Characteristics and risk factors associated with mortality during the first cycle of prone secondary to ARDS due to SARS-CoV-2 pneumonia / Características y factores de riesgo asociados a mortalidad durante el primer ciclo de prono por SDRA secundario a neumonía por SARS-CoV-2

Objective To analyze characteristics, changes in oxygenation, and pulmonary mechanics, in mechanically ventilated patients with ARDS due to SARS-CoV-2 treated with prone position and evaluate the response to this maneuver.Design Cohort study including patients with PaO2/FiO2 <150mmHg requiring prone position over 18 months. We classified patients according to PaO2/FiO2 changes from basal to 24h after the first prone cycle as: 1) no increase 2) increase <25%, 3) 25%–50% increase 4) increase >50%. Setting 33-bed medical-surgical Intensive Care Unit (ICU) in Argentina. Patients 273 patients. Interventions None. Main variables of interest Epidemiological characteristics, respiratory mechanics and oxygenation were compared between survivors and non-survivors. Independent factors associated with in-hospital mortality were identified. Results Baseline PaO2/FiO2 was 116 [97–135]mmHg (115 [94–136] in survivors vs. 117 [98–134] in non-survivors; p=0.50). After prone positioning, 22 patients (8%) had similar PaO2/FiO2 values; 46(16%) increased PaO2/FiO2 ≤25%; 55 (21%) increased it 25%–50%; and 150 (55%), >50%. Mortality was 86%, 87%, 72% and 50% respectively (p<0.001). Baseline PaO2/FiO2, <100mmHg did not imply that patients were refractory to prone position. Factors independently associated with mortality were age, percentage increase in PaO2/FiO2 after 24h being in prone, and number of prone cycles. Conclusions Older patients unable to improve PaO2/FiO2 after 24h in prone position and who require >1 cycle might early receive additional treatments for refractory hypoxemia. After the first 24h in the prone position, a low percentage of PaO2/FiO2 increase over baseline, beyond the initial value, was independently associated with higher mortality. (AU)

Objetivo Analizar las características, cambios en la oxigenación y mecánica pulmonar, en pacientes ventilados mecánicamente con SDRA por SARS-CoV-2 tratados con posición prona, y evaluar la respuesta a esta maniobra. Diseño Estudio de cohorte que incluyó pacientes con PaO2/FiO2 <150mmHg que requirieron posición prona durante 18 meses. Se clasificaron los pacientes según los cambios de PaO2/FiO2 desde el basal y 24horas después del primer ciclo prono como: 1) Sin aumento 2) Aumento <25%, 3) 25–50% de aumento 4) Aumento >50%. Ambito Unidad de Cuidados Intensivos (UCI) médico-quirúrgica de 33 camas en Argentina. Pacientes 273 pacientes. Intervenciones Ninguna. Principales variables de interés Se compararon características epidemiológicas, mecánica respiratoria y oxigenación entre sobrevivientes y no sobrevivientes. Se identificaron factores independientes asociados a la mortalidad hospitalaria. Resultados La PaO2/FiO2 basal fue de 116 [97–135]mmHg (115 [94–136] en sobrevivientes vs. 117 [98–134] en no sobrevivientes; p=0,50). Después de la posición prona, 22 pacientes (8%) tenían valores similares de PaO2/FiO2; 46 (16%) aumentaron PaO2/FiO2 ≤25%; 55 (21%) lo aumentaron 25%–50%; y 150 (55%), >50%. La mortalidad fue de 86%, 87%, 72% y 50% respectivamente (p<0,001). La PaO2/FiO2 basal, <100mmHg no implicó que los pacientes fueran refractarios a la posición prona. Los factores asociados independientemente con la mortalidad fueron la edad, el aumento porcentual de PaO2/FiO2 después de 24horas en prona, y el número de ciclos prono. Conclusiones Los pacientes mayores que no pueden mejorar PaO2/FiO2 después de 24 horas en posición prona y que requieren más de 1 ciclo podrían recibir tratamientos adicionales para la hipoxemia refractaria. Después de las primeras 24horas en decúbito prono, un bajo porcentaje de aumento de PaO2/FiO2 sobre el valor basal, más allá del valor inicial, se asoció de forma independiente con una mayor mortalidad. (AU)

Epidemiology of Tracheostomized Adult Patients Admitted to Specialized Weaning Centers After Acute COVID-19.

BACKGROUND: Epidemiological data on patients with COVID-19 referred to specialized weaning centers (SWCs) are sparse, particularly in low- and middle-income countries. Our aim was to describe clinical features, epidemiology, and outcomes of subjects admitted to SWCs in Argentina. METHODS: We conducted a prospective, multi-center, observational study between July 2020-December 2021 in 12 SWCs. We collected demographic characteristics, laboratory results, pulmonary function, and dependence on mechanical ventilation at admission, decannulation, weaning from mechanical ventilation, and status at discharge. A multiple logistic model was built to predict home discharge. RESULTS: We enrolled 568 tracheostomized adult subjects after the acute COVID-19 phase who were transferred to SWCs. Age was 62 [52-71], males 70%, Charlson comorbidity index was 2 [0-3], and length of stay in ICU was 42 [32-56] d. Of the 315 ventilator-dependent subjects, 72.4% were weaned, 427 (75.2%) were decannulated, and 366 subjects (64.5%) were discharged home. The mortality rate was 6.0%. In multivariate analysis, age (odds ratio 0.30 [95% CI 0.16-0.56], P < .001), Charlson comorbidity index (odds ratio 0.43 [95% CI 0.22-0.84], P < .01), mechanical ventilation duration in ICU (odds ratio 0.80 [95% CI 0.72-0.89], P < .001), renal failure (odds ratio 0.40 [95% CI 0.22-0.73], P = .003), and expiratory muscle weakness (odds ratio 0.35 [95% CI 0.19-0.62], P < .001) were independently associated with home discharge. CONCLUSIONS: Most subjects with COVID-19 transferred to SWCs were weaned, achieved decannulation, and were discharged to home. Age, high-comorbidity burden, prolonged mechanical ventilation in ICU, renal failure at admission, and expiratory muscle weakness were inversely associated with home discharge.

