PHF2-mediated H3K9me balance orchestrates heterochromatin stability and neural progenitor proliferation.

Heterochromatin stability is crucial for progenitor proliferation during early neurogenesis. It relays on the maintenance of local hubs of H3K9me. However, understanding the formation of efficient localized levels of H3K9me remains limited. To address this question, we used neural stem cells to analyze the function of the H3K9me2 demethylase PHF2, which is crucial for progenitor proliferation. Through mass-spectroscopy and genome-wide assays, we show that PHF2 interacts with heterochromatin components and is enriched at pericentromeric heterochromatin (PcH) boundaries where it maintains transcriptional activity. This binding is essential for silencing the satellite repeats, preventing DNA damage and genome instability. PHF2's depletion increases the transcription of heterochromatic repeats, accompanied by a decrease in H3K9me3 levels and alterations in PcH organization. We further show that PHF2's PHD and catalytic domains are crucial for maintaining PcH stability, thereby safeguarding genome integrity. These results highlight the multifaceted nature of PHF2's functions in maintaining heterochromatin stability and regulating gene expression during neural development. Our study unravels the intricate relationship between heterochromatin stability and progenitor proliferation during mammalian neurogenesis.

The histone demethylase PHF8 regulates astrocyte differentiation and function.

Epigenetic factors have been shown to play a crucial role in X-linked intellectual disability (XLID). Here, we investigate the contribution of the XLID-associated histone demethylase PHF8 to astrocyte differentiation and function. Using genome-wide analyses and biochemical assays in mouse astrocytic cultures, we reveal a regulatory crosstalk between PHF8 and the Notch signaling pathway that balances the expression of the master astrocytic gene Nfia. Moreover, PHF8 regulates key synaptic genes in astrocytes by maintaining low levels of H4K20me3. Accordingly, astrocytic-PHF8 depletion has a striking effect on neuronal synapse formation and maturation in vitro. These data reveal that PHF8 is crucial in astrocyte development to maintain chromatin homeostasis and limit heterochromatin formation at synaptogenic genes. Our studies provide insights into the involvement of epigenetics in intellectual disability.

Choosing Variant Interpretation Tools for Clinical Applications: Context Matters.

Pathogenicity predictors are computational tools that classify genetic variants as benign or pathogenic; this is currently a major challenge in genomic medicine. With more than fifty such predictors available, selecting the most suitable tool for clinical applications like genetic screening, molecular diagnostics, and companion diagnostics has become increasingly challenging. To address this issue, we have developed a cost-based framework that naturally considers the various components of the problem. This framework encodes clinical scenarios using a minimal set of parameters and treats pathogenicity predictors as rejection classifiers, a common practice in clinical applications where low-confidence predictions are routinely rejected. We illustrate our approach in four examples where we compare different numbers of pathogenicity predictors for missense variants. Our results show that no single predictor is optimal for all clinical scenarios and that considering rejection yields a different perspective on classifiers.

PHF2 histone demethylase prevents DNA damage and genome instability by controlling cell cycle progression of neural progenitors.

Histone H3 lysine 9 methylation (H3K9me) is essential for cellular homeostasis; however, its contribution to development is not well established. Here, we demonstrate that the H3K9me2 demethylase PHF2 is essential for neural progenitor proliferation in vitro and for early neurogenesis in the chicken spinal cord. Using genome-wide analyses and biochemical assays we show that PHF2 controls the expression of critical cell cycle progression genes, particularly those related to DNA replication, by keeping low levels of H3K9me3 at promoters. Accordingly, PHF2 depletion induces R-loop accumulation that leads to extensive DNA damage and cell cycle arrest. These data reveal a role of PHF2 as a guarantor of genome stability that allows proper expansion of neural progenitors during development.

Towards a New, Endophenotype-Based Strategy for Pathogenicity Prediction in BRCA1 and BRCA2: In Silico Modeling of the Outcome of HDR/SGE Assays for Missense Variants.

