Reductions in the mitochondrial ABC transporter Abcb10 affect the transcriptional profile of heme biosynthesis genes.

ATP-binding cassette subfamily B member 10 (Abcb10) is a mitochondrial ATP-binding cassette (ABC) transporter that complexes with mitoferrin1 and ferrochelatase to enhance heme biosynthesis in developing red blood cells. Reductions in Abcb10 levels have been shown to reduce mitoferrin1 protein levels and iron import into mitochondria, resulting in reduced heme biosynthesis. As an ABC transporter, Abcb10 binds and hydrolyzes ATP, but its transported substrate is unknown. Here, we determined that decreases in Abcb10 did not result in protoporphyrin IX accumulation in morphant-treated zebrafish embryos or in differentiated Abcb10-specific shRNA murine Friend erythroleukemia (MEL) cells in which Abcb10 was specifically silenced with shRNA. We also found that the ATPase activity of Abcb10 is necessary for hemoglobinization in MEL cells, suggesting that the substrate transported by Abcb10 is important in mediating increased heme biosynthesis during erythroid development. Inhibition of 5-aminolevulinic acid dehydratase (EC 4.2.1.24) with succinylacetone resulted in both 5-aminolevulinic acid (ALA) accumulation in control and Abcb10-specific shRNA MEL cells, demonstrating that reductions in Abcb10 do not affect ALA export from mitochondria and indicating that Abcb10 does not transport ALA. Abcb10 silencing resulted in an alteration in the heme biosynthesis transcriptional profile due to repression by the transcriptional regulator Bach1, which could be partially rescued by overexpression of Alas2 or Gata1, providing a mechanistic explanation for why Abcb10 shRNA MEL cells exhibit reduced hemoglobinization. In conclusion, our findings rule out that Abcb10 transports ALA and indicate that Abcb10's ATP-hydrolysis activity is critical for hemoglobinization and that the substrate transported by Abcb10 provides a signal that optimizes hemoglobinization.

Selecting causal genes from genome-wide association studies via functionally coherent subnetworks.

Genome-wide association (GWA) studies have linked thousands of loci to human diseases, but the causal genes and variants at these loci generally remain unknown. Although investigators typically focus on genes closest to the associated polymorphisms, the causal gene is often more distal. Reliance on published work to prioritize candidates is biased toward well-characterized genes. We describe a 'prix fixe' strategy and software that uses genome-scale shared-function networks to identify sets of mutually functionally related genes spanning multiple GWA loci. Using associations from ∼100 GWA studies covering ten cancer types, our approach outperformed the common alternative strategy in ranking known cancer genes. As more GWA loci are discovered, the strategy will have increased power to elucidate the causes of human disease.

Novel cardiovascular gene functions revealed via systematic phenotype prediction in zebrafish.

Comprehensive functional annotation of vertebrate genomes is fundamental to biological discovery. Reverse genetic screening has been highly useful for determination of gene function, but is untenable as a systematic approach in vertebrate model organisms given the number of surveyable genes and observable phenotypes. Unbiased prediction of gene-phenotype relationships offers a strategy to direct finite experimental resources towards likely phenotypes, thus maximizing de novo discovery of gene functions. Here we prioritized genes for phenotypic assay in zebrafish through machine learning, predicting the effect of loss of function of each of 15,106 zebrafish genes on 338 distinct embryonic anatomical processes. Focusing on cardiovascular phenotypes, the learning procedure predicted known knockdown and mutant phenotypes with high precision. In proof-of-concept studies we validated 16 high-confidence cardiac predictions using targeted morpholino knockdown and initial blinded phenotyping in embryonic zebrafish, confirming a significant enrichment for cardiac phenotypes as compared with morpholino controls. Subsequent detailed analyses of cardiac function confirmed these results, identifying novel physiological defects for 11 tested genes. Among these we identified tmem88a, a recently described attenuator of Wnt signaling, as a discrete regulator of the patterning of intercellular coupling in the zebrafish cardiac epithelium. Thus, we show that systematic prioritization in zebrafish can accelerate the pace of developmental gene function discovery.

Fine mapping of the 1p36 deletion syndrome identifies mutation of PRDM16 as a cause of cardiomyopathy.

Deletion 1p36 syndrome is recognized as the most common terminal deletion syndrome. Here, we describe the loss of a gene within the deletion that is responsible for the cardiomyopathy associated with monosomy 1p36, and we confirm its role in nonsyndromic left ventricular noncompaction cardiomyopathy (LVNC) and dilated cardiomyopathy (DCM). With our own data and publically available data from array comparative genomic hybridization (aCGH), we identified a minimal deletion for the cardiomyopathy associated with 1p36del syndrome that included only the terminal 14 exons of the transcription factor PRDM16 (PR domain containing 16), a gene that had previously been shown to direct brown fat determination and differentiation. Resequencing of PRDM16 in a cohort of 75 nonsyndromic individuals with LVNC detected three mutations, including one truncation mutant, one frameshift null mutation, and a single missense mutant. In addition, in a series of cardiac biopsies from 131 individuals with DCM, we found 5 individuals with 4 previously unreported nonsynonymous variants in the coding region of PRDM16. None of the PRDM16 mutations identified were observed in more than 6,400 controls. PRDM16 has not previously been associated with cardiac disease but is localized in the nuclei of cardiomyocytes throughout murine and human development and in the adult heart. Modeling of PRDM16 haploinsufficiency and a human truncation mutant in zebrafish resulted in both contractile dysfunction and partial uncoupling of cardiomyocytes and also revealed evidence of impaired cardiomyocyte proliferative capacity. In conclusion, mutation of PRDM16 causes the cardiomyopathy in 1p36 deletion syndrome as well as a proportion of nonsyndromic LVNC and DCM.

