The Rise of Adaptive Platform Trials in Critical Care

As durable learning research systems, adaptive platform trials represent a transformative new approach to accelerating clinical evaluation and discovery in critical care. This Perspective provides a brief introduction to the concept of adaptive platform trials, describes several established and emerging platforms in critical care, and surveys some opportunities and challenges for their implementation and impact.<br/

Life Cycle Impact Assessment

International audienceThis chapter is dedicated to the third phase of an LCA study, the Life Cycle Impact Assessment (LCIA) where the life cycle inventory's information on elementary flows is translated into environmental impact scores. In contrast to the three other LCA phases, LCIA is in practice largely automated by LCA software, but the underlying principles, models and factors should still be well understood by practitioners to ensure the insight that is needed for a qualified interpretation of the results.This chapter teaches the fundamentals of LCIA and opens the black box of LCIA with its characterisation models and factors to inform the reader about: (1) the main purpose and characteristics of LCIA, (2) the mandatory and optional steps of LCIA according to the ISO standard, and (3) the science and methods underlying the assessment for each environmental impact category. For each impact category, the reader is taken through (a) the underlying environmental problem, (b) the underlying environmental mechanism and its fundamental modelling principles, (c) the main anthropogenic sources causing the problem and (d) the main methods available in LCIA. An annex to this book offers a comprehensive qualitative comparison of the main elements and properties of the most widely used and also the latest LCIAmethods for each impact category, to further assist the advanced practitioner to make an informed choice between LCIA methods

Observations on the variability of corticospinal tract excitability during the reaction time period for simple human finger movements

There is extensive evidence that movements are prepared prior to their release. Transcranial magnetic stimulation, and in particular the motor evoked potential produced when stimulating over the primary motor cortex, has given a great deal of insight into the processes involved in preparation for voluntary movements. The excitability of the primary motor cortex remains in a state of dynamic fluctuation even when in the “resting” state, with the TMS MEP being exquisitely sensitive to this as evidenced by its tremendous trial to trial variability. Interestingly there is growing body of evidence to suggest that modulation of signal noise can provide insight into biological processes including movement preparation – indeed the output of the corticospinal tract would logically need to adapt to resting variability to enable the precise reproduction of movements. While much of the TMS literature has addressed MEP variability as a “noisy” signal, this thesis aims to assess whether elements of this “noise” can be utilized as a marker of biologic process during the reaction time period for simple human finger movements. Through successive chapters we demonstrate that the variability of corticospinal tract output, as evidenced by the TMS MEP, declines during the process of preparation for simple human finger movements. We demonstrate that the reaction time decline in variability is focal to muscles directly involved in the task. Furthermore, the rate of decline in MEP amplitude variability during the reaction time period appears intimately linked to the speed of movement initiation. Additionally, the changes we see here precede changes in mean excitability in agonists, and indeed are seen to be associated with a decline in mean excitability when surround muscles are tasked with deliberate inactivity. Finally, observations in stroke patients suggest an alteration in variability control during movement preparation and appear to be associated with concordant changes in task performance

In a search for efficient treatment for amyotrophic lateral sclerosis: Old drugs for new approaches

Recent progress in understanding the pathological changes in the nervous system and in certain other body systems (e.g., immune system) that lead to the development and progression of amyotrophic lateral sclerosis (ALS) revealed a number of molecular and cellular processes that can potentially be used as therapeutic targets. Many of these processes are compromised not only in ALS but also in other diseases and a repertoire of drugs able to restore, at least partially, their functionality has been developed. In this review, we briefly describe current approaches to the repurposing of such “old” drugs for treatment of patients with ALS

Mapping the human genetic architecture of COVID-19

The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-191,2, host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases3–7. They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease