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First-episode psychosis is a critical period for early interventions to reduce the risk of poor outcomes and relapse as much as possible. However, uncertainties about the long-term outcomes of symptomatology remain to be ascertained.The aim of the present study was to use network analysis to investigate first-episode and long-term stages of psychosis at three levels of analysis: micro, meso and macro. The sample was a cohort of 510 patients with first-episode psychoses from the SEGPEP study, who were reassessed at the long-term follow-up (n = 243). We used the Comprehensive Assessment of Symptoms and History for their assessments and lifetime outcome variables of clinical relevance.Our results showed a similar pattern of clustering between first episodes and long-term follow-up in seven psychopathological dimensions at the micro level, 3 and 4 dimensions at the meso level, and one at the macro level. They also revealed significant differences between first-episode and long-term network structure and centrality measures at the three levels, showing that disorganization symptoms have more influence in long-term stabilized patients.Our findings suggest a relative clustering invariance at all levels, with the presence of two domains of disorganization as the most notorious difference over time at micro level. The severity of disorganization at the follow-up was associated with a more severe course of the psychosis. Moreover, a relative stability in global strength of the interconnections was found, even though the network structure varied significantly in the long-term follow-up. The macro level was helpful in the integration of all dimensions into a common psychopathology factor, and in unveiling the strong relationships of psychopathological dimensions with lifetime outcomes, such as negative with poor functioning, disorganization with high antipsychotic dose-years, and delusions with poor adherence to treatment. These results add evidence to the hierarchical, dimensional and longitudinal structure of psychopathological symptoms and their clinical relevance in first-episode psychoses.

Background Inflammatory bowel diseases (IBD) are chronic, heterogeneous, and inflammatory conditions mainly affecting the gastrointestinal tract. Currently, endoscopy is the gold standard test for assessing mucosal activity and healing in clinical practice; however, it is a costly, time-consuming, invasive, and uncomfortable procedure for patients. There is, therefore, a need for sensitive, specific, fast and non-invasive biomarkers for the diagnosis of IBD. Methods Label-free quantification by nanoscale liquid chromatography coupled to tandem mass spectrometry (nLC MS/MS) was performed to profile the urinary and serum proteomes of 100 patients with newly diagnosed IBD, before starting any treatment [50 patients with Crohn′s disease (CD) and 50 patients with ulcerative colitis (UC)] and 50 healthy controls (HC). Data Mining and Pattern Recognition techniques were used to identify hidden relationships that are not detectable by using the classical and most commonly used lineal classifiers; and thus, identifying potential markers able to discriminate the studied cohorts. Finally, we applied Ingenuity Pathway Analysis (IPA) to analyze the pathways and functions of differentially expressed proteins. Results Serum proteomics results revealed 45 differentially expressed proteins in the comparison between UC and HC groups, 32 proteins significantly expressed in CD versus HC, and 12 proteins in CD compared with UC. In urine samples, 110 proteins were significantly changed in UC versus HC, 50 proteins were differentially expressed between CD and HC, and a total of 31 proteins were significantly changed in CD compared with UC patients. Receiver operating characteristic curve (ROC) analysis found multiple proteins with high area under the curve values, up to 0.94, indicating that these serum and urine proteins are of value as new non-invasive diagnostic classifiers of IBD patients. For each study comparative, the 5 most significant classifiers were selected (Figures 1 and 2). IPA revealed multiple signaling pathways, including prothrombin activation, acute phase response signaling, complement and coagulation system and liver X receptor/retinoid X receptor (LXR/RXR) activation, altered in IBD patients compared to HC (p-value < 0.05) (Figures 3 and 4). Conclusion Our findings indicate that analysis of the urine and serum proteome using nLC MS/MS is a feasible approach for biomarker discovery. We identified several serum and urine proteins that could serve as new non-invasive markers for the diagnosis of IBD patients after further validation. After bioinformatic analyses, we found multiple proteins that may play important roles in the pathogenesis of IBD.

Background The etiology and pathogenesis of inflammatory bowel disease (IBD), Crohn's disease (CD), and ulcerative colitis (UC) are complex and the mechanisms that lead to the development of these diseases remain unclear. Extracellular vesicles (EVs) are small particles covered with a cell membrane, originating from the emitting cell, excreted into the extracellular medium, and subsequently captured by receptor cells. EVs have a role in multiple diseases and they could also have a function in IBD pathogenesis. Therefore, the analysis of EVs isolated from the serum of newly diagnosed IBD patients (before starting any treatment) may represent an appropriate experimental approach to elucidate their role in IBD pathogenesis. We aimed to evaluate EVs’ composition and potential effects in the pathogenesis of IBD. Methods The protein content of EVs isolated by size exclusion chromatography from the 500 µl of serum from 100 patients with IBD (50 patients with CD and 50 patients with UC) recently diagnosed and 50 healthy controls (HC) was characterized by proteomics and their size and concentration in serum by Nanoparticle tracking analysis (NTA). The biological function of EVs and alterations in signaling pathways related to IBD were determined using Ingenuity Pathways Analysis (IPA) to analyze the OMICs results. Results A total of 1,100 proteins have been identified, of which 105 proteins were differentially expressed by patients with CD versus HC, 111 proteins by patients with UC versus HC, and 32 proteins by patients with UC versus CD. IPA analysis revealed that proteins carried in EVs are involved in the dysregulation of immune pathways such as the acute phase response (Figure 1), LXR/RXR activation pathway (Figure 2), and the complement pathway. These pathways were regulated differentially in IBD patients compared with HC, but also when the CU group was compared with the CD group (Figure 3) being upregulated nuclear receptors signaling and cytotoxicity pathways. Conclusion EVs carry proteins that can be involved in the dysregulation of the immune system in IBD; this effect would be different in UC and CD since their EVs show a differential profile. Consequently, EVs may play role in IBD pathogenesis and source of strong biomarkers candidates for diagnosis in UC and CD. Further studies on their specific function during IBD are warranted.

