Monitorización ambulatoria de la presión arterial en adultos y población pediátrica. Una revisión narrativa / Ambulatory blood pressure monitoring, adult and pediatric population. A narrative review

La hipertensión arterial (HTA) se ha convertido en un factor de riesgo central para el desarrollo de enfermedades cardiovasculares (CV), lo que subraya la importancia de su diagnóstico preciso. Numerosos estudios han establecido una estrecha relación entre los valores elevados de la presión arterial sistólica (PAS) y diastólica (PAD) y un incremento en el riesgo de padecer algún evento cardiovascular (ECV). Tradicionalmente, las mediciones de la presión arterial (PA) realizadas en entornos clínicos han sido el principal método para diagnosticar y evaluar la HTA. No obstante, en los últimos años, se ha reconocido que las mediciones de la PA obtenidas fuera del ambiente clínico, mediante la automedida de la presión arterial (AMPA) y la monitorización ambulatoria de la presión arterial (MAPA), ofrecen una perspectiva más realista de la vida cotidiana de los pacientes y, por lo tanto, brindan resultados más fiables. Dada la evolución de los dispositivos médicos, los criterios diagnósticos y la creciente relevancia de componentes de la MAPA en la predicción de ECV, se requiere una actualización integral que sea práctica para la clínica. Esta revisión tiene como objetivo proporcionar una actualización de la MAPA, enfocándose en su importancia en la evaluación de la HTA. Además, se analizarán los umbrales diagnósticos, los distintos fenotipos según el ciclo circadiano y las recomendaciones en diferentes poblaciones, asimismo, se ofrecerán sugerencias concretas para la implementación efectiva de la MAPA en la práctica clínica, lo que permitirá a los profesionales de la salud tomar decisiones fundamentadas y mejorar la atención de sus pacientes.(AU)

Hypertension has become a central risk factor for the development of cardiovascular disease, underscoring the importance of its accurate diagnosis. Numerous studies have established a close relationship between elevated systolic (SBP) and diastolic (DBP) blood pressure and an increased risk of cardiovascular event (CVE). Traditionally, blood pressure (BP) measurements performed in clinical settings have been the main method for diagnosing and assessing hypertension. However, in recent years, it has been recognized that BP measurements obtained outside the clinical setting, using self-monitoring blood pressure (SMBP) and ambulatory blood pressure monitoring (ABPM), offer a more realistic perspective of patients’ daily lives and therefore provide more reliable results. Given the evolution of medical devices, diagnostic criteria, and the increasing relevance of certain components of ABPM in the prediction of adverse cardiovascular outcomes, a comprehensive update that is practical for daily clinical practice is required. The main objective of this article is to provide an updated review of ABPM, focusing on its importance in the evaluation of hypertension and its impact on public health in Colombia. In addition, it will discuss the implications of changes in diagnostic thresholds and provide concrete recommendations for the effective implementation of ABPM in clinical practice, allowing health professionals to make informed decisions and improve the care of their patients.(AU)

Sleeve Gastrectomy Reduces Oxidative Stress and Reverses Mitochondrial Dysfunction Associated with Metabolic Syndrome.

INTRODUCTION: Previous studies have detected mitochondrial alterations in tissues of individuals with obesity and type 2 diabetes mellitus (T2DM). Metabolic surgery could be an effective treatment to improve mitochondrial morphology and reduce oxidative stress (OS). METHODS: An experimental study was carried out using 48 male Wistar rats, divided into 6 groups (n = 8): control (C), induced Metabolic Syndrome (MS); intervention with sleeve gastrectomy (SG), MS + SG with 6 weeks postoperatively (MS + SG6), MS + SG with 12 weeks postoperatively (MS + SG12), and MS + SG with 24 weeks postoperatively (MS + SG24). Biochemical markers indicative of MS (glycemia, cholesterol, and triglyceride levels) and oxidative stress markers (nitric oxide levels, Superoxide dismutase and Myeloperoxidase activity) were determined. To study mitochondrial morphology, tissue sections of the thoracic aorta, stomach, liver, heart, and kidney were observed by electron microscopy. RESULTS: MS group exhibited elevated glycemic values and dyslipidemia. SG and MS + SG groups showed improvements in glycemia and lipid profiles compared to MS. OS biomarkers indicated reduced oxidative stress in SG and MS + SG groups compared to MS. Electron microscopy revealed mitochondrial alterations in MS. SG group showed no changes compared to the control. MS + SG6 and MS + SG12 groups showed a recovery of mitochondrial morphology until reaching images similar to the control in MS + SG24. CONCLUSION: Metabolic surgery could improve mitochondrial function by restoring mitochondrial morphology and architecture and, consequently, reducing systemic oxidative stress and remitting associated metabolic alterations.

