Measurement of IFN-γ and IL-2 for the assessment of the cellular immunity against SARS-CoV-2.

The study of specific T-cell responses against SARS-CoV-2 is important for understanding long-term immunity and infection management. The aim of this study was to assess the dual IFN-γ and IL-2 detection, using a SARS-CoV-2 specific fluorescence ELISPOT, in patients undergoing acute disease, during convalescence, and after vaccination. We also evaluated humoral response and compared with T-cells with the aim of correlating both types of responses, and increase the number of specific response detection. Blood samples were drawn from acute COVID-19 patients and convalescent individuals classified according to disease severity; and from unvaccinated and vaccinated uninfected individuals. IgGs against Spike and nucleocapsid, IgMs against nucleocapsid, and neutralizing antibodies were also analyzed. Our results show that IFN-γ in combination with IL-2 increases response detection in acute and convalescent individuals (p = 0.023). In addition, IFN-γ detection can be a useful biomarker for monitoring severe acute patients, as our results indicate that those individuals with a poor outcome have lower levels of this cytokine. In some cases, the lack of cellular immunity is compensated by antibodies, confirming the role of both types of immune responses in infection, and confirming that their dual detection can increase the number of specific response detections. In summary, IFN-γ/IL-2 dual detection is promising for characterizing and assessing the immunization status, and helping in the patient management.

HLA-DR Expression on Monocytes and Sepsis Index Are Useful in Predicting Sepsis.

The reduction of mortality in patients with sepsis depends on the early identification and treatment of at-risk patients. The aim was to evaluate the HLA-DR expression on the surface of monocytes (MHLA-DR ratio), the sepsis index (CD64 expression on neutrophils/MHLA-DR ratio), and C-reactive protein (CRP) with the development of sepsis. We prospectively enrolled 77 critically ill patients, 59 with stroke and 18 with traumatic brain injuries. The biomarkers were tested at the baseline and 3, 6, 9, 12, and 15 days later. Most patients (71%) developed sepsis (4.2 ± 1.3 days after admission). On day 3, those subsequently developing sepsis had lower levels of MHLA-DR+ (81.7 ± 16.2% vs. 88.5 ± 12.1%, p < 0.05) and higher sepsis indexes (0.19 ± 0.19 vs. 0.08 ± 0.08, p < 0.01) than those not developing sepsis. The MHLA-DR ratio slowly recovered before day 6, while the sepsis index remained raised in septic patients up to day 9 (p < 0.05). To predict the development of sepsis, optimal cut-offs were CRP levels > 106.90 mg/mL (74.19% sensitivity, 69.49 specificity) and MHLA-DR expression rate < 72.80% (45.31% sensitivity, 89.47% specificity). The periodic monitoring of the MHLA-DR expression together with CRP and sepsis index may help to identify patients in the ICU at increased risk of developing sepsis.

Measuring T-Cell Responses against SARS-CoV-2 Is of Utility for Disease and Vaccination Management.

The measurement of specific T-cell responses can be a useful tool for COVID-19 diagnostics and clinical management. In this study, we evaluated the IFN-γ T-cell response against the main SARS-CoV-2 antigens (spike, nucleocapsid and membrane) in acute and convalescent individuals classified according to severity, and in vaccinated and unvaccinated controls. IgG against spike and nucleocapsid were also measured. Spike antigen triggered the highest number of T-cell responses. Acute patients showed a low percentage of positive responses when compared to convalescent (71.6% vs. 91.7%, respectively), but increased during hospitalization and with severity. Some convalescent patients showed an IFN-γ T-cell response more than 200 days after diagnosis. Only half of the vaccinated individuals displayed an IFN-γ T-cell response after the second dose. IgG response was found in a higher percentage of individuals compared to IFN-γ T-cell responses, and moderate correlations between both responses were seen. However, in some acute COVID-19 patients specific T-cell response was detected, but not IgG production. We found that the chances of an IFN-γ T-cell response against SARS-CoV-2 is low during acute phase, but may increase over time, and that only half of the vaccinated individuals had an IFN-γ T-cell response after the second dose.

Kinetics of humoral immune response over 17 months of COVID-19 pandemic in a large cohort of healthcare workers in Spain: the ProHEpiC-19 study.