Background Inflammatory bowel disease (IBD) is a complex multi-factorial disease characterized by chronic inflammation of the gastrointestinal tract. Despite significant efforts to understand the pathogenetic mechanisms of IBD, the elucidation of its etiopathology and progression is far from fully understood. The direct analysis of the intestinal tissue from the endoscopy which leads to IBD diagnosis (before starting any treatment) would be the ideal sample to elucidate IBD pathogenesis. Methods High-throughput mass-spectrometry-based quantitative proteomic analysis was performed using formalin-fixed paraffin-embedded human intestinal samples from newly diagnosed patients to elucidate the potential mechanisms responsible for gut inflammation in Crohn′s disease (CD) and ulcerative colitis (UC). For this purpose, 192 formalin-fixed paraffin-embedded samples from 40 active UC patients, 67 active CD patients and 46 normal biopsies from healthy controls (HC) were analyzed (Figure 1). Proteins with p-value < 0.05 were considered as significantly dysregulated. Moreover, we used Ingenuity Pathway Analysis (IPA) to analyze the pathways and functions in different locations of the gut (ileum or left colon) that could be related to IBD pathogenesis. Results A total of 2,903 proteins were identified, of which 1,010 were differentially expressed between left colon from CD patients and HC. 1,242 proteins were differentially expressed between left colon from UC patients and HC, and 952 differential proteins discriminated between left colon from CD and UC patients. In the comparative study of ileum biopsies from Crohn's disease patients and healthy controls, 956 proteins were differentially expressed (Figure 2). IPA revealed multiple canonical pathways, including EIF2 signaling, regulation of eIF4 and serine/threonine kinase P7056K signaling, mitochondrial dysfunction, and oxidative phosphorylation altered in ileum biopsies from CD patients compared to HC (Figure 3). Regarding the proteomic study in left colon samples, the main canonical pathways enrichment in the comparison of UC and CD with HC were the following: neutrophil extracellular trap signaling pathways, fatty acid oxidation, sirtuin signaling pathway, tRNA charging, and mitochondrial dysfunction (Figure 4). Conclusion The proteomic results revealed dysregulated proteins and pathways in ileum and left colon biopsies from patients with active CD and UC compared to HC that may unravel key mechanisms contributing to the pathogenesis of these diseases. The results of the study serve as a starting point for hypotheses to understand the pathogenesis and search for therapeutic targets.

Little is known about long-term outcomes of the first episode of psychosis (FEP) other than in the symptomatic domain. We hypothesised that cognitive impairment is associated with poorer multi-domain outcomes at a long-term follow-up of FEP patients. We followed-up 172 FEP patients for a mean of 20.3 years. Ten outcome dimensions were assessed (symptomatic, functional and personal recovery, social disadvantage, physical health, suicide attempts, number of episodes, current drug use, chlorpromazine equivalent doses (CPZ), and schizophrenia/schizoaffective disorder final diagnosis). Cognition was assessed at follow-up. Processing speed and verbal memory deficits showed significant associations with poor outcomes on symptomatic, social functioning, social disadvantage, higher number of episodes, and higher CPZ. Significant associations were found between visual memory impairments were significantly associated with low symptomatic and functional recovery, between attentional deficits and a final diagnosis of schizophrenia/schizoaffective disorder, and between social cognition deficits and poor personal recovery.Lower cognitive global scores were significantly associated with all outcome dimensions except for drug abuse and physical status. Using multiple outcome dimensions allowed for the inclusion of the patients' perspective and other commonly neglected outcome measures. Taken together, cognitive impairment in FEP patients is strongly related to poor performance on several outcome dimensions beyond symptomatic remission.

