Cooperative insulation of regulatory domains by CTCF-dependent physical insulation and promoter competition.

The specificity of gene expression during development requires the insulation of regulatory domains to avoid inappropriate enhancer-gene interactions. In vertebrates, this insulator function is mostly attributed to clusters of CTCF sites located at topologically associating domain (TAD) boundaries. However, TAD boundaries allow some physical crosstalk across regulatory domains, which is at odds with the specific and precise expression of developmental genes. Here we show that developmental genes and nearby clusters of CTCF sites cooperatively foster the robust insulation of regulatory domains. By genetically dissecting a couple of representative loci in mouse embryonic stem cells, we show that CTCF sites prevent undesirable enhancer-gene contacts (i.e. physical insulation), while developmental genes preferentially contribute to regulatory insulation through non-structural mechanisms involving promoter competition rather than enhancer blocking. Overall, our work provides important insights into the insulation of regulatory domains, which in turn might help interpreting the pathological consequences of certain structural variants.

Cost-effectiveness and cost-utility study of a psychoeducational group intervention for people with depression and physical comorbidity in primary care.

OBJECTIVE: To evaluate the cost-effectiveness and cost-utility of a psychoeducational group intervention led by primary care (PC) nurses in relation to customary care to prevent the depression and improve quality of life in patients with physical comorbidity. DESIGN: Economic evaluation based on data from randomized, multicenter clinical trial with blind response variables and a one-year follow-up, carried in the context of the PSICODEP study. LOCATION: 7 PC teams from Catalonia. PARTICIPANTS: >50 year-old patients with depression and some physical comorbidity: diabetes mellitus type 2, ischemic heart disease, chronic obstructive pulmonary disease, and/or asthma. INTERVENTION: 12 psychoeducational group sessions, 1 per week, led by 2 PC nurses with prior training. MEASUREMENTS: Effectiveness: depression-free days (DFD) calculated from the BDI-II and quality-adjusted life years (QALYs) from the Euroqol-5D. Direct costs: PC visits, mental health, emergencies and hospitalizations, drugs. Indirect costs: days of temporary disability (TD). The incremental cost-effectiveness ratios (ICER), cost-effectiveness (ΔCost/ΔDLD) and cost-utility (ΔCost/ΔQALY) were estimated. RESULTS: The study includes 380 patients (intervention group [IG] = 204; control group [CG] = 176). 81.6% women; mean age 68.4 (SD = 8.8). The IG had a higher mean cost of visits, less of hospitalizations and less TD than the CG. The difference in costs between the IG and the CG was -357.95€ (95% CI: -2026.96 to 1311.06) at one year of follow-up. There was a mean of 11.95 (95% CI: -15.98 to 39.88) more DFD in the IG than in the CG. QALYs were similar (difference -0.01, 95% CI -0.04 to 0.05). The ICERs were 29.95€/DLD and 35,795€/QALY. CONCLUSIONS: Psychoeducational intervention is associated with an improvement in DFD, as well as a reduction in costs at 12 months, although not significantly. QALYs were very similar between groups.

Efectos de la pandemia por COVID-19 en la atención de pacientes con diabetes mellitus, Partido de General Pueyrredon, Argentina / Efectos de la pandemia por COVID-19 en la atención de pacientes con diabetes mellitus, Partido de General Pueyrredon, Argentina

