Publications by authors named "Riccardo Colombo"

73 Publications

Comment on: Effectiveness of remdesivir in patients with COVID-19 under mechanical ventilation in an Italian ICU.

J Antimicrob Chemother 2021 Feb 9. Epub 2021 Feb 9.

Department of Infectious Diseases, ASST Fatebenefratelli-Sacco, Luigi Sacco University Hospital, Milan, Italy.

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http://dx.doi.org/10.1093/jac/dkab033DOI Listing
February 2021

Transesophageal echocardiography in patients with cardiac arrest: from high-quality chest compression to effective resuscitation.

J Echocardiogr 2020 Nov 27. Epub 2020 Nov 27.

Cardiology Unit and LTTA Center, University of Ferrara, Ferrara, Italy.

Background: Survival after cardiac arrest depends on prompt and effective cardiopulmonary resuscitation (CPR). Transesophageal echocardiography (TEE) can be applied to evaluate the effectiveness of chest compression-decompression maneuvers in the setting of cardiac arrest undergoing CPR. The efficacy of chest compression can be continuously assessed by TEE that can improve the effectiveness of CPR guiding the rescuer to optimize or correct chest compression and decompression by directly examining the movements of the cardiac walls and valve leaflets.

Purpose: The review describes how to perform TEE in the emergency setting of cardiopulmonary arrest, its advantages, and limitations, and ultimately propose an echo-guided approach to CPR.
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http://dx.doi.org/10.1007/s12574-020-00492-8DOI Listing
November 2020

Broncho-alveolar inflammation in COVID-19 patients: a correlation with clinical outcome.

BMC Pulm Med 2020 Nov 16;20(1):301. Epub 2020 Nov 16.

University of Pavia and Pneumology Unit, IRCCS Policlinico S. Matteo Foundation, Pavia, Italy.

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) rapidly reached pandemic proportions. Given that the main target of SARS-CoV-2 are lungs leading to severe pneumonia with hyperactivation of the inflammatory cascade, we conducted a prospective study to assess alveolar inflammatory status in patients with moderate to severe COVID-19.

Methods: Diagnostic bronchoalveolar lavage (BAL) was performed in 33 adult patients with SARS-CoV-2 infection by real-time PCR on nasopharyngeal swab admitted to the Intensive care unit (ICU) (n = 28) and to the Intermediate Medicine Ward (IMW) (n = 5). We analyze the differential cell count, ultrastructure of cells and Interleukin (IL)6, 8 and 10 levels.

Results: ICU patients showed a marked increase in neutrophils (1.24 × 10 ml, 0.85-2.07), lower lymphocyte (0.97 × 10 ml, 0.024-0.34) and macrophages fractions (0.43 × 10 ml, 0.34-1.62) compared to IMW patients (0.095 × 10 ml, 0.05-0.73; 0.47 × 10 ml, 0.28-1.01 and 2.14 × 10 ml, 1.17-3.01, respectively) (p < 0.01). Study of ICU patients BAL by electron transmission microscopy showed viral particles inside mononuclear cells confirmed by immunostaining with anti-viral capsid and spike antibodies. IL6 and IL8 were significantly higher in ICU patients than in IMW (IL6 p < 0.01, IL8 p < 0.0001), and also in patients who did not survive (IL6 p < 0.05, IL8 p = 0.05 vs. survivors). IL10 did not show a significant variation between groups. Dividing patients by treatment received, lower BAL concentrations of IL6 were found in patients treated with steroids as compared to those treated with tocilizumab (p < 0.1) or antivirals (p < 0.05).

Conclusions: Alveolitis, associated with COVID-19, is mainly sustained by innate effectors which showed features of extensive activation. The burden of pro-inflammatory cytokines IL6 and IL8 in the broncho-alveolar environment is associated with clinical outcome.
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http://dx.doi.org/10.1186/s12890-020-01343-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7668012PMC
November 2020

Sigh in Patients With Acute Hypoxemic Respiratory Failure and ARDS: The PROTECTION Pilot Randomized Clinical Trial.

Chest 2020 Nov 13. Epub 2020 Nov 13.

Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy; Department of Anesthesia, Critical Care and Emergency, Foundation IRCCS Cà Granda Maggiore Policlinico Hospital, Milan, Italy.

Background: Sigh is a cyclic brief recruitment maneuver: previous physiologic studies showed that its use could be an interesting addition to pressure support ventilation to improve lung elastance, decrease regional heterogeneity, and increase release of surfactant.

Research Question: Is the clinical application of sigh during pressure support ventilation (PSV) feasible?

Study Design And Methods: We conducted a multicenter noninferiority randomized clinical trial on adult intubated patients with acute hypoxemic respiratory failure or ARDS undergoing PSV. Patients were randomized to the no-sigh group and treated by PSV alone, or to the sigh group, treated by PSV plus sigh (increase in airway pressure to 30 cm HO for 3 s once per minute) until day 28 or death or successful spontaneous breathing trial. The primary end point of the study was feasibility, assessed as noninferiority (5% tolerance) in the proportion of patients failing assisted ventilation. Secondary outcomes included safety, physiologic parameters in the first week from randomization, 28-day mortality, and ventilator-free days.

Results: Two-hundred and fifty-eight patients (31% women; median age, 65 [54-75] years) were enrolled. In the sigh group, 23% of patients failed to remain on assisted ventilation vs 30% in the no-sigh group (absolute difference, -7%; 95% CI, -18% to 4%; P = .015 for noninferiority). Adverse events occurred in 12% vs 13% in the sigh vs no-sigh group (P = .852). Oxygenation was improved whereas tidal volume, respiratory rate, and corrected minute ventilation were lower over the first 7 days from randomization in the sigh vs no-sigh group. There was no significant difference in terms of mortality (16% vs 21%; P = .337) and ventilator-free days (22 [7-26] vs 22 [3-25] days; P = .300) for the sigh vs no-sigh group.

Interpretation: Among hypoxemic intubated ICU patients, application of sigh was feasible and without increased risk.

Trial Registry: ClinicalTrials.gov; No.: NCT03201263; URL: www.clinicaltrials.gov.
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http://dx.doi.org/10.1016/j.chest.2020.10.079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7664474PMC
November 2020

Clinical characteristics and respiratory support of 310 COVID-19 patients, diagnosed at the emergency room: a single-center retrospective study.