The present limitations in the pathogenicity prediction of BRCA1 and BRCA2 (BRCA1/2) missense variants constitute an important problem with negative consequences for the diagnosis of hereditary breast and ovarian cancer. However, it has been proposed that the use of endophenotype predictions, i.e., computational estimates of the outcomes of functional assays, can be a good option to address this bottleneck. The application of this idea to the BRCA1/2 variants in the CAGI 5-ENIGMA international challenge has shown promising results. Here, we developed this approach, exploring the predictive performances of the regression models applied to the BRCA1/2 variants for which the values of the homology-directed DNA repair and saturation genome editing assays are available. Our results first showed that we can generate endophenotype estimates using a few molecular-level properties. Second, we show that the accuracy of these estimates is enough to obtain pathogenicity predictions comparable to those of many standard tools. Third, endophenotype-based predictions are complementary to, but do not outperform, those of a Random Forest model trained using variant pathogenicity annotations instead of endophenotype values. In summary, our results confirmed the usefulness of the endophenotype approach for the pathogenicity prediction of the BRCA1/2 missense variants, suggesting different options for future improvements.

BRCA1- and BRCA2-specific in silico tools for variant interpretation in the CAGI 5 ENIGMA challenge.

BRCA1 and BRCA2 (BRCA1/2) germline variants disrupting the DNA protective role of these genes increase the risk of hereditary breast and ovarian cancers. Correct identification of these variants then becomes clinically relevant, because it may increase the survival rates of the carriers. Unfortunately, we are still unable to systematically predict the impact of BRCA1/2 variants. In this article, we present a family of in silico predictors that address this problem, using a gene-specific approach. For each protein, we have developed two tools, aimed at predicting the impact of a variant at two different levels: Functional and clinical. Testing their performance in different datasets shows that specific information compensates the small number of predictive features and the reduced training sets employed to develop our models. When applied to the variants of the BRCA1/2 (ENIGMA) challenge in the fifth Critical Assessment of Genome Interpretation (CAGI 5) we find that these methods, particularly those predicting the functional impact of variants, have a good performance, identifying the large compositional bias towards neutral variants in the CAGI sample. This performance is further improved when incorporating to our prediction protocol estimates of the impact on splicing of the target variant.

Assessment of blind predictions of the clinical significance of BRCA1 and BRCA2 variants.

Testing for variation in BRCA1 and BRCA2 (commonly referred to as BRCA1/2), has emerged as a standard clinical practice and is helping countless women better understand and manage their heritable risk of breast and ovarian cancer. Yet the increased rate of BRCA1/2 testing has led to an increasing number of Variants of Uncertain Significance (VUS), and the rate of VUS discovery currently outpaces the rate of clinical variant interpretation. Computational prediction is a key component of the variant interpretation pipeline. In the CAGI5 ENIGMA Challenge, six prediction teams submitted predictions on 326 newly-interpreted variants from the ENIGMA Consortium. By evaluating these predictions against the new interpretations, we have gained a number of insights on the state of the art of variant prediction and specific steps to further advance this state of the art.

SeMPI: a genome-based secondary metabolite prediction and identification web server.

The secondary metabolism of bacteria, fungi and plants yields a vast number of bioactive substances. The constantly increasing amount of published genomic data provides the opportunity for an efficient identification of gene clusters by genome mining. Conversely, for many natural products with resolved structures, the encoding gene clusters have not been identified yet. Even though genome mining tools have become significantly more efficient in the identification of biosynthetic gene clusters, structural elucidation of the actual secondary metabolite is still challenging, especially due to as yet unpredictable post-modifications. Here, we introduce SeMPI, a web server providing a prediction and identification pipeline for natural products synthesized by polyketide synthases of type I modular. In order to limit the possible structures of PKS products and to include putative tailoring reactions, a structural comparison with annotated natural products was introduced. Furthermore, a benchmark was designed based on 40 gene clusters with annotated PKS products. The web server of the pipeline (SeMPI) is freely available at: http://www.pharmaceutical-bioinformatics.de/sempi.

