Prenatal cortisol exposure impairs adrenal function but not glucose metabolism in adult sheep.

Adverse environmental conditions before birth are known to programme adult metabolic and endocrine phenotypes in several species. However, whether increments in fetal cortisol concentrations of the magnitude commonly seen in these conditions can cause developmental programming remains unknown. Thus, this study investigated the outcome of physiological increases in fetal cortisol concentrations on glucose-insulin dynamics and pituitary-adrenal function in adult sheep. Compared with saline treatment, intravenous fetal cortisol infusion for 5 days in late gestation did not affect birthweight but increased lamb body weight at 1-2 weeks after birth. Adult glucose dynamics, insulin sensitivity and insulin secretion were unaffected by prenatal cortisol overexposure, assessed by glucose tolerance tests, hyperinsulinaemic-euglycaemic clamps and acute insulin administration. In contrast, prenatal cortisol infusion induced adrenal hypo-responsiveness in adulthood with significantly reduced cortisol responses to insulin-induced hypoglycaemia and exogenous adrenocorticotropic hormone (ACTH) administration relative to saline treatment. The area of adrenal cortex expressed as a percentage of the total cross-sectional area of the adult adrenal gland was also lower after prenatal cortisol than saline infusion. In adulthood, basal circulating ACTH but not cortisol concentrations were significantly higher in the cortisol than saline-treated group. The results show that cortisol overexposure before birth programmes pituitary-adrenal development with consequences for adult stress responses. Physiological variations in cortisol concentrations before birth may, therefore, have an important role in determining adult phenotypical diversity and adaptability to environmental challenges.

Understanding the mechanism by which Gd(III) coiled coils achieve magnetic resonance relaxivity - a study into the water coordination chemistry.

A class of Gd(III) coiled coils achieve high MRI relaxivity, in part due to their slow rotational correlation time. However, extending their length is unable to further enhance performance, as the mechanism by which relaxivity is achieved is dominated by the presence of three inner sphere waters in rapid exchange, through an associative mechanism.

Root reinforcement and extracellular products reduce streambank fluvial erosion.

A detailed understanding of the factors that impact bank erodibility is necessary to effectively model changes in channel form. This study evaluated the combined contributions of roots and soil microorganisms to soil resistance against fluvial erosion. To do this, three flume walls were constructed to simulate unvegetated and rooted streambanks. Unamended and organic material (OM) amended soil treatments with either no-roots (bare soil), synthetic (inert) roots, or living roots (Panicum virgatum) were created and tested with the corresponding flume wall treatment. OM stimulated the production of extracellular polymeric substances (EPS) and appeared to increase the applied stress required to initiate soil erosion. Synthetic fibers alone provided a base reduction in soil erosion, regardless of the flow rate used. When used in combination, synthetic roots and OM-amendments reduced erosion rates by 86 % or more compared to bare soil; this reduction was identical to the live rooted treatments (95 % to 100 %). In summary, a synergistic relationship between roots and organic carbon inputs can significantly reduce soil erosion rates due to fiber reinforcement and EPS production. These results indicate that root-biochemical interactions, like root physical mechanisms, play an important role in influencing channel migration rates due to reductions in streambank erodibility.

Can probiotic gargles reduce post-tonsillectomy morbidity in adult patients? A pilot, triple-blind, randomised, controlled trial and feasibility study.

OBJECTIVE: This study aimed to determine the efficacy of probiotic gargles compared with placebo gargles on reducing post-tonsillectomy morbidity in adults. METHOD: This was a triple-blind, randomised, controlled trial and feasibility study. Thirty adults underwent elective tonsillectomy and were randomly assigned to receive either probiotic or placebo gargles for 14 days after surgery. Daily pain scores and requirement of analgesia were measured for 14 days post-operatively. Secondary outcomes assessed probiotic safety and tolerability and the feasibility of the trial. RESULTS: The probiotic group experienced less pain at rest on day 2. However, the amount of oxycodone (5 mg) tablets used was greater in the probiotic group compared with placebo. There were no statistically significant differences in the frequency of adverse effects between both groups. This trial was feasible. CONCLUSION: This pilot study suggested that probiotic gargles do not reduce post-tonsillectomy pain or bleeding, highlighting the importance of pilot and feasibility studies in clinical research.

