Validación externa de un modelo de predicción de síndrome de ojo seco asociado a enfermedad injerto contra huesped

OBJETIVO: Realizar la validación externa de un modelo ajustado de predicción de SOS asociado a EICH basado en la expresión de 5 genes (IFN-γ, EGFR, CCL18, TNFSF4 e IL-9) en epitelio conjuntival. Analizar, además, la expresión diferencial de 84 genes de citoquinas en epitelio conjuntival y determinar los niveles en lágrima citoquinas y quimioquinas en estos pacientes con SOS asociado a EICH y sujetos sanos para su comparación con los datos obtenidos anteriormente. MÉTODOS: Se evaluaron 12 pacientes con SOS asociado a EICH y 11 controles sanos (edad y género comparable). Los pacientes se encontraban controlados medicamente suspendieron sus tratamientos tópicos una semana antes del estudio, que se realizó en una cámara de ambiente controlado. Se evaluó clínicamente a los pacientes, se recogieron muestras de lágrima, y se realizó una CIC para la recolección de células epiteliales de conjuntiva bulbar superior. Se estudió la expresión diferencial de 84 genes de moléculas inflamatorias mediante qRT2-PCR en la células epiteliales conjuntivales, y se determinaron en lágrima los niveles de EGF, IL-1RA, IL-1β, IL-2, IL-6, IL-8/CXCL8, IL-10, IL-12p70, IL-17A, IP-10/CXCL10, eotaxina 1/CCL11, IFN-γ, VEGF, TNF- α, RANTES/ CCL5 y Fractalquina con un ensayo multianalito en un Luminex IS-100. Se realizó la validación externa del modelo de predicción y se compararon los resultados con los obtenidos en un estudio previo RESULTADOS: La expresión de 15 genes se vio incrementada significativamente, y de otros 5 rozando la significación, mientras que 2 de ellos mostraron menor expresión respecto a los controles. El modelo de predicción se validó y demostró tener una alta precisión, la curva ROC obtuvo un AUC de 0.9, con sensibilidad del 100% y especificidad de 80% a la hora de clasificar nuevos casos de SOS asociado a EICH. Todas las citoquinas fueron detectadas en lágrima. La concentración de EGF e IL-17 fue menor en pacientes, mientras que la de IL-10, IL-1RA, IL-6 e IL-8 estaba aumentada respecto a los controles. CONCLUSIONES: En este estudio se confirma la validez del modelo de predicción diseñado a partir de la expresión de un panel de 5 genes en epitelio conjuntival bulbar. Además, proporciona más información sobre los mecanismos etiopatogénicos del SOS asociado a EICH, observándose diferencias en la concentración de citoquinas en lágrima y la expresión génica en epitelio conjuntival. 3Universidad de Valladolid. Instituto Universitario de Oftalmobiología Aplicada (IOBA)Máster en Subespecialidades Oftalmológica

Búsqueda de biomarcadores moleculares en el síndrome de ojo seco asociado a enfermedad injerto contra huésped (EICH)

En esta tesis doctoral se trató de determinar la existencia de biomarcadores en células del epitelio conjuntival y lágrima de pacientes con síndrome de ojo seco (SOS) debido a enfermedad de injerto contra huésped (EICH) ocular que iban a ser sometidos a trasplante alogénico de progenitores hematopoyéticos (TAPH), así como de encontrar correlaciones significativas entre estos biomarcadores y signos clínicos de la enfermedad. Con ello se pretendía desarrollar modelos predictivos basados en estos parámetros con capacidad diagnóstica y predictiva de la enfermedad.Departamento de Cirugía, Oftalmología, Otorrinolaringología y FisioterapiaDoctorado en Ciencias de la Visió

Multimodal Imaging of White Dot Syndromes

White dot syndromes are an uncommon group of posterior uveitis affecting the outer retina, retinal pigment epithelium, choriocapillaris, and/or choroidal stroma. Multimodal imaging, including fundus fluorescein angiography, indocyanine green angiography, autofluorescence, and optical coherence tomography angiography, has improved our understanding regarding their pathophysiology, helping us to rename or even regroup some of these disorders as one disease in opposition to the historical description. It also provides useful information to evaluate disease activity and monitor response to treatment. This chapter will review the different findings on multimodal imaging of these heterogenous disorders and classify them according to their primary anatomic involvement

Biomarkers in ocular chronic graft versus host disease: tear cytokine- and chemokine-based predictive model.

