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Successful awake proning is associated with improved clinical outcomes in patients with COVID-19: single-centre high-dependency unit experience.
The SARS-CoV-2 can lead to severe illness with COVID-19. Outcomes of patients requiring mechanical ventilation are poor. Awake proning in COVID-19 improves oxygenation, but on data clinical outcomes is limited. This single-centre retrospective study aimed to assess whether successful awake proning of patients with COVID-19, requiring respiratory support (continuous positive airways pressure (CPAP) or high-flow nasal oxygen (HFNO)) on a respiratory high-dependency unit (HDU), is associated with improved outcomes. HDU care included awake proning by respiratory physiotherapists. Of 565 patients admitted with COVID-19, 71 (12.6%) were managed on the respiratory HDU, with 48 of these (67.6%) requiring respiratory support. Patients managed with CPAP alone 22/48 (45.8%) were significantly less likely to die than patients who required transfer onto HFNO 26/48 (54.2%): CPAP mortality 36.4%; HFNO mortality 69.2%, (p=0.023); however, multivariate analysis demonstrated that increasing age and the inability to awake prone were the only independent predictors of COVID-19 mortality. The mortality of patients with COVID-19 requiring respiratory support is considerable. Data from our cohort managed on HDU show that CPAP and awake proning are possible in a selected population of COVID-19, and may be useful. Further prospective studies are required.
Design and conduct of 'Xtreme Alps': a double-blind, randomised controlled study of the effects of dietary nitrate supplementation on acclimatisation to high altitude.
The study of healthy human volunteers ascending to high altitude provides a robust model of the complex physiological interplay that emulates human adaptation to hypoxaemia in clinical conditions. Nitric oxide (NO) metabolism may play an important role in both adaptation to high altitude and response to hypoxaemia during critical illness at sea level. Circulating nitrate and nitrite concentrations can be augmented by dietary supplementation and this is associated with improved exercise performance and mitochondrial efficiency. We hypothesised that the administration of a dietary substance (beetroot juice) rich in nitrate would improve oxygen efficiency during exercise at high altitude by enhancing tissue microcirculatory blood flow and oxygenation. Furthermore, nitrate supplementation would lead to measurable increases in NO bioactivity throughout the body. This methodological manuscript describes the design and conduct of the 'Xtreme Alps' expedition, a double-blind randomised controlled trial investigating the effects of dietary nitrate supplementation on acclimatisation to hypobaric hypoxia at high altitude in healthy human volunteers. The primary outcome measure was the change in oxygen efficiency during exercise at high altitude between participants allocated to receive nitrate supplementation and those receiving a placebo. A number of secondary measures were recorded, including exercise capacity, peripheral and microcirculatory blood flow and tissue oxygenation. Results from this study will further elucidate the role of NO in adaption to hypoxaemia and guide clinical trials in critically ill patients. Improved understanding of hypoxaemia in critical illness may provide new therapeutic avenues for interventions that will improve survival in critically ill patients.
Severe Achromobacter xylosoxidans infection and loss of sputum bacterial diversity in an adult patient with cystic fibrosis.
Achromobacter spp. are emerging pathogens in the lungs of patients with cystic fibrosis. We report the case of an adult patient with cystic fibrosis and chronic A. xylosoxidans infection who experienced rapid, progressive clinical deterioration. Metagenomic analysis of the sputum revealed that the airway microbiota was almost entirely dominated by A. xylosoxidans. We review the impact of this organism on lung function and the airway microbiome in cystic fibrosis, and discuss the potential for cross-infection between patients.
Systemic oxygen extraction during exercise at high altitude.
BACKGROUND: Classic teaching suggests that diminished availability of oxygen leads to increased tissue oxygen extraction yet evidence to support this notion in the context of hypoxaemia, as opposed to anaemia or cardiac failure, is limited. METHODS: At 75 m above sea level, and after 7-8 days of acclimatization to 4559 m, systemic oxygen extraction [C(a-v)O2] was calculated in five participants at rest and at peak exercise. Absolute [C(a-v)O2] was calculated by subtracting central venous oxygen content (CcvO2) from arterial oxygen content [Formula: see text] in blood sampled from central venous and peripheral arterial catheters, respectively. Oxygen uptake [Formula: see text] was determined from expired gas analysis during exercise. RESULTS: Ascent to altitude resulted in significant hypoxaemia; median (range) [Formula: see text] 87.1 (82.5-90.7)% and [Formula: see text] 6.6 (5.7-6.8) kPa. While absolute C(a-v)O2 was reduced at maximum exercise at 4559 m [83.9 (67.5-120.9) ml litre(-1) vs 99.6 (88.0-151.3) ml litre(-1) at 75 m, P=0.043], there was no change in oxygen extraction ratio (OER) [C(a-v)O2/CaO2] between the two altitudes [0.52 (0.48-0.71) at 4559 m and 0.53 (0.49-0.73) at 75 m, P=0.500]. Comparison of C(a-v)O2 at peak [Formula: see text] at 4559 m and the equivalent [Formula: see text] at sea level for each participant also revealed no significant difference [83.9 (67.5-120.9) ml litre(1) vs 81.2 (73.0-120.7) ml litre(-1), respectively, P=0.225]. CONCLUSION: In acclimatized individuals at 4559 m, there was a decline in maximum absolute C(a-v)O2 during exercise but no alteration in OER calculated using central venous oxygen measurements. This suggests that oxygen extraction may have become limited after exposure to 7-8 days of hypoxaemia.
