Do NPM1 and FLT3-ITD mutations modify prognosis in patients treated with non-intensive regimens?

FLT3-ITD and NPM1 mutations are key to defining the genetic risk profile of acute myeloid leukemia (AML). We aimed to assess the prognostic features of the FLT3-ITD and NPM1 mutations in old and/or unfit individuals with AML treated with non-intensive therapies in the era before azacitidine-venetoclax approbation. The results of various non-intensive regimens were also compared. We conducted a retrospective analysis that included patients treated with different non-intensive regimens, between 2007 and 2020 from PETHEMA AML registry. We compiled 707 patients with a median age of 74 years and median follow-up time of 37.7 months. FLT3-ITD patients (N = 98) showed a non-significant difference in overall survival (OS) compared to FLT3-ITD negative-patients (N = 608) (P = 0.17, median OS was 5 vs 7.3 months respectively). NPM1-mutated patients (N = 144) also showed a non-significant difference with NPM1 wild type (N = 519) patients (P = 0.25, median OS 7.2 vs 6.8 respectively). In the Cox regression analysis neither NPM1 nor FLT3-ITD nor age were significant prognostic variables for OS prediction. Abnormal karyotype and a high leukocyte count showed a statistically significant deleterious effect. Azacitidine also showed better survival compared to FLUGA (low dose cytarabine plus fludarabine). NPM1 and FLT3-ITD seem to lack prognostic value in older/unfit AML patients treated with non-intensive regimens other than azacitidine-venetoclax combination.

Developmental ethanol exposure produces deficits in long-term potentiation in vivo that persist following postnatal choline supplementation.

BACKGROUND: Fetal alcohol spectrum disorder (FASD) is one of the leading causes of neurodevelopmental disorder for which there is a pressing need for an effective treatment. Recent studies have investigated the essential nutrient choline as a postnatal treatment option. Supplementation with choline has produced improvements in behavioral tasks related to learning and memory and reverted changes in methylation signature following third-trimester equivalent ethanol exposure. We examined whether there are related improvements in hippocampal synaptic plasticity in vivo. METHODS: Sprague-Dawley offspring were administered binge-levels of ethanol from postnatal day (PND) 4 to 9, then treated with choline chloride (100 mg/kg/day) from PND 10 to 30. In vivo electrophysiology was performed on male and female offspring from PND 55 to 70. Long-term potentiation (LTP) was induced in the medial perforant pathway of the dentate gyrus using a theta-burst stimulation (TBS) protocol, and field-evoked postsynaptic potentials (EPSPs) were evoked for 60 min following the conditioning stimulus. RESULTS: Developmental ethanol exposure caused long-lasting deficits in LTP of the slope of the evoked responses and in the amplitude of the population spike potentiation. Neither deficit was rescued by postnatal choline supplementation. CONCLUSIONS: In contrast to our prior findings that choline can improve hippocampal plasticity (Nutrients, 2022, 14, 2004), here we found that deficits in hippocampal synaptic plasticity due to developmental ethanol exposure persisted into adulthood despite adolescent choline supplementation. Future research should examine more subtle changes in synaptic plasticity to identify synaptic changes that mirror behavioral improvements.

Longitudinal outcomes of obeticholic acid therapy in ursodiol-nonresponsive primary biliary cholangitis: Stratifying the impact of add-on fibrates in real-world practice.