BACKGROUND: Understanding the immune response to the SARS-CoV-2 virus is critical for efficient monitoring and control strategies. The ProHEpic-19 cohort provides a fine-grained description of the kinetics of antibodies after SARS-CoV-2 infection with an exceptional resolution over 17 months. METHODS: We established a cohort of 769 healthcare workers including healthy and infected with SARS-CoV-2 in northern Barcelona to determine the kinetics of the IgM against the nucleocapsid (N) and the IgG against the N and spike (S) of SARS-CoV-2 in infected healthcare workers. The study period was from 5 May 2020 to 11 November 2021.We used non-linear mixed models to investigate the kinetics of IgG and IgM measured at nine time points over 17 months from the date of diagnosis. The model included factors of time, gender, and disease severity (asymptomatic, mild-moderate, severe-critical) to assess their effects and their interactions. FINDINGS: 474 of the 769 participants (61.6%) became infected with SARS-CoV-2. Significant effects of gender and disease severity were found for the levels of all three antibodies. Median IgM(N) levels were already below the positivity threshold in patients with asymptomatic and mild-moderate disease at day 270 after the diagnosis, while IgG(N and S) levels remained positive at least until days 450 and 270, respectively. Kinetic modelling showed a general rise in both IgM(N) and IgG(N) levels up to day 30, followed by a decay with a rate depending on disease severity. IgG(S) levels remained relatively constant from day 15 over time. INTERPRETATION: IgM(N) and IgG(N, S) SARS-CoV-2 antibodies showed a heterogeneous kinetics over the 17 months. Only the IgG(S) showed a stable increase, and the levels and the kinetics of antibodies varied according to disease severity. The kinetics of IgM and IgG observed over a year also varied by clinical spectrum can be very useful for public health policies around vaccination criteria in adult population. FUNDING: Regional Ministry of Health of the Generalitat de Catalunya (Call COVID19-PoC SLT16_04; NCT04885478).

Negative predictive value of procalcitonin to rule out bacterial respiratory co-infection in critical covid-19 patients.

BACKGROUND: Procalcitonin (PCT) and C-Reactive Protein (CRP) are useful biomarkers to differentiate bacterial from viral or fungal infections, although the association between them and co-infection or mortality in COVID-19 remains unclear. METHODS: The study represents a retrospective cohort study of patients admitted for COVID-19 pneumonia to 84 ICUs from ten countries between (March 2020-January 2021). Primary outcome was to determine whether PCT or CRP at admission could predict community-acquired bacterial respiratory co-infection (BC) and its added clinical value by determining the best discriminating cut-off values. Secondary outcome was to investigate its association with mortality. To evaluate the main outcome, a binary logistic regression was performed. The area under the curve evaluated diagnostic performance for BC prediction. RESULTS: 4635 patients were included, 7.6% fulfilled BC diagnosis. PCT (0.25[IQR 0.1-0.7] versus 0.20[IQR 0.1-0.5]ng/mL, p<0.001) and CRP (14.8[IQR 8.2-23.8] versus 13.3 [7-21.7]mg/dL, p=0.01) were higher in BC group. Neither PCT nor CRP were independently associated with BC and both had a poor ability to predict BC (AUC for PCT 0.56, for CRP 0.54). Baseline values of PCT<0.3ng/mL, could be helpful to rule out BC (negative predictive value 91.1%) and PCT≥0.50ng/mL was associated with ICU mortality (OR 1.5,p<0.001). CONCLUSIONS: These biomarkers at ICU admission led to a poor ability to predict BC among patients with COVID-19 pneumonia. Baseline values of PCT<0.3ng/mL may be useful to rule out BC, providing clinicians a valuable tool to guide antibiotic stewardship and allowing the unjustified overuse of antibiotics observed during the pandemic, additionally PCT≥0.50ng/mL might predict worsening outcomes.

Bronchoscopy in Critically Ill COVID-19 Patients: Findings, Microbiological Profile, and Coinfection.