Therapeutic manipulation of the HIF hydroxylases.
The hypoxia-inducible factor (HIF) family of transcription factors is responsible for coordinating the cellular response to low oxygen levels in animals. By regulating the expression of a large array of target genes during hypoxia, these proteins also direct adaptive changes in the hematopoietic, cardiovascular, and respiratory systems. They also play roles in pathological processes, including tumorogenesis. In recent years, several oxygenases have been identified as key molecular oxygen sensors within the HIF system. The HIF hydroxylases regulate the stability and transcriptional activity of the HIF-alpha subunit by catalyzing hydroxylation of specific proline and asparaginyl residues, respectively. They require oxygen and 2-oxoglutarate (2OG) as co-substrates, and depend upon non-heme ferrous iron (Fe(II)) as a cofactor. This article summarizes current understanding of the biochemistry of the HIF hydroxylases, identifies targets for their pharmacological manipulation, and discusses their potential in the therapeutic manipulation of the HIF system.
Prolyl hydroxylases and therapeutics.
Prolyl hydroxylases are members of the iron- and 2-oxoglutarate-dependent dioxygenase enzyme family. Collagen prolyl hydroxylase is well known for its involvement in scurvy, in which ascorbate deficiency inhibits the enzyme and results in characteristic signs of the disease. Several distinct prolyl hydroxylases that hydroxylate (and thereby regulate) the hypoxia-inducible factor (HIF) transcription factors were discovered in 2001. These HIF prolyl hydroxylases, termed prolyl hydroxylase domain enzymes (PHDs), are the subject of this forum. HIF coordinates the cellular response to hypoxia, and the PHDs have attracted widespread interest as potential therapeutic targets in a wide range of diseases including anemia, ischemic heart disease, stroke, cancer, and pulmonary hypertension. Novel PHD-based pharmaceutical agents are now undergoing clinical trials. As well as original data, this forum includes reviews discussing recent advances in the biochemistry and therapeutic manipulation of PHDs, the potential role of PHD inhibitors in neuroprotection, and the involvement of PHDs in the complex interaction between oxygen homeostasis and iron homeostasis.
Medium-term effects of SARS-CoV-2 infection on multiple vital organs, exercise capacity, cognition, quality of life and mental health, post-hospital discharge.
Background: The medium-term effects of Coronavirus disease (COVID-19) on organ health, exercise capacity, cognition, quality of life and mental health are poorly understood. Methods: Fifty-eight COVID-19 patients post-hospital discharge and 30 age, sex, body mass index comorbidity-matched controls were enrolled for multiorgan (brain, lungs, heart, liver and kidneys) magnetic resonance imaging (MRI), spirometry, six-minute walk test, cardiopulmonary exercise test (CPET), quality of life, cognitive and mental health assessments. Findings: At 2-3 months from disease-onset, 64% of patients experienced breathlessness and 55% reported fatigue. On MRI, abnormalities were seen in lungs (60%), heart (26%), liver (10%) and kidneys (29%). Patients exhibited changes in the thalamus, posterior thalamic radiations and sagittal stratum on brain MRI and demonstrated impaired cognitive performance, specifically in the executive and visuospatial domains. Exercise tolerance (maximal oxygen consumption and ventilatory efficiency on CPET) and six-minute walk distance were significantly reduced. The extent of extra-pulmonary MRI abnormalities and exercise intolerance correlated with serum markers of inflammation and acute illness severity. Patients had a higher burden of self-reported symptoms of depression and experienced significant impairment in all domains of quality of life compared to controls (p<0.0001 to 0.044). Interpretation: A significant proportion of patients discharged from hospital reported symptoms of breathlessness, fatigue, depression and had limited exercise capacity. Persistent lung and extra-pulmonary organ MRI findings are common in patients and linked to inflammation and severity of acute illness. Funding: NIHR Oxford and Oxford Health Biomedical Research Centres, British Heart Foundation Centre for Research Excellence, UKRI, Wellcome Trust, British Heart Foundation.
NRF2 and Hypoxia-Inducible Factors: Key Players in the Redox Control of Systemic Iron Homeostasis.