Characteristics and risk factors associated with mortality during the first cycle of prone secondary to ARDS due to SARS-CoV-2 pneumonia.

OBJECTIVE: To analyze characteristics, changes in oxygenation, and pulmonary mechanics, in mechanically ventilated patients with ARDS due to SARS-CoV-2 treated with prone position and evaluate the response to this maneuver. DESIGN: Cohort study including patients with PaO2/FiO2 <150mmHg requiring prone position over 18 months. We classified patients according to PaO2/FiO2 changes from basal to 24h after the first prone cycle as: 1) no increase 2) increase <25%, 3) 25%-50% increase 4) increase >50%. SETTING: 33-bed medical-surgical Intensive Care Unit (ICU) in Argentina. PATIENTS: 273 patients. INTERVENTIONS: None. MAIN VARIABLES OF INTEREST: Epidemiological characteristics, respiratory mechanics and oxygenation were compared between survivors and non-survivors. Independent factors associated with in-hospital mortality were identified. RESULTS: Baseline PaO2/FiO2 was 116 [97-135]mmHg (115 [94-136] in survivors vs. 117 [98-134] in non-survivors; p=0.50). After prone positioning, 22 patients (8%) had similar PaO2/FiO2 values; 46(16%) increased PaO2/FiO2 ≤25%; 55 (21%) increased it 25%-50%; and 150 (55%), >50%. Mortality was 86%, 87%, 72% and 50% respectively (p<0.001). Baseline PaO2/FiO2, <100mmHg did not imply that patients were refractory to prone position. Factors independently associated with mortality were age, percentage increase in PaO2/FiO2 after 24h being in prone, and number of prone cycles. CONCLUSIONS: Older patients unable to improve PaO2/FiO2 after 24h in prone position and who require >1 cycle might early receive additional treatments for refractory hypoxemia. After the first 24h in the prone position, a low percentage of PaO2/FiO2 increase over baseline, beyond the initial value, was independently associated with higher mortality.

Drivers of mortality in COVID ARDS depend on patient sub-type.

The most common cause of death in people with COVID-19 is Acute Respiratory Distress Syndrome (ARDS). Prior studies have demonstrated that ARDS is a heterogeneous syndrome and have identified ARDS sub-types (phenoclusters). However, non-COVID-19 ARDS phenoclusters do not clearly apply to COVID-19 ARDS patients. In this retrospective cohort study, we implemented an iterative approach, combining supervised and unsupervised machine learning methodologies, to identify clinically relevant COVID-19 ARDS phenoclusters, as well as characteristics that are predictive of the outcome for each phenocluster. To this end, we applied a supervised model to identify risk factors for hospital mortality for each phenocluster and compared these between phenoclusters and the entire cohort. We trained the models using a comprehensive, preprocessed dataset of 2,864 hospitalized COVID-19 ARDS patients. Our research demonstrates that the risk factors predicting mortality in the overall cohort of COVID-19 ARDS may not necessarily apply to specific phenoclusters. Additionally, some risk factors increase the risk of hospital mortality in some phenoclusters but decrease mortality in others. These phenocluster-specific risk factors would not have been observed with a single predictive model. Heterogeneity in phenoclusters of COVID-19 ARDS as well as the drivers of mortality may partially explain challenges in finding effective treatments for all patients with ARDS.

Tissue-Engineered Disease Modeling of Lymphangioleiomyomatosis Exposes a Therapeutic Vulnerability to HDAC Inhibition.

Lymphangioleiomyomatosis (LAM) is a rare disease involving cystic lung destruction by invasive LAM cells. These cells harbor loss-of-function mutations in TSC2, conferring hyperactive mTORC1 signaling. Here, tissue engineering tools are employed to model LAM and identify new therapeutic candidates. Biomimetic hydrogel culture of LAM cells is found to recapitulate the molecular and phenotypic characteristics of human disease more faithfully than culture on plastic. A 3D drug screen is conducted, identifying histone deacetylase (HDAC) inhibitors as anti-invasive agents that are also selectively cytotoxic toward TSC2-/- cells. The anti-invasive effects of HDAC inhibitors are independent of genotype, while selective cell death is mTORC1-dependent and mediated by apoptosis. Genotype-selective cytotoxicity is seen exclusively in hydrogel culture due to potentiated differential mTORC1 signaling, a feature that is abrogated in cell culture on plastic. Importantly, HDAC inhibitors block invasion and selectively eradicate LAM cells in vivo in zebrafish xenografts. These findings demonstrate that tissue-engineered disease modeling exposes a physiologically relevant therapeutic vulnerability that would be otherwise missed by conventional culture on plastic. This work substantiates HDAC inhibitors as possible therapeutic candidates for the treatment of patients with LAM and requires further study.

