Search

PDF file - 102KB, Supplementary figure 4: BIAcore analysis.

PDF file - 82KB, Supplementary figure 3: cytotoxicity data.

PDF file - 162KB

It is generally thought that the anticancer efficacy of antibody–drug conjugates (ADC) relies on their internalization by cancer cells. However, recent work on an ADC that targets fibronectin in the tumor microenvironment suggests this may not be necessary. The alternatively spliced extra domains A and B (EDA and EDB) of fibronectin offer appealing targets for ADC development, because the antigen is strongly expressed in many solid human tumors and nearly undetectable in normal tissues except for the female reproductive system. In this study, we describe the properties of a set of ADCs based on an antibody targeting the alternatively spliced EDA of fibronectin coupled to one of a set of potent cytotoxic drugs (DM1 or one of two duocarmycin derivatives). The DM1 conjugate SIP(F8)-SS-DM1 mediated potent antitumor activity in mice bearing DM1-sensitive F9 tumors but not DM1-insensitive CT26 tumors. Quantitative biodistribution studies and microscopic analyses confirmed a preferential accumulation of SIP(F8)-SS-DM1 in the subendothelial extracellular matrix of tumors, similar to the pattern observed for unmodified antibody. Notably, we found that treatments were well tolerated at efficacious doses that were fully curative and compatible with pharmaceutical development. Our findings offer a preclinical proof-of-concept for curative ADC targeting the tumor microenvironment that do not rely upon antigen internalization. Cancer Res; 74(9); 2569–78. ©2014 AACR.

PDF file - 81KB, Supplementary figures 1: SDS-PAGE monitoring of stability of antibody drug conjugates in mouse serum and 2: tumor appearance.

Many children have difficulties with accurate self-monitoring and effective regulation of study, and this may cause them to miss learning opportunities. In the classroom, teachers play a key role in supporting children with metacognition and learning. The present study aimed to acquire insights into how teachers’ cognitive and metacognitive strategy instruction, as well as teacher-directed and child-centered instructional practices are related to children’s self-monitoring accuracy, regulation of study, and learning performance. Twenty-one teachers and 308 children (2nd and 4th grade elementary school) participated. Teachers instructed a secret code task, children had to learn the match between letters of the alphabet and corresponding symbols. Teachers were observed and audio-recordings were made of their instructions. Then, children were asked to (a) make restudy selections, (b) complete a test, and (c) self-monitor test performance. Although teachers both addressed cognitive and metacognitive strategies, they more often instructed children about cognitive strategies. Further, teaching practices were more often teacher-directed than child-centered. Although there were no relations between teachers’ instructions for metacognitive strategies and children’s outcome measures, teaching cognitive strategies was positively associated with children’s performance and self-monitoring accuracy. However, teaching cognitive strategies did not predict effective restudy selections. Rather, child-centered instructions (i.e., giving children autonomy to regulate their own learning) positively predicted children’s restudy, and further, children’s self-monitoring was more accurate in classrooms where teachers more often used child-centered instructional practices. This seems to imply that not only the content of the instructions itself, but particularly the way these are given, affects children’s metacognition.

Metacognitive monitoring is a significant predictor of academic achievement and is assumed to be related to language competencies. Hence, it may explain academic performance differences between native and non-native speaking students. We compared metacognitive monitoring (in terms of resolution) between native and non-native speaking fourth graders (~ 10 year olds) in two studies. In Study 1, we matched 30 native and 30 non-native speakers and assessed their monitoring in the context of a paired-associates task, including a recognition test and confidence judgements. Study 1 revealed that recognition and monitoring did not differ between native and non-native speaking children. In Study 2, we matched 36 native and 36 non-native speakers and assessed their monitoring with the same paired-associates task. Additionally, we included a text comprehension task with open-ended questions and confidence judgments. We replicated the findings of Study 1, suggesting that recognition and monitoring do not necessarily differ between native and non-native speakers. However, native speaking students answered more open-ended questions correctly than non-native speaking students did. Nevertheless, the two groups did not differ in monitoring their answers to open-ended questions. Our results indicate that native and non-native speaking children may monitor their metacognitive resolution equally, independent of task performance and characteristics. In conclusion, metacognitive monitoring deficits may not be the primary source of the academic performance differences between native and non-native speaking students.

This study investigated age-dependent improvements of monitoring and control in 7/8- and 9/10-year-old children. We addressed prospective (judgments of learning and restudy selections) and retrospective metacog- nitive skills (confidence judgments and withdrawal of answers). Children (N = 305) completed a paired-asso- ciate learning task twice, with a 1-year delay. Results revealed improvements in retrospective, but not in prospective monitoring and control. Furthermore, control remained suboptimal, seemingly a consequence of overoptimistic monitoring. Both age groups showed stronger monitoring-based control at the second com- pared to the first assessment. The comparison with a cross-sectional sample (N = 144) revealed that improve- ments in retrospective monitoring can be mainly attributed to naturally occurring development, whereas retrospective control seemed to improve due to increased task familiarity.

Resumen Introduccion Los pacientes con enfermedades autoinmunes inflamatorias (EAII) en tratamiento biologico deben recibir la vacunacion antigripal anualmente. Objetivo Estudiar si la respuesta serologica a la vacuna antigripal en pacientes con EAII con tratamiento biologico es diferente de la obtenida en enfermos en tratamiento con farmacos modificadores de la enfermedad (FAME) sinteticos y de la conseguida en sujetos sanos. Metodos Se diseno un estudio de cohortes en el que se incluyeron pacientes con EAII, 68 tratados con biologicos (grupo biologicos) y 46 con tratamiento con FAME sinteticos (grupo FAME), asi como 48 personas sanas. Todos recibieron la vacuna antigripal 2015-2016. Se midieron, mediante ELISA, los titulos de anticuerpos (Ac) frente a los antigenos (Ag) A y B, antes y despues de la vacunacion. Resultados Tras la vacunacion, el 88,24% de los enfermos del grupo biologicos, el 71,74% del grupo FAME y el 89,58% de las personas sanas fueron seropositivos frente al Ag A, mientras que el 42,65% del grupo biologicos, el 41,30% del grupo FAME y el 54,17% de las personas sanas fueron seropositivos frente al Ag B. No hubo diferencias significativas entre los grupos. Conclusiones En nuestro estudio, el tratamiento biologico no se asocio a una peor respuesta serologica.

