Characterisation and Outcomes of Patients with Solid Organ Malignancies Admitted to the Intensive Care Unit: Mortality and Impact on Functional Status and Oncological Treatment.

BACKGROUND: Despite the increasing number of ICU admissions among patients with solid tumours, there is a lack of tools with which to identify patients who may benefit from critical support. We aim to characterize the clinical profile and outcomes of patients with solid malignancies admitted to the ICU. METHODS: Retrospective observational study of patients with cancer non-electively admitted to the ICU of the Hospital Clinic of Barcelona (Spain) between January 2019 and December 2019. Data regarding patient and neoplasm characteristics, ICU admission features and outcomes were collected from medical records. RESULTS: 97 ICU admissions of 84 patients were analysed. Lung cancer (22.6%) was the most frequent neoplasm. Most of the patients had metastatic disease (79.5%) and were receiving oncological treatment (75%). The main reason for ICU admission was respiratory failure (38%). Intra-ICU and in-hospital mortality rates were 9.4% and 24%, respectively. Mortality rates at 1, 3 and 6 months were 19.6%, 36.1% and 53.6%. Liver metastasis, gastrointestinal cancer, hypoalbuminemia, elevated basal C-reactive protein, ECOG-PS greater than 2 at ICU admission, admission from ward and an APACHE II score over 14 were related to higher mortality. Functional status was severely affected at discharge, and oncological treatment was definitively discontinued in 40% of the patients. CONCLUSION: Medium-term mortality and functional deterioration of patients with solid cancers non-electively admitted to the ICU are high. Surrogate markers of cachexia, liver metastasis and poor ECOG-PS at ICU admission are risk factors for mortality.

Is the Endothelium the Missing Link in the Pathophysiology and Treatment of COVID-19 Complications?

Patients with COVID-19 present a wide spectrum of disease severity, from asymptomatic cases in the majority to serious disease leading to critical care and even death. Clinically, four different scenarios occur within the typical disease timeline: first, an incubation and asymptomatic period; second, a stage with mild symptoms due mainly to the virus itself; third, in up to 20% of the patients, a stage with severe symptoms where a hyperinflammatory response with a cytokine storm driven by host immunity induces acute respiratory distress syndrome; and finally, a post-acute sequelae (PASC) phase, which present symptoms that can range from mild or annoying to actually quite incapacitating. Although the most common manifestation is acute respiratory failure of the lungs, other organs are also frequently involved. The clinical manifestations of the COVID-19 infection support a key role for endothelial dysfunction in the pathobiology of this condition. The virus enters into the organism via its interaction with angiotensin-converting enzyme 2-receptor that is present prominently in the alveoli, but also in endothelial cells, which can be directly infected by the virus. Cytokine release syndrome can also drive endothelial damage independently. Consequently, a distinctive feature of SARS-CoV-2 infection is vascular harm, with severe endothelial injury, widespread thrombosis, microangiopathy, and neo-angiogenesis in response to endothelial damage. Therefore, endothelial dysfunction seems to be the pathophysiological substrate for severe COVID-19 complications. Biomarkers of endothelial injury could constitute strong indicators of disease progression and severity. In addition, the endothelium could represent a very attractive target to both prevent and treat these complications. To establish an adequate therapy, the underlying pathophysiology and corresponding clinical stage should be clearly identified. In this review, the clinical features of COVID-19, the central role of the endothelium in COVID-19 and in other pathologies, and the potential of specific therapies aimed at protecting the endothelium in COVID-19 patients are addressed.

Distinctive Biomarker Features in the Endotheliopathy of COVID-19 and Septic Syndromes.