Background Some patients with Inflammatory Bowel Disease (IBD) who are treated with anti-TNFα therapy develop a drug-induced psoriasis (IP) as an adverse event. There are some therapeutic approaches, being more frequent to change the biologic therapy to ustekinumab, effective and approved for the treatment of both entities. This could be the best option, but available data are lacking and it could increase the risk of IBD relapse. Our aim is to assess the management of anti-TNF IP in IBD, and the subsequent evolution of both diseases in a large nationwide cohort of patients. Methods Retrospective, observational multicenter study from the prospectively maintained Spanish ENEIDA registry. Participants were patients with IBD and anti-TNFα IP. At baseline, psoriasis severity was classified as mild, moderate or severe, and remission was defined as the resolution of skin lesions, clinical response as an improvement without complete resolution, and no response as the absence of improvement. IBD clinical activity was defined based on Harvey-Bradshaw Index and Partial Mayo Score. All items were evaluated when available at baseline and 16, 32 and 54 weeks. Results Anti-TNFα IP was reported in 234 patients (CD: 185, UC: 46, unclassified IBD: 3). SWAP strategy was chosen in 76 patients (32.5%), most of them to ustekinumab (90.8%), 71 (30.3%) patients continued anti-TNF, 49 (20.9%) discontinued it, and in 38 (16.2%) a switch to a second anti-TNF was made. The decision to continue or not anti-TNF was associated to psoriasis severity (p Conclusion Evaluating IBD activity and psoriasis severity is essential before modifying IBD treatment due to IP. Continuing anti-TNF treatment in mild psoriasis cases, and considering SWAP to ustekinumab in moderate-severe ones, could be a suitable strategy.

Background The use of ustekinumab (UST) and vedolizumab (VDZ) as first line therapy for inflammatory bowel disease (IBD) is increasing due to safety reasons and contraindications of anti-TNFs. However, there are no studies evaluating their efficacy and safety in clinical practice under these circumstances. Thus, our aims were to describe bionaïve patients’ characteristics starting VDZ or UST and to evaluate treatment persistence of these drugs and their safety profile in this scenario. Methods Descriptive, retrospective and multicenter study based on the ENEIDA registry (a large, prospectively maintained database of the Spanish Working Group in IBD –GETECCU). All IBD patients never exposed to biological agents who started VDZ or UST as first-line biological treatment were identified. Results Out of 29,450 IBD patients ever exposed to biological drugs included in the ENEIDA registry, 924 patients met the inclusion criteria. Of these, 366 (40%) started UST and 558 (60%) VDZ as first line biological therapy. UST group: 48% women, 90% Crohn's disease (43% ileal; 13% colic; 43.5% ileocolic; 31% upper gastrointestinal involvement; 25% stricturing behaviour; 12% penetrating, 18% perianal disease), 10% ulcerative colitis (74% extensive, 17% left-sided, 9% proctitis), 27% had extraintestinal manifestations (EIM). Median age at the beginning of UST was 57 years (IQR 57-70), 17% patients had a past history of malignancy and, 34% had associated comorbidities. UST indication was luminal activity except in 2% for perianal disease and 5% for EIM. At the end of follow-up (median 14 months [IQR 6-30]), 12 patients (3.3%) developed adverse effects (AEs) that led to treatment discontinuation in the majority of them (92%). VDZ group: 44% women, 42% Crohn's disease (44% ileal; 18% colic; 38% ileocolic; 25% upper gastrointestinal involvement; 28% stricturing behaviour; 13% penetrating; 7% perianal disease), 58% ulcerative colitis (50% extensive, 42% left-sided, 8% proctitis), 17% had EIM. The median age at the beginning was 61 years (IQR 48-71), 24% had past history of malignancy and, 34% associated comorbidities. The indication was exclusively luminal activity. At the end of follow-up (median 21 months [IQR 8-36]), 36 patients (6.5%) had AEs, that lead to treatment withdrawal in 67% of them (24 patients). Cumulative treatment persistence rates were 78%, 60% and 50% for VDZ and 85%, 75% and 66% for UST at 12, 24 and 36 months, respectively (P Conclusion In clinical practice, VDZ and UST are used first-line particularly in elderly patients with comorbidities. Both treatments have a good safety profile and a high persistence of treatment, being superior for ustekinumab.

Background Female sex has been associated with a worse response to anti-TNF drugs and with discontinuation of these drugs in immune-mediated diseases. Data in Inflammatory Bowel Disease (IBD) are unclear. The aims of study are to assess possible differences in long-term treatment persistence and safety of biological drugs between women and men with IBD. Methods Multicenter observational study carried out with data from the ENEIDA registry. Patients diagnosed with Crohn's disease (CD) or ulcerative colitis (UC) who receive or have received biological drugs, and have had a minimum treatment follow-up of 6 months, were included. We evaluated the first biological treatment used in the patient. Statistic analysis; Regression logistic models were used for safety evaluation. Kaplan-Meier curves, Log-Rank test and COX regression were used to treatment persistance. Results A total of 51,595 patients with IBD were evaluated [ 25,947 with CD (13238 men and 12709 women) and 25,648 with UC (13596 men and 12052 women)]. Mean follow up of 13 years. Biologic use: 28.7% of the evaluated patients had been treated with at least one biologic drug. Biologics use in UC was less common in women than in men (15.5% vs. 17.2%, OR (95%CI): 0.88 (0.81-0.94), p= 0.001) and there were no differences between sexes in CD ( 45.7% in men, 44.7% in women). Infliximab (IFX) and adalimumab (ADA) were the most used drugs (in 8914 and 5269 patients, respectively). Safety evaluation. Women suffered more frequently adverse effects to IFX and ADA than men, being the withdrawal of IFX and ADA due to adverse effects also significantly more frequent in women than in men. Biological treatment persistence in patients with IBD was longer in men than in women [median 3.1 years vs. 2.3 years, p < 0.001]. Female sex was a risk factor of biologic discontinuation [adjusted hazard ratio [aHR] (95%CI): 1.20 (1.14-1.25), p Figure 1. Conclusion 1.The use of biologics in ulcerative colitis seems to be higher in men than in women. 2. Female sex is an independent risk factor for the development of adverse effects to IFX and ADA and for the discontinuation of these drugs. 3. The long-term persistence of IFX and ADA (as first biological treatments) is low, being higher in men compared to women.

