the gastrointestinal tract and the skin producing leakage of luminal contents. Additional data describing the ECF and its medical or surgical management were gathered. The main endpoint was any ECF-related surgical intervention. Fistula closure was defined as the absence of drainage, with no new abscess or surgery for at least 6 months. A comparison of the characteristics and outcomes after the availability of biologic agents (Jan/2000) was also performed. The baseline characteristics were analyzed by means of descriptive statistics and were compared by non-parametric tests. Factors associated with surgery were further evaluated in a binary multivariable regression and survival analysis. Results A total of 301 ECF in 286 patients from 46 hospitals diagnosed between Jan/1970-Sept/2020 were included (median age 34 years (IQR, 27–46); 59% male; 67% L3). ECF had a median of 1 external opening (range 1–10), 59% with concomitant internal fistulas, and usually involved the ileum (67%) or colon (23%). After 146 months (IQR, 69–233) of follow-up, 37% received thiopurines, 40% anti-TNF, 6% ustekinumab and 2% vedolizumab. Surgery was performed in 208 patients (69%) after a median of 4 months (IQR, 1.4–12). Fistula closure was achieved in 253 patients (84%) after 30 months (IQR, 4–84), mostly after surgery (54%) and in one third after medical therapy. Fistula recurrence was uncommon (11%) after closure. Patient and fistula characteristics were significantly different after the availability of biologics. In fact, anti-TNF biologics and thiopurines reduced surgery risk (HR 0.5; 0.38–0.67; HR 0.64; 0.47–0.86, respectively). The surgery rate in the biologic era tends to be lower than before (OR 0.63;0.33–1.09) while timing is similar. Closure rates are also comparable, but it was obtained more frequently after medical therapy once biologicals were available (OR 2.21; 1.13–4.29). Conclusion ECF complicating CD entail a high burden of medical and surgical resources. Closure rates are high, usually after surgery, and fistula recurrence is uncommon. A number of patients can benefit from medical therapy and achieve fistula closure.

Background Clinical trials and real-life studies with Ustekinumab in Crohn’s disease show its good efficacy and safety profile. However, there are hardly any data on elderly patients, who are excluded from these clinical trials. Our aim is to evaluate these variables in real-life practice. Methods Retrospective analysis of patients from the prospectively maintained ENEIDA registry treated with Ustekinumab for Crohn’s disease. Elderly patients were selected as those over 60 years old at the start of treatment. They were compared with 2 randomised controls from the same centre, aged less than 60 years, matched for smoking habit. The degree of comorbidity was assessed using the Charlson’s index. Clinical and biochemical activity and effectiveness were defined based on Harvey-Bradshaw index and calprotectin and CRP levels at weeks 16, 32 and 54, when available. Results A total of 648 patients were analysed, 212 elderly (mean age 67 [63.6;72.8] years) and 436 young (mean age 41.6 [32.6;50.0] years). No differences were observed between both groups in baseline variables except for the degree of comorbidity, higher in elderly patients (1.00 [0.00;2.00] vs 0.00 [0.00;0.00], p Clinical response rate was similar in both groups at week 16 (70.5% vs 76.6%, p=0.199), week 32 (67.6% vs 70.2% p=0.104) and week 54 (74% vs 74.9%, p=0.326). Steroid-free remission and biochemical response also showed no differences throughout follow-up. The rate of adverse effects was similar in both groups (14.2% vs 11.2%, p=0.350) except for the occurrence of de novo neoplasms, which was higher in the elderly group (0.69% vs 4.25%, p=0.003). The rate of severe infections (7.08 vs 7.34, p=1.000), the need for surgery (16.5% vs 20.0%, p=0.345) and the need for hospital admission (21.7% vs 19.0%, p=0.489) did not differ. Persistence of UST treatment was similar in both groups (log Rank test p=0.91). Conclusion Ustekinumab achieved clinical response in almost three-quarters of elderly patients, similar to the younger population, with no increase in the rate of infections or other adverse effects, with the exception of de novo neoplasms.