Background Influenza vaccine is recommended for patients with autoimmune inflammatory diseases (AIID) on biological therapy. Objective To evaluate whether serological response to Influenza vaccine obtained in patients on biological therapy is similar to that achieved in patients on synthetic disease-modifying anti-rheumatic drugs (DMARDs) and that obtained in healthy controls. Methods We designed a cohort study in which patients with AIID, 68 on biological therapy and 46 on synthetic DMARDs, as well as 48 healthy controls, were included and vaccinated during the 2015–2016 influenza season. ELISA was used to measure Influenza antigen (Ag) A and B antibodies, before and after vaccination. Results After vaccination, 88.24% of patients on biologics, 71.74% of those on synthetic DMARDs and 89.58% of healthy controls, presented detectable antibodies against antigen A, while 42.65% of subjects on biologics, 41.30% of those on DMARDs and 54.17% of healthy subjects were seropositive against Ag B. We did not find statistical differences. Conclusions In our study, biological therapy is not associated with worse serological response.

espanolObjetivo El objetivo de este estudio es describir los hallazgos de una evaluacion odontologica protocolizada en pacientes con sindrome de Sjogren primario (SSp) atendidos en las consultas de reumatologia de la Comunidad de Madrid. Metodos Estudio descriptivo multicentrico en el que se incluyeron pacientes con SSp clasificados segun criterios del consenso Europeo-Americano de 2002. Se recogieron datos demograficos, clinicos y serologicos. Se realizo una exploracion oral, se recogio el flujo salival y el indice de caries CAOD. Los pacientes rellenaron la escala visual analogica para xerostomia, el cuestionario Oral Health Impact Profile-14 y un cuestionario de salud oral. Resultados Se reclutaron 61 pacientes. El 98% fueron mujeres y la edad media fue de 57 anos. El 52,5% presentaban signos orales patologicos (flujo salival no estimulado/sialografia/gammagrafia de glandulas salivales) y el 90,2% antiRo/antiLa+. El 92% de los pacientes referian xerostomia y un 61% hiposialia. Treinta y cinco pacientes presentaron lesiones de la mucosa oral. El indice CAOD fue de 16,97 ± 7,93 y la escala visual analogica para la xerostomia fue de 46,69 ± 14,43. Los resultados del Oral Health Impact Profile-14 fueron de 23,13 ± 14,16. Los pacientes con signos orales patologicos obtuvieron una puntuacion en el Oral Health Impact Profile-14 significativamente mayor (p = 0,03), al igual que los pacientes con afectacion del sistema nervioso periferico (p = 0,001). Conclusiones La prevalencia de xerostomia en esta cohorte de pacientes con SSp fue muy elevada y el 61% de los enfermos presentaron hiposialia. Mas de la mitad de los pacientes sufrieron lesiones orales. La salud oral presento un impacto negativo en la calidad de vida de los pacientes con SSp, siendo mayor en aquellos pacientes con signos orales objetivos patologicos y en los que presentaban afectacion del sistema nervioso periferico. EnglishObjective The aim of this study is to describe the findings of a protocolised odontological evaluation of patients with primary Sjogren's syndrome (pSS) treated in rheumatology units in the Community of Madrid. Methods Multicentric descriptive study in which pSS patients classified according to the American-European consensus of 2002 criteria were included. We collected the demographic, clinical and serological data of each patient. A complete oral examination was performed and salivary flow and the CAOD caries index were collected. The patients completed the visual analogue scale for xerostomia, the Oral Health Impact Profile-14 questionnaire and an oral health questionnaire. Results Sixty-one patients were recruited. Ninety-eight percent were women and the mean age of the patients was 57 years. Pathological oral signs (unstimulated salivary flow/salivary glands sialography/scintigraphy) were present in 52.5% of the patients, anti-Ro/anti-La were positive in 90.2%. Ninety-two percent of the patients reported xerostomia and 61% of the patients suffered from hyposialia. Thirty-five patients presented oral mucosa lesions. CAOD index was 16.97 ± 7.93 and visual analogue scale for xerostomia was 46.69 ± 14.43. The results of the OHIP-14 questionnaire were 23.13 ± 14.16. Patients with pathological oral signs obtained a significantly higher Oral Health Impact Profile-14 score (P = .03). We also found that patients with peripheral nervous system involvement obtained a significantly higher Oral Health Impact Profile-14 score (P = .001) Conclusions The presence of xerostomia in this cohort of pSS patients was high and hyposialia was present in 61% of the patients. Oral lesions appeared in more than half of the subjects. Oral health had a negative impact on the quality of life of patients with pSS, being higher in those with pathological objective oral signs and in those with peripheral nervous system involvement.

Resumen Objetivo La tomografia de coherencia optica de dominio espectral (SD-OCT) es la herramienta de mayor utilidad para medir el grosor coroideo (GC). El GC puede estar aumentado tanto en las enfermedades oftalmologicas como en las sistemicas. No obstante, existen ciertas inquietudes en relacion con la reproducibilidad y la validez externa de la OCT. El objetivo de este estudio fue determinar la variabilidad interobservador e intraobservador de la medicion manual de la OCT. Metodos El GC fue medido de manera manual en la region central en 40 ojos de 21 sujetos (11 sanos y 10 con espondilitis anquilosante) utilizando RTVue-100 OCT (Optovue Inc., Fremont, CA, EE. UU.). Las mediciones fueron obtenidas por 9 oftalmologos independientes de 6 centros diferentes. Para determinar la variabilidad interobservador se utilizo el calculo del coeficiente de correlacion intraclase (CCI). Tambien la variabilidad intraobservador fue determinada en 2 de los oftalmologos. Resultados La media del GC subfoveal fue de 364,9 ± 85,1 μm (rango, 170-572). El CCI interobservador fue 0,823 (IC 95%, 0,749-0,888; p Conclusiones En este estudio la medicion manual del GC ha demostrado buena concordancia. Los resultados sugieren que la medicion manual con la OCT es un metodo valido para los estudios multicentricos.