Coronavirus disease 2019 subphenotypes and differential treatment response to convalescent plasma in critically ill adults: secondary analyses of a randomized clinical trial.

PURPOSE: Benefit from convalescent plasma therapy for coronavirus disease 2019 (COVID-19) has been inconsistent in randomized clinical trials (RCTs) involving critically ill patients. As COVID-19 patients are immunologically heterogeneous, we hypothesized that immunologically similar COVID-19 subphenotypes may differ in their treatment responses to convalescent plasma and explain inconsistent findings between RCTs . METHODS: We tested this hypothesis in a substudy involving 1239 patients, by measuring 26 biomarkers (cytokines, chemokines, endothelial biomarkers) within the randomized, embedded, multifactorial, adaptive platform trial for community-acquired pneumonia (REMAP-CAP) that assigned 2097 critically ill COVID-19 patients to either high-titer convalescent plasma or usual care. Primary outcome was organ support free days at 21 days (OSFD-21) . RESULTS: Unsupervised analyses identified three subphenotypes/endotypes. In contrast to the more homogeneous subphenotype-2 (N = 128 patients, 10.3%; with elevated type i and type ii effector immune responses) and subphenotype-3 (N = 241, 19.5%; with exaggerated inflammation), the subphenotype-1 had variable biomarker patterns (N = 870 patients, 70.2%). Subphenotypes-2, and -3 had worse outcomes, and subphenotype-1 had better outcomes with convalescent plasma therapy compared with usual care (median (IQR). OSFD-21 in convalescent plasma vs usual care was 0 (- 1, 21) vs 10 (- 1, to 21) in subphenotype-2; 1.5 (- 1, 21) vs 12 (- 1, to 21) in suphenotype-3, and 0 (- 1, 21) vs 0 (- 1, to 21) in subphenotype-1 (test for between-subphenotype differences in treatment effects p = 0.008). CONCLUSIONS: We reported three COVID-19 subphenotypes, among critically ill adults, with differential treatment effects to ABO-compatible convalescent plasma therapy. Differences in subphenotype prevalence between RCT populations probably explain inconsistent results with COVID-19 immunotherapies.

Glucocorticoid maturation of mitochondrial respiratory capacity in skeletal muscle before birth.

In adults, glucocorticoids act to match the supply and demand for energy during physiological challenges, partly through actions on tissue mitochondrial oxidative phosphorylation (OXPHOS) capacity. However, little is known about the role of the natural prepartum rise in fetal glucocorticoid concentrations in preparing tissues for the increased postnatal energy demands. This study examined the effect of manipulating cortisol concentrations in fetal sheep during late gestation on mitochondrial OXPHOS capacity of two skeletal muscles with different postnatal locomotive functions. Mitochondrial content, biogenesis markers, respiratory rates and expression of proteins and genes involved in the electron transfer system (ETS) and OXPHOS efficiency were measured in the biceps femoris (BF) and superficial digital flexor (SDF) of fetuses either infused with cortisol before the prepartum rise or adrenalectomised to prevent this increment. Cortisol infusion increased mitochondrial content, biogenesis markers, substrate-specific respiration rates and abundance of ETS complex I and adenine nucleotide translocator (ANT1) in a muscle-specific manner that was more pronounced in the SDF than BF. Adrenalectomy reduced mitochondrial content and expression of PGC1α and ANT1 in both muscles, and ETS complex IV abundance in the SDF near term. Uncoupling protein gene expression was unaffected by cortisol manipulations in both muscles. Gene expression of the myosin heavy chain isoform, MHCIIx, was increased by cortisol infusion and reduced by adrenalectomy in the BF alone. These findings show that cortisol has a muscle-specific role in prepartum maturation of mitochondrial OXPHOS capacity with important implications for the health of neonates born pre-term or after intrauterine glucocorticoid overexposure.