Intern Emerg Med 2020 Nov 11. Epub 2020 Nov 11.

Department of Emergency Medicine, ASST Grande Ospedale Metropolitano Niguarda, Piazza Ospedale Maggiore 3, 20162, Milan, Italy.

An ongoing outbreak of pneumonia associated with severe acute respiratory coronavirus 2 (SARS-CoV-2) occurred at the end of February 2020 in Lombardy, Italy. We analyzed data from a retrospective, single-center case series of 310 consecutive patients, with confirmed SARS-CoV-2 infection, admitted to the emergency room. We aimed to describe the clinical course, treatment and outcome of a cohort of patients with COVID-19 pneumonia, with special attention to oxygen delivery and ventilator support. Throughout the study period, 310 consecutive patients, with confirmed SARS-CoV-2 infection, attended the Emergency Room (ER), of these, 34 were discharged home directly from the ER. Of the remaining 276 patients, the overall mortality was 30.4%: 7 patients died in the ER and 77 during hospitalization. With respect to oxygen delivery: 22 patients did not need any oxygen support (8.0%), 151 patients were treated with oxygen only (54.7%), and 49 (17.8%) were intubated. 90 patients (32.6%) were treated with CPAP (Continuous Positive Airway Pressure) or NIV (Non Invasive Ventilation); in this group, 27 patients had a Do Not Intubate (DNI) order and were treated with CPAP/NIV as an upper threshold therapy, showing high mortality rate (88.9%). Among the 63 patients treated with CPAP/NIV without DNI, NIV failure occurred in 36 patients (57.1%), with mortality rate of 47.2%. Twenty-seven (27) patients were treated with CPAP/NIV without needing mechanical ventilation and 26 were discharged alive (96.3%). The study documents the poor prognosis of patients with severe respiratory failure, although a considerable minority of patients treated with CPAP/NIV had a positive outcome.
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http://dx.doi.org/10.1007/s11739-020-02548-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7656099PMC
November 2020

Unexpectedly High Frequency of Enterococcal Bloodstream Infections in Coronavirus Disease 2019 Patients Admitted to an Italian ICU: An Observational Study.

Crit Care Med 2021 01;49(1):e31-e40

Department of Infectious Diseases, ASST Fatebenefratelli-Sacco, Luigi Sacco University Hospital, Milan, Italy.

Objectives: We aimed to assess the frequency of ICU-acquired bloodstream infections in coronavirus disease 2019 patients.

Design: Retrospective observational study.

Setting: The emergency expansion of an ICU from eight general beds to 30 coronavirus disease 2019 beds.

Participants: Patients with coronavirus disease 2019 admitted to the ICU of Luigi Sacco Hospital (Milan, Italy) for greater than or equal to 48 hours between February 21, 2020, and April 30, 2020.

Interventions: None.

Measurements And Main Results: The frequency of bloodstream infections per 1,000 days of ICU stay was calculated in 89 coronavirus disease 2019 patients, and the cumulative probability of bloodstream infection was estimated using death and ICU discharge as competing events. Sixty patients (67.4%) experienced at least one of the 93 recorded episodes of bloodstream infection, a frequency of 87 per 1,000 days of ICU stay (95% CI, 67-112).The patients who experienced a bloodstream infection had a higher Sequential Organ Failure Assessment score upon ICU admission (9.5; interquartile range, 8-12 vs 8, interquartile range, 5-10; p = 0.042), a longer median ICU stay (15 d; interquartile range, 11-23 vs 8, interquartile range, 5-12; p < 0.001), and more frequently required invasive mechanical ventilation (98.3% vs 82.8%; p = 0.013) than those who did not. The median time from ICU admission to the first bloodstream infection episode was 10 days. Gram-positive bacteria accounted for 74 episodes (79.6%), with Enterococcus species being the most prevalent (53 episodes, 55.8%). Thirty-two isolates (27.3%) showed multidrug resistance.

Conclusions: Coronavirus disease 2019 seemed to increase the frequency of bloodstream infections (particularly Enterococcus-related bloodstream infection) after ICU admission. This may have been due to enteric involvement in patients with severe coronavirus disease 2019 and/or limitations in controlling the patient-to-patient transmission of infectious agents in extremely challenging circumstances.
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http://dx.doi.org/10.1097/CCM.0000000000004748DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7737701PMC
January 2021

Sitagliptin Treatment at the Time of Hospitalization Was Associated With Reduced Mortality in Patients With Type 2 Diabetes and COVID-19: A Multicenter, Case-Control, Retrospective, Observational Study.

Diabetes Care 2020 12 29;43(12):2999-3006. Epub 2020 Sep 29.

International Center for T1D, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, Dipartimento di Scienze Biomediche e Cliniche L. Sacco, Università di Milano, Milan, Italy

Objective: Poor outcomes have been reported in patients with type 2 diabetes and coronavirus disease 2019 (COVID-19); thus, it is mandatory to explore novel therapeutic approaches for this population.

Research Design And Methods: In a multicenter, case-control, retrospective, observational study, sitagliptin, an oral and highly selective dipeptidyl peptidase 4 inhibitor, was added to standard of care (e.g., insulin administration) at the time of hospitalization in patients with type 2 diabetes who were hospitalized with COVID-19. Every center also recruited at a 1:1 ratio untreated control subjects matched for age and sex. All patients had pneumonia and exhibited oxygen saturation <95% when breathing ambient air or when receiving oxygen support. The primary end points were discharge from the hospital/death and improvement of clinical outcomes, defined as an increase in at least two points on a seven-category modified ordinal scale. Data were collected retrospectively from patients receiving sitagliptin from 1 March through 30 April 2020.

Results: Of the 338 consecutive patients with type 2 diabetes and COVID-19 admitted in Northern Italy hospitals included in this study, 169 were on sitagliptin, while 169 were on standard of care. Treatment with sitagliptin at the time of hospitalization was associated with reduced mortality (18% vs. 37% of deceased patients; hazard ratio 0.44 [95% CI 0.29-0.66]; = 0.0001), with an improvement in clinical outcomes (60% vs. 38% of improved patients; = 0.0001) and with a greater number of hospital discharges (120 vs. 89 of discharged patients; = 0.0008) compared with patients receiving standard of care, respectively.