Background and objectives Influenza vaccine is recommended for patients with autoimmune inflammatory rheumatic diseases who receive biological therapy. To evaluate if biological therapy impairs immunization after seasonal influenza vaccine. Material and methods Patients with inflammatory arthopathies, psoriasis, inflammatory bowel disease or connective tissue diseases who were receiving or were going to initiate biological therapy were included and vaccinated during 2014–2015 influenza season. ELISA was used to measure influenza antigen A and B antibodies, before and after vaccination. Demographic parameters, diagnosis and kind of treatment were recorded and their influence on the final serological status against influenza was studied. Results 253 subjects were analyzed. After vaccination, 77% of participants presented detectable antibodies against antigen A and 50.6% of them had detectable antibodies against antigen B. Final seropositivity rate against antigen B antibodies increased from baseline (50.6% vs 43.5%, p

This study investigated elementary school children’s development of monitoring and control when learning from texts. Second (N = 138) and fourth (N = 164) graders were tested in the middle (T1) and end (T2) of the school year. The study focused on the cross-sectional and longitudinal development of monitoring and control, and aimed to investigate the development of metacognition for two test formats. After reading expository texts, children completed a comprehension test consisting of open-ended and true-false questions. They monitored their test performance by making confidence judgments, and controlled performance by deciding whether to maintain or withdraw their given answers. Overall, monitoring and control accuracy was higher for open-ended questions than for true-false questions. For open-ended questions, results indicated higher metacognitive accuracy for fourth graders than second graders. No such age effects were found for monitoring and control for true-false questions. Longitudinally, children of both age groups improved their monitoring and control accuracy from T1 to T2, for open-ended and true-false questions. For both test types, improvement mainly occurred for the monitoring and controlling of incorrect, rather than correct answers. Additionally, the results indicated inter-individual stability of performance, but no stability of monitoring and control accuracy over time. The findings indicate that developmental as well as task-related factors affect children’s metacognitive accuracy.

espanolAims To describe the methodology of REAPSER (Spanish Registry of Recent-onset Psoriatic Arthritis), its strengths and limitations. The aim of this study is to identify prognostic factors for the clinical and radiographic course in a cohort of patients with psoriatic arthritis (PsA) diagnosed within 2 years of symptom evolution. Methods Multicenter, observational and prospective study (with 2-year follow-up including annual visits). Baseline visit intended to reflect patient situation before the disease course was modified by treatments prescribed in rheumatology departments. Patients were invited to participate consecutively in one of their routine visits to the rheumatologist. 211 patients were included. Following data were collected: sociodemographic variables; employment situation; family history; personal history and comorbidities; anthropometric data; lifestyle; use of healthcare services; clinical situation at the time of PsA diagnosis; joint involvement and spinal pain; pain and overall assessment; enthesitis, dactylitis and uveitis; skin and nail involvement; functional situation and quality of life; radiographic evaluation; analytical determinations; treatment; axial and peripheral flare-ups. Conclusions The REAPSER study includes a cohort of patients with recent-onset PsA, before the disease course was modified by disease-modifying antirheumatic drugs prescribed in rheumatology departments. Exhaustive information collected in each visit is expected to be an important data source for future analysis. espanolObjetivos Describir la metodologia del Registro Espanol de Artritis Psoriasica de reciente comienzo de la Sociedad Espanola de Reumatologia (REAPSER), asi como sus fortalezas y limitaciones. El objetivo principal del proyecto es identificar factores pronosticos de la evolucion clinica y radiografica en una cohorte de pacientes que padecen artritis psoriasica (APs) diagnosticada con menos de 2 anos de evolucion. Material y metodo Estudio observacional, prospectivo (2 anos de seguimiento; periodicidad anual de las visitas), multicentrico. La intencion en la visita basal fue reflejar la situacion del paciente antes de que la evolucion de la enfermedad se viese modificada por los tratamientos pautados en los servicios de reumatologia. Los pacientes fueron invitados a participar consecutivamente en una de sus visitas habituales al reumatologo. El tamano muestral finalmente alcanzado fue de 211 pacientes. Se recogen datos sociodemograficos; de situacion laboral; historia familiar; antecedentes personales y comorbilidad; antropometricos; estilo de vida; uso de los servicios de salud; situacion clinica al diagnostico de APs; afectacion articular y dolor espinal; dolor y valoracion global de la enfermedad; entesitis, dactilitis y uveitis; afectacion cutanea y ungueal; situacion funcional y calidad de vida; evaluacion radiografica; determinaciones analiticas; tratamiento; brotes en esqueleto axial y periferico. Conclusiones El estudio REAPSER incluye una cohorte de pacientes con APs de inicio reciente reclutados antes de que la evolucion de la enfermedad se viese modificada por la prescripcion de FAME en los servicios de reumatologia. Se espera que la informacion exhaustiva recogida en las visitas suponga una amplia fuente de datos para futuros analisis.

The present study investigated age-related development in children's metacognitive self-monitoring skills; eight-year-olds (N = 140) and ten-year-olds (N = 164) were compared. Children learned paired associates and completed a recognition test. Two types of monitoring judgments were compared: predictions and postdictions of performance. To investigate the rank-order stability of monitoring judgments, the task was repeated one year later. Prediction accuracy was low for both age groups and did not improve over time. Postdictions were more accurate than predictions; this indicates that self-test experiences support children to take actual performance into account when monitoring learning. For the second graders, postdiction accuracy improved over one year. Annual rank-order stability was found for predictions and postdictions, suggesting that habitual judgment tendencies affect children's monitoring judgments and judgment accuracy.