Gating of the mammalian inward rectifier Kir1.1 at the helix bundle crossing (HBC) by intracellular pH is believed to be mediated by conformational changes in the C-terminal domain (CTD). However, the exact motion of the CTD during Kir gating remains controversial. Crystal structures and single-molecule fluorescence resonance energy transfer of KirBac channels have implied a rigid body rotation and/or a contraction of the CTD as possible triggers for opening of the HBC gate. In our study, we used lanthanide-based resonance energy transfer on single- Cys dimeric constructs of the mammalian renal inward rectifier, Kir1.1b, incorporated into anionic liposomes plus PIP 2 , to determine unambiguous, state-dependent distances between paired Cys residues on diagonally opposite subunits. Functionality and pH dependence of our proteoliposome channels were verified in separate electrophysiological experiments. The lanthanide-based resonance energy transfer distances measured in closed (pH 6) and open (pH 8) conditions indicated neither expansion nor contraction of the CTD during gating, whereas the HBC gate widened by 8.8 ± 4 A, from 6.3 ± 2 to 15.1 ± 6 A, during opening. These results are consistent with a Kir gating model in which rigid body rotation of the large CTD around the permeation axis is correlated with opening of the HBC hydrophobic gate, allowing permeation of a 7 A hydrated K ion.

Central nervous system (CNS) demyelination represents the pathological hallmark of multiple sclerosis (MS) and contributes to other neurological conditions. Quantitative and specific imaging of demyelination would thus provide critical clinical insight. Here, we investigated the possibility of targeting axonal potassium channels to image demyelination by positron emission tomography (PET). These channels, which normally reside beneath the myelin sheath, become exposed upon demyelination and are the target of the MS drug, 4-aminopyridine (4-AP). We demonstrate using autoradiography that 4-AP has higher binding in non-myelinated and demyelinated versus well-myelinated CNS regions, and describe a fluorine-containing derivative, 3-F-4-AP, that has similar pharmacological properties and can be labeled with 18F for PET imaging. Additionally, we demonstrate that [18F]3-F-4-AP can be used to detect demyelination in rodents by PET. Further evaluation in Rhesus macaques shows higher binding in non-myelinated versus myelinated areas and excellent properties for brain imaging. Together, these data indicate that [18F]3-F-4-AP may be a valuable PET tracer for detecting CNS demyelination noninvasively.

Without a templated mechanism, a new corner-like complex ([Fe(C25H32N8S)2]2+=[Fe]) and a new grid-like one ([Fe4(C23H28N8S)4]8+=[Fe4]) were obtained from the self-assembly of two structurally related bis(hydrazones) (C25H32N8S = 1; C23H28N8S = 2) with Fe(II) under identical reaction conditions, commonly employed for the efficient synthesis of grid-like complexes. The electrochemical and magnetic properties of these complexes were studied. Both complexes undergo a Fe(II)/Fe(I) reduction process in each of their metal centers, but only the grid-like complex exhibits easily oxidizable metal centers. In the solid state, both complexes are in the low spin state within a wide range of temperatures, but the corner also exhibits several types of high spin states coexisting at all times. From an exploratory viewpoint, our results are important to carry out the eventual synthesis of metal complexes with suitable properties for nanotechnological applications.

4-Aminopyridine (4AP) is a specific blocker of voltage-gated potassium channels (KV1 family) clinically approved for the symptomatic treatment of patients with multiple sclerosis (MS). It has recently been shown that [18F]3F4AP, a radiofluorinated analog of 4AP, also binds to KV1 channels and can be used as a PET tracer for the detection of demyelinated lesions in rodent models of MS. Here, we investigate four novel 4AP derivatives containing methyl (-CH3), methoxy (-OCH3) as well as trifluoromethyl (-CF3) in the 2 and 3 position as potential candidates for PET imaging and/or therapy. We characterized the physicochemical properties of these compounds (basicity and lipophilicity) and analyzed their ability to block Shaker K+ channel under different voltage and pH conditions. Our results demonstrate that three of the four derivatives are able to block voltage-gated potassium channels. Specifically, 3-methyl-4-aminopyridine (3Me4AP) was found to be approximately 7-fold more potent than 4AP and 3F4AP; 3-methoxy- and 3-trifluoromethyl-4-aminopyridine (3MeO4AP and 3CF34AP) were found to be about 3- to 4-fold less potent than 4AP; and 2-trifluoromethyl-4-AP (2CF34AP) was found to be about 60-fold less active. These results suggest that these novel derivatives are potential candidates for therapy and imaging.

