An Interlaboratory Study to Identify Potential Visible Protein-Like Particle Standards.

Visible protein-like particle standards may improve visual inspection and/or appearance testing practices used in the biotechnology industry. They may improve assay performance resulting in better alignment and more standardized training among different companies. The National Institute of Standards and Technology (NIST) has conducted an interlaboratory study to test whether the standards under development mimic typical proteinaceous particles found in biotherapeutics and if they can be implemented during the visual inspection process. Fourteen organizations from industry and government have participated. A total of 20 labs from these 14 organizations participated with analysts from 6 formulation, 7 analytical, 4 quality control, and 3 manufacturing labs. The circulated samples consisted of abraded ethylene tetrafluoroethylene (ETFE) particles or photolithographic particles. The results consist of qualitative ratings, which varied substantially among organizations and within labs. Polydisperse ETFE particle suspensions, containing particles enriched in greater than 150 µm in size, were rated more favorably than the photolithographic particles by formulation and analytical scientists. The largest monodisperse photolithographic particles (approximately 300 µm in size) were favored equally compared to ETFE by all scientists. Solution modifications to decrease the settling rate or to alter optical properties of the ETFE solutions yielded lower ratings by the analysts. Both particle types received mixed ratings for their usability and for their application for visual inspection and for training purposes. Industry feedback will assist NIST in developing reference material(s) for visible protein-like particles.

Markers of blood-brain barrier disruption increase early and persistently in COVID-19 patients with neurological manifestations.

Background: Coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 infection is associated with disorders affecting the peripheral and the central nervous system. A high number of patients develop post-COVID-19 syndrome with the persistence of a large spectrum of symptoms, including neurological, beyond 4 weeks after infection. Several potential mechanisms in the acute phase have been hypothesized, including damage of the blood-brain-barrier (BBB). We tested weather markers of BBB damage in association with markers of brain injury and systemic inflammation may help in identifying a blood signature for disease severity and neurological complications. Methods: Blood biomarkers of BBB disruption (MMP-9, GFAP), neuronal damage (NFL) and systemic inflammation (PPIA, IL-10, TNFα) were measured in two COVID-19 patient cohorts with high disease severity (ICUCovid; n=79) and with neurological complications (NeuroCovid; n=78), and in two control groups free from COVID-19 history, healthy subjects (n=20) and patients with amyotrophic lateral sclerosis (ALS; n=51). Samples from COVID-19 patients were collected during the first and the second wave of COVID-19 pandemic in Lombardy, Italy. Evaluations were done at acute and chronic phases of the COVID-19 infection. Results: Blood biomarkers of BBB disruption and neuronal damage are high in COVID-19 patients with levels similar to or higher than ALS. NeuroCovid patients display lower levels of the cytokine storm inducer PPIA but higher levels of MMP-9 than ICUCovid patients. There was evidence of different temporal dynamics in ICUCovid compared to NeuroCovid patients with PPIA and IL-10 showing the highest levels in ICUCovid patients at acute phase. On the contrary, MMP-9 was higher at acute phase in NeuroCovid patients, with a severity dependency in the long-term. We also found a clear severity dependency of NFL and GFAP levels, with deceased patients showing the highest levels. Discussion: The overall picture points to an increased risk for neurological complications in association with high levels of biomarkers of BBB disruption. Our observations may provide hints for therapeutic approaches mitigating BBB disruption to reduce the neurological damage in the acute phase and potential dysfunction in the long-term.

Time course of the Bioelectrical Impedance Vector Analysis and muscular ultrasound in critically ill patients.

PURPOSE: Several different tools have been developed to integrate the clinical and biochemical nutritional evaluations in critical care patients. Aims of this study were to evaluate the changes in the Bioelectrical Impedance Vector Analysis (BIVA) and ultrasonographic features of the diaphragm (DTee) and rectus femoris (RFCSA) during the first week of ICU stay. MATERIALS AND METHODS: Ninety-six adult mechanically ventilated patients enrolled within 24 h after the admission to the ICU (T1). RFCSA and diaphragm end-expiratory thickness were measured, as well as BIVA parameters. Anthropometric data and biochemical parameters were collected. The measurements were repeated on the 3rd (T3) and 7th (T7) days of ICU stay. RESULTS: During the study period, the phase angle significantly decreased by 21%, reactance by 27%, and resistance by 11%. Both RFCSA and DTee significantly decreased, while neither were correlated to any BIVA parameter. DTee was considerably higher in survivors vs. non-survivors. CONCLUSIONS: Body composition is significantly modified after one week of ICU stay. BIVA may be useful in the definition of hydration state, while it does not seem to track muscle mass. Different temporal trends of specific BIVA and muscle ultrasound parameters were found in patients with high or low severity of illness.

The assessment of esophageal pressure using different devices: a validation study.

BACKGROUND: Although esophageal pressure measurement could help clinicians to improve the ventilatory management of acute respiratory distress syndrome (ARDS) patients, it has been mainly used in clinical research. Aim of this study was to compare the measurements of end-expiratory esophageal pressure, end-expiratory transpulmonary pressure and lung stress by three systems: a dedicated manual device, taken as gold standard, a new automatic system (Optivent) and a bedside equipment, consisting of a mechanical ventilator and a hemodynamic monitor. METHODS: In sedated and paralyzed mechanically ventilated ARDS patients the esophageal pressure was measured at three PEEP levels in random fashion (baseline level, 50% higher and 50% lower). RESULTS: Forty patients were enrolled (BMI 25 [23-28] kg/m2, PaO2/FiO2 187 [137-223] and PEEP 9±3 cmH2O). The mean esophageal pressure measured during an expiratory pause by the dedicated system, the bedside system and Optivent were 10.0±4.2, 10±4 and 9.9±4.0 cmH2O, respectively. The respective bias and limits of agreement between the dedicated system and Optivent and between the dedicated system and the bedside system were as follows: end-expiratory esophageal pressure, 0.2 cmH2O, (-0.4 to 0.9) and -0.1 cmH2O (-1.9 to 1.7); end-expiratory transpulmonary pressure, -0.6 cmH2O (-1.7 to 0.4) and -0.4 cmH2O, (-2.2 to 1.5); lung stress -0.9 cmH2O (-3.0 to 1.1) and -1.5 cmH2O (-4.4 to 1.4). CONCLUSIONS: Both Optivent and the bedside system showed clinically acceptability if compared to the gold standard device. The possibility to apply one of these systems could allow a wider use of esophageal pressure in clinical practice.

Dynamic hyperinflation and intrinsic positive end-expiratory pressure in ARDS patients.

BACKGROUND: In ARDS patients, changes in respiratory mechanical properties and ventilatory settings can cause incomplete lung deflation at end-expiration. Both can promote dynamic hyperinflation and intrinsic positive end-expiratory pressure (PEEP). The aim of this study was to investigate, in a large population of ARDS patients, the presence of intrinsic PEEP, possible associated factors (patients' characteristics and ventilator settings), and the effects of two different external PEEP levels on the intrinsic PEEP. METHODS: We made a secondary analysis of published data. Patients were ventilated with a tidal volume of 6-8 mL/kg of predicted body weight, sedated, and paralyzed. After a recruitment maneuver, a PEEP trial was run at 5 and 15 cmH2O, and partitioned mechanics measurements were collected after 20 min of stabilization. Lung computed tomography scans were taken at 5 and 45 cmH2O. Patients were classified into two groups according to whether or not they had intrinsic PEEP at the end of an expiratory pause. RESULTS: We enrolled 217 sedated, paralyzed patients: 87 (40%) had intrinsic PEEP with a median of 1.1 [1.0-2.3] cmH2O at 5 cmH2O of PEEP. The intrinsic PEEP significantly decreased with higher PEEP (1.1 [1.0-2.3] vs 0.6 [0.0-1.0] cmH2O; p < 0.001). The applied tidal volume was significantly lower (480 [430-540] vs 520 [445-600] mL at 5 cmH2O of PEEP; 480 [430-540] vs 510 [430-590] mL at 15 cmH2O) in patients with intrinsic PEEP, while the respiratory rate was significantly higher (18 [15-20] vs 15 [13-19] bpm at 5 cmH2O of PEEP; 18 [15-20] vs 15 [13-19] bpm at 15 cmH2O). At both PEEP levels, the total airway resistance and compliance of the respiratory system were not different in patients with and without intrinsic PEEP. The total lung gas volume and lung recruitability were also not different between patients with and without intrinsic PEEP (respectively 961 [701-1535] vs 973 [659-1433] mL and 15 [0-32] % vs 22 [0-36] %). CONCLUSIONS: In sedated, paralyzed ARDS patients without a known obstructive disease, the amount of intrinsic PEEP during lung-protective ventilation is negligible and does not influence respiratory mechanical properties.

A Simple Effective Pharmacological Treatment of Hypoxemia During One-Lung Ventilation.

Hypoxemia during one-lung ventilation is a challenge in the clinical practice. Moving from the results of the study conducted by Choi et al., we discuss the possibility to modulate hypoxemia by administering iloprost via inhalation, in the light of the physiological mechanisms.