Producción CientíficaPurpose: To develop a tear molecule level-based predictive model based on a panel of tear cytokines and their correlation with clinical features in ocular chronic graft versus host disease (cGVHD). Methods: Twenty-two ocular cGVHD patients and 21 healthy subjects were evaluated in a controlled environmental research laboratory (CERLab). Clinical parameters were recorded, and tears were collected. Levels of 15 molecules (epidermal growth factor [EGF], IL receptor antagonist [IL-1Ra], IL-1β, IL-2, IL-6, IL-8/CXCL8, IL-10, IL-12p70, IL-17A, interferon inducible protein [IP]-10/CXCL10, IFN-γ, VEGF, TNF-α, eotaxin 1, and regulated on activation normal T cell expressed and secreted [RANTES]) were measured by multiplex-bead assay and correlated with clinical parameters. Logistic regression was used to develop a predictive model. Leave-one-out cross-validation was applied. Classification capacity was evaluated in a cohort of individuals with dry eye (DE) of other etiologies different from GVHD. Results: Epidermal growth factor and IP-10/CXCL10 levels were significantly decreased in ocular cGVHD, positively correlating with tear production and stability and negatively correlating with symptoms, hyperemia, and vital staining. Interleukin-1Ra, IL-8/CXCL8, and IL-10 were significantly increased in ocular cGVHD, and the first two correlated positively with symptoms, hyperemia, and ocular surface integrity while negatively correlating with tear production and stability. Predictive models were generated, and the best panel was based on IL-8/CXCL8 and IP-10/CXCL10 tear levels along with age and sex, with an area under the receiving operating curve of 0.9004, sensitivity of 86.36%, and specificity of 95.24%. Conclusions: A predictive model based on tear levels of IL-8/CXCL8 and IP-10/CXCL10 resulted in optimal sensitivity and specificity. These results add further knowledge to the search for potential biomarkers in this devastating ocular inflammatory disease.Ministry of Economy and Competitiveness, Madrid, Spain, SAF-2010 15631 (AES)

Efficacy, Safety and Cost-Effectiveness of Methotrexate, Adalimumab or Their Combination in Non-infectious Non-anterior Uveitis: A Protocol for a Multicentre, Randomised, Parallel Three Arms, Active-Controlled, Phase III Open Label With Blinded Outcome Assessment Study

[Abstract] Introduction: Non-infectious uveitis include a heterogeneous group of sight-threatening and incapacitating conditions. Their correct management sometimes requires the use of immunosuppressive drugs (ISDs), prescribed in monotherapy or in combination. Several observational studies showed that the use of ISDs in combination could be more effective than and as safe as their use in monotherapy. However, a direct comparison between these two treatment strategies has not been carried out yet. Methods and analysis: The Combination THerapy with mEthotrexate and adalImumAb for uveitis (CoTHEIA) study is a phase III, multicentre, prospective, randomised, single-blinded with masked outcome assessment, parallel three arms with 1:1:1 allocation, active-controlled, superiority study design, comparing the efficacy, safety and cost-effectiveness of methotrexate, adalimumab or their combination in non-infectious non-anterior uveitis. We aim to recruit 192 subjects. The duration of the treatment and follow-up will last up to 52 weeks, plus 70 days follow-up with no treatment. The complete and maintained resolution of the ocular inflammation will be assessed by masked evaluators (primary outcome). In addition to other secondary measurements of efficacy (quality of life, visual acuity and costs) and safety, we will identify subjects’ subgroups with different treatment responses by developing prediction models based on machine learning techniques using genetic and proteomic biomarkers. Ethics and dissemination: The protocol, annexes and informed consent forms were approved by the Reference Clinical Research Ethic Committee at the Hospital Clínico San Carlos (Madrid, Spain) and the Spanish Agency for Medicines and Health Products. We will elaborate a dissemination plan including production of materials adapted to several formats to communicate the clinical trial progress and findings to a broad group of stakeholders. The promoter will be the only access to the participant-level data, although it can be shared within the legal situation. Trial registration number: 2020-000130-18; NCT04798755.This work was supported by the Instituto de Salud Carlos III, grant number [ICI19/00020]. Sponsor: Fundación para la Investigacion Biomédica del Hospital Clínico San Carlos. Executive Committee: Administrative and executive arm of the clinical trial, providing overall oversight for the study and making decisions on day-to-day operational issues (Study Coordinator (Luis Rodriguez-Rodriguez), a representative from the Spanish Clinical Trial Network (Amanda López Picado), and 5 Site Directors (these seats will be rotatory, with changes every 6 months months)); Data Coordinating and Analysis Committee: Supervising data collection,management and quality control, designing the statistical analysis plan, performing unmasked data analysis and preparing interim and final reports for the Data Security Monitoring Board and the Executy Committee (Study Coordinator (Luis Rodriguez-Rodriguez), a representative from the Spanish Clinical Trial Network (Amanda López Picado) and Ester Carreño); Biobank and Biomarker Identification Committee (Maintaining an up-to-date manual of operations for blood extraction, processing and storage, and monitoring procedures adherence, supervising biological sample collection, sample shipment coordination, coordinating the phamacogenetic and proteomic analysis (Study Coordinator (Luis Rodriguez-Rodriguez), a representative from the Instituto de Salud Carlos III Biobank Platform (Elena Molino), a representative the Instituto de Investigación Biomédica de A Coruña, a representative from, the Data Coordinating and Analysis Committee); Data Security Monitoring Committee (PierGiogio Neri, Andrew Dick, Loreto Carmona