4-Aminopyridine (4AP) is a specific blocker of voltage-gated potassium channels (KV1 family) clinically approved for the symptomatic treatment of patients with multiple sclerosis (MS). It has recently been shown that [18F]3F4AP, a radiofluorinated analog of 4AP, also binds to KV1 channels and can be used as a PET tracer for the detection of demyelinated lesions in rodent models of MS. Here, we investigate four novel 4AP derivatives containing methyl (-CH3), methoxy (-OCH3) as well as trifluoromethyl (-CF3) in the 2 and 3 position as potential candidates for PET imaging and/or therapy. We characterized the physicochemical properties of these compounds (basicity and lipophilicity) and analyzed their ability to block Shaker K+ channel under different voltage and pH conditions. Our results demonstrate that three of the four derivatives are able to block voltage-gated potassium channels. Specifically, 3-methyl-4-aminopyridine (3Me4AP) was found to be approximately 7-fold more potent than 4AP and 3F4AP; 3-methoxy- and 3-trifluoromethyl-4-aminopyridine (3MeO4AP and 3CF34AP) were found to be about 3- to 4-fold less potent than 4AP; and 2-trifluoromethyl-4-AP (2CF34AP) was found to be about 60-fold less active. These results suggest that these novel derivatives are potential candidates for therapy and imaging.

Un varon de 52 anos es remitido a consultas de hepatologia por presentar de manera persistente cifras levemente elevadas de transaminasas de unos 6 anos de evolucion. Lo que motivo la derivacion fue la deteccion de unas cifras elevadas de ferritina. Como antecedentes personales destacan una hipertension arterial esencial, diabetes mellitus, hipercolesterolemia y sobrepeso (indice de masa corporal –IMC– 29,6 kg/m2). No tiene historia de consumo de toxicos. Como tratamiento habitual recibe losartan, metformina e insulina, Adiro® y simvastatina. No presenta antecedentes familiares de interes. Desde el punto de vista clinico, el paciente refiere unicamente astenia leve-moderada que no le impide realizar una actividad fisica normal y no le afecta en sus actividades diarias. No refiere ninguna otra sintomatologia. En la exploracion fisica se constata un peso de 83 kg y una talla de 1,69 metros, lo que supone un IMC de 29,6 kg/m2 (sobrepeso). En la inspeccion se observa un ligero y tenue tinte icterico conjuntival. La auscultacion cardiopulmonar es normal. En la exploracion abdominal se palpa una hepatomegalia leve de 2 cm, sin observarse datos de ascitis ni presencia de edema en las extremidades inferiores. El paciente aporta una serie de pruebas complementarias que se detallan a continuacion. Determinaciones analiticas: creatinina 0,7 mg/dl; Na 136 mEq/l; K 4,3 mEq/l; bilirrubina 2,7 mg/dl; AST 78 U/l; ALT 87 U/l; GGT 90 U/; FA 110 U/l; albumina 2,9 g/dl; hemoglobina 14,7 g/dl; plaquetas 170.000/μl; leucocitos 5.300/μl; INR 1,3, ferritina 880 ng/ml; ceruloplasmina 17 ng/ml; anticuerpos de la hepatitis autoinmune (anticuerpos antinucleares –ANA–; anticuerpos antimusculo liso –AML–; anticuerpos contra el microsoma de rinon e higado –LKM–) negativos. En la ecografia abdominal se observa parenquima hiperecogenico de forma difusa con borramiento de los vasos intrahepaticos ( fig. 1 ). El tamano de la vena porta y del bazo son normales. No se observan lesiones focales hepaticas ni presencia de ascitis. Elastometria de transicion (Fibroscan®): mediana de rigidez hepatica 19 kPa (tecnicamente bien realizado).

