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Purpose: To evaluate olaparib in advanced triple negative breast cancer (TNBC) patients with homologous recombination deficiency (HRD) and no germline BRCA1/2 mutations (gBRCA1/2mut). Methods: NOBROLA (NCT03367689) is a single-arm, open-label, multicenter, phase IIa trial, enrolling adult patients with advanced TNBC without gBRCA1/2mut and with HRD, who were treated with olaparib. The primary endpoint was clinical benefit rate (CBR) per RECIST v.1.1. Results: Six of 114 patients were eligible and received olaparib. Median follow up was 8.5 months. CBR and overall response rate (ORR) were 50 % (95 % CI, 11.8–88.2). Conclusions: The observed results could prompt further investigation. Trial: ClinicalTrials.gov identifier NCT03367689.

Abstract Background A substantial proportion of patients with giant cell arteritis (GCA) relapse despite standard therapy with glucocorticoids, methotrexate and tocilizumab. The Janus kinase/signal transducer and activator of transcription (JAK/STAT) signalling pathway is involved in the pathogenesis of GCA and JAK inhibitors (JAKi) could be a therapeutic alternative. We evaluated the effectiveness of JAKi in relapsing GCA patients in a real-world setting and reviewed available literature. Methods Retrospective analysis of GCA patients treated with JAKi for relapsing disease at thirteen centers in Spain and one center in United States (01/2017-12/2022). Outcomes assessed included clinical remission, complete remission and safety. Clinical remission was defined as the absence of GCA signs and symptoms regardless of the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) values. Complete remission was defined as the absence of GCA signs and symptoms along with normal ESR and CRP values. A systematic literature search for other JAKi-treated GCA cases was conducted. Results Thirty-five patients (86% females, mean age 72.3) with relapsing GCA received JAKi therapy (baricitinib, n = 15; tofacitinib, n = 10; upadacitinib, n = 10). Before JAKi therapy, 22 (63%) patients had received conventional synthetic immunosuppressants (e.g., methotrexate), and 30 (86%) biologics (e.g., tocilizumab). After a median (IQR) follow-up of 11 (6-15.5) months, 20 (57%) patients achieved and maintained clinical remission, 16 (46%) patients achieved and maintained complete remission, and 15 (43%) patients discontinued the initial JAKi due to relapse (n = 11 [31%]) or serious adverse events (n = 4 [11%]). A literature search identified another 36 JAKi-treated GCA cases with clinical improvement reported for the majority of them. Conclusions This real-world analysis and literature review suggest that JAKi could be effective in GCA, including in patients failing established glucocorticoid-sparing therapies such as tocilizumab and methotrexate. A phase III randomized controlled trial of upadacitinib is currently ongoing (ClinicalTrials.gov ID NCT03725202).

Dactylitis is a clinical concept that corresponds to the swelling of the whole finger or toe giving a sausage appearance. Although it can be observed in different diseases, it is a distinctive clinical feature of psoriatic arthritis and is associated with a poor prognosis. Ultrasound has made it possible to improve our understanding of the pathogenesis of psoriatic arthritis dactylitis, identifying associated structural alterations, namely, flexor tenosynovitis, subcutaneous tissue edema, pulley inflammation with thickening and intra-pulley Doppler signals, extensor paratenonitis, synovitis, pericapsular bone formation, and flexor enthesitis. Given its complexity, a consensus has yet to be reached on an ultrasound-based definition of dactylitis. In addition, enthesitis is one of the characteristic features of spondyloartritis. Enthesitis, like dactylitis, is among the clinical manifestations in the Assessment of SpondyloArthritis international Society classification criteria for both axial and peripheral spondyloartritis and is a key feature for classifying psoriatic arthritis with the Classification criteria for Psoriatic Arthritis criteria. Ultrasonography is a very useful tool for exploring the enthesis. We have a good sonographic definition, although ultrasound findings do not always allow us to differentiate between mechanical or inflammatory lesions. Elementary lesions that characterize enthesopathy are hypoechogenicity at the enthesis, thickened enthesis, calcification/enthesophyte at enthesis, erosion at enthesis, and Doppler signal at enthesis. Different composite indices have been proposed in order to classify spond yloarthropathies. This article reviews the evaluation of dactylitis and enthesitis from the sonographic perspective.

