Intermediate Repeat Expansion in the ATXN2 Gene as a Risk Factor in the ALS and FTD Spanish Population

Intermediate CAG expansions in the gene ataxin-2 (ATXN2) are a known risk factor for ALS, but little is known about their role in FTD risk. Moreover, their contribution to the risk and phenotype of patients might vary in populations with different genetic backgrounds. The aim of this study was to assess the relationship of intermediate CAG expansions in ATXN2 with the risk and phenotype of ALS and FTD in the Spanish population. Repeat-primed PCR was performed in 620 ALS and 137 FTD patients in three referral centers in Spain to determine the exact number of CAG repeats. In our cohort, >= 27 CAG repeats in ATXN2 were associated with a higher risk of developing ALS (odds ratio [OR] = 2.666 [1.471-4.882]; p = 0.0013) but not FTD (odds ratio [OR] = 1.446 [0.558-3.574]; p = 0.44). Moreover, ALS patients with >= 27 CAG repeats in ATXN2 showed a shorter survival rate compared to those with = 27 repeats in ATXN2 are associated with ALS risk but not with FTD in the Spanish population. ALS patients carrying an intermediate expansion in ATXN2 show more frequent limb onset but a worse prognosis than those without expansions. In patients carrying C9orf72 expansions, the intermediate ATXN2 expansion might increase the penetrance and modify the phenotype

Prevalence of hyponatraemia in patients over the age of 65 who have an in-hospital fall

Background and aim: Hyponatraemia is the most common electrolyte disorder. Some studies have found that it increases morbidity and mortality. There are new lines of research that are investigating the link between hyponatraemia and patient falls. Aim: To determine if hyponatraemia is associated with falls in elderly hospitalised patients. Methods: Design observational, analytical, case-control study. Study population: Patients older than 65 years who had fallen during their hospitalisation at Gregorio Marañón Hospital (Madrid) were considered cases. Patients who did not fall were considered to be controls, paired according to the following variables: hospital ward, age, length of hospital stay, gender and Downton fall risk index. The sample size was 206 subjects. Data collection: Socio-demographic factors, variables included in the falls record sheet, Downton fall risk index and sodium levels were studied (hyponatraemia was considered Na+&lt; 135 mmol/l). Analysis: A descriptive analysis was performed to determine the sample homogeneity. The OR was calculated, and an analytical analysis using Chi-square test and a multivariate logistic regression analysis were also performed. Results: Of 103 cases recruited, 61 were men (50.4%) and 42 were women (49.4%). Hyponatraemia was detected in 29 cases with an association with falls of P: 0.002. The adjusted OR was 3.708 (1.6-8.3), 95% CI. Risk factors for falls were identified as hyponatraemia and limb sensory deficits. Conclusions: Given that hyponatraemia could be considered a risk factor for falls, the inclusion of the determination of sodium level would be important for fall prevention strategies in the elderly.Fundamento y objetivo: La hiponatremia es el trastorno electrolítico más frecuente. Algunos estudios afirman que aumenta la morbimortalidad. Existen nuevas líneas de investigación que buscan la relación entre hiponatremia y caídas. Objetivo: Determinar si la hiponatremia es un factor relacionado con las caídas en ancianos hospitalizados. Método: Disen˜ o observacional analítico de casos y controles. Población de estudio: Se consideraron casos los pacientes mayores de 65 an˜ os que experimentaron una caída durante su ingreso en unidades de hospitalización del Hospital General Universitario Gregorio Maran˜ ón de Madrid. Los controles fueron pacientes que no wxperimentaron caída, pareados según las variables: unidad, edad, periodo de ingreso, género y Downton. El taman˜ o fue de 206 sujetos. Recogida de datos: Se estudiaron factores sociodemográficos, las variables incluidas en la ficha de registro de caídas y escala de Downton, y el sodio sérico. Se consideró hiponatremia Na+ < 135 mmol/l. Análisis: Se realizó un análisis descriptivo para valorar la homogeneidad de la muestra, un análisis analítico utilizando el test chi cuadrado, calculando la OR y un análisis multivariante con regresión logística. Resultados: De 103 casos, 61 eran hombres (50,4%) y 42 mujeres (49,4%). En 29 se detectó hiponatremia; la relación con las caídas fue p: 0,002. La OR ajustada fue de 3,708 (1,6-8,3), IC 95%. Se identificaron como factores de riesgo para las caídas: hiponatremia y déficits sensoriales en extremidade