Eye movement function captured via an electronic tablet informs on cognition and disease severity in Parkinson's disease.

Studying the oculomotor system provides a unique window to assess brain health and function in various clinical populations. Although the use of detailed oculomotor parameters in clinical research has been limited due to the scalability of the required equipment, the development of novel tablet-based technologies has created opportunities for fast, easy, cost-effective, and reliable eye tracking. Oculomotor measures captured via a mobile tablet-based technology have previously been shown to reliably discriminate between Parkinson's Disease (PD) patients and healthy controls. Here we further investigate the use of oculomotor measures from tablet-based eye-tracking to inform on various cognitive abilities and disease severity in PD patients. When combined using partial least square regression, the extracted oculomotor parameters can explain up to 71% of the variance in cognitive test scores (e.g. Trail Making Test). Moreover, using a receiver operating characteristics (ROC) analysis we show that eye-tracking parameters can be used in a support vector classifier to discriminate between individuals with mild PD from those with moderate PD (based on UPDRS cut-off scores) with an accuracy of 90%. Taken together, our findings highlight the potential usefulness of mobile tablet-based technology to rapidly scale eye-tracking use and usefulness in both research and clinical settings by informing on disease stage and cognitive outcomes.

[Ambulatory blood pressure monitoring, adult and pediatric population. A narrative review]. / Monitorización ambulatoria de la presión arterial en adultos y población pediátrica. Una revisión narrativa.

Hypertension has become a central risk factor for the development of cardiovascular disease, underscoring the importance of its accurate diagnosis. Numerous studies have established a close relationship between elevated systolic (SBP) and diastolic (DBP) blood pressure and an increased risk of cardiovascular event (CVE). Traditionally, blood pressure (BP) measurements performed in clinical settings have been the main method for diagnosing and assessing hypertension. However, in recent years, it has been recognized that BP measurements obtained outside the clinical setting, using self-monitoring blood pressure (SMBP) and ambulatory blood pressure monitoring (ABPM), offer a more realistic perspective of patients' daily lives and therefore provide more reliable results. Given the evolution of medical devices, diagnostic criteria, and the increasing relevance of certain components of ABPM in the prediction of adverse cardiovascular outcomes, a comprehensive update that is practical for daily clinical practice is required. The main objective of this article is to provide an updated review of ABPM, focusing on its importance in the evaluation of hypertension and its impact on public health in Colombia. In addition, it will discuss the implications of changes in diagnostic thresholds and provide concrete recommendations for the effective implementation of ABPM in clinical practice, allowing health professionals to make informed decisions and improve the care of their patients.

Breast Tumor Metastasis and Its Microenvironment: It Takes Both Seed and Soil to Grow a Tumor and Target It for Treatment.

Metastasis remains a major challenge in treating breast cancer. Breast tumors metastasize to organ-specific locations such as the brain, lungs, and bone, but why some organs are favored over others remains unclear. Breast tumors also show heterogeneity, plasticity, and distinct microenvironments. This contributes to treatment failure and relapse. The interaction of breast cancer cells with their metastatic microenvironment has led to the concept that primary breast cancer cells act as seeds, whereas the metastatic tissue microenvironment (TME) is the soil. Improving our understanding of this interaction could lead to better treatment strategies for metastatic breast cancer. Targeted treatments for different subtypes of breast cancers have improved overall patient survival, even with metastasis. However, these targeted treatments are based upon the biology of the primary tumor and often these patients' relapse, after therapy, with metastatic tumors. The advent of immunotherapy allowed the immune system to target metastatic tumors. Unfortunately, immunotherapy has not been as effective in metastatic breast cancer relative to other cancers with metastases, such as melanoma. This review will describe the heterogeneic nature of breast cancer cells and their microenvironments. The distinct properties of metastatic breast cancer cells and their microenvironments that allow interactions, especially in bone and brain metastasis, will also be described. Finally, we will review immunotherapy approaches to treat metastatic breast tumors and discuss future therapeutic approaches to improve treatments for metastatic breast cancer.