Summary: Background: Hyperglycaemia is an early and frequent adverse event during alpelisib treatment. METALLICA aimed to evaluate prophylactic metformin to prevent or reduce hyperglycaemia occurrence in patients with HR+/HER2−/PIK3CA-mutated advanced breast cancer (ABC). Methods: Between August 13th, 2020 and March 23rd, 2022, this 2-cohort, phase 2, multicentre, single-arm trial (NCT04300790) enrolled patients with HR+/HER2−/PIK3CA-mutated ABC: cohort A, normal glycaemia (fasting plasma glucose

Abstract Background Neoadjuvant endocrine therapy (NET) in oestrogen receptor-positive (ER+) /HER2-negative (HER2-) breast cancer allows real-time evaluation of drug efficacy as well as investigation of the biological and molecular changes that occur after estrogenic deprivation. Clinical and pathological evaluation after NET may be used to obtain prognostic and predictive information of tumour response to decide adjuvant treatment. In this setting, clinical scales developed to evaluate response after neoadjuvant chemotherapy are not useful and there are not validated biomarkers to assess response to NET beyond Ki67 levels and preoperative endocrine prognostic index score (mPEPI). Methods In this prospective study, we extensively analysed radiological (by ultrasound scan (USS) and magnetic resonance imaging (MRI)) and pathological tumour response of 104 postmenopausal patients with ER+ /HER2- resectable breast cancer, treated with NET for a mean of 7 months prior to surgery. We defined a new score, tumour cellularity size (TCS), calculated as the product of the residual tumour cellularity in the surgical specimen and the tumour pathological size. Results Our results show that radiological evaluation of response to NET by both USS and MRI underestimates pathological tumour size (path-TS). Tumour size [mean (range); mm] was: path-TS 20 (0–80); radiological-TS by USS 9 (0–31); by MRI: 12 (0–60). Nevertheless, they support the use of MRI over USS to clinically assess radiological tumour response (rad-TR) due to the statistically significant association of rad-TR by MRI, but not USS, with Ki67 decrease (p = 0.002 and p = 0.3, respectively) and mPEPI score (p = 0.002 and p = 0.6, respectively). In addition, we propose that TCS could become a new tool to standardize response assessment to NET given its simplicity, reproducibility and its good correlation with existing biomarkers (such as ΔKi67, p = 0.001) and potential added value. Conclusion Our findings shed light on the dynamics of tumour response to NET, challenge the paradigm of the ability of NET to decrease surgical volume and point to the utility of the TCS to quantify the scattered tumour response usually produced by endocrine therapy. In the future, these results should be validated in independent cohorts with associated survival data.

IntroductionFree-living amoebae are an extensive group of protistans that can be found in a wide variety of environments. Among them, the Acanthamoeba genus and Naegleria fowleri stand out as two of the most pathogenic amoebae and with a higher number of reported cases. N. fowleri is mainly found in warm freshwater water bodies whereas amoebae of the Acanthamoeba genus are broadly distributed through natural and anthropogenic environments. In this regard, the management and the control of the amoebic populations in swimming pools has become a major public health challenge for institutions.MethodsThe aim of this work was to evaluate the growth pattern of trophozoites of A. griffini and N. fowleri at different temperatures and salt concentrations.Results and discussionOur results showed that A. griffini resisted a higher concentration of salt than N. fowleri. Moreover, no trophozoites could withstand the salt levels of the sea in in vitro conditions. This work supports the contention that salinity could represent an important and useful tool for the control of the most pathogenic amoebic populations in recreational water bodies.

