Epigenetic control over the cell-intrinsic immune response antagonizes self-renewal in acute myeloid leukemia.

ABSTRACT: Epigenetic modulation of the cell-intrinsic immune response holds promise as a therapeutic approach for leukemia. However, current strategies designed for transcriptional activation of endogenous transposons and subsequent interferon type-I (IFN-I) response, show limited clinical efficacy. Histone lysine methylation is an epigenetic signature in IFN-I response associated with suppression of IFN-I and IFN-stimulated genes, suggesting histone demethylation as key mechanism of reactivation. In this study, we unveil the histone demethylase PHF8 as a direct initiator and regulator of cell-intrinsic immune response in acute myeloid leukemia (AML). Site-specific phosphorylation of PHF8 orchestrates epigenetic changes that upregulate cytosolic RNA sensors, particularly the TRIM25-RIG-I-IFIT5 axis, thereby triggering the cellular IFN-I response-differentiation-apoptosis network. This signaling cascade largely counteracts differentiation block and growth of human AML cells across various disease subtypes in vitro and in vivo. Through proteome analysis of over 200 primary AML bone marrow samples, we identify a distinct PHF8/IFN-I signature in half of the patient population, without significant associations with known clinically or genetically defined AML subgroups. This profile was absent in healthy CD34+ hematopoietic progenitor cells, suggesting therapeutic applicability in a large fraction of patients with AML. Pharmacological support of PHF8 phosphorylation significantly impairs the growth in samples from patients with primary AML. These findings provide novel opportunities for harnessing the cell-intrinsic immune response in the development of immunotherapeutic strategies against AML.

Isovaleric Acidemia: A Case Report.

Isovaleric acidemia is an autosomal recessive disease of leucine metabolism. The clinical presentation is variable and three phenotypes are described, asymptomatic, acute neonatal, and chronic intermittent. Infections are the most important trigger for catabolic crises. Diagnosis is based on the detection of isovalerylglycine CoA in urine and elevated levels of isovaleryl (C5) carnitine in blood. Long-term treatment consists of prevention of catabolic state, dietary restriction, and supplementation with L-carnitine and/or L-glycine. We present the case of a three-year-old female patient with multiple episodes of decompensation since the age of two years. The episode in which she was diagnosed had encephalopathy, with no neurological sequelae. Currently, the patient continues with dietary restrictions and supplementation with good nutritional and growth results for her age.

A multimodal strategy to improve health care for pediatric patients with cancer and fever in Peru.

Objective: The DoTT (Decreasing Time to Therapy) project aimed to minimize the interval between fever onset and medical interventions for children with febrile neutropenia. The objective of this study was to determine the effect of implementing the DoTT project on the hospital time to antibiotic (TTA) and patient time to arrival (PTA) at the hospital in children with febrile neutropenia admitted to the emergency department. Methods: The DoTT project was implemented at a Peruvian hospital and followed the World Health Organization (WHO) multimodal improvement strategy model. Components included creating a healthcare delivery bundle and antibiotic selection pathways, training users of the bundle and pathways, monitoring patient outcomes and obtaining user feedback, encouraging use of the new system, and promoting the integration of DoTT into the institutional culture. Emergency room providers were trained in the care delivery for children with cancer and fever and taught to use the bundle and pathways. DoTT was promoted via pamphlets and posters, with a view to institutionalizing the concept and disseminating it to other hospital services. Results: Admission data for 129 eligible patients in our registry were analyzed. The TTA and PTA were compared before and after the DoTT intervention. The median TTA was 146 minutes (interquartile range [IQR] 97-265 minutes) before the intervention in 99 patients, and 69 minutes (IQR 50-120 minutes) afterwards in 30 patients (p < 0.01). The median PTA was reduced from 1 483 minutes at baseline to 660 minutes after the intervention (p < 0.01). Conclusions: Applying the WHO multimodal improvement strategy model to the care of children with febrile neutropenia arriving at the hospital had a positive impact on the PTA and TTA, thus potentially increasing the survival of these patients.

High expression of transcription factor POU2F1 confers improved survival on smokers with lung adenocarcinoma: a retrospective study of two cohorts.