BACKGROUND: Bronchoscopy is a widely use technique in critically ill patients. Nosocomial coinfections are a cause of morbidity and mortality in intensive care units. OBJECTIVES: Our aim was to describe bronchoscopy findings and analyze microbiological profile and probably coinfection through bronchial aspirate (BA) samples in patients with coronavirus disease 2019 pneumonia requiring intensive care unit admission. METHODS: Retrospective observational study analyzing the BA samples collected from intubated patients with coronavirus disease 2019 in a referral Hospital (Spain). RESULTS: One hundred fifty-five consecutive BA samples were collected from 75 patients. Ninety (58%) were positive cultures for different microorganisms, 11 (7.1%) were polymicrobial, and 37 (23.7%) contained resistant microorganisms. There was a statistically significant association between increased days of orotracheal intubation and positive BA (18.9 vs. 10.9 d, P<0.01), polymicrobial infection (22.11 vs. 13.54, P<0.01) and isolation of resistant microorganisms (18.88 vs. 10.94, P<0.01). In 88% of the cases a new antibiotic or change in antibiotic treatment was made. CONCLUSION: Bronchoscopy in critically ill patient was safe and could be useful to manage these patients and conduct the microbiological study, that seems to be higher and different than in nonepidemic periods. The longer the intubation period, the greater the probability of coinfection, isolation of resistant microorganisms and polymicrobial infection.

Major bleeding in patients with pulmonary embolism presenting with syncope.

INTRODUCTION: Syncope has been shown to be a risk factor of bleeding in patients receiving thrombolytic therapy for acute pulmonary embolism (PE). Whether syncope predicts bleeding in a broader population of patients with PE remains unknown. METHODS: We used the RIETE registry data to assess whether initial presentation with syncope could predict bleeding in PE patients receiving anticoagulant therapy, and to explore the association between presence of syncope and timing and site of major bleeding events. RESULTS: Among 45,765 patients with acute PE from March 2001 to January 2021, 6760 (14.8%) had syncope. Patients with syncope were older and more likely to have hypotension, tachycardia, hypoxaemia or elevated troponin levels than those without syncope. They also were more likely to receive thrombolytics. During the first 90 days, 1097 patients (2.4%) suffered major bleeding (gastrointestinal 335, hematoma 271 and intracranial 163) and 3611 died (158 had fatal bleeding). Patients with syncope had a higher rate of major bleeding (odds ratio [OR]: 1.63; 95% CI: 1.41-1.89) and a nonsignificantly higher rate of fatal bleeding (OR: 1.47; 95% CI: 0.99-2.17) than those without syncope. Multivariable analysis confirmed that patients with syncope were at increased risk for major bleeding (adjusted hazard ratio [aHR]: 1.34; 95% CI: 1.15-1.55). On sensitivity analysis, the increased risk for major bleeding was confirmed in patients initially receiving anticoagulant therapy without thrombolytics at 7 days (aHR: 1.47; 95% CI: 1.13-1.91) and 90 days (aHR: 1.33; 95%CI: 1.13-1.56). DISCUSSION: Syncope is a predictor of major bleeding events in patients with PE, even among those receiving anticoagulation monotherapy.

Mortality comparison between the first and second/third waves among 3,795 critical COVID-19 patients with pneumonia admitted to the ICU: A multicentre retrospective cohort study.