Comparación de la violencia y agresiones sufridas por el personal de salud durante la pandemia de COVID-19 en Argentina y el resto de Latinoamérica / Comparison of violence and aggressions suffered by health personnel during the COVID-19 pandemic in Argentina and the rest of Latin America

RESUMEN Objetivos. Explorar la frecuencia e impacto de la violencia contra los trabajadores de salud de Argentina y compararlo con el resto de sus pares de Latinoamérica en el contexto de la pandemia por COVID-19. Materiales y métodos. Estudio de corte transversal a través de una encuesta electrónica al personal médico y no médico de Latinoamérica que desempeño tareas asistenciales desde marzo de 2020. Se utilizó una regresión de Poisson para estimar las Razones de Prevalencia crudas (RP) y ajustadas (RPa) con sus respectivos intervalos de confianza al 95%. Resultados. Un total de 3544 participantes de 19 países respondieron la encuesta; 1992 (56,0%) residían en Argentina. Entre los mismos, el 62,9% padeció al menos un hecho de violencia: 97,7% refirió violencia verbal y 11,8% violencia física. El 41,5% de los agredidos padecieron situaciones de violencia al menos una vez por semana. El personal de salud de Argentina vivenció más frecuentemente violencia que los de otros países (62,9% vs. 54,6%, p<0,001), siendo estos eventos más habituales y estresantes (p<0,05). Además, refirieron más frecuentemente haber considerado cambiar sus tareas asistenciales y/o deseos de abandonar su profesión (p<0,001). En la regresión de Poisson, los participantes de Argentina tuvieron una prevalencia de violencia mayor que los trabajadores de salud de la región (14,6%; p<0,001). Conclusiones. Existió una elevada prevalencia de violencia contra el personal de salud de Argentina durante la pandemia por COVID-19. Estos hechos tuvieron un alto impacto negativo entre quienes los padecieron. Nuestros datos sugieren que, esto podría haber sido más frecuente en Argentina respecto de otras regiones del continente.

ABSTRACT Objectives. To explore the frequency and impact of violence against healthcare workers in Argentina and to compare it with the rest of their Latin American peers during the COVID-19 pandemic. Materials and methods. A cross-sectional study was conducted by applying an electronic survey on Latin American medical and non-medical personnel who carried out health care tasks since March 2020. We used Poisson regression to estimate crude (PR) and adjusted (aPR) Prevalence Ratios with their respective 95% confidence intervals. Results. A total of 3544 participants from 19 countries answered the survey; 1992 (56.0%) resided in Argentina. Of these, 62.9% experienced at least one act of violence; 97.7% reported verbal violence and 11.8% physical violence. Of those who were assaulted, 41.5% experienced violence at least once a week. Health personnel from Argentina experienced violence more frequently than those from other countries (62.9% vs. 54.6%, p<0.001), and these events were more frequent and stressful (p<0.05). In addition, Argentinean health personnel reported having considered changing their healthcare tasks and/or desired to leave their profession more frequently (p<0.001). In the Poisson regression, we found that participants from Argentina had a higher prevalence of violence than health workers from the region (14.6%; p<0.001). Conclusions. There was a high prevalence of violence against health personnel in Argentina during the COVID-19 pandemic. These events had a strong negative impact on those who suffered them. Our data suggest that violence against health personnel may have been more frequent in Argentina than in other regions of the continent.

Seguimiento a largo plazo de pacientes traqueostomizados post injuria cerebral adquirida grave / Long-term follow-up of tracheostomized patients post severe acquired brain injury

Resumen Introducción: Alrededor del 50% de los pacientes hos pitalizados por injuria cerebral adquirida grave requie ren traqueostomía y cuidados a largo plazo. El objetivo principal de este estudio fue describir la evolución de enfermos con injuria cerebral adquirida grave (ICAg) traqueostomizados que ingresaron a rehabilitación. Se cundariamente se estudió el fracaso de la decanulación y la supervivencia a los 12 meses del alta. Métodos: estudio cuantitativo observacional prospec tivo de centro único. Se incorporó al estudio, de forma prospectiva y consecutiva, usuarios mayores de 18 años, traqueostomizados posterior a ICAg ingresados a un cen tro de rehabilitación entre abril de 2018 y marzo de 2020. Resultados: se incluyeron para el análisis 50 pacien tes. La estancia en el centro fue de 203 (RIQ 93-320) días. Al alta de la institución, 32 (64%) pacientes pudieron ser decanulados exitosamente. El tiempo transcurrido desde el ingreso al centro hasta la decanulación fue de 49 (12-172) días. No se observó fracaso de la decanula ción. La mortalidad a los 12 meses de seguimiento fue de 32%, cinco (16%) de los 32 pacientes que pudieron ser decanulados y 11 (61%) de los 18 que no lograron la decanulación fallecieron dentro de los 12 meses de seguimiento. La relación entre la decanulación y la mortalidad a los 12 meses de seguimiento resultó esta dísticamente significativa (p = 0.002). Discusión: La supervivencia global fue relativamente elevada, el proceso de decanulación resulta relevante ya que puede tener impacto en la supervivencia a largo plazo.

Abstract Introduction: About 50% of patients hospitalized for severe acquired brain injury require tracheostomy, and many of them need long-term care. The main objective of this study was to describe the evolution of patients with severe acquired brain injury (sABI) tracheotomized who entered rehabilitation. Secondarily, mortality re lated to the success or failure of decannulation and survival at 12 months of discharge were studied. Methods: A single-center prospective observational quantitative study. Users over 18 years of age were recruited prospectively and consecutively, tracheosto mized after sABI, and admitted to a rehabilitation center between April 2018 and March 2020. Results: Fifty patients were included for analysis. The stay in the center was 203 (RIQ 93-320) days. At discharge to the institution, 32 (64%) patients managed to be successfully decannulated. The median number of days from admission to the center to decannulation was 49 (12-172). No decannulation failure was observed. Mortality at 12 months follow-up was 32%, five (16%) of the 32 patients who managed to be decannulated, and 11 (61%) of 18 who failed to achieve decannulation died within 12 months of follow-up. The relationship between decannulation success and mortality at 12 months of follow-up was statistically significant (p= 0.002). Discussion: Addressing the decannulation process early and properly guided is relevant as it may impact long-term survival.