INTRODUCCIÓN: La pandemia por COVID-19 condujo a la adopción de medidas de confinamiento con impacto en el control de la diabetes mellitus (DM). El objetivo fue evaluar el efecto de la pandemia en la atención de personas con DM del subsector público y privado de salud del Partido de General Pueyrredon (PGP). MÉTODOS: Se utilizó un diseño cuasiexperimental que comparó dos períodos: pandemia (3 de marzo de 2020 al 2 de marzo de 2021) y prepandemia (3 de marzo de 2019 al 2 de marzo de 2020). Se incluyó a personas de 18 años y más del PGP con diagnóstico de DM; se conformaron dos grupos según cobertura de salud. Los criterios de valoración principal fueron la hemoglobina glicosilada (HbA1c) y el control metabólico; los secundarios: glucemia basal, índice de masa corporal (IMC), triglicéridos, colesterol, consultas médicas, internación, fondo de ojo e índice albúmina/creatinina. Las diferencias con valor p<0,05 se consideraron estadísticamente significativas. Se ajustaron modelos multivariados. RESULTADOS: Se incluyeron 327 participantes (51,7% del subsector público). La mediana de HbA1c aumentó de 8,1% (rango intercuartílico [RIC] 2,7) a 8,8% (RIC 2,8). La pandemia, la atención en el subsector público y el tratamiento incompleto de la DM fueron predictores independientes del aumento de HbA1c; en tanto que el tratamiento con insulina lo fue del deterioro del control glucémico. DISCUSIÓN: La pandemia impactó negativamente en la atención de la DM, evidenciando desigualdades en los subsectores del sistema de salud.

Burnout en los médicos de familia de Cataluña durante la quinta ola de la pandemia COVID-19 / Burnout among Catalan family doctors during the fifth wave of the COVID-19 pandemic

Objetivo: la pandemia de la COVID-19 ha tenido un impacto psicológico en los profesionales sanitarios, a menudo manifestándose como burnout. Nuestro objetivo fue estimar la prevalencia del burnout en médicas y médicos de familia de Cataluña durante la pandemia e identificar factores sociodemográficos, laborales y de salud mental asociados.Métodos: estudio descriptivo transversal basado en una encuesta online realizada entre junio y julio de 2021. Se invitó a participar a los 4.700 socios y socias de la Societat Catalana de Medicina Familiar i Comunitària (CAMFiC) y se obtuvo un 11% de respuesta (n = 522).Medidas principales: Maslach Burnout Inventory, con tres dimensiones: agotamiento emocional, despersonalización y realización personal. Análisis bivariante y regresión logística múltiple (variable dependiente: nivel elevado de afectación para cada dimensión de burnout).Resultados: el 67,5% de encuestados presentó niveles altos de agotamiento emocional, el 42,7% de despersonalización y el 29,9% de niveles bajos de realización personal. La prevalencia de agotamiento emocional elevado fue mayor entre las mujeres y los expuestos a pacientes con COVID-19. La edad y años de antigüedad laboral se asoció de forma inversa a agotamiento emocional y despersonalización alta. En el análisis multivariante, la depresión se asoció a despersonalización alta y realización personal baja, la ansiedad a agotamiento emocional alto, y el estrés a las tres dimensiones.Conclusiones: después de 1 año de pandemia, existen niveles elevados de burnout en los médicos y médicas de familia, particularmente en la dimensión de agotamiento emocional. Son necesarias medidas organizativas para proteger la salud mental de las/los profesionales.(AU)

Aim: the COVID-19 pandemic has had a psychological impact on health professionals, often manifesting as burnout. Our purpose was to estimate the prevalence of burnout in family doctors in Catalonia during the pandemic and to identify associated sociodemographic, occupational and mental health factors.Methods: cross-sectional descriptive study based on an online survey conducted June-July 2021. The 4700 members of the Catalan Society of Family and Community Medicine were invited to take part. An 11% response was obtained (n=522).Primary endpoints: Maslach Burnout Inventory, with three dimensions: emotional exhaustion, depersonalization and personal accomplishment. Bivariate analysis and multiple logistic regression (dependent variable: high level of affectation for each area dimension of burnout).Results: a total of 67.5%, 42.7% and 29.9% of respondents presented high levels of emotional exhaustion, depersonalization and low sense of personal accomplishment, respectively. The prevalence of high emotional exhaustion was higher among women and those exposed to COVID-19 patients. Age and seniority were inversely associated with emotional exhaustion and high depersonalization. Multivariate analysis revealed that depression was associated with high depersonalization and low personal accomplishment, anxiety with high emotional exhaustion, and stress with all three areas.Conclusions: One year after onset of the pandemic, we detected high levels of burnout in family doctors, particularly in terms of emotional exhaustion. Organizational measures are necessary to protect the mental health of professionals.(AU)

Inhibition of pro-inflammatory signaling in human primary macrophages by enhancing arginase-2 via target site blockers.