El propósito del trabajo es analizar el uso de la tecnología, antes y durante la pandemia de COVID-19, en instituciones educativas durante 2018-2021. Los datos utilizados corresponden a PISA 2018 para 52 países: a) cuestionarios estudiantes con 1118 variables y 612004 observaciones y b) cuestionario escuelas, con 197 variables y 21903 observaciones. Se realizó un análisis estadístico usando la matriz de correlaciones y la técnica de análisis clúster jerárquico. Los resultados muestran la clasificación de los 52 países en cinco clústeres con las características de uso de la tecnología en cuatro ejes: infraestructura, comunicación, capacitación a docentes y autonomía estudiantil.

Hoy en día la tecnología forma parte de la mayoría de las actividades cotidianas personales. En el ámbito educativo, concretamente, las herramientas tecnológicas son utilizadas como facilitadoras del aprendizaje. Esto, junto a la necesidad de facilitar herramientas variadas para formar a los estudiantes, generando, en muchos países, un cambio del paradigma educativo, pasando de una educación contenidista a una educación por competencias. Por ello el PC ha ganado relevancia a nivel internacional. El Pensamiento Computacional refiere al conjunto de competencias para la expresión y resolución de problemas utilizando la lógica de la programación. En el ámbito educativo la adquisición de estas competencias permitirá a los niños hacer frente a un futuro cada vez más tecnológico. Para conocer el estado de adquisición de estas competencias es necesario tener instrumentos de medida validados. Esta investigación pretende verificar la estructura teórica del desafío Bebras aplicado en Uruguay durante 2021 y a partir de esta realizar un análisis preliminar de la situación. Para ello, a las respuestas de 20,393 participantes en Bebras de 5° y 6° de Educación Pública, se le aplicó un Análisis Factorial Confirmatorio, Pruebas T de Student y ANOVAs. Los principales resultados obtenidos son: La estructura factorial coincide con la definición teórica de cada ítem. Existen diferencias estadísticamente significativas por género (p.valor < .05), grado (p.valor

En este trabajo se analiza, para el caso de España, la influencia de la familiarización con las TIC sobre la adquisición de competencias en matemáticas y ciencias. Los participantes analizados corresponden a 35943 estudiantes de 15 años de edad que realizaron la prueba PISA en el año 2018. Los datos son analizados mediante Análisis de Correspondencias Múltiples y los principales resultados permiten concluir que, en cuanto a la familiarización (tenencia y/o uso) con las TIC, más de un 50% de los estudiantes declaran tener y usar los dispositivos analizados, y que esta proporción es aún mayor cuando se trata de Internet y Celular con internet (más de 95%). Los dispositivos que menos uso tienen son Celular sin internet y Lector de ebook. En cuanto a la asociación entre la familiarización con las TIC y la adquisición de las competencias se tiene que: 1. niveles bajos en las competencias se asocian a la no familiarización con las TIC; 2. niveles medios se asocian a tenencia/uso de Internet, Laptop, Celular con internet y Disco USB, y 3. niveles altos se asocian con tenencia y uso de Ordenador, Tablet e Impresora, además de los dispositivos asociados al nivel medio.

Abstract Background Many patients with metastatic breast cancer experience cancer- and treatment-related side effects that impair activities of daily living and negatively affect the quality of life. There is a need for interventions that improve quality of life by alleviating fatigue and other side effects during palliative cancer treatment. Beneficial effects of exercise have been observed in the curative setting, but, to date, comparable evidence in patients with metastatic breast cancer is lacking. The aim of this study is to assess the effects of a structured and individualized 9-month exercise intervention in patients with metastatic breast cancer on quality of life, fatigue, and other cancer- and treatment-related side effects. Methods The EFFECT study is a multinational, randomized controlled trial including 350 patients with metastatic breast cancer. Participants are randomly allocated (1:1) to an exercise or control group. The exercise group participates in a 9-month multimodal exercise program, starting with a 6-month period where participants exercise twice a week under the supervision of an exercise professional. After completing this 6-month period, one supervised session is replaced by one unsupervised session for 3 months. In addition, participants are instructed to be physically active for ≥30 min/day on all remaining days of the week, while being supported by an activity tracker and exercise app. Participants allocated to the control group receive standard medical care, general written physical activity advice, and an activity tracker, but no structured exercise program. The primary outcomes are quality of life (EORTC QLQ-C30, summary score) and fatigue (EORTC QLQ-FA12), assessed at baseline, 3, 6 (primary endpoint), and 9 months post-baseline. Secondary outcomes include physical fitness, physical performance, physical activity, anxiety, depression, pain, sleep problems, anthropometric data, body composition, and blood markers. Exploratory outcomes include quality of working life, muscle thickness, urinary incontinence, disease progression, and survival. Additionally, the cost-effectiveness of the exercise program is assessed. Adherence and safety are monitored throughout the intervention period. Discussion This large randomized controlled trial will provide evidence regarding the (cost-) effectiveness of exercise during treatment of metastatic breast cancer. If proven (cost-)effective, exercise should be offered to patients with metastatic breast cancer as part of standard care. Trial registration ClinicalTrials.gov NCT04120298 . Registered on October 9, 2019.