Mitochondrial targets for pharmacological intervention in human disease.

Over the past several years, mitochondrial dysfunction has been linked to an increasing number of human illnesses, making mitochondrial proteins (MPs) an ever more appealing target for therapeutic intervention. With 20% of the mitochondrial proteome (312 of an estimated 1500 MPs) having known interactions with small molecules, MPs appear to be highly targetable. Yet, despite these targeted proteins functioning in a range of biological processes (including induction of apoptosis, calcium homeostasis, and metabolism), very few of the compounds targeting MPs find clinical use. Recent work has greatly expanded the number of proteins known to localize to the mitochondria and has generated a considerable increase in MP 3D structures available in public databases, allowing experimental screening and in silico prediction of mitochondrial drug targets on an unprecedented scale. Here, we summarize the current literature on clinically active drugs that target MPs, with a focus on how existing drug targets are distributed across biochemical pathways and organelle substructures. Also, we examine current strategies for mitochondrial drug discovery, focusing on genetic, proteomic, and chemogenomic assays, and relevant model systems. As cell models and screening techniques improve, MPs appear poised to emerge as relevant targets for a wide range of complex human diseases, an eventuality that can be expedited through systematic analysis of MP function.

Yeast mitochondrial protein-protein interactions reveal diverse complexes and disease-relevant functional relationships.

Although detailed, focused, and mechanistic analyses of associations among mitochondrial proteins (MPs) have identified their importance in varied biological processes, a systematic understanding of how MPs function in concert both with one another and with extra-mitochondrial proteins remains incomplete. Consequently, many questions regarding the role of mitochondrial dysfunction in the development of human disease remain unanswered. To address this, we compiled all existing mitochondrial physical interaction data for over 1200 experimentally defined yeast MPs and, through bioinformatic analysis, identified hundreds of heteromeric MP complexes having extensive associations both within and outside the mitochondria. We provide support for these complexes through structure prediction analysis, morphological comparisons of deletion strains, and protein co-immunoprecipitation. The integration of these MP complexes with reported genetic interaction data reveals substantial crosstalk between MPs and non-MPs and identifies novel factors in endoplasmic reticulum-mitochondrial organization, membrane structure, and mitochondrial lipid homeostasis. More than one-third of these MP complexes are conserved in humans, with many containing members linked to clinical pathologies, enabling us to identify genes with putative disease function through guilt-by-association. Although still remaining incomplete, existing mitochondrial interaction data suggests that the relevant molecular machinery is modular, yet highly integrated with non-mitochondrial processes.

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.

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.

[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.

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.

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.

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.

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.

Global functional atlas of Escherichia coli encompassing previously uncharacterized proteins.

One-third of the 4,225 protein-coding genes of Escherichia coli K-12 remain functionally unannotated (orphans). Many map to distant clades such as Archaea, suggesting involvement in basic prokaryotic traits, whereas others appear restricted to E. coli, including pathogenic strains. To elucidate the orphans' biological roles, we performed an extensive proteomic survey using affinity-tagged E. coli strains and generated comprehensive genomic context inferences to derive a high-confidence compendium for virtually the entire proteome consisting of 5,993 putative physical interactions and 74,776 putative functional associations, most of which are novel. Clustering of the respective probabilistic networks revealed putative orphan membership in discrete multiprotein complexes and functional modules together with annotated gene products, whereas a machine-learning strategy based on network integration implicated the orphans in specific biological processes. We provide additional experimental evidence supporting orphan participation in protein synthesis, amino acid metabolism, biofilm formation, motility, and assembly of the bacterial cell envelope. This resource provides a "systems-wide" functional blueprint of a model microbe, with insights into the biological and evolutionary significance of previously uncharacterized proteins.

[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.

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.

[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.

Genetic interactions reveal the evolutionary trajectories of duplicate genes.

The characterization of functional redundancy and divergence between duplicate genes is an important step in understanding the evolution of genetic systems. Large-scale genetic network analysis in Saccharomyces cerevisiae provides a powerful perspective for addressing these questions through quantitative measurements of genetic interactions between pairs of duplicated genes, and more generally, through the study of genome-wide genetic interaction profiles associated with duplicated genes. We show that duplicate genes exhibit fewer genetic interactions than other genes because they tend to buffer one another functionally, whereas observed interactions are non-overlapping and reflect their divergent roles. We also show that duplicate gene pairs are highly imbalanced in their number of genetic interactions with other genes, a pattern that appears to result from asymmetric evolution, such that one duplicate evolves or degrades faster than the other and often becomes functionally or conditionally specialized. The differences in genetic interactions are predictive of differences in several other evolutionary and physiological properties of duplicate pairs.

Retention of protein complex membership by ancient duplicated gene products in budding yeast.

To investigate functional divergence of gene duplicates, we examined the protein-protein interactions and coexistence in complexes of paralogs resulting from an ancient whole-genome duplication in yeast. Strikingly, half the surveyed paralog pairs were found to be co-clustered in protein complexes, and were more conserved and highly expressed than non-co-clustered paralogs; however, their discordant expression patterns and conservation rates indicate differential regulation of subfunctionalized paralogs. These results highlight the value of protein complex membership in studying functional divergence among gene duplicates.

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.