Effects of Neurally Adjusted Ventilatory Assist (NAVA) levels in non-invasive ventilated patients: titrating NAVA levels with electric diaphragmatic activity and tidal volume matching

BACKGROUND: Neurally adjusted ventilatory assist (NAVA) delivers pressure in proportion to diaphragm electrical activity (Eadi). However, each patient responds differently to NAVA levels. This study aims to examine the matching between tidal volume (Vt) and patients' inspiratory demand (Eadi), and to investigate patient-specific response to various NAVA levels in non-invasively ventilated patients. METHODS: 12 patients were ventilated non-invasively with NAVA using three different NAVA levels. NAVA100 was set according to the manufacturer's recommendation to have similar peak airway pressure as during pressure support. NAVA level was then adjusted ±50% (NAVA50, NAVA150). Airway pressure, flow and Eadi were recorded for 15 minutes at each NAVA level. The matching of Vt and integral of Eadi (ʃEadi) were assessed at the different NAVA levels. A metric, Range90, was defined as the 5-95% range of Vt/ʃEadi ratio to assess matching for each NAVA level. Smaller Range90 values indicated better matching of supply to demand. RESULTS: Patients ventilated at NAVA50 had the lowest Range90 with median 25.6 uVs/ml [Interquartile range (IQR): 15.4-70.4], suggesting that, globally, NAVA50 provided better matching between ʃEadi and Vt than NAVA100 and NAVA150. However, on a per-patient basis, 4 patients had the lowest Range90 values in NAVA100, 1 patient at NAVA150 and 7 patients at NAVA50. Robust coefficient of variation for ʃEadi and Vt were not different between NAVA levels. CONCLUSIONS: The patient-specific matching between ʃEadi and Vt was variable, indicating that to obtain the best possible matching, NAVA level setting should be patient specific. The Range90 concept presented to evaluate Vt/ʃEadi is a physiologic metric that could help in individual titration of NAVA level.Peer reviewe

Performance of lung recruitment model in healthy anesthetised pigs

peer reviewe

Mathematical multi-scale model of the cardiovascular system including mitral valve dynamics. Application to ischemic mitral insufficiency

Valve dysfunction is a common cardiovascular pathology. Despite significant clinical research, there is little formal study of how valve dysfunction affects overall circulatory dynamics. Validated models would offer the ability to better understand these dynamics and thus optimize diagnosis, as well as surgical and other interventions. A cardiovascular and circulatory system (CVS) model has already been validated in silico, and in several animal model studies. It accounts for valve dynamics using Heaviside functions to simulate a physiologically accurate “open on pressure, close on flow” law. However, it does not consider real-time valve opening dynamics and therefore does not fully capture valve dysfunction, particularly where the dysfunction involves partial closure. This research describes an updated version of this previous closed-loop CVS model that includes the progressive opening of the mitral valve, and is defined over the full cardiac cycle. Simulations of the cardiovascular system with healthy mitral valve are performed, and, the global hemodynamic behaviour is studied compared with previously validated results. The error between resulting pressure-volume (PV) loops of already validated CVS model and the new CVS model that includes the progressive opening of the mitral valve is assessed and remains within typical measurement error and variability. Simulations of ischemic mitral insufficiency are also performed. Pressure-Volume loops, transmitral flow evolution and mitral valve aperture area evolution follow reported measurements in shape, amplitude and trends. The resulting cardiovascular system model including mitral valve dynamics provides a foundation for clinical validation and the study of valvular dysfunction in vivo. The overall models and results could readily be generalised to other cardiac valves

Evaluation of a Model-Based Hemodynamic Monitoring Method in a Porcine Study of Septic Shock

Introduction. The accuracy and clinical applicability of an improved model-based system for tracking hemodynamic changes is assessed in an animal study on septic shock. Methods. This study used cardiovascular measurements recorded during a porcine trial studying the efficacy of large-pore hemofiltration for treating septic shock. Four Pietrain pigs were instrumented and induced with septic shock. A subset of the measured data, representing clinically available measurements, was used to identify subjectspecific cardiovascular models. These models were then validated against the remaining measurements. Results. The system accurately matched independent measures of left and right ventricle end diastolic volumes and maximum left and right ventricular pressures to percentage errors less than 20% (except for the 95th percentile error in maximum right ventricular pressure) and all 2 > 0.76. An average decrease of 42% in systemic resistance, a main cardiovascular consequence of septic shock, was observed 120 minutes after the infusion of the endotoxin, consistent with experimentally measured trends. Moreover, modelled temporal trends in right ventricular end systolic elastance and afterload tracked changes in corresponding experimentally derived metrics. Conclusions. These results demonstrate that this model-based method can monitor disease-dependent changes in preload, afterload, and contractility in porcine study of septic shock