Roadmap for the expression of canonical and extended endocannabinoid system receptors and metabolic enzymes in peripheral organs of preclinical animal models.

The endocannabinoid system is widely expressed throughout the body and is comprised of receptors, ligands, and enzymes that maintain metabolic, immune, and reproductive homeostasis. Increasing interest in the endocannabinoid system has arisen due to these physiologic roles, policy changes leading to more widespread recreational use, and the therapeutic potential of Cannabis and phytocannabinoids. Rodents have been the primary preclinical model of focus due to their relative low cost, short gestational period, genetic manipulation strategies, and gold-standard behavioral tests. However, the potential for lack of clinical translation to non-human primates and humans is high as cross-species comparisons of the endocannabinoid system have not been evaluated. To bridge this gap in knowledge, we evaluate the relative gene expression of 14 canonical and extended endocannabinoid receptors in seven peripheral organs of C57/BL6 mice, Sprague-Dawley rats, and non-human primate rhesus macaques. Notably, we identify species- and organ-specific heterogeneity in endocannabinoid receptor distribution where there is surprisingly limited overlap among the preclinical models. Importantly, we determined there were no receptors with identical expression patterns among mice (three males and two females), rats (six females), and rhesus macaques (four males). Our findings demonstrate a critical, yet previously unappreciated, contributor to challenges of rigor and reproducibility in the cannabinoid field, which has implications in hampering progress in understanding the complexity of the endocannabinoid system and development of cannabinoid-based therapies.

Multivariate word properties in fluency tasks reveal markers of Alzheimer's dementia.

INTRODUCTION: Verbal fluency tasks are common in Alzheimer's disease (AD) assessments. Yet, standard valid response counts fail to reveal disease-specific semantic memory patterns. Here, we leveraged automated word-property analysis to capture neurocognitive markers of AD vis-à-vis behavioral variant frontotemporal dementia (bvFTD). METHODS: Patients and healthy controls completed two fluency tasks. We counted valid responses and computed each word's frequency, granularity, neighborhood, length, familiarity, and imageability. These features were used for group-level discrimination, patient-level identification, and correlations with executive and neural (magnetic resonanance imaging [MRI], functional MRI [fMRI], electroencephalography [EEG]) patterns. RESULTS: Valid responses revealed deficits in both disorders. Conversely, frequency, granularity, and neighborhood yielded robust group- and subject-level discrimination only in AD, also predicting executive outcomes. Disease-specific cortical thickness patterns were predicted by frequency in both disorders. Default-mode and salience network hypoconnectivity, and EEG beta hypoconnectivity, were predicted by frequency and granularity only in AD. DISCUSSION: Word-property analysis of fluency can boost AD characterization and diagnosis. HIGHLIGHTS: We report novel word-property analyses of verbal fluency in AD and bvFTD. Standard valid response counts captured deficits and brain patterns in both groups. Specific word properties (e.g., frequency, granularity) were altered only in AD. Such properties predicted cognitive and neural (MRI, fMRI, EEG) patterns in AD. Word-property analysis of fluency can boost AD characterization and diagnosis.

Survey of NF1 inactivation by surrogate immunohistochemistry in ovarian carcinomas.