Background: Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related mortality worldwide and its most important risk factor is tobacco smoking. While smoking is associated with inferior outcome in NSCLC patients, smoking also correlates with a higher tumor mutational burden. In contrast to adenocarcinomas (ADC) of non-smokers, that frequently harbor targetable gain-of-function mutations, NSCLC smokers largely present with non-targetable loss-of-function mutations of genes associated with DNA-damage repair. The transcription factor Pit-1, Oct1/2, Unc-86 (POU) domain class 2 transcription factor 1 (POU2F1) is a widely expressed bipotential stabilizer of repressed and inducible transcriptional states and frequently deregulated in cancer. Methods: Via immunohistochemistry, we evaluated POU2F1 protein expression on a tissue micro array of 217 operable stage I-III NSCLC patients. Findings were reproduced in a gene expression database of 1144 NSCLC patients, filtered for POU2F1 mRNA expression. After retroviral overexpression of POU2F1 in A549 cells, we evaluated for clonogenic growth and proliferation. Additionally, CRISPR-Cas9 mediated POU2F1 knockdown in A549 cells was likewise analyzed. Results: High protein expression of POU2F1 in 217 NSCLC patients resulted in improved outcome of smokers with ADC [hazard ratio (HR) 0.30 (0.09-0.99), P=0.035]. Moreover, gene expression analysis confirmed favorable outcome of high POU2F1 mRNA expression in smokers with ADC [HR 0.41 (0.24-0.69), P<0.001]. Other than that, retrovirally induced overexpression of POU2F1 in A549 cells significantly reduced both, clonogenic growth as well as proliferation of NSCLC cells, whereas CRISPR-Cas9 mediated knockdown of the protein did not have any impact. Conclusions: Our data suggest that high expression of POU2F1 mediates a less aggressive cancer phenotype in smokers with ADC NSCLC. Pharmacological induction of genes and signaling pathways controlled by POU2F1 may provide novel avenues for future targeted NSCLC therapies in smokers.

Time to Awakening and Self-Fulfilling Prophecies After Cardiac Arrest.

OBJECTIVES: Withdrawal of life-sustaining therapies for perceived poor neurologic prognosis (WLST-N) is common after resuscitation from cardiac arrest and may bias outcome estimates from models trained using observational data. We compared several approaches to outcome prediction with the goal of identifying strategies to quantify and reduce this bias. DESIGN: Retrospective observational cohort study. SETTING: Two academic medical centers ("UPMC" and "University of Alabama Birmingham" [UAB]). PATIENTS: Comatose adults resuscitated from cardiac arrest. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: As potential predictors, we considered clinical, laboratory, imaging, and quantitative electroencephalography data available early after hospital arrival. We followed patients until death, discharge, or awakening from coma. We used penalized Cox regression with a least absolute shrinkage and selection operator penalty and five-fold cross-validation to predict time to awakening in UPMC patients and then externally validated the model in UAB patients. This model censored patients after WLST-N, considering subsequent potential for awakening to be unknown. Next, we developed a penalized logistic model predicting awakening, which treated failure to awaken after WLST-N as a true observed outcome, and a separate logistic model predicting WLST-N. We scaled and centered individual patients' Cox and logistic predictions for awakening to allow direct comparison and then explored the difference in predictions across probabilities of WLST-N. Overall, 1,254 patients were included, and 29% awakened. Cox models performed well (mean area under the curve was 0.93 in the UPMC test sets and 0.83 in external validation). Logistic predictions of awakening were systematically more pessimistic than Cox-based predictions for patients at higher risk of WLST-N, suggesting potential for self-fulfilling prophecies to arise when failure to awaken after WLST-N is considered as the ground truth outcome. CONCLUSIONS: Compared with traditional binary outcome prediction, censoring outcomes after WLST-N may reduce potential for bias and self-fulfilling prophecies.

Self-fulfilling prophecies and machine learning in resuscitation science.

INTRODUCTION: Growth of machine learning (ML) in healthcare has increased potential for observational data to guide clinical practice systematically. This can create self-fulfilling prophecies (SFPs), which arise when prediction of an outcome increases the chance that the outcome occurs. METHODS: We performed a scoping review, searching PubMed and ArXiv using terms related to machine learning, algorithmic fairness and bias. We reviewed results and selected manuscripts for inclusion based on expert opinion of well-designed or key studies and review articles. We summarized these articles to explore how use of ML can create, perpetuate or compound SFPs, and offer recommendations to mitigate these risks. RESULTS: We identify-four key mechanisms through which SFPs may be reproduced or compounded by ML. First, imperfect human beliefs and behavior may be encoded as SFPs when treatment decisions are not accounted for. Since patient outcomes are influenced by a myriad of clinical actions, many of which are not collected in data, this is common. Second, human-machine interaction may compound SFPs through a cycle of mutual reinforcement. Third, ML may introduce new SFPs stemming from incorrect predictions. Finally, historically correct clinical choices may become SFPs in the face of medical progress. CONCLUSION: There is a need for broad recognition of SFPs as ML is increasingly applied in resuscitation science and across medicine. Acknowledging this challenge is crucial to inform research and practice that can transform ML from a tool that risks obfuscating and compounding SFPs into one that sheds light on and mitigates SFPs.