The modulation of macrophage phenotype from a pro-inflammatory to an anti-inflammatory state holds therapeutic potential in the treatment of inflammatory disease. We have previously shown that arginase-2 (Arg2), a mitochondrial enzyme, is a key regulator of the macrophage anti-inflammatory response. Here, we investigate the therapeutic potential of Arg2 enhancement via target site blockers (TSBs) in human macrophages. TSBs are locked nucleic acid antisense oligonucleotides that were specifically designed to protect specific microRNA recognition elements (MREs) in human ARG2 3' UTR mRNA. TSBs targeting miR-155 (TSB-155) and miR-3202 (TSB-3202) MREs increased ARG2 expression in human monocyte-derived macrophages. This resulted in decreased gene expression and cytokine production of TNF-α and CCL2 and, for TSB-3202, in an increase in the anti-inflammatory macrophage marker, CD206. Proteomic analysis demonstrated that a network of pro-inflammatory responsive proteins was modulated by TSBs. In silico bioinformatic analysis predicted that TSB-3202 suppressed upstream pro-inflammatory regulators including STAT-1 while enhancing anti-inflammatory associated proteins. Proteomic data were validated by confirming increased levels of sequestosome-1 and decreased levels of phosphorylated STAT-1 and STAT-1 upon TSB treatment. In conclusion, upregulation of Arg2 by TSBs inhibits pro-inflammatory signaling and is a promising novel therapeutic strategy to modulate inflammatory signaling in human macrophages.

COVID-19 Serological Study in Non-infected Vaccinated Subjects: Differences among Age, Sex, and Vaccine Brand.

OBJECTIVE: To evaluate IgG antibody levels against SARS-CoV-2 in non-infected vaccinated subjects among vaccine brand, sex, and age. METHODS: Abbott's AdviseDx SARS-CoV-2 IgG II immunoassay was used to measure IgG levels within 6-9 months after the second dose vaccination; level >50 AU/mL was classified as a positive test. RESULTS: Data of 183 non-infected vaccinated subjects was analyzed according to the vaccine brand, time after second vaccination, sex, and age. Bivariate analysis showed that receiving the Moderna brand vaccine, being female, and younger were associated with higher antibody levels, p<.001. Conversely, no differences were observed between the IgG antibody levels against SARS-CoV-2 and time after second vaccination (6-7 months as compared to 8-9 months), p=.49. CONCLUSION: After six to nine months post-vaccination, receiving the Moderna vaccine, being female, and being younger were significantly associated to higher IgG antibody levels to SARS-CoV-2 in non-infected vaccinated subjects.

Relato de caso de intoxicación con superwarfarinas: un desafío terapéutico / Managing Superwarfarin Poisoning: A Challenging Case

La intoxicación humana por rodenticidas anticoagulantes de acción prolongada, conocidos como superwarfarinas, provoca coagulopatía de prolongado manejo. Presentamos el caso de un hombre de 42 años que ingirió una dosis tóxica de rodenticida en un intento suicida, evolucionando con epistaxis, INR de 11,6 y necesidad de hospitalización. Durante 7 días se realizaron controles seriados de pruebas de coagulación, con optimización de diferentes dosis de suplementación de Vitamina K. El caso destaca la potencia y vida media prolongada (aproximadamente 6 semanas) de este tipo de anticoagulantes, hecho que requiere un control clínico regular y una adherencia al tratamiento satisfactoria.

Human intoxication by long-acting anticoagulant rodenticides, known as superwarfarins, causes coagulopathy that is difficult to manage. We present the case of a 42-year-old man who ingested a toxic dose of rodenticide in a suicide attempt, evolving with epistaxis, INR of 11.6, and needing hospitalization. For seven days, serial controls of coagulation tests were carried out, with optimization of different doses of Vitamin K supplementation. The case highlights this type of anticoagulant's potency and prolonged half-life (approximately six weeks), which requires regular clinical control and satisfactory treatment adherence.

miRNA Signature in CSF From Patients With Primary Progressive Multiple Sclerosis.

