There is increasing recognition that traumatic brain injury (TBI) may initiate long-term neurodegenerative processes, particularly chronic traumatic encephalopathy. However, insight into the mechanisms transforming an initial biomechanical injury into a neurodegenerative process remain elusive, partly as a consequence of the paucity of informative pre-clinical models. This study shows the functional, whole brain imaging and neuropathological consequences at up to one year survival from single severe TBI by controlled cortical impact in mice. TBI mice displayed persistent sensorimotor and cognitive deficits. Longitudinal T2 weighted magnetic resonance imaging (MRI) showed progressive ipsilateral (il) cortical, hippocampal and striatal volume loss, with diffusion tensor imaging demonstrating decreased fractional anisotropy (FA) at up to one year in the il-corpus callosum (CC: -30%) and external capsule (EC: -21%). Parallel neuropathological studies indicated reduction in neuronal density, with evidence of microgliosis and astrogliosis in the il-cortex, with further evidence of microgliosis and astrogliosis in the il-thalamus. One year after TBI there was also a decrease in FA in the contralateral (cl) CC (-17%) and EC (-13%), corresponding to histopathological evidence of white matter loss (cl-CC: -68%; cl-EC: -30%) associated with ongoing microgliosis and astrogliosis. These findings indicate that a single severe TBI induces bilateral, long-term and progressive neuropathology at up to one year after injury. These observations support this model as a suitable platform for exploring the mechanistic link between acute brain injury and late and persistent neurodegeneration.

Background Nasal high flow delivered at flow rates higher than 60 L/min in patients with acute hypoxemic respiratory failure might be associated with improved physiological effects. However, poor comfort might limit feasibility of its clinical use. Methods We performed a prospective randomized cross-over physiological study on 12 ICU patients with acute hypoxemic respiratory failure. Patients underwent three steps at the following gas flow: 0.5 L/kg PBW/min, 1 L/kg PBW/min, and 1.5 L/kg PBW/min in random order for 20 min. Temperature and FiO2 remained unchanged. Toward the end of each phase, we collected arterial blood gases, lung volumes, and regional distribution of ventilation assessed by electrical impedance tomography (EIT), and comfort. Results In five patients, the etiology was pulmonary; infective disease characterized seven patients; median PaO2/FiO2 at enrollment was 213 [IQR 136–232]. The range of flow rate during NHF 1.5 was 75–120 L/min. PaO2/FiO2 increased with flow, albeit non significantly (p = 0.064), PaCO2 and arterial pH remained stable (p = 0.108 and p = 0.105). Respiratory rate decreased at higher flow rates (p = 0.014). Inhomogeneity of ventilation decreased significantly at higher flows (p = 0.004) and lung volume at end-expiration significantly increased (p = 0.007), but mostly in the non-dependent regions. Comfort was significantly poorer during the step performed at the highest flow (p < 0.001). Conclusions NHF delivered at rates higher than 60 L/min in critically ill patients with acute hypoxemic respiratory failure is associated with reduced respiratory rate, increased lung homogeneity, and additional positive pressure effect, but also with worse comfort.

This author conceived, planned and carried out the experiments, interpreted the results, and wrote the manuscript. A.M, L.M., Y.W.: These authors carried out the experiments and collected the results. G.C.: This author processed experimental data. O.B., M.B.: These authors helped in the implementation of the experiments. F.R.: This author collected and processed biological samples and analyzed the results.

Purpose In the acute respiratory distress syndrome (ARDS), decreasing Ventilation-Perfusion $$\left( {{{\dot{V}} \mathord{\left/ {\vphantom {{\dot{V}} {\dot{Q}}}} \right. \kern-\nulldelimiterspace} {\dot{Q}}}} \right)$$ V ˙ / Q ˙ mismatch might enhance lung protection. We investigated the regional effects of higher Positive End Expiratory Pressure (PEEP) on $${{\dot{V}} \mathord{\left/ {\vphantom {{\dot{V}} {\dot{Q}}}} \right. \kern-\nulldelimiterspace} {\dot{Q}}}$$ V ˙ / Q ˙ mismatch and their correlation with recruitability. We aimed to verify whether PEEP improves regional $${{\dot{V}} \mathord{\left/ {\vphantom {{\dot{V}} {\dot{Q}}}} \right. \kern-\nulldelimiterspace} {\dot{Q}}}$$ V ˙ / Q ˙ mismatch, and to study the underlying mechanisms. Methods In fifteen patients with moderate and severe ARDS, two PEEP levels (5 and 15 cmH2O) were applied in random order. $${{\dot{V}} \mathord{\left/ {\vphantom {{\dot{V}} {\dot{Q}}}} \right. \kern-\nulldelimiterspace} {\dot{Q}}}$$ V ˙ / Q ˙ mismatch was assessed by Electrical Impedance Tomography at each PEEP. Percentage of ventilation and perfusion reaching different ranges of $${{\dot{V}} \mathord{\left/ {\vphantom {{\dot{V}} {\dot{Q}}}} \right. \kern-\nulldelimiterspace} {\dot{Q}}}$$ V ˙ / Q ˙ ratios were analyzed in 3 gravitational lung regions, leading to precise assessment of their distribution throughout different $${{\dot{V}} \mathord{\left/ {\vphantom {{\dot{V}} {\dot{Q}}}} \right. \kern-\nulldelimiterspace} {\dot{Q}}}$$ V ˙ / Q ˙ mismatch compartments. Recruitability between the two PEEP levels was measured by the recruitment-to-inflation ratio method. Results In the non-dependent region, at higher PEEP, ventilation reaching the normal $${{\dot{V}} \mathord{\left/ {\vphantom {{\dot{V}} {\dot{Q}}}} \right. \kern-\nulldelimiterspace} {\dot{Q}}}$$ V ˙ / Q ˙ compartment (p = 0.018) increased, while it decreased in the high $${{\dot{V}} \mathord{\left/ {\vphantom {{\dot{V}} {\dot{Q}}}} \right. \kern-\nulldelimiterspace} {\dot{Q}}}$$ V ˙ / Q ˙ one (p = 0.023). In the middle region, at PEEP 15 cmH2O, ventilation and perfusion to the low $${{\dot{V}} \mathord{\left/ {\vphantom {{\dot{V}} {\dot{Q}}}} \right. \kern-\nulldelimiterspace} {\dot{Q}}}$$ V ˙ / Q ˙ compartment decreased (p = 0.006 and p = 0.011) and perfusion to normal $${{\dot{V}} \mathord{\left/ {\vphantom {{\dot{V}} {\dot{Q}}}} \right. \kern-\nulldelimiterspace} {\dot{Q}}}$$ V ˙ / Q ˙ increased (p = 0.003). In the dependent lung, the percentage of blood flowing through the non-ventilated compartment decreased (p = 0.041). Regional $${{\dot{V}} \mathord{\left/ {\vphantom {{\dot{V}} {\dot{Q}}}} \right. \kern-\nulldelimiterspace} {\dot{Q}}}$$ V ˙ / Q ˙ mismatch improvement was correlated to lung recruitability and changes in regional tidal volume. Conclusions In patients with ARDS, higher PEEP optimizes the distribution of both ventilation (in the non-dependent areas) and perfusion (in the middle and dependent lung). Bedside measure of recruitability is associated with improved $${{\dot{V}} \mathord{\left/ {\vphantom {{\dot{V}} {\dot{Q}}}} \right. \kern-\nulldelimiterspace} {\dot{Q}}}$$ V ˙ / Q ˙ mismatch.

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