The long-term stability of neuromotor domains assessed at the first episode of psychosis (FEP) and their ability for predicting a number of outcomes remains largely unknown, and this study addressed these issues.This was a longitudinal study of 243 participants with FEP who were assessed at baseline for background variables and parkinsonism, dyskinesia, neurological soft signs (NSS) and catatonia, and reassessed 21 years later for the same neuromotor variables, psychopathology, functioning, personal recovery, cognitive performance and medical comorbidity. Stability of neuromotor ratings was assessed using the intraclass correlations coefficient and associations between the predictors and outcomes were examined using univariate and multivariate statistics.Baseline dyskinesia and NSS ratings showed excellent stability over time whereas that for parkinsonism and catatonia was relatively low. Neuromotor dysfunction at follow-up was independently predicted by a family history of schizophrenia, obstetric complications, neurodevelopmental delay, low premorbid IQ and baseline ratings of dyskinesia and NSS. Moreover, baseline dyskinesia and NSS ratings independently predicted more positive and negative symptoms, poor functioning and less personal recovery; catatonia predicted less personal recovery and more medical comorbidity. Baseline neuromotor ratings explained between 4% (for medical comorbidity) and 34% (for neuromotor dysfunction) of the variance in the outcomes. Lastly, neuromotor dysfunction at baseline highly predicted clinical staging at follow-up.Baseline neuromotor domains show variable stability over time and relate distinctively to very long-term outcomes. Both baseline dyskinesia and NSS are trait markers of the disease process and robust predictors of the outcomes.

14 páginas, 16 figuras, 2 tablasc, The study of thermal properties of frozen salt solutions representative of ice layers in Jovian moons is crucial to support the JUpiter ICy moons Explorer (JUICE) (ESA) and Europa Clipper (NASA) missions, which will be launched in the upcoming years to make detailed observations of the giant gaseous planet Jupiter and three of its largest moons (Ganymede, Europa, and Callisto), due to the scarcity of experimental measurements. Therefore, we have conducted a set of experiments to measure and study the thermal conductivity of macroscopic frozen salt solutions of particular interest in these regions, including sodium chloride (NaCl), magnesium sulphate (MgSO4 ), sodium sulphate (Na2 SO4 ), and magnesium chloride (MgCl2 ). Measurements were performed at atmospheric pressure and temperatures from 0 to −70 ◦C in a climatic chamber. Temperature and calorimetry were measured during the course of the experiments. An interesting side effect of these measurements is that they served to spot phase changes in the frozen salt solutions, even for very low salt concentrations. A small sample of the liquid salt-water solution was set aside for the calorimetry measurements. These experiments and the measurements of thermal conductivity and calorimetry will be valuable to constrain the chemical composition, physical state, and temperature of the icy crusts of Ganymede, Europa, and Callisto., This project received financial support of The European Space Agency (ESA) contracts No.: RFP/3-15589/18/ES/CM and 4000126441/19/ES/CM: ‘Measurements of thermal and dielectric properties of ices in support to future radar measurements of Jovian Icy moons’, The Unidad de Excelencia ‘Mar ́ıa de Maeztu’ MDM-2017-0737– Centro de Astrobiolog ́ıa (INTA-CSIC), The Spanish Ministry of Science, Innovation and Universities AYA2017-85322-R and PID2020-118974GB-C21 (AEI/FEDER, UE), Retos Investigaci ́on BIA2016-77992-R (AEI/FEDER, UE), and ‘Explora Ciencia y Explora Tecnolog ́ıa’ [AYA2017-91062- EXP]. We are grateful to Anezina Solomonidou for assistance in the project proposal. The view expressed in this article can in no way be taken to reflect the official opinion of the European Space Agency. We thank the reviewer of this article for his constructive comments.