OBJECTIVES: The aim of this study was to examine the incidence of coronavirus disease 2019 (COVID-19) among patients with immunomediated inflammatory diseases (IMIDs) treated with biologic or targeted synthetic disease-modifying antirheumatic drugs (bDMARDs and tsDMARDs) and to evaluate the influence of either IMIDs or related therapies on the incidence and evolution of COVID-19. METHODS: This observational, cross-sectional study was conducted from January 31, 2020, to May 15, 2020. Data of 902 patients were obtained from clinical records in hospitals, primary care units, and community pharmacies. Inclusion criteria were adults with IMIDs treated with bDMARDs or tsDMARDs who started therapy 3 months prior to study commencement. Patients with poor adherence to treatments were excluded. COVID-19 was classified as "definitive" (severe acute respiratory syndrome coronavirus 2 polymerase chain reaction [PCR]-positive), "possible" (characteristic symptoms and negative PCR), and "suspected" (characteristic symptoms but PCR not performed). RESULTS: COVID-19 was diagnosed in 70 patients (11 definitive, 19 possible, and 40 suspected). The cumulative incidence of definitive COVID-19 was 1.2%. When considering all cases, the incidence was 7.8%. Patients on biosimilars tumor necrosis factor blockers were more likely to have a diagnosis of COVID-19 (odds ratio, 2.308; p < 0.001). Patients on anti-B-cell therapies had a lower incidence of infections (p = 0.046). Low rates of hospitalization (14.3%), pneumonia (14.3%), death (2.9%), or thrombosis (2.9%) were observed, and 94.3% of patients recovered. CONCLUSIONS: The cumulative incidence of confirmed cases of COVID-19 was similar to the general population, with generally low hospitalization, intensive care management, and mortality rates. COVID-19 incidence was less frequent in patients with more severe immunosuppression.

Patients with different autoimmune inflammatory diseases (AIID) on biological therapy are at risk of pneumococcal disease. Adults with inflammatory arthropathies, connective tissue diseases, psoriasis, or inflammatory bowel disease on biological therapy such as anti-TNFα, rituximab, tocilizumab, abatacept, or anakinra were included in this study. Patients completed a protocol combining the pneumococcal vaccines PCV13 and PPV23. Immune response against pneumococcal serotypes 1, 3, 7F, 14, 19A, and 19F were assessed evaluating functional antibodies by an opsonophagocytosis killing assay (OPKA). In this study, 182 patients with AIID completed the sequential vaccination protocol. Patients on etanercept tended to achieve OPKA titers against a larger number of serotypes than the rest of patients on other biological therapies, while adalimumab was associated to a lower number of serotypes with OPKA titers. Rituximab was not associated with a worse response when compared with the rest of biological agents. Not glucocorticoids, nor synthetic disease-modifying antirheumatic drugs, interfered with the immune response. OPKA titers against serotype 3 which is one of the most prevalent, was obtained in 44% of patients, increasing up to 58% in those on etanercept. Hence, almost 50% of patients on biological therapy achieved functional antibodies after the administration of a complete pneumococcal vaccination protocol. Ministerio de Economía, Industria y Competitividad, Gobierno de España (SAF2017-83388) Sociedad de Reumatología de la Comunidad de Madrid (SORCOM)/ MSD (204151) Pfizer (14151) 4.961 JCR (2021) Q2, 77/161 Immunology 1.004 SJR (2021) Q1, 26/153 Drug Discovery No data IDR 2021 UEM

Two independent data sets assessing children's metacognitive monitoring abilities were used to explore the psychometric properties of classical and often-used monitoring measures in primary school age. Theoretically, monitoring is an overarching skill that helps individuals evaluate task mastery, strategy use, and correctness of performance. Monitoring skills are increasingly targeted when addressing individual differences in scholastic achievement and intervention approaches to foster students' self-regulated learning early on. In such contexts, knowledge about central psychometric properties is essential. Results of both studies revealed high internal consistency of prospective and retrospective monitoring judgments. When equivalent item sets (in terms of item difficulty) were considered (Study 1), split-half reliabilities were also satisfying. However, analyses revealed that the monitoring judgments' reliability depends on the reliability of the first-order task (recognition memory test). Retesting children of Study 2 after six months revealed considerable fluctuations in the monitoring measures. Among the included monitoring measures, reliabilities of within-person correlations (Gammas) between performance and confidence and recognition response times and confidence were poorest. Results are discussed in the context of the underlying theoretical construct and implications for research and practice.

OBJECTIVE Choroidal thickness (CT) has been evaluated as a marker of systemic inflammation in ankylosing spondylitis (AS). This study evaluates the CT of AS patients before and after 6 months of biological treatment. METHODS This longitudinal multicenter study evaluated CT in 44 AS patients. The correlations between CT and C-reactive protein (CRP) with disease activity indices were calculated. The concordance between CT and CRP was determined. We assessed factors associated with response to treatment. Clinically important improvement was defined as a decrease in Ankylosing Spondylitis Disease Activity Score of 1.1 points or greater. RESULTS Forty-four eyes in patients aged 18 to 65 years were included. Mean CT values were significantly higher at baseline than after 6 months of treatment (baseline: 355.28 ± 80.46 μm; 6 months: 341.26 ± 81.06 μm; p < 0.001). There was a 95% concordance between CT and CRP at baseline and 6 months. Clinically important improvement was associated with lower baseline CT and age as independent factors (odds ratios, 0.97 [95% confidence interval, 0.91-0.93; p = 0.009] and 0.81 [95% confidence interval, 0.7-0.95; p = 0.005]), with baseline CT of less than 374 μm (sensitivity 78%, specificity 78%, area under the curve 0.70, likelihood ratio 3.6). CONCLUSIONS Choroidal thickness decreased significantly after 6 months of biological treatment in all treatment groups. Choroidal thickness and CRP had a 95% concordance. A high CT was associated with a risk of biological treatment failure. Choroidal thickness can be considered a useful biomarker of inflammation and a factor associated with response to treatment in AS.

Background and objective Ankylosing spondylitis (AS) is an inflammatory disease, and choroidal thickness (CT) has been proposed and evaluated as a potential marker of systemic inflammation associated with AS and other inflammatory diseases. This study compared CT measurements taken from patients with severe AS disease activity without eye inflammation with those taken from healthy subjects. Methods This cross-sectional, multicenter study compared CT in 44 patients with high AS disease activity, and no history of eye inflammation with CT in 44 matched healthy subjects aged between 18 and 65 years. In the AS group, the correlation between CT and C-reactive protein, human leukocyte antigen (HLA) B27 positivity, disease duration, and disease activity was calculated. Results Mean CT values of patients with AS were significantly higher in the right eye, the left eye, and the thickest choroid eye. The right eye mean CT was 338.3 ± 82.8 μm among patients with AS and 290.5 ± 71.2 μm among healthy subjects (p = 0.005). The left eye mean CT was 339.5 ± 84.7 μm for patients with AS and 298.4 ± 68.9 μm for healthy subjects (P = 0.015). The thickest choroid eye CT was 358.4 ± 82.1 μm among patients with AS and 314.1 ± 65.2 μm among healthy subjects (P = 0.006). We did not find a significant correlation between CT and disease activity, C-reactive protein, human leukocyte antigen B27 positivity, or disease duration. Conclusions Patients with active AS but without a history of eye inflammation had a thicker choroid than healthy subjects. This finding suggests that CT is a marker of systemic inflammation in patients with inflammatory disease, regardless of known eye symptoms.