[Long-term follow-up of tracheostomized patients post severe acquired brain injury]. / Seguimiento a largo plazo de pacientes traqueostomizados post injuria cerebral adquirida grave.

INTRODUCTION: About 50% of patients hospitalized for severe acquired brain injury require tracheostomy, and many of them need long-term care. The main objective of this study was to describe the evolution of patients with severe acquired brain injury (sABI) tracheotomized who entered rehabilitation. Secondarily, mortality related to the success or failure of decannulation and survival at 12 months of discharge were studied. METHODS: A single-center prospective observational quantitative study. Users over 18 years of age were recruited prospectively and consecutively, tracheostomized after sABI, and admitted to a rehabilitation center between April 2018 and March 2020. RESULTS: Fifty patients were included for analysis. The stay in the center was 203 (RIQ 93-320) days. At discharge to the institution, 32 (64%) patients managed to be successfully decannulated. The median number of days from admission to the center to decannulation was 49 (12-172). No decannulation failure was observed. Mortality at 12 months follow-up was 32%, five (16%) of the 32 patients who managed to be decannulated, and 11 (61%) of 18 who failed to achieve decannulation died within 12 months of follow-up. The relationship between decannulation success and mortality at 12 months of follow-up was statistically significant (p= 0.002). DISCUSSION: Addressing the decannulation process early and properly guided is relevant as it may impact long-term survival.

Introducción: Alrededor del 50% de los pacientes hospitalizados por injuria cerebral adquirida grave requieren traqueostomía y cuidados a largo plazo. El objetivo principal de este estudio fue describir la evolución de enfermos con injuria cerebral adquirida grave (ICAg) traqueostomizados que ingresaron a rehabilitación. Secundariamente se estudió el fracaso de la decanulación y la supervivencia a los 12 meses del alta. Métodos: estudio cuantitativo observacional prospectivo de centro único. Se incorporó al estudio, de forma prospectiva y consecutiva, usuarios mayores de 18 años, traqueostomizados posterior a ICAg ingresados a un centro de rehabilitación entre abril de 2018 y marzo de 2020. Resultados: se incluyeron para el análisis 50 pacientes. La estancia en el centro fue de 203 (RIQ 93-320) días. Al alta de la institución, 32 (64%) pacientes pudieron ser decanulados exitosamente. El tiempo transcurrido desde el ingreso al centro hasta la decanulación fue de 49 (12-172) días. No se observó fracaso de la decanulación. La mortalidad a los 12 meses de seguimiento fue de 32%, cinco (16%) de los 32 pacientes que pudieron ser decanulados y 11 (61%) de los 18 que no lograron la decanulación fallecieron dentro de los 12 meses de seguimiento. La relación entre la decanulación y la mortalidad a los 12 meses de seguimiento resultó estadísticamente significativa (p = 0.002). Discusión: La supervivencia global fue relativamente elevada, el proceso de decanulación resulta relevante ya que puede tener impacto en la supervivencia a largo plazo.

Discriminating Acute Respiratory Distress Syndrome from other forms of respiratory failure via iterative machine learning.

Acute Respiratory Distress Syndrome (ARDS) is associated with high morbidity and mortality. Identification of ARDS enables lung protective strategies, quality improvement interventions, and clinical trial enrolment, but remains challenging particularly in the first 24 hours of mechanical ventilation. To address this we built an algorithm capable of discriminating ARDS from other similarly presenting disorders immediately following mechanical ventilation. Specifically, a clinical team examined medical records from 1263 ICU-admitted, mechanically ventilated patients, retrospectively assigning each patient a diagnosis of "ARDS" or "non-ARDS" (e.g., pulmonary edema). Exploiting data readily available in the clinical setting, including patient demographics, laboratory test results from before the initiation of mechanical ventilation, and features extracted by natural language processing of radiology reports, we applied an iterative pre-processing and machine learning framework. The resulting model successfully discriminated ARDS from non-ARDS causes of respiratory failure (AUC = 0.85) among patients meeting Berlin criteria for severe hypoxia. This analysis also highlighted novel patient variables that were informative for identifying ARDS in ICU settings.

Comparison of violence and aggressions suffered by health personnel during the COVID-19 pandemic in Argentina and the rest of Latin America. / Comparación de la violencia y agresiones sufridas por el personal de salud durante la pandemia de COVID-19 en Argentina y el resto de Latinoamérica.