Background Very few studies have reported updated data on the incidence, clinical evolution and treatment of inflammatory bowel disease (IBD) in Europe. Aims i) To assess the incidence of IBD in Spain; ii) to describe the main epidemiological and clinical characteristics of patients at diagnosis and the evolution of the disease; and iii) to explore the use of drug treatments in the biological era. Methods Prospective and population-based nationwide registry. Adult patients diagnosed with IBD -Crohn’s disease (CD), ulcerative colitis (UC) or IBD unclassified (IBD-U)- during 2017 in all the 17 Spanish administrative regions were included and will be followed-up for 5 years after diagnosis. Treatment was grouped into 5 categories: mesalazine (oral or topical), steroids (intravenous, oral or topical), immunomodulators (thiopurines, methotrexate or cyclosporine), biologics (anti-TNF, vedolizumab or ustekinumab) and surgery. Results 3627 incident cases of IBD diagnosed during 2017 in 108 hospitals covering over 22 millions of adult inhabitants (about 50% of the Spanish population) comprise the study cohort (Table 1). The overall incidence (cases/100.000 person-years) was 16 for IBD, 7.5 for CD, 8 for UC, and 0.5 for IBD-U. Incidence of CD was somewhat higher in Central Spain, while that of UC was higher in Northern Spain (Asturias and Navarra) (Figure 1). About 46% of patients had CD and 50% UC. Diagnosis delay was longer in CD than in UC (5 vs. 2 months, p < 0.01). The proportion of patients with symptoms at diagnosis was higher in UC than CD (94 vs. 89%, p < 0.01). By contrast, those with CD vs. UC had higher frequency of family history of the disease (18 vs. 13%, p < 0.01), tobacco smoking (38 vs. 12%, p < 0.01) and extraintestinal manifestations (12 vs. 6%, p < 0.01). At diagnosis, 18% of CD patients had structuring or fistulising behaviour, and 69% of UC patients had extensive colitis or left-sided colitis. During a median of 12-month of follow-up, 28% of patients were hospitalised (35% of CD and 22% of UC patients, p < 0.01). A total of 2.6% CD patients progressed to a more severe phenotype, and 2% UC patients developed a more extensive involvement. The cumulative exposure to different treatments is shown in Figure 2. Conclusion The incidence of IBD in Spain is quite high and similar to that reported in Northern Europe. IBD patients require the use of substantial therapeutic resources, which are greater in CD than in UC, and much greater than previously reported. One third of patients are hospitalised in the first year after diagnosis and over 5% undergo surgery. These results highlight the high burden of IBD as well as some of the important challenges faced by clinicians and healthcare systems to manage this costly and complex disease.

Background There are limited data of long-term ustekinumab administered according to the doses recommended in the UNITI studies. The objective of this study was to assess the real-world, long-term effectiveness of ustekinumab in refractory Crohn’s disease (CD) (LONG-CROHNUSK Study). Methods Multicentre study of CD patients starting ustekinumab at the recommended dose based on weight ~6 mg/kg IV week 0, 90 mg SC week 8 and maintenance 90 mg SC every 8 or 12 weeks and with 1 year of follow-up. Values for 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), surgeries and hospitalisations were documented. Potential predictors of clinical and endoscopic remission were examined. Results Four hundred and seven patients were analysed (Table 1). For the maintenance dose, ustekinumab 90 mg was administered SC every 12, 8 and 4 weeks in 56 (14%), 318 (84.5%) and 7 (1.5%) patients, respectively. An interval reduction was applied for 118 patients (29%). Before 52 weeks, treatment discontinuation occurred in 71 patients (17%). 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 ( Conclusion This is the first study to show the real-world long-term effectiveness, endoscopic improvement and safety of ustekinumab administered according to the recommended induction regimen in a cohort of highly refractory CD patients.

Resumen Objetivos Identificar los efectos de los ejercicios de fortalecimiento muscular sobre las habilidades motoras y la fuerza de miembros inferiores en ninos y adolescentes con paralisis cerebral, asi como, conocer las caracteristicas principales de los ejercicios y de los sujetos, identificar los instrumentos de medicion utilizados, y conocer si los cambios en las variables se mantienen en el tiempo. Estrategia de busqueda La busqueda se realizo en las bases de datos de Pubmed, BVS, Cochrane Library, PEDro, WoS, Science Direct y EBSCO entre los meses de noviembre de 2017 y enero de 2018, asi como en revistas especializadas. Seleccion de estudios Tras el proceso inicial de identificacion de estudios, finalmente se seleccionaron 10 estudios que cumplieron los criterios de seleccion. Sintesis de resultados Dos estudios presentaron un bajo riesgo de sesgo. Seis de ellos, muestran resultados significativos en las habilidades motoras, dos estudios en la capacidad de caminar y cuatro estudios en la movilidad. Tambien se encontraron diferencias significativas en la fuerza estatica y dinamica, en dos y cuatro estudios, respectivamente. Dos estudios no obtienen resultados significativos en la unica variable que analizan, y finalmente, en tres estudios, los resultados se mantienen en el tiempo. Conclusiones Los ejercicios de fortalecimiento parecen mejorar tanto la fuerza como las habilidades motoras, pero solo existe una fuerte evidencia en la mejora de la fuerza de grupos musculares aislados. Son necesarias mas investigaciones con una mayor calidad metodologica para evidenciar de manera mas contundente los efectos de los ejercicios de fortalecimiento sobre las dos variables analizadas.