A multimodal strategy to improve health care for pediatric patients with cancer and fever in Peru / Una estrategia multimodal para mejorar la atención médica de pacientes pediátricos con cáncer y fiebre en Perú / Uma estratégia multimodal para melhorar a prestação de serviços de saúde para pacientes pediátricos com câncer e febre no Peru

ABSTRACT Objective. The DoTT (Decreasing Time to Therapy) project aimed to minimize the interval between fever onset and medical interventions for children with febrile neutropenia. The objective of this study was to determine the effect of implementing the DoTT project on the hospital time to antibiotic (TTA) and patient time to arrival (PTA) at the hospital in children with febrile neutropenia admitted to the emergency department. Methods. The DoTT project was implemented at a Peruvian hospital and followed the World Health Organization (WHO) multimodal improvement strategy model. Components included creating a healthcare delivery bundle and antibiotic selection pathways, training users of the bundle and pathways, monitoring patient outcomes and obtaining user feedback, encouraging use of the new system, and promoting the integration of DoTT into the institutional culture. Emergency room providers were trained in the care delivery for children with cancer and fever and taught to use the bundle and pathways. DoTT was promoted via pamphlets and posters, with a view to institutionalizing the concept and disseminating it to other hospital services. Results. Admission data for 129 eligible patients in our registry were analyzed. The TTA and PTA were compared before and after the DoTT intervention. The median TTA was 146 minutes (interquartile range [IQR] 97-265 minutes) before the intervention in 99 patients, and 69 minutes (IQR 50-120 minutes) afterwards in 30 patients (p < 0.01). The median PTA was reduced from 1 483 minutes at baseline to 660 minutes after the intervention (p < 0.01). Conclusions. Applying the WHO multimodal improvement strategy model to the care of children with febrile neutropenia arriving at the hospital had a positive impact on the PTA and TTA, thus potentially increasing the survival of these patients.

RESUMEN Objetivo. El proyecto DoTT (Disminuyendo el tiempo a la terapia, sigla en inglés) busca minimizar el intervalo entre el inicio de la fiebre y las intervenciones médicas en la población infantil con neutropenia febril. El objetivo de este estudio fue determinar el efecto de la implementación del proyecto DoTT sobre el tiempo transcurrido desde el inicio de la fiebre hasta la llegada del paciente (TLP) al hospital y el tiempo transcurrido en el hospital hasta la administración del antibiótico (TAA) en niños con neutropenia febril ingresados en el servicio de urgencias. Métodos. El proyecto DoTT se puso en marcha en un hospital peruano, según el modelo de estrategia multimodal de mejora de la Organización Mundial de la Salud (OMS). Entre sus componentes se encontraban crear un conjunto de servicios de atención de salud y de algoritmos para la selección de antibióticos; capacitar a los usuarios en la utilización del conjunto de servicios y de los algoritmos; realizar un seguimiento de los resultados de los pacientes y recabar la opinión de los usuarios; fomentar el uso del nuevo sistema; y promover la integración del proyecto en la cultura institucional. Se capacitó al personal de la sala de urgencias en la atención de pacientes pediátricos con cáncer y fiebre, y en el uso del conjunto de servicios y de los algoritmos. Se informó sobre el proyecto DoTT mediante folletos y carteles, con vistas a institucionalizar el concepto y difundirlo a otros servicios hospitalarios. Resultados. Se analizaron los datos de ingreso de 129 pacientes de nuestro registro que cumplían con los requisitos. Se compararon el TAA y el TLP al hospital antes y después de la intervención con las pautas del proyecto DoTT. La mediana del TAA fue de 146 minutos (intervalo intercuartílico [II]: 97-265 minutos) en 99 pacientes antes de la intervención y de 69 minutos (II: 50-120 minutos) en 30 pacientes después de ella (p <0,01). La mediana del TLP disminuyó de 1 483 minutos en el momento de la evaluación inicial a 660 minutos después de la intervención (p <0,01). Conclusiones. La aplicación del modelo de estrategia multimodal de mejora de la OMS a la atención de la población infantil con neutropenia febril que acude al hospital tuvo un efecto positivo sobre el TLP y el TAA, lo que podría aumentar la supervivencia de estos pacientes.

RESUMO Objetivo. O projeto DoTT (Redução do Tempo para o Tratamento, na sigla em inglês) tem como objetivo reduzir ao máximo o intervalo entre o início da febre e as intervenções médicas em crianças com neutropenia febril. O objetivo deste estudo foi determinar o efeito da implementação do projeto DoTT no tempo desde o início da febre até a chegada do paciente (TCP) ao hospital e no tempo no hospital até a administração de antibióticos (TAA) em crianças com neutropenia febril admitidas no departamento de emergência. Métodos. O projeto DoTT foi implementado em um hospital do Peru e seguiu o modelo de estratégia de melhoria multimodal da Organização Mundial da Saúde (OMS). Os componentes incluíram a criação de um pacote de prestação de serviços de saúde e de protocolos de seleção de antibióticos, o treinamento de usuários no pacote e nos protocolos de seleção, o monitoramento da evolução dos pacientes e obtenção de feedback dos usuários, o incentivo ao uso do novo sistema e a promoção da integração do DoTT à cultura institucional. Os profissionais do pronto-socorro foram capacitados na prestação de cuidados a crianças com câncer e febre e no uso do pacote e dos protocolos de seleção. O DoTT foi divulgado por meio de panfletos e pôsteres, com o objetivo de institucionalizar o conceito e disseminá-lo para outros serviços hospitalares. Resultados. Foram analisados os dados de internação de 129 pacientes elegíveis em nosso registro. O TAA e o TCP foram comparados antes e depois da intervenção DoTT. O TAA mediano era de 146 minutos (intervalo interquartil: 97-265 minutos) antes da intervenção em 99 pacientes e de 69 minutos (intervalo interquartil: 50-120 minutos) depois da intervenção em 30 pacientes (p < 0,01). O TCP mediano diminuiu de 1483 minutos na linha de base para 660 minutos após a intervenção (p < 0,01). Conclusão. A aplicação do modelo de estratégia multimodal de melhoria da OMS ao atendimento de crianças com neutropenia febril que chegam ao hospital teve um impacto positivo no TCP e no TAA, potencialmente aumentando a sobrevida desses pacientes.

Paciente adulto con alteraciones cardiacas secundarias a enfermedad de Fabry / An adult patient with heart abnormalities secondary to Fabry disease

Resumen Introducción: La enfermedad de Fabry es una entidad crónica, progresiva, poco frecuente, de origen genético y patrón de herencia recesivo ligado al cromosoma X. Se caracteriza por déficit enzimático de alfa-galactosidasa causado por mutaciones en el gen GLA, lo que produce almacenamiento anormal de esfingolípidos celulares y tisulares Caso clínico: Se describe el caso de un paciente de 53 años, con antecedente familiar y compromiso cardíaco predominante, dado por hipertrofia ventricular izquierda, arritmias auriculares e insuficiencia cardiaca congestiva secundaria, quien, adicionalmente, tiene manifestaciones multisistémicas que han evolucionado desde la infancia. Entre los pilares de tratamiento requirió implantación definitiva de marcapasos y terapia de reemplazo enzimático. Conclusiones: La enfermedad de Fabry es una entidad de compromiso sistémico y progresivo, de baja prevalencia, cuya importancia se debe reflejar en el entrenamiento del personal de salud para el adecuado diagnóstico, con miras a mejorar la calidad de vida de los pacientes.

Abstract Introduction: Fabry’s disease is a chronic, progressive and a multisystemic disease of genetic origin, with a recessive pattern of inheritance tied to the X chromosome, characterized by the lisosomal deposit of globotriaosylceramide as a consequence of a deficiency in the activity of the alpha-galactosidase A enzyme. Clinical case: We present a clinical case of a 53-year old male patient carrying this disease with family history of Fabry’s disease, who suffers cardiac compromise as the main clinical manifestation. He is a patient who required the implantation of a permanent pacemaker and enzyme replacement therapy. Conclusions: Fabry´s disease is a systemic and progressive disease, low fre-quency, and not well known by the health personnel, which implies a late diagnosis, being the cardiac compromise the second in frequency after renal compromise, which can lead to the patient to a hypertrophic cardiomyopathy and a rhythm and cardiac conduction disorder.

Does Domestication Affect Structural and Functional Leaf Epidermal Traits? A Comparison between Wild and Cultivated Mexican Chili Peppers (Capsicum annuum).

During domestication, lineages diverge phenotypically and genetically from wild relatives, particularly in preferred traits. In addition to evolutionary divergence in selected traits, other fitness-related traits that are unselected may change in concert. For instance, the selection of chili pepper fruits was not intended to change the structure and function of the leaf epidermis. Leaf stomata and trichome densities play a prominent role in regulating stomatal conductance and resistance to herbivores. Here, we assessed whether domestication affected leaf epidermis structure and function in Capsicum annuum. To do this, we compared leaf stomata and trichome densities in six cultivated varieties of Mexican Capsicum annuum and their wild relative. We measured stomatal conductance and resistance to herbivores. Resistance to (defense against) herbivores was measured as variation in the herbivory rate and larvae mortality of Spodoptera frugiperda fed with leaves of wild and cultivated plants. As expected, the different varieties displayed low divergence in stomatal density and conductance. Leaf trichome density was higher in the wild relative, but variation was not correlated with the herbivory rate. In contrast, a higher mortality rate of S. frugiperda larvae was recorded when fed with the wild relative and two varieties than larvae fed with four other varieties. Overall, although domestication did not aim at resistance to herbivores, this evolutionary process produced concerted changes in defensive traits.

[Implementation of a protocol for neuropsychiatric disease surveillance in a general hospital]. / Implementación de un sistema protocolizado de pesquisa temprana de patología psiquiátrica en un hospital general. Protocolo de Vigilancia Neuropsiquiátrica (VNP): avanzando hacia un modelo de psiquiatría de enlace proactivo.

BACKGROUND: The COVID-19 pandemic increased the incidence of neuropsychiatric diseases. Proactive models of consultation-liaison psychiatry (CLP-p) could play a key role in the prevention and management of these diseases in a general hospital. AIM: To develop a protocol for implementing screening tools for neuropsychiatric symptoms in routine clinical practice. MATERIAL AND METHODS: Elements of the Plan-Do-Study-Act (PDSA) model were used to modify the Neuropsychiatric Surveillance protocol implemented at a clinical hospital during the COVID-19 pandemic by members of the hospital's CLP team. RESULTS: A flowchart for active follow-up of neuropsychiatric symptoms during hospitalization is presented, with sequential management and referral flows, accompanied by suggestions for pre-discharge evaluation to define continuity of care actions. The COSMOS tool is also presented, designed for the detection of risk factors and actions for the prevention of neuropsychiatric diseases in general hospitals. CONCLUSIONS: The neuropsychiatric surveillance protocol facilitates early and timely interventions and establishes criteria for the continuity of post-discharge care. These changes could improve the quality of care in general hospitals and reduce the gap between mental and physical health.

Human activities disturb haul out and nursing behavior of Pacific harbor seals at Punta Banda Estuary, Mexico.

Humans frequently interact with Pacific harbor seals (Phoca vitulina richardii) at Punta Banda Estuary, Baja California, Mexico, due to the high incidence of recreational activities people undertake there. The immediate effect of these interactions is that seals flush to the water, reducing their time on land and, probably, increasing their energy expenditure. On-land observations were used to study the impact of different sources of disturbance on seal behavior and evaluate their effect on the amount of time dedicated to nursing over three pupping seasons, (2015-2017), with 0.58-0.81 disturbance events/hour recorded over the entire sampling period. Terrestrial vehicles were the source with the highest disturbance rate (number of disturbance events/h), followed closely by pedestrians. However, the proportion of seals affected was highest when pedestrians were the disturbance source. Recovery events (seals hauling out after flushing) occurred after 34% of disturbance events, after less than half of which the same number of hauled-out seals as there were prior to the disturbance were observed. Recovery time varied among the years studied, of which 2017 saw the longest recovery time. In addition, pedestrians were the disturbance source with the longest recovery time. Given that resting on land is essential for pup survival, which depends on both the establishment of the mother-pup bond from birth and its maintenance throughout nursing, flushing behavior may have significant implications for the entire colony during the nursing season. We recorded a decrease in nursing duration, which did not return to the same level even after recovery and the resumption of nursing. Terrestrial vehicles were found to be the disturbance source that shortened nursing events most significantly.