The art of coarse Stokes: Richardson extrapolation improves the accuracy and efficiency of the method of regularized stokeslets.

The method of regularized stokeslets is widely used in microscale biological fluid dynamics due to its ease of implementation, natural treatment of complex moving geometries, and removal of singular functions to integrate. The standard implementation of the method is subject to high computational cost due to the coupling of the linear system size to the numerical resolution required to resolve the rapidly varying regularized stokeslet kernel. Here, we show how Richardson extrapolation with coarse values of the regularization parameter is ideally suited to reduce the quadrature error, hence dramatically reducing the storage and solution costs without loss of accuracy. Numerical experiments on the resistance and mobility problems in Stokes flow support the analysis, confirming several orders of magnitude improvement in accuracy and/or efficiency.

Simulations of particle tracking in the oligociliated mouse node and implications for left-right symmetry-breaking mechanics.

The concept of internal anatomical asymmetry is familiar-usually in humans the heart is on the left and the liver is on the right; however, how does the developing embryo know to produce this consistent laterality? Symmetry-breaking initiates with left-right asymmetric cilia-driven fluid mechanics in a small fluid-filled structure called the ventral node in mice. However, the question of what converts this flow into left-right asymmetric development remains unanswered. A leading hypothesis is that flow transports morphogen-containing vesicles within the node, the absorption of which results in asymmetrical gene expression. To investigate how vesicle transport might result in the situs patterns observe in wild-type and mutant experiments, we extend the open-source Stokes flow package, NEAREST, to consider the hydrodynamic and Brownian motion of particles in a mouse model with flow driven by one, two and 112 beating cilia. Three models for morphogen-containing particle released are simulated to assess their compatibility with observed results in oligociliated and wild-type mouse embryos: uniformly random release, localized cilium stress-induced release and localized release from motile cilia themselves. Only the uniformly random release model appears consistent with the data, with neither localized release model resulting in significant transport in the oligociliated embryo. This article is part of the Theo Murphy meeting issue 'Unity and diversity of cilia in locomotion and transport'.

Recommended medical and non-medical factors to assess military preventable deaths: subject matter experts provide valuable insights.

INTRODUCTION: Historically, there has been variability in the methods for determining preventable death within the US Department of Defense. Differences in methodologies partially explain variable preventable death rates ranging from 3% to 51%. The lack of standard review process likely misses opportunities for improvement in combat casualty care. This project identified recommended medical and non-medical factors necessary to (1) establish a comprehensive preventable death review process and (2) identify opportunities for improvement throughout the entire continuum of care. METHODS: This qualitative study used a modified rapid assessment process that includes the following steps: (1) identification and recruitment of US government subject matter experts (SMEs); (2) multiple cycles of data collection via key informant interviews and focus groups; (3) consolidation of information collected in these interviews; and (4) iterative analysis of data collected from interviews into common themes. Common themes identified from SME feedback were grouped into the following subject areas: (1) prehospital, (2) in-hospital and (3) forensic pathology. RESULTS: Medical recommendations for military preventable death reviews included the development, training, documentation, collection, analysis and reporting of the implementation of the Tactical Combat Casualty Care Guidelines, Joint Trauma System Clinical Practice Guidelines and National Association of Medical Examiners autopsy standards. Non-medical recommendations included training, improved documentation, data collection and analysis of non-medical factors needed to understand how these factors impact optimal medical care. CONCLUSIONS: In the operational environment, medical care must be considered in the context of non-medical factors. For a comprehensive preventable death review process to be sustainable in the military health system, the process must be based on an appropriate conceptual framework implemented consistently across all military services.

Rapid sperm capture: high-throughput flagellar waveform analysis.