BACKGROUND: It is unclear whether the changes in critical care throughout the pandemic have improved the outcomes in coronavirus disease 2019 (COVID-19) patients admitted to the intensive care units (ICUs). METHODS: We conducted a retrospective cohort study in adults with COVID-19 pneumonia admitted to 73 ICUs from Spain, Andorra and Ireland between February 2020 and March 2021. The first wave corresponded with the period from February 2020 to June 2020, whereas the second/third waves occurred from July 2020 to March 2021. The primary outcome was ICU mortality between study periods. Mortality predictors and differences in mortality between COVID-19 waves were identified using logistic regression. FINDINGS: As of March 2021, the participating ICUs had included 3795 COVID-19 pneumonia patients, 2479 (65·3%) and 1316 (34·7%) belonging to the first and second/third waves, respectively. Illness severity scores predicting mortality were lower in the second/third waves compared with the first wave according with the Acute Physiology and Chronic Health Evaluation system (median APACHE II score 12 [IQR 9-16] vs 14 [IQR 10-19]) and the organ failure assessment score (median SOFA 4 [3-6] vs 5 [3-7], p<0·001). The need of invasive mechanical ventilation was high (76·1%) during the whole study period. However, a significant increase in the use of high flow nasal cannula (48·7% vs 18·2%, p<0·001) was found in the second/third waves compared with the first surge. Significant changes on treatments prescribed were also observed, highlighting the remarkable increase on the use of corticosteroids to up to 95.9% in the second/third waves. A significant reduction on the use of tocilizumab was found during the study (first wave 28·9% vs second/third waves 6·2%, p<0·001), and a negligible administration of lopinavir/ritonavir, hydroxychloroquine, and interferon during the second/third waves compared with the first wave. Overall ICU mortality was 30·7% (n = 1166), without significant differences between study periods (first wave 31·7% vs second/third waves 28·8%, p = 0·06). No significant differences were found in ICU mortality between waves according to age subsets except for the subgroup of 61-75 years of age, in whom a reduced unadjusted ICU mortality was observed in the second/third waves (first 38·7% vs second/third 34·0%, p = 0·048). Non-survivors were older, with higher severity of the disease, had more comorbidities, and developed more complications. After adjusting for confounding factors through a multivariable analysis, no significant association was found between the COVID-19 waves and mortality (OR 0·81, 95% CI 0·64-1·03; p = 0·09). Ventilator-associated pneumonia rate increased significantly during the second/third waves and it was independently associated with ICU mortality (OR 1·48, 95% CI 1·19-1·85, p<0·001). Nevertheless, a significant reduction both in the ICU and hospital length of stay in survivors was observed during the second/third waves. INTERPRETATION: Despite substantial changes on supportive care and management, we did not find significant improvement on case-fatality rates among critical COVID-19 pneumonia patients. FUNDING: Ricardo Barri Casanovas Foundation (RBCF2020) and SEMICYUC.

Elevated Neopterin Levels Predict Fatal Outcome in SARS-CoV-2-Infected Patients.

Highlights: Innate immune activation during Covid-19 infection is associated with pernicious clinical outcome. Background: Coronavirus disease 2019 (Covid-19) is a worldwide threat that has already caused more than 3 000 000 deaths. It is characterized by different patterns of disease evolution depending on host factors among which old-age and pre-existing comorbidities play a detrimental role. Previous coronavirus epidemics, notably SARS-CoV, were associated with increased serum neopterin levels, which can be interpreted as a sign of acute innate immunity in response to viral infection. Here we hypothesize that neopterin may serve as a biomarker of SARS-CoV-2 viral infection and Covid-19 disease severity. Methods: We measured neopterin blood levels by ELISA. Seric concentration was quantified from 256 healthy donors and 374 Covid-19 patients at hospital admission. Enrolled Covid-19 patients were all symptomatic and displayed a large spectrum of comorbidities. Patients were followed until disease resolution or death. Results: Severe and critically ill SARS-CoV-2 infected patients were characterized by a profound exacerbation of immune activation characterized by elevated neopterin blood levels. Systemic neopterin levels above 19nM stratified healthy individuals from Covid-19 patients with 87% specificity and 100% sensitivity. Moreover, systemic neopterin levels above 53nM differentiated non-survivors from survivors with 64% specificity and 100% sensitivity. Conclusion: We propose that neopterin concentration measured at arrival to hospital is a hallmark of severe Covid-19 and identifies a high-risk population of pernicious clinical outcome with a need for special medical care.

Genotypic and Phenotypic Characterization of Staphylococcus aureus Isolates from the Respiratory Tract in Mechanically-Ventilated Patients.

