NetMHCpan-4.1 and NetMHCIIpan-4.0: improved predictions of MHC antigen presentation by concurrent motif deconvolution and integration of MS MHC eluted ligand data.

Major histocompatibility complex (MHC) molecules are expressed on the cell surface, where they present peptides to T cells, which gives them a key role in the development of T-cell immune responses. MHC molecules come in two main variants: MHC Class I (MHC-I) and MHC Class II (MHC-II). MHC-I predominantly present peptides derived from intracellular proteins, whereas MHC-II predominantly presents peptides from extracellular proteins. In both cases, the binding between MHC and antigenic peptides is the most selective step in the antigen presentation pathway. Therefore, the prediction of peptide binding to MHC is a powerful utility to predict the possible specificity of a T-cell immune response. Commonly MHC binding prediction tools are trained on binding affinity or mass spectrometry-eluted ligands. Recent studies have however demonstrated how the integration of both data types can boost predictive performances. Inspired by this, we here present NetMHCpan-4.1 and NetMHCIIpan-4.0, two web servers created to predict binding between peptides and MHC-I and MHC-II, respectively. Both methods exploit tailored machine learning strategies to integrate different training data types, resulting in state-of-the-art performance and outperforming their competitors. The servers are available at http://www.cbs.dtu.dk/services/NetMHCpan-4.1/ and http://www.cbs.dtu.dk/services/NetMHCIIpan-4.0/.

NNAlign_MA; MHC Peptidome Deconvolution for Accurate MHC Binding Motif Characterization and Improved T-cell Epitope Predictions.

The set of peptides presented on a cell's surface by MHC molecules is known as the immunopeptidome. Current mass spectrometry technologies allow for identification of large peptidomes, and studies have proven these data to be a rich source of information for learning the rules of MHC-mediated antigen presentation. Immunopeptidomes are usually poly-specific, containing multiple sequence motifs matching the MHC molecules expressed in the system under investigation. Motif deconvolution -the process of associating each ligand to its presenting MHC molecule(s)- is therefore a critical and challenging step in the analysis of MS-eluted MHC ligand data. Here, we describe NNAlign_MA, a computational method designed to address this challenge and fully benefit from large, poly-specific data sets of MS-eluted ligands. NNAlign_MA simultaneously performs the tasks of (1) clustering peptides into individual specificities; (2) automatic annotation of each cluster to an MHC molecule; and (3) training of a prediction model covering all MHCs present in the training set. NNAlign_MA was benchmarked on large and diverse data sets, covering class I and class II data. In all cases, the method was demonstrated to outperform state-of-the-art methods, effectively expanding the coverage of alleles for which accurate predictions can be made, resulting in improved identification of both eluted ligands and T-cell epitopes. Given its high flexibility and ease of use, we expect NNAlign_MA to serve as an effective tool to increase our understanding of the rules of MHC antigen presentation and guide the development of novel T-cell-based therapeutics.

GibbsCluster: unsupervised clustering and alignment of peptide sequences.

Receptor interactions with short linear peptide fragments (ligands) are at the base of many biological signaling processes. Conserved and information-rich amino acid patterns, commonly called sequence motifs, shape and regulate these interactions. Because of the properties of a receptor-ligand system or of the assay used to interrogate it, experimental data often contain multiple sequence motifs. GibbsCluster is a powerful tool for unsupervised motif discovery because it can simultaneously cluster and align peptide data. The GibbsCluster 2.0 presented here is an improved version incorporating insertion and deletions accounting for variations in motif length in the peptide input. In basic terms, the program takes as input a set of peptide sequences and clusters them into meaningful groups. It returns the optimal number of clusters it identified, together with the sequence alignment and sequence motif characterizing each cluster. Several parameters are available to customize cluster analysis, including adjustable penalties for small clusters and overlapping groups and a trash cluster to remove outliers. As an example application, we used the server to deconvolute multiple specificities in large-scale peptidome data generated by mass spectrometry. The server is available at http://www.cbs.dtu.dk/services/GibbsCluster-2.0.

Computational Tools for the Identification and Interpretation of Sequence Motifs in Immunopeptidomes.