STUDY QUESTION: Can flagellar analyses be scaled up to provide automated tracking of motile sperm, and does knowledge of the flagellar waveform provide new insight not provided by routine head tracking? SUMMARY ANSWER: High-throughput flagellar waveform tracking and analysis enable measurement of experimentally intractable quantities such as energy dissipation, disturbance of the surrounding medium and viscous stresses, which are not possible by tracking the sperm head alone. WHAT IS KNOWN ALREADY: The clinical gold standard for sperm motility analysis comprises a manual analysis by a trained professional, with existing automated sperm diagnostics [computer-aided sperm analysis (CASA)] relying on tracking the sperm head and extrapolating measures. It is not currently possible with either of these approaches to track the sperm flagellar waveform for large numbers of cells in order to unlock the potential wealth of information enclosed within. STUDY DESIGN, SIZE, DURATION: The software tool in this manuscript has been developed to enable high-throughput, repeatable, accurate and verifiable analysis of the sperm flagellar beat. PARTICIPANTS/MATERIALS, SETTING, METHODS: Using the software tool [Flagellar Analysis and Sperm Tracking (FAST)] described in this manuscript, we have analysed 176 experimental microscopy videos and have tracked the head and flagellum of 205 progressive cells in diluted semen (DSM), 119 progressive cells in a high-viscosity medium (HVM) and 42 stuck cells in a low-viscosity medium. Unscreened donors were recruited at Birmingham Women's and Children's NHS Foundation Trust after giving informed consent. MAIN RESULTS AND THE ROLE OF CHANCE: We describe fully automated tracking and analysis of flagellar movement for large cell numbers. The analysis is demonstrated on freely motile cells in low- and high-viscosity fluids and validated on published data of tethered cells undergoing pharmacological hyperactivation. Direct analysis of the flagellar beat reveals that the CASA measure 'beat cross frequency' does not measure beat frequency; attempting to fit a straight line between the two measures gives ${\mathrm{R}}^2$ values of 0.042 and 0.00054 for cells in DSM and HVM, respectively. A new measurement, track centroid speed, is validated as an accurate differentiator of progressive motility. Coupled with fluid mechanics codes, waveform data enable extraction of experimentally intractable quantities such as energy dissipation, disturbance of the surrounding medium and viscous stresses. We provide a powerful and accessible research tool, enabling connection of the mechanical activity of the sperm to its motility and effect on its environment. LARGE SCALE DATA: The FAST software package and all documentation can be downloaded from www.flagellarCapture.com. LIMITATIONS, REASONS FOR CAUTION: The FAST software package has only been tested for use with negative phase contrast microscopy. Other imaging modalities, with bright cells on a dark background, have not been tested but may work. FAST is not designed to analyse raw semen; it is specifically for precise analysis of flagellar kinematics, as that is the promising area for computer use. Flagellar capture will always require that cells are at a dilution where their paths do not frequently cross. WIDER IMPLICATIONS OF THE FINDINGS: Combining tracked flagella with mathematical modelling has the potential to reveal new mechanistic insight. By providing the capability as a free-to-use software package, we hope that this ability to accurately quantify the flagellar waveform in large populations of motile cells will enable an abundant array of diagnostic, toxicological and therapeutic possibilities, as well as creating new opportunities for assessing and treating male subfertility. STUDY FUNDING/COMPETING INTEREST(S): M.T.G., G.C., J.C.K-B. and D.J.S. gratefully acknowledge funding from the Engineering and Physical Sciences Research Council, Healthcare Technologies Challenge Award (Rapid Sperm Capture EP/N021096/1). J.C.K-B. is funded by a National Institute of Health Research (NIHR) and Health Education England, Senior Clinical Lectureship Grant: The role of the human sperm in healthy live birth (NIHRDH-HCS SCL-2014-05-001). This article presents independent research funded in part by the NIHR and Health Education England. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. The data for experimental set (2) were funded through a Wellcome Trust-University of Birmingham Value in People Fellowship Bridging Award (E.H.O.).The authors declare no competing interests.

Mathematical modelling of the vitamin C clock reaction.