Evaluation of a Model-Based Hemodynamic Monitoring Method in a Porcine Study of Septic Shock

Introduction. The accuracy and clinical applicability of an improved model-based system for tracking hemodynamic changes is assessed in an animal study on septic shock. Methods. This study used cardiovascular measurements recorded during a porcine trial studying the efficacy of large-pore hemofiltration for treating septic shock. Four Pietrain pigs were instrumented and induced with septic shock. A subset of the measured data, representing clinically available measurements, was used to identify subjectspecific cardiovascular models. These models were then validated against the remaining measurements. Results. The system accurately matched independent measures of left and right ventricle end diastolic volumes and maximum left and right ventricular pressures to percentage errors less than 20% (except for the 95th percentile error in maximum right ventricular pressure) and all 2 > 0.76. An average decrease of 42% in systemic resistance, a main cardiovascular consequence of septic shock, was observed 120 minutes after the infusion of the endotoxin, consistent with experimentally measured trends. Moreover, modelled temporal trends in right ventricular end systolic elastance and afterload tracked changes in corresponding experimentally derived metrics. Conclusions. These results demonstrate that this model-based method can monitor disease-dependent changes in preload, afterload, and contractility in porcine study of septic shock

Comparison of the Full Outline of UnResponsiveness and Glasgow Liege Scale/Glasgow Coma Scale in an Intensive Care Unit Population.

peer reviewedBACKGROUND: The Full Outline of UnResponsiveness (FOUR) has been proposed as an alternative for the Glasgow Coma Scale (GCS)/Glasgow Liege Scale (GLS) in the evaluation of consciousness in severely brain-damaged patients. We compared the FOUR and GLS/GCS in intensive care unit patients who were admitted in a comatose state. METHODS: FOUR and GLS evaluations were performed in randomized order in 176 acutely (<1 month) brain-damaged patients. GLS scores were transformed in GCS scores by removing the GLS brainstem component. Inter-rater agreement was assessed in 20% of the studied population (N = 35). A logistic regression analysis adjusted for age, and etiology was performed to assess the link between the studied scores and the outcome 3 months after injury (N = 136). RESULTS: GLS/GCS verbal component was scored 1 in 146 patients, among these 131 were intubated. We found that the inter-rater reliability was good for the FOUR score, the GLS/GCS. FOUR, GLS/GCS total scores predicted functional outcome with and without adjustment for age and etiology. 71 patients were considered as being in a vegetative/unresponsive state based on the GLS/GCS. The FOUR score identified 8 of these 71 patients as being minimally conscious given that these patients showed visual pursuit. CONCLUSIONS: The FOUR score is a valid tool with good inter-rater reliability that is comparable to the GLS/GCS in predicting outcome. It offers the advantage to be performable in intubated patients and to identify non-verbal signs of consciousness by assessing visual pursuit, and hence minimal signs of consciousness (11% in this study), not assessed by GLS/GCS scales

Age-dependent impact of the major common genetic risk factor for COVID-19 on severity and mortality