Background Mycophenolate mofetil (MMF) is an immunomodulatory drug that inhibits T and B cells, through a reversible inhibition of inositol monophosphate dehydrogenase. MMF is commonly used for prophylaxis of organ rejection after transplant. Studies to evaluate its use in inflammatory bowel disease (IBD) are limited especially after the appearance of biological treatments (BT). The aim of this study was to evaluate the efficacy and safety of MMF in IBD. Methods IBD patients who had received MMF were identified in the ENEIDA registry (prospective database of GETECCU). Patients with Crohn′s disease (CD) or Ulcerative colitis (UC) in whom oral MMF was prescribed for this condition were evaluated. Demographic and IBD clinical data were collected. Clinical activity was assessed through Harvey-Bradshaw Index (HBI) and partial Mayo score (pMS); C-reactive protein (CRP) and faecal calprotectin (FC) were reviewed at baseline (at MMF starting), 3 and 6 months and at the end of follow-up (at MMF stopping or the last visit while on MMF). Adverse events (AEs) during MMF treatment were documented. Statistical analyses were performed by descriptive statistics and non-parametric tests. Results Between June 1999 and November 2018 a total of 83 patients received MMF (mean age 36.4 (SD12.3) years; 52F/31M; 66 CD and 17 UC). Indication for MMF use was maintenance of remission (50%), induction of remission (44%) and post-surgical prophylaxis (6%). Mean MMF dose used was 1269.8 (SD 741) mg/day. In 61% of cases, systemic steroids were administered starting MMF and it was used concomitantly to BT in 27% of patients. In CD, statistically significant differences in HBI at 6 months (mean 5.9 (SD 4.8), p = 0.04) and at the end of follow-up (mean 5.7 (SD 5), p = 0.014) compared with baseline (mean 7.6 (SD 4.3)) were observed. In UC, statistically significant differences in pMS at 6 months (mean 2.1 (SD 2.7), p = 0.018) and at the end of follow-up (mean 1.8 (SD 2.6), p = 0.003) compared with baseline (mean 4.8 (SD 2.5)) were determined. No significant differences in CRP or CF values during follow-up were observed. Concomitant use of BT was significantly associated with clinical response (OR 1.36 95% CI 1.08–1.73). MMF was maintained for a median time of 28.9 months (IQR 20.4–37.5) and was stopped in 84% of patients due to lack of response (50%), loss of response (17%) and remission (15%). Overall, 23% of patients presented MMF-related AEs (60% abdominal pain). MMF was withdrawn in 11% of patients due to AEs. Conclusion MMFshows a clinical benefit in the long term in both CD and UC patients with a favourable safety profile. MMF could be a treatment option alone or in combination with biologics in patients with IBD in clinical practice.

Background Evaluation of Ustekinumab induction therapy is generally performed at week 16. Our aim was to evaluate if a delayed response may be expected beyond that time. Methods Retrospective study including patients with CD who received Ustekinumab since 1 June 2017 to 1 May 2019. Iv induction dose was based on weight while maintenance was conducted with 90 mg subcutaneous every 8 weeks. Results Twenty-five patients (52% male) were enrolled, of whom 28% (7/25) had ileal, 28(7/25) colonic, 44% (11/25) ileocolonic and 8% (2/25) upper tract involvement. Sixty-eight per cent (17/25) presented an inflammatory, 16% (4/25) a stricturing and 16% (4/25) a penetrating behaviour. Perianal disease was diagnosed in 20% of patients (5/25). All patients 100% (25/25) had previously taken immunosuppressants and 96% (24/25) biological therapy (mean 1.8 ± 0.87 (0–3) per patient): 36% (9/25) one, 36% (9/25) two and 24% (6/25) three agents. Ustekinumab was prescribed for achieving remission in 92% (23/25) of the patients, fistulising disease in 4% (1/25) and for maintenance of remission in the same percentage. Follow-up was 373.16 ± 182.53(59–683) days. Discontinuation rate was 24% (6/25), due to primary failure in 100% (6/6). For those who stopped the drug, average treatment time was 137.17 ± 95.11(61–1320) days whereas that of those who continued was 346.84 ± 192.10(32–669) days. Clinical response was evaluated at week 8, week 14–16, week 22–24 and during long-term maintenance (Table 1). All comparisons were statistically significant (p < 0.05). We recorded Harvey-Bradshaw index(H-B), CRP and faecal calprotectin (FC) before induction with ustekinumab, at weeks 14–16, at weeks 22–24 and during maintenance. Results are presented in Table 2. Conclusion Evaluation of induction effectiveness at week 22–24 may allow to rescue those patients who present a delayed response to UST. During a 373.16 days follow-up, loss of response to Ustekinumab is low.