Paclitaxel is a widely used chemotherapeutic agent for the treatment of breast cancer (BC), including as a front-line treatment for triple-negative breast cancer (TNBC) patients. However, resistance to paclitaxel remains one of the major causes of death associated with treatment failure. Multiple studies have demonstrated that miRNAs play a role in paclitaxel resistance and are associated with both disease progression and metastasis. In the present study, we used a miRNA-encoding lentiviral library as a gain-of-function screen for paclitaxel resistance in the MDA-MB-231 TNBC cell line. We identified that miR-181b, miR-29a, miR-30c, miR-196 and miR-1295 conferred a resistant phenotype to cells. The expression of miR-29a also induced resistance to eribulin and vinorelbine, while miR-181b and miR-30c induced resistance to vinorelbine. We measured the levels of these miRNAs in breast cancer patients and observed higher levels of miR-29a in treatment-refractory patients. Taken together, we suggest that miR-29a and miR-181b may be good candidates for miRNA inhibition to overcome resistance to chemotherapy. [ABSTRACT FROM AUTHOR]

Background: Certolizumab is an Fc‐free PEGylated tumor necrosis factor‐alpha (TNFα) inhibitor recently approved for the treatment of moderate‐to‐severe plaque psoriasis, although there is limited real‐world evidence on the effectiveness and safety in patients with plaque psoriasis treated with certolizumab. The objective of this article is to determine the effectiveness, drug survival, and safety, including pregnancy, childbirth, and lactation, of certolizumab in moderate‐to‐severe plaque psoriasis under real‐world conditions. Methods: This is a retrospective, multicenter, observational study performed in 15 hospitals in Spain. It evaluates the effectiveness and safety of certolizumab in plaque psoriasis in the clinical practice setting. Results: A total of 67 patients (73% female) were evaluated with a mean baseline Psoriasis Area Severity Index (PASI) of 8.9. At Week 12, the mean PASI was 2.3 (n = 67), 1.3 (n = 57) at Week 24 and 1.3 at Week 52 (n = 34). Absolute PASI < 3 was achieved in 69, 86, and 92% of patients at Weeks 12, 24, and 52, respectively, as observed. For its part, using the under‐response imputation analysis, PASI < 3 at Weeks 12, 24, and 52 were achieved by 69, 73, and 49% of the patients, respectively. A total of 35 patients (52%) had concomitant psoriatic arthritis, and, in 24 of them, Disease Activity in Psoriatic Arthritis Score (DAPSA) was recorded at baseline, with a mean value of 17.9 which decreased to 8.2 at Week 12 (n = 22) and to 3.6 at Week 24 (n = 18). Certolizumab treatment was discontinued in 14 out of 67 patients (21%), due to lack/loss of cutaneous or articular effectiveness (n = 11) or patient decision (n = 2) or adverse event in only one patient who developed active tuberculosis. A lower baseline PASI [hazard ratio (HR): 1.12 (1.02–1.23); P = 0.023] and a more significant reduction in PASI at Week 12 [HR: 1.16 (1.07–1.27); P < 0.001] and Week 52 [HR: 1.47 (1.11–1.96); P = 0.007] was shown to be significantly related with better survival for the entire follow‐up period. Fourteen patients were treated during pregnancy and/or lactation without reporting adverse events in either the patient or the newborn. Conclusions: Certolizumab consistently showed high effectiveness and drug survival rates in this real‐life cohort. The safety demonstrated in clinical trials during pregnancy and lactation seems to be confirmed in clinical practice. [ABSTRACT FROM AUTHOR]