Staphylococcus aureus is a commensal and frequent colonizer of the upper respiratory tract. When mechanical ventilation disrupts natural defenses, S. aureus is frequently isolated from the lower airways, but distinguishing between colonization and infection is difficult. The objectives of this study were (1) to investigate the bacterial genome sequence in consecutive isolates in order to identify changes related to the pathological adaptation to the lower respiratory tract and (2) to explore the relationship between specific phenotypic and genotypic features with the patient's study group, persistence of the clinical isolate and clinical outcome. A set of 94 clinical isolates were selected and corresponded to 34 patients that were classified as having pneumonia (10), tracheobronchitis (11) and bronchial colonization (13). Clinical strains were phenotypically characterized by conventional identification and susceptibility testing methods. Isolates underwent whole genome sequencing using Illumina HiSeq4000. Genotypic characterization was performed with an in-house pipeline (BacterialTyper). Genomic variation arising within-host was determined by comparing mapped sequences and de novo assemblies. Virulence factors important in staphylococcal colonization and infection were characterized using previously established functional assays. (1) Toxin production was assessed using a THP-1 cytotoxicity assay, which reports on the gross cytotoxicity of individual isolates. In addition, we investigated the expression of the major virulence factor, alpha-toxin (Hla) by Western blot. (2) Adhesion to the important extracellular matrix molecule, fibronectin, was determined using a standardized microtitre plate assay. Finally, invasion experiments using THP-1 and A539 cell lines and selected clinical strains were also performed. Repeated isolation of S. aureus from endotracheal aspirate usually reflects persistence of the same strain. Within-host variation is detectable in this setting, but it shows no evidence of pathological adaptation related to virulence, resistance or niche adaptations. Cytotoxicity was variable among isolates with 14 strains showing no cytotoxicity, with these latter presenting an unaltered Fn binding capacity. No changes on cytotoxicity were reported when comparing study groups. Fn binding capacity was reported for almost all strains, with the exception of two strains that presented the lowest values. Strains isolated from patients with pneumonia presented a lower capacity of adhesion in comparison to those isolated during tracheobronchitis (p = 0.002). Hla was detected in 71 strains (75.5%), with most of the producer strains in pneumonia and bronchial colonization group (p = 0.06). In our cohort, Hla expression (presence or absence) in sequential isolates was usually preserved (70%) although in seven cases the expression varied over time. No relationship was found between low cytotoxicity and intracellular persistence in invasion experiments. In our study population, persistent S. aureus isolation from airways in ventilated patients does not reflect pathological adaptation. There is an important diversity of sequence types. Cytotoxicity is variable among strains, but no association with study groups was found, whereas isolates from patients with pneumonia had lower adhesion capability. Favorable clinical outcome correlated with increased bacterial adhesion in vitro. Most of the strains isolated from the lower airways were Hla producers and no correlation with an adverse outcome was reported. The identification of microbial factors that contribute to virulence is relevant to optimize patient management during lower respiratory tract infections.

Insuficiencia respiratoria secundaria a fístula pancreático-torácica / Respiratory Failure Due to Pancreatic-Thoracic Fistula

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Persistent Isolation of Staphylococcus aureus in Mechanically-ventilated Patients: Impact of Host-Pathogen Factors on Outcome / Aislamiento persistente de Staphylococcus aureus en pacientes sometidos a ventilación mecánica: impacto de factores del huésped y del patógeno en la evolución clínica

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Evaluation of the Broad-Range PCR/ESI-MS Technology in Blood Specimens for the Molecular Diagnosis of Bloodstream Infections.

BACKGROUND: Rapid identification of the etiological agent in bloodstream infections is of vital importance for the early administration of the most appropriate antibiotic therapy. Molecular methods may offer an advantage to current culture-based microbiological diagnosis. The goal of this study was to evaluate the performance of IRIDICA, a platform based on universal genetic amplification followed by mass spectrometry (PCR/ESI-MS) for the molecular diagnosis of sepsis-related pathogens directly from the patient's blood. METHODS: A total of 410 whole blood specimens from patients admitted to Emergency Room (ER) and Intensive Care Unit (ICU) with clinical suspicion of sepsis were tested with the IRIDICA BAC BSI Assay (broad identification of bacteria and Candida spp.). Microorganisms grown in culture and detected by IRIDICA were compared considering blood culture as gold standard. When discrepancies were found, clinical records and results from other cultures were taken into consideration (clinical infection criterion). RESULTS: The overall positive and negative agreement of IRIDICA with blood culture in the analysis by specimen was 74.8% and 78.6%, respectively, rising to 76.9% and 87.2% respectively, when compared with the clinical infection criterion. Interestingly, IRIDICA detected 41 clinically significant microorganisms missed by culture, most of them from patients under antimicrobial treatment. Of special interest were the detections of one Mycoplasma hominis and two Mycobacterium simiae in immunocompromised patients. When ICU patients were analyzed separately, sensitivity, specificity, positive and negative predictive values compared with blood culture were 83.3%, 78.6%, 33.9% and 97.3% respectively, and 90.5%, 87.2%, 64.4% and 97.3% respectively, in comparison with the clinical infection criterion. CONCLUSIONS: IRIDICA is a promising technology that offers an early and reliable identification of a wide variety of pathogens directly from the patient's blood within 6h, which brings the opportunity to improve management of septic patients, especially for those critically ill admitted to the ICU.

