Investigating the role of ephrin signalling in spinal cord injury.

Spinal cord injury in adult mammals commonly leads to the permanent loss of motor and sensory function in regions of the body below the level of injury. The inability of the central nervous system to regenerate is, in part, due to the presence of growth-inhibitory agents surrounding the lesion site. This thesis presents a previously unreported, inhibitory interaction between ephrinB2 expressed on reactive astrocytes and the EphA4 receptor present on lesioned corticospinal tract axons. This interaction appears to mediate the unusually large retraction of the corticospinal tract away from spinal cord injury sites. An attempt to interfere with this interaction by implanting a cell line secreting the ephrinA5 receptor binding domain is reported. While this approach induced improvements in regenerative sprouting from the corticospinal tract, complications with immune rejection and cell proliferation stopped further investigation. A second intervention using a small peptide with high affinity and specificity for the EphA4 receptor is also reported. Intrathecal infusion of this peptide for 14 or 28 days after injury reversed the retraction of the corticospinal tract and induced improvements in regenerative sprouting from corticospinal and rubrospinal tracts following dorsal or lateral white matter transection injuries. Sprouts were seen to migrate long distances, often to the astrocyte margin of the lesion cavity. Astrocyte behaviour following injury was also altered with the formation of astrocytic 'bridges' into the lesion cavity along which regenerating axons grew. Functional recovery was also enhanced with improvements in the paw reaching assay within 10 days of a unilateral dorsal column lesion with a 30% recovery of function at 28 days post-operation. The simplicity of this intervention and direct translation to human application make it a promising candidate for use in combinatorial approaches to human spinal cord injury treatment

Prospective Cohort Study Assessing the Use of Peripheral Saphenous Venous Pressure Monitoring as a Marker of the Transcaval Venous Pressure Gradient in Liver Transplant Surgery

Objectives: Assessment of the transcaval venous pressure gradient, the central venous to inferior vena caval pressure, assists anesthetists and surgeons in management of liver transplant recipients. Traditionally, this entails insertion of a femoral central line with increased patient risk and health care cost. Here, we assessed the ability of a saphenous vein cannula to act as a surrogate for the femoral central line as a means to assess the transcaval pressure gradient in a safer and less invasive manner. / Materials and Methods: A prospective cohort of 22 patients undergoing liver transplant underwent saphenous vein cannulation in addition to insertion of a femoral and internal jugular central venous catheter. Data were collected throughout each phase of surgery to assess the central, femoral, and saphenous vein pressures; results of a range of relevant physiological and ventilatory data were also collected. / Results: The primary outcome, the correlation between saphenous and femoral venous pressure throughout surgery, was acceptable (r2 = 0.491, P < .001). During the anhepatic phase of surgery, this correlation improved (r2 = 0.912, P < .001). The correlation between the femoral to central venous pressure and saphenous to central venous pressure gradients was also reasonable throughout surgery (r2 = 0.386, P < .001), and this correlation was significantly stronger during the anhepatic phase (r2 = 0.935, P < .001). / Conclusions: Saphenous venous pressure, provided by peripheral cannulation, provided a reliable, less invasive, and safer alternative to femoral central line insertion for determination of the transcaval pressure gradient during the anhepatic phase of liver transplant

Vanishing Viscosity Limits and Boundary Layers for Circularly Symmetric 2D Flows

We continue the work of Lopes Filho, Mazzucato and Nussenzveig Lopes [LMN], on the vanishing viscosity limit of circularly symmetric viscous flow in a disk with rotating boundary, shown there to converge to the inviscid limit in $L^2$-norm as long as the prescribed angular velocity $\alpha(t)$ of the boundary has bounded total variation. Here we establish convergence in stronger $L^2$ and $L^p$-Sobolev spaces, allow for more singular angular velocities $\alpha$, and address the issue of analyzing the behavior of the boundary layer. This includes an analysis of concentration of vorticity in the vanishing viscosity limit. We also consider such flows on an annulus, whose two boundary components rotate independently. [LMN] Lopes Filho, M. C., Mazzucato, A. L. and Nussenzveig Lopes, H. J., Vanishing viscosity limit for incompressible flow inside a rotating circle, preprint 2006

Sharp two-sided heat kernel estimates for critical Schr\"odinger operators on bounded domains