Objectives To evaluate effectiveness and safety of certolizumab pegol (CZP) in uveitis due to immune-mediated inflammatory diseases (IMID).Methods Multicentre study of CZP-treated patients with IMID uveitis refractory to conventional immunosuppressant. Effectiveness was assessed through the following ocular parameters: best-corrected visual acuity, anterior chamber cells, vitritis, macular thickness and retinal vasculitis. These variables were compared between the baseline, and first week, first, third, sixth months, first and second year.Results We studied 80 (33 men/47 women) patients (111 affected eyes) with a mean age of 41.6±11.7 years. The IMID included were: spondyloarthritis (n=43), Behçet’s disease (n=10), psoriatic arthritis (n=8), Crohn’s disease (n=4), sarcoidosis (n=2), juvenile idiopathic arthritis (n=1), reactive arthritis (n=1), rheumatoid arthritis (n=1), relapsing polychondritis (n=1),Conclusions CZP seems to be effective and safe in uveitis related to different IMID, even in patients refractory to previous biological drugs.

Naegleria. fowleri, a protozoa belonging to the free-living amoeba group, is the causative agent of a central nervous system affecting disease that is fatal in more than the 95% of the reported cases. This parasite can be found in warm water bodies such as lakes, rivers or inadequately disinfected swimming pools. On the other hand, chlorination and UV light treatment are two of the most extensively used disinfection methods in recreational water facilities.In this study the effect of chlorination and UV light on N. fowleri trophozoites was studied in a close water circuit with the aim to assess the efficacy of this disinfection methods in large pools. The obtained results showed that the chlorination was able to decrease the number of viable cells despite the elimination was not totally achieved. Nonetheless, the combination of the UV light with the chlorination allowed the complete removal of the N. fowleri trophozoites from the water in experimental testing conditions.

Abstract The medium-chain fatty acids octanoic acid (C8) and decanoic acid (C10) are gaining attention as beneficial brain fuels in several neurological disorders. The protective effects of C8 and C10 have been proposed to be driven by hepatic production of ketone bodies. However, plasma ketone levels correlates poorly with the cerebral effects of C8 and C10, suggesting that additional mechanism are in place. Here we investigated cellular C8 and C10 metabolism in the brain and explored how the protective effects of C8 and C10 may be linked to cellular metabolism. Using dynamic isotope labeling, with [U-13C]C8 and [U-13C]C10 as metabolic substrates, we show that both C8 and C10 are oxidatively metabolized in mouse brain slices. The 13C enrichment from metabolism of [U-13C]C8 and [U-13C]C10 was particularly prominent in glutamine, suggesting that C8 and C10 metabolism primarily occurs in astrocytes. This finding was corroborated in cultured astrocytes in which C8 increased the respiration linked to ATP production, whereas C10 elevated the mitochondrial proton leak. When C8 and C10 were provided together as metabolic substrates in brain slices, metabolism of C10 was predominant over that of C8. Furthermore, metabolism of both [U-13C]C8 and [U-13C]C10 was unaffected by etomoxir indicating that it is independent of carnitine palmitoyltransferase I (CPT-1). Finally, we show that inhibition of glutamine synthesis selectively reduced 13C accumulation in GABA from [U-13C]C8 and [U-13C]C10 metabolism in brain slices, demonstrating that the glutamine generated from astrocyte C8 and C10 metabolism is utilized for neuronal GABA synthesis. Collectively, the results show that cerebral C8 and C10 metabolism is linked to the metabolic coupling of neurons and astrocytes, which may serve as a protective metabolic mechanism of C8 and C10 supplementation in neurological disorders.

