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BackgroundCombined therapy with dabrafenib plus trametinib was approved in several countries for treatment of BRAF V600E-mutant anaplastic thyroid cancer (ATC) based on an earlier interim analysis of 23 response-assessable patients in the ATC cohort of the phase II Rare Oncology Agnostic Research (ROAR) basket study. We report an updated analysis describing the efficacy and safety of dabrafenib plus trametinib in the full ROAR ATC cohort of 36 patients with ∼4 years of additional study follow-up.Patients and methodsROAR (NCT02034110) is an open-label, nonrandomized, phase II basket study evaluating dabrafenib plus trametinib in BRAF V600E-mutant rare cancers. The ATC cohort comprised 36 patients with unresectable or metastatic ATC who received dabrafenib 150 mg twice daily plus trametinib 2 mg once daily orally until disease progression, unacceptable toxicity, or death. The primary endpoint was investigator-assessed overall response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1. Secondary endpoints were duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety.ResultsAt data cutoff (14 September 2020), median follow-up was 11.1 months (range, 0.9-76.6 months). The investigator-assessed ORR was 56% (95% confidence interval, 38.1% to 72.1%), including three complete responses; the 12-month DOR rate was 50%. Median PFS and OS were 6.7 and 14.5 months, respectively. The respective 12-month PFS and OS rates were 43.2% and 51.7%, and the 24-month OS rate was 31.5%. No new safety signals were identified with additional follow-up, and adverse events were consistent with the established tolerability of dabrafenib plus trametinib.ConclusionsThese updated results confirm the substantial clinical benefit and manageable toxicity of dabrafenib plus trametinib in BRAF V600E-mutant ATC. Dabrafenib plus trametinib notably improved long-term survival and represents a meaningful treatment option for this rare, aggressive cancer.

Inherited and somatic mitochondrial DNA mutations in Guam amyotrophic lateral sclerosis and parkinsonism-dementia. Ataxin-2 intermediate-length polyglutamine expansions are associated with increased risk for ALS. Ataxin-2 intermediate-length polyglutamine expansions are associated with increased risk for ALS. [Extracted from the article]

Nos interesa en el presente trabajo tratar el problema del agua y su uso, como un componente central del paquete tecnológico producido y utilizado dentro de la racionalidad económica, social cultural de las economías campesinas andinas. El interés por tratar este tema nos viene de las siguientes cuestiones que, al parecer, son parte del sentido común de muchos técnicos y profesionales relacionados con las actividades agrarias: por ejemplo, unos afirman que el problema agrario en el Perú no es la tierra sino el agua; otros afirman que la transferencia de las tecnologías modernas en general y en particular en riego moderno son la solución parta el desarrollo productivo del agro peruano.

The aim of this study was to describe children's hospitalization and to analyse gender differences by selected diagnostic and procedure groups. Using the Clinical Classification for Health Policy Research Version 2 (CCHPR), 81 888 hospitalizations from the Minimum Basic Data Set of Hospital Discharge (CMBDAH) of 1995 related to children under 15 y of age in Catalonia, Spain, were studied. Hospitalization rates, number of days in hospital, average length of stay (d) in hospital and the standardized hospitalization ratio (SHR) (hospitalization rate in boys/hospitalization rate in girls) were computed. Two independent approaches were taken: (i) gender-specific categories were excluded in order to compare hospitalizations by sex; (ii) a selected group of 17 diagnostic and procedure categories were chosen in order to carry out the specific gender comparison. In both approaches, the selected indicators were compared by age groups, and totals were standardized by age using the direct method. An excess of hospitalization in boys was observed (SHR = 1.18; 95% CI: 1.17-1.19). The number of days spent in hospital and hospitalization rates were higher in infants and were also higher for boys than for girls. The average length of stay in hospital was higher in infants and in girls at all ages. These differences were systematic when stratified by health region, admission and discharge circumstances and hospital category. Except for urinary infection, which was higher in girls (SHR: 0.65; CI 95%: 0.54-0.76), the SHR was higher in boys in all diagnostic and procedure categories analysed (all SHR > 1). Specific sex categories, injuries and poisonings cannot on their own explain a higher level of hospitalization among boys. More specific studies are needed to explain the role of the family and the healthcare system in gender inequalities in children's hospitalization. [ABSTRACT FROM AUTHOR]