Recent advances in proteomics and mass-spectrometry have widely expanded the detectable peptide repertoire presented by major histocompatibility complex (MHC) molecules on the cell surface, collectively known as the immunopeptidome. Finely characterizing the immunopeptidome brings about important basic insights into the mechanisms of antigen presentation, but can also reveal promising targets for vaccine development and cancer immunotherapy. This report describes a number of practical and efficient approaches to analyze immunopeptidomics data, discussing the identification of meaningful sequence motifs in various scenarios and considering current limitations. Guidelines are provided for the filtering of false hits and contaminants, and to address the problem of motif deconvolution in cell lines expressing multiple MHC alleles, both for the MHC class I and class II systems. Finally, it is demonstrated how machine learning can be readily employed by non-expert users to generate accurate prediction models directly from mass-spectrometry eluted ligand data sets.

Recognising angiosarcoma presenting as an enlarging ecchymotic plaque.

Cutaneous angiosarcoma (cAS) is a rare malignant neoplasm of vascular endothelial origin with an unfavourable prognosis. Its diagnosis often faces delays due to its manifestation as an inconspicuous 'bruise-like' lesion in an otherwise asymptomatic individual, leading to a generally low index of suspicion for angiosarcoma. Here, we present a case of a man who presented to his general practitioner with an ecchymotic plaque on his forehead, initially thought to be benign. Over the subsequent 6 weeks, the lesion progressively enlarged and became ulcerated, prompting the patient to represent to his general practitioner. He was urgently referred to a dermatologist and a subsequent biopsy confirmed the diagnosis of cAS. Our presentation of this case serves as a reminder for physicians to maintain a high index of suspicion and low threshold for biopsy for patients with atraumatic ecchymotic lesions.

Accurate MHC Motif Deconvolution of Immunopeptidomics Data Reveals a Significant Contribution of DRB3, 4 and 5 to the Total DR Immunopeptidome.

Mass spectrometry (MS) based immunopeptidomics is used in several biomedical applications including neo-epitope discovery in oncology, next-generation vaccine development and protein-drug immunogenicity assessment. Immunopeptidome data are highly complex given the expression of multiple HLA alleles on the cell membrane and presence of co-immunoprecipitated contaminants. The absence of tools that deal with these challenges effectively and guide the analysis and interpretation of this complex type of data is currently a major bottleneck for the large-scale application of this technique. To resolve this, we here present the MHCMotifDecon that benefits from state-of-the-art HLA class-I and class-II predictions to accurately deconvolute immunopeptidome datasets and assign individual ligands to the most likely HLA molecule, allowing to identify and characterize HLA binding motifs while discarding co-purified contaminants. We have benchmarked the tool against other state-of-the-art methods and illustrated its application on experimental datasets for HLA-DR demonstrating a previously underappreciated role for HLA-DRB3/4/5 molecules in defining HLA class II immune repertoires. With its ease of use, MHCMotifDecon can efficiently guide interpretation of immunopeptidome datasets, serving the discovery of novel T cell targets. MHCMotifDecon is available at https://services.healthtech.dtu.dk/service.php?MHCMotifDecon-1.0.

Use of peripherally inserted central catheters with a dedicated vascular access specialists team versus centrally inserted central catheters in the management of septic shock patients in the ICU.

OBJECTIVES: Peripherally inserted central catheters (PICCs) are increasingly recognized as an alternative to centrally inserted central catheters (CICCs) in critical care, yet the data regarding the safety and feasibility of this choice in septic shock management is growing but still lacking. In this study, we aimed to determine the feasibility, safety, and impact on outcomes of using dedicated vascular access specialist (VAS) teams to insert PICCs versus CICCs on patients admitted to the ICU with septic shock. DESIGN: Retrospective cohort study. SETTING: Mayo Clinic Rochester Medical ICU and Mayo Clinic Arizona Multidisciplinary ICU from 2013 to 2016. PATIENTS: All adult patients hospitalized with diagnosis of septic shock excluding patients who declined authorization for review of their medical records, mixed shock states, and readmissions. INTERVENTIONS: None. MEASUREMENT AND MAIN RESULTS: Comprehensive data regarding septic shock diagnosis and resuscitation were abstracted from electronic medical records. A total of 562 patients with septic shock were included in the study; 215 patients were resuscitated utilizing a PICC and 347 were resuscitated using a CICC. On univariate analysis, the time to central line insertion and time to vasopressor initiation were found to be reduced in those who received PICC at time of ICU admission versus CICC. Other favorable outcomes were also observed in those who received PICC versus CICC including shorter ICU length of stay and lower unadjusted hospital mortality. A multivariable analysis for hospital mortality showed that after adjusting for important covariates, neither the time to central line insertion nor the time to vasopressor initiation was associated with a lower hospital mortality. CONCLUSIONS: Across two tertiary referral centers within the same enterprise, use of a dedicated VAS team for insertion of PICCs for initial resuscitation in patients with septic shock was feasible and associated with shorter time to central venous access and initiation of vasopressors; however, adjusted hospital mortality was not different between the two groups.