OBJECTIVES.: Motivation for the study. The COVID-19 pandemic has caused profound repercussions at different socio-environmental levels. Its impact on violence against healthcare team workers in Argentina has not been well documented. Main findings. The present study evidenced high rates of aggression, particularly verbal aggression. In addition, almost half of the participants reported having suffered these events on a weekly basis. All participants who experienced violence reported having experienced post-event symptoms, and up to one-third reported having considered changing their profession after these acts. Implications. It is imperative to take action to prevent acts of violence against health personnel, or to mitigate its impact on the victims. . To explore the frequency and impact of violence against healthcare workers in Argentina and to compare it with the rest of their Latin American peers during the COVID-19 pandemic. MATERIALS AND METHODS.: A cross-sectional study was conducted by applying an electronic survey on Latin American medical and non-medical personnel who carried out health care tasks since March 2020. We used Poisson regression to estimate crude (PR) and adjusted (aPR) Prevalence Ratios with their respective 95% confidence intervals. RESULTS.: A total of 3544 participants from 19 countries answered the survey; 1992 (56.0%) resided in Argentina. Of these, 62.9% experienced at least one act of violence; 97.7% reported verbal violence and 11.8% physical violence. Of those who were assaulted, 41.5% experienced violence at least once a week. Health personnel from Argentina experienced violence more frequently than those from other countries (62.9% vs. 54.6%, p<0.001), and these events were more frequent and stressful (p<0.05). In addition, Argentinean health personnel reported having considered changing their healthcare tasks and/or desired to leave their profession more frequently (p<0.001). In the Poisson regression, we found that participants from Argentina had a higher prevalence of violence than health workers from the region (14.6%; p<0.001). CONCLUSIONS.: There was a high prevalence of violence against health personnel in Argentina during the COVID-19 pandemic. These events had a strong negative impact on those who suffered them. Our data suggest that violence against health personnel may have been more frequent in Argentina than in other regions of the continent.

OBJETIVOS.: Explorar la frecuencia e impacto de la violencia contra los trabajadores de salud de Argentina y compararlo con el resto de sus pares de Latinoamérica en el contexto de la pandemia por COVID-19. MATERIALES Y MÉTODOS.: Estudio de corte transversal a través de una encuesta electrónica al personal médico y no médico de Latinoamérica que desempeño tareas asistenciales desde marzo de 2020. Se utilizó una regresión de Poisson para estimar las Razones de Prevalencia crudas (RP) y ajustadas (RPa) con sus respectivos intervalos de confianza al 95%. RESULTADOS.: Un total de 3544 participantes de 19 países respondieron la encuesta; 1992 (56,0%) residían en Argentina. Entre los mismos, el 62,9% padeció al menos un hecho de violencia: 97,7% refirió violencia verbal y 11,8% violencia física. El 41,5% de los agredidos padecieron situaciones de violencia al menos una vez por semana. El personal de salud de Argentina vivenció más frecuentemente violencia que los de otros países (62,9% vs. 54,6%, p<0,001), siendo estos eventos más habituales y estresantes (p<0,05). Además, refirieron más frecuentemente haber considerado cambiar sus tareas asistenciales y/o deseos de abandonar su profesión (p<0,001). En la regresión de Poisson, los participantes de Argentina tuvieron una prevalencia de violencia mayor que los trabajadores de salud de la región (14,6%; p<0,001). CONCLUSIONES.: Existió una elevada prevalencia de violencia contra el personal de salud de Argentina durante la pandemia por COVID-19. Estos hechos tuvieron un alto impacto negativo entre quienes los padecieron. Nuestros datos sugieren que, esto podría haber sido más frecuente en Argentina respecto de otras regiones del continente.

[Survival and decannulation at 90 days after percutaneous dilation tracheostomy in the COVID-19 intensive care unit]. / Supervivencia y decanulación a los 90 días luego de traqueostomía por dilatación percutánea en unidad de cuidados intensivos COVID-19.

INTRODUCTION: Tracheostomy (TCT) is the most frequently performed surgical procedure among COVID-19 patients. In Argentina, survival and decannulation rates are unknown. The main objectives of this study were to evaluate mortality and decannulation rates after 90 days of the percutaneous TCT performance. Secondarily, airway injury rate, days on invasive mechanical ventilation (IMV) and days of hospitalization in the intensive care unit (ICU) were also evaluated. METHODS: This observational analytic prospective cohort study included patients over 18 years old with SARS-CoV-2 who were admitted into the ICU requiring IMV and percutaneous TCT in the period covering from 1 February 2021 to 31 July 2021. RESULTS: the mortality rate in 95 patients was 66.3%. Among the survivors, 67% were decannulated. The youngest patients were the ones who survived [mean 50.6 (SD 10.2) years versus mean 58.9 (SD 13.4) years; p = 0.001] and presented lower Charlson index scores [median 1 (IQR 0-2) versus 2 (1-3) points; p = 0.007]. Patients who were tracheostomized ten days before the start of IMV were fewer days on IMV and had a shorter stay in the ICU, p < 0.01 and p = 0.01, respectively. Charlson Index was identified as an independent factor of mortality for both decannulation mortality at 90 days. DISCUSSION: In our cohort of patients, those who were younger and presented less c omorbidities benefited from TCT. Charlson Index could be used as a prognostic marker among this patient population.