Topical administration of active substances may be promoted by optimizing not only the vehicle formulation but also the application protocol. The formulation aspects are widely studied in the literature while a few works are dedicated to the development of application methods. In this context, we studied an application protocol usable as a part of skincare routine by investigating the effect of massage on the skin penetration of retinol. Retinol is a lipophilic molecule widely used as an anti-ageing firming agent in cosmetic formulations. Massage was applied to pig skin explants mounted to Franz diffusion cells after or before the deposit of the retinol-loaded formulation. Thetype of skin massage (roll or rotary type) and its duration were varied.The massage protocol had a significant influence on retinol skin penetration. Due to its highly lipophilic character, retinol accumulated into the stratum corneum but, depending on the massage protocol, a significant retinol concentration was obtained after 4 h in epidermis and dermis layers. Results showed that the roll-type massage was significantly more efficient than the rotary process that exhibited little effect on retinol cutaneous penetration. Such results could be interesting for the development of massage devices in association with cosmetic formulations., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with an estimated heritability between 40 and 50%. DNA methylation patterns can serve as proxies of (past) exposures and disease progression, as well as providing a potential mechanism that mediates genetic or environmental risk. Here, we present a blood-based epigenome-wide association study meta-analysis in 9706 samples passing stringent quality control (6763 patients, 2943 controls). We identified a total of 45 differentially methylated positions (DMPs) annotated to 42 genes, which are enriched for pathways and traits related to metabolism, cholesterol biosynthesis, and immunity. We then tested 39 DNA methylation-based proxies of putative ALS risk factors and found that high-density lipoprotein cholesterol, body mass index, white blood cell proportions, and alcohol intake were independently associated with ALS. Integration of these results with our latest genome-wide association study showed that cholesterol biosynthesis was potentially causally related to ALS. Last, DNA methylation at several DMPs and blood cell proportion estimates derived from DNA methylation data were associated with survival rate in patients, suggesting that they might represent indicators of underlying disease processes potentially amenable to therapeutic interventions.

Aim: To adapt, translate, and utilize the Dimensional Apathy Scale (DAS) in Amyotrophic Lateral Sclerosis (ALS) to the Spanish population. Method: We recruited 104 ALS patients (67 of their caregivers) and 49 controls. Participants completed the Spanish-translated DAS, Geriatric Depression Scale- Short form. Patients were also administered the ALS Functional Rating Scale-Revised (ALSFRS-R). Caregivers additionally completed the informant/caregiver-rated Spanish-translated DAS. The DAS was translated to Spanish using a back-translation method. Test-retest and internal consistency reliability were examined. Divergent validity was assessed by comparing the DAS with the depression scale (GDS-15). Principal Component Analysis (PCA) was applied to explore the substructure of the Spanish DAS. Results: The internal consistency reliability of self-rated Spanish DAS was 0.72 and of the informant/caregiver-rated Spanish DAS was 0.84. Correlations between self-rated DAS subscales and GDS-15 were not statistically significant, with a good test-retest reliability. PCA analysis showed a similar substructure to the original DAS. ALS patients had significantly higher Initiation apathy than controls. Additionally, ALS patient informant/caregiver-rated DAS Emotional apathy was significantly higher than the self-rated, with no significant differences observed in the Executive and Initiation subscales. No association was found between DAS and functional impairment using the ALS Functional Rating Scale (ALSFRS-R). Conclusion: The Spanish translation of the DAS is valid and reliable for use in assessing multidimensional apathy in the Spanish population. Availability of the Spanish DAS will allow for future research to explore different apathy subtypes and their impact in ALS and other conditions., (Copyright © 2020 Salas, Radakovic, Rodriguez-Castillo, Marín, Chaverri and Rodriguez-Santos.)

Purpose: Low prolactin (PRL) serum levels are associated with glucose intolerance and type 2 diabetes in adults, and with metabolic syndrome and obesity in children. In obese rodents, PRL treatment promotes insulin sensitivity by maintaining adipose tissue fitness, and lack of PRL signaling exacerbates obesity-derived metabolic alterations. Since adipose tissue dysfunction is a key factor triggering metabolic alterations, we evaluated whether PRL serum levels are associated with adipocyte hypertrophy (a marker of adipose tissue dysfunction), insulin resistance, and metabolic syndrome in lean, overweight, and obese adult men and women., Methods: Samples of serum and adipose tissue from 40 subjects were obtained to evaluate insulin resistance index (homeostasis model assessment of insulin resistance (HOMA-IR)), signs of metabolic syndrome (glucose levels, high-density lipoproteins, triglycerides, blood pressure, and waist circumference), as well as adipocyte size and gene expression in fat., Results: Lower PRL serum levels are associated with adipocyte hypertrophy, in visceral but not in subcutaneous fat, and with a higher HOMA-IR. Furthermore, low systemic PRL levels together with high waist circumference predict an elevated HOMA-IR whereas low serum PRL values in combination with high blood glucose predicts visceral adipocyte hypertrophy. In agreement, visceral fat from insulin resistant subjects shows reduced expression of prolactin receptor. However, there is no association between PRL levels and obesity or signs of metabolic syndrome., Conclusions: Our results support that low levels of PRL are markers of visceral fat dysfunction and insulin resistance, and suggest the potential therapeutic value of medications elevating PRL levels to help maintain metabolic homeostasis.