Joint Recommendations From The Latin American Association of Cardiac and Endovascular Surgery (LACES) and The Cardiovascular Anesthesia Committee of The Latin American Confederation of Anesthesia Societies (CLASA) on the Timing for Cardiac Surgery After COVID-19 Infection.

INTRODUCTION: Since the coronavirus disease 2019 (COVID-19) pandemic, cardiac surgeries in patients with previous infection by COVID-19 were suspended or postponed, which led to surgeries performed in patients with an advanced stage of their disease and an increase in the waiting list. There is a heterogeneous attitude in Latin America on the optimal timing to cardiac surgery in patients with previous COVID-19 infection due to scarce data on its outcome. Two Latin American associations joined to establish common suggestions on the optimal timing of surgery in patients with previous COVID-19 infection. METHODS: Data collection was performed using a pre-established form, which included year of publication, objective, type of study (prospective/retrospective, descriptive/analytical), number of patients, year of study, waiting time between infection and surgery, type of surgery, morbidity, mortality, and conclusions regarding the association between mortality and morbidity. Final recommendations were approved by the board of directors of Latin American Association of Cardiac and Endovascular Surgery (LACES) and Latin American Confederation of Anesthesia Societies (CLASA). RESULTS: Of the initial 1,016 articles, 11 comprised the final selection. Only six of them included patients who underwent cardiac surgery. According to the analyzed literature, optimal timing for cardiac surgery needs to consider the following aspects: deferable surgery, symptomatic COVID-19 infection, completeness of COVID-19 vaccination. CONCLUSION: These recommendations derive from the analysis of the scarce literature published at present on outcomes after cardiac surgery in patients with previous COVID-19 infection. These are to be taken as a dynamic recommendation in which Latin American reality was taken into consideration.

Footprints of antigen processing boost MHC class II natural ligand predictions.

BACKGROUND: Major histocompatibility complex class II (MHC-II) molecules present peptide fragments to T cells for immune recognition. Current predictors for peptide to MHC-II binding are trained on binding affinity data, generated in vitro and therefore lacking information about antigen processing. METHODS: We generate prediction models of peptide to MHC-II binding trained with naturally eluted ligands derived from mass spectrometry in addition to peptide binding affinity data sets. RESULTS: We show that integrated prediction models incorporate identifiable rules of antigen processing. In fact, we observed detectable signals of protease cleavage at defined positions of the ligands. We also hypothesize a role of the length of the terminal ligand protrusions for trimming the peptide to the MHC presented ligand. CONCLUSIONS: The results of integrating binding affinity and eluted ligand data in a combined model demonstrate improved performance for the prediction of MHC-II ligands and T cell epitopes and foreshadow a new generation of improved peptide to MHC-II prediction tools accounting for the plurality of factors that determine natural presentation of antigens.

Joint Recommendations From The Latin American Association of Cardiac and Endovascular Surgery (LACES) and The Cardiovascular Anesthesia Committee of The Latin American Confederation of Anesthesia Societies (CLASA) on the Timing for Cardiac Surgery After COVID-19 Infection

ABSTRACT Introduction: Since the coronavirus disease 2019 (COVID-19) pandemic, cardiac surgeries in patients with previous infection by COVID-19 were suspended or postponed, which led to surgeries performed in patients with an advanced stage of their disease and an increase in the waiting list. There is a heterogeneous attitude in Latin America on the optimal timing to cardiac surgery in patients with previous COVID-19 infection due to scarce data on its outcome. Two Latin American associations joined to establish common suggestions on the optimal timing of surgery in patients with previous COVID-19 infection. Methods: Data collection was performed using a pre-established form, which included year of publication, objective, type of study (prospective/retrospective, descriptive/analytical), number of patients, year of study, waiting time between infection and surgery, type of surgery, morbidity, mortality, and conclusions regarding the association between mortality and morbidity. Final recommendations were approved by the board of directors of Latin American Association of Cardiac and Endovascular Surgery (LACES) and Latin American Confederation of Anesthesia Societies (CLASA). Results: Of the initial 1,016 articles, 11 comprised the final selection. Only six of them included patients who underwent cardiac surgery. According to the analyzed literature, optimal timing for cardiac surgery needs to consider the following aspects: deferable surgery, symptomatic COVID-19 infection, completeness of COVID-19 vaccination. Conclusion: These recommendations derive from the analysis of the scarce literature published at present on outcomes after cardiac surgery in patients with previous COVID-19 infection. These are to be taken as a dynamic recommendation in which Latin American reality was taken into consideration.