OBJECTIVE: Inhibition of the MAPK pathway by MEK inhibitors (MEKi) is currently a therapeutic standard in several cancer types, including ovarian low-grade serous carcinoma (LGSC). A common MAPK pathway alteration in tubo-ovarian high-grade serous carcinoma (HGSC) is the genomic inactivation of neurofibromin 1 (NF1). The primary objectives of our study were to survey the prevalence of NF1 inactivation in the principal ovarian carcinoma histotype as well as to evaluate its associations with clinico-pathological parameters and key biomarkers including BRCA1/2 status in HGSC. METHODS: A recently commercialized NF1 antibody (clone NFC) was orthogonally validated on an automated immunohistochemistry (IHC) platform and IHC was performed on tissue microarrays containing 2140 ovarian carcinoma cases. Expression was interpreted as loss/inactivated (complete or subclonal) versus normal/retained. RESULTS: Loss of NF1 expression was detected in 250/1429 (17.4%) HGSC including 11% with subclonal loss. Survival of NF1-inactivated HGSC patients was intermediate between favorable BRCA1/2 mutated HGSC and unfavorable CCNE1 high-level amplified HGSC. NF1 inactivation was mutually exclusive with CCNE1 high-level amplifications, co-occurred with RB1 loss and occurred at similar frequencies in BRCA1/2 mutated versus wild-type HGSC. NF1 loss was found in 21/286 (7.3%) endometrioid carcinomas with a favorable prognostic association (p = 0.048), and in 4/64 (5.9%) LGSC, mutually exclusive with other driver events. CONCLUSIONS: NF1 inactivation occurs in a significant subset of BRCA1/2 wild-type HGSC and a subset of LGSC. While the functional effects of NF1 inactivation need to be further characterized, this signifies a potential therapeutic opportunity to explore targeting NF1 inactivation in these tumors.

Cross-species conservation in the regulation of parvalbumin by perineuronal nets.

Parvalbumin (PV) neurons play an integral role in regulating neural dynamics and plasticity. Therefore, understanding the factors that regulate PV expression is important for revealing modulators of brain function. While the contribution of PV neurons to neural processes has been studied in mammals, relatively little is known about PV function in non-mammalian species, and discerning similarities in the regulation of PV across species can provide insight into evolutionary conservation in the role of PV neurons. Here we investigated factors that affect the abundance of PV in PV neurons in sensory and motor circuits of songbirds and rodents. In particular, we examined the degree to which perineuronal nets (PNNs), extracellular matrices that preferentially surround PV neurons, modulate PV abundance as well as how the relationship between PV and PNN expression differs across brain areas and species and changes over development. We generally found that cortical PV neurons that are surrounded by PNNs (PV+PNN neurons) are more enriched with PV than PV neurons without PNNs (PV-PNN neurons) across both rodents and songbirds. Interestingly, the relationship between PV and PNN expression in the vocal portion of the basal ganglia of songbirds (Area X) differed from that in other areas, with PV+PNN neurons having lower PV expression compared to PV-PNN neurons. These relationships remained consistent across development in vocal motor circuits of the songbird brain. Finally, we discovered a causal contribution of PNNs to PV expression in songbirds because degradation of PNNs led to a diminution of PV expression in PV neurons. These findings in reveal a conserved relationship between PV and PNN expression in sensory and motor cortices and across songbirds and rodents and suggest that PV neurons could modulate plasticity and neural dynamics in similar ways across songbirds and rodents.

Oculomotor analysis to assess brain health: preliminary findings from a longitudinal study of multiple sclerosis using novel tablet-based eye-tracking software.

A growing body of evidence supports the link between eye movement anomalies and brain health. Indeed, the oculomotor system is composed of a diverse network of cortical and subcortical structures and circuits that are susceptible to a variety of degenerative processes. Here we show preliminary findings from the baseline measurements of an ongoing longitudinal cohort study in MS participants, designed to determine if disease and cognitive status can be estimated and tracked with high accuracy based on eye movement parameters alone. Using a novel gaze-tracking technology that can reliably and accurately track eye movements with good precision without the need for infrared cameras, using only an iPad Pro embedded camera, we show in this cross-sectional study that several eye movement parameters significantly correlated with clinical outcome measures of interest. Eye movement parameters were extracted from fixation, pro-saccade, anti-saccade, and smooth pursuit visual tasks, whereas the clinical outcome measures were the scores of several disease assessment tools and standard cognitive tests such as the Expanded Disability Status Scale (EDSS), Brief International Cognitive Assessment for MS (BICAMS), the Multiple Sclerosis Functional Composite (MSFC) and the Symbol Digit Modalities Test (SDMT). Furthermore, partial least squares regression analyses show that a small set of oculomotor parameters can explain up to 84% of the variance of the clinical outcome measures. Taken together, these findings not only replicate previously known associations between eye movement parameters and clinical scores, this time using a novel mobile-based technology, but also the notion that interrogating the oculomotor system with a novel eye-tracking technology can inform us of disease severity, as well as the cognitive status of MS participants.