Spectral-domain optical coherence tomography (SD-OCT) is the most useful tool to measure choroidal thickness (CT). CT may be increased in ocular and systemic diseases. However, there are concerns relating reproducibility and external validity of OCT. The aim of this study was to assess the inter-observer and intra-observer variability of manual OCT measurements.CT was manually measured in the central choroid of 40 eyes from 21 subjects (11 healthy and 10 with ankylosing spondylitis) using RTVue-100 OCT (Optovue Inc., Fremont, CA, EE.UU.). Measurements were performed by 9 independent ophthalmologists from 6 different centers. To assess the inter-observer variability, the intra-class correlation coefficient (ICC) method was calculated. Also, intra-observer variability was assessed in 2 of the ophthalmologists.The mean subfoveal CT was 364.9±85.1μm (range, 170 to 572). The inter-observer ICC was 0.823 (CI 95%, 0.749 to 0.888, p0.001). The intra-observer ICCs were 0.885 (CI 95%, 0.783 to 0.939, p0.001) and 0.925 (CI 95%, 0.859 to 0.960. p0.001).In this study, manual measurements of CT with OCT showed a good concordance. These results suggest that manual OCT is a valid tool for multicenter studies.

To evaluate the response to hepatitis B virus (HBV) vaccine in patients on biological therapy. Adults with autoimmune inflammatory diseases on biological therapy such as anti-TNFα, rituximab, tocilizumab, abatacept, or anakinra were included. Hepatitis B surface antibody (anti-HBs) was measured by ELISA before and after vaccination. Seroconversion was considered when an anti-HBs titer 10 mIU/mL was achieved. The effect of treatment on the immunoprotective state was studied. The response was compared with that obtained in patients on synthetic disease modifying anti-rheumatic drugs (DMARDs) and healthy controls. A total of 187 patients on biologicals, 48 on synthetic DMARDs, and 49 on healthy controls were analyzed. More than 80% of patients on biologics responded to the vaccine but required more boosters and second vaccine series. Patients who achieved seroconversion were younger than those who did not (47.10 ± 12.99 vs. 53.18 ± 10.54 years, p = 0.012). Being on etanercept or golimumab was associated with seroconversion, while being on rituximab was not. Seroconversion was achieved in 93.75% of patients on synthetic DMARDs and 97.96% of healthy controls. The seroconversion rate in the biologics group was lower than in the synthetic DMARD group (p = 0.043) and tended to be lower than in the healthy group (p = 0.056). In patients on biological therapy, a high rate of HBV vaccine response can be achieved when a complete vaccination schedule is administered. Vaccination while not on biological agents reduces the requirement for boosters and revaccination. Key points: • Patients on biological therapy can achieve high rates of immune response to HBV vaccine when complete vaccination schedules are administered. • However, to achieve such a high seroconversion rate, more boosters and second vaccination series are required. • This supports the proposal already made to provide HBV vaccination to all patients with an autoimmune inflammatory disease after the diagnosis is made and not when the use of a biological treatment is under consideration.

The article Development of Children’s monitoring and control when learning from texts: effects of age and test format, written by Martina Steiner, Mariette H. van Loon, Natalie S. Bayard and Claudia M. Roebers, was originally published electronically on September 7, 2019 without open access.

Although the literature consistently documents strong improvements in metacognitive skills over the elementary school years, relatively little is known about the mechanisms fueling these developments. One factor that is being discussed in the literature and targeted in the present approach is cue utilization. Cue utilization quantifies the degree to which an individual uses mnemonic experiences during task mastery to inform monitoring processes. In the present study, retrieval fluency as a valid and ubiquitous cue during recognition was assessed by recording children's choice latencies in a recognition test and by relating these to confidence ratings. A sample of second graders and fourth graders was assessed 3 times over one year in terms of their recognition performance, the time needed to select an alternative, and their monitoring accuracy. Results revealed age differences in monitoring accuracy, cue utilization, and cue validity. Moreover, while monitoring accuracy increased over time in both age groups, cue utilization increased only in the younger children. Analyses were completed by an individual differences approach showing that cue utilization is a factor driving recognition improvements over time, underlining the importance of metacognitive experiences for development. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Background Tendon involvement is common in patients with juvenile idiopathic arthritis (JIA). Differentiating tenosynovitis and underlying arthritis may be challenging on the basis of clinical examination (CE) alone. In daily clinical practice, ultrasound (US) imaging with Doppler information can be more versatile as it allows a dynamic assessment of joint inflammation and can be done quickly at the bedside. US can reliably evaluate the location of inflammation and provide direct visualization when local steroid injection is considered as treatment for children with JIA. Objectives To present the published data concerning the US assessment of tenosynovitis and the US metric properties investigated in JIA. Methods A systematic literature review (SLR) was conducted comprising PubMed, Embase and the Cochrane Library (before June 2018). Search terms: “arthritis, juvenile” AND, “tenosynovitis OR tendinopathy” AND “ultrasonography” OR “Doppler” AND “diagnosis OR therapy management”. Selection criteria: Original articles published in English reporting US, tenosynovitis and tendinopathy in the paediatric population (up to18 years old) with JIA. Data were extracted from manuscripts meeting the selection criteria, with particular focus on the definition used, scoring system applied and the US metric properties investigated. The quality of the studies was assessed using the same methodology developed for the SLR on paediatric synovitis [1]. Results After selection, 11 articles were analysed. The tibialis posterior tendon group and peroneal tendons were the most commonly evaluated. Most authors applied the OMERACT definition proposed to rheumatoid arthritis (RA) [2] for evaluating paediatric tenosynovitis. Binary scoring system on both grey scale and Doppler was applied in most of studies. Doppler function was commonly included, with only five specifying the Doppler parameters that were used. Construct validity was reported in roughly 50% of articles, including the CE as the main comparator. However, some of those articles have shown that clinical evaluation underestimates tendon involvement. US reliability and responsiveness for tenosynovitis in JIA was rarely included. Conclusion Although US seems a promising image modality to assess tenosynovitis in JIA, this SLR emphasizes the definitions of US elementary lesions of RA are frequently used in children. Moreover, there is insufficient evidence of studies exploring the construct validity of the US-determined tenosynovitis in JIA. Further validation studies are needed for implementation in clinical practice and trials. References [1] Collado P. Arthritis Care Res2012; 64:1011 [2] Wakefield R. J Rheumatol. 2005;32:2485 Disclosure of Interests PAZ COLLADO: None declared, Silvia Magni-Manzoni Consultant for: Abbvie, Speakers bureau: Abbvie, MARTINA STEINER: None declared, Tracy Ting : None declared, Patricia Vega Fernandez: None declared, Clara Malattia: None declared, Ana Rodriguez: None declared, George Bruyn : None declared, Helen Keen: None declared, Lene Terslev Speakers bureau: Speakers fee from : Roche, Novartis, Pfizer, MSD, BMS, Celgene