BACKGROUND: Suboptimal response to ursodeoxycholic acid occurs in 40% of primary biliary cholangitis (PBC) patients, affecting survival. Achieving a deep response (normalisation of alkaline phosphatase [ALP] and bilirubin ≤0.6 upper limit of normal) improves survival. Yet, the long-term effectiveness of second-line treatments remains uncertain. AIMS: To evaluate the long-term effectiveness of obeticholic acid (OCA) ± fibrates. Focusing on biochemical response (ALP ≤1.67 times the upper limit of normal, with a decrease of at least 15% from baseline and normal bilirubin levels), normalisation of ALP, deep response and biochemical remission (deep response plus aminotransferase normalisation). METHODS: We conducted a longitudinal, observational, multicentre study involving ursodeoxyccholic acid non-responsive PBC patients (Paris-II criteria) from Spain and Portugal who received OCA ± fibrates. RESULTS: Of 255 patients, median follow-up was 35.1 months (IQR: 20.2-53). The biochemical response in the whole cohort was 47.2%, 61.4% and 68.6% at 12, 24 and 36 months. GLOBE-PBC and 5-year UK-PBC scores improved (p < 0.001). Triple therapy (ursodeoxycholic acid plus OCA plus fibrates) had significantly higher response rates than dual therapy (p = 0.001), including ALP normalisation, deep response and biochemical remission (p < 0.001). In multivariate analysis, triple therapy remained independently associated with biochemical response (p = 0.024), alkaline phosphatase normalisation, deep response and biochemical remission (p < 0.001). Adverse effects occurred in 41.2% of cases, leading to 18.8% discontinuing OCA. Out of 55 patients with cirrhosis, 12 developed decompensation. All with baseline portal hypertension. CONCLUSION: Triple therapy was superior in achieving therapeutic goals in UDCA-nonresponsive PBC. Decompensation was linked to pre-existing portal hypertension.

[Experience of patients with immune-mediated inflammatory diseases seen in a multidisciplinary integrated care unit]. / Experiencia de los pacientes con enfermedades inflamatorias inmunomediadas atendidos en una unidad de atención integral multidisciplinar.

OBJECTIVE: To describe the aspects with the greatest impact on the satisfaction of patients treated in a multidisciplinary unit specialising in immune-mediated inflammatory diseases (IMIDs) and to identify areas for improvement in the care model. METHODS: Cross-sectional descriptive study using a satisfaction survey structured in three blocks: sociodemographic variables, functional aspects of the unit and satisfaction with the professionals. Immediate satisfaction was measured on aspects related to the care received, the physical structure and the likelihood of recommending the unit. RESULTS: A total of 168 patients completed the surveys, the mean score of overall satisfaction with the unit was 4.75 (SD:0.4). The regression model showed the relationship between overall satisfaction and unit signage (OR:3.558, p=0.045, 95% CI: 1.027-12.33), coordination between professionals (OR:9.043, p=0.000, 95% CI: 2.79-29.28) and participation in decision making (OR: 44.836, p=0.000, 95% CI: 5.49-365.97). In terms of immediate satisfaction, the overall Net Promoter Score (NPS) was 87 (excellent). The mean score for coordination with Primary Care was 4.54 (SD:0.8) and they scored waiting time to be seen with 4.49 (SD:0.8), so they have been considered an area for improvement The mean score for coordination with Primary Care was 4.54 (SD:0.8) and they scored waiting time to be seen with 4.49 (SD:0.8), so both were considered areas for improvement. CONCLUSIONS: Coordination between intra-centre professionals and patient participation in decision-making explain the excellent level of patient satisfaction. The monitoring of satisfaction has made it possible to implement immediate improvement actions.

Plastocapillarity: Partial and full Newtonian drop embedding into immiscible yield stress substrates.

HYPOTHESIS: Recent advances have been made in elastocapillarity; reversible 3D deformations of solid substrates with low elastic moduli from the surface tension of deposited drops. This study explores permanent deformations caused by liquid drops on immiscible yield stress substrates. We hypothesize that the substrate's rheological properties play a major role in determining the shape and stability of the drop-substrate interface, and govern partial or full embedding into the substrate. EXPERIMENTS: Substrate yield stress magnitudes are modified through altering the mixture ratios of petroleum jelly to paraffin oil. Water drops are deposited on substrates and deformation profiles of the deformed interface are quantified. FINDINGS: Above a critical Bingham-Capillary number, which characterizes the ratio of yield stress magnitude to surface tension, deposited water drops deform the substrate surface permanently, but minimally. Below this value, drops become increasingly embedded as the substrate yield stress magnitude decreases, with larger indentation depths and increased circumferential ridge heights. With sufficiently low yield stress magnitudes, where surface tension forces dominate over yield stress forces, the plastically deformed ridges fully encapsulate the liquid drop surface, resulting in full drop embedding within the substrate. These results advance knowledge of interfacial wetting on soft yield stress substrates and has implications for binary fluids, functional materials, and new drug delivery systems.