Zika virus-induced neurological critical illness in Latin America: Severe Guillain-Barre Syndrome and encephalitis.

Zika virus (ZIKAV) is classically described as causing minor symptoms in adult patients, however neurologic complications have been recognized. The recent outbreak in Central and South America has resulted in serious illness in some adult patients. We report adult patients in Latin America diagnosed with ZIKAV infection admitted to Intensive Care Units (ICUs). METHODS: Multicenter, prospective case series of adult patients with laboratory diagnosis of ZIKAV in 16 ICUs in 8 countries. RESULTS: Between December 1st 2015 and April 2nd 2016, 16 ICUs in 8 countries enrolled 49 critically ill patients with diagnosis of ZIKAV infection. We included 10 critically ill patients with ZIKAV infection, as diagnosed with RT-PCR, admitted to the ICU. Neurologic manifestations concordant with Guillain-Barre Syndrome (GBS) were present in all patients, although 2 evolved into an encephalitis-like picture. 2 cases died, one due to encephalitis, the other septic shock. CONCLUSIONS: Differing from what was usually reported, ZIKAV infection can result in life-threatening neurologic illness in adults, including GBS and encephalitis. Collaborative reporting to identify severe illness from an emerging pathogen can provide valuable insights into disease epidemiology and clinical presentation, and inform public health authorities about acute care priorities.

Analysis of the Revised Trauma Score (RTS) in 200 victims of different trauma mechanisms.

OBJECTIVE:: to analyze the epidemiological profile and mortality associated with the Revised Trauma Score (RTS) in trauma victims treated at a university hospital. METHODS:: we conducted a descriptive, cross-sectional study of trauma protocols (prospectively collected) from December 2013 to February 2014, including trauma victims admitted in the emergency room of the Cajuru University Hospital. We set up three groups: (G1) penetrating trauma to the abdomen and chest, (G2) blunt trauma to the abdomen and chest, and (G3) traumatic brain injury. The variables we analyzed were: gender, age, day of week, mechanism of injury, type of transportation, RTS, hospitalization time and mortality. RESULTS:: we analyzed 200 patients, with a mean age of 36.42 ± 17.63 years, and 73.5% were male. The mean age was significantly lower in G1 than in the other groups (p <0.001). Most (40%) of the visits occurred on weekends and the most common pre-hospital transport service (58%) was the SIATE (Emergency Trauma Care Integrated Service). The hospital stay was significantly higher in G1 compared with the other groups (p <0.01). Regarding mortality, there were 12%, 1.35% and 3.95% of deaths in G1, G2 and G3, respectively. The median RTS among the deaths was 5.49, 7.84 and 1.16, respectively, for the three groups. CONCLUSION:: the majority of patients were young men. RTS was effective in predicting mortality in traumatic brain injury, however failing to predict it in patients suffering from blunt and penetrating trauma. OBJETIVO:: analisar o perfil epidemiológico e a mortalidade associada ao escore de trauma revisado (RTS) em vítimas de trauma atendidas em um hospital universitário. MÉTODOS:: estudo transversal descritivo de protocolos de trauma (coletados prospectivamente) de dezembro de 2013 a fevereiro de 2014, incluindo vítimas de trauma admitidas na sala de emergência do Hospital Universitário Cajuru. Três grupos foram criados: (G1) trauma penetrante em abdome e tórax, (G2) trauma contuso em abdome e tórax, e (G3) trauma cranioencefálico. As variáveis analisadas foram: sexo, idade, dia da semana, mecanismo de trauma, tipo de transporte, RTS, tempo de internamento e mortalidade. RESULTADOS:: analisou-se 200 pacientes, com média de idade de 36,42 ± 17,63 anos, sendo 73,5% do sexo masculino. A média de idade no G1 foi significativamente menor do que nos demais grupos (p <0,001). A maioria (40%) dos atendimentos ocorreu nos finais de semana e o serviço de transporte pré-hospitalar mais frequente (58%) foi o SIATE (Serviço Integrado de Atendimento ao Trauma em Emergência). O tempo de internamento foi significativamente maior no G1, em comparação aos demais grupos (p <0,01). Quanto à mortalidade, houve 12%, 1,35% e 3,95% de óbitos nos grupos G1, G2 e G3, respectivamente. A mediana do RTS entre os óbitos foi 5,49, 7,84 e 1,16, respectivamente, para os três grupos. CONCLUSÃO:: a maioria dos pacientes eram homens jovens. O RTS mostrou-se efetivo na predição de mortalidade no trauma cranioencefálico, entretanto falhou ao analisar pacientes vítimas de trauma contuso e penetrante.