BACKGROUND AND OBJECTIVES: Primary progressive multiple sclerosis (PPMS) displays a highly variable disease progression with a characteristic accumulation of disability, what makes difficult its diagnosis and efficient treatment. The identification of microRNAs (miRNAs)-based signature for the early detection in biological fluids could reveal promising biomarkers to provide new insights into defining MS clinical subtypes and potential therapeutic strategies. The objective of this cross-sectional study was to describe PPMS miRNA profiles in CSF and serum samples compared with other neurologic disease individuals (OND) and relapsing-remitting MS (RRMS). METHODS: First, a screening stage analyzing multiple miRNAs in few samples using OpenArray plates was performed. Second, individual quantitative polymerase chain reactions (qPCRs) were used to validate specific miRNAs in a greater number of samples. RESULTS: A specific profile of dysregulated circulating miRNAs (let-7b-5p and miR-143-3p) was found downregulated in PPMS CSF samples compared with OND. In addition, in serum samples, miR-20a-5p and miR-320b were dysregulated in PPMS against RRMS and OND, miR-26a-5p and miR-485-3p were downregulated in PPMS vs RRMS, and miR-142-5p was upregulated in RRMS compared with OND. DISCUSSION: We described a 2-miRNA signature in CSF of PPMS individuals and several dysregulated miRNAs in serum from patients with MS, which could be considered valuable candidates to be further studied to unravel their actual role in MS. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that specific miRNA profiles accurately distinguish PPMS from RRMS and other neurologic disorders.

[Managing Superwarfarin Poisoning: A Challenging Case]. / Relato de caso de intoxicación con superwarfarinas: un desafío terapéutico.

Human intoxication by long-acting anticoagulant rodenticides, known as superwarfarins, causes coagulopathy that is difficult to manage. We present the case of a 42-year-old man who ingested a toxic dose of rodenticide in a suicide attempt, evolving with epistaxis, INR of 11.6, and needing hospitalization. For seven days, serial controls of coagulation tests were carried out, with optimization of different doses of Vitamin K supplementation. The case highlights this type of anticoagulant's potency and prolonged half-life (approximately six weeks), which requires regular clinical control and satisfactory treatment adherence.

Role of Epstein-Barr Virus and Human Papilloma Virus in the Development of Oropharyngeal Cancer: A Literature Review.

The aim of this review was to describe the association and related mechanisms between HPV, EBV, and the development of oral and oropharyngeal cancer. A search for scientific evidence was carried out in electronic databases (MEDLINE/PubMed, SciELO). It was found that, among the carcinogenic mechanisms of HPV, E6 and E7 proteins are responsible for the malignization process, inhibiting tumor suppressors p53 and pRb. As to EBV, it was noted that its "hit and run" phenomenon manipulates the host epigenetic mechanism, triggering the tumor process without the virus being currently present; a "cellular reprogramming" is essentially generated, causing heritable changes in gene expression without DNA mutation. In conclusion, there is an association between oropharyngeal carcinogenesis and HPV and also between the former and EBV. Further studies are required to clarify the causal mechanisms and impact of both viruses on cancer development and to obtain biomarkers of greater specificity in the case of EBV.

Psychological impact of the COVID-19 pandemic on primary care workers: a cross-sectional study.

BACKGROUND: The COVID-19 pandemic has had a major impact on the mental health of healthcare workers, yet studies in primary care workers are scarce. AIM: To investigate the prevalence of and associated factors for psychological distress in primary care workers during the first COVID-19 outbreak. DESIGN AND SETTING: This was a multicentre, cross-sectional, web-based survey conducted in primary healthcare workers in Spain, between May and September 2020. METHOD: Healthcare workers were invited to complete a survey to evaluate sociodemographic and work-related characteristics, COVID-19 infection status, exposure to patients with COVID-19, and resilience (using the Connor-Davidson Resilience Scale), in addition to being screened for common mental disorders (depression, anxiety disorders, post-traumatic stress disorder, panic attacks, and substance use disorder). Positive screening for any of these disorders was analysed globally using the term 'any current mental disorder'. RESULTS: A total of 2928 primary care professionals participated in the survey. Of them, 43.7% (95% confidence interval [CI] = 41.9 to 45.4) tested positive for a current mental disorder. Female sex (odds ratio [OR] 1.61, 95% CI = 1.25 to 2.06), having previous mental disorders (OR 2.58, 95% CI = 2.15 to 3.10), greater occupational exposure to patients with COVID-19 (OR 2.63, 95% CI = 1.98 to 3.51), having children or dependents (OR 1.35, 95% CI = 1.04 to 1.76 and OR 1.59, 95% CI = 1.20 to 2.11, respectively), or having an administrative job (OR 2.24, 95% CI = 1.66 to 3.03) were associated with a higher risk of any current mental disorder. Personal resilience was shown to be a protective factor. CONCLUSION: Almost half of primary care workers showed significant psychological distress. Strategies to support the mental health of primary care workers are necessary, including designing psychological support and resilience-building interventions based on risk factors identified.