Conclusions: In this multicenter, case-control, retrospective, observational study of patients with type 2 diabetes admitted to the hospital for COVID-19, sitagliptin treatment at the time of hospitalization was associated with reduced mortality and improved clinical outcomes as compared with standard-of-care treatment. The effects of sitagliptin in patients with type 2 diabetes and COVID-19 should be confirmed in an ongoing randomized, placebo-controlled trial.
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http://dx.doi.org/10.2337/dc20-1521DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7770266PMC
December 2020

Early administration of lopinavir/ritonavir plus hydroxychloroquine does not alter the clinical course of SARS-CoV-2 infection: A retrospective cohort study.

J Med Virol 2021 03 28;93(3):1421-1427. Epub 2020 Sep 28.

Department of Infectious Diseases, ASST Fatebenefratelli-Sacco, Luigi Sacco University Hospital, Milan, Italy.

As it has been shown that lopinavir (LPV) and hydroxychloroquine (HCQ) have in vitro activity against coronaviruses, they were used to treat COVID-19 during the first wave of the epidemic in Lombardy, Italy. To compare the rate of clinical improvement between those who started LPV/ritonavir (LPV/r)+HCQ within 5 days of symptom onset (early treatment, ET) and those who started later (delayed treatment, DT). This was a retrospective intent-to-treat analysis of the hospitalized patients who started LPV/r + HCQ between 21 February and 20 March 2020. The association between the timing of treatment and the probability of 30-day mortality was assessed using univariable and multivariable logistic models. The study involved 172 patients: 43 (25%) in the ET and 129 (75%) in the DT group. The rate of clinical improvement increased over time to 73.3% on day 30, without any significant difference between the two groups (Gray's test P = .213). After adjusting for potentially relevant clinical variables, there was no significant association between the timing of the start of treatment and the probability of 30-day mortality (adjusted odds ratio [aOR] ET vs DT = 1.45, 95% confidence interval 0.50-4.19). Eight percent of the patients discontinued the treatment becausebecause of severe gastrointestinal disorders attributable to LPV/r. The timing of the start of LPV/r + HCQ treatment does not seem to affect the clinical course of hospitalized patients with COVID-19. Together with the severe adverse events attributable to LPV/r, this raises concerns about the benefit of using this combination to treat COVID-19.
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http://dx.doi.org/10.1002/jmv.26407DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7436522PMC
March 2021

Pulmonary post-mortem findings in a series of COVID-19 cases from northern Italy: a two-centre descriptive study.

Lancet Infect Dis 2020 10 8;20(10):1135-1140. Epub 2020 Jun 8.

Department of Pathology, Papa Giovanni XXIII Hospital, Bergamo, Italy; Department of Biomedical and Clinical Sciences, University of Milan, Milan, Italy. Electronic address:

Background: COVID-19 is characterised by respiratory symptoms, which deteriorate into respiratory failure in a substantial proportion of cases, requiring intensive care in up to a third of patients admitted to hospital. Analysis of the pathological features in the lung tissues of patients who have died with COVID-19 could help us to understand the disease pathogenesis and clinical outcomes.

Methods: We systematically analysed lung tissue samples from 38 patients who died from COVID-19 in two hospitals in northern Italy between Feb 29 and March 24, 2020. The most representative areas identified at macroscopic examination were selected, and tissue blocks (median seven, range five to nine) were taken from each lung and fixed in 10% buffered formalin for at least 48 h. Tissues were assessed with use of haematoxylin and eosin staining, immunohistochemical staining for inflammatory infiltrate and cellular components (including staining with antibodies against CD68, CD3, CD45, CD61, TTF1, p40, and Ki-67), and electron microscopy to identify virion localisation.

Findings: All cases showed features of the exudative and proliferative phases of diffuse alveolar damage, which included capillary congestion (in all cases), necrosis of pneumocytes (in all cases), hyaline membranes (in 33 cases), interstitial and intra-alveolar oedema (in 37 cases), type 2 pneumocyte hyperplasia (in all cases), squamous metaplasia with atypia (in 21 cases), and platelet-fibrin thrombi (in 33 cases). The inflammatory infiltrate, observed in all cases, was largely composed of macrophages in the alveolar lumina (in 24 cases) and lymphocytes in the interstitium (in 31 cases). Electron microscopy revealed that viral particles were predominantly located in the pneumocytes.

Interpretation: The predominant pattern of lung lesions in patients with COVID-19 patients is diffuse alveolar damage, as described in patients infected with severe acute respiratory syndrome and Middle East respiratory syndrome coronaviruses. Hyaline membrane formation and pneumocyte atypical hyperplasia are frequent. Importantly, the presence of platelet-fibrin thrombi in small arterial vessels is consistent with coagulopathy, which appears to be common in patients with COVID-19 and should be one of the main targets of therapy.

Funding: None.
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http://dx.doi.org/10.1016/S1473-3099(20)30434-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7279758PMC
October 2020

Tethering role of the autonomic nervous system on cardioventilatory coupling.

Respir Physiol Neurobiol 2020 08 23;279:103466. Epub 2020 May 23.

Department of Anesthesiology and Intensive Care, ASST Fatebenefratelli Sacco, Luigi Sacco Hospital - Polo Universitario, University of Milan, Milan, Italy.

Hypovolemia and intermittent positive pressure ventilation are conditions that frequently characterize the state of critical illness, but their interaction and resulting cardioventilatory coupling is poorly understood even in healthy humans. We explored heart rate variability, baroreflex activity, and their interaction in an experimental protocol involving twelve mildly hypovolemic healthy subjects during spontaneous breathing and noninvasive positive-pressure ventilation. In seven subjects, an echocardiographic assessment was also performed. Correction of hypovolemia, raising cardiac preload, produced an increase in high-frequency spectral power density of heart rate, left low-frequency spectral power density unchanged but enhanced baroreflex sensitivity. Cardioventilatory coupling was affected by both central blood volume and ventilatory mode and was mainly entrained by the respiratory oscillation. In conclusion, the autonomic nervous system and baroreflex have a significant role in compensating the hemodynamic perturbation due to changes of volemia and ventilatory-induced fluctuations of venous return. They exert an integrative function on the adaptive pattern of cardioventilatory coupling.
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http://dx.doi.org/10.1016/j.resp.2020.103466DOI Listing
August 2020

Off-label use of tocilizumab for the treatment of SARS-CoV-2 pneumonia in Milan, Italy.

Eur J Intern Med 2020 06 21;76:36-42. Epub 2020 May 21.