Background: Comprehensive assessment of integrated care deployment constitutes a major challenge to ensure quality, sustainability and transferability of both healthcare policies and services in the transition toward a coordinated service delivery scenario. To this end, the manuscript articulates four different protocols aiming at assessing large-scale implementation of integrated care, which are being developed within the umbrella of the regional project Nextcare (2016-2019), undertaken to foster innovation in technologically-supported services for chronic multimorbid patients in Catalonia (ES) (7.5 M inhabitants). Whereas one of the assessment protocols is designed to evaluate population-based deployment of care coordination at regional level during the period 2011-2017, the other three are service-based protocols addressing: i) Home hospitalization; ii) Prehabilitation for major surgery; and, iii) Community-based interventions for frail elderly chronic patients. All three services have demonstrated efficacy and potential for health value generation. They reflect different implementation maturity levels. While full coverage of the entire urban health district of Barcelona-Esquerra (520 k inhabitants) is the main aim of home hospitalization, demonstration of sustainability at Hospital Clinic of Barcelona constitutes the core goal of the prehabilitation service. Likewise, full coverage of integrated care services addressed to frail chronic patients is aimed at the city of Badalona (216 k inhabitants)., Methods: The population-based analysis, as well as the three service-based protocols, follow observational and experimental study designs using a non-randomized intervention group (integrated care) compared with a control group (usual care) with a propensity score matching method. Evaluation of cost-effectiveness of the interventions using a Quadruple aim approach is a central outcome in all protocols. Moreover, multi-criteria decision analysis is explored as an innovative method for health delivery assessment. The following additional dimensions will also be addressed: i) Determinants of sustainability and scalability of the services; ii) Assessment of the technological support; iii) Enhanced health risk assessment; and, iv) Factors modulating service transferability., Discussion: The current study offers a unique opportunity to undertake a comprehensive assessment of integrated care fostering deployment of services at regional level. The study outcomes will contribute refining service workflows, improving health risk assessment and generating recommendations for service selection., Trials Registration: NCT03130283 (date released 04/06/2018), NCT03768050 (date released 12/05/2018), NCT03767387 (date released 12/05/2018).

Objective: Adaptation of the ECAS to the Spanish population., Methods: The ECAS test was adapted and implemented in a random sample of 102 ALS patients. A test-retest reliability of the instrument and internal consistency assessment were carried out. Its convergent validity was determined by comparing the ECAS screen with the ALS Cognitive Behavioural Screen (ALS-CBS), another standard tool., Results: The Spanish adaptation of the ECAS scale preserves the statistical characteristics of the original version. Its analysis revealed a high internal consistency, similar to that of the original version. A significant correlation was found between the ECAS scale and the ALS-CBS, with the highest degree of correlation values shown at the Executive and Lack of empathy domains scales. Additionally, significant differences were observed between the scores obtained in ALS patients and healthy individuals. Furthermore, the analysis of the screen discrimination ability resulted acceptable., Conclusion: The results of this study prove that the Spanish adaptation of the ECAS scale preserves the internal consistency and construct validity of its original version.

Perovskite (La 0.8 Sr 0.2 ) 1-x Mn 1-x Ir x O 3 (x = 0 (LSM) and 0.05 (LSMI)) nanoparticles with particle size of 20-50 nm are prepared by the polymer-assisted chemical solution method and demonstrated as high performance bifunctional oxygen catalyst in alkaline solution. As compared with LSM, LSMI with the A-site deficiency and the B-site iridium (Ir)-doping has a larger lattice, lower valence state of transition metal, and weaker metal-OH bonding; therefore, it increases the concentration of oxygen vacancy and enhances both oxygen evolution reaction (OER) and oxygen reduction reaction (ORR). LSMI exhibits superior ORR performance with only 30 mV onset potential difference from the commercial Pt/C catalyst and significant enhancement in electrocatalytic activity in the OER process, resulting in the best oxygen electrode material among all the reported perovskite oxides. LSMI also exhibits high durability for both ORR (only 18 mV negative shift for the half-wave potential compared with the initial ORR) and OER process with 10% decay. The electrochemical results indicate that the A-site deficiency and Ir-doping in perovskite oxides could be promising catalysts for the applications in fuel cells, metal-air batteries, and solar fuel synthesis.