Therapeutic benefits of proning to improve pulmonary gas exchange in severe respiratory failure: Focus on fundamentals of physiology

NEW FINDINGS: What is the topic of this review? The use of proning for improving pulmonary gas exchange in critically ill patients. What advances does it highlight? Proning places the lung in its ‘natural’ posture, and thus optimises the ventilation‐perfusion distribution, which enables lung protective ventilation and the alleviation of potentially life‐threatening hypoxaemia in COVID‐19 and other types of critical illness with respiratory failure. ABSTRACT: The survival benefit of proning patients with acute respiratory distress syndrome (ARDS) is well established and has recently been found to improve pulmonary gas exchange in patients with COVID‐19‐associated ARDS (CARDS). This review outlines the physiological implications of transitioning from supine to prone on alveolar ventilation‐perfusion ([Formula: see text]) relationships during spontaneous breathing and during general anaesthesia in the healthy state, as well as during invasive mechanical ventilation in patients with ARDS and CARDS. Spontaneously breathing, awake healthy individuals maintain a small vertical (ventral‐to‐dorsal) [Formula: see text] ratio gradient in the supine position, which is largely neutralised in the prone position, mainly through redistribution of perfusion. In anaesthetised and mechanically ventilated healthy individuals, a vertical [Formula: see text] ratio gradient is present in both postures, but with better [Formula: see text] matching in the prone position. In ARDS and CARDS, the vertical [Formula: see text] ratio gradient in the supine position becomes larger, with intrapulmonary shunting in gravitationally dependent lung regions due to compression atelectasis of the dorsal lung. This is counteracted by proning, mainly through a more homogeneous distribution of ventilation combined with a largely unaffected high perfusion dorsally, and a consequent substantial improvement in arterial oxygenation. The data regarding proning as a therapy in patients with CARDS is still limited and whether the associated improvement in arterial oxygenation translates to a survival benefit remains unknown. Proning is nonetheless an attractive and lung protective manoeuvre with the potential benefit of improving life‐threatening hypoxaemia in patients with ARDS and CARDS

Insights into the evolutionary conserved regulation of Rio ATPase activity

Department of Biochemistry III ‘House of the Ribosome’ and by the DFG Collaborative Research Center [SFB960-AP1] ‘Ribosome formation: principles of RNP biogenesis and control of their function’ (to S.F.-C.).; Work in the MacNeill laboratory was funded by Forskningsrådet for Natur og Univers (FNU) [sagsnr. 272-05-0446]; Scottish Universities Life Sciences Alliance (SULSA); Research in the Medenbach laboratory is supported by the Bavarian Research Network for Molecular Biosystems (BioSysNet); German Research Foundation (DFG) [ME4238/1-1]; DFG Collaborative Research Center [SFB960-B11] ‘Ribosome formation: principles of RNP biogenesis and control of their function’; German Federal Ministry of Education and Research (BMBF) within the framework of the e:Med research and funding concept [01ZX1401D]; Work in the Siebers laboratory was funded by a grant from the German Science Foundation (DFG) [SI642/10-1] from the Federal Ministry of Education and Research (BMBF) [0316188A]; Work in the LaRonde laboratory was funded by National Science Foundation [MCB0953493]; Publishing of this work was supported by the German Research Foundation (DFG) within the funding program Open Access Publishing. Funding for open access charge: DFG—Open Access program.Eukaryotic ribosome biogenesis is a complex dynamic process which requires the action of numerous ribosome assembly factors. Among them, the eukaryotic Rio protein family members (Rio1, Rio2 and Rio3) belong to an ancient conserved atypical protein kinase/ ATPase family required for the maturation of the small ribosomal subunit (SSU). Recent structure-function analyses suggested an ATPase-dependent role of the Rio proteins to regulate their dynamic association with the nascent pre-SSU. However, the evolutionary origin of this feature and the detailed molecular mechanism that allows controlled activation of the catalytic activity remained to be determined. In this work we provide functional evidence showing a conserved role of the archaeal Rio proteins for the synthesis of the SSU in archaea. Moreover, we unravel a conserved RNA-dependent regulation of the Rio ATPases, which in the case of Rio2 involves, at least, helix 30 of the SSU rRNA and the P-loop lysine within the shared RIO domain. Together, our study suggests a ribosomal RNA-mediated regulatory mechanism enabling the appropriate stimulation of Rio2 catalytic activity and subsequent release of Rio2 from the nascent pre- 40S particle. Based on our findings we propose a unified release mechanism for the Rio proteins.Publisher PDFPeer reviewe

The circadian schedule for childhood acute lymphoblastic leukemia maintenance therapy does not influence event-free survival in the NOPHO ALL92 protocol.

To access publisher's full text version of this article click on the hyperlink at the bottom of the pageThe event-free survival of childhood acute lymphoblastic leukemia (ALL) has been reported to be superior when oral methotrexate (MTX) and 6-mercaptopurine (6MP) maintenance therapy (MT) is administered in the evening compared to the morning.In the ALL92 MT study we prospectively registered the intake of MTX/6MP. The registration was done when blood samples for erythrocyte MTX/6MP metabolite measurements were collected, and referred to the time of intake in the period since last registration. Nine thousand one hundred ninety-five registrations in total. The administration of MTX/6MP was scored as morning, midday, or evening.Of 532 patients, 296 took their medication consistently in the evening, 129 in the evening 50.0-99.9% of the time, and 101 in the evening <50% of the time, six did not have any registrations. The circadian schedule did not differ significantly by age, sex, MTX/6MP doses, and average absolute neutrophil counts. The circadian schedule groups did differ on risk groups (P = 0.003) with fewer HR patients in the 50-99.9% group, and there was a negative correlation between percentage of time on evening schedule and average WBC (Spearman's rho -0.15; P = 0.0004). Average WBC was not associated with relapse on ALL92. In a Cox multivariate model the circadian schedule of MTX/6MP was not of prognostic significance for the risk of relapse, and the 10-year cumulative relapse risk was below 20% in all groups.An evening schedule may still be recommended based on the previous publications, but in this study morning administration of MTX and 6MP does not seem to impact EFS.The Danish Cancer Society; Grant numbers: 91-048, 92- 017, 93-017, 95-100-28, R28-A1354-10-S7; Grant sponsor: The Swedish Childhood Cancer Foundation; Grant numbers: 53/91, 62/ 94, 72/96, 98/59; Grant sponsor: The Lundbeck Foundation; Grant number: 38/99; Grant sponsor: The Danish Childhood Cancer Foundation; Grant number: 2010-3