Implementación de un sistema protocolizado de pesquisa temprana de patología psiquiátrica en un hospital general. Protocolo de Vigilancia Neuropsiquiátrica (VNP): avanzando hacia un modelo de psiquiatría de enlace proactivo / Implementation of a protocol for neuropsychiatric disease surveillance in a general hospital

BACKGROUND: The COVID-19 pandemic increased the incidence of neuropsychiatric diseases. Proactive models of consultation-liaison psychiatry (CLP-p) could play a key role in the prevention and management of these diseases in a general hospital. AIM: To develop a protocol for implementing screening tools for neuropsychiatric symptoms in routine clinical practice. MATERIAL AND METHODS: Elements of the Plan-Do-Study-Act (PDSA) model were used to modify the Neuropsychiatric Surveillance protocol implemented at a clinical hospital during the COVID-19 pandemic by members of the hospital's CLP team. RESULTS: A flowchart for active follow-up of neuropsychiatric symptoms during hospitalization is presented, with sequential management and referral flows, accompanied by suggestions for pre-discharge evaluation to define continuity of care actions. The COSMOS tool is also presented, designed for the detection of risk factors and actions for the prevention of neuropsychiatric diseases in general hospitals. CONCLUSIONS: The neuropsychiatric surveillance protocol facilitates early and timely interventions and establishes criteria for the continuity of post-discharge care. These changes could improve the quality of care in general hospitals and reduce the gap between mental and physical health.

Environmental conditions drive zooplankton community structure in the epipelagic oceanic water of the southern Gulf of Mexico: A molecular approach.

Zooplankton plays a pivotal role in sustaining the majority of marine ecosystems. The distribution patterns and diversity of zooplankton provide key information for understanding the functioning of these ecosystems. Nevertheless, due to the numerous cryptic and sibling species and the lack of diagnostic characteristics for early developmental stages, the identification of the global-to-local patterns of zooplankton biodiversity and biogeography remains challenging in different research fields. The spatial and temporal changes in the zooplankton community in the open waters of the southern Gulf of Mexico were assessed using metabarcoding analysis of the V9 region of 18S rRNA and mitochondrial cytochrome oxidase c subunit I (COI). Additionally, a multiscale analysis was implemented to evaluate which environmental predictors may explain the variability in the structure of the zooplankton community. Our findings suggest that the synergistic effects of dissolved oxygen concentration, temperature, and longitude (intended as a proxy for still unidentified predictors) may explain both spatial and temporal zooplankton variability even with low contribution. Furthermore, the zooplankton distribution probably reflects the coexistence of three heterogeneous ecoregions and a bio-physical partitioning of the studied area. Finally, some taxa were either exclusive or predominant with either 18S or COI markers. This may suggest that comprehensive assessments of the zooplankton community may be more accurately met by the use of multilocus approaches.

Imputation Strategies Under Clinical Presence: Impact on Algorithmic Fairness.

Biases have marked medical history, leading to unequal care affecting marginalised groups. The patterns of missingness in observational data often reflect these group discrepancies, but the algorithmic fairness implications of group-specific missingness are not well understood. Despite its potential impact, imputation is too often an overlooked preprocessing step. When explicitly considered, attention is placed on overall performance, ignoring how this preprocessing can reinforce groupspecific inequities. Our work questions this choice by studying how imputation affects downstream algorithmic fairness. First, we provide a structured view of the relationship between clinical presence mechanisms and groupspecific missingness patterns. Then, through simulations and real-world experiments, we demonstrate that the imputation choice influences marginalised group performance and that no imputation strategy consistently reduces disparities. Importantly, our results show that current practices may endanger health equity as similarly performing imputation strategies at the population level can affect marginalised groups differently. Finally, we propose recommendations for mitigating inequities that may stem from a neglected step of the machine learning pipeline.

Sex differences in post cardiac arrest discharge locations.

BACKGROUND: We explored sex-based differences in discharge location after resuscitation from cardiac arrest. METHODS: We performed a single-center retrospective cohort study including patients hospitalized after resuscitation from cardiac arrest from January 2010 to May 2020. We identified patients from a prospective registry, from which we extracted standard demographic and clinical variables. We explored favorable discharge location, defined as discharge to home or acute rehabilitation for survivors to hospital discharge. We tested the association of sex with the residuals of a multivariable logistic regression built using bidirectional selection to control for clinically relevant covariates. RESULTS: We included 2,278 patients. Mean age was 59 (SD 16), 40% were women, and 77% were admitted after out-of-hospital cardiac arrest. A total of 970 patients (43%) survived to discharge; of those, 607 (63% of survivors) had a favorable discharge location. Female sex showed a weak independent association with unfavorable discharge location (adjusted OR 0.94 (95%CI 0.89-0.99)). CONCLUSIONS: Our results suggest a possible sex-based disparity in discharge location after cardiac arrest.