Background Thiopurine (TP) withdrawal in patients with Crohn’s disease (CD) in clinical remission (CR) is controversial. Our aim was to describe the evolution of CD patients in CR who discontinued TP prescribed to maintain a remission previously achieved with medical treatment, and to detect predictors of reactivation after withdrawal. Methods Multicentric observational retrospective study including CD patients in RC under TP treatment, who electively discontinued TP. Relapse was defined as the need to start any specific treatment for CD, including surgery. Informed consent was obtained from the inclusion in the Eneida database. Results We included 78 patients (52.6% females, age 45(19–77) years) of whom 57 presented an inflammatory, 12 a stricturing and 9 a penetrating behaviour; 31 patients had terminal ileum involvement, 9 colonic, 36 ilecolonic, and 2 ileocolonic plus upper gastrointestinal involvement, whilst 17 also had perianal disease. Mean disease duration was 13.47 (3.02–35.02) years. 48.7% had never smoked whilst 24.4% were active smokers. TP was started to maintain remission previously achieved with medical therapies in 78 patients (100%). Median azathioprine dose was 2.11 (1.3–2.6) mg/kg/d, and of 6-mercaptopurine (6MP) 1.44 (1–2) mg/kg/day. The median duration of TP treatment was 52.79 (3–268) months and of steroid-free remission 49.41 (1–177) months. Reasons for TP withdrawal were: patient choice/request in 20 (25.6%), physician proposal in 28 (25.7%), drug-related adverse events in 19 (24.4%) and miscellaneous in 11 (14.1%). By the time of TP discontinuation, median CRP was 5.08 mg/l (0.1–157.9), fecal calprotectin(FC) 282.38 µg/g (2.4-4430) and a mean 0.45 (0–4) in Harvey–Bradshaw Index (HBI); those who relapsed presented median CRP of 15.31 mg/l (0.1–125.31), fecal calprotectin (FC) 462.22 µg/g (90–1240) and a mean 5.46 (0–15) in HBI. These differences were statistically significant. During a 5.08 (0.12–13.05) years follow-up, 38 (48.1%) patients relapsed, with treatment duration being the only factor associated to risk of relapse (Or = 0.659 IC95 0.43–0.98, p = 0.04) in the multivariant analysis (IMAGE1). Conclusion Thiopurine withdrawal in the context of sustained remission in CD is associated with relapse in almost half of the patients after a median follow-up of 5 years. Thiopurine treatment duration of shorter than 5 years was shown to carry greater risk for relapse.

Background Anti-TNF and thiopurines are the only drugs that demonstrated efficacy in preventing postoperative recurrence (POR) in Crohn’s disease (CD). However, in some cases, these drugs are contraindicated or have previously failed. Vedolizumab was licensed for CD some years ago but scarce data on its efficacy for the prevention of POR is available. Methods All CD patients in whom vedolizumab was prescribed for primary prevention of POR within the first 3 months after ileocecal or ileocolonic resection with anastomosis were identified from the ENEIDA registry (a large, prospectively maintained database of the Spanish Working Group in IBD, GETECCU). We evaluated the rates of Endoscopic, clinical or surgical POR in the first 18 months. Endoscopic POR was defined by a Rutgeerts score >i1 and advanced endoscopic POR by >i2. Results Twenty-three patients were included; vedolizumab was started after a median time of 23 days (IIQ21-73). Concomitant immunosuppressants were used in 17%; 18% received an additional 3-month course of metronidazole after surgery. Regarding risk factors for POR: 13% were active smokers, 62% had prior resections, 33% had penetrating CD behaviour, and 22% had a history of perianal disease. Thirty-four per cent had been exposed to vedolizumab prior to the index surgery (26% within the last 6 months). The median time of follow-up on ustekinumab was 26 months (IQR 11–31). Eighty-three per cent of patients had at least one endoscopic assessment within 18 months after surgery: 40 % had endoscopic POR and 15% advanced endoscopic POR. Additionally, 22% presented clinical POR at the discretion of the treating physician and 9% developed surgical POR. Conclusion In a small clinical practice cohort, vedolizumab showed similar efficacy as that reported with anti-TNF in the prevention of endoscopic POR.

Acute pancreatitis is an entity of notable importance due to its high incidence and its non-negligible morbidity and mortality. Idiopathic acute pancreatitis is that in which the cause of the clinical condition cannot be determined after an initial basic study. Understanding the underlying aetiology enables clinicians to propose a targeted treatment to reduce the risk of recurrence. Endoscopic ultrasonography and magnetic resonance cholangiopancreatography are the tests of choice to deepen the aetiological study. The main cause is undiagnosed lithiasic disease in the initial study, whose treatment of choice is cholecystectomy. Moreover, recurrent acute pancreatitis is diagnosed after 2 or more episodes of acute pancreatitis. The objective of this review is to provide an updated approach for these 2 entities, reviewing aspects of their epidemiology, diagnosis and available alternative therapies.