Analysis of the Revised Trauma Score (RTS) in 200 victims of different trauma mechanisms / Avaliação do Escore de Trauma Revisado (RTS) em 200 vítimas de trauma com mecanismos diferentes

ABSTRACT Objective: to analyze the epidemiological profile and mortality associated with the Revised Trauma Score (RTS) in trauma victims treated at a university hospital. Methods: we conducted a descriptive, cross-sectional study of trauma protocols (prospectively collected) from December 2013 to February 2014, including trauma victims admitted in the emergency room of the Cajuru University Hospital. We set up three groups: (G1) penetrating trauma to the abdomen and chest, (G2) blunt trauma to the abdomen and chest, and (G3) traumatic brain injury. The variables we analyzed were: gender, age, day of week, mechanism of injury, type of transportation, RTS, hospitalization time and mortality. Results: we analyzed 200 patients, with a mean age of 36.42 ± 17.63 years, and 73.5% were male. The mean age was significantly lower in G1 than in the other groups (p <0.001). Most (40%) of the visits occurred on weekends and the most common pre-hospital transport service (58%) was the SIATE (Emergency Trauma Care Integrated Service). The hospital stay was significantly higher in G1 compared with the other groups (p <0.01). Regarding mortality, there were 12%, 1.35% and 3.95% of deaths in G1, G2 and G3, respectively. The median RTS among the deaths was 5.49, 7.84 and 1.16, respectively, for the three groups. Conclusion: the majority of patients were young men. RTS was effective in predicting mortality in traumatic brain injury, however failing to predict it in patients suffering from blunt and penetrating trauma.

RESUMO Objetivo: analisar o perfil epidemiológico e a mortalidade associada ao escore de trauma revisado (RTS) em vítimas de trauma atendidas em um hospital universitário. Métodos: estudo transversal descritivo de protocolos de trauma (coletados prospectivamente) de dezembro de 2013 a fevereiro de 2014, incluindo vítimas de trauma admitidas na sala de emergência do Hospital Universitário Cajuru. Três grupos foram criados: (G1) trauma penetrante em abdome e tórax, (G2) trauma contuso em abdome e tórax, e (G3) trauma cranioencefálico. As variáveis analisadas foram: sexo, idade, dia da semana, mecanismo de trauma, tipo de transporte, RTS, tempo de internamento e mortalidade. Resultados: analisou-se 200 pacientes, com média de idade de 36,42 ± 17,63 anos, sendo 73,5% do sexo masculino. A média de idade no G1 foi significativamente menor do que nos demais grupos (p <0,001). A maioria (40%) dos atendimentos ocorreu nos finais de semana e o serviço de transporte pré-hospitalar mais frequente (58%) foi o SIATE (Serviço Integrado de Atendimento ao Trauma em Emergência). O tempo de internamento foi significativamente maior no G1, em comparação aos demais grupos (p <0,01). Quanto à mortalidade, houve 12%, 1,35% e 3,95% de óbitos nos grupos G1, G2 e G3, respectivamente. A mediana do RTS entre os óbitos foi 5,49, 7,84 e 1,16, respectivamente, para os três grupos. Conclusão: a maioria dos pacientes eram homens jovens. O RTS mostrou-se efetivo na predição de mortalidade no trauma cranioencefálico, entretanto falhou ao analisar pacientes vítimas de trauma contuso e penetrante.