Calcitonin receptor-like (CALCRL) is a marker of stemness and an independent predictor of outcome in pediatric AML.

We have recently identified the G protein-coupled neuropeptide receptor calcitonin receptor-like (CALCRL) as an independent prognostic biomarker and a therapeutic target in more than 1500 adult patients with acute myeloid leukemia (AML). Here, we confirmed CALCRL expression as a prognostic factor in a cohort of 284 pediatric patients with AML. High CALCRL expression was independently associated with event-free survival (hazard ratio [HR], 1.87; 95% confidence interval [CI], 1.36-2.57; P = .0001), overall survival (HR, 1.55; 95% CI, 1.06-2.27; P = .025), and cumulative incidence of relapse (HR, 2.10; 95% CI, 1.49-1.96; P < .0001) when adjusting for age, white blood cell count, and genetic risk. Despite its association with leukemia stem cell signatures, CALCRL expression remained associated with all end points when compared with the 17-gene leukemic stem cell score. The strong association of CALCRL expression with the risk of relapse also in the pediatric population supports its role as novel age-independent master regulator of relapse-initiating, drug-tolerant AML cells in humans.

C/EBPß is a MYB- and p300-cooperating pro-leukemogenic factor and promising drug target in acute myeloid leukemia.

Transcription factor MYB has recently emerged as a promising drug target for the treatment of acute myeloid leukemia (AML). Here, we have characterized a group of natural sesquiterpene lactones (STLs), previously shown to suppress MYB activity, for their potential to decrease AML cell proliferation. Unlike what was initially thought, these compounds inhibit MYB indirectly via its cooperation partner C/EBPß. C/EBPß-inhibitory STLs affect the expression of a large number of MYB-regulated genes, suggesting that the cooperation of MYB and C/EBPß broadly shapes the transcriptional program of AML cells. We show that expression of GFI1, a direct MYB target gene, is controlled cooperatively by MYB, C/EBPß, and co-activator p300, and is down-regulated by C/EBPß-inhibitory STLs, exemplifying that they target the activity of composite MYB-C/EBPß-p300 transcriptional modules. Ectopic expression of GFI1, a zinc-finger protein that is required for the maintenance of hematopoietic stem and progenitor cells, partially abrogated STL-induced myelomonocytic differentiation, implicating GFI1 as a relevant target of C/EBPß-inhibitory STLs. Overall, our data identify C/EBPß as a pro-leukemogenic factor in AML and suggest that targeting of C/EBPß may have therapeutic potential against AML.

Factors associated with long-term retention of treatment with golimumab in rheumatoid arthritis, axial spondyloarthritis, and psoriatic arthritis: an analysis of the Spanish BIOBADASER registry.

BACKGROUND: Retention of biological treatment provides a marker of drug effectiveness and patient satisfaction. Retention of golimumab was high in clinical trial extensions and real-world studies up to 5 years in patients with immune-mediated rheumatic diseases. OBJECTIVE: To assess the probability of real-world long-term retention of treatment with golimumab up to 7 years after treatment initiation. METHODS: This retrospective noninterventional study involved analysis of the Spanish biological drugs registry, BIOBADASER. Adults who had ever received golimumab for rheumatoid arthritis (RA), axial spondyloarthritis (SpA), or psoriatic arthritis (PsA), and had initiated it > 6 months before the analysis date, were included. RESULTS: Among 685 patients (28.5% RA, 42.9% SpA, 28.6% PsA), the overall probability of retention of golimumab treatment since initiation was 71.7% (95% confidence interval 68.1-74.9) at year 1, 60.5% (56.5-64.2%) at year 2, 55.6% (51.5-59.5%) at year 3, 50.6% (46.2-54.8%) at year 4, 45.1% (40.1-50.0%) at year 5, 44.2% (39.0-49.3) at year 6, and 39.5% (32.8-46.2) at year 7. Retention was greater in patients with axial SpA or PsA versus RA (p < 0.001) and when golimumab was used as first-line treatment versus third or later lines (p < 0.001). Factors associated with greater golimumab retention in Cox regression included use as first-line biological therapy, having axial SpA or PsA rather than RA, and concomitant methotrexate therapy. Steroids were associated with lower retention. CONCLUSION: In this real-world study of RA, axial SpA, and PsA patients, the retention rate of golimumab was 39.5% at year 7. Key Points • Retention of biological treatment provides a marker of drug effectiveness and patient satisfaction. • This real-world study of 685 patients with rheumatoid arthritis (RA), axial spondyloarthritis (SpA), or psoriatic arthritis (PsA) showed that golimumab treatment had a retention rate up to 39.5% at year 7. • Greater golimumab retention was associated with use as first-line biological therapy, having axial SpA or PsA rather than RA, and concomitant methotrexate therapy.