A novel tablet-based software for the acquisition and analysis of gaze and eye movement parameters: a preliminary validation study in Parkinson's disease.

The idea that eye movements can reflect certain aspects of brain function and inform on the presence of neurodegeneration is not a new one. Indeed, a growing body of research has shown that several neurodegenerative disorders, such as Alzheimer's and Parkinson's Disease, present characteristic eye movement anomalies and that specific gaze and eye movement parameters correlate with disease severity. The use of detailed eye movement recordings in research and clinical settings, however, has been limited due to the expensive nature and limited scalability of the required equipment. Here we test a novel technology that can track and measure eye movement parameters using the embedded camera of a mobile tablet. We show that using this technology can replicate several well-known findings regarding oculomotor anomalies in Parkinson's disease (PD), and furthermore show that several parameters significantly correlate with disease severity as assessed with the MDS-UPDRS motor subscale. A logistic regression classifier was able to accurately distinguish PD patients from healthy controls on the basis of six eye movement parameters with a sensitivity of 0.93 and specificity of 0.86. This tablet-based tool has the potential to accelerate eye movement research via affordable and scalable eye-tracking and aid with the identification of disease status and monitoring of disease progression in clinical settings.

Integration of cancer-related genetic landscape of Eph receptors and ephrins with proteomics identifies a crosstalk between EPHB6 and EGFR.

Eph receptors and their ephrin ligands are viewed as promising targets for cancer treatment; however, targeting them is hindered by their context-dependent functionalities. To circumvent this, we explore molecular landscapes underlying their pro- and anti-malignant activities. Using unbiased bioinformatics approaches, we construct a cancer-related network of genetic interactions (GIs) of all Ephs and ephrins to assist in their therapeutic manipulation. We also apply genetic screening and BioID proteomics and integrate them with machine learning approaches to select the most relevant GIs of one Eph receptor, EPHB6. This identifies a crosstalk between EPHB6 and EGFR, and further experiments confirm the ability of EPHB6 to modulate EGFR signaling, enhancing the proliferation of cancer cells and tumor development. Taken together, our observations show EPHB6 involvement in EGFR action, suggesting its targeting might be beneficial in EGFR-dependent tumors, and confirm that the Eph family genetic interactome presented here can be effectively exploited in developing cancer treatment approaches.

Dynamics of coexisting rotating waves in unidirectional rings of bistable Duffing oscillators.

We study the dynamics of multistable coexisting rotating waves that propagate along a unidirectional ring consisting of coupled double-well Duffing oscillators with different numbers of oscillators. By employing time series analysis, phase portraits, bifurcation diagrams, and basins of attraction, we provide evidence of multistability on the route from coexisting stable equilibria to hyperchaos via a sequence of bifurcations, including the Hopf bifurcation, torus bifurcations, and crisis bifurcations, as the coupling strength is increased. The specific bifurcation route depends on whether the ring comprises an even or odd number of oscillators. In the case of an even number of oscillators, we observe the existence of up to 32 coexisting stable fixed points at relatively weak coupling strengths, while a ring with an odd number of oscillators exhibits 20 coexisting stable equilibria. As the coupling strength increases, a hidden amplitude death attractor is born in an inverse supercritical pitchfork bifurcation in the ring with an even number of oscillators, coexisting with various homoclinic and heteroclinic orbits. Additionally, for stronger coupling, amplitude death coexists with chaos. Notably, the rotating wave speed of all coexisting limit cycles remains approximately constant and undergoes an exponential decrease as the coupling strength is increased. At the same time, the wave frequency varies among different coexisting orbits, exhibiting an almost linear growth with the coupling strength. It is worth mentioning that orbits originating from stronger coupling strengths possess higher frequencies.

Generation of a SARS-CoV-2 Reverse Genetics System and Novel Human Lung Cell Lines That Exhibit High Virus-Induced Cytopathology.