Dactylitis is a clinical concept that corresponds to the swelling of the whole finger or toe giving a sausage appearance. Although it can be observed in different diseases, it is a distinctive clinical feature of psoriatic arthritis and is associated with a poor prognosis. Ultrasound has made it possible to improve our understanding of the pathogenesis of psoriatic arthritis dactylitis, identifying associated structural alterations, namely, flexor tenosynovitis, subcutaneous tissue edema, pulley inflammation with thickening and intra-pulley Doppler signals, extensor paratenonitis, synovitis, pericapsular bone formation, and flexor enthesitis. Given its complexity, a consensus has yet to be reached on an ultrasound-based definition of dactylitis. In addition, enthesitis is one of the characteristic features of spondyloartritis. Enthesitis, like dactylitis, is among the clinical manifestations in the Assessment of SpondyloArthritis international Society classification criteria for both axial and peripheral spondyloartritis and is a key feature for classifying psoriatic arthritis with the Classification criteria for Psoriatic Arthritis criteria. Ultrasonography is a very useful tool for exploring the enthesis. We have a good sonographic definition, although ultrasound findings do not always allow us to differentiate between mechanical or inflammatory lesions. Elementary lesions that characterize enthesopathy are hypoechogenicity at the enthesis, thickened enthesis, calci ficat ion/e nthes ophyt e at enthesis, erosion at enthesis, and Doppler signal at enthesis. Different composite indices have been proposed in order to classify spond yloar throp athie s. This article reviews the evaluation of dactylitis and enthesitis from the sonographic perspective. [ABSTRACT FROM AUTHOR]

Introduction: The Spanish Educational System proposes repetition as a leveling mechanismof thereal performance of thescholarand theiracademiclevel. Although the negativeconsequences of repetition in theshort,mediumand long termhave been shown to outweigh the benefits, the possibility of using this mechanism has made it the OECD country with the highest rate of repeaters. With this as a starting point, the question is if the repetition is fulfilling the aim for which it was created. Research objective: Grade repetition children and non-grade repetition children performance comparation. Method: To achieve this aim, were analyzed 25,245 responses of fourth grade students of Primary Education to the test “Evaluación General de Diagnóstico” of 2009. The methodological strategy used is mean differenceanalysis, using the Welch testand the HJ-Biplot. Results: 6.83% of the sample are repeaters. All study competencies (Linguistic communication, Mathematics, Interaction with the physical and Social world and citizens) correlate positively, the strongest correlation is between the physical and Social world and linguistics (.68) and between the physical and Social world and citizen (.68), and the weakest correlation between citizen and linguistics (.57). Non-grade repetition students obtain higher average scores in all the competences and these differences are significant (p-value .001) in the Welch test. Conclusion: in most cases, Repetition does not serve to improve performance. Discussion: repetition generates inequality for children in society and that it is not a useful mechanism, it is necessary to carry out other types of interventionsto improvethe performance of students who are susceptible to repeat.

In this paper it is analyzed which factors are associated with the academic performance of fourth grade children, considering variables of the boy or girl, theirschoolenvironment and their family context. The analyzed participants correspond to 25245 fourth level Primary Education students, evaluated by the “Evaluación General de Diagnóstico” in Spain at 2009. The statistical analysis was Multiple Correspondence Analysis. The main results obtained allow us to conclude that there is an association between high performance and non-repetition in school, the taste (quite a lot) for attending school, the language in which the students took the test (assessment in Spanish) and ownership of the school (private). High academic performance is also associated with a parents’ high educational level. In terms of factors associated with an academic performance considered medium, there is a taste for attending school (very happy), the language in which they carried out the evaluations (Valencian and Catalan), the ownership of the school (public) and the family’s educational level (ESO/EGB). Finally, the factors associated with low values of academic performance are identified with little taste for attending school (not at all), repetition of at least one year of primary school,conducting tests in Basque and single-parent homes. No associations between academic performance and the sex of the scholar were detected.