Development of pathogenicity predictors specific for variants that do not comply with clinical guidelines for the use of computational evidence.

BACKGROUND: Strict guidelines delimit the use of computational information in the clinical setting, due to the still moderate accuracy of in silico tools. These guidelines indicate that several tools should always be used and that full coincidence between them is required if we want to consider their results as supporting evidence in medical decision processes. Application of this simple rule certainly decreases the error rate of in silico pathogenicity assignments. However, when predictors disagree this rule results in the rejection of potentially valuable information for a number of variants. In this work, we focus on these variants of the protein sequence and develop specific predictors to help improve the success rate of their annotation. RESULTS: We have used a set of 59,442 protein sequence variants (15,723 pathological and 43,719 neutral) from 228 proteins to identify those cases for which pathogenicity predictors disagree. We have repeated this process for all the possible combinations of five known methods (SIFT, PolyPhen-2, PON-P2, CADD and MutationTaster2). For each resulting subset we have trained a specific pathogenicity predictor. We find that these specific predictors are able to discriminate between neutral and pathogenic variants, with a success rate different from random. They tend to outperform the constitutive methods but this trend decreases as the performance of the constitutive predictor improves (e.g. with PON-P2 and PolyPhen-2). We also find that specific methods outperform standard consensus methods (Condel and CAROL). CONCLUSION: Focusing development efforts on the case of variants for which known methods disagree we may obtain pathogenicity predictors with improved performances. Although we have not yet reached the success rate that allows the use of this computational evidence in a clinical setting, the simplicity of the approach indicates that more advanced methods may reach this goal in a close future.

Elucidating the molecular basis of MSH2-deficient tumors by combined germline and somatic analysis.

In a proportion of patients presenting mismatch repair (MMR)-deficient tumors, no germline MMR mutations are identified, the so-called Lynch-like syndrome (LLS). Recently, MMR-deficient tumors have been associated with germline mutations in POLE and MUTYH or double somatic MMR events. Our aim was to elucidate the molecular basis of MSH2-deficient LS-suspected cases using a comprehensive analysis of colorectal cancer (CRC)-associated genes at germline and somatic level. Fifty-eight probands harboring MSH2-deficient tumors were included. Germline mutational analysis of MSH2 (including EPCAM deletions) and MSH6 was performed. Pathogenicity of MSH2 variants was assessed by RNA analysis and multifactorial likelihood calculations. MSH2 cDNA and methylation of MSH2 and MSH6 promoters were studied. Matched blood and tumor DNA were analyzed using a customized next generation sequencing panel. Thirty-five individuals were carriers of pathogenic or probably pathogenic variants in MSH2 and EPCAM. Five patients harbored 4 different MSH2 variants of unknown significance (VUS) and one had 2 novel MSH6 promoter VUS. Pathogenicity assessment allowed the reclassification of the 4 MSH2 VUS and 6 probably pathogenic variants as pathogenic mutations, enabling a total of 40 LS diagnostics. Predicted pathogenic germline variants in BUB1, SETD2, FAN1 and MUTYH were identified in 5 cases. Three patients had double somatic hits in MSH2 or MSH6, and another 2 had somatic alterations in other MMR genes and/or proofreading polymerases. In conclusion, our comprehensive strategy combining germline and somatic mutational status of CRC-associated genes by means of a subexome panel allows the elucidation of up to 86% of MSH2-deficient suspected LS tumors.

The Complementarity Between Protein-Specific and General Pathogenicity Predictors for Amino Acid Substitutions.