Women in Radiology: A perspective from Spain.

INTRODUCTION: There are gender inequalities in all fields, including radiology. Although the situation is improving, the presence of radiologists in leadership positions continues to be a minority. The objective of this article is to analyse the situation of women in the spanish radiology, comparing it with Europe and the United States. MATERIALS AND METHODS: We selected the years 2000-2022 as reference period to make a comparison with feminization data throughout history. In addition, relevant specific data from the just begun 2023 were also included. The variables in which we investigated feminization were the following: medical students, medical graduates, radiology residents and specialists, section chiefs, department chairs, radiology residency programme directors, radiology university professors, presidents of the main radiological entities and societies in Spain, Europe and the United States, recipients of the main awards given by these radiological societies and chief editors of their journals. In order to perform this analysis we conducted an in-depth bibliographic research, we contacted the radiological societies of Spain, Europe and the USA and we carried out a survey in the main Spanish radiology departments. RESULTS: The female presence in radiology decreases as we rise to leadership positions, a situation that is patent in Spain, Europe and the US, comparison that will be analysed in depth throughout the article. In Spanish hospitals in 2021 there were 58.1% female radiology residents, 55% female radiologists, 42.9% female section chiefs and 24.4% female department chairs. In SERAM's history there have been 10% female presidents, 22% female gold medallists and 5% female editors-in-chief. If we analyse data from 2000 to 2023, female presidents reach 32% and female gold medallists 31%. CONCLUSIONS: Although gender inequality is declining, in radiology women continue to be underrepresented in leadership positions. Work must be done in order to build a diverse and inclusive profession that reflects demographic reality.

Outcomes for people with TB by disease severity at presentation.

There is substantial heterogeneity in disease presentation for individuals with TB disease, which may correlate with disease outcomes. We estimated disease outcomes by disease severity at presentation among individuals with TB during the pre-chemotherapy era.We extracted data on people with TB enrolled between 1917 and 1948 in the USA, stratified by three disease severity categories at presentation using the U.S. National Tuberculosis Association diagnostic criteria. These criteria were based largely on radiographic findings ("minimal", "moderately advanced", and "far advanced"). We used Bayesian parametric survival analysis to model the survival distribution overall, and by disease severity and Bayesian logistic regression to estimate the severity-level specific natural recovery odds within 3 years.People with minimal TB at presentation had a 2% (95% CrI 0-11%) probability of TB death within 5 years vs. 40% (95% CrI 15-68) for those with far advanced disease. Individuals with minimal disease had 13.62 times the odds (95% CrI 9.87-19.10) of natural recovery within 3 years vs. those with far advanced disease.Mortality and natural recovery vary by disease severity at presentation. This supports continued work to evaluate individualized (e.g., shortened or longer) regimens based on disease severity at presentation, identified using radiography..

Medical students' perceptions on preparedness and care delivery for patients with autism or intellectual disability.

Introduction: To provide competent care to patients with autism spectrum disorder (ASD) or intellectual developmental disorder (IDD), healthcare professionals must recognize the needs of neurodivergent populations and adapt their clinical approach. We assessed the perceived preparedness of medical students to adapt care delivery for patients with ASD/IDD, as well as their perceptions on neurodiversity education. Methods: We conducted a sequential explanatory mixed-methods study on undergraduate medical students at McGill University during the academic year 2020-2021. We administered an online survey, followed by semi-structured interviews. We analyzed data using descriptive statistics and thematic analysis. We integrated findings at the interpretation level. Results: We included two-hundred-ten survey responses (~29% of class), and 12 interviews. Few students felt prepared to adjust care for patients with ASD/IDD despite most indicating doing so was important. Ninety-seven percent desired more training regarding care accommodation for neurodivergent patients. Thematic analysis unveiled the perception of current insufficient education, and the value of experiential learning. Discussion/Conclusions: This study highlights low perceived preparedness of medical students to accommodate care for neurodivergent patients, and a desire for more instruction. Incorporating interactive training in medical school curricula regarding modifying care delivery for neurodivergent individuals may improve the perceived preparedness of medical trainees to work with these patients and care quality.