Introducción: La traqueostomía (TQT) es el procedimiento quirúrgico más frecuentemente realizado en pacientes COVID-19. La tasa de supervivencia y decanulación en Argentina se desconoce. El objetivo principal de este estudio fue evaluar la mortalidad y la tasa de decanulación al día 90 de realizada la TQT percutánea. Secundariamente se evaluó la tasa de lesión en la vía aérea, días de ventilación mecánica invasiva (VMI) y días de internación en unidad de cuidados intensivos (UCI). Métodos: Estudio observacional analítico de cohorte prospectiva que incluyó 95 pacientes mayores de 18 años infectados por SARS-CoV-2 ingresados de forma consecutiva a la UCI con requerimiento de VMI y TQT percutánea en el periodo comprendido entre 1 de febrero al 31 de julio del 2021. Resultados: La mortalidad fue del 66.3%. De los supervivientes se logró decanular al 67%. Los supervivientes fueron más jóvenes [media 50.6 (DE 10.2) años versus media 58.9 (DE 13.4) años; p = 0.001] y presentaron puntajes más bajos de índice de Charlson [mediana 1 (RIQ 0-2) versus 2 (1-3) puntos; p = 0.007]. Los pacientes TQT antes del día 10 desde el inicio de VMI tuvieron menos días de VMI y menor estadía en UCI, p < 0.01 y p = 0.01 respectivamente. El índice de Charlson se identificó como factor independiente de mortalidad a los 90 días y de decanulación a los 90 días. Discusión: En nuestra cohorte de pacientes fueron los más jóvenes y con menos comorbilidades los que se beneficiaron con la TQT. El índice de Charlson podría utilizarse como marcador pronóstico en esta población de pacientes.

Supervivencia y decanulación a los 90 días luego de traqueostomía por dilatación percutánea en unidad de cuidados intensivos COVID-19 / Survival and decannulation at 90 days after percutaneous dilation tracheostomy in the COVID-19 intensive care unit

Resumen Introducción: La traqueostomía (TQT) es el procedimiento quirúrgico más frecuentemente realizado en pacientes COVID-19. La tasa de supervivencia y decanulación en Argentina se desconoce. El objetivo principal de este estudio fue evaluar la mortalidad y la tasa de decanulación al día 90 de realizada la TQT percutánea. Secundariamente se evaluó la tasa de lesión en la vía aérea, días de ventilación mecánica invasiva (VMI) y días de internación en unidad de cuidados intensivos (UCI). Métodos: Estudio observacional analítico de cohorte prospectiva que incluyó 95 pacientes mayores de 18 años infectados por SARS-CoV-2 ingresados de forma consecutiva a la UCI con requerimiento de VMI y TQT percutánea en el periodo compren dido entre 1 de febrero al 31 de julio del 2021. Resultados: La mortalidad fue del 66.3%. De los supervivientes se logró decanular al 67%. Los supervivientes fueron más jóvenes [media 50.6 (DE 10.2) años versus media 58.9 (DE 13.4) años; p = 0.001] y presentaron puntajes más bajos de índice de Charlson [mediana 1 (RIQ 0-2) versus 2 (1-3) puntos; p = 0.007]. Los pacientes TQT antes del día 10 desde el inicio de VMI tuvieron menos días de VMI y menor estadía en UCI, p < 0.01 y p = 0.01 respectivamente. El índice de Charlson se identificó como factor independiente de mortalidad a los 90 días y de decanulación a los 90 días. Discusión: En nuestra cohorte de pacientes fueron los más jóvenes y con menos comorbilidades los que se beneficiaron con la TQT. El índice de Charlson podría utilizarse como marcador pronóstico en esta población de pacientes.

Abstract Introduction: Tracheostomy (TCT) is the most frequently performed surgical procedure among COVID-19 patients. In Argentina, survival and decannulation rates are unknown. The main objectives of this study were to evaluate mortality and decannulation rates after 90 days of the percutaneous TCT performance. Secondarily, airway injury rate, days on invasive mechanical ventilation (IMV) and days of hospitalization in the intensive care unit (ICU) were also evaluated. Methods: This observational analytic prospective cohort study included patients over 18 years old with SARS-CoV-2 who were admitted into the ICU requiring IMV and percutaneous TCT in the period covering from 1 February 2021 to 31 July 2021. Results: the mortality rate in 95 patients was 66.3%. Among the survivors, 67% were decannulated. The youngest patients were the ones who survived [mean 50.6 (SD 10.2) years versus mean 58.9 (SD 13.4) years; p = 0.001] and presented lower Charlson index scores [median 1 (IQR 0-2) versus 2 (1-3) points; p = 0.007]. Patients who were tracheostomized ten days before the start of IMV were fewer days on IMV and had a shorter stay in the ICU, p < 0.01 and p = 0.01, respectively. Charlson Index was identified as an independent factor of mortality for both decannulation mortality at 90 days. Discussion: In our cohort of patients, those who were younger and presented less c omorbidities benefited from TCT. Charlson Index could be used as a prognostic marker among this patient population.

[Comparison between the first and second COVID-19 wave of patients who required invasive mechanical ventilation in an intensive care unit in Argentina]. / Comparación entre la primera y segunda ola de pacientes con COVID-19 que requirieron ventilación mecánica invasiva en una unidad de cuidados intensivos de Argentina.

INTRODUCTION: the information regarding characteristics and ventilatory results comparing the first (W1) and the second wave (W2) in Argentina are limited. The main objective of this study was to describe general characteristics and ventilatory variables in COVID-19 patients who required invasive mechanical ventilation (IMV) and compare differences between waves. Secondarily, factors associated with mortality in intensive care unit (ICU) were studied. METHODS: We conducted a prospective observational cohort study that included patients older than 18 years infected with SARS-CoV-2 consecutively admitted to ICU with IMV between August 1, 2020, and June 30, 2021. We included 412 patients. RESULTS: We found statistically significant differences (p < 0.001) in age [W1 64(55-72) vs W2 59 (50-66) years], presence of COPD [W1 n = 42 (19.8%) vs. W2 n = 13(6.3%)], plateau pressure [W1 27(25-30) cm H2O vsW2 24 (22-27) cmH2O], driving pressure (ΔP) [W1 15 (13-17) cmH2O vs. W2 12 (11-14) cm H2O] compliance [W1 40 mL/cmH2O (32-46) vs. W2 = 33 mL/cm H2O (27-40)]; reintubation [W1 30.4% (n = 63/207) vs. W2 13.7% (n = 28/205)]. We identified as independent factors associated with mortality the following variables: age [OR 1.07(95% CI 1.05-1.09)], the ΔP in the first 24 hours [OR 1.19(95% CI 1.10-1.28)] and W2 [OR 1.81 (95% IC1.12-2.93); p = 0.015. DISCUSSION: During W2 the patients were younger. It was possible to achieve ventilatory mechanics more adjusted to a protective ventilation strategy. In conclusion, in the patients studied, age and ΔP were independent predictors of mortality.