BACKGROUND: Endotheliopathy is a key element in COVID-19 pathophysiology, contributing to both morbidity and mortality. Biomarkers distinguishing different COVID-19 phenotypes from sepsis syndrome remain poorly understood. OBJECTIVE: To characterize circulating biomarkers of endothelial damage in different COVID-19 clinical disease stages compared with sepsis syndrome and normal volunteers. METHODS: Patients with COVID-19 pneumonia (n = 49) were classified into moderate, severe, or critical (life-threatening) disease. Plasma samples were collected within 48 to 72 h of hospitalization to analyze endothelial activation markers, including soluble Vascular Cell Adhesion Molecule-1 (sVCAM-1), von Willebrand Factor (VWF), A disintegrin-like and metalloprotease with thrombospondin type 1 motif no. 13 (ADAMTS-13) activity, thrombomodulin (TM), and soluble TNF receptor I (sTNFRI); heparan sulfate (HS) for endothelial glycocalyx degradation; C5b9 deposits on endothelial cells in culture and soluble C5b9 for complement activation; circulating dsDNA for neutrophil extracellular traps (NETs) presence, and α2-antiplasmin and PAI-1 as parameters of fibrinolysis. We compared the level of each biomarker in all three COVID-19 groups and healthy donors as controls (n = 45). Results in critically ill COVID-19 patients were compared with other intensive care unit (ICU) patients with septic shock (SS, n = 14), sepsis (S, n = 7), and noninfectious systemic inflammatory response syndrome (NI-SIRS, n = 7). RESULTS: All analyzed biomarkers were increased in COVID-19 patients versus controls (P < 0.001), except for ADAMTS-13 activity that was normal in both groups. The increased expression of sVCAM-1, VWF, sTNFRI, and HS was related to COVID-19 disease severity (P < 0.05). Several differences in these parameters were found between ICU groups: SS patients showed significantly higher levels of VWF, TM, sTNFRI, and NETS compared with critical COVID-19 patients and ADAMTS-13 activity was significantly lover in SS, S, and NI-SIRS versus critical COVID-19 (P < 0.001). Furthermore, α2-antiplasmin activity was higher in critical COVID-19 versus NI-SIRS (P < 0.01) and SS (P < 0.001), whereas PAI-1 levels were significantly lower in COVID-19 patients compared with NI-SIRS, S, and SS patients (P < 0.01). CONCLUSIONS: COVID-19 patients present with increased circulating endothelial stress products, complement activation, and fibrinolytic dysregulation, associated with disease severity. COVID-19 endotheliopathy differs from SS, in which endothelial damage is also a critical feature of pathobiology. These biomarkers could help to stratify the severity of COVID-19 disease and may also provide information to guide specific therapeutic strategies to mitigate endotheliopathy progression.

Progressive endothelial cell damage in correlation with sepsis severity. Defibrotide as a contender.

BACKGROUND: The vascular endothelium plays a key role in sepsis pathophysiology and the associated organ dysfunction. METHODS: We evaluated endothelial function in an experimental in vitro model of sepsis, using endothelial cells grown in the presence of serum from patients with septic syndromes (sepsis, severe sepsis, and septic shock), noninfectious systemic inflammatory response syndrome (NI-SIRS) and healthy volunteers. Experiments were performed in the absence and presence of defibrotide (DF) (100 µg/ml) to evaluate its potential protective effect. RESULTS: After exposure to patients' sera, there was a progressive endothelial cell activation in correlation with sepsis severity, with a proinflammatory and prothrombotic phenotype, exhibiting significantly increased expression of adhesion receptors at the surface (intercellular adhesion molecule-1, p < .05 and vascular cell adhesion molecule-1, p < .05); higher production and release to the extracellular matrix (ECM) of von Willebrand factor (p < .001); augmented thrombogenicity of the ECM toward platelets (p < .001); and increased phosphorylation of intracellular p38MAPK. DF prevented these changes in all groups. CONCLUSIONS: Markers of endothelial damage increased progressively in association with the severity of septic syndromes. The endothelium is therefore an important therapeutic target to prevent complications of sepsis. DF shows promising potential to modulate the endothelial damage associated with sepsis and may constitute a pharmacological tool to decrease its sequelae including multiorgan failure.

Displacement-free stereoscopic phase measuring deflectometry based on phase difference minimization.

In this paper, we propose a phase difference minimization algorithm to measure the specular surface shape in a displacement-free stereoscopic phase measuring deflectometry (PMD) system. The presented system is capable of solving the height-normal ambiguity appearing in a PMD system without moving any system component. Both the surface normal and the absolute height are simultaneously obtained by implementing phase difference minimization between the phase distributions in the LCD screen and the camera image plane. In particular, phase difference minimization is performed by using a second order polynomial fitting iteration method. Bi-cubic sub-pixel interpolation combined with 2D Fourier integration is used to reconstruct the surface. Finally, the performance of the proposed stereoscopic PMD system is verified by measuring the surface shapes of different mirrors and performing repeatability tests.

Multi-pitch self-calibration measurement using a nano-accuracy surface profiler for X-ray mirror metrology.

For high accuracy X-ray mirror measurement, the analysis and corrections of minute systematic errors of the measuring instrument are required. As an X-ray mirror metrology tool, the nano-accuracy surface profiler (NSP) consists of two autocollimators (AC) serving its reference and sample beams, in which the sample-beam AC maintains a fixed distance from the mirror. In this work, the multi-pitch self-calibration method is applied to an NSP instrument to reconstruct both the mirror slope and the instrument error of the sample-beam AC through a series of x scans and pitch angle scans. It is more technically sound to apply this multi-pitch self-calibration method to a working-distance-fixed slope scanner, such as the NSP. First of all, we introduce the principle of the multi-pitch self-calibration method, discuss its ambiguities, and provide our regularization illustrated with simulations. Second, some real measurements of a spherical mirror with 10-mrad total slope are demonstrated to verify the effectiveness of the multi-pitch self-calibration technique with an NSP. Furthermore, the experimental reconstruction of the low- and high-frequency signals of the instrument error with different settings in x and pitch steps are addressed and studied in terms of repeatability, reproducibility, self-consistency, and effectiveness in compensation for single-pitch scans.

Biostatistics Disruptive Acculturation Through Serious Gaming: A New Hope.

Biostatistics is one of the transversal subjects that all future doctors must acquire and master. Nonetheless, it is a subject that has the reputation of being difficult, which has not been able to be corrected even with the application of new pedagogical methods such as blended learning. We address this problem with our acculturative and disruptive approach in the form of a serious game scenario in clinical research that integrates biostatistics with our R4Web adapted tools. Our approach was launched in 2008 for the second year of medical school. Here we describe this LOE scenario for serious game including the biostatistics disruptive acculturation task and present its new international version.

Two-dimensional stitching interferometry for self-calibration of high-order additive systematic errors.

Stitching interferometry is performed by collecting interferometric data from overlapped sub-apertures and stitching these data together to provide a full surface map. The propagation of the systematic error in the measured subset data is one of the main error sources in stitching interferometry for accurate reconstruction of the surface topography. In this work, we propose, using the redundancy of the captured subset data, two types of two-dimensional (2D) self-calibration stitching algorithms to overcome this issue by in situ estimating the repeatable high-order additive systematic errors, especially for the application of measuring X-ray mirrors. The first algorithm, called CS short for "Calibrate, and then Stitch", calibrates the high-order terms of the reference by minimizing the de-tilted discrepancies of the overlapped subsets and then stitches the reference-subtracted subsets. The second algorithm, called SC short for "Stitch, and then Calibrate", stitches a temporarily result and then calibrates the reference from the de-tilted discrepancies of the measured subsets and the temporarily stitched result. In the implementation of 2D scans in x- and y-directions, step randomization is introduced to generate nonuniformly spaced subsets which can diminish the periodic stitching errors commonly observed in evenly spaced subsets. The regularization on low-order terms enables a highly flexible option to add the curvature and twist acquired by another system. Both numerical simulations and experiments are carried out to verify the proposed method. All the results indicate that 2D high-order repeatable additive systematic errors can be retrieved from the 2D redundant overlapped data in stitching interferometry.