AG has received support by NordForsk Nordic Trial Alliance (NTA) grant, by Academy of Finland Fellow grant N. 323116 and the Academy of Finland for PREDICT consortium N. 340541. The Richards research group is supported by the Canadian Institutes of Health Research (CIHR) (365825 and 409511), the Lady Davis Institute of the Jewish General Hospital, the Canadian Foundation for Innovation (CFI), the NIH Foundation, Cancer Research UK, Genome Québec, the Public Health Agency of Canada, the McGill Interdisciplinary Initiative in Infection and Immunity and the Fonds de Recherche Québec Santé (FRQS). TN is supported by a research fellowship of the Japan Society for the Promotion of Science for Young Scientists. GBL is supported by a CIHR scholarship and a joint FRQS and Québec Ministry of Health and Social Services scholarship. JBR is supported by an FRQS Clinical Research Scholarship. Support from Calcul Québec and Compute Canada is acknowledged. TwinsUK is funded by the Welcome Trust, the Medical Research Council, the European Union, the National Institute for Health Research-funded BioResource and the Clinical Research Facility and Biomedical Research Centre based at Guy’s and St. Thomas’ NHS Foundation Trust in partnership with King’s College London. The Biobanque Québec COVID19 is funded by FRQS, Genome Québec and the Public Health Agency of Canada, the McGill Interdisciplinary Initiative in Infection and Immunity and the Fonds de Recherche Québec Santé. These funding agencies had no role in the design, implementation or interpretation of this study. The COVID19-Host(a)ge study received infrastructure support from the DFG Cluster of Excellence 2167 “Precision Medicine in Chronic Inflammation (PMI)” (DFG Grant: “EXC2167”). The COVID19-Host(a)ge study was supported by the German Federal Ministry of Education and Research (BMBF) within the framework of the Computational Life Sciences funding concept (CompLS grant 031L0165). Genotyping in COVID19-Host(a)ge was supported by a philantropic donation from Stein Erik Hagen. The COVID GWAs, Premed COVID-19 study (COVID19-Host(a)ge_3) was supported by "Grupo de Trabajo en Medicina Personalizada contra el COVID-19 de Andalucia"and also by the Instituto de Salud Carlos III (CIBERehd and CIBERER). Funding comes from COVID-19-GWAS, COVID-PREMED initiatives. Both of them are supported by "Consejeria de Salud y Familias" of the Andalusian Government. DMM is currently funded by the the Andalussian government (Proyectos Estratégicos-Fondos Feder PE-0451-2018). The Columbia University Biobank was supported by Columbia University and the National Center for Advancing Translational Sciences, NIH, through Grant Number UL1TR001873. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH or Columbia University. The SPGRX study was supported by the Consejería de Economía, Conocimiento, Empresas y Universidad #CV20-10150. The GEN-COVID study was funded by: the MIUR grant “Dipartimenti di Eccellenza 2018-2020” to the Department of Medical Biotechnologies University of Siena, Italy; the “Intesa San Paolo 2020 charity fund” dedicated to the project NB/2020/0119; and philanthropic donations to the Department of Medical Biotechnologies, University of Siena for the COVID-19 host genetics research project (D.L n.18 of March 17, 2020). Part of this research project is also funded by Tuscany Region “Bando Ricerca COVID-19 Toscana” grant to the Azienda Ospedaliero Universitaria Senese (CUP I49C20000280002). Authors are grateful to: the CINECA consortium for providing computational resources; the Network for Italian Genomes (NIG) (http://www.nig.cineca.it) for its support; the COVID-19 Host Genetics Initiative (https://www.covid19hg.org/); the Genetic Biobank of Siena, member of BBMRI-IT, Telethon Network of Genetic Biobanks (project no. GTB18001), EuroBioBank, and RD-Connect, for managing specimens. Genetics against coronavirus (GENIUS), Humanitas University (COVID19-Host(a)ge_4) was supported by Ricerca Corrente (Italian Ministry of Health), intramural funding (Fondazione Humanitas per la Ricerca). The generous contribution of Banca Intesa San Paolo and of the Dolce&Gabbana Fashion Firm is gratefully acknowledged. Data acquisition and sample processing was supported by COVID-19 Biobank, Fondazione IRCCS Cà Granda Milano; LV group was supported by MyFirst Grant AIRC n.16888, Ricerca Finalizzata Ministero della Salute RF-2016-02364358, Ricerca corrente Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, the European Union (EU) Programme Horizon 2020 (under grant agreement No. 777377) for the project LITMUS- “Liver Investigation: Testing Marker Utility in Steatohepatitis”, Programme “Photonics” under grant agreement “101016726” for the project “REVEAL: Neuronal microscopy for cell behavioural examination and manipulation”, Fondazione Patrimonio Ca’ Granda “Liver Bible” PR-0361. DP was supported by Ricerca corrente Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, CV PREVITAL “Strategie di prevenzione primaria nella popolazione Italiana” Ministero della Salute, and Associazione Italiana per la Prevenzione dell’Epatite Virale (COPEV). Genetic modifiers for COVID-19 related illness (BeLCovid_1) was supported by the "Fonds Erasme". The Host genetics and immune response in SARS-Cov-2 infection (BelCovid_2) study was supported by grants from Fondation Léon Fredericq and from Fonds de la Recherche Scientifique (FNRS). The INMUNGEN-CoV2 study was funded by the Consejo Superior de Investigaciones Científicas. KUL is supported by the German Research Foundation (LU 1944/3-1) SweCovid is funded by the SciLifeLab/KAW national COVID-19 research program project grant to Michael Hultström (KAW 2020.0182) and the Swedish Research Council to Robert Frithiof (2014-02569 and 2014-07606). HZ is supported by