The usage of next-generation sequencing with biomedical/clinical purposes has fuelled the demand for tools that assess the functional impact of sequence variants. For single amino acid variants, general methods (GM), based on biophysics/evolutionary principles and trained by pooling variants from many proteins, are already available. Until now, their accuracy range (∼80%) has limited their usage in clinical applications. In parallel, a series of studies indicate that protein-specific predictors (PSP), using only information from the protein of interest, could frequently surpass the performance of GM. However, two reasons suggest that this may not always be the case: the existence of a performance threshold affecting both GM and PSP, and the effect of training data scarcity. Here, we characterize the relationship between the two approaches deriving 82 PSP and comparing them with several GM (PolyPhen-2, SIFT, PON-P2, MutationTaster2, CADD). We find a complementary relationship between PSP and GM, with no approach always outperforming the other. However, the relationship varies between two limiting situations, for example, PSP are frequently outperformed by PON-P2, the best GM; however, the opposite happens when we compare PSP and SIFT. Finally, we explore how the observed complementarity could lead to increased success rates in pathogenicity prediction.

Novel Mutations Causing C5 Deficiency in Three North-African Families.

The complement system plays a central role in defense to encapsulated bacteria through opsonization and membrane attack complex (MAC) dependent lysis. The three activation pathways (classical, lectin, and alternative) converge in the cleavage of C5, which initiates MAC formation and target lysis. C5 deficiency is associated to recurrent infections by Neisseria spp. In the present study, complement deficiency was suspected in three families of North-African origin after one episode of invasive meningitis due to a non-groupable and two uncommon Meningococcal serotypes (E29, Y). Activity of alternative and classical pathways of complement were markedly reduced and the measurement of terminal complement components revealed total C5 absence. C5 gene analysis revealed two novel mutations as causative of the deficiency: Family A propositus carried a homozygous deletion of two adenines in the exon 21 of C5 gene, resulting in a frameshift and a truncated protein (c.2607_2608del/p.Ser870ProfsX3 mutation). Families B and C probands carried the same homozygous deletion of three consecutive nucleotides (CAA) in exon 9 of the C5 gene, leading to the deletion of asparagine 320 (c.960_962del/p.Asn320del mutation). Family studies confirmed an autosomal recessive inheritance pattern. Although sharing the same geographical origin, families B and C were unrelated. This prompted us to investigate this mutation prevalence in a cohort of 768 North-African healthy individuals. We identified one heterozygous carrier of the p.Asn320del mutation (allelic frequency = 0.065 %), indicating that this mutation is present at low frequency in North-African population.

A New Set of in Silico Tools to Support the Interpretation of ATM Missense Variants Using Graphical Analysis.

Establishing the pathogenic nature of variants in ATM, a gene associated with breast cancer and other hereditary cancers, is crucial for providing patients with adequate care. Unfortunately, achieving good variant classification is still difficult. To address this challenge, we extended the range of in silico tools with a series of graphical tools devised for the analysis of computational evidence by health care professionals. We propose a family of fast and easy-to-use graphical representations in which the impact of a variant is considered relative to other pathogenic and benign variants. To illustrate their value, the representations are applied to three problems in variant interpretation. The assessment of computational pathogenicity predictions showed that the graphics provide an intuitive view of prediction reliability, complementing and extending conventional numerical reliability indexes. When applied to variant of unknown significance populations, the representations shed light on the nature of these variants and can be used to prioritize variants of unknown significance for further studies. In a third application, the graphics were used to compare the two versions of the ATM-adapted American College of Medical Genetics and Genomics and Association for Molecular Pathology guidelines, obtaining valuable information on their relative virtues and weaknesses. Finally, a server [ATMision (ATM missense in silico interpretation online)] was generated for users to apply these representations in their variant interpretation problems, to check the ATM-adapted guidelines' criteria for computational evidence on their variant(s) and access different sources of information.

Evaluation of enzyme activity predictions for variants of unknown significance in Arylsulfatase A.