Factores pronósticos tras paro cardiorrespiratorio. Utilidad del vídeo-electroencefalograma precoz / Prognostic factors after cardiac arrest. Usefulness of early video-electroencephalogram

Fundamento y objetivo: La valoración de los enfermos tras un paro cardiorrespiratorio (PCR) es importante para la toma de decisiones sobre la limitación del esfuerzo terapéutico. El estudio buscó factores pronósticos en los pacientes tras un PCR recuperado. Material y método: Estudio retrospectivo de enfermos en coma tras un PCR. Se analizaron la edad, el sexo, el Glasgow Score Coma (GCS), los reflejos pupilares, las variables relacionadas con el PCR (causa, duración, presenciado o no presenciado), el estatus mioclónico y los patrones del electroencefalograma (EEG): mal pronóstico, pronóstico incierto y benigno. Resultados: Se estudiaron 50 enfermos. Las variables asociadas con mortalidad fueron la ausencia de reflejos pupilares (riesgo relativo [RR] 0,277, intervalo de confianza del 95% [IC 95%] 0,103-0,741, p = 0,01), el GCS bajo (RR 0,701, IC 95% 0,542-0,908, p = 0,007) y el estatus mioclónico (RR 0,38, IC 95% 0,176-0,854, p = 0,01). En 22 pacientes se analizaron los patrones del EEG, sin apreciarse significación estadística. Conclusiones: La ausencia de reflejos pupilares, la baja puntuación del GCS y el estatus mioclónico son factores de mal pronóstico en pacientes tras un PCR. Los patrones del EEG mostraron una tendencia no significativa de asociación con el pronóstico (AU)

Background and objective: Predictors of unfavorable outcome in patients after cardiopulmonary arrest (CPA) are important to make decisions about the limitation of therapeutic efforts. The aim was to analyze the clinical variables in the prognosis of patients recovered after CPA. Material and method: Retrospective study on comatose patients with recovered CPA. The variables were: age, sex, Glasgow Coma Score (GCS), pupillary light reflex, other variables related to CPA (cause, duration, witnessed or not witnessed), myoclonic status and electroencephalographic (EEG) patterns. Results: Fifty patients were studied. The variables associated with mortality were the absence of pupillary light reflex (hazard ratio [HR] 0.277, 95% confidence interval [95% CI] 0.103-0.741, P = .01), a low GCS (HR 0.701, 95% CI 0.542-0.908, P = .007) and myoclonic state (HR 0.38, 95% CI 0.176-0.854, P = .01). We evaluated the EEG patterns in 22 patients. No statistical significance was observed. Conclusions: The absence of pupillary light reflex, a low GCS and myoclonic state are prognostic factors in patients recovered after a CPA. The EEG patterns showed a nonsignificant association with prognosis (AU)

[Prognostic factors after cardiac arrest. Usefulness of early video-electroencephalogram]. / Factores pronósticos tras paro cardiorrespiratorio. Utilidad del vídeo-electroencefalograma precoz.

BACKGROUND AND OBJECTIVE: Predictors of unfavorable outcome in patients after cardiopulmonary arrest (CPA) are important to make decisions about the limitation of therapeutic efforts. The aim was to analyze the clinical variables in the prognosis of patients recovered after CPA. MATERIAL AND METHOD: Retrospective study on comatose patients with recovered CPA. The variables were: age, sex, Glasgow Coma Score (GCS), pupillary light reflex, other variables related to CPA (cause, duration, witnessed or not witnessed), myoclonic status and electroencephalographic (EEG) patterns. RESULTS: Fifty patients were studied. The variables associated with mortality were the absence of pupillary light reflex (hazard ratio [HR] 0.277, 95% confidence interval [95% CI] 0.103-0.741, P=.01), a low GCS (HR 0.701, 95% CI 0.542-0.908, P=.007) and myoclonic state (HR 0.38, 95% CI 0.176-0.854, P=.01). We evaluated the EEG patterns in 22 patients. No statistical significance was observed. CONCLUSIONS: The absence of pupillary light reflex, a low GCS and myoclonic state are prognostic factors in patients recovered after a CPA. The EEG patterns showed a nonsignificant association with prognosis.

Disfunción cardiaca asociada a miositis granulomatosa / Granulomatous myositis and cardiac dysfunction

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