Jeansson Stiftelser, Magnus Bergvalls Stiftelse. The COMRI cohort is funded by Technical University of Munich, Munich, Germany. Genotyping for the COMRI cohort was performed and funded by the Genotyping Laboratory of Institute for Molecular Medicine Finland FIMM Technology Centre, University of Helsinki, Helsinki, Finland. These funding agencies had no role in the design, implementation or interpretation of this study.Background: There is considerable variability in COVID-19 outcomes amongst younger adults—and some of this variation may be due to genetic predisposition. We characterized the clinical implications of the major genetic risk factor for COVID-19 severity, and its age-dependent effect, using individual-level data in a large international multi-centre consortium. Method: The major common COVID-19 genetic risk factor is a chromosome 3 locus, tagged by the marker rs10490770. We combined individual level data for 13,424 COVID-19 positive patients (N=6,689 hospitalized) from 17 cohorts in nine countries to assess the association of this genetic marker with mortality, COVID-19-related complications and laboratory values. We next examined if the magnitude of these associations varied by age and were independent from known clinical COVID-19 risk factors. Findings: We found that rs10490770 risk allele carriers experienced an increased risk of all-cause mortality (hazard ratio [HR] 1·4, 95% confidence interval [CI] 1·2–1·6) and COVID-19 related mortality (HR 1·5, 95%CI 1·3–1·8). Risk allele carriers had increased odds of several COVID-19 complications: severe respiratory failure (odds ratio [OR] 2·0, 95%CI 1·6-2·6), venous thromboembolism (OR 1·7, 95%CI 1·2-2·4), and hepatic injury (OR 1·6, 95%CI 1·2-2·0). Risk allele carriers ≤ 60 years had higher odds of death or severe respiratory failure (OR 2·6, 95%CI 1·8-3·9) compared to those > 60 years OR 1·5 (95%CI 1·3-1·9, interaction p-value=0·04). Amongst individuals ≤ 60 years who died or experienced severe respiratory COVID-19 outcome, we found that 31·8% (95%CI 27·6-36·2) were risk variant carriers, compared to 13·9% (95%CI 12·6-15·2%) of those not experiencing these outcomes. Prediction of death or severe respiratory failure among those ≤ 60 years improved when including the risk allele (AUC 0·82 vs 0·84, p=0·016) and the prediction ability of rs10490770 risk allele was similar to, or better than, most established clinical risk factors. Interpretation: The major common COVID-19 risk locus on chromosome 3 is associated with increased risks of morbidity and mortality—and these are more pronounced amongst individuals ≤ 60 years. The effect on COVID-19 severity was similar to, or larger than most established risk factors, suggesting potential implications for clinical risk management.Academy of Finland Fellow grant N. 323116Academy of Finland for PREDICT consortium N. 340541.Canadian Institutes of Health Research (CIHR) (365825 and 409511)Lady Davis Institute of the Jewish General HospitalCanadian Foundation for Innovation (CFI)NIH FoundationCancer Research UKGenome QuébecPublic Health Agency of CanadaMcGill Interdisciplinary Initiative in Infection and Immunity and the Fonds de Recherche Québec Santé (FRQS)Japan Society for the Promotion of Science for Young ScientistsCIHR scholarship and a joint FRQS and Québec Ministry of Health and Social Services scholarshipFRQS Clinical Research ScholarshipCalcul QuébecCompute CanadaWelcome TrustMedical Research CouncEuropean UnionNational Institute for Health Research-funded BioResourceClinical Research Facility and Biomedical Research Centre based at Guy’s and St. Thomas’ NHS Foundation TrustKing’s College LondonGenome QuébecPublic Health Agency of CanadaMcGill Interdisciplinary Initiative in Infection and ImmunityFonds de Recherche Québec Santé(DFG Grant: “EXC2167”)(CompLS grant 031L0165)Stein Erik Hagen"Grupo de Trabajo en Medicina Personalizada contra el COVID-19 de Andalucia"Instituto de Salud Carlos III (CIBERehd and CIBERER)COVID-19-GWASCOVID-PREMED initiatives"Consejeria de Salud y Familias" of the Andalusian GovernmentAndalusian government (Proyectos Estratégicos-Fondos Feder PE-0451-2018)Columbia UniversityNational Center for Advancing Translational SciencesNIH Grant Number UL1TR001873Consejería de Economía, Conocimiento, Empresas y Universidad #CV20-10150MIUR grant “Dipartimenti di Eccellenza 2018-2020”“Intesa San Paolo 2020 charity fund” dedicated to the project NB/2020/0119Tuscany Region “Bando Ricerca COVID-19 Toscana”CINECA consortiumNetwork for Italian Genomes (NIG)COVID-19 Host Genetics InitiativeGenetic Biobank of SienaEuroBioBankRD-ConnectRicerca Corrente (Italian Ministry of Health)Fondazione Humanitas per la RicercaBanca Intesa San PaoloDolce&Gabbana Fashion FirmCOVID-19 BiobankFondazione IRCCS Cà Granda MilanoMyFirst Grant AIRC n.16888Ricerca Finalizzata Ministero della Salute RF-2016-02364358Ricerca corrente Fondazione IRCCS Ca’ Granda Ospedale Maggiore PoliclinicoEuropean Union (EU) Programme Horizon 2020 (under grant agreement No. 777377)“Photonics” “101016726”Fondazione Patrimonio Ca’ Granda “Liver Bible” PR-0361CV PREVITAL “Strategie di prevenzione primaria nella popolazione Italiana” Ministero della Salute, and Associazione Italiana per la Prevenzione dell’Epatite Virale (COPEV)"Fonds Erasme"Fondation Léon FredericqFonds de la Recherche Scientifique (FNRS)Consejo Superior de Investigaciones CientíficasGerman Research Foundation (LU 1944/3-1)SciLifeLab/KAW national COVID-19 research program project (KAW 2020.0182)Swedish Research Council (2014-02569 and 2014-07606)Jeansson Stiftelser, Magnus Bergvalls StiftelseTechnical University of Munich, Munich, GermanyGenotyping Laboratory of Institute for Molecular Medicine Finland FIMM Technology Centre, University of Helsinki, Helsinki, Finlan