On a smooth bounded domain \Omega \subset R^N we consider the Schr\"odinger operators -\Delta -V, with V being either the critical borderline potential V(x)=(N-2)^2/4 |x|^{-2} or V(x)=(1/4) dist (x,\partial\Omega)^{-2}, under Dirichlet boundary conditions. In this work we obtain sharp two-sided estimates on the corresponding heat kernels. To this end we transform the Scr\"odinger operators into suitable degenerate operators, for which we prove a new parabolic Harnack inequality up to the boundary. To derive the Harnack inequality we have established a serier of new inequalities such as improved Hardy, logarithmic Hardy Sobolev, Hardy-Moser and weighted Poincar\'e. As a byproduct of our technique we are able to answer positively to a conjecture of E.B.Davies.Comment: 40 page

Does the implementation of a novel intensive care discharge risk score and nurse-led inpatient review tool improve outcome? A prospective cohort study in two intensive care units in the UK.

OBJECTIVE: To develop a clinical prediction model for poor outcome after intensive care unit (ICU) discharge in a large observational data set and couple this to an acute post-ICU ward-based review tool (PIRT) to identify high-risk patients at the time of ICU discharge and improve their acute ward-based review and outcome. DESIGN: Retrospective patient cohort of index ICU admissions between June 2006 and October 2011 receiving routine inpatient review. Prospective cohort between March 2012 and March 2013 underwent risk scoring (PIRT) which subsequently guided inpatient ward-based review. SETTING: Two UK adult ICUs. PARTICIPANTS: 4212 eligible discharges from ICU in the retrospective development cohort and 1028 patients included in the prospective intervention cohort. INTERVENTIONS: Multivariate analysis was performed to determine factors associated with poor outcome in the retrospective cohort and used to generate a discharge risk score. A discharge and daily ward-based review tool incorporating an adjusted risk score was introduced. The prospective cohort underwent risk scoring at ICU discharge and inpatient review using the PIRT. OUTCOMES: The primary outcome was the composite of death or readmission to ICU within 14 days of ICU discharge following the index ICU admission. RESULTS: PIRT review was achieved for 67.3% of all eligible discharges and improved the targeting of acute post-ICU review to high-risk patients. The presence of ward-based PIRT review in the prospective cohort did not correlate with a reduction in poor outcome overall (P=0.876) or overall readmission but did reduce early readmission (within the first 48 hours) from 4.5% to 3.6% (P=0.039), while increasing the rate of late readmission (48 hours to 14 days) from 2.7% to 5.8% (P=0.046). CONCLUSION: PIRT facilitates the appropriate targeting of nurse-led inpatient review acutely after ICU discharge but does not reduce hospital mortality or overall readmission rates to ICU

Not All Piggybacks Are Equal: A Retrospective Cohort Analysis of Variation in Anhepatic Transcaval Pressure Gradient and Acute Kidney Injury During Liver Transplant

Objectives: Complete inferior vena cava clamping in caval replacement during liver transplant is associated with substantial physiological derangement and postoperative morbidity. Partial clamping in the piggyback technique may be relatively protective, but evidence is lacking. Having observed substantial variation in transhepatic inferior vena cava pressure gradient with piggyback, we hypothesized that the causative mechanism is the extent of caval clamping rather than the surgical approach. Materials and Methods: We used internal jugular and femoral catheters to estimate suprahepatic and infrahepatic inferior vena cava pressures during clamping. Pressure gradients were calculated, and distributions were compared by surgical technique. We estimated adjusted odds ratios for pressure gradient on acute kidney injury at 72 hours. Results: In 115 case records, we observed substantial variation in maximum pressure gradient; median values were 18.0 mm Hg (interquartile range, 8.0-25.0 mm Hg) with the piggyback technique and 24.0 mm Hg (interquartile range, 19.5-27.0 mm Hg) with caval replacement. Incidence of acute kidney injury was 25% (29 patients). Pressure gradient was linearly associated with probability of acute kidney injury (odds ratio, 1.06; 95% CI, 1.01-1.13). Conclusions: We report 2 novel findings. (1) Anhepatic inferior vena cava pressure gradient varied substantially in individuals undergoing piggyback, and (2) gradient was positively associated with early acute kidney injury. We hypothesize that this (unmeasured) variation explains the conflicting findings of previous studies that compared surgical techniques. Also, we propose that caval pressure gradient could be routinely assessed to optimize real-time piggyback clamp position during liver transplant surgery

Protocol for a prospective double-blind, randomised, placebo-controlled feasibility trial of octreotide infusion during liver transplantation