Background: Systemic Juvenile Idiopathic Arthritis (SJIA) and adult onset Still’s disease are rare diseases of unknown etiology that share several clinical and laboratory features. The pathogenesis of these two diseases is complex and multifactorial, with an important role of innate immunity: activation of neutrophils and macrophages and increased levels of cytokines dependent on the activation of the inflammosome. A proportion of these patients will develop a Macrophage activation syndrome (MAS), a serious and life-threatening complication. Objectives: To identify immunological markers that allow a differential diagnosis between patients with inactive SJIA, active SJIA or MAS. To evaluate if there are differences between biomarkers in SJIA and adult onset Still’s disease Methods: Observational, prospective and multicenter study. Inclusion criteria: patients with SJIA or adult onset Still’s disease, followed in Paediatric or Adult Rheumatology Department from 5 Madrid hospitals. Group 1: Patients with active SJIA or adult onset Still’s disease +/- diagnosis of secondary MAS at the first visit, have been followed-up performing a second clinical and analytical visit at 3 months. Group 2: Patients with inactive SJIA or adult onset Still’s. Clinical and analytical data were collected, PBMCs were obtained before and after treatment, and several leukocyte subtypes were evaluated by flow cytometry (FACS). The intracytoplasmic expression of TNF-α, IL-1b and IL-6 in monocytes was determined by flow cytometry before and after stimulation with lipopolysaccharides (LPS) in the presence of monensin (Golgi inhibitor). In addition, IL-18 levels were determined by ELISA in all visits. Results: A total of 25 patients were included (18 SJIA and 7 adult onset Still’s diseases), 2 of them being excluded from the analysis because exclusions criteria. 30,4% patients presented MAS at the first visit (5 SJIA and 2 adult onset Still’s disease) and other 2 at some time during the disease. The median of IL-18 was 296.1 (CI 108.3-346.0) in patients who have never had MAS and 899.85 (CI: 397.32-1095.6) in the other group. Patients with active MAS had a CD4/CD8 ratio close to the lower limit (1.1 +/- 0.1 SD) reflecting a decrease in the CD4 + population and an increase in CD8 +. On the other hand, the rest of the groups presented a CD4/CD8 ratio of 2.6 +/- 0.5 SD in patients without disease activity and 2.0 +/- 0.7 SD in patients with active SJIA or adult onset Still’s disease but without MAS. No significant differences were found between patients with SJIA or adult onset Still’s disease. Conclusion: The results of this study show that the analysis of three determinations:%CD4,%CD8 and the CD4/CD8 ratio can help in the early detection of patients with MAS secondary to SJIA or adult onset Still’s disease. The determination of IL-18 has been in our study a marker of MAS, similar to several published studies. No significant differences were found in the immunological tests between patients with SJIA and adult onset Still’s disease with active or inactive disease. Reference: [1] Weiss ES et all Interleukin-18 diagnostically distinguishes and pathogenically promotes human and murine macrophage activation syndrome. Blood. 2018 Mar 29;131(13):1442-1455 Disclosure of Interests: None declared

Aims: To describe the methodology of REAPSER (Spanish Registry of Recent-onset Psoriatic Arthritis), its strengths and limitations. The aim of this study is to identify prognostic factors for the clinical and radiographic course in a cohort of patients with psoriatic arthritis (PsA) diagnosed within 2 years of symptom evolution. Methods: Multicenter, observational and prospective study (with 2-year follow-up including annual visits). Baseline visit intended to reflect patient situation before the disease course was modified by treatments prescribed in rheumatology departments. Patients were invited to participate consecutively in one of their routine visits to the rheumatologist. 211 patients were included. Following data were collected: sociodemographic variables; employment situation; family history; personal history and comorbidities; anthropometric data; lifestyle; use of healthcare services; clinical situation at the time of PsA diagnosis; joint involvement and spinal pain; pain and overall assessment; enthesitis, dactylitis and uveitis; skin and nail involvement; functional situation and quality of life; radiographic evaluation; analytical determinations; treatment; axial and peripheral flare-ups. Conclusions: The REAPSER study includes a cohort of patients with recent-onset PsA, before the disease course was modified by disease-modifying antirheumatic drugs prescribed in rheumatology departments. Exhaustive information collected in each visit is expected to be an important data source for future analysis. (C) 2018 Elsevier Espafia, S.L.U. and Sociedad Espailola de Reumatologia y Colegio Mexicano de Reumatologia. All rights reserved.

