The Effects of an Extracorporeal Circulation on Cerebral Perfusion during Paediatric Critical Care and Cardiothoracic Procedures

The developing brain is highly vulnerable to physiological and pharmacological insults, which can impact cerebral blood flow (CBF), resulting in neurological deficit. Within the clinical environment, a group of patients at particular risk of neurological insult are those who require an extracorporeal circulation. This has a profound effect on CBF due to the use of non-pulsatile blood flow, pharmacological agents and periods of hypo/hyperperfusion. As a result, effective cerebral monitoring is essential to prevent periods of ischaemia and subsequently, enhance quality of life in survivors. Patients requiring an extracorporeal circulation include those treated for acute respiratory and/or cardiac failure using extracorporeal membrane oxygenation (ECMO), and the use of cardiopulmonary bypass (CPB) during cardiac surgery for congenital heart defects. The overarching aim of this thesis was to examine how an extracorporeal circulation impacts cerebral perfusion throughout the entire treatment process and following recovery in paediatric intensive care. Measurements of cerebral perfusion used throughout the thesis are described in the experimental methods chapter. These include transcranial doppler ultrasound (TCD) and near infrared spectroscopy (NIRS). Another aim of the experimental chapter was to collect TCD data and compare the values to previously published research. Measurements were taken in a ‘healthy’ neonatal population and then compared to previously published age-matched comparisons. Measurements were also taken in clinically ill patients and then compared to values from previously published ventilated population. Values were comparable to previously published data which suggested the TCD operator was proficient in isonating the middle cerebral artery (MCA). An observational study was conducted using TCD to measure CBFv at multiple time points during ECMO with a focus on the weaning period in a paediatric population. Fourteen patients that underwent veno-arterial (V-A) ECMO were enrolled. Eight (mean age 69 days) had central cannulation for post-cardiac surgery support, while six (mean age 84 days) had neck cannulation for respiratory support. CBFv was measured from the MCA during weaning at several time points: full flow ECMO, ¾ flow, ½ flow, ¼ flow, minimum flow, when off ECMO and post decannulation. NIRS, blood pressure, heart rate and arterial oxygen saturation were recorded at the same time points. During the first 5 days of full flow ECMO, CBFv remained relatively stable (p=0.54). During weaning, those that successfully decannulated had on average a higher CBFv of 9.1 cm/s compared to those that failed weaning. From the patients decannulated, those receiving conventional treatment had an average higher CBFv of 9.9 cm/s compared to patients on high frequency oscillatory ventilation. Overall, the relationship between NIRS and TCD was positive but weak. Another study was undertaken to examine CBFv and an extracorporeal circulation during aortic arch repair. Neonates requiring aortic arch repair are unable to maintain adequate oxygenation levels and require surgical intervention. A high percentage of survivor’s exhibit signs of neurological deficit possibly due to inadequate CBF during surgery. The aim was to continuously monitor MCA velocity (MCAv) during surgery. A secondary aim was to examine the impact of temperature on CBF, with cooling ranging from 18 to 25°C based on surgeon preference. MCAv was monitored in 24 neonates (age 19±6 days, body mass 3.6±0.6 kg) undergoing surgery on the aortic arch, alongside NIRS, blood pH, pO2, pCO2, HCO3, lactate, Hb, Htc (%) and temperature (core and rectal). Using general linear models, MCAv was compared at several time points. These included: initial sedation; cardiopulmonary bypass (CBP); cooling at 30°c, 25°c, the lowest temperature; during selective cerebral perfusion; whole body perfusion; rewarming at 25°c, 30°c, 36°c; off cardiopulmonary bypass; and after surgery. During and following surgery, MCAv was lower compared to previously published healthy age-matched controls, except during cooling period. CBFv increased during cooling at 30°c, 25°c and the lowest temperature respectively when compared to CBP (p=0.03). Once off CBP, MCAv returned to pre-surgery values. No significant difference was noted between patients cooled to 20 or 25°c. Overall, this thesis provides evidence of disruptions in cerebral perfusion during different stages of treatments involving an extracorporeal circulation. The current clinical tool for monitoring cerebral perfusion is NIRS, which may not provide sufficiently sensitive data on cerebral perfusion during treatments using an extracorporeal circulation. Taken together, the findings provide important data for clinicians treating paediatric patients requiring an extracorporeal circulation. It provides data identifying specific time periods of reduced cerebral perfusion, while highlighting limitations of current methods of monitoring