This paper discusses games where cooperation is restricted by a hierarchical structure. The model assumes that there is a hierarchy between certain coalitions given by a partition. Face games (Gonzalez-Diaz and Sanchez-Rodriguez in Games Econ Behav 62:100–105, 2008) play a central role in the definition of the proposed hierarchical game. It turns out that the Shapley value of the hierarchical game coincides with the Faigle and Kern precedence constraint value (Faigle and Kern in Int J Game Theory 21:249–266, 1992) and with some particular weighted Shapley value (Kalai and Samet in Int J Game Theory 16:205–222, 1987). Two new characterizations of this hierarchical value are given. Finally, an application of the model is given for bankruptcy problems.

To estimate radiologistś level of knowledge of and their implication in radioprotection.An anonymous and supervised survey was conducted during a work meeting.Of the 65 questionnaires handed out, 63 were returned. In general, the radiologists surveyed considered their level of knowledge to be low, and it was statistically demonstrated (P = 0.018) that the level of knowledge they believed they had was related to the number of correct answers. The level of knowledge that radiologists believed they had was also related (p0.05) with the years of experience, and it was higher in the more experienced radiologists.There is an important margin of improvement in knowledge about radiation protection.

Septic shock sometimes starts with unspecific symptoms that hamper the clinical diagnosis and, therefore an appropriate treatment. When the septic shock follows a fulminating course with a fatal outcome, the etiological diagnosis has to be conducted post-mortem. Sudden unexpected deaths in children and young adults are frequently the object of medico-legal autopsies. Some sudden unexpected deaths have an infectious origin, which requires further analyses, including microbiology, to establish the cause of death. Here, the case of a fatal septic shock in a 19-month old male infant is presented. After a mild foot injury, an infection by Streptococcus pyogenes progressed to septic shock with a fatal outcome as post-mortem studies demonstrated.

Background Polymedication (PM) can complicate course and management of chronic diseases, and is currently a poorly explored issue in patients with inflammatory bowel disease (IBD). Our aims were to determine the prevalences of PM, and of inappropriate and high-risk drugs use (APINCH) in a clinical series of IBD patients, describing epidemiological factors associated with PM, and evaluating a possible association of PM with poor disease outcomes. Methods A retrospective observational study of a unicentric series, including patients with IBD visited at our Unit (September-October 2018). Prescriptions, demographic data, and clinical features were collected reviewing clinical files and electronic drug prescriptions. PM was defined as the simultaneous use of more than 5 drugs (Gnjidic D, J Clin Epidemiol. 2012). APINCH drugs included insulin, antibiotics, anticoagulants, chemotherapies, narcotics, and potassium supplements (Clinical Excellence Australian Commission 2017). Disease outcomes (flares, hospitalisations, surgeries), non-adherence to treatment and undertreatment were evaluated 12 months after the index visit. Results We included 407 patients (56% males, median age 48 yo, range 17–92, 60.2% Crohn′s disease, 38.8% ulcerative colitis). Chronic comorbidity was present in 54% (29% metabolic, 25.5% cardiovascular, 12.8% psychiatric), and 27% presented multiple comorbidities (≥3). Median patient number of prescriptions was 3 (r 0–15); 14.3% were on more than three drugs, and 15.7% between four and five drugs. Most frequent prescriptions are represented in Figure 1. PM was identified in 18.4% of cases, inappropriate medication in 8.8%, and high-risk drugs in 6.1% (mainly opioids). In multivariate analysis, factors significantly associated with PM were chronic comorbidity (OR 11, CI 2.3-51,2, p˂0.002), multiple comorbidities (OR 4.02, CI 1.93–8.38, p˂0.001), and age >62 years (OR 3.66, CI 1.7–7.7, p˂0.001). In univariate analysis, both undertreatment (54% vs. 16%, p˂0.01) and non-adherence (26% vs. 12%, p˂0.02) were associated with PM after 12 months. No association of PM with poor disease outcomes was found. In multivariate analysis, only undertreatment was significantly associated with PM (OR 5.9, CI 1.4–29.4, p˂0.014). Conclusion PM occurs in around one of the five patients with IBD, mainly in the elderly and in those with comorbidity. This scenario could interfere with appropriate IBD treatment and therapeutic success.