Continued advances in variant effect prediction are necessary to demonstrate the ability of machine learning methods to accurately determine the clinical impact of variants of unknown significance (VUS). Towards this goal, the ARSA Critical Assessment of Genome Interpretation (CAGI) challenge was designed to characterize progress by utilizing 219 experimentally assayed missense VUS in the Arylsulfatase A (ARSA) gene to assess the performance of community-submitted predictions of variant functional effects. The challenge involved 15 teams, and evaluated additional predictions from established and recently released models. Notably, a model developed by participants of a genetics and coding bootcamp, trained with standard machine-learning tools in Python, demonstrated superior performance among submissions. Furthermore, the study observed that state-of-the-art deep learning methods provided small but statistically significant improvement in predictive performance compared to less elaborate techniques. These findings underscore the utility of variant effect prediction, and the potential for models trained with modest resources to accurately classify VUS in genetic and clinical research.

Gain and loss of function variants in EZH1 disrupt neurogenesis and cause dominant and recessive neurodevelopmental disorders.

Genetic variants in chromatin regulators are frequently found in neurodevelopmental disorders, but their effect in disease etiology is rarely determined. Here, we uncover and functionally define pathogenic variants in the chromatin modifier EZH1 as the cause of dominant and recessive neurodevelopmental disorders in 19 individuals. EZH1 encodes one of the two alternative histone H3 lysine 27 methyltransferases of the PRC2 complex. Unlike the other PRC2 subunits, which are involved in cancers and developmental syndromes, the implication of EZH1 in human development and disease is largely unknown. Using cellular and biochemical studies, we demonstrate that recessive variants impair EZH1 expression causing loss of function effects, while dominant variants are missense mutations that affect evolutionarily conserved aminoacids, likely impacting EZH1 structure or function. Accordingly, we found increased methyltransferase activity leading to gain of function of two EZH1 missense variants. Furthermore, we show that EZH1 is necessary and sufficient for differentiation of neural progenitor cells in the developing chick embryo neural tube. Finally, using human pluripotent stem cell-derived neural cultures and forebrain organoids, we demonstrate that EZH1 variants perturb cortical neuron differentiation. Overall, our work reveals a critical role of EZH1 in neurogenesis regulation and provides molecular diagnosis for previously undefined neurodevelopmental disorders.

Mechanism of KMT5B haploinsufficiency in neurodevelopment in humans and mice.

Pathogenic variants in KMT5B, a lysine methyltransferase, are associated with global developmental delay, macrocephaly, autism, and congenital anomalies (OMIM# 617788). Given the relatively recent discovery of this disorder, it has not been fully characterized. Deep phenotyping of the largest (n = 43) patient cohort to date identified that hypotonia and congenital heart defects are prominent features that were previously not associated with this syndrome. Both missense variants and putative loss-of-function variants resulted in slow growth in patient-derived cell lines. KMT5B homozygous knockout mice were smaller in size than their wild-type littermates but did not have significantly smaller brains, suggesting relative macrocephaly, also noted as a prominent clinical feature. RNA sequencing of patient lymphoblasts and Kmt5b haploinsufficient mouse brains identified differentially expressed pathways associated with nervous system development and function including axon guidance signaling. Overall, we identified additional pathogenic variants and clinical features in KMT5B-related neurodevelopmental disorder and provide insights into the molecular mechanisms of the disorder using multiple model systems.

Placenta Accreta Spectrum Prenatal Diagnosis Performance: Are Ultrasound False-positive Results Acceptable in Limited-resources Settings?