Clinical characteristics, health care resource utilization and direct medical costs of Rotavirus hospitalizations in Spain (2013-2018).

Rotavirus (RV) is the most common cause of severe gastroenteritis (GE) in infants and young children worldwide and is associated with a significant clinical and economic burden. The objective of this study was to analyze the characteristics, healthcare resource utilization and the direct medical costs related to RVGE hospitalizations in Spain. An observational, multicenter, cross-sectional study was conducted from June 2013 to May 2018 at the pediatric departments of 12 hospitals from different Spanish regions. Children under 5 years of age admitted to the hospital with a confirmed diagnosis of RVGE were selected. Data on clinical characteristics, healthcare resource use and costs were collected from patient records and hospital databases. Most children hospitalized for RVGE did not have any previous medical condition or chronic disease. Forty-seven percent had previously visited the Emergency Room (ER), 27% had visited a primary care pediatrician, and 15% had received pharmacological treatment prior to hospital admission due to an RVGE episode. The average length of a hospital stay for RVGE was 5.6 days, and the mean medical costs of RVGE hospitalizations per episode ranged from 3,940€ to 4,100€. The highest direct medical cost was due to the hospital stay. This study showed a high burden of health resource utilization and costs related to the management of cases of RVGE requiring hospitalization. RV vaccination with high coverage rates should be considered to minimize the clinical and economic impacts of this disease on the health-care system.

Measuring depression in Primary Health Care in Spain: Psychometric properties and diagnostic accuracy of HSCL-5 and HSCL-10.

Background: Depression has a high prevalence among European countries. Several instruments have been designed to assess its symptoms in different populations. The Hopkins Symptom Checklist 25 (HSCL-25) scale has been identified as valid, reproducible, effective, and easy to use. There are short versions of this scale that could be useful in Primary Care (PC) settings, but their psychometric properties are unknown. Aim: To assess in PC patients the psychometric properties and diagnostic accuracy of the Spanish version of the HSCL-10 and the HSCL-5 consisting of 10 and 5 items, respectively. Methods: A multicenter, cross-sectional study was carried out at six PC centers in Spain. The HSCL-25 was administered to outpatients aged 45-75 who also participated in the structured Composite International Diagnostic Interview (CIDI). HSCL-10 and HSCL-5 were assessed and compared to HSCL-25 regarding total score correlation, internal consistency, and criterion validity against the gold-standard CIDI. This is a methodological study from a secondary data analysis and the primary data has been previously published. Results: Out of 790 patients, 767 completed the HSCL-25 and 736 the CIDI interview (96.0%). Cronbach's Alpha was 0.84 for HSCL-10 and 0.77 for HSCL-5. The known-group method and confirmatory factor analysis were acceptable for the establishment of construct validity. Sensitivity was 79.7% (CI95%, 67.7-88.0%) for HSCL-10, and 78.0% (CI95%, 65.9-86.6%) for HSCL-5, whereas specificity was 83% (CI95%, 80.0-85.7%) for HSCL-10, and 72.8% (CI95%, 69.3-76.0%) for HSCL-5. Area under the curve against CIDI was 0.88 (CI95%, 0.84-0.92%) for HSCL-10, and 0.85 (CI95%, 0.81-0.89%) for HSCL-5. Optimum cutoff point calculated with Youden Index was 1.90 for the HSCL-10 and 1.80 for the HSCL-5. Conclusion: HSCL-10 and HSCL-5 are reliable and valid tools to detect depression symptoms and can be used in PC settings.