The global COVID-19 pandemic continues with continued cases worldwide and the emergence of new SARS-CoV-2 variants. In our study, we have developed novel tools with applications for screening antivirals, identifying virus-host dependencies, and characterizing viral variants. Using reverse genetics, we rescued SARS-CoV-2 Wuhan1 (D614G variant) wild type (WTFL) and reporter virus (NLucFL) using molecular BAC clones. The replication kinetics, plaque morphology, and titers were comparable between viruses rescued from molecular clones and a clinical isolate (VIDO-01 strain). Furthermore, the reporter SARS-CoV-2 NLucFL virus exhibited robust luciferase values over the time course of infection and was used to develop a rapid antiviral assay using remdesivir as proof-of-principle. In addition, as a tool to study lung-relevant virus-host interactions, we established novel human lung cell lines that support SARS-CoV-2 infection with high virus-induced cytopathology. Six lung cell lines (NCI-H23, A549, NCI-H1703, NCI-H520, NCI-H226, and HCC827) and HEK293T cells were transduced to stably express ACE2 and tested for their ability to support virus infection. A549ACE2 B1 and HEK293TACE2 A2 cell lines exhibited more than 70% virus-induced cell death, and a novel lung cell line, NCI-H23ACE2 A3, showed about ~99% cell death post-infection. These cell lines are ideal for assays relying on live-dead selection, such as CRISPR knockout and activation screens.

Roadmap For The Expression Of Canonical and Extended Endocannabinoid System Receptors and Proteins in Peripheral Organs of Preclinical Animal Models.

The endocannabinoid system is widely expressed throughout the body and is comprised of receptors, ligands, and enzymes that maintain metabolic, immune, and reproductive homeostasis. Increasing interest in the endocannabinoid system has arisen due to these physiologic roles, policy changes leading to more widespread recreational use, and the therapeutic potential of Cannabis and phytocannabinoids. Rodents have been the primary preclinical model of focus due to their relative low cost, short gestational period, genetic manipulation strategies, and gold-standard behavioral tests. However, the potential for lack of clinical translation to non-human primates and humans is high as cross-species comparisons of the endocannabinoid system has not been evaluated. To bridge this gap in knowledge, we evaluate the relative gene expression of 14 canonical and extended endocannabinoid receptors in seven peripheral organs of C57/BL6 mice, Sprague-Dawley rats, and non-human primate rhesus macaques. Notably, we identify species- and organ-specific heterogeneity in endocannabinoid receptor distribution where there is surprisingly limited overlap among the preclinical models. Importantly, we determined there were only five receptors (CB2, GPR18, GPR55, TRPV2, and FAAH) that had identical expression patterns in mice, rats, and rhesus macaques. Our findings demonstrate a critical, yet previously unappreciated, contributor to challenges of rigor and reproducibility in the cannabinoid field, which has profound implications in hampering progress in understanding the complexity of the endocannabinoid system and development of cannabinoid-based therapies.

Hydration and clinical warning signs of dengue fever in primary care: An observational prospective study.

OBJECTIVES: Dengue fever is an arbovirosis expanding worldwide, for which hydration has been reported to reduce the risk of hospitalization. Our objective was to estimate the volume of hydration in Reunionese patients with dengue. METHODS: A prospective observational study included patients presenting with a 'dengue-like' syndrome in ambulatory care. General practitioners recruited patients during consultation, and beverage consumption over the previous 24 hours was reported at two different times. Warning signs were defined according to the 2009 WHO guidelines. RESULTS: GPs included 174 patients from April to July 2019. Average oral hydration volume was 1863 mL and 1944 mL, at the 1st and 2nd medical consultations, respectively. Water was the most wide consumed liquid. Drinking at least 5 glasses of liquid was significantly associated with fewer clinical warning signs at the 1st medical consultation (p = 0.044). CONCLUSIONS: Sufficient hydration volume could prevent dengue warning signs. Further studies with standardized measurement of hydration would be needed.

[Tools available in Spanish for clinical assessment of delirium. Systematic review]. / Herramientas disponibles en español para la valoración clínica del delirium. Revisión sistemática.