Examining the immune signatures of SARS-CoV-2 infection in pregnancy and the impact on neurodevelopment: Protocol of the SIGNATURE longitudinal study.

The COVID-19 pandemic represents a valuable opportunity to carry out cohort studies that allow us to advance our knowledge on pathophysiological mechanisms of neuropsychiatric diseases. One of these opportunities is the study of the relationships between inflammation, brain development and an increased risk of suffering neuropsychiatric disorders. Based on the hypothesis that neuroinflammation during early stages of life is associated with neurodevelopmental disorders and confers a greater risk of developing neuropsychiatric disorders, we propose a cohort study of SARS-CoV-2-infected pregnant women and their newborns. The main objective of SIGNATURE project is to explore how the presence of prenatal SARS-CoV-2 infection and other non-infectious stressors generates an abnormal inflammatory activity in the newborn. The cohort of women during the COVID-19 pandemic will be psychological and biological monitored during their pregnancy, delivery, childbirth and postpartum. The biological information of the umbilical cord (foetus blood) and peripheral blood from the mother will be obtained after childbirth. These samples and the clinical characterisation of the cohort of mothers and newborns, are tremendously valuable at this time. This is a protocol report and no analyses have been conducted yet, being currently at, our study is in the recruitment process step. At the time of this publication, we have identified 1,060 SARS-CoV-2 infected mothers and all have already given birth. From the total of identified mothers, we have recruited 537 SARS-COV-2 infected women and all of them have completed the mental health assessment during pregnancy. We have collected biological samples from 119 mothers and babies. Additionally, we have recruited 390 non-infected pregnant women

Examining the immune signatures of SARS-CoV-2 infection in pregnancy and the impact on neurodevelopment: Protocol of the SIGNATURE longitudinal study

The COVID-19 pandemic represents a valuable opportunity to carry out cohort studies that allow us to advance our knowledge on pathophysiological mechanisms of neuropsychiatric diseases. One of these opportunities is the study of the relationships between inflammation, brain development and an increased risk of suffering neuropsychiatric disorders. Based on the hypothesis that neuroinflammation during early stages of life is associated with neurodevelopmental disorders and confers a greater risk of developing neuropsychiatric disorders, we propose a cohort study of SARS-CoV-2-infected pregnant women and their newborns. The main objective of SIGNATURE project is to explore how the presence of prenatal SARS-CoV-2 infection and other non-infectious stressors generates an abnormal inflammatory activity in the newborn. The cohort of women during the COVID-19 pandemic will be psychological and biological monitored during their pregnancy, delivery, childbirth and postpartum. The biological information of the umbilical cord (foetus blood) and peripheral blood from the mother will be obtained after childbirth. These samples and the clinical characterisation of the cohort of mothers and newborns, are tremendously valuable at this time. This is a protocol report and no analyses have been conducted yet, being currently at, our study is in the recruitment process step. At the time of this publication, we have identified 1,060 SARS-CoV-2 infected mothers and all have already given birth. From the total of identified mothers, we have recruited 537 SARS-COV-2 infected women and all of them have completed the mental health assessment during pregnancy. We have collected biological samples from 119 mothers and babies. Additionally, we have recruited 390 non-infected pregnant women.This work has received support from the Fundación Alicia Koplowitz to realize the epigenetic wide association study and to the clinical assessment to the children. This work has also received public support from the Consejería de Salud y Familias para la financiación de la investigación, desarrollo e innovación (i + d + i) biomédica y en ciencias de la salud en Andalucía (CSyF 2021 - FEDER). Grant Grant number PECOVID- 0195-2020. Convocatoria financiada con Fondo Europeo de Desarrollo Regional (FEDER) al 80% dentro del Programa Operativo de Andalucía FEDER 2014-2020. Andalucía se mueve con Europa. NG-T received payment under Rio Hortega contract CM20-00015 with the Carlos III Health Institute.Peer reviewe