The NER-related gene GTF2H5 predicts survival in high-grade serous ovarian cancer patients

We aimed to evaluate the prognostic and predictive value of the nucleotide excision repair-related gene GTF2H5, which is localized at the 6q24.2-26 deletion previously reported by our group to predict longer survival of high-grade serous ovarian cancer patients. In order to test if protein levels of GTF2H5 are associated with patients' outcome, we performed GTF2H5 immunohistochemical staining in 139 high-grade serous ovarian carcinomas included in tissue microarrays. Upon stratification of cases into high- and low-GTF2H5 staining categories (> and ≤ median staining, respectively) Kaplan-Meier and log-rank test were used to estimate patients' survival and assess statistical differences. We also evaluated the association of GTF2H5 with survival at the transcriptional level by using the on-line Kaplan-Meier plotter tool, which includes gene expression and survival data of 855 high-grade serous ovarian cancer patients from 13 different datasets. Finally, we determined whether stable short hairpin RNA-mediated GTF2H5 downregulation modulates cisplatin sensitivity in the SKOV3 and COV504 cell lines by using cytotoxicity assays. Low expression of GTF2H5 was associated with longer 5-year survival of patients at the protein (hazard ratio [HR], 0.52; 95% CI, 0.29 to 0.93; p=0.024) and transcriptional level (HR, 0.80; 95% CI, 0.65 to 0.97; p=0.023) in high-grade serous ovarian cancer patients. We confirmed the association with 5-year overall survival (HR, 0.55; 95% CI, 0.38 to 0.78; p=0.0007) and also found an association with progression-free survival (HR, 0.72; 95% CI, 0.54 to 0.96; p=0.026) in a homogenous group of 388 high-stage (stages III-IV using the International Federation of Gynecology and Obstetrics staging system), optimally debulked high-grade serous ovarian cancer patients. GTF2H5- silencing induced a decrease of the half maximal inhibitory concentration upon cisplatin treatment in GTF2H5 -silenced ovarian cancer cells. Low levels of GTF2H5 are associated with enhanced prognosis in high-grade serous ovarian cancer patients and may contribute to cisplatin sensitization

Eculizumab in secondary atypical haemolytic uraemic syndrome

Background. Complement dysregulation occurs in thrombotic microangiopathies (TMAs) other than primary atypical haemolytic uraemic syndrome (aHUS). A few of these patients have been reported previously to be successfully treated with eculizumab. Methods. We identified 29 patients with so-called secondary aHUS who had received eculizumab at 11 Spanish nephrology centres. Primary outcome was TMA resolution, defined by a normalization of platelet count (>150 × 109/L) and haemoglobin, disappearance of all the markers of microangiopathic haemolytic anaemia (MAHA), and improvement of renal function, with a ≥25% reduction of serum creatinine from the onset of eculizumab administration. Results. Twenty-nine patients with secondary aHUS (15 drug-induced, 8 associated with systemic diseases, 2 with postpartum, 2 with cancer-related, 1 associated with acute humoral rejection and 1 with intestinal lymphangiectasia) were included in this study. The reason to initiate eculizumab treatment was worsening of renal function and persistence of TMA despite treatment of the TMA cause and plasmapheresis. All patients showed severe MAHA and renal function impairment (14 requiring dialysis) prior to eculizumab treatment and 11 presented severe extrarenal manifestations. A rapid resolution of the TMA was observed in 20 patients (68%), 15 of them showing a ≥50% serum creatinine reduction at the last follow-up. Comprehensive genetic and molecular studies in 22 patients identified complement pathogenic variants in only 2 patients. With these two exceptions, eculizumab was discontinued, after a median of 8 weeks of treatment, without the occurrence of aHUS relapses. Conclusion. Short treatment with eculizumab can result in a rapid improvement of patients with secondary aHUS in whom TMA has persisted and renal function worsened despite treatment of the TMA-inducing conditionWork in this report was funded by the Instituto de Salud Carlos III: REDinREN (RD 016/009 Feder Funds), the Fondo de Investigaciones Sanitarias (13/02502 and ICI14/00350), the Ministerio de Economia y Competitividad (SAF2015-66287R) and the Autonomous Region of Madrid (S2010/BMD-2316; Grupo de Investigación Complemento-CM). SRdeC is funded by the Seventh Framework Programme European Union Project EURenOmics (305608