Significance: Oxygen metabolism and iron homeostasis are closely linked. Iron facilitates the oxygen-carrying capacity of blood, and its deficiency causes anemia. Conversely, excess free iron is detrimental for stimulating the formation of reactive oxygen species, causing tissue damage. The amount and distribution of iron thus need to be tightly regulated by the liver-expressed hormone hepcidin. This review analyzes the roles of key oxygen-sensing pathways in cellular and systemic regulation of iron homeostasis; specifically, the prolyl hydroxylase domain (PHD)/hypoxia-inducible factor (HIF) and the Kelch-like ECH-associated protein 1/NF-E2 p45-related factor 2 (KEAP1/NRF2) pathways, which mediate tissue adaptation to low and high oxygen, respectively. Recent Advances: In macrophages, NRF2 regulates genes involved in hemoglobin catabolism, iron storage, and iron export. NRF2 was recently identified as the molecular sensor of iron-induced oxidative stress and is responsible for BMP6 expression by liver sinusoidal endothelial cells, which in turn activates hepcidin synthesis by hepatocytes to restore systemic iron levels. Moreover, NRF2 orchestrates the activation of antioxidant defenses that are crucial to protect against iron toxicity. On the contrary, low iron/hypoxia stabilizes renal HIF2a via inactivation of iron-dependent PHD dioxygenases, causing an erythropoietic stimulus that represses hepcidin via an inhibitory effect of erythroferrone on bone morphogenetic proteins. Intestinal HIF2a is also stabilized, increasing the expression of genes involved in dietary iron absorption. Critical Issues: An intimate crosstalk between oxygen-sensing pathways and iron regulatory mechanisms ensures that fluctuations in systemic iron levels are promptly detected and restored. Future Directions: The realization that redox-sensitive transcription factors regulate systemic iron levels suggests novel therapeutic approaches.
Apical length governs computational diversity of L5 pyramidal neurons
<jats:title>Abstract</jats:title><jats:p>Anatomical similarity across the neocortex has led to the common assumption that the circuitry is modular and performs stereotyped computations. Layer 5 pyramidal neurons (L5PNs) in particular are thought to be central to cortical computation because of their extensive arborisation and nonlinear dendritic operations. Here, we demonstrate that computations associated with dendritic Ca<jats:sup>2+</jats:sup> plateaus in L5PNs vary substantially between the primary and secondary visual cortices. L5PNs in the secondary visual cortex show reduced dendritic excitability and smaller propensity for burst firing. This reduced excitability is correlated with shorter apical dendrites. Using numerical modelling, we uncover a universal principle underlying the influence of apical length on dendritic backpropagation and excitability, based on a Na<jats:sup>+</jats:sup> channel-dependent broadening of backpropagating action potentials. In summary, we provide new insights into the modulation of dendritic excitability by apical dendrite length and show that the operational repertoire of L5 neurons is not universal throughout the brain.</jats:p>
Dimension-selective attention as a possible driver of dynamic, context-dependent re-weighting in speech processing.
The contribution of acoustic dimensions to an auditory percept is dynamically adjusted and reweighted based on prior experience about how informative these dimensions are across the long-term and short-term environment. This is especially evident in speech perception, where listeners differentially weight information across multiple acoustic dimensions, and use this information selectively to update expectations about future sounds. The dynamic and selective adjustment of how acoustic input dimensions contribute to perception has made it tempting to conceive of this as a form of non-spatial auditory selective attention. Here, we review several human speech perception phenomena that might be consistent with auditory selective attention although, as of yet, the literature does not definitively support a mechanistic tie. We relate these human perceptual phenomena to illustrative nonhuman animal neurobiological findings that offer informative guideposts in how to test mechanistic connections. We next present a novel empirical approach that can serve as a methodological bridge from human research to animal neurobiological studies. Finally, we describe four preliminary results that demonstrate its utility in advancing understanding of human non-spatial dimension-based auditory selective attention.
Apical length governs computational diversity of layer 5 pyramidal neurons.
Anatomical similarity across the neocortex has led to the common assumption that the circuitry is modular and performs stereotyped computations. Layer 5 pyramidal neurons (L5PNs) in particular are thought to be central to cortical computation because of their extensive arborisation and nonlinear dendritic operations. Here, we demonstrate that computations associated with dendritic Ca2+ plateaus in mouse L5PNs vary substantially between the primary and secondary visual cortices. L5PNs in the secondary visual cortex show reduced dendritic excitability and smaller propensity for burst firing. This reduced excitability is correlated with shorter apical dendrites. Using numerical modelling, we uncover a universal principle underlying the influence of apical length on dendritic backpropagation and excitability, based on a Na+ channel-dependent broadening of backpropagating action potentials. In summary, we provide new insights into the modulation of dendritic excitability by apical dendrite length and show that the operational repertoire of L5PNs is not universal throughout the brain.