Tear and Plasma Levels of Cytokines in Patients with Uveitis: Search for Active Disease Biomarkers

Uveitis accounts for up to 20% of blindness in Europe, making the development of new non-invasive biomarkers which could help in its management a field of interest. It has been hypothesised that tear levels of cytokines and chemokines could be used as a potential biomarker in patients with anterior uveitis, and this could be correlated with their concentration in plasma. Therefore, we measured twelve cytokines/chemokines in tear and plasma samples of 22 patients diagnosed with active anterior uveitis. Levels of these molecules in tears and plasma were compared and associated with the degree of activity of the uveitis. It is notable that the percentage of tear interleukin (IL)-6 detection was significantly reduced in the inactive phase (p p < 0.05) from the counterpart levels in plasma. In conclusion, no isolated cytokine/chemokine in the tears has been found in a concentration which could be used as a potential biomarker of disease activity and treatment response

Statins do not increase Markers of Cerebral Angiopathies in patients with Cardioembolic Stroke

We investigated whether pre-treatment with statins is associated with surrogate markers of amyloid and hypertensive angiopathies in patients who need to start long-term oral anticoagulation therapy. A prospective multicenter study of patients naive for oral anticoagulants, who had an acute cardioembolic stroke. MRI was performed at admission to evaluate microbleeds, leukoaraiosis and superficial siderosis. We collected data on the specific statin compound, the dose and the statin intensity. We performed bivariate analyses and a logistic regression to investigate variables associated with microbleeds. We studied 470 patients (age 77.5 ± 6.4 years, 43.7% were men), and 193 (41.1%) of them received prior treatment with a statin. Microbleeds were detected in 140 (29.8%), leukoaraiosis in 388 (82.5%) and superficial siderosis in 20 (4.3%) patients. The presence of microbleeds, leukoaraiosis or superficial siderosis was not related to pre-treatment with statins. Microbleeds were more frequent in patients with prior intracerebral hemorrhage (OR 9.7, 95% CI 1.06-90.9) and in those pre-treated antiplatelets (OR 1.66, 95% CI 1.09-2.53). Prior treatment with statins was not associated with markers of bleeding-prone cerebral angiopathies in patients with cardioembolic stroke. Therefore, previous statin treatment should not influence the decision to initiate or withhold oral anticoagulation if these neuroimaging markers are detected

Statins do not increase Markers of Cerebral Angiopathies in patients with Cardioembolic Stroke

We investigated whether pre-treatment with statins is associated with surrogate markers of amyloid and hypertensive angiopathies in patients who need to start long-term oral anticoagulation therapy. A prospective multicenter study of patients naive for oral anticoagulants, who had an acute cardioembolic stroke. MRI was performed at admission to evaluate microbleeds, leukoaraiosis and superficial siderosis. We collected data on the specific statin compound, the dose and the statin intensity. We performed bivariate analyses and a logistic regression to investigate variables associated with microbleeds. We studied 470 patients (age 77.5 ± 6.4 years, 43.7% were men), and 193 (41.1%) of them received prior treatment with a statin. Microbleeds were detected in 140 (29.8%), leukoaraiosis in 388 (82.5%) and superficial siderosis in 20 (4.3%) patients. The presence of microbleeds, leukoaraiosis or superficial siderosis was not related to pre-treatment with statins. Microbleeds were more frequent in patients with prior intracerebral hemorrhage (OR 9.7, 95% CI 1.06-90.9) and in those pre-treated antiplatelets (OR 1.66, 95% CI 1.09-2.53). Prior treatment with statins was not associated with markers of bleeding-prone cerebral angiopathies in patients with cardioembolic stroke. Therefore, previous statin treatment should not influence the decision to initiate or withhold oral anticoagulation if these neuroimaging markers are detected