Deflectometry encoding the measured angle in a time-dependent intensity signal.

We propose a new concept of a deflectometer, aimed to provide high accuracy measurements with high sampling rate and low noise, as required by state-of-the-art slope-measuring profilometers, like Long Trace Profilometers or Nanometer Optics Measuring instruments. For this purpose, we introduce certain modifications to the usual working principle of autocollimators so that the measured angle is not given by the displacement of the pattern captured by a CCD, but by the harmonic contents of the time-modulated intensity signal acquired by a photodiode. By doing this, the signal can be sampled not by just a few thousand pixels but by millions of samples/s.

Completeness condition for unambiguous profile reconstruction by sub-aperture stitching.

We describe the conditions required for a set of displaced sub-aperture measurements to contain sufficient information to reconstruct the stitched mirror profile removing all additive systematic errors of the measuring instrument, independent of the reference surface and of the guidance error of the linear stage used for the translation. We show that even-spaced stitching must be avoided and that the pitch error of the linear stage or the curvature of the reference must be measured, to avoid periodic errors and curvature errors in the reconstructed profile. We show that once these uncertainties are solved, the 1D profile can be reconstructed free of any additive systematic error. The theory is supported by computer simulations and by experimental results using two different instruments.

Repeatability analysis of one-dimensional angular-measurement-based stitching interferometry.

Recently we presented one-dimensional Angular-measurement-based Stitching Interferometry (ASI) technique for synchrotron mirror metrology coupling an autocollimator and a white light interferometer. In this work, we conduct a further study on the measurement repeatability of this technique under different conditions, e.g. different scanning time or lengths with/without system drift. The similarity between the angle measuring stitching technique in ASI and the slope integration technique in deflectometry is addressed. The analytic expression of the height repeatability is derived while the slope noise is a zero-mean uncorrelated additive noise. In addition, we use a set of typical stationary signals from the autocollimator and the white light interferometer in a real experiment to simulate numerous virtual scans for the numerical calculation of the measurement repeatability under different measurement conditions. The simulation result predicts a link between the measurement repeatability and the scanning time with a constant speed. Moreover, it indicates that the major factor affecting the repeatability of our current ASI system is the system drift error.

Design and performance of BOREAS, the beamline for resonant X-ray absorption and scattering experiments at the ALBA synchrotron light source.

The optical design of the BOREAS beamline operating at the ALBA synchrotron radiation facility is described. BOREAS is dedicated to resonant X-ray absorption and scattering experiments using soft X-rays, in an unusually extended photon energy range from 80 to above 4000 eV, and with full polarization control. Its optical scheme includes a fixed-included-angle, variable-line-spacing grating monochromator and a pair of refocusing mirrors, equipped with benders, in a Kirkpatrick-Baez arrangement. It is equipped with two end-stations, one for X-ray magnetic circular dichroism and the other for resonant magnetic scattering. The commissioning results show that the expected beamline performance is achieved both in terms of energy resolution and of photon flux at the sample position.

Predictive performance of glomerular filtration rate estimation equations based on cystatin C versus serum creatinine values in critically ill patients.