Introducción: la información sobre características y resultados ventilatorios que comparen la primera (O1) y segunda (O2) ola de COVID-19 en Argentina son limitados. El objetivo principal de este estudio fue describir las características generales y variables ventilatorias en pacientes COVID-19 que requirieron ventilación mecánica invasiva (VMI) y comparar las diferencias entre olas. Secundariamente se estudiaron factores asociados con mortalidad en la unidad de cuidados intensivos (UCI). Métodos: Realizamos un estudio observacional analítico de cohorte prospectiva que incluyó pacientes mayores de 18 años infectados por SARS-CoV-2 ingresados de forma consecutiva a la unidad de cuidados intensivos, con requerimiento de VMI, entre el 1 de agosto de 2020 y el 30 de junio de 2021. Se incluyeron 412 pacientes. Resultados: Encontramos diferencias estadísticamente significativas (p < 0.001) en: la edad [O1 64 (55-72) años versus O2 59 (50-66) años]; presencia de EPOC [O1 n = 41 (19.8%) versus O2 n = 13 (6.3%)]; Presión meseta [O1 27 (25-30) cmH2O versus O224 (22-27) cmH2O],presión de conducción (ΔP) [O1 15 (13-17) cmH2O versus O2 12 (11-14) cmH2O]; complacencia [O1 40 mL/cmH2O (32-46) versus O2 33 mL/cmH2O (27-40)]; reintubación [O1 30.4% (n=63/207) versus O2 13.7% (n=28/205)]. Se identificaron como factores independientes asociados a mortalidad las siguientes variables: edad [(OR 1.07 (IC 95% 1.05-1.09)], el ΔP en las primeras 24 h [(OR 1.19 (IC 95% 1.10-1.28)] y O2 [OR 1.81 (IC 95% 1.12-2.93); p = 0.015]. Discusión: Durante O2, los pacientes eran más jóvenes. Fue posible lograr una mecánica ventilatoria más ajustada a una estrategia de ventilación protectora. Como conclusión, en los pacientes estudiados la edad y ΔP fueron predictores independientes de mortalidad.

Quantitative Comparison of Statistical Methods for Analyzing Human Metabolomics Data.

Emerging technologies now allow for mass spectrometry-based profiling of thousands of small molecule metabolites ('metabolomics') in an increasing number of biosamples. While offering great promise for insight into the pathogenesis of human disease, standard approaches have not yet been established for statistically analyzing increasingly complex, high-dimensional human metabolomics data in relation to clinical phenotypes, including disease outcomes. To determine optimal approaches for analysis, we formally compare traditional and newer statistical learning methods across a range of metabolomics dataset types. In simulated and experimental metabolomics data derived from large population-based human cohorts, we observe that with an increasing number of study subjects, univariate compared to multivariate methods result in an apparently higher false discovery rate as represented by substantial correlation between metabolites directly associated with the outcome and metabolites not associated with the outcome. Although the higher frequency of such associations would not be considered false in the strict statistical sense, it may be considered biologically less informative. In scenarios wherein the number of assayed metabolites increases, as in measures of nontargeted versus targeted metabolomics, multivariate methods performed especially favorably across a range of statistical operating characteristics. In nontargeted metabolomics datasets that included thousands of metabolite measures, sparse multivariate models demonstrated greater selectivity and lower potential for spurious relationships. When the number of metabolites was similar to or exceeded the number of study subjects, as is common with nontargeted metabolomics analysis of relatively small cohorts, sparse multivariate models exhibited the most-robust statistical power with more consistent results. These findings have important implications for metabolomics analysis in human disease.

Comparación entre la primera y segunda ola de pacientes con COVID-19 que requirieron ventilación mecánica invasiva en una unidad de cuidados intensivos de Argentina / Comparison between the first and second COVID-19 wave of patients who required invasive mechanical ventilation in an intensive care unit in Argentina