Chemical clock reactions are characterized by a relatively long induction period followed by a rapid 'switchover' during which the concentration of a clock chemical rises rapidly. In addition to their interest in chemistry education, these reactions are relevant to industrial and biochemical applications. A substrate-depletive, non-autocatalytic clock reaction involving household chemicals (vitamin C, iodine, hydrogen peroxide and starch) is modelled mathematically via a system of nonlinear ordinary differential equations. Following dimensional analysis, the model is analysed in the phase plane and via matched asymptotic expansions. Asymptotic approximations are found to agree closely with numerical solutions in the appropriate time regions. Asymptotic analysis also yields an approximate formula for the dependence of switchover time on initial concentrations and the rate of the slow reaction. This formula is tested via 'kitchen sink chemistry' experiments, and is found to enable a good fit to experimental series varying in initial concentrations of both iodine and vitamin C. The vitamin C clock reaction provides an accessible model system for mathematical chemistry.

A non-randomised single centre cohort study, comparing standard and modified bowel preparations, in adults with cystic fibrosis requiring colonoscopy.

BACKGROUND: Adults with cystic fibrosis (CF) have been reported to be at five to ten-fold risk (25 to 30 fold risk after solid organ transplant) of colorectal cancer (CRC) than the general population. Limited publications to date have reported on practical aspects of achieving adequate colonic cleanse producing good visualisation. In this study, we compared two bowel preparation regimens, standard bowel preparation and a modified CF bowel preparation. METHODS: A non-randomised study of adults with CF attending a single centre, requiring colonoscopy investigation were selected. Between 2001 and 2015, 485 adults with CF attended the clinic; 70 adults with CF had an initial colonoscopy procedure. After five exclusions, standard bowel preparation was prescribed for 27 patients, and modified CF bowel preparation for 38 patients. Demographic and clinical data were collected for all consenting patients. RESULTS: There was a significant difference between modified CF bowel preparation group and standard bowel preparation group in bowel visualisation outcomes, with the modified CF bowel preparation group having a higher proportion of "excellent/good" GI visualisation cleanse (50.0% versus 25.9%) and lower rates of "poor" visualisation cleanse (10.5% versus 44.5%) than standard bowel preparation (p = 0.006). Rates of "fair" GI cleanse visualisation were similar between the two groups (39.4% versus 29.6%) (Additional file 1: Table S1). Detection rates of adenomatous polyps at initial colonoscopy was higher in modified CF bowel preparation cohort than with standard preparation group (50.0% versus 18.5%, p < 0.01). Positive adenomatous polyp detection rate in patient's age > 40 years of age was higher (62.5%) than those < 40 years of age (24.3%) (p = 0.003). Colonic adenocarcinoma diagnosis was similar in both groups. CONCLUSION: This study primarily highlights that standard colonoscopy bowel preparation is often inadequate in patients with CF, and that colonic lavage using modified CF bowel preparation is required to obtain good colonic visualisation. A higher rate of polyps in patients over 40 years of age (versus less than 40 years) was evident. These results support adults with CF considered for colonoscopy screening at 40 years of age, or prior to this if symptomatic; which is earlier than CRC screening in the non-CF Australian population.

Simultaneous parameter estimation and variable selection via the logit-normal continuous analogue of the spike-and-slab prior.

We introduce a Bayesian prior distribution, the logit-normal continuous analogue of the spike-and-slab, which enables flexible parameter estimation and variable/model selection in a variety of settings. We demonstrate its use and efficacy in three case studies-a simulation study and two studies on real biological data from the fields of metabolomics and genomics. The prior allows the use of classical statistical models, which are easily interpretable and well known to applied scientists, but performs comparably to common machine learning methods in terms of generalizability to previously unseen data.

Review: High-throughput phenotyping to enhance the use of crop genetic resources.