OBJECTIVE: The immediate referral of patients with risk factors for placenta accreta spectrum (PAS) to specialized centers is recommended, thus favoring an early diagnosis and an interdisciplinary management. However, diagnostic errors are frequent, even in referral centers (RCs). We sought to evaluate the performance of the prenatal diagnosis for PAS in a Latin American hospital. METHODS: A retrospective descriptive study including patients referred due to the suspicion of PAS was conducted. Data from the prenatal imaging studies were compared with the final diagnoses (intraoperative and/or histological). RESULTS: A total of 162 patients were included in the present study. The median gestational age at the time of the first PAS suspicious ultrasound was 29 weeks, but patients arrived at the PAS RC at 34 weeks. The frequency of false-positive results at referring hospitals was 68.5%. Sixty-nine patients underwent surgery based on the suspicion of PAS at 35 weeks, and there was a 28.9% false-positive rate at the RC. In 93 patients, the diagnosis of PAS was ruled out at the RC, with a 2.1% false-negative frequency. CONCLUSION: The prenatal diagnosis of PAS is better at the RC. However, even in these centers, false-positive results are common; therefore, the intraoperative confirmation of the diagnosis of PAS is essential.

OBJETIVO: Recomenda-se o encaminhamento imediato de pacientes com fatores de risco para espectro placentário acreta (PAS, na sigla em inglês) para centros especializados, favorecendo assim o diagnóstico precoce e o manejo interdisciplinar. No entanto, erros diagnósticos são frequentes, mesmo em centros de referência (CRs). Buscou-se avaliar o desempenho do diagnóstico pré-natal para PAS em um hospital latino-americano. MéTODOS: Um estudo descritivo retrospectivo incluindo pacientes encaminhados por suspeita de SAP foi realizado. Os dados dos exames de imagem do pré-natal foram comparados com os diagnósticos finais (intraoperatórios e/ou histológicos). RESULTADOS: Foram incluídos 162 pacientes no presente estudo. A idade gestacional mediana no momento da primeira ultrassonografia suspeita de PAS foi de 29 semanas, mas as pacientes chegaram ao CR de PAS com 34 semanas. A frequência de resultados falso-positivos nos hospitais de referência foi de 68,5%. Sessenta e nove pacientes foram operadas com base na suspeita de PAS com 35 semanas e houve 28,9% de falso-positivos no CR. Em 93 pacientes, o diagnóstico de PAS foi descartado no CR, com frequência de falso-negativos de 2,1%. CONCLUSãO: O diagnóstico pré-natal de PAS é melhor no CR. Entretanto, mesmo nestes centros, resultados falso-positivos são comuns; portanto, a confirmação intraoperatória do diagnóstico de SAP é essencial.

Damage control surgery for splenic trauma: "preserve an organ - preserve a life".

The spleen is one of the most commonly injured solid organs of the abdominal cavity and an early diagnosis can reduce the associated mortality. Over the past couple of decades, management of splenic injuries has evolved to a prefered non-operative approach even in severely injured cases. However, the optimal surgical management of splenic trauma in severely injured patients remains controversial. This article aims to present an algorithm for the management of splenic trauma in severely injured patients, that includes basic principles of damage control surgery and is based on the experience obtained by the Trauma and Emergency Surgery Group (CTE) of Cali, Colombia. The choice between a conservative or a surgical approach depends on the hemodynamic status of the patient. In hemodynamically stable patients, a computed tomography angiogram should be performed to determine if non-operative management is feasible and if angioembolization is required. While hemodynamically unstable patients should be transferred immediately to the operating room for damage control surgery, which includes splenic packing and placement of a negative pressure dressing, followed by angiography with embolization of any ongoing arterial bleeding. It is our recommendation that both damage control principles and emerging endovascular technologies should be applied to achieve splenic salvage when possible. However, if surgical bleeding persists a splenectomy may be required as a definitive lifesaving maneuver.