Resumen Introducción: la información sobre características y resultados ventilatorios que comparen la primera (O1) y segunda (O2) ola de COVID-19 en Argentina son limitados. El objetivo principal de este estudio fue describir las características generales y variables ventilatorias en pacientes COVID-19 que requirieron ventilación mecánica invasiva (VMI) y comparar las diferencias entre olas. Secundariamente se es tudiaron factores asociados con mortalidad en la unidad de cuidados intensivos (UCI). Métodos: Realizamos un estudio observacional analítico de cohorte prospectiva que incluyó pacientes mayores de 18 años infectados por SARS-CoV-2 ingresados de forma consecutiva a la unidad de cuidados intensivos, con requerimiento de VMI, entre el 1 de agosto de 2020 y el 30 de junio de 2021. Se incluyeron 412 pacientes. Resultados: Encontramos diferencias estadísticamente significativas (p < 0.001) en: la edad [O1 64 (55-72) años versus O2 59 (50-66) años]; presencia de EPOC [O1 n = 41 (19.8%) versus O2 n = 13 (6.3%)]; Presión meseta [O1 27 (25-30) cmH2O versus O224 (22-27) cmH2O],presión de conducción (ΔP) [O1 15 (13-17) cmH2O versus O2 12 (11-14) cmH2O]; complacencia [O1 40 mL/cmH2O (32-46) versus O2 33 mL/cmH2O (27-40)]; reintubación [O1 30.4% (n=63/207) versus O2 13.7% (n=28/205)]. Se identificaron como factores independientes asociados a mortalidad las siguientes variables: edad [(OR 1.07 (IC 95% 1.05-1.09)], el ΔP en las primeras 24 h [(OR 1.19 (IC 95% 1.10-1.28)] y O2 [OR 1.81 (IC 95% 1.12-2.93); p = 0.015]. Discusión: Durante O2, los pacientes eran más jóvenes. Fue posible lograr una mecánica ventilatoria más ajustada a una estrategia de ventilación protectora. Como conclusión, en los pacientes estudiados la edad y ΔP fueron predictores independientes de mortalidad.

Abstract Introduction: the information regarding characteristics and ventilatory results comparing the first (W1) and the second wave (W2) in Argentina are limited. The main objective of this study was to describe general charac teristics and ventilatory variables in COVID-19 patients who required invasive mechanical ventilation (IMV) and compare differences between waves. Secondarily, factors associated with mortality in intensive care unit (ICU) were studied. Methods: We conducted a prospective observational cohort study that included patients older than 18 years infected with SARS-CoV-2 consecutively admitted to ICU with IMV between August 1, 2020, and June 30, 2021. We included 412 patients. Results: We found statistically significant differences (p < 0.001) in age [W1 64(55-72) vs W2 59 (50-66) years], presence of COPD [W1 n = 42 (19.8%) vs. W2 n = 13(6.3%)], plateau pressure [W1 27(25-30) cm H2O vsW2 24 (22-27) cmH2O], driving pressure (ΔP) [W1 15 (13-17) cmH2O vs. W2 12 (11-14) cm H2O] compliance [W1 40 mL/cmH2O (32-46) vs. W2 = 33 mL/cm H2O (27-40)]; reintubation [W1 30.4% (n = 63/207) vs. W2 13.7% (n = 28/205)]. We identified as independent factors associated with mortality the following variables: age [OR 1.07(95% CI 1.05-1.09)], the ΔP in the first 24 hours [OR 1.19(95% CI 1.10- 1.28)] and W2 [OR 1.81 (95% IC1.12-2.93); p = 0.015. Discussion: During W2 the patients were younger. It was possible to achieve ventilatory mechanics more adjusted to a protective ventilation strategy. In conclusion, in the patients studied, age and ΔP were independent predictors of mortality.

Author Correction: Caenorhabditis elegans is a useful model for anthelmintic discovery.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Rewiring of the Human Mitochondrial Interactome during Neuronal Reprogramming Reveals Regulators of the Respirasome and Neurogenesis.

Mitochondrial protein (MP) assemblies undergo alterations during neurogenesis, a complex process vital in brain homeostasis and disease. Yet which MP assemblies remodel during differentiation remains unclear. Here, using mass spectrometry-based co-fractionation profiles and phosphoproteomics, we generated mitochondrial interaction maps of human pluripotent embryonal carcinoma stem cells and differentiated neuronal-like cells, which presented as two discrete cell populations by single-cell RNA sequencing. The resulting networks, encompassing 6,442 high-quality associations among 600 MPs, revealed widespread changes in mitochondrial interactions and site-specific phosphorylation during neuronal differentiation. By leveraging the networks, we show the orphan C20orf24 as a respirasome assembly factor whose disruption markedly reduces respiratory chain activity in patients deficient in complex IV. We also find that a heme-containing neurotrophic factor, neuron-derived neurotrophic factor [NENF], couples with Parkinson disease-related proteins to promote neurotrophic activity. Our results provide insights into the dynamic reorganization of mitochondrial networks during neuronal differentiation and highlights mechanisms for MPs in respirasome, neuronal function, and mitochondrial diseases.

Identification of specific metabolic pathways as druggable targets regulating the sensitivity to cyanide poisoning.

Cyanide is a potent toxic agent, and the few available antidotes are not amenable to rapid deployment in mass exposures. As a result, there are ongoing efforts to exploit different animal models to identify novel countermeasures. We have created a pipeline that combines high-throughput screening in zebrafish with subsequent validation in two mammalian small animal models as well as a porcine large animal model. We found that zebrafish embryos in the first 3 days post fertilization (dpf) are highly resistant to cyanide, becoming progressively more sensitive thereafter. Unbiased analysis of gene expression in response to several hours of ultimately lethal doses of cyanide in both 1 and 7 dpf zebrafish revealed modest changes in iron-related proteins associated with the age-dependent cyanide resistance. Metabolomics measurements demonstrated significant age-dependent differences in energy metabolism during cyanide exposure which prompted us to test modulators of the tricarboxylic acid cycle and related metabolic processes as potential antidotes. In cyanide-sensitive 7 dpf larvae, we identified several such compounds that offer significant protection against cyanide toxicity. Modulators of the pyruvate dehydrogenase complex, as well as the small molecule sodium glyoxylate, consistently protected against cyanide toxicity in 7 dpf zebrafish larvae. Together, our results indicate that the resistance of zebrafish embryos to cyanide toxicity during early development is related to an altered regulation of cellular metabolism, which we propose may be exploited as a potential target for the development of novel antidotes against cyanide poisoning.