Background The development program (UNIFI) has shown promising results of ustekinumab in ulcerative colitis (UC) treatment that should be confirmed in clinical practice. Aims Primary: to evaluate the durability of ustekinumab treatment in UC patients in clinical practice. Secondary: to assess the short-term response (at week 16) and the long-term effectiveness (at maximum follow-up) and to assess the safety of ustekinumab in clinical practice. Methods Patients included in the prospectively maintained ENEIDA registry who received at least one intravenous dose of ustekinumab due to active UC [Partial Mayo Score (PMS) >2] were included. Clinical activity and effectiveness were defined based on PMS. Results 95 patients were included (table 1). At week 16, 53% of patients had clinical response (including 35% of patients in remission) (figure 1). In the multivariate analysis, elevated serum C-reactive protein was the only variable significantly associated with clinical remission. Long-term remission is represented in figure 2. 36% of patients discontinued the treatment with ustekinumab during a median follow-up of 31 weeks. The probability of maintaining ustekinumab treatment was 87% at week 16, 63% at week 56, and 59% at week 72 (figure 3); primary failure was the main reason for ustekinumab discontinuation. No variable was associated with risk of discontinuation. Three patients reported adverse events; one of them had a fatal severe SARS-CoV-2 infection. Conclusion Ustekinumab is effective both in the short and the long-term in real-life, even in a highly refractory cohort. Higher inflammatory burden at baseline correlated with lower probability of achieving remission. Safety was consistent with the known profile of ustekinumab.

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.

Background It has been reported that familial aggregation occurs in 10–20% of inflammatory bowel disease (IBD) patients1. Familial IBD has been associated with disease anticipation2 and with an increased need for immunosuppressants3 and surgery4. However, most studies were performed before the widespread use of biological agents and this may impact on the need for surgery. We aimed to compare the clinical outcomes of IBD (by means of the need for biological therapy and abdominal surgery) between familial and sporadic forms of IBD in the era of biological therapies. Methods Data were extracted from the ENEIDA registry by GETECCU, a Spanish, prospectively-maintained, IBD database in which more than 80 centers are participating. Only adult patients diagnosed with IBD since 2005 and prospectively followed in the registry since diagnosis were included. Familial IBD was defined as those cases with at least one first-degree relative diagnosed with IBD. Sporadic IBD was defined as those cases with no familial relative (of any degree) with IBD. Kaplan-Meier survival curves were performed to evaluate the cumulative probabilities of remaining biologic-free and surgery-free. Log-rank test was performed to compare them between familial and sporadic IBD forms. Chi-square test was performed for the rest of variables. Results A total of 5,263 patients (2,627 Crohn’s disease [CD]; 2,636 ulcerative colitis [UC]) were included. Of them, 507 (10%) were familial cases (274 CD, 233 UC; P=0.05). The median follow-up was 38,4 and 35.5 months, respectively (P=0.086). Familial cases were younger (P=0.022) and had a higher proportion of females among UC cases (P=0.048). No differences were observed in the need for biological therapy in both CD and UC between familial and sporadic IBD. Regarding surgery, no differences were observed in the cumulative probabilities of a first intestinal resection for CD and colectomy for UC. Similar results were obtained when all the analyses were restricted to those subgroups at high-risk for surgery (i.e. CD with ileal involvement and extensive UC). Conclusion In patients diagnosed with IBD in the era of biological therapies, familial forms have the same requirements for biological agents and resectional surgery as sporadic forms. Therefore, familial aggregation does not seem to be a factor for a more aggressive disease.

One very important matter in hearing-impaired pupils is to know whether they use different learning strategies to hearing pupils students. Similarly, knowing if they have the same cognitive capacities as their hearing peers is also interesting. Research was done to compare the cognitive capacities of hearing-impaired pupils to hearing pupils in years 4, 5 and 6 of primary education with the TEA1 test. In parallel, use of learning strategies by both pupil types was studied. The study sample was formed by 223 pupils aged between 9 and 12 years (distributed in the above three primary education years). The results barely showed any differences in cognitive capacities, but a significant difference was observed in study habits and using certain strategies between students with and without hearing impairments.

Background Ustekinumab has shown promising results in ulcerative colitis (UC) in the development program (UNIFI) that should be confirmed in clinical practice. Our aim was to evaluate the effectiveness and safety of ustekinumab in UC in real life. Methods Patients included in the prospectively maintained ENEIDA registry that received at least 1 dose of ustekinumab intravenously due to active UC were included. Clinical activity and effectiveness were defined based on Partial Mayo Score (PMS). The short-term response was assessed at week 8 and 16. The last-observation-carried-forward method was used in patients that stopped ustekinumab treatment before week 8 or 16. Variables associated with short-term remission were identified by logistic regression analysis. Data quality was assessed by remote monitoring. Results Forty-seven patients were included (Table 1); all of them had been previously exposed to biologic agents (70% to >2): 100% to anti-TNF and 83% to vedolizumab. A total of 26% had been exposed to tofacitinib. Seventeen patients (36%) had response at week 8 [3 of them (6%) had remission]; 16 patients (34%) had response at week 16 [5 of them (11%) had remission] (Figure 1). There was a statistically significant decrease in C-reactive protein (CRP) concentration during the induction only in patients with a response at week 16 (Figure 2). The proportion of patients with CRP elevated at baseline and at week 8 was higher among non-responders at week 16 (Table 2). In the multivariate analysis, higher PMS at week 8 [odds ratio (OR) = 0.5; 95% confidence interval (CI) = 0.3–0.9)] and CRP over the upper normal limit at week 8 (OR = 0.1; 95% CI = 0.01–0.8) were associated with lower probability of response at week 16; steroids during induction increased the probability of response at week 16 (OR = 8; 95% CI = 1–71). Of patients without response at week 8, only 7% achieved response at week 16. Seventeen out of 31 patients continued ustekinumab beyond week 16, despite being non-responders. Of these 17 patients, 4 reached remission after the third dose, 1 after the fifth and 1 after the seventh one. There were 2 infections, one of them with fatal consequences (in a patient under steroids and tacrolimus due to renal transplant). Conclusion Ustekinumab shows benefit in some UC patients in real practice, even in a very refractory cohort in which the drug was prescribed as last resort. Patient status at week 8 seems to be a good predictor of response after the induction. Safety was consistent with the known profile of ustekinumab.