Attentional modulation of neural phase is enhanced by short-term training and linked to musical experience
<jats:title>Abstract</jats:title><jats:p>How does the brain follow a sound that is mixed with others in a noisy environment? A possible strategy is to allocate attention to task-relevant time intervals while suppressing irrelevant intervals - a strategy that could be implemented by aligning neural modulations with critical moments in time. Here we tested whether selective attention to non-verbal sound streams is linked to shifts in the timing of attentional modulations of EEG activity, and investigated whether this neural mechanism can be enhanced by short-term training and musical experience. Participants performed a memory task on a target auditory stream presented at 4 Hz while ignoring a distractor auditory stream also presented at 4 Hz, but with a 180-degree shift in phase. The two attention conditions were linked to a roughly 180-degree shift in phase in the EEG signal at 4 Hz. Moreover, there was a strong relationship between performance on the 1-back task and the timing of the EEG modulation with respect to the attended band. EEG modulation timing was also enhanced after several days of training on the selective attention task and enhanced in experienced musicians. These results support the hypothesis that modulation of neural timing facilitates attention to particular moments in time and indicate that phase timing is a robust and reliable marker of individual differences in auditory attention. Moreover, these results suggest that nonverbal selective attention can be enhanced in the short term by only a few hours of practice and in the long term by years of musical training.</jats:p>
Attentional modulation of neural entrainment to sound streams in children with and without ADHD.
To extract meaningful information from complex auditory scenes like a noisy playground, rock concert, or classroom, children can direct attention to different sound streams. One means of accomplishing this might be to align neural activity with the temporal structure of a target stream, such as a specific talker or melody. However, this may be more difficult for children with ADHD, who can struggle with accurately perceiving and producing temporal intervals. In this EEG study, we found that school-aged children's attention to one of two temporally-interleaved isochronous tone 'melodies' was linked to an increase in phase-locking at the melody's rate, and a shift in neural phase that aligned the neural responses with the attended tone stream. Children's attention task performance and neural phase alignment with the attended melody were linked to performance on temporal production tasks, suggesting that children with more robust control over motor timing were better able to direct attention to the time points associated with the target melody. Finally, we found that although children with ADHD performed less accurately on the tonal attention task than typically developing children, they showed the same degree of attentional modulation of phase locking and neural phase shifts, suggesting that children with ADHD may have difficulty with attentional engagement rather than attentional selection.
Python-Microscope: High performance control of arbitrarily complex and scalable bespoke microscopes
<jats:title>Abstract</jats:title><jats:p>Bespoke microscopes often require control of multiple hardware devices and precise hardware coordination. It is also desirable to have a control solution that is scalable to more complex systems and translatable between components from different manufacturers. Here we report Python-Microscope, a free and open source Python library for high performance control of arbitrarily complex and scalable bespoke microscopes. Python-Microscope offers an elegant pythonic software platform to control microscopes, abstracting differences between physical devices by providing a defined interface for different device types. These include cameras, filter wheels, light sources, deformable mirrors, and stages. Concrete implementations are provided for a range of specific hardware and a framework is in place for further expansion. Python-Microscope supports the distribution of devices over multiple computers while maintaining synchronisation via highly precise hardware triggers. We discuss the architecture choices of Python-Microscope that overcome the performance problems often raised against Python and demonstrate the different use cases that drove its design: its integration in user facing projects, namely in the Microscope-Cockpit project; in controlling complex microscopes at high speed while using the Python programming language; and as a microscope simulation tool for software development.</jats:p>
Microscope-AOtools: A generalised adaptive optics implementation
<jats:title>Abstract</jats:title><jats:p>Microscope-AOtools is a software package which allows for a simple, robust and generalised implementation of adaptive optics (AO) elements. It contains all the necessary methods for set-up, calibration, and aberration correction which are simple to use and function in a robust manner. Aberrations arising from sources such as sample hetero-geneity and refractive index mismatches are constant problems in biological imaging. These aberrations reduce image quality and the achievable depth of imaging, particularly in super-resolution microscopy techniques. AO technology has been proven to be effective in correcting for these aberrations and thereby improving the image quality. However, it has not been widely adopted by the biological imaging community due, in part, to difficulty in set-up and operation of AO, particularly by non-specialist users. Microscope-AOtools offers a robust, easy-to-use implementation of the essential methods for set-up and use of AO techniques. These methods are constructed in a generalised manner that can utilise a range of adaptive optics elements, wavefront sensing techniques and sensorless AO correction methods. Furthermore, the methods are designed to be easily extensible as new techniques arise, leading to a streamlined pipeline for new AO technology and techniques to be adopted by the wider microscopy community.</jats:p>