Improved genetic, genomic and statistical technologies have increased the capacity to enrich breeding populations for key alleles underpinning adaptation and continued genetic gain. In turn, directed genomic selection together with increased heritability will reduce genetic variance to narrow the genetic base in many crop breeding programs. Diverse genetic resources (GR), including wild and weedy relatives, landraces and reconstituted synthetics, have potential to contribute novel alleles for key traits. Targeted trait identification may also identify genetic diversity in addressing new challenges including the need for modified root architecture, greater nutrient-use efficiency, and adaptation to warmer air and soil temperatures forecast with climate change. Yet while core collections and other GR sources have historically been invaluable for major gene control of disease and subsoil constraints, the mining of genetically (and phenotypically) complex traits in GR remains a significant challenge owing to reduced fertility, limited seed quantities and poor adaptation through linkage drag with undesirable alleles. High-throughput field phenomics (HTFP) offers the opportunity to capture phenotypically complex variation underpinning adaptation in traditional phenotypic selection or statistics-based breeding programs. Targeted HTFP will permit the reliable phenotyping of greater numbers of GR-derived breeding lines using smaller plot sizes and at earlier stages of population development to reduce the duration of breeding cycles and the loss of potentially important alleles with linkage drag. Two key opportunities are highlighted for use of HTFP in selection among GR-derived wheat breeding lines for greater biomass and stomatal conductance through canopy temperature.

The Molecular Basis for Antigenic Drift of Human A/H2N2 Influenza Viruses.

Influenza A/H2N2 viruses caused a pandemic in 1957 and continued to circulate in humans until 1968. The antigenic evolution of A/H2N2 viruses over time and the amino acid substitutions responsible for this antigenic evolution are not known. Here, the antigenic diversity of a representative set of human A/H2N2 viruses isolated between 1957 and 1968 was characterized. The antigenic change of influenza A/H2N2 viruses during the 12 years that this virus circulated was modest. Two amino acid substitutions, T128D and N139K, located in the head domain of the H2 hemagglutinin (HA) molecule, were identified as important determinants of antigenic change during A/H2N2 virus evolution. The rate of A/H2N2 virus antigenic evolution during the 12-year period after introduction in humans was half that of A/H3N2 viruses, despite similar rates of genetic change.IMPORTANCE While influenza A viruses of subtype H2N2 were at the origin of the Asian influenza pandemic, little is known about the antigenic changes that occurred during the twelve years of circulation in humans, the role of preexisting immunity, and the evolutionary rates of the virus. In this study, the antigenic map derived from hemagglutination inhibition (HI) titers of cell-cultured virus isolates and ferret postinfection sera displayed a directional evolution of viruses away from earlier isolates. Furthermore, individual mutations in close proximity to the receptor-binding site of the HA molecule determined the antigenic reactivity, confirming that individual amino acid substitutions in A/H2N2 viruses can confer major antigenic changes. This study adds to our understanding of virus evolution with respect to antigenic variability, rates of virus evolution, and potential escape mutants of A/H2N2.

Non-identifiability of parameters for a class of shear-thinning rheological models, with implications for haematological fluid dynamics.

Choosing a suitable model and determining its associated parameters from fitting to experimental data is fundamental for many problems in biomechanics. Models of shear-thinning complex fluids, dating from the work of Bird, Carreau, Cross and Yasuda, have been applied in highly-cited computational studies of hemodynamics for several decades. In this manuscript we revisit these models, first to highlight a degree of uncertainty in the naming conventions in the literature, but more importantly to address the problem of inferring model parameters by fitting to rheology experiments. By refitting published data, and also by simulation, we find large, flat regions in likelihood surfaces that yield families of parameter sets which fit the data equally well. Despite having almost indistinguishable fits to experimental data these varying parameter sets can predict very different flow profiles, and as such these parameters cannot be used to draw conclusions about physical properties of the fluids, such as zero-shear viscosity or relaxation time of the fluid, or indeed flow behaviours. We verify that these features are not a consequence of the experimental data sets through simulations; by sampling points from the rheological models and adding a small amount of noise we create a synthetic data set which reveals that the problem of parameter identifiability is intrinsic to these models.

Oriented suspension mechanics with application to improving flow linear dichroism spectroscopy.