Department of Infectious Diseases, ASST Fatebenefratelli Sacco, Milan, Italy.

Background: Tocilizumab, a humanized monoclonal antibody, targets IL-6 receptors blocking downstream pro-inflammatory effects of IL-6. In preliminary reports it was suggested to be beneficial in patients with severe COVID-19.

Methods: In this open-label prospective study we describe clinical characteristics and outcome of 51 patients hospitalized with confirmed and severe COVID-19 pneumonia treated with tocilizumab intravenously. All patients had elevated IL-6 plasma level (>40 pg/mL) and oxygen saturation <93% in ambient air. Clinical outcomes, oxygen support, laboratory data and adverse events were collected over a follow-up of 30 days.

Results: Forty-five patients (88%) were on high-flow oxygen supplementation, six of whom with invasive ventilation. From baseline to day 7 after tocilizumab we observed a dramatic drop of body temperature and CRP value with a significant increase in lymphocyte count (p<0.001). Over a median follow-up time of 34 days from tocilizumab, 34 patients (67%) showed an improvement in their clinical severity class; 31 were discharged; 17 (33%) showed a worsening of their clinical status, of these 14 died (27%). The mortality rate was significantly associated with mechanical ventilation at baseline (83.3% vs 20% of patients on non-invasive oxygen support; p=0.0001). The most frequent side effects were an increase of hepatic enzymes (29%), thrombocytopenia (14%), and serious bacterial and fungal infections (27%).

Conclusion: Tocilizumab exerts a rapidly beneficial effect on fever and inflammatory markers, although no significant impact on the clinical outcome can be inferred by our results. Critically ill patients seem to have a high risk of serious infections with this drug.
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http://dx.doi.org/10.1016/j.ejim.2020.05.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7241995PMC
June 2020

30-day mortality in patients hospitalized with COVID-19 during the first wave of the Italian epidemic: A prospective cohort study.

Pharmacol Res 2020 08 22;158:104931. Epub 2020 May 22.

Department of Infectious Diseases, ASST Fatebenefratelli-Sacco, Luigi Sacco University Hospital, Milan, Italy; Luigi Sacco Department of Biomedical and Clinical Sciences DIBIC, University of Milan, Italy.

Italy was the first European country hit by the COVID-19 pandemic and has the highest number of recorded COVID-19 deaths in Europe. This prospective cohort study of the correlates of the risk of death in COVID-19 patients was conducted at the Infectious Diseases and Intensive Care units of Luigi Sacco Hospital, Milan, Italy. The clinical characteristics of all the COVID-19 patients hospitalised in the early days of the epidemic (21 February -19 March 2020) were recorded upon admission, and the time-dependent probability of death was evaluated using the Kaplan-Meier method (censored as of 20 April 2020). Cox proportional hazard models were used to assess the factors independently associated with the risk of death. Forty-eight (20.6 %) of the 233 patients followed up for a median of 40 days (interquartile range 33-47) died during the follow-up. Most were males (69.1 %) and their median age was 61 years (IQR 50-72). The time-dependent probability of death was 19.7 % (95 % CI 14.6-24.9 %) 30 days after hospital admission. Age (adjusted hazard ratio [aHR] 2.08, 95 % CI 1.48-2.92 per ten years more) and obesity (aHR 3.04, 95 % CI 1.42-6.49) were independently associated with an increased risk of death, which was also associated with critical disease (aHR 8.26, 95 % CI 1.41-48.29), C-reactive protein levels (aHR 1.17, 95 % CI 1.02-1.35 per 50 mg/L more) and creatinine kinase levels above 185 U/L (aHR 2.58, 95 % CI 1.37-4.87) upon admission. Case-fatality rate of patients hospitalized with COVID-19 in the early days of the Italian epidemic was about 20 %. Our study adds evidence to the notion that older age, obesity and more advanced illness are factors associated to an increased risk of death among patients hospitalized with COVID-19.
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http://dx.doi.org/10.1016/j.phrs.2020.104931DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7242199PMC
August 2020

Compassionate remdesivir treatment of severe Covid-19 pneumonia in intensive care unit (ICU) and Non-ICU patients: Clinical outcome and differences in post-treatment hospitalisation status.

Pharmacol Res 2020 08 11;158:104899. Epub 2020 May 11.

Luigi Sacco Department of Biomedical and Clinical Sciences, University of Milan, Italy; Department of Infectious Diseases, ASST Fatebenefratelli-Sacco, Milan, Italy.

SARS-CoV-2 is causing an increasing number of deaths worldwide because no effective treatment is currently available. Remdesivir has shown in vitro activity against coronaviruses and is a possible antiviral treatment for SARS-CoV-2 infection. This prospective (compassionate), open-label study of remdesivir, which was conducted at Luigi Sacco Hospital, Milan, Italy, between February 23 and March 20, 2020, involved patients with SARS-CoV-2 pneumonia aged ≥18 years undergoing mechanical ventilation or with an oxygen saturation level of ≤94 % in air or a National Early Warning Score 2 of ≥4. The primary outcome was the change in clinical status based on a 7-category ordinal scale (1 = not hospitalised, resuming normal daily activities; 7 = deceased). The 35 patients enrolled from February 23 to March 20, 2020, included 18 in intensive care unit (ICU), and 17 in our infectious diseases ward (IDW). The 10-day course of remdesivir was completed by 22 patients (63 %) and discontinued by 13, of whom eight (22.8 %) discontinued because of adverse events. The median follow-up was 39 days (IQR 25-44). At day 28, 14 (82.3 %) patients from IDW were discharged, two were still hospitalized and one died (5.9 %), whereas in ICU 6 (33.3 %) were discharged, 8 (44.4 %) patients died, three (16.7 %) were still mechanically ventilated and one (5.6 %) was improved but still hospitalized. Hypertransaminasemia and acute kidney injury were the most frequent severe adverse events observed (42.8 % and 22.8 % of the cases, respectively). Our data suggest that remdesivir can benefit patients with SARS-CoV-2 pneumonia hospitalised outside ICU where clinical outcome was better and adverse events are less frequently observed. Ongoing randomised controlled trials will clarify its real efficacy and safety, who to treat, and when.
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http://dx.doi.org/10.1016/j.phrs.2020.104899DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7212963PMC
August 2020

The effects of severe hemoconcentration on acid-base equilibrium in critically ill patients: the forgotten role of buffers in whole blood.