Efficacy and tolerability of an endogenous metabolic modulator (AXA1125) in fatigue-predominant long COVID: a single-centre, double-blind, randomised controlled phase 2a pilot study

Background: ‘Long COVID’ describes persistent symptoms, commonly fatigue, lasting beyond 12 weeks following SARS-CoV-2 infection. Potential causes include reduced mitochondrial function and cellular bioenergetics. AXA1125 has previously increased β-oxidation and improved bioenergetics in preclinical models along with certain clinical conditions, and therefore may reduce fatigue associated with Long COVID. We aimed to assess the efficacy, safety and tolerability of AXA1125 in Long COVID. / Methods: Patients with fatigue dominant Long COVID were recruited in this single-centre, double-blind, randomised controlled phase 2a pilot study completed in the UK. Patients were randomly assigned (1:1) using an Interactive Response Technology to receive either AXA1125 or matching placebo in a clinical based setting. Each dose (33.9 g) of AXA1125 or placebo was administered orally in a liquid suspension twice daily for four weeks with a two week follow-up period. The primary endpoint was the mean change from baseline to day 28 in the phosphocreatine (PCr) recovery rate following moderate exercise, assessed by 31P-magnetic resonance spectroscopy (MRS). All patients were included in the intention to treat analysis. This trial was registered at ClinicalTrials.gov, NCT05152849. / Findings: Between December 15th 2021, and May 23th 2022, 60 participants were screened and 41 participants were randomised and included in the final analysis. Changes in skeletal muscle phosphocreatine recovery time constant (τPCr) and 6-min walk test (6MWT) did not significantly differ between treatment (n = 21) and placebo group (n = 20). However, treatment with AXA1125 was associated with significantly reduced day 28 Chalder Fatigue Questionnaire [CFQ-11] fatigue score when compared with placebo (least squares mean difference [LSMD] −4.30, 95% confidence interval (95% CI) −7.14, −1.47; P = 0.0039). Eleven (52.4%, AXA1125) and four (20.0%, placebo) patients reported treatment-emergent adverse events; none were serious, or led to treatment discontinuation. / Interpretation: Although treatment with AXA1125 did not improve the primary endpoint (τPCr-measure of mitochondrial respiration), when compared to placebo, there was a significant improvement in fatigue-based symptoms among patients living with Long COVID following a four week treatment period. Further multicentre studies are needed to validate our findings in a larger cohort of patients with fatigue-dominant Long COVID. / Funding: Axcella Therapeutics

Radiopharmaceuticals for Relapsed or Refractory Ovarian Cancers

Targeted radiopharmaceuticals for therapeutic use deliver radionuclides directly to tumor anywhere in the body, and therefore, have renewed interest for clinical development in women with disseminated chemorefractory ovarian cancers. About two in every five women with advanced stage ovarian cancer outlive their disease after the first treatment phase, with the rest rendered incurable due to the chemorefractory nature of their disease. The National Cancer Institute (NCI) Cancer Therapy Evaluation Program conducted 67 phase I or phase Ib trials among women with relapsed or refractory ovarian cancer between 1989 and 2017 in an effort to uncover tolerable and effective drug combinations intended to increase survival rates. None of these early clinical development phase trials involved radiopharmaceuticals. Here, the NCI provides its perspective on targeted radiopharmaceutical conjugates alone or in combination with its experimental therapeutics portfolio for women with relapsed or refractory ovarian cancer. An infrastructure build for Federal radiopharmaceutical medical monitoring and adverse event reporting has begun

Energy- and flux-budget turbulence closure model for stably stratified flows. Part II: the role of internal gravity waves

We advance our prior energy- and flux-budget turbulence closure model (Zilitinkevich et al., 2007, 2008) for the stably stratified atmospheric flows and extend it accounting for additional vertical flux of momentum and additional productions of turbulent kinetic energy, turbulent potential energy (TPE) and turbulent flux of potential temperature due to large-scale internal gravity waves (IGW). Main effects of IGW are following: the maximal value of the flux Richardson number (universal constant 0.2-0.25 in the no-IGW regime) becomes strongly variable. In the vertically homogeneous stratification, it increases with increasing wave energy and can even exceed 1. In the heterogeneous stratification, when IGW propagate towards stronger stratification, the maximal flux Richardson number decreases with increasing wave energy, reaches zero and then becomes negative. In other words, the vertical flux of potential temperature becomes counter-gradient. IGW also reduce anisotropy of turbulence and increase the share of TPE in the turbulent total energy. Depending on the direction (downward or upward), IGW either strengthen or weaken the total vertical flux of momentum. Predictions from the proposed model are consistent with available data from atmospheric and laboratory experiments, direct numerical simulations and large-eddy simulations.Comment: 37 pages, 5 figures, revised versio