Introduction: Pour fournir des soins compétents aux patients atteints d'un trouble du spectre de l'autisme (TSA) ou d'un trouble du développement intellectuel (TDI), les professionnels de la santé doivent reconnaître les besoins des populations neurodivergentes et adapter leur approche clinique. Nous avons évalué le degré perçu de préparation des étudiants en médecine à adapter la prestation de soins aux patients atteints de TSA/TDI, ainsi que leurs perceptions de la formation relative à la neurodiversité. Méthodes: Nous avons mené une étude séquentielle explicative à méthodes mixtes auprès d'étudiants en médecine de premier cycle de l'Université McGill au cours de l'année universitaire 2020-2021. Nous avons administré un sondage en ligne, suivi d'entretiens semi-structurés. Nous avons analysé les données en faisant appel à la statistique descriptive et à une analyse thématique. Nous avons intégré les résultats sur le plan interprétatif. Résultats: Nous avons inclus deux cent dix réponses à l'enquête (~29% de la classe), et 12 entretiens. Peu d'étudiants se sentaient préparés à adapter les soins aux patients atteints de TSA/TDI, bien que la plupart d'entre eux aient indiqué qu'il était important de le faire. Quatre-vingt-dix-sept pour cent d'entre eux souhaitaient davantage de formation sur l'adaptation des soins aux patients neurodivergents. L'analyse thématique a révélé que les participants considéraient la formation actuelle insuffisante et jugeaient utile l'apprentissage par l'expérience. Discussion/Conclusions: Cette étude met en évidence le faible niveau de préparation perçu par les étudiants en médecine en ce qui concerne l'adaptation des soins aux patients neurodivergents, ainsi que le désir d'une formation plus poussée. L'intégration dans les programmes des facultés de médecine d'une formation interactive portant sur la modification de la prestation des soins pour les personnes neurodivergentes pourrait améliorer la perception des étudiants en médecine de leur degré de préparation à travailler avec ce type de patients et de la qualité des soins.

Effect of nanoporous membranes thickness in electrochemical biosensing performance: application for the detection of a wound infection biomarker.

Introduction: Nanoporous alumina membranes present a honeycomb-like structure characterized by two main parameters involved in their performance in electrochemical immunosening: pore diameter and pore thickness. Although this first one has been deeply studied, the effect of pore thickness in electrochemical-based nanopore immunosensors has been less taken into consideration. Methods: In this work, the influence of the thickness of nanoporous membranes in the steric blockage is studied for the first time, through the formation of an immunocomplex in their inner walls. Finally, the optimal nanoporous membranes were applied to the detection of catalase, an enzyme related with chronic wound infection and healing. Results: Nanoporous alumina membranes with a fixed pore diameter (60 nm) and variable pore thicknesses (40, 60, 100 µm) have been constructed and evaluated as immunosensing platform for protein detection. Our results show that membranes with a thickness of 40 µm provide a higher sensitivity and lower limit-of-detection (LOD) compared to thicker membranes. This performance is even improved when compared to commercial membranes (with 20 nm pore diameter and 60 µm pore thickness), when applied for human IgG as model analyte. A label-free immunosensor using a monoclonal antibody against anti-catalase was also constructed, allowing the detection of catalase in the range of 50-500 ng/mL and with a LOD of 1.5 ng/mL. The viability of the constructed sensor in real samples was also tested by spiking artificial wound infection solutions, providing recovery values of 110% and 118%. Discussion: The results obtained in this work evidence the key relevance of the nanochannel thickness in the biosensing performance. Such findings will illuminate nanoporous membrane biosensing research, considering thickness as a relevant parameter in electrochemical-based nanoporous membrane sensors.

Child and adolescent COVID-19 vaccination coverage by educational setting, United States.

