Mononuclear cell therapy of neonatal hypoxic‐ischemic encephalopathy in preclinical versus clinical studies : a systematic analysis of therapeutic efficacy and study design

Background: Hypoxic‐ischemic encephalopathy (HIE) is a devastating condition affecting around 8.5 in 1000 newborns globally. Therapeutic hypothermia (TH) can reduce mortality and, to a limited extent, disability after HIE. Nevertheless, there is a need for new and effective treatment strategies. Cell‐based treatments using mononuclear cells (MNCs), which can be sourced from umbilical cord blood, are currently being investigated. Despite promising preclinical results, there is currently no strong indicator for the clinical efficacy of the approach. This analysis aimed to provide potential explanations for this discrepancy. Methods: A systematic review and meta‐analysis were conducted according to the Preferred Reporting Items for Systematic Reviews and Meta‐Analysis guidelines. Preclinical and clinical studies were retrieved from PubMed, Web of Science, Scopus, and clinicaltrials.gov using a predefined search strategy. A total of 17 preclinical and 7 clinical studies were included. We analyzed overall MNC efficacy in preclinical trials, the methodological quality of preclinical trials, and relevant design features in preclinical versus clinical trials. Results: There was evidence for MNC therapeutic efficacy in preclinical models of HIE. The methodological quality of preclinical studies was not optimal, and statistical design quality was particularly poor. However, methodological quality was above the standard in other fields. There were significant differences in preclinical versus clinical study design including the use of TH as a baseline treatment (only in clinical studies) and much higher MNC doses being applied in preclinical studies. Conclusions: Based on the analyzed data, it is unlikely that therapeutic effect size is massively overestimated in preclinical studies. It is more plausible that the many design differences between preclinical and clinical trials are responsible for the so far lacking proof of the efficacy of MNC treatments in HIE. Additional preclinical and clinical research is required to optimize the application of MNC for experimental HIE treatment

The fundamental constants and their variation: observational status and theoretical motivations

This article describes the various experimental bounds on the variation of the fundamental constants of nature. After a discussion on the role of fundamental constants, of their definition and link with metrology, the various constraints on the variation of the fine structure constant, the gravitational, weak and strong interactions couplings and the electron to proton mass ratio are reviewed. This review aims (1) to provide the basics of each measurement, (2) to show as clearly as possible why it constrains a given constant and (3) to point out the underlying hypotheses. Such an investigation is of importance to compare the different results, particularly in view of understanding the recent claims of the detections of a variation of the fine structure constant and of the electron to proton mass ratio in quasar absorption spectra. The theoretical models leading to the prediction of such variation are also reviewed, including Kaluza-Klein theories, string theories and other alternative theories and cosmological implications of these results are discussed. The links with the tests of general relativity are emphasized.Comment: 56 pages, l7 figures, submitted to Rev. Mod. Phy

Mononuclear cell therapy of neonatal hypoxic‐ischemic encephalopathy in preclinical versus clinical studies: A systematic analysis of therapeutic efficacy and study design

Publication status: PublishedAbstractBackgroundHypoxic‐ischemic encephalopathy (HIE) is a devastating condition affecting around 8.5 in 1000 newborns globally. Therapeutic hypothermia (TH) can reduce mortality and, to a limited extent, disability after HIE. Nevertheless, there is a need for new and effective treatment strategies. Cell‐based treatments using mononuclear cells (MNCs), which can be sourced from umbilical cord blood, are currently being investigated. Despite promising preclinical results, there is currently no strong indicator for the clinical efficacy of the approach. This analysis aimed to provide potential explanations for this discrepancy.MethodsA systematic review and meta‐analysis were conducted according to the Preferred Reporting Items for Systematic Reviews and Meta‐Analysis guidelines. Preclinical and clinical studies were retrieved from PubMed, Web of Science, Scopus, and clinicaltrials.gov using a predefined search strategy. A total of 17 preclinical and 7 clinical studies were included. We analyzed overall MNC efficacy in preclinical trials, the methodological quality of preclinical trials, and relevant design features in preclinical versus clinical trials.ResultsThere was evidence for MNC therapeutic efficacy in preclinical models of HIE. The methodological quality of preclinical studies was not optimal, and statistical design quality was particularly poor. However, methodological quality was above the standard in other fields. There were significant differences in preclinical versus clinical study design including the use of TH as a baseline treatment (only in clinical studies) and much higher MNC doses being applied in preclinical studies.ConclusionsBased on the analyzed data, it is unlikely that therapeutic effect size is massively overestimated in preclinical studies. It is more plausible that the many design differences between preclinical and clinical trials are responsible for the so far lacking proof of the efficacy of MNC treatments in HIE. Additional preclinical and clinical research is required to optimize the application of MNC for experimental HIE treatment.</jats:sec

The Looe, south Devon and Tavy Basins : the Devonian rifted passive margin successions

The majority of ‘Marine Devonian’ GCR sites are located on the Early to Latest Devonian rocks of central and north Cornwall and south Devon, within the successions of the east–west Looe, South Devon and Tavy basins, their sub-basins and associated highs. This half-graben and full graben complex developed sequentially northwards during the Devonian period by rifting of the Rhenohercynian passive margin. Basin formation and development was initiated in a terrestrial setting, but from the late Early Devonian marine environments prevailed. Each basin and high had its own stratigraphical succession, and there is variation between those of composite sub-basins. From Mid-Devonian times basins were characterised by hemipelagic deposits with turbid flow incursions of predominantly fine-grained northerly derived terrigenous clastics, and the highs developed carbonate platforms with reefs that persisted into the Late Devonian. Associated alkaline basaltic rocks are typical of the continental rifting regime with high extension. The complex basin and high architecture directly determined major structures, folds and thrusts, developed during regional contraction, and review of those structures permits placement of the sites in that structural context. Thirty eight GCR site reports in this chapter are grouped to describe the stratigraphical successions of named basins and highs from south to north through the sub-province. The oldest deposits are in the south, with basins developing later to the north, but there are differing coeval basin and high successions that extend up to the Latest Devonian through the belt. Amongst the sites there are those that provided definitive descriptions of limestone reefs and their changes in time and space through their acme in the Mid-Devonian, and others that are significant for their fossils, such as the ammonoids, corals or conodonts, which fostered classic studies internationally important in Devonian stratigraphy. Together they describe the variety of stratigraphical sequences and their evolution, environmental, sedimentological and palaeontological, in this major setting of the marine Devonian of Britain

Donor-Acceptor Distance Sampling Enhances the Performance of "better than Nature" Nicotinamide Coenzyme Biomimetics

Understanding the mechanisms of enzymatic hydride transfer with nicotinamide coenzyme biomimetics (NCBs) is critical to enhancing the performance of nicotinamide coenzyme-dependent biocatalysts. Here the temperature dependence of kinetic isotope effects (KIEs) for hydride transfer between "better than nature" NCBs and several ene reductase biocatalysts is used to indicate transfer by quantum mechanical tunneling. A strong correlation between rate constants and temperature dependence of the KIE (ΔΔH) for H/D transfer implies that faster reactions with NCBs are associated with enhanced donor-acceptor distance sampling. Our analysis provides the first mechanistic insight into how NCBs can outperform their natural counterparts and emphasizes the need to optimize donor-acceptor distance sampling to obtain high catalytic performance from H-transfer enzymes.BT/Biocatalysi