Evidence of the high prevalence of neurological disorders in nonsyndromic X-linked recessive ichthyosis: a retrospective case series

[Background]: X-linked recessive ichthyosis (XLI) is a relatively common type of ichthyosis caused by a deficiency in the steroid sulfatase (STS) enzyme. It is the only type of ichthyosis that can be both syndromic and nonsyndromic. Typical clinical features include dark-brown scale of variable size favouring the extensor surfaces of the extremities.[Objectives]: To characterize clinically nonsyndromic XLI, with a particular focus on extracutaneous manifestations.[Methods]: This was a multicentre retrospective review of clinical findings from a case series of patients with a clinical and genetic diagnosis of XLI.[Results]: We identified 30 patients with XLI belonging to 25 different families carrying a deletion in the STS locus. All patients had dark scales of variable size on the extensor surfaces of the extremities. Lack of flexural involvement and pruritus were common but inconsistent findings, whereas palmoplantar hyperlinearity was absent in all but one patient. A history of orchiopexy was present in 10% and thus was more common than expected vs. the general population (3%). Neurological disorders including epilepsy (13%) and attention deficit hyperactivity disorder (ADHD; 30%) were over-represented in patients with XLI.[Conclusions]: This was a retrospective study with a limited number of patients. In the absence of confirmatory genetic testing and family history of the disease, dark-brown scale of the extensor surfaces and the absence of palmoplantar hyperlinearity appear to be the most reliable clinical findings supporting a diagnosis of XLI. Dermatologists should be aware of the high prevalence of ADHD and epilepsy in patients with nonsyndromic XLI

An engineered cytidine deaminase for biocatalytic production of a key intermediate of the COVID-19 antiviral Molnupiravir

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Процесс анализа угроз, влияющих на экономическую устойчивость предприятия

На основании проведенного исследования были выявлены факторы возникновения угроз, их группировка по степени воздействию на экономическую устойчивость предприятий и рассмотрена формализация процесса анализа угроз экономической устойчивости предприятий. В условиях рыночной экономики невозможно управлять предприятием без учета влияния угроз, а для эффективного управления важно не только знать об их присутствии, а и правильно идентифицировать конкретную угрозу.На підставі проведеного дослідження були виявлені чинники виникнення загроз, їх угруповання по степені впливу на економічну стійкість підприємств і розглянута формалізація процесу аналізу загроз економічної стійкості підприємств. В умовах ринкової економіки неможливо керувати підприємством без вивчення впливу загроз, а для ефективного керування важливо не тільки знати про їх присутність, а і правильно ідентифікувати конкретну загрозу.On the basis of the conducted research the factors of origin of threats were exposed, their gourmet on a degree to influence on economic stability of enterprises and formalization of process of analysis of threats of economic stability of enterprises is considered. In the conditions of market economy it is impossible to manage an enterprise without taking into account influencing of threats, and for the effective management it is important not only to know about their presence, and to identify the concrete threat correctly

Electrospun Polyurethane Fibers for Absorption of Volatile Organic Compounds from Air

Electrospun polyurethane fibers for removal of volatile organic compounds (VOC) from air with rapid VOC absorption and desorption have been developed. Polyurethanes based on 4,4-methylenebis(phenylisocyanate) (MDI) and aliphatic isophorone diisocyanate as the hard segments and butanediol and tetramethylene glycol as the soft segments were electrospun from their solutions in N,N-dimethylformamide to form micrometer-sized fibers. Although activated carbon possessed a many-fold higher surface area than the polyurethane fiber meshes, the sorption capacity of the polyurethane fibers was found to be similar to that of activated carbon specifically designed for vapor adsorption. Furthermore, in contrast to VOC sorption on activated carbon, where complete regeneration of the adsorbent was not possible, the polyurethane fibers demonstrated a completely reversible absorption and desorption, with desorption obtained by a simple purging with nitrogen at room temperature. The fibers possessed a high affinity toward toluene and chloroform, but aliphatic hexane lacked the necessary strong attractive interactions with the polyurethane chains and therefore was less strongly absorbed. The selectivity of the polyurethane fibers toward different vapors, along with the ease of regeneration, makes them attractive materials for VOC filtration.Boeing CompanyNetherlands Organisation for Scientific Research (NWO) (Talent Scholarship