Assessing the presence of oligoclonal IgM bands as a prognostic biomarker of cognitive decline in the early stages of multiple sclerosis.

BACKGROUND: An association has been found between the presence of lipid-specific oligoclonal IgM bands (LS-OCMB) in cerebrospinal fluid and a more severe clinical multiple sclerosis course. OBJECTIVE: To investigate lipid-specific oligoclonal IgM bands as a prognostic biomarker of cognitive impairment in the early stages of multiple sclerosis. METHODS: Forty-four patients underwent neuropsychological assessment at baseline and 4 years. Cognitive performance at follow-up was compared adjusting by age, education, anxiety-depression, and baseline performance. RESULTS: LS-OCMB+ patients only performed worse for Long-Term Storage in the Selective Reminding Test (p = .018). CONCLUSION: There are no remarkable cognitive differences between LS-OCMB- and LS-OCMB+ patients in the early stages of MS.

Prospective cohort study in the early stage of the COVID-19 pandemic, District of General Pueyrredón, Argentina (INECOVID): infection dynamics and risk factors / Estudio de cohortes prospectivo en etapa temprana de la pandemia COVID-19, Partido de General Pueyrredón, Argentina (INECOVID): dinámica de infección y factores de riesgo

Objective: to establish the magnitude and risk factors for SARS-CoV-2 infection in the District of General Pueyrredón, Buenos Aires, Argentina: the INECOVID study. Methodology: a prospective cohort was designed with participants from the District general population. The follow-up period was from June 22 to December 18, 2020, with a minimum appointment interval of 21 days. Data were obtained via questionnaires and serum or plasma samples. The primary event was considered as the time through seroconversion as evidence of SARS-CoV-2 infection. The accumulated risk of infection was estimated using the Kaplan Meier method. Cox models were built with time-dependent variables. Results: 345 participants were recruited (n = 222 women, 64.3%; 123 men, 35.7%), with a median age of 45 years in women (Interquartile range: 19) and 49 in men (Interquartile range: 26). 12.8% of participants (n = 44) had evidence of SARS-CoV-2 infection [incidence density of 9.1 cases (women: 11.1, men: 5.1) per 10,000 person-day]. 36.4% of the cases (n=16) were asymptomatic. The following factors were associated to the risk of infection: being a close contact of a confirmed COVID-19 case (HR=5,56; IC95% 2,85-10,83), being a health worker (HR=2,93; IC95% 1,55-5,52), living in crowded conditions (HR= 2,23; IC95% 1,13-4,49) and age (HR= 0,98; IC95% 0,95-1,00). Conclusion: the identified risk factors endorse the protection policies and protocols adopted by the Argentinian sanitary authorities for the general population and the care programs for health workers in the pre-vaccination phase.

Objetivo: establecer la magnitud y los factores de riesgo de infección por SARS-CoV-2 en el Partido de General Pueyrredón, Buenos Aires, Argentina: estudio INECOVID. Métodos: diseño de cohortes prospectivo con participantes de población general del partido. El período de seguimiento fue del 22 de junio al 18 de diciembre de 2020, con un intervalo mínimo de citación de 21 días. Los datos se obtuvieron mediante cuestionarios y muestras de suero o plasma. El evento primario fue el tiempo hasta la seroconversión (IgG) como evidencia de infección por SARS-CoV-2. Se estimó el riesgo acumulado de infección por el método de Kaplan Meier. Se construyeron modelos de Cox con variables tiempo-dependientes. Resultados: fueron reclutados 345 participantes (n=222 mujeres, 64,3%; 123 varones, 35,7%), con una edad mediana de 45 años en mujeres (Rango intercuartílico: 19) y 49 en varones (Rango intercuartílico: 26).  El 12,8% de los participantes (n=44) tuvo evidencia de infección por SARS-CoV-2 [densidad de incidencia de 9,1 casos (mujeres: 11,1, varones: 5,1) por 10.000 días-persona]. El 36,4% de los casos (n=16) fue asintomático. Se mostraron asociados al riesgo de infección: ser contacto estrecho de un caso confirmado de COVID-19 (HR=5,56; IC95% 2,85-10,83), ser trabajador de salud (HR=2,93; IC95% 1,55-5,52), vivir en hacinamiento (HR= 2,23; IC95% 1,13-4,49) y edad (HR= 0,98; IC95% 0,95-1,00). Conclusión: los factores de riesgo de infección hallados avalan las políticas y protocolos de protección adoptadas por las autoridades sanitarias de Argentina para población general y los programas de cuidado de los trabajadores de salud en la etapa pre-vacunación.