Flow linear dichroism is a biophysical spectroscopic technique that exploits the shear-induced alignment of elongated particles in suspension. Motivated by the broad aim of optimizing the sensitivity of this technique, and more specifically by a hand-held synthetic biotechnology prototype for waterborne-pathogen detection, a model of steady and oscillating pressure-driven channel flow and orientation dynamics of a suspension of slender microscopic fibres is developed. The model couples the Fokker-Planck equation for Brownian suspensions with the narrow channel flow equations, the latter modified to incorporate mechanical anisotropy induced by the particles. The linear dichroism signal is estimated through integrating the perpendicular components of the distribution function via an appropriate formula which takes the biaxial nature of the orientation into account. For the specific application of pathogen detection via binding of M13 bacteriophage, it is found that increases in the channel depth are more significant in improving the linear dichroism signal than increases in the channel width. Increasing the channel depth to 2 mm and pressure gradient to 5 × 104 Pa m-1 essentially maximizes the alignment. Oscillating flow can produce nearly equal alignment to steady flow at appropriate frequencies, which has significant potential practical value in the analysis of small sample volumes.

Craniomaxillofacial trauma management in austere and war zone environments - A role for composite tissue allotransplantation?

Facial composite tissue allotransplantation (CTA) is a powerful reconstructive option in cases of extensive severe facial injury and tissue loss. Despite the risk of allograft rejection and the post-operative need for lifelong immunosuppression, facial CTA can be used to restore the normal structural appearance and function of the face. Areas of socioeconomic deprivation and armed conflict zones have a high preponderance of patients with facial burns and other severe injuries. However, these regions often also suffer from lack of resources, expert surgical care and limited facilities. The purpose of this manuscript is to provide a comprehensive review of key principles relevant to facial CTA and their potential applicability in such austere environments. We present a concise literature review of the surgical and immunological basis of facial CTA aimed at the plastic surgery readership, as well as issues surrounding organ transplantations in low- and middle- income countries. We then consider the particular challenges posed by austere settings and countries of active armed conflict and discuss how these may impact the suitability of facial CTA for treating severe facial injuries in these circumstances. Facial CTA is recognised as giving huge benefits for patients with severe facial defects with potentially superior results compared with conventional autograft techniques. Its performance in austere settings is limited by scarce resources and increased pre-, intra- and post- operative risks. However, a case can be made for its use even in these more challenging situations when general organ transplantation compliance and expertise input have been addressed.

L'allotransplantation faciale de tissu composite (ATTC) est une stratégie efficace de reconstruction des pertes de substance faciales étendue. Malgré la nécessité d'un traitement immunosuppresseur ad vitam aeternam, elle peut être utilisée pour restaurer une face fonctionnelle d'apparence normale. Les atteintes faciales graves par brûlure et/ou traumatisme sont fréquentes dans les zones défavorisées et de conflit armés. En outre, les moyens humains, structurels et financiers y sont limités. Cet article a pour but de présenter une revue des bases chirurgicales et immunologique de l'ATTC et de son application par les plasticiens dans des zones faiblement développées ou en conflit. L'efficacité de l'ACT en reconstruction faciale semble supérieure aux techniques de greffes classiques. Toutefois, les risques pré-, per- et post- opératoires sont augmentés en zone hostile. Elle semble toutefois utilisable si les nécessités inhérentes au suivi d'une allogreffe sont couvertes.

Wall stress enhanced exocytosis of extracellular vesicles as a possible mechanism of left-right symmetry-breaking in vertebrate development.

In certain vertebrate species, the developing embryo breaks left-right symmetry in a transient organising structure: the "Left-Right Organiser" (LRO) known as the "node" in mice, and "Kupffer's vesicle" in fish. Directional cilia-driven flow is integral to this symmetry-breaking process, however the mechanism by which this flow is translated into an asymmetric signal remains contested; the principal theories are either flow transport of vesicles containing morphogens, or flow mechanosensing by cilia. Whilst some recent work favours the morphogen theory, other findings seem to support mechanosensing. In this study, we consider a hypothesis whereby the cilia themselves drive the release of morphogen-carrying extracellular vesicles (EVs) into the LRO; namely, that fluid stresses on the cell membrane induce/enhance exocytosis of EVs. Using a mathematical model, we calculate significant wall normal and shear stresses for a range of typical cilium parameter values comparable to levels capable of enhancing exocytosis. This mechanism may be able to reconcile the apparently conflicting experimental evidence.