Table2_Expanding the phenotype of THRB: a range of macular dystrophies as the major clinical manifestations in patients with a dominant splicing variant.PDF

Supplementary Table 2 Different THRB in vivo and in vitro knock-out and knockdown models and its phenotypic effect.Inherited retinal dystrophies (IRDs) are a clinically and genetically heterogeneous group of disorders that often severely impair vision. Some patients manifest poor central vision as the first symptom due to cone-dysfunction, which is consistent with cone dystrophy (COD), Stargardt disease (STGD), or macular dystrophy (MD) among others. Here, we aimed to identify the genetic cause of autosomal dominant COD in one family. WGS was performed in 3 affected and 1 unaffected individual using the TruSeq Nano DNA library kit and the NovaSeq 6,000 platform (Illumina). Data analysis identified a novel spliceogenic variant (c.283 + 1G>A) in the thyroid hormone receptor beta gene (THRB) as the candidate disease-associated variant. Further genetic analysis revealed the presence of the same heterozygous variant segregating in two additional unrelated dominant pedigrees including 9 affected individuals with a diagnosis of COD (1), STGD (4), MD (3) and unclear phenotype (1). THRB has been previously reported as a causal gene for autosomal dominant and recessive thyroid hormone resistance syndrome beta (RTHβ); however, none of the IRD patients exhibited RTHβ. Genotype-phenotype correlations showed that RTHβ can be caused by both truncating and missense variants, which are mainly located at the 3′ (C-terminal/ligand-binding) region, which is common to both THRB isoforms (TRβ1 and TRβ2). In contrast, the c.283 + 1G>A variant is predicted to disrupt a splice site in the 5′-region of the gene that encodes the N-terminal domain of the TRβ1 isoform protein, leaving the TRβ2 isoform intact, which would explain the phenotypic variability observed between RTHβ and IRD patients. Interestingly, although monochromacy or cone response alterations have already been described in a few RTHβ patients, herein we report the first genetic association between a pathogenic variant in THRB and non-syndromic IRDs. We thereby expand the phenotype of THRB pathogenic variants including COD, STGD, or MD as the main clinical manifestation, which also reflects the extraordinary complexity of retinal functions mediated by the different THRB isoforms.Peer reviewe

Sensitization to isothiazolinones in the Spanish Contact Dermatitis Registry (REIDAC): 2019–2021 epidemiological situation