Positron annihilation lifetime spectroscopy is used to experimentally demonstrate the direct relationship between vacancies and the shift of the martensitic transformation temperature in a Ni55Fel7Ga28 alloy. The evolution of vacancies assisting the ordering enables shifts of the martensitic transformation up to 50 K. Our results confirm the role that both vacancy concentration and different vacancy dynamics play in samples quenched from the L2(1) and B2 phases, which dictate the martensitic transformation temperature and its subsequent evolution. Finally, by electron-positron density functional calculations V-Ni is identified as the most probable vacancy present in Ni55Fe17Ga28. This work evidences the capability of vacancies for the fine-tuning of the martensitic transformation temperature, paving the way for defect engineering of multifunctional properties. This work is supported by the Basque Government Grant No. IT-1005-16 and by the Spanish Ministry of Economy and Competitiveness under the Projects No. MAT2015-65165-C2-R (MINECO/FEDER) and No. MAT2014-56116-C4-1-R (AEI/FEDER). I. U. acknowledges the Basque Government Grant No. PRE-2014-214.

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.

Objective Osteoid osteoma is the third most common benign bone tumor and complete surgical resection is definitive treatment. There are a limited number of publications on the use of radioguided surgery in this type of lesion. To assess the utility of radioguided surgery in our environment as a method of surgical treatment of this tumor. Material and methods We retrospectively evaluated 12 patients (2 women and 10 men, age range 9-44 years) with clinical and radiological suspicion of osteoid osteoma. Bone scintigraphy showed foci of pathology uptake compatible with suspected lesion in the femur (4 cases), tibia (3), vertebral column (3), humerus (1) and talus (1). Subsequently patients underwent surgical treatment by radioguided surgery after injection of a dose of (99m)Tc-hydroxy diphosphonate. The nidus was removed using gamma probe and mini gamma camera, considering the technique to be completed when its counts decreased to the levels of the surrounding bone counts. Results Lesions were located in all patients (12 of 12), and were confirmed histologically in 8 of them, including an osteoblastoma. The cure rate was 100%, based on the disappearance of pain after a minimum follow-up of 6 months. Conclusion Use of radioguided surgery in the surgical treatment of osteoid osteoma showed satisfactory results, with 100% efficiency in both lesion location and outcome of treatment and without major postoperative complications.

Objective Osteoid osteoma is the third most common benign bone tumor and complete surgical resection is definitive treatment. There are a limited number of publications on the use of radioguided surgery in this type of lesion. To assess the utility of radioguided surgery in our environment as a method of surgical treatment of this tumor. Material and methods We retrospectively evaluated 12 patients (2 women and 10 men, age range 9–44 years) with clinical and radiological suspicion of osteoid osteoma. Bone scintigraphy showed foci of pathology uptake compatible with suspected lesion in the femur (4 cases), tibia (3), vertebral column (3), humerus (1) and talus (1). Subsequently patients underwent surgical treatment by radioguided surgery after injection of a dose of 99mTc-hydroxy diphosphonate. The nidus was removed using gamma probe and mini gamma camera, considering the technique to be completed when its counts decreased to the levels of the surrounding bone counts. Results Lesions were located in all patients (12 of 12), and were confirmed histologically in eight of them, including an osteoblastoma. The cure rate was 100%, based on the disappearance of pain after a minimum follow-up of 6 months. Conclusion Use of radioguided surgery in the surgical treatment of osteoid osteoma showed satisfactory results, with 100% efficiency in both lesion location and outcome of treatment and without major postoperative complications.

Intense pulsed light (IPL) systems have evolved since they were introduced into medical practice 20 years ago. Pulsed light is noncoherent, noncollimated, polychromatic light energy emitted at different wavelengths that target specific chromophores. This selective targeting capability makes IPL a versatile therapy with many applications, from the treatment of pigmented or vascular lesions to hair removal and skin rejuvenation. Its large spot size ensures a high skin coverage rate. The nonablative nature of IPL makes it an increasingly attractive alternative for patients unwilling to accept the adverse effects associated with other procedures, which additionally require prolonged absence from work and social activities. In many cases, IPL is similar to laser therapy in effectiveness, and its versatility, convenience, and safety will lead to an expanded range of applications and possibilities in coming years.