OBJECTIVES: The COVID-19 pandemic changed the setting of education for many children in the U.S. Understanding COVID-19 vaccination coverage by educational setting is important for developing targeted messages, increasing parents' confidence in COVID-19 vaccines, and protecting all children from severe effects of COVID-19 infection. STUDY DESIGN/METHODS: Using data from the Household Pulse Survey (n = 25,173) collected from December 9-19, 2022, January 4-16, 2023, and February 1-13, 2023, this study assessed factors associated with COVID-19 vaccination and reasons for non-vaccination among school-aged children 5-11 and adolescents 12-17 by educational setting. RESULTS: Among children 5-11 years, COVID-19 vaccination coverage was higher among those who received in-person instruction (53.7%) compared to those who were homeschooled (32.5%). Furthermore, among adolescents 12-17 years, COVID-19 vaccination coverage was higher among those who received in-person instruction (73.5%) or virtual/online instruction (70.1%) compared to those who were homeschooled (51.0%). Children and adolescents were more likely to be vaccinated if the parental respondent had been vaccinated compared to those who had not. Among children and adolescents who were homeschooled, main reasons for non-vaccination were concern about side effects (45.4-51.6%), lack of trust in COVID-19 vaccines (45.0-50.9%), and lack of trust in the government (32.7-39.2%). CONCLUSIONS: Children and adolescents who were home-schooled during the pandemic had lower vaccination coverage than those who attended school in person, and adolescents who were home-schooled had lower vaccination coverage than those who received virtual instruction. Based on the reasons for non-vaccination identified in this study, increasing parental confidence in vaccines, and reducing barriers to access are important for supporting COVID-19 vaccination for school-age children.

Impact of a pulmonary embolism response team (PERT) in the prognosis of patients with acute symptomatic pulmonary embolism.

BACKGROUND: The effect of a pulmonary embolism response team (PERT) in the short-term prognosis of patients with acute symptomatic pulmonary embolism (PE) lacks clarity. We therefore aimed at evaluating the effect of a PERT team on short-term mortality among patients with acute PE. METHODS: We retrospectively reviewed consecutive patients with acute symptomatic PE enrolled in a single-center registry between 2007 and 2022. We used propensity score matching to compare treatment effects for patients with similar predicted probabilities of receiving management by the PERT team. The primary outcome was all-cause mortality within 30 days following the diagnosis of PE. The secondary outcome was 30-day PE-related mortality. RESULTS: Of the 2,902 eligible patients who had acute symptomatic PE, 223 (7.7%; 95% confidence interval [CI], 6.7%-8.7%) were managed by the PERT team. Two hundred and seven patients who were treated by the PERT were matched with 207 patients who were not. Matched pairs did not show a statistically significant lower all-cause (odds ratio [OR], 1.09; 95% CI, 0.63-1.89) or PE-related death (OR, 1.30; 95% CI, 0.47-3.62) for PERT management compared with no PERT management through 30 days after diagnosis of PE. CONCLUSIONS: Our results suggest that multidisciplinary care of patients with acute symptomatic PE by a PERT team is not associated with a significant reduction in short-term all-cause or PE-related mortality.

Considerations for the development of guidance on dose level selection for developmental and reproductive toxicity studies.

In 2022, the European Chemicals Agency issued advice on the selection of high dose levels for developmental and reproductive toxicity (DART) studies indicating that the highest dose tested should aim to induce clear evidence of reproductive toxicity without excessive toxicity and severe suffering in parental animals. In addition, a recent publication advocated that a 10% decrease in body weight gain should be replaced with a 10% decrease in bodyweight as a criterion for dose adequacy. Experts from the European Centre for Ecotoxicology and Toxicology of Chemicals evaluated these recent developments and their potential impact on study outcomes and interpretation and identified that the advice was not aligned with OECD test guidelines or with humane endpoints guidance. Furthermore, data analysis from DART studies indicated that a 10% decrease in maternal body weight during gestation equates to a 25% decrease in body weight gain, which differs from the consensus of experts at a 2010 ILSI/HESI workshop. Dose selection should be based on a biological approach that considers a range of other factors. Excessive dose levels that cause frank toxicity and overwhelm homeostasis should be avoided as they can give rise to effects that are not relevant to human health assessments.

APPS-S: A Tool for Measuring the Attitudes Toward Prostitution and Women in Prostitution in the Spanish Population.