J Crit Care 2020 06 4;57:177-184. Epub 2020 Mar 4.

Department of Anesthesiology and Intensive Care, ASST Fatebenefratelli Sacco, Luigi Sacco Hospital, Polo Universitario, University of Milan, Via G.B. Grassi 74, 20157 Milan, Italy.

Purpose: Idiopathic Systemic Capillary Leak Syndrome (ISCLS) is a paroxysmal permeability disorder characterized by abrupt onset of shock and hemoconcentration due to massive shift of fluids and proteins from the intravascular to the interstitial compartment. We hypothesize that increased hemoglobin concentration has a pivotal role in the acid-base imbalance during life-threatening crises.

Materials And Methods: Analysis of the acid-base balance fluctuations during six severe ISCLS flares admitted to ICU of a referral center for ISCLS.

Results: Acid-base equilibrium was assessed for plasma and the whole blood by single and multicompartmental models. The acute phase of ISCLS was characterized by shock, hypoalbuminemia, severe hemoconcentration, and acidosis. The physical-chemical approach for plasma found a remarkable component of unmeasured anions (SIG) during the acute phase. After correction of the physical-chemical model for the whole blood, the SIG variations disappeared because the buffer role of hemoglobin was relevant.

Conclusion: Hemoglobin has a remarkable role in buffering metabolic acidosis during the shock phase of ISCLS. In these circumstances, the assessment of acid-base equilibrium in plasma alone may overestimate unmeasured anions. On the contrary, the physical-chemical model corrected for whole blood better explains the metabolic component of acid-base imbalance when marked shift of hemoglobin concentration occurs.
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http://dx.doi.org/10.1016/j.jcrc.2020.02.016DOI Listing
June 2020

Legionellosis Complicated by Invasive Aspergillosis in a Patient With Rheumatoid Arthritis.

J Clin Rheumatol 2020 Feb 11. Epub 2020 Feb 11.

From the III Infectious Diseases Unit, ASST-FBF-Sacco.

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http://dx.doi.org/10.1097/RHU.0000000000001342DOI Listing
February 2020

Myocardial edema in paroxysmal permeability disorders: The paradigm of Clarkson's disease.

J Crit Care 2020 06 15;57:13-18. Epub 2020 Jan 15.

Department of Anesthesiology and Intensive Care, ASST Fatebenefratelli Sacco, "Luigi Sacco" Hospital - Polo Universitario - University of Milan, Via G.B. Grassi 74, 20157 Milan, Italy. Electronic address:

Purpose: Paroxysmal Permeability Disorders (PPDs) comprise a variety of diseases characterized by recurrent and transitory increase of endothelial permeability. Idiopathic Systemic Capillary Leak Syndrome (ISCLS) is a rare PPD that leads to an abrupt massive shift of fluids and proteins from the intravascular to the interstitial compartment. In some cases, tissue edema may involve the myocardium, but its role in the development of shock has not been elucidated so far.

Materials And Methods: Assessment of cardiac involvement during ten life-threatening ISCLS episodes admitted to ICU.

Results: Transthoracic echocardiographic examination was performed in eight episodes, whereas a poor acoustic window prevented cardiac ultrasound assessment in two episodes. Myocardial edema was detected by echocardiography in eight episodes and marked pericardial effusion in one-episode. Cardiac magnetic resonance showed diffuse myocardial edema in another episode. In one case, myocardial edema caused fulminant left ventricular dysfunction, which required extracorporeal life support. The mean septum thickness was higher during the shock phase compared to the recovery phase [15.5 mm (13.1-21 mm) vs. 9.9 mm (9-11.3 mm), p = .0003]. Myocardial edema resolved within 72 h.

Conclusions: During early phases of ISCLS, myocardial edema commonly occurs and can induce transient myocardial dysfunction, potentially contributing to the pathogenesis of shock.
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http://dx.doi.org/10.1016/j.jcrc.2020.01.014DOI Listing
June 2020

The effect of prolonged steep head-down laparoscopy on the optical nerve sheath diameter.

J Clin Monit Comput 2020 Dec 5;34(6):1295-1302. Epub 2019 Nov 5.

Department of Anesthesiology and Intensive Care Unit, ASST Fatebenefratelli Sacco, Luigi Sacco Hospital, Polo Universitario - University of Milan, Via G.B. Grassi 74, 20157, Milan, Italy.

Both the steep head-down position and pneumoperitoneum increase the intracranial pressure (ICP), and their combination for a prolonged period during laparoscopic radical prostatectomy (LRP) might influence the central nervous system homeostasis. Changes in optic nerve sheath diameter (ONSD) may reflect those in ICP. This study aims to quantify the change in ONSD in response to peritoneal CO insufflation and steep Trendelenburg position during LRP. ONSD was measured by ultrasound in 20 patients undergoing LRP and ten awake healthy volunteers. In patients, ONSD was assessed at baseline immediately after induction of general anesthesia in supine position, 10 and 60 min from baseline in a 25° head-down position during pneumoperitoneum, and after deflation of pneumoperitoneum with the patient supine at 0° angle. ONSD in controls was assessed at baseline with the patient lying supine, after 10 and 60 min of 25° head-down position, and 10 min after repositioning at 0° angle. ONSD increased significantly in both patients and controls (p < 0.0001) without between-group differences. The mean increase was 10.3% (95% CI 7.7-12.9%) in patients versus 7.5% (95% CI 2.5-12.6%) in controls (p = 0.28), and didn't affect the time to recovery from anesthesia. In the studied patients, with a limited increase of end-tidal CO and airway pressure, and low volume fluid infusion, the maximal ONSD was always below the cut-off value suspect for increased ICP. ONSD reflects the changes in hydrostatic pressure in response to steep Trendelenburg position, and its increase might be minimized by careful handling of general anesthesia.
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http://dx.doi.org/10.1007/s10877-019-00418-5DOI Listing
December 2020

Kinetics of manual and automated mechanical chest compressions.

Resuscitation 2019 12 19;145:70-74. Epub 2019 Oct 19.

Department of Anesthesia and Intensive Care Unit, ASST Fatebenefratelli Sacco, Luigi Sacco Hospital, Polo Universitario, University of Milan, Milan, Italy.