To identify the risk of relapse and subclinical inflammatory stages of systemic autoimmune diseases, new tools are needed. In the recent years, choroidal thickness and retinal thickness measured with ocular coherence tomography (OCT) have been proposed as an inflammatory marker for different systemic diseases, especially for conditions with a vascular component. Our aim in this article is to review the literature regarding the role of choroidal and retinal thickness as a potential inflammatory marker in systemic autoimmune and inflammatory diseases measured by OCT. Current literature suggests that the choroid of patients thickens in active phases of inflammatory diseases with vascular involvement. This pattern is observed in lupus, systemic sclerosis, Behçet disease, spondylitis, and familial Mediterranean fever. Choroidal thickness may decrease with biological treatments, along with systemic inflammation. Repeated flares and long-term disease, however, may thin the choroid, as a result of prolonged insult to the microvasculature and subsequent atrophy. Less is known about the effect of these diseases on retinal thickness. In summary, choroidal and retinal thickness measured by OCT may be promising markers for inflammation in systemic autoimmune and inflammatory diseases; however, more studies are warranted before generalizing choroidal thickness measurements by OCT as a marker for disease activity. The role of retinal thickness is more unclear due to a lack of studies in this field. Sin financiación 4.195 JCR (2019) Q1, 6/60 Ophthalmology 2.002 SJR (2019) Q1, 7/125 Ophthalmology No data IDR 2019 UEM

Background Plasma concentrations of lipoprotein (a) (Lp(a)), a lipoprotein with atherogenic and thrombogenic properties, have a strong genetic basis, although high concentrations of Lp(a) have also been reported in the context of inflammation, as in rheumatoid arthritis (RA). Few studies evaluate the impact of biologic therapies (BT) on Lp(a) in RA, taking into account that with these new therapies a better control of inflammation is achieved. Objective The aim of the study was to evaluate the plasma concentrations of Lp(a) in Spanish RA patients on BT attending rheumatology outpatient clinics. Methods Baseline analysis of the CARdiovascular in rheuMAtology project, a 10-year prospective study, evaluating the risk of cardiovascular events in RA and other forms of inflammatory arthritis. RA patients were classified according to treatment: no biologic, anti-tumor necrosis factor, anti-interleukin-6 receptor tocilizumab (TCZ), and other biologic (rituximab or abatacept). A model of linear multivariate regression was built in which the dependent variable was Lp(a) concentration and the explanatory variable was BT. The model was adjusted for confounding factors. Results Seven hundred and seventy-five RA patients were analyzed. Plasma concentrations of total cholesterol and triglyceride were significantly higher in TCZ-treated patients. Nevertheless, no significant difference in the atherogenic index between TCZ-treated patients and patients without BT was found. After adjusting for confounding factors, patients with BT had lower concentrations of Lp(a) than those without BT; however, only TCZ-treated patients achieved statistically significant differences (?: ?0.303, 95% confidence interval: ?0.558 to ?0.047; P = .02). Conclusions RA patients treated with TCZ show lower plasma concentrations of Lp(a) compared with patients without BT. This project has been supported by an unrestricted grant from Abbvie, Spain. The design, analysis, interpretation of results, and preparation of the article have been done independently of Abbvie. Dr González-Gay's studies have been supported by grants from “Fondo de Investigaciones Sanitarias” PI06/0024, PS09/00748, and PI12/00060 and RD12/0009/0013 (RIER) from “Instituto de Salud Carlos III” (ISCIII) (Spain).

Low-dose radon hyperthermia balneo treatment (LDRnHBT) is applied as a traditional measure in the non-pharmacological treatment of rheumatic diseases in Europe. During the last decades, the main approach of LDRnHBT was focused on the treatment of musculoskeletal disorders, but scientific evidence for the biological background of LDRnHBT is weak. Recently, evidence emerged that LDRnHBT influences bone metabolism. We investigated, whether combined LDRnHBT and exercise treatment has an impact on bone metabolism and quality of life in a study population in an age group at risk for developing osteoporosis. This randomized, double-blind, placebo-controlled trial comprised guided hiking tours and hyperthermia treatment in either radon thermal water (LDRnHBT) or radon-free thermal water (PlaceboHBT). Markers of bone metabolism, quality of life and somatic complaints were evaluated. Statistics was performed by linear regression and a linear mixed model analysis. Significant changes over time were observed for most analytes investigated as well as an improvement in self-assessed health in both groups. No significant impact from the LDRnHBT could be observed. After 6 months, the LDRnHBT group showed a slightly stronger reduction of the osteoclast stimulating protein receptor activator of nuclear kB-ligand compared to the PlaceboHBT group, indicating a possible trend. A combined hyperthermia balneo and exercise treatment has significant immediate and long-term effects on regulators of bone metabolism as well as somatic complaints. LDRnHBT and placeboHBT yielded statistically equal outcomes.

We systematically investigated how the therapeutic efficacy of a traceless vascular targeting antibody drug conjugate (ADC) is affected by the length of a spacer introduced between the antibody's globular fold and the site of drug attachment. Homogeneous ADCs were prepared from the direct conjugation of engineered C terminal cysteines with a potent thiol containing drug which was separated from the antibody surface by unstructured spacers of increasing length. We found that a smaller spacer length is reflected in enhanced stability and therapeutic efficacy of the conjugates in a syngeneic model of murine cancer. © 2013 The Royal Society of Chemistry.

Objetivos Caracterizar a una cohorte de pacientes con espondiloartritis (SpA) precoz, demostrar la utilidad de la ecografia de entesis en el diagnostico y seguimiento, y desarrollar un modelo para predecir actividad persistente. Pacientes y metodos Estudio prospectivo a 1 ano de los pacientes con SpA del EStudio PIloto de Derivacion de pacientes con Espondiloartritis Precoz (ESPIDEP). Se llevo a cabo una evaluacion clinica, radiologica y ecografica. La ecografica de entesis se realizo con el MAdrid Sonographic Enthesis Index (MASEI), y su utilidad diagnostica se determino con el punto de corte = 18. Se examino la evolucion clinica, radiologica y del MASEI. Finalmente se desarrollo un modelo a partir de los factores que predicen actividad persistente. Resultados Se realizo el seguimiento durante 1 ano a 32 pacientes. El MASEI basal alcanzo una sensibilidad y especificidad de 78,12% y 83,37%, un valor predictivo positivo y negativo del 83,3% y el 79,41%, y una razon de verosimilitud positiva y negativa de 5 y 0,26, respectivamente. La mejoria del BASMI y el MASEI fue significativa (p = 0,001 y p = 0,007, respectivamente). Las mujeres tuvieron mas afectacion periferica desde el inicio y los hombres mayor progresion radiologica axial y PCR mas elevada (p < 0,05). El modelo que mejor predijo actividad persistente estaba formado por dolor axial nocturno, BASDAI y PCR. Conclusiones La ecografia de entesis puede ser util en la evaluacion inicial y el seguimiento de las SpA precoces. El patron de enfermedad difiere segun el sexo. Predecir actividad persistente en estadios precoces apoya la utilizacion de tratamientos mas intensivos.