Background Anti-TNF and thiopurines are the only drugs that demonstrated efficacy in preventing postoperative recurrence (POR) in Crohn’s disease (CD). However, in some cases these drugs are contraindicated or have previously failed. Recently, ustekinumab was licensed for CD but no data on its efficacy in the prevention of POR is still available. Methods All CD patients in whom ustekinumab was prescribed for primary prevention of POR within the first 3 months after ileocecal or ileocolonic resection with anastomosis were identified from the ENEIDA registry (a prospectively maintained database of the Spanish Working Group in IBD –GETECCU-). We evaluated the rates of endoscopic, clinical or surgical POR in the first 18 months. Endoscopic POR was defined by a Rutgeerts score >i1 and advanced endoscopic POR by >i2. Results Thirty patients were included; ustekinumab was started after a median time of 60 days (IIQ 31–90). Concomitant immunosuppressants were used in 17%, 27% received an additional 3-month course of metronidazole after surgery. Regarding risk factors for POR: 23% were active smokers, 62% had prior resections, 33% had penetrating CD behaviour, and 22% had a history of perianal disease. In total, 36% of them had more than one risk factor. 50% had been exposed to ustekinumab prior to the index surgery (46% within the last 6 months). The median time of follow-up on ustekinumab was 17 months (IQR 11–21). Fifty-six per cent of patients had at least one endoscopic assessment within 18 months after surgery: 58% had endoscopic POR and 23% advanced endoscopic POR. Additionally, 13% presented clinical POR at the discretion of the treating physician and none developed surgical POR. Conclusion In a small clinical practice cohort, ustekinumab showed similar efficacy as that reported with anti-TNF in the prevention of endoscopic POR. Unfortunately, the lack of early endoscopic monitoring is still frequent despite the recommendations from guidelines.

Aim To assess whether low voltage chest computed tomography (CT) can be used to successfully diagnose disease in patients with asbestos exposure. Materials and methods Fifty-six former employees of the shipbuilding industry, who were candidates to receive a standard-dose chest CT due to their occupational exposure to asbestos, underwent a routine CT. Immediately after this initial CT, they underwent a second acquisition using low-dose chest CT parameters, based on a low potential (80 kV) and limited tube current. The findings of the two CT protocols were compared based on typical diseases associated with asbestos exposure. The kappa coefficient for each parameter and for an overall rating (grouping them based on mediastinal, pleural, and pulmonary findings) were calculated in order to test for correlations between the two protocols. Results A good correlation between routine and low-dose CT was demonstrated for most parameters with a mean radiation dose reduction of up to 83% of the effective dose based on the dose–length product between protocols. Conclusions Low-dose chest CT, based on a limited tube potential, is useful for patients with an asbestos exposure background. Low-dose chest CT can be successfully used to minimise the radiation dose received by patients, as this protocol produced an estimated mean effective dose similar to that of an abdominal or pelvis plain film.

Large-conductance Ca(2+)- and voltage-activated K(+) (BK) channels are involved in a large variety of physiological processes. Regulatory β-subunits are one of the mechanisms responsible for creating BK channel diversity fundamental to the adequate function of many tissues. However, little is known about the structure of its voltage sensor domain. Here, we present the external architectural details of BK channels using lanthanide-based resonance energy transfer (LRET). We used a genetically encoded lanthanide-binding tag (LBT) to bind terbium as a LRET donor and a fluorophore-labeled iberiotoxin as the LRET acceptor for measurements of distances within the BK channel structure in a living cell. By introducing LBTs in the extracellular region of the α- or β1-subunit, we determined (i) a basic extracellular map of the BK channel, (ii) β1-subunit-induced rearrangements of the voltage sensor in α-subunits, and (iii) the relative position of the β1-subunit within the α/β1-subunit complex.