This study was designed with the purpose of testing the psychometric properties of the Spanish version of the Attitudes toward Prostitution and Prostitutes Scale through three studies with different samples. The first one explores the test's dimensional structure or constructs validity through confirmatory factor analysis, as well as internal consistency and test-retest reliability. The second one focuses on discriminant and criteria validity. Finally, the third one examines the scale's convergent validity and its sensitivity to detecting changes. The results support two subscales with an optimal index of internal consistency, structural stability over time, and discriminative power between groups of participants. It is, therefore, an adequate tool for adults as well as young people and teenagers, and for detecting changes in the context of intervention or awareness workshops.

An explainable machine learning approach for hospital emergency department visits forecasting using continuous training and multi-model regression.

BACKGROUND AND OBJECTIVE: In the last years, the Emergency Department (ED) has become an important source of admissions for hospitals. Since late 90s, the number of ED visits has been steadily increasing, and since Covid19 pandemic this trend has been much stronger. Accurate prediction of ED visits, even for moderate forecasting time-horizons, can definitively improve operational efficiency, quality of care, and patient outcomes in hospitals. METHODS: In this paper we propose two different interpretable approaches, based on Machine Learning algorithms, to accurately forecast hospital emergency visits. The proposed approaches involve a first step of data segmentation based on two different criteria, depending on the approach considered: first, a threshold-based strategy is adopted, where data is divided depending on the value of specific predictor variables. In a second approach, a cluster-based ensemble learning is proposed, in such a way that a clustering algorithm is applied to the training dataset, and ML models are then trained for each cluster. RESULTS: The two proposed methodologies have been evaluated in real data from two hospital ED visits datasets in Spain. We have shown that the proposed approaches are able to obtain accurate ED visits forecasting, in short-term and also long-term prediction time-horizons up to one week, improving the efficiency of alternative prediction methods for this problem. CONCLUSIONS: The proposed forecasting approaches have a strong emphasis on providing explainability to the problem. An analysis on which variables govern the problem and are pivotal for obtaining accurate predictions is finally carried out and included in the discussion of the paper.

Long anterior zonule trait, lessons learned about an uncommon form of secondary angle closure: a case report.

A 62-year-old black woman with uncontrolled chronic narrow-angle glaucoma on 3-drug therapy underwent phaco-non-perforating deep sclerectomy of her left eye. During surgery it was revealed that she had long zonule trait. She later required goniopuncture and conjuntival needling, presenting an iris herniation in the goniopuncture that could be reduced conservatively. Long anterior zonule trait should be suspected in those patients presenting with a combination of narrow angle and pigment dispersion syndrome. The management of ocular hypertension and glaucoma associated to this trait is not protocolized. This communication discusses on the best action in this rare form of glaucoma.

Drug Survival in Cyclosporine Treatment for Moderate to Severe Atopic Dermatitis: Analysis of the Spanish Atopic Dermatitis Registry (BIOBADATOP). / Supervivencia de la ciclosporina en el tratamiento de la dermatitis atópica moderada-grave: Registro Español de Dermatitis Atópica (BIOBADATOP).

BACKGROUND: The past 5 years have seen a proliferation of new treatments for atopic dermatitis (AD). We analyzed recent drug survival data for cyclosporine in this setting. Because the Spanish National Healthcare system requires patients with AD to be treated with cyclosporine before they can be prescribed other systemic treatments, drug survival for cyclosporine may be shorter than in other diseases. MATERIAL AND METHOD: Multicenter, observational, prospective cohort study using data from the Spanish Atopic Dermatitis Registry (BIOBADATOP). Data from the Spanish Registry of Systemic Treatments in Psoriasis (BIOBADADERM) were used to create a comparison cohort. RESULTS: We analyzed data for 130 patients with AD treated with cyclosporine (median drug survival, 1 year). Median cyclosporine survival in the psoriasis comparison group (150 patients) was 0.37 years. Drug survival was significantly longer in AD than in psoriasis (P<.001). CONCLUSION: Drug survival of cyclosporine in the BIOBADATOP registry is similar to that described in other series of patients with AD and longer than that observed in the BIOBADADERM psoriasis registry.