DNA-encoded chemical libraries, i.e., collections of compounds individually coupled to distinctive DNA fragments serving as amplifiable identification barcodes, represent a new tool for the de novo discovery of small molecule ligands to target proteins of pharmaceutical interest. Here, we describe the design and synthesis of a novel DNA-encoded chemical library containing one million small molecules. The library was synthesized by combinatorial assembly of three sets of chemical building blocks using Diels-Alder cycloadditions and by the stepwise build-up of the DNA barcodes. Model selections were performed to test library performance and to develop a statistical method for the analysis of high-throughput sequencing data. A library selection against carbonic anhydrase IX revealed a new class of submicromolar bis(sulfonamide) inhibitors. One of these inhibitors was synthesized in the absence of the DNA-tag and showed accumulation in hypoxic tumor tissue sections in vitro and tumor targeting in vivo.

When delivered at a sufficient dose and dose rate to a neoplastic mass, radiation can kill tumor cells. Because cancer frequently presents as a disseminated disease, it is imperative to deliver cytotoxic radiation not only to the primary tumor but also to distant metastases, while reducing exposure of healthy organs as much as possible. Monoclonal antibodies and their fragments, labeled with therapeutic radionuclides, have been used for many years in the development of anticancer strategies, with the aim of concentrating radioactivity at the tumor site and sparing normal tissues. This review surveys important milestones in the development and clinical implementation of radioimmunotherapy and critically examines new trends for the antibody-mediated targeted delivery of radionuclides to sites of cancer. Clin Cancer Res; 17(20); 6406–16. ©2011 AACR.

a b s t r a c t Objectives: To characterize a cohort of early spondyloarthritis (SpA) patients, to demonstrate the usefulness of enthesis ultrasonography for the diagnosis and follow up, and to develop a statistical model to predict persitent activity. Patients and methods: A 1 year prospective study with clinical, radiological and ultrasonographic evaluations was performed in patients with SpA from the Pilot Study for the Referral of Patients with Early SpA (ESPIDEP). Enthesis ultrasonography was explored by the MAdrid Sonographic Enthesis Index (MASEI), and its diagnostic utility was determined to be a cutoff score of ≥18 points. The clinical, radiological and MASEI scores were studied. Finally, a statistical model from factors predicting persitent activity was developed. Results: A 1 year follow-up of 32 patients was carried out. The baseline MASEI reached a sensitivity and specificity of 78.12% and 84.37% respectively, positive and negative predictive value was 83.3% and 79.41% respectively, and positive and negative likelihood ratios were 5 and 0.26, respectively. The improvement of BASMI and the MASEI scores were significant (P=.001 and P=.007, respectively). From the beginning, women had more peripheral affectation, and men had higher axial radiological progression and higher CRP (P

Chikungunya Fever is a mosquito-transmitted viral disease that causes fever, rash and musculoskeletal complaints. The latest may persist for several months, or even years or developed a relapsing course, that deserve an adequate treatment. Due to the large outbreak declared in the Caribbean in 2013, imported cases of Chikungunya as well as the risk of autochthonous transmission in case of available vectors have increased in non-endemic countries, like Spain. We described four cases of Chikungunya treated in our clinic.

Chikungunya Fever is a mosquito-transmitted viral disease that causes fever, rash and musculoskeletal complaints. The latest may persist for several months, or even years or developed a relapsing course, that deserve an adequate treatment. Due to the large outbreak declared in the Caribbean in 2013, imported cases of Chikungunya as well as the risk of autochthonous transmission in case of available vectors have increased in non-endemic countries, like Spain. We described four cases of Chikungunya treated in our clinic.

Objective To assess whether dexamethasone (DXM) decreases the time to recovery in patients with parapneumonic pleural effusion. Study design This was a multicenter, randomized, double blind, parallel-group, placebo-controlled clinical trial of 60 children, ranging in age from 1 month to 14 years, with community-acquired pneumonia (CAP) and pleural effusion. Patients received either intravenous DXM (0.25 mg/kg/dose) or placebo every 6 hours over a period of 48 hours, along with antibiotics. The primary endpoint was the time to recovery in hours, defined objectively. We also evaluated complications and adverse events. Results Among the 60 randomized patients (mean age, 4.7 years; 58% female), 57 (95%) completed the study. Compared with placebo recipients, the patients receiving DXM had a shorter time to recovery, after adjustment by severity group and stratification by center (hazard ratio, 1.95; 95% CI, 1.10-3.45; P = .021). The median time to recovery for patients receiving DXM was 68 hours (2.8 days) shorter than patients receiving placebo (109 hours vs 177 hours; P = .037). In exploratory subgroup analysis, the median time to recovery for patients with simple effusion receiving DXM was 76 hours (3.1 days) shorter than for patients with simple effusion receiving placebo ( P = .017). The median time to recovery for patients with complicated effusion receiving DXM was 14 hours (0.5 days) shorter than for patients with complicated effusion receiving placebo ( P = .66). The difference in the effect of DXM in the 2 severity groups was not statistically significant ( P = .138 for interaction). There were no significant differences in complications or adverse events attributable to the study drugs, except for hyperglycemia. Conclusion In this trial, DXM seemed to be a safe and effective adjunctive therapy for parapneumonic pleural effusion. Trial registration ClinicalTrials.gov : NCT01261546 .

Kohler’s disease is an osteochondrosis of the tarsal navicular bone. The exact causes of osteochondrosis remain unknown. We report a 4-year-old girl with a haematogenous tarsal arthritis who developed a Kohler’s disease immediately after the infection. It is hypothesised that avascular necrosis of the navicular bone was developed secondary to pyogenic arthritis.