Effectiveness and persistence of golimumab as a second biological drug in patients with spondyloarthritis: A retrospective study.

ABSTRACT: This observational, longitudinal retrospective, noncomparative study was designed to assess the persistence and effectiveness of golimumab as a second anti-tumor necrosis factor (TNF) drug in patients with spondyloarthritis requiring discontinuation from a first anti-TNF drug.Data were collected retrospectively for all patients with axial spondyloarthritis or psoriatic arthritis from 20 rheumatology clinics in Spain who started golimumab as a second anti-TNF drug between January 2013 and December 2015. Golimumab persistence was assessed with Kaplan-Meier survival analysis, and associated factors were assessed with Cox regression analysis.210 patients started golimumab as a second anti-TNF drug: 131 with axial spondyloarthritis and 79 with psoriatic arthritis. In axial spondyloarthritis patients, the mean (standard deviation) Bath Ankylosing Spondylitis Disease Activity Index score at baseline was 5.5 (2.1), decreasing to 3.9 (2.0) at month 3 and 3.5 (2.0) at year 1, and remaining stable thereafter. In psoriatic arthritis patients, mean (standard deviation) baseline Disease Activity Score was 4.0 (1.3), reducing to 2.5 (1.2) at month 3 and to 2.2 (1.3) at year 1. Corresponding improvements were recorded from baseline in C-reactive protein levels and erythrocyte sedimentation rates. The probability of persistence of treatment with golimumab was 80% at year 1, 70% at year 2 and 65% at years 3 and year 4, and was similar in those who had stopped the first anti-TNF due to loss of efficacy or other reasons. Cox regression analysis showed that the probability of survival with golimumab was higher in patients with higher erythrocyte sedimentation rate, in patients with axial spondyloarthritis than with psoriatic arthritis, and in those who had discontinued adalimumab as first anti-TNF. Seventy-two patients (34.3%) discontinued golimumab during follow-up, 50 of them due to lack of efficacy.In patients with spondyloarthritis requiring discontinuation from a first anti-TNF drug, treatment with golimumab was effective and showed a high probability of persistence up to 4 years of treatment.

Trasplante facial generalidades / Facial trasplant generalities

Resumen El trasplante facial es un alotrasplante compuesto vascularizado que busca la reconstrucción de defectos masivos faciales permitiendo la reinserción social del receptor, generando un impacto positivo sobre su calidad de vida. El objetivo de este artículo fue realizar una revisión de la literatura sobre generalidades del trasplante facial, enfocándose en los cuidados pre, intra y postoperatorios concernientes a la temática. La búsqueda bibliográfica se realizó desde el 13 de septiembre del 2018 hasta el 31 de marzo del 2019 utilizando los términos MESH "Face Transplant" y "Face Transplantation". Aplicando los criterios de inclusión y exclusión se obtuvieron 43 artículos sobre los cuales se desarrolló la revisión. El trasplante facial es un procedimiento nuevo en el cual hay muchas áreas por explorar, sin embargo, es una alternativa prometedora a los métodos utilizados para la reconstrucción de lesiones faciales complejas, que se optimizará a medida que se extienda su uso. MÉD.UIS.2020;33(3): 29-36

Abstract The facial transplant is a vascularized compound allogeneic transplant that seeks the reconstruction of massive facial defects allowing the social reintegration of the recipient, generating a positive impact on their quality of life. The objective of this article was to review the literature on generalities of facial transplantation, focusing on the pre, intra and postoperative care regarding the subject. The bibliographic search was performed from September 13, 2018 to March 31, 2019 using the MESH terms "Face Transplant" and "Face Transplantation". Applying the inclusion and exclusion criteria, 43 articles were obtained on which the review was developed. Facial transplantation is a new procedure in which there are many areas to explore, however, it is a promising alternative to the methods used for the reconstruction of complex facial injuries, which will be optimized as its use expands. MÉD.UIS.2020;33(3): 29-36