Aim: Early onset of adequate chest compression is mandatory for cardiopulmonary resuscitation (CPR) following cardiac arrest. Transmission of forces from chest strain to the heart may be variable between manual and mechanical chest compressions. Furthermore, automated mechanical chest devices can deliver an active decompression, thus improving the venous return to the heart. This pilot study investigated the kinetics of cardiac deformation during these two CPR methods.

Methods: Transesophageal echocardiographic analysis of the right ventricular wall behind the sternum during CPR was assessed during manual and mechanical chest compression in adult patients admitted to the emergency department for out-of-hospital cardiac arrest.

Results: 9 patients had manual and 11 mechanical chest compression. Mechanical chest compression was characterized by greater right ventricular lateral wall displacement [with a median (IQR) of 3.7 (3.12-4.27) vs. 2.53 (2.27-2.6) cm, p < 0.0001], and lower rising time [123 (102-169) vs. 187 (164-215) ms, p = 0.002], relaxing time [109 (102-127) vs. 211 (133-252) ms, p = 0.0003], compression rate [100.6 (99.6-102.2) vs. 131.9 (125.4-151.4) bpm, p < 0.0001], with compression-decompression time ratio of [1.04 (0.86-1.1) vs. 0.86 (0.78-0.96), p = 0.046].

Conclusion: Mechanical compared to manual chest compression delivered a more rapid compression and decompression of the cardiac structures at an adequate rate, with broader inward-outward movement of the ventricular walls suggesting greater emptying and filling of the ventricles. Transesophageal echocardiography may be a useful tool to assess the adequacy of chest compression without CPR interruption.
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http://dx.doi.org/10.1016/j.resuscitation.2019.10.009DOI Listing
December 2019

Handling shock in idiopathic systemic capillary leak syndrome (Clarkson's disease) less is more: reply.

Intern Emerg Med 2020 03 24;15(2):349-350. Epub 2019 Jul 24.

Department of Biomedical and Clinical Sciences "Luigi Sacco", ASST Fatebenefratelli Sacco, Luigi Sacco Hospital, University of Milan, Via Giovanni Battista Grassi, 74, 20157, Milan, Italy.

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http://dx.doi.org/10.1007/s11739-019-02155-8DOI Listing
March 2020

Handling shock in idiopathic systemic capillary leak syndrome (Clarkson's disease): less is more.

Intern Emerg Med 2019 08 1;14(5):723-730. Epub 2019 Jun 1.

IRCCS-Istituti Clinici Scientifici Maugeri, University of Milan, Milan, Italy.

Idiopathic systemic capillary leak syndrome (ISCLS) presents with recurrent potentially life-threatening episodes of hypovolemic shock associated with severe hemoconcentration and hypoproteinemia. Timely recognition is of paramount importance because ISCLS, despite resembling other kinds of hypovolemic shock, requires a peculiar approach, to prevent life-threatening iatrogenic damage. Due to the rarity of this condition with only scattered cases described worldwide, evidence-based recommendations are still lacking. Here, we summarize our 40 years' experience in treating shock in ISCLS patients to derive a therapeutic algorithm. Records from 12 ISCLS patients (mean follow-up is 6 years, with a mean age at symptoms' onset of 51.5 years) were informative for treatment modalities and outcome of 66 episodes of shock. Episodes are divided in three phases and treatment recommendations are the following: prodromal symptoms-signs (growing malaise, oligo-anuria, orthostatic dizziness) last 6-12 h and patients should maintain rigorous bed rest. The acute shock phase lasts 24-36 h. Patients should be admitted to ICU, placed on restrictive infusion of fluids favoring cautious boluses of high-molecular-weight plasma expanders when SAP < 70 mmHg; monitored for cerebral/cardiac perfusion, myocardial edema and signs of compartment syndrome. The post-acute (recovery) phase may last from 48 h to 1 week. Monitor for cardiac overload to prevent cardiac failure; in case of persistent renal failure, hemodialysis may be necessary; consider albumin infusion. Complications listed by frequency in our patients were acute renal failure, compartment syndrome and neuropathy, rhabdomyolysis, myocardial edema, pericardial-pleural-abdominal effusion, cerebral involvement, acute pulmonary edema and deep vein thrombosis.
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http://dx.doi.org/10.1007/s11739-019-02113-4DOI Listing
August 2019

Association between left ventricular outflow tract opening and successful resuscitation after cardiac arrest.

Resuscitation 2019 05 27;138:8-14. Epub 2019 Feb 27.

Department of Anesthesia and Intensive Care Unit, ASST Fatebenefratelli Sacco, Luigi Sacco Hospital, Polo Universitario, University of Milan, Milan, Italy. Electronic address:

Background: Survival after cardiac arrest depends on adequate cardiopulmonary resuscitation (CPR). Manual or mechanical external chest compression may be ineffective to restore circulation: structures subjected to external chest compression may differ in forces transfer to intrathoracic structures due to anatomic characteristics and physiological changes. This clinical study aims to assess the association of trans-oesophageal findings during CPR and successful resuscitation.

Methods: Retrospective cohort study. Trans-oesophageal assessment of right ventricular fractional area change, right ventricular outflow tract fractional shortening, left ventricular volumes, ejection fraction, and aortic diameters were performed in refractory out-of-hospital cardiac arrest patients admitted to emergency department for extracorporeal CPR.

Results: 19 patients were analyzed. 15 of 19 patients (79%) received venous-arterial extracorporeal membrane oxygenation support. Resuscitation was successful with return of spontaneous circulation or electromechanical activity in 7 patients (group-SUXX) and failed in 12 patients (group-FAIL). 6 patients (32%) were alive at 24 h from the cardiac arrest, one patient (5%) survived to hospital discharge. Left ventricular outflow tract (LVOT) was open during CPR in all patients in group-SUXX and in 1 patient in group-FAIL (p 0.0002). None of the patients with closed LVOT had successful resuscitation. Patients in group-SUXX had a higher ejection fraction (p 0.03), ascending aortic diameter (p 0.04), and survival rate than those in group-FAIL (p 0.015). In a multiple variable Cox's proportional model LVOT opening was the only variable associated with successful resuscitation.

Conclusions: Trans-oesophageal echocardiography can be useful in the emergency setting of cardiopulmonary arrest for discriminating between successful and failing resuscitation.
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http://dx.doi.org/10.1016/j.resuscitation.2019.02.027DOI Listing
May 2019

Integration of single-cell RNA-seq data into population models to characterize cancer metabolism.