Introduction Liver transplantation is a complex operation that can provide significant improvements in quality of life and survival to the recipients. However, serious complications are common and include major haemorrhage, hypotension and renal failure. Blood transfusion and the development of acute kidney injury lead to both short-term and long-term poor patient outcomes, including an increased risk of death, graft failure, length of stay and reduced quality of life. Octreotide may reduce the incidence of renal dysfunction, perioperative haemorrhage and enhance intraoperative blood pressure. However, octreotide does have risks, including resistant bradycardia, hyperglycaemia and hypoglycaemia and QT prolongation. Hence, a randomised controlled trial of octreotide during liver transplantation is needed to determine the cost-efficacy and safety of its use; this study represents a feasibility study prior to this trial. Methods and analysis We describe a multicentre, double-blind, randomised, placebo-controlled feasibility study of continuous infusion of octreotide during liver transplantation surgery. We will recruit 30 adult patients at two liver transplant centres. A blinded infusion during surgery will be administered in a 2:1 ratio of octreotide:placebo. The primary outcomes will determine the feasibility of this study design. These include the recruitment ratio, correct administration of blinded study intervention, adverse event rates, patient and clinician enrolment refusal and completion of data collection. Secondary outcome measures of efficacy and safety will help shape future trials by assessing potential primary outcome measures and monitoring safety end points. No formal statistical tests are planned. This manuscript represents study protocol number 1.3, dated 2 June 2021. Ethics and dissemination This study has received Research Ethics Committee approval. The main study outcomes will be submitted to an open-access journal. Trial sponsor The Joint Research Office, University College London, UK. Neither the sponsor nor the funder have any role in study design, collection, management, analysis and interpretation of data, writing of the study report or the decision to submit the report for publication. Trial registration The study is registered with ClinicalTrials.gov (NCT04941911) with recruitment due to start in August 2021 with anticipated completion in July 2022. Clinical trials unit Surgical and Interventional Group, Division of Surgery & Interventional Science, University College London

Predicting and Controlling Resolution and Surface Finish of Ceramic Objects Produced by Stereodeposition Processes

Stereodeposition techniques are well suited for the Solid Freeform Fabrication of dense ceramic components. As opposed to forming a pattern in a particle bed or polymer bath, stereodeposition processes deposit material directly onto the previously created layer. The key to stereodeposition is a material's ability to be dispensed as a fluid, yet rapidly stiffen to hold the shape of the object. This is accomplished by either solidification of a thermoplastic binder upon cooling from a melt (Fused Deposition) or by polymerization of a binder (Reactive Stereodeposition). We are developing both techniques for the production of functional ceramic and engineering polymer objects. A key issue in developing a successful stereodeposition system is controlling the rate of bead transformation from liquid to solid. Control is critical to achieving high resolution and low surface roughness of the finished product, but is made complex by the large number of parameters involved. These include binder parameters (surface tension, gelling characteristics), slurry parameters (viscosity, particle loading and size distribution), and process parameters (deposition rate, temperature). Current efforts at the University of Arizona are focused on modeling and controlling the deposition and transformation of ceramic slurries used in the Reactive Stereodeposition process.Mechanical Engineerin

The mixed problem for the Laplacian in Lipschitz domains

We consider the mixed boundary value problem or Zaremba's problem for the Laplacian in a bounded Lipschitz domain in R^n. We specify Dirichlet data on part of the boundary and Neumann data on the remainder of the boundary. We assume that the boundary between the sets where we specify Dirichlet and Neumann data is a Lipschitz surface. We require that the Neumann data is in L^p and the Dirichlet data is in the Sobolev space of functions having one derivative in L^p for some p near 1. Under these conditions, there is a unique solution to the mixed problem with the non-tangential maximal function of the gradient of the solution in L^p of the boundary. We also obtain results with data from Hardy spaces when p=1.Comment: Version 5 includes a correction to one step of the main proof. Since the paper appeared long ago, this submission includes the complete paper, followed by a short section that gives the correction to one step in the proo

Sharp constants in weighted trace inequalities on Riemannian manifolds

We establish some sharp weighted trace inequalities W^{1,2}(\rho^{1-2\sigma}, M)\hookrightarrow L^{\frac{2n}{n-2\sigma}}(\pa M) on $n+1$ dimensional compact smooth manifolds with smooth boundaries, where $\rho$ is a defining function of $M$ and $\sigma\in (0,1)$. This is stimulated by some recent work on fractional (conformal) Laplacians and related problems in conformal geometry, and also motivated by a conjecture of Aubin.Comment: 34 page