Background: Current frequency and risk factors for sensitization to methylisothiazolinone (MI), methylchloroisothiazolinone/methylisothiazolinone (MCI/MI), benzisothiazolinone (BIT) and octylisothiazolinone (OIT) in Spain are not well known. Objectives: To study the frequency of sensitization, risk factors and simultaneous sensitization between the four isothiazolinones. Materials and Methods: We analysed all 2019-2021 consecutive patients patch-tested with MI (0.2% aq.), MCI/MI (0.02% aq.), BIT (0.1% pet.) and OIT (0.1% pet) within the Spanish Contact Dermatitis Registry (REIDAC). Results: A total of 2511 patients were analysed. Frequencies of sensitization were: any isothiazolinone 15.7%, MI 6.8%, MCI/MI 4.8%, BIT 3.5% and OIT 0.5%. MI and MCI/MI sensitization was associated with being occupationally active, hand dermatitis, detergents and age over 40. BIT sensitization was associated with leg dermatitis and age over 40. About one in nine MI-positive patients were positive to BIT, whereas one in five BIT-positive patients were positive to MI. Conclusions: Sensitization to MI, MCI/MI and BIT is still common in Spain, while sensitization to OIT is rare. Currently, sensitization to MI and MCI/MI seems to be occupationally related. Although its origin is unknown, sensitization to BIT is more frequent in patients aged over 40 years. Simultaneous sensitization between MI and BIT is uncommon.The Spanish Registry of Contact Dermatitis (REIDAC) is promoted by the Fundación Piel Sana (Academia Española de Dermatología y Venereología), which has received financial support from the Spanish Medicines and Health Products Agency (Agencia Española de Medicamentos y Productos Sanitarios. https://www.boe.es/boe/dias/2022/04/11/pdfs/BOE-A-2022-5975.pdf) and Sanofi. The funders were not involved in the design and conduct of the study, collection, management, analysis and interpretation of data, preparation, review, approval of the manuscript, or decision to submit the manuscript for publication

Health-related quality of life with palbociclib plus endocrine therapy versus capecitabine in postmenopausal patients with hormone receptor–positive metastatic breast cancer: Patient-reported outcomes in the PEARL study

Background: The PEARL study showed that palbociclib plus endocrine therapy (palbociclib/ET) was not superior to capecitabine in improving progression-free survival in postmenopausal patients with metastatic breast cancer resistant to aromatase inhibitors, but was better tolerated. This analysis compared patient-reported outcomes. Patients and methods: The PEARL quality of life (QoL) population comprised 537 patients, 268 randomised to palbociclib/ET (exemestane or fulvestrant) and 269 to capecitabine. Patients completed the European Organisation for Research and Treatment of Cancer QLQC30 and QLQ-BR23 and EQ-5D-3L questionnaires. Changes from the baseline and time to deterioration (TTD) were analysed using linear mixed-effect and stratified Cox regression models, respectively. Results: Questionnaire completion rate was high and similar between treatment arms. Significant differences were observed in the mean change in global health status (GHS)/QoL scores from the baseline to cycle 3 (2.9 for palbociclib/ET vs.-2.1 for capecitabine (95% confidence interval [CI], 1.4-8.6; P = 0.007). The median TTD in GHS/QoL was 8.3 months for palbociclib/ET versus 5.3 months for capecitabine (adjusted hazard ratio, 0.70; 95% CI, 0.55-0.89; P = 0.003). Similar improvements for palbociclib/ET were also seen for other scales as physical, role, cognitive, social functioning, fatigue, nausea/vomiting and appetite loss. No differences were observed between the treatment arms in change from the baseline in any item of the EQ-5D-L3 questionnaire as per the overall index score and visual analogue scale. Conclusion: Patients receiving palbociclib/ET experienced a significant delay in deterioration of GHS/QoL and several functional and symptom scales compared with capecitabine, providing additional evidence that palbociclib/ET is better tolerated. Trial registration number: NCT02028507 (ClinTrials.gov). EudraCT study number: 2013-003170-27. 2021 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)

La Enseñanza de la Religión Cultural: la mirada de la Literatura y el Arte a las tres religiones del Libro. Innovación y Transferencia en y entre las EE.MM./Bachillerato y la Universidad en una perspectiva europea

El presente documento contiene el informe final relativo al Proyecto de Innovación Docente "La Enseñanza de la Religión Cultural", en el que distintos investigadores, docentes universitarios y de institutos y centros educativos han colaborado para el análisis sobre las posibilidades de la religión cultural en el sistema educativo, así como en el desarrollo de diferentes materiales e instrumentos educativos, que han sido aplicados en distintas sesiones en el aula durante el desarrollo del proyecto