PLoS Comput Biol 2019 02 28;15(2):e1006733. Epub 2019 Feb 28.

Dept. of Informatics, Systems and Communication, University of Milan-Bicocca, 20126, Milan, Italy.

Metabolic reprogramming is a general feature of cancer cells. Regrettably, the comprehensive quantification of metabolites in biological specimens does not promptly translate into knowledge on the utilization of metabolic pathways. By estimating fluxes across metabolic pathways, computational models hold the promise to bridge this gap between data and biological functionality. These models currently portray the average behavior of cell populations however, masking the inherent heterogeneity that is part and parcel of tumorigenesis as much as drug resistance. To remove this limitation, we propose single-cell Flux Balance Analysis (scFBA) as a computational framework to translate single-cell transcriptomes into single-cell fluxomes. We show that the integration of single-cell RNA-seq profiles of cells derived from lung adenocarcinoma and breast cancer patients into a multi-scale stoichiometric model of a cancer cell population: significantly 1) reduces the space of feasible single-cell fluxomes; 2) allows to identify clusters of cells with different growth rates within the population; 3) points out the possible metabolic interactions among cells via exchange of metabolites. The scFBA suite of MATLAB functions is available at https://github.com/BIMIB-DISCo/scFBA, as well as the case study datasets.
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http://dx.doi.org/10.1371/journal.pcbi.1006733DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6413955PMC
February 2019

Unusual case of traumatic carotid artery dissection occurred during a work-related activity. A case report.

Med Lav 2018 Oct 30;110(5):387-390. Epub 2018 Oct 30.

.

Carotid artery dissection secondary to cervical blunt trauma is a rare and potentially life-threatening condition that can cause a variety of clinical presentations, including stroke, headache, neck pain, tinnitus, Horner syndrome and cranial neuropathies and is associated with long-term sequelae. We report a case of a 49-year-old industrial vehicles mechanic who was projected to the ground by the explosion of the tire of a heavy truck he was inflating. In the following hours he presented various neurological signs and symptoms and was admitted to the Emergency Department. During hospitalization the patient underwent clinical and instrumental investigations with AngioCT and MR finding of left internal carotid artery dissection in correspondence of its cervical segment and three acute ischemic lesions in the left temporal, parietal and occipital lobes. Medical management was successful and the patient was discharged from the hospital three weeks after the admission but he wasn't able to get back to work due to neurological sequelae. This case report illustrates that traumatic carotid artery dissection, although rare, should be considered in patients who present neurological symptoms after an explosion, can meet the criteria for a work-related injury and may lead to a permanent decrease in the ability to work.
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http://dx.doi.org/10.23749/mdl.v110i5.7642DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7682173PMC
October 2018

Myocardial injury after non cardiac surgery: troponin assay is not enough… We need perioperative bearings.

Authors:
Riccardo Colombo

Minerva Anestesiol 2018 10 13;84(10):1131-1133. Epub 2018 Sep 13.

ASST Fatebenefratelli Sacco, Luigi Sacco Hospital, Milan, Italy -

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http://dx.doi.org/10.23736/S0375-9393.18.13164-6DOI Listing
October 2018

Emerging ensembles of kinetic parameters to characterize observed metabolic phenotypes.

BMC Bioinformatics 2018 07 9;19(Suppl 7):251. Epub 2018 Jul 9.

SYSBIO - Centre of Systems Biology, Piazza della Scienza, 2, Milan, 20126, Italy.

Background: Determining the value of kinetic constants for a metabolic system in the exact physiological conditions is an extremely hard task. However, this kind of information is of pivotal relevance to effectively simulate a biological phenomenon as complex as metabolism.

Results: To overcome this issue, we propose to investigate emerging properties of ensembles of sets of kinetic constants leading to the biological readout observed in different experimental conditions. To this aim, we exploit information retrievable from constraint-based analyses (i.e. metabolic flux distributions at steady state) with the goal to generate feasible values for kinetic constants exploiting the mass action law. The sets retrieved from the previous step will be used to parametrize a mechanistic model whose simulation will be performed to reconstruct the dynamics of the system (until reaching the metabolic steady state) for each experimental condition. Every parametrization that is in accordance with the expected metabolic phenotype is collected in an ensemble whose features are analyzed to determine the emergence of properties of a phenotype. In this work we apply the proposed approach to identify ensembles of kinetic parameters for five metabolic phenotypes of E. Coli, by analyzing five different experimental conditions associated with the ECC2comp model recently published by Hädicke and collaborators.

Conclusions: Our results suggest that the parameter values of just few reactions are responsible for the emergence of a metabolic phenotype. Notably, in contrast with constraint-based approaches such as Flux Balance Analysis, the methodology used in this paper does not require to assume that metabolism is optimizing towards a specific goal.
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http://dx.doi.org/10.1186/s12859-018-2181-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6201900PMC
July 2018

The Role of Failing Autonomic Nervous System on Life-Threatening Idiopathic Systemic Capillary Leak Syndrome.

Front Med (Lausanne) 2018 20;5:111. Epub 2018 Apr 20.

Department of Biomedical and Clinical Sciences, ASST Fatebenefratelli Sacco, Luigi Sacco Hospital - Polo ospedaliero, University of Milan, Milan, Italy.

Idiopathic systemic capillary leak syndrome (ISCLS) is a rare disease that involves the endothelium and microcirculation, leading to an abrupt shift of fluids and proteins from the intravascular to the interstitial compartment. The consequence of the capillary leakage is a life-threatening hypovolemic shock that can lead to lethal multiple organ dysfunction. The autonomic nervous system (ANS) is central in regulating the cardiovascular response to hypovolemia, but ANS modulation in ISCLS has not yet been investigated. Here, we report ANS activity during acute phase and recovery from a severe ISCLS shock and speculate on the possibility that autonomic mechanisms underlie the pathogenesis of attacks.
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http://dx.doi.org/10.3389/fmed.2018.00111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5919959PMC
April 2018

Association between autonomic control indexes and mortality in subjects admitted to intensive care unit.

Sci Rep 2018 02 22;8(1):3486. Epub 2018 Feb 22.

Department of Anesthesia and Intensive Care, IRCCS Humanitas Clinical and Research Center, Rozzano, 20089, Italy.