Intense pulsed light (IPL) systems have evolved since they were introduced into medical practice 20 years ago. Pulsed light is noncoherent, noncollimated, polychromatic light energy emitted at different wavelengths that target specific chromophores. This selective targeting capability makes IPL a versatile therapy with many applications, from the treatment of pigmented or vascular lesions to hair removal and skin rejuvenation. Its large spot size ensures a high skin coverage rate. The nonablative nature of IPL makes it an increasingly attractive alternative for patients unwilling to accept the adverse effects associated with other procedures, which additionally require prolonged absence from work and social activities. In many cases, IPL is similar to laser therapy in effectiveness, and its versatility, convenience, and safety will lead to an expanded range of applications and possibilities in coming years.

A schwannoma is a benign nerve sheath tumor derived from Schwann cells. They are usually small and solitary tumors more frequently localized in cranial nerves and the spinal cord and rarely in the limbs. Some cases have been reported involving extremities (mainly the upper ones) but with a small size. Cases of big size schwannomas unrelated to a neurofibromatosis are very rare. We report the case of a 25 year old patient, with a giant schwannoma which invaded the ischiatic region reaching the triceps surae.El schwannoma es un tumor benigno derivado de la vaina neural de las células de Schwann. Habitualmente suele ser pequeño y solitario, siendo más frecuente en los pares craneales y en la médula espinal, aunque menos frecuente en las extremidades. Se han descrito casos de aparición en las extremidades (principalmente superiores). Son muy raros los casos de schwannomas de gran tamaño sin relación con la neurofibromatosis. Presentamos a una paciente de 25 años de edad, con un schwannoma gigante que invadía desde la región isquiática al tríceps sural.

Controversial findings have been reported regarding the association between cannabis use and cognitive performance in psychosis. Although greater vulnerability to the adverse cognitive effects of long-term cannabis use would be expected in clinical populations, some studies point to better cognitive functioning in psychotic patients with a lifetime history of cannabis use. In this chapter, we review the research on this topic and discuss the methodological aspects to be aware of when interpreting these results, and the hypothesis proposed to explain these predominantly counterintuitive findings.

Osteoid osteoma is the third most common benign bone tumor and complete surgical resection is definitive treatment. There are a limited number of publications on the use of radioguided surgery in this type of lesion. To assess the utility of radioguided surgery in our environment as a method of surgical treatment of this tumor.We retrospectively evaluated 12 patients (2 women and 10 men, age range 9-44 years) with clinical and radiological suspicion of osteoid osteoma. Bone scintigraphy showed foci of pathology uptake compatible with suspected lesion in the femur (4 cases), tibia (3), vertebral column (3), humerus (1) and talus (1). Subsequently patients underwent surgical treatment by radioguided surgery after injection of a dose of (99m)Tc-hydroxy diphosphonate. The nidus was removed using gamma probe and mini gamma camera, considering the technique to be completed when its counts decreased to the levels of the surrounding bone counts.Lesions were located in all patients (12 of 12), and were confirmed histologically in 8 of them, including an osteoblastoma. The cure rate was 100%, based on the disappearance of pain after a minimum follow-up of 6 months.Use of radioguided surgery in the surgical treatment of osteoid osteoma showed satisfactory results, with 100% efficiency in both lesion location and outcome of treatment and without major postoperative complications.

Simple Summary Drug resistance is the principal limiting factor to achieving good survival rates in patients with cancer. The identification of potential biomarkers for diagnosis and prognostic prediction, as well as the design of new molecular-targeted treatments, will be essential to improving head and neck squamous cell carcinoma (HNSCC) patient outcomes. In this sense, the sensitization of resistant cells and cancer stem cells (CSCs) represents a major challenge in cancer therapy. We conducted a proteomic study involving cisplatin-resistance and CSCs with the aim to unravel the molecular and cellular mechanisms by which tumor cells acquire resistance to chemotherapy. Syntenin-1 (SDCBP) was identified as an important protein involved in the chemoresistance and stemness of HNSCC tumors. Abstract To characterize the mechanisms that govern chemoresistance, we performed a comparative proteomic study analyzing head and neck squamous cell carcinoma (HNSCC) cells: CCL-138 (parental), CCL-138-R (cisplatin-resistant), and cancer stem cells (CSCs). Syntenin-1 (SDCBP) was upregulated in CCL-138-R cells and CSCs over parental cells. SDCBP depletion sensitized biopsy-derived and established HNSCC cell lines to cisplatin (CDDP) and reduced CSC markers, Src activation being the main SDCBP downstream target. In mice, SDCBP-depleted cells formed tumors with decreased mitosis, Ki-67 positivity, and metastasis over controls. Moreover, the fusocellular pattern of CCL-138-R cell-derived tumors reverted to a more epithelial morphology upon SDCBP silencing. Importantly, SDCBP expression was associated with Src activation, poor differentiated tumor grade, advanced tumor stage, and shorter survival rates in a series of 382 HNSCC patients. Our results reveal that SDCBP might be a promising therapeutic target for effectively eliminating CSCs and CDDP resistance.