The interaction of either H(+) or Cl(-) ions with the fast gate is the major source of voltage (V(m)) dependence in ClC Cl(-) channels. However, the mechanism by which these ions confer V(m) dependence to the ClC-2 Cl(-) channel remains unclear. By determining the V(m) dependence of normalized conductance (G(norm)(V(m))), an index of open probability, ClC-2 gating was studied at different [H(+)](i), [H(+)](o) and [Cl(-)](i). Changing [H(+)](i) by five orders of magnitude whilst [Cl(-)](i)/[Cl(-)](o) = 140/140 or 10/140 mm slightly shifted G(norm)(V(m)) to negative V(m) without altering the onset kinetics; however, channel closing was slower at acidic pH(i). A similar change in [H(+)](o) with [Cl(-)](i)/[Cl(-)](o) = 140/140 mm enhanced G(norm) in a bell-shaped manner and shifted G(norm)(V(m)) curves to positive V(m). Importantly, G(norm) was >0 with [H(+)](o) = 10(-10) m but channel closing was slower when [H(+)](o) or [Cl(-)](i) increased implying that ClC-2 was opened without protonation and that external H(+) and/or internal Cl(-) ions stabilized the open conformation. The analysis of kinetics and steady-state properties at different [H(+)](o) and [Cl(-)](i) was carried out using a gating Scheme coupled to Cl(-) permeation. Unlike previous results showing V(m)-dependent protonation, our analysis revealed that fast gate protonation was V(m) and Cl(-) independent and the equilibrium constant for closed–open transition of unprotonated channels was facilitated by elevated [Cl(-)](i) in a V(m)-dependent manner. Hence a V(m) dependence of pore occupancy by Cl(-) induces a conformational change in unprotonated closed channels, before the pore opens, and the open conformation is stabilized by Cl(-) occupancy and V(m)-independent protonation.

It has been shown that the voltage (Vm) dependence of ClC Cl− channels is conferred by interaction of the protopore gate with H+ ions. However, in this paper we present evidence which indicates that permeant Cl− ions contribute to Vm-dependent gating of the broadly distributed ClC-2 Cl− channel. The apparent open probability (PA) of ClC-2 was enhanced either by changing the [Cl−]i from 10 to 200 mm or by keeping the [Cl−]i low (10 mm) and then raising [Cl−]o from 10 to 140 mm. Additionally, these changes in [Cl−] slowed down channel closing at positive Vm suggesting that high [Cl−] increased pore occupancy thus hindering closing of the protopore gate. The identity of the permeant anion was also important since the PA(Vm) curves were nearly identical with Cl− or Br− but shifted to negative voltages in the presence of SCN− ions. In addition, gating, closing rate and reversal potential displayed anomalous mole fraction behaviour in a SCN−/Cl− mixture in agreement with the idea that pore occupancy by different permeant anions modifies the Vm dependence ClC-2 gating. Based on the ec1-ClC anion pathway, we hypothesized that opening of the protopore gate is facilitated when Cl− ions dwell in the central binding site. In contrast, when Cl− ions dwell in the external binding site they prevent the gate from closing. Finally, this Cl−-dependent gating in ClC-2 channels is of physiological relevance since an increase in [Cl−]o enhances channel opening when the [Cl−]i is in the physiological range.

Anti-smoking legislation has been associated with an improvement in health indicators. Since the cadmium (Cd) body burden in the general population is markedly increased by smoke exposure, we analyzed the impact of the more restrictive legislation that came into force in Spain in 2011 by measuring Cd and cotinine in first morning urine samples from 83 adults in Madrid (Spain) before (2010) and after (2011) introduction of this law. Individual pair-wise comparisons showed a reduction of creatinine corrected Cotinine and Cd levels for non-active smokers, i. e. those which urinary cotinine levels are below 50 μg/L. After the application of the stricter law, cotinine levels in urine only decreased in non-active smokers who self-reported not to be exposed to second-hand smoke. The reduction in second hand smoke exposure was significantly higher in weekends (Friday to Sunday) than in working days (Monday to Thursday). The decrease in U-Cd was highly significant in non-active smokers and, in general, correlated with lower creatinine excretion. Therefore correction by creatinine could bias urinary Cd results, at least for cotinine levels higher than 500 μg/L. The biochemical/toxicological benefits detected herein support the stricter application of anti-smoking legislation and emphasize the need to raise the awareness of the population as regards exposure at home. The research was supported by Spanish Ministry of Agriculture,Food and Environment (MAGRAMA) and Instituto de Salud CarlosIII, Ministry of Economy and Competitiviness (MINECO) (SEG 1251/07 and SEG 1112/10 Projects)