This study checks whether autonomic markers derived from spontaneous fluctuations of heart period (HP) and systolic arterial pressure (SAP) and from their interactions with spontaneous or mechanical respiration (R) are associated with mortality in patients admitted to intensive care unit (ICU). Three-hundred consecutive HP, SAP and R values were recorded during the first day in ICU in 123 patients. Population was divided into survivors (SURVs, n = 83) and non-survivors (NonSURVs, n = 40) according to the outcome. SURVs and NonSURVs were aged- and gender-matched. All subjects underwent modified head-up tilt (MHUT) by tilting the bed back rest segment to 60°. Autonomic control indexes were computed using time-domain, spectral, cross-spectral, complexity, symbolic and causality techniques via univariate, bivariate and conditional approaches. SAP indexes derived from time-domain, model-free complexity and symbolic approaches were associated with the endpoint, while none of HP variability markers was. The association was more powerful during MHUT. Linear cross-spectral and causality indexes were useless to separate SURVs from NonSURVs, while nonlinear bivariate symbolic markers were successful. When indexes were combined with clinical scores, only SAP variance provided complementary information. Cardiovascular control variability indexes, especially when derived after an autonomic challenge such as MHUT, can improve mortality risk stratification in ICU.
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http://dx.doi.org/10.1038/s41598-018-21888-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5823868PMC
February 2018

Effects of laparoscopic radical prostatectomy on intraoperative autonomic nervous system control of hemodynamics.

Minerva Anestesiol 2017 Dec 4;83(12):1265-1273. Epub 2017 Oct 4.

Department of Biomedical Sciences for Health, University of Milan, Milan, Italy.

Background: Laparoscopic radical prostatectomy induces hemodynamic changes that have been supposed due to autonomic nervous system activity. The aim of this study is to measure the sympathetic and vagal modulation on hemodynamic response to steep Trendelenburg and pneumoperitoneum for laparoscopic surgery.

Methods: Autonomic nervous system modulation was assessed noninvasively through heart rate variability and arterial pressure variability analysis in patients undergoing elective laparoscopic radical prostatectomy and in awake volunteers during head-down tilt.

Results: Forty patients and 14 awake volunteers were studied. The induction of general anesthesia significantly decreased the heart rate, arterial pressure, vagal modulation, and sympathetic modulation. Steep Trendelenburg increased vagal and sympathetic modulation both in anesthetized and awake subjects. Pneumoperitoneum increased arterial pressure without effect on autonomic nervous system control in anesthetized patients.

Conclusions: Hemodynamic changes occurring during laparoscopic radical prostatectomy reveal autonomic response to the challenges (i.e. general anesthesia and head down position), and non-neurally mediated increase of arterial pressure caused by pneumoperitoneum. This study supports the notion that during laparoscopic radical prostatectomy the association between the vagal stimulation due to Trendelenburg positioning and sympathetic withdrawal caused by general anesthesia could lead to severe bradycardia and cardiac arrest in risky patients.
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http://dx.doi.org/10.23736/S0375-9393.17.12024-9DOI Listing
December 2017

A metabolic core model elucidates how enhanced utilization of glucose and glutamine, with enhanced glutamine-dependent lactate production, promotes cancer cell growth: The WarburQ effect.

PLoS Comput Biol 2017 Sep 28;13(9):e1005758. Epub 2017 Sep 28.

SYSBIO Centre of Systems Biology, Milano, Italy.

Cancer cells share several metabolic traits, including aerobic production of lactate from glucose (Warburg effect), extensive glutamine utilization and impaired mitochondrial electron flow. It is still unclear how these metabolic rearrangements, which may involve different molecular events in different cells, contribute to a selective advantage for cancer cell proliferation. To ascertain which metabolic pathways are used to convert glucose and glutamine to balanced energy and biomass production, we performed systematic constraint-based simulations of a model of human central metabolism. Sampling of the feasible flux space allowed us to obtain a large number of randomly mutated cells simulated at different glutamine and glucose uptake rates. We observed that, in the limited subset of proliferating cells, most displayed fermentation of glucose to lactate in the presence of oxygen. At high utilization rates of glutamine, oxidative utilization of glucose was decreased, while the production of lactate from glutamine was enhanced. This emergent phenotype was observed only when the available carbon exceeded the amount that could be fully oxidized by the available oxygen. Under the latter conditions, standard Flux Balance Analysis indicated that: this metabolic pattern is optimal to maximize biomass and ATP production; it requires the activity of a branched TCA cycle, in which glutamine-dependent reductive carboxylation cooperates to the production of lipids and proteins; it is sustained by a variety of redox-controlled metabolic reactions. In a K-ras transformed cell line we experimentally assessed glutamine-induced metabolic changes. We validated computational results through an extension of Flux Balance Analysis that allows prediction of metabolite variations. Taken together these findings offer new understanding of the logic of the metabolic reprogramming that underlies cancer cell growth.
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http://dx.doi.org/10.1371/journal.pcbi.1005758DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5634631PMC
September 2017

popFBA: tackling intratumour heterogeneity with Flux Balance Analysis.

Bioinformatics 2017 Jul;33(14):i311-i318

SYSBIO Centre of Systems Biology, Milan, Italy.

Motivation: Intratumour heterogeneity poses many challenges to the treatment of cancer. Unfortunately, the transcriptional and metabolic information retrieved by currently available computational and experimental techniques portrays the average behaviour of intermixed and heterogeneous cell subpopulations within a given tumour. Emerging single-cell genomic analyses are nonetheless unable to characterize the interactions among cancer subpopulations. In this study, we propose popFBA , an extension to classic Flux Balance Analysis, to explore how metabolic heterogeneity and cooperation phenomena affect the overall growth of cancer cell populations.

Results: We show how clones of a metabolic network of human central carbon metabolism, sharing the same stoichiometry and capacity constraints, may follow several different metabolic paths and cooperate to maximize the growth of the total population. We also introduce a method to explore the space of possible interactions, given some constraints on plasma supply of nutrients. We illustrate how alternative nutrients in plasma supply and/or a dishomogeneous distribution of oxygen provision may affect the landscape of heterogeneous phenotypes. We finally provide a technique to identify the most proliferative cells within the heterogeneous population.

Availability And Implementation: the popFBA MATLAB function and the SBML model are available at https://github.com/BIMIB-DISCo/popFBA .

Contact: chiara.damiani@unimib.it.
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http://dx.doi.org/10.1093/bioinformatics/btx251DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5870635PMC
July 2017