Identidad Onubense: Opinión y prácticas sociales respecto a urbanismo, patrimonio y entorno

Presentation of the research results on the Huelva [Onubense] Identity, 2020-2021. The results were presented at the Conference on Knowledge Transfer held on November 25, 2021 (University of Huelva, ETSI). It corresponds to the project: Huelva Identity: Opinion and social practices regarding urban planning, heritage, and environment. See more information at: https://eseis.es/investigacion/identidad-onubensePresentation of the research results on the Huelva [Onubense] Identity, 2020-2021. The results were presented at the Conference on Knowledge Transfer held on November 25, 2021 (University of Huelva, ETSI). It corresponds to the project: Huelva Identity: Opinion and social practices regarding urban planning, heritage, and environment. See more information at: https://eseis.es/investigacion/identidad-onubenseCátedra de la Provincia, UHU - Diputación de Huelva. Facultad de Trabajo Social. Autoridad Portuaria de Huelva. Consejo Social, UHU. Grupo de investigación Estudios Sociales E Intervención Social (Grupo ESEIS). Centro de Pensamiento Contemporáneo e Innovación para el Desarrollo Social (COIDESO

Phase III Trial of Adjuvant Capecitabine After Standard Neo-/Adjuvant Chemotherapy in Patients With Early Triple-Negative Breast Cancer (GEICAM/2003-11_CIBOMA/2004-01)

Altres ajuts: Agustí Barnadas: Honoraria: Pfizer. Consulting or Advisory Role: Pfizer, Novartis, Eli Lilly. Speakers'Bureau: Roche, Pfizer, Novartis, Genomic Health International. Travel, Accommodations, Expenses: Roche, Pfizer; Miguel A. Seguí: Consulting or Advisory Role: Roche, Pfizer, Novartis, Amgen, Eisai, Eli Lilly. Speakers' Bureau: Roche, Pfizer, Amgen. Research Funding: Roche (Inst), Novartis (Inst). Travel, Accommodations, Expenses: Roche, Pfizer, Novartis, Amgen.Operable triple-negative breast cancers (TNBCs) have a higher risk of relapse than non-TNBCs with standard therapy. The GEICAM/2003-11_CIBOMA/2004-01 trial explored extended adjuvant capecitabine after completion of standard chemotherapy in patients with early TNBC. Eligible patients were those with operable, node-positive-or node negative with tumor 1 cm or greater-TNBC, with prior anthracycline- and/or taxane-containing chemotherapy. After central confirmation of TNBC status by immunohistochemistry, patients were randomly assigned to either capecitabine or observation. Stratification factors included institution, prior taxane-based therapy, involved axillary lymph nodes, and centrally determined phenotype (basal v nonbasal, according to cytokeratins 5/6 and/or epidermal growth factor receptor positivity by immunohistochemistry). The primary objective was to compare disease-free survival (DFS) between both arms. Eight hundred seventy-six patients were randomly assigned to capecitabine (n = 448) or observation (n = 428). Median age was 49 years, 55.9% were lymph node negative, 73.9% had a basal phenotype, and 67.5% received previous anthracyclines plus taxanes. Median length of follow-up was 7.3 years. DFS was not significantly prolonged with capecitabine versus observation [hazard ratio (HR), 0.82; 95% CI, 0.63 to 1.06; P =.136]. In a preplanned subgroup analysis, nonbasal patients seemed to derive benefit from the addition of capecitabine with a DFS HR of 0.53 versus 0.94 in those with basal phenotype (interaction test P =.0694) and an HR for overall survival of 0.42 versus 1.23 in basal phenotype (interaction test P =.0052). Tolerance of capecitabine was as expected, with 75.2% of patients completing the planned 8 cycles. This study failed to show a statistically significant increase in DFS by adding extended capecitabine to standard chemotherapy in patients with early TNBC. In a preplanned subset analysis, patients with nonbasal phenotype seemed to obtain benefit with capecitabine, although this will require additional validation