PURPOSE: The predictive performance of glomerular filtration rate (GFR) estimation equations based on cystatin C versus serum creatinine (SCr) values in critically ill patients was evaluated. METHODS: A retrospective observational study was performed in the medical intensive care unit (ICU) of a university hospital from October 2006 through September 2007. All consecutively admitted critically ill patients older than 18 years who stayed in the ICU for more than 48 hours with a urinary bladder catheter in place were included in the study. Data collected included SCr, cystatin C, serum albumin, blood urea nitrogen, and 24-hour urine creatinine clearance [Formula: see text] levels. The following equations were also used to determine the estimated GFR that was compared with the reference [Formula: see text] for all patients in the study: Arnal-Dade using cystatin C, Cockcroft-Gault using actual body weight, Cockcroft-Gault using ideal body weight, Jelliffe, Modification of Diet in Renal Disease (MDRD), and four-variable version MDRD (MDRD-4). RESULTS: This study included 241 measurements corresponding to 131 critically ill patients. The cystatin C-based equation underestimated [Formula: see text], whereas overestimation by every SCr-based formula was observed in the whole cohort and in the [Formula: see text] subgroup; MDRD-4 was the most biased equation in every analysis. There were no significant differences in precision, except for great variability in the subgroup with a [Formula: see text] of <60 mL/min/1.73 m(2), where the MDRD equation showed better results than the cystatin C-based equation (33.5% versus 38.9%). No equations fulfilled concordance requirements with [Formula: see text]. CONCLUSION: A retrospective observational study showed no evidence of superiority of a cystatin C-based equation over SCr-based equations to estimate the GFR in an ICU population.

MISTRAL: a transmission soft X-ray microscopy beamline for cryo nano-tomography of biological samples and magnetic domains imaging.

The performance of MISTRAL is reported, the soft X-ray transmission microscopy beamline at the ALBA light source (Barcelona, Spain) which is primarily dedicated to cryo soft X-ray tomography (cryo-SXT) for three-dimensional visualization of whole unstained cells at spatial resolutions down to 30 nm (half pitch). Short acquisition times allowing for high-throughput and correlative microscopy studies have promoted cryo-SXT as an emerging cellular imaging tool for structural cell biologists bridging the gap between optical and electron microscopy. In addition, the beamline offers the possibility of imaging magnetic domains in thin magnetic films that are illustrated here with an example.

Pattern of soluble CD5 and CD6 lymphocyte receptors in critically ill patients with septic syndromes.

PURPOSE: Soluble forms of CD5 and CD6 lymphocyte surface receptors (sCD5 and sCD6) are molecules that seem to prevent experimental sepsis when exogenously administered. The aim of this study was to assess sCD5 and sCD6 levels in patients with septic syndromes. MATERIALS AND METHODS: The study population consisted of 218 patients admitted to the medical intensive care unit (ICU) presenting either septic syndromes or noninfectious systemic inflammatory response syndrome at admission or within the first 48 hours. The sCD5 and sCD6 levels were analyzed by sandwich enzyme-linked immunosorbent assay. RESULTS: Almost 50% of the patients had undetectable levels of sCD5 or sCD6, with no differences in clinical or biological variables with detectable patients. There was a correlation between the delta Sequential Organ Failure Assessment score and both sCD6 and sCD5 levels in all groups. Patients with sCD5 or sCD6 levels greater than 1500 ng/mL presented a higher in-ICU mortality (P < .05). Logistic regression analysis showed that increased sCD6 levels were associated with an increased risk of in-ICU mortality. CONCLUSIONS: Levels of sCD5 and sCD6 in critically ill patients with systemic inflammatory response syndrome present a high variation and an elevated proportion of undetectability. Levels of sCD6 are associated with an increased risk of mortality in these patients.

The ALBA spectroscopic LEEM-PEEM experimental station: layout and performance.

The spectroscopic LEEM-PEEM experimental station at the CIRCE helical undulator beamline, which started user operation at the ALBA Synchrotron Light Facility in 2012, is presented. This station, based on an Elmitec LEEM III microscope with electron imaging energy analyzer, permits surfaces to be imaged with chemical, structural and magnetic sensitivity down to a lateral spatial resolution better than 20 nm with X-ray excited photoelectrons and 10 nm in LEEM and UV-PEEM modes. Rotation around the surface normal and application of electric and (weak) magnetic fields are possible in the microscope chamber. In situ surface preparation capabilities include ion sputtering, high-temperature flashing, exposure to gases, and metal evaporation with quick evaporator exchange. Results from experiments in a variety of fields and imaging modes will be presented in order to illustrate the ALBA XPEEM capabilities.