SARS-CoV-2 susceptibility and COVID-19 disease severity are associated with genetic variants affecting gene expression in a variety of tissues

Variability in SARS-CoV-2 susceptibility and COVID-19 disease severity between individuals is partly due to genetic factors. Here, we identify 4 genomic loci with suggestive associations for SARS-CoV-2 susceptibility and 19 for COVID-19 disease severity. Four of these 23 loci likely have an ethnicity-specific component. Genome-wide association study (GWAS) signals in 11 loci colocalize with expression quantitative trait loci (eQTLs) associated with the expression of 20 genes in 62 tissues/cell types (range: 1:43 tissues/gene), including lung, brain, heart, muscle, and skin as well as the digestive system and immune system. We perform genetic fine mapping to compute 99% credible SNP sets, which identify 10 GWAS loci that have eight or fewer SNPs in the credible set, including three loci with one single likely causal SNP. Our study suggests that the diverse symptoms and disease severity of COVID-19 observed between individuals is associated with variants across the genome, affecting gene expression levels in a wide variety of tissue types

A first update on mapping the human genetic architecture of COVID-19

peer reviewe

Dog Bite in a Splenectomized Patient

peer reviewedWe present a case of Capnocytophaga canimorsus fulminant infection linked to a dog bite in a splenectomized patient. Capnocytophaga canimorsus is a gram-negative rod that typically causes septicaemia with disseminated intravascular coagulation in both immunocompromised and immunocompetent hosts. It is associated with high mortality. We also reviewed the literature and provide some recommendations on the management of bite wound as well as on both prevention and treatment of infection in asplenic state