Validation and Psychometric Properties of the Spanish Version of the Hopkins Symptom Checklist-25 Scale for Depression Detection in Primary Care.

Depression constitutes a major public health problem due to its high prevalence and difficulty in diagnosis. The Hopkins Symptom Checklist-25 (HSCL-25) scale has been identified as valid, reproducible, effective, and easy to use in primary care (PC). The purpose of the study was to assess the psychometric properties of the HSCL-25 and validate its Spanish version. A multicenter cross-sectional study was carried out at six PC centers in Spain. Validity and reliability were assessed against the structured Composite International Diagnostic Interview (CIDI). Out of the 790 patients, 769 completed the HSCL-25; 738 answered all the items. Global Cronbach's alpha was 0.92 (0.88 as calculated for the depression dimension and 0.83 for the anxiety one). Confirmatory factor analysis (CFA) showed one global factor and two correlated factors with a correlation of 0.84. Area under the curve (AUC) was 0.89 (CI 95%, 0.86-0.93%). For a 1.75 cutoff point, sensibility was 88.1% (CI 95%, 77.1-95.1%) and specificity was 76.7% (CI 95%, 73.3-79.8%). The Spanish version of the HSCL-25 has a high response percentage, validity, and reliability and is well-accepted by PC patients.

Description of a CSF-Enriched miRNA Panel for the Study of Neurological Diseases.

BACKGROUND: The study of circulating miRNAs in CSF has gained tremendous attention during the last years, as these molecules might be promising candidates to be used as biomarkers and provide new insights into the disease pathology of neurological disorders. OBJECTIVE: The main aim of this study was to describe an OpenArray panel of CSF-enriched miRNAs to offer a suitable tool to identify and characterize new molecular signatures in different neurological diseases. METHODS: Two hundred and fifteen human miRNAs were selected to be included in the panel, and their expression and abundance in CSF samples were analyzed. In addition, their stability was studied in order to propose suitable endogenous controls for CSF miRNA studies. RESULTS: miR-143-3p and miR-23a-3p were detected in all CSF samples, while another 80 miRNAs were detected in at least 70% of samples. miR-770-5p was the most abundant miRNA in CSF, presenting the lowest mean Cq value. In addition, miR-26b-5p, miR-335-5p and miR-92b-3p were the most stable miRNAs and could be suitable endogenous normalizers for CSF miRNA studies. CONCLUSIONS: These OpenArray plates might be a suitable and efficient tool to identify and characterize new molecular signatures in different neurological diseases and would improve the yield of miRNA detection in CSF.

Orphan CpG islands amplify poised enhancer regulatory activity and determine target gene responsiveness.

CpG islands (CGIs) represent a widespread feature of vertebrate genomes, being associated with ~70% of all gene promoters. CGIs control transcription initiation by conferring nearby promoters with unique chromatin properties. In addition, there are thousands of distal or orphan CGIs (oCGIs) whose functional relevance is barely known. Here we show that oCGIs are an essential component of poised enhancers that augment their long-range regulatory activity and control the responsiveness of their target genes. Using a knock-in strategy in mouse embryonic stem cells, we introduced poised enhancers with or without oCGIs within topologically associating domains harboring genes with different types of promoters. Analysis of the resulting cell lines revealed that oCGIs act as tethering elements that promote the physical and functional communication between poised enhancers and distally located genes, particularly those with large CGI clusters in their promoters. Therefore, by acting as genetic determinants of gene-enhancer compatibility, CGIs can contribute to gene expression control under both physiological and potentially pathological conditions.