El bazo es uno de los órganos sólidos comprometidos con mayor frecuencia en el trauma abdominal y el diagnóstico oportuno disminuye la mortalidad. El manejo del trauma esplénico ha cambiado considerablemente en las últimas décadas y hoy en día se prefiere un abordaje conservador incluso en casos de lesión severa. Sin embargo, la estrategia óptima para el manejo del trauma esplénico en el paciente severamente traumatizado aún es controvertida. El objetivo de este artículo es proponer una estrategia de manejo para el trauma esplénico en pacientes politraumatizados que incluye los principios de la cirugía de control de daños en base a la experiencia obtenida por el grupo de Cirugía de Trauma y Emergencias (CTE) de Cali, Colombia. La decisión entre un abordaje conservador o quirúrgico depende del estado hemodinámico del paciente. En pacientes hemodinámicamente estables, se debe realizar una tomografía axial computarizada con contraste endovenoso para determinar si es posible un manejo conservador y si requiere angio-embolización. Mientras que los pacientes hemodinámicamente inestables deben ser trasladados inmediatamente al quirófano para empaquetamiento esplénico y colocación de un sistema de presión negativa, seguido de angiografía con embolización de cualquier sangrado arterial persistente. Es nuestra recomendación aplicar conjuntamente los principios del control de daños y las tecnologías endovasculares emergentes para lograr la conservación del bazo, cuando sea posible. Sin embargo, si el sangrado persiste puede requerirse una esplenectomía como medida definitiva para salvaguardar la vida del paciente.

New genes involved in Angelman syndrome-like: Expanding the genetic spectrum.

Angelman syndrome (AS) is a neurogenetic disorder characterized by severe developmental delay with absence of speech, happy disposition, frequent laughter, hyperactivity, stereotypies, ataxia and seizures with specific EEG abnormalities. There is a 10-15% of patients with an AS phenotype whose genetic cause remains unknown (Angelman-like syndrome, AS-like). Whole-exome sequencing (WES) was performed on a cohort of 14 patients with clinical features of AS and no molecular diagnosis. As a result, we identified 10 de novo and 1 X-linked pathogenic/likely pathogenic variants in 10 neurodevelopmental genes (SYNGAP1, VAMP2, TBL1XR1, ASXL3, SATB2, SMARCE1, SPTAN1, KCNQ3, SLC6A1 and LAS1L) and one deleterious de novo variant in a candidate gene (HSF2). Our results highlight the wide genetic heterogeneity in AS-like patients and expands the differential diagnosis.

Damage control in the emergency department, a bridge to life.

Patients with hemodynamic instability have a sustained systolic blood pressure less or equal to 90 mmHg, a heart rate greater or equal to 120 beats per minute and an acute compromise of the ventilation/oxygenation ratio and/or an altered state of consciousness upon admission. These patients have higher mortality rates due to massive hemorrhage, airway injury and/or impaired ventilation. Damage control resuscitation is a systematic approach that aims to limit physiologic deterioration through strategies that address the physiologic debt of trauma. This article aims to describe the experience earned by the Trauma and Emergency Surgery Group (CTE) of Cali, Colombia in the management of the severely injured trauma patient in the emergency department following the basic principles of damage control surgery. Since bleeding is the main cause of death, the management of the severely injured trauma patient in the emergency department requires a multidisciplinary team that performs damage control maneuvers aimed at rapidly controlling bleeding, hemostatic resuscitation, and/or prompt transfer to the operating room, if required.

Un paciente politraumatizado hemodinámicamente inestable es aquel que ingresa al servicio de urgencias con una presión arterial sistólica menor o igual de 90 mmHg, una frecuencia cardiaca mayor o igual a 120 latidos por minuto y un compromiso agudo de la relación ventilación/oxigenación y/o del estado de conciencia. Por esta razón, existe una alta mortalidad dentro de las primeras horas de un trauma severo ya sea por una hemorragia masiva, una lesión de la vía aérea y/o una alteración de la ventilación. Siendo el objetivo de este artículo describir el manejo en urgencias del paciente politraumatizado hemodinámicamente inestable de acuerdo con los principios de control de daños. El manejo del paciente politraumatizado es una estrategia dinámica de alto impacto que requiere de un equipo multidisciplinario de experiencia. El cual debe de evolucionar conjunto a las nuevas herramientas de diagnóstico y tratamiento endovascular que buscan ser un puente para lograr una menor repercusión hemodinámica en el paciente y una más rápida y efectiva estabilización con mayores tasas de sobrevida.