Development of a Mortality Prediction Model in Hospitalised SARS-CoV-2 Positive Patients Based on Routine Kidney Biomarkers

Acute kidney injury (AKI) is a prevalent complication in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) positive inpatients, which is linked to an increased mortality rate compared to patients without AKI. Here we analysed the difference in kidney blood biomarkers in SARS-CoV-2 positive patients with non-fatal or fatal outcome, in order to develop a mortality prediction model for hospitalised SARS-CoV-2 positive patients. A retrospective cohort study including data from suspected SARS-CoV-2 positive patients admitted to a large National Health Service (NHS) Foundation Trust hospital in the Yorkshire and Humber regions, United Kingdom, between 1 March 2020 and 30 August 2020. Hospitalised adult patients (aged ≥ 18 years) with at least one confirmed positive RT-PCR test for SARS-CoV-2 and blood tests of kidney biomarkers within 36 h of the RT-PCR test were included. The main outcome measure was 90-day in-hospital mortality in SARS-CoV-2 infected patients. The logistic regression and random forest (RF) models incorporated six predictors including three routine kidney function tests (sodium, urea; creatinine only in RF), along with age, sex, and ethnicity. The mortality prediction performance of the logistic regression model achieved an area under receiver operating characteristic (AUROC) curve of 0.772 in the test dataset (95% CI: 0.694–0.823), while the RF model attained the AUROC of 0.820 in the same test cohort (95% CI: 0.740–0.870). The resulting validated prediction model is the first to focus on kidney biomarkers specifically on in-hospital mortality over a 90-day period.     

Analysis of the stress and interfacial reactions in Pt/Ti/SiO2/Si for use with ferroelectric thin films

The microstructure of the Pt/Ti/SiO₂/Si structure has been investigated by scanning and transmission electron microscopy. Pt films of 100 nm thickness deposited by sputtering or evaporation onto unheated substrates gave complete coverage of the underlying Ti layer and showed a granular and faceted structure with grains ∼20 nm in diameter. They did not exhibit hillocks or surface TiO_x formation. X-ray diffraction was used to examine the film stress through use of the sin²ψ method with bulk values for the elastic constants (v=0.39, E=162 GPa). The as-deposited sputtered film had a compressive stress of ∼540 MPa, while the evaporated films had tensile stresses of ∼630 MPa. The films then received a 400°C rapid thermal anneal (RTA) for 90 s and a subsequent RTA of 650°C for 30s. Further investigation of the film stresses and microstructure were made after each annealing step. After the low temperature anneal, the film stress for the sputtered film became tensile. Plan-view sections examined by transmission electron microscopy (TEM) showed that the as-deposited sputtered films were dense but became porous after annealing. Initially, the evaporated films had a less dense microstructure, but were more stable with annealing. Little change in the stress for the evaporated film was observed after this initial low temperature annealing step. Additional annealing of the evaporated and sputtered samples caused complete consumption of the Ti layer including some TiO_x formation from the underlying SiO₂ layer and marked interaction with the Pt; however, little change in the stress was found. The surface of the Pt film revealed larger grains, but otherwise remained unaffected. The underlying phase changes were minimized once the Ti layer had reacted with the Pt. Due to the ratio of the layers, Pt:Ti of 2:1, the surface of the Pt was unaffected.     

The stability of supply chains

A continuous time version of the well-known beer game model is derived and its stability and robust stability properties are investigated. Novelty originates from the treatment of pure process delays rather than exponential lags and it is shown that this can lead to diametrically different dynamics to the exponential lag case. The stability properties of the system are shown to support and quantify the qualitative empirical results of the beer game. Additional insight into the influence of certain model parameters is attained by their interpretation as the degree of mismatch in a Smith predictor regulator. The transient inability to supply all that is demanded is mimicked and shown to constitute an influential source of demand amplification. The analytical nature of these calculations engenders the capacity to improve supply chain dynamics through the synthesis and calibration of strategic supply chain trade-off problems.     

Production-inventory system controller design and supply chain dynamics

The paper deals with the modelling and control of aggregated production-inventory systems as described by differential equations. Hitherto, research in the area has been characterized by the approximation of production delays by first-order lags rather than more realistic pure delays. We demonstrate the substantial qualitative differences between these two approaches and thus generate the motivation for the rest of the paper, which tackles pure delay systems. The application of some relatively new design methodologies for delay systems yields four design choices that are tested for their performance over a range of criteria including stability robustness. The investigation is then extended to the model of a supply chain comprising many such productioninventory systems. The mechanism by which disturbances can be transmitted along the supply chain causing disruption and incurring costs to other supply chain echelons is elucidated. A heuristic feedback policy designed adaptively to tune the individual system designs in response to such disturbances is presented.     

Ligand Binding to Dynamically Populated G-Quadruplex DNA

Several small-molecule ligands specifically bind and stabilize G-quadruplex (G4) nucleic acid structures, which are considered to be promising therapeutic targets. G4s are polymorphic structures of varying stability, and their formation is dynamic. Here, we investigate the mechanisms of ligand binding to dynamically populated human telomere G4 DNA by using the bisquinolinium based ligand Phen-DC3 and a combination of single-molecule FRET microscopy, ensemble FRET and CD spectroscopies. Different cations are used to tune G4 polymorphism and folding dynamics. We find that ligand binding occurs to pre-folded G4 structures and that Phen-DC3 also induces G4 formation in unfolded single strands. Following ligand binding to dynamically populated G4s, the DNA undergoes pronounced conformational redistributions that do not involve direct ligand-induced G4 conformational interconversion. On the contrary, the redistribution is driven by ligand-induced G4 folding and trapping of dynamically populated short-lived conformation states. Thus, ligand-induced stabilization does not necessarily require the initial presence of stably folded G4s.     

Fluorescent Amino Acid Initiated de novo Cyclic Peptides for the Label-Free Assessment of Cell Permeability**

The major obstacle in applying peptides to intracellular targets is their low inherent cell permeability. Standard approaches to attach a fluorophore (e. g. FITC, TAMRA) can change the physicochemical properties of the parent peptide and influence their ability to penetrate and localize in cells. We report a label-free strategy for evaluating the cell permeability of cyclic peptide leads. Fluorescent tryptophan analogues 4-cyanotryptophan (4CNW) and β-(1-azulenyl)-L-alanine (AzAla) were incorporated into in vitro translated macrocyclic peptides by initiator reprogramming. We then demonstrate these efficient blue fluorescent emitters are good tools for monitoring peptide penetration into cells.