INTRODUCTION: Delirium assessment is difficult because it involves the alteration of different mental functions in patients of any age who have serious medical-surgical conditions or dementia. Therefore, concrete assessment tools for specific needs are required. This systematic review synthetizes the information about the tools available in Spanish for delirium clinical assessment. MATERIALS AND METHODS: This is a systematic review that follows the PRISMA Diagnostic Test Accuracy guideline. Using a search algorithm, two researchers assessed five scientific indexing systems and searched for additional papers and grey literature. Other two researchers recorded in a standardized way the data of the papers included. The quality of translations, cultural adaptations, and validations were assessed. RESULTS: We identified 21 reports on translation, cultural adaptation, or validation of 14 tools for 1) detailed evaluation, diagnosis, and quantification of severity by experts, 2) assessment of concrete aspects of delirium, 3) screening in adults, 4) pediatric screening, and 5) diagnosis and weighting of severity by treating staff. 78.6% of translations and all adaptations are of good quality. 52.9% of validations have a low risk of bias, 41.2% have a moderate risk, and only 5.9% have a high risk. CONCLUSIONS: As the first step to correctly treat patients is an accurate diagnosis, and the selection of the appropriate instruments is essential for the validity of any study, the available tools should be chosen according to the specific clinical and research needs.

TITLE: Herramientas disponibles en español para la valoración clínica del delirium. Revisión sistemática.Introducción. La evaluación del delirium es difícil, porque implica la alteración de diferentes funciones mentales en pacientes de cualquier edad con patologías medicoquirúrgicas graves o demencia. Por tanto, se requieren herramientas de evaluación concretas para necesidades específicas. Esta revisión sistemática sintetiza la información sobre las herramientas disponibles en español para la evaluación clínica del delirium. Materiales y métodos. Ésta es una revisión sistemática que sigue la guía PRISMA-Diagnostic Test Accuracy. Usando un algoritmo de búsqueda, dos investigadores evaluaron cinco sistemas de indexación científica y buscaron artículos adicionales y bibliografía gris. Otros dos investigadores registraron de forma estandarizada los datos de los trabajos incluidos. Se evaluó la calidad de las traducciones, adaptaciones culturales y validaciones. Resultados. Identificamos 21 trabajos sobre traducción, adaptación cultural o validación de 14 herramientas para: a) evaluación detallada, diagnóstico y cuantificación de la gravedad por parte de expertos; b) evaluación de aspectos concretos del delirium; c) cribado en adultos; d) cribado pediátrico; y e) diagnóstico y ponderación de gravedad por técnicos tratantes. El 78,6% de las traducciones y todas las adaptaciones son de buena calidad. El 52,9% de las validaciones tiene riesgo bajo de sesgo; el 41,2%, riesgo moderado; y sólo el 5,9%, riesgo alto. Conclusiones. Dado que el primer paso para tratar correctamente a los pacientes es un diagnóstico preciso y que la selección de los instrumentos adecuados es fundamental para la validez de cualquier estudio, las herramientas disponibles deben elegirse de acuerdo con las necesidades clínicas y de investigación específicas.

A Multipronged Unbiased Strategy Guides the Development of an Anti-EGFR/EPHA2-Bispecific Antibody for Combination Cancer Therapy.

PURPOSE: Accumulating analyses of pro-oncogenic molecular mechanisms triggered a rapid development of targeted cancer therapies. Although many of these treatments produce impressive initial responses, eventual resistance onset is practically unavoidable. One of the main approaches for preventing this refractory condition relies on the implementation of combination therapies. This includes dual-specificity reagents that affect both of their targets with a high level of selectivity. Unfortunately, selection of target combinations for these treatments is often confounded by limitations in our understanding of tumor biology. Here, we describe and validate a multipronged unbiased strategy for predicting optimal co-targets for bispecific therapeutics. EXPERIMENTAL DESIGN: Our strategy integrates ex vivo genome-wide loss-of-function screening, BioID interactome profiling, and gene expression analysis of patient data to identify the best fit co-targets. Final validation of selected target combinations is done in tumorsphere cultures and xenograft models. RESULTS: Integration of our experimental approaches unambiguously pointed toward EGFR and EPHA2 tyrosine kinase receptors as molecules of choice for co-targeting in multiple tumor types. Following this lead, we generated a human bispecific anti-EGFR/EPHA2 antibody that, as predicted, very effectively suppresses tumor growth compared with its prototype anti-EGFR therapeutic antibody, cetuximab. CONCLUSIONS: Our work not only presents a new bispecific antibody with a high potential for being developed into clinically relevant biologics, but more importantly, successfully validates a novel unbiased strategy for selecting biologically optimal target combinations. This is of a significant translational relevance, as such multifaceted unbiased approaches are likely to augment the development of effective combination therapies for cancer treatment. See related commentary by Kumar, p. 2570.