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Background Updatable estimates of COVID-19 onset, progression, and trajectories underpin pandemic mitigation efforts. To identify and characterise disease trajectories, we aimed to define and validate ten COVID-19 phenotypes from nationwide linked electronic health records (EHR) using an extensible framework. Methods In this cohort study, we used eight linked National Health Service (NHS) datasets for people in England alive on Jan 23, 2020. Data on COVID-19 testing, vaccination, primary and secondary care records, and death registrations were collected until Nov 30, 2021. We defined ten COVID-19 phenotypes reflecting clinically relevant stages of disease severity and encompassing five categories: positive SARS-CoV-2 test, primary care diagnosis, hospital admission, ventilation modality (four phenotypes), and death (three phenotypes). We constructed patient trajectories illustrating transition frequency and duration between phenotypes. Analyses were stratified by pandemic waves and vaccination status. Findings Among 57 032 174 individuals included in the cohort, 13 990 423 COVID-19 events were identified in 7 244 925 individuals, equating to an infection rate of 12·7% during the study period. Of 7 244 925 individuals, 460 737 (6·4%) were admitted to hospital and 158 020 (2·2%) died. Of 460 737 individuals who were admitted to hospital, 48 847 (10·6%) were admitted to the intensive care unit (ICU), 69 090 (15·0%) received non-invasive ventilation, and 25 928 (5·6%) received invasive ventilation. Among 384 135 patients who were admitted to hospital but did not require ventilation, mortality was higher in wave 1 (23 485 [30·4%] of 77 202 patients) than wave 2 (44 220 [23·1%] of 191 528 patients), but remained unchanged for patients admitted to the ICU. Mortality was highest among patients who received ventilatory support outside of the ICU in wave 1 (2569 [50·7%] of 5063 patients). 15 486 (9·8%) of 158 020 COVID-19-related deaths occurred within 28 days of the first COVID-19 event without a COVID-19 diagnoses on the death certificate. 10 884 (6·9%) of 158 020 deaths were identified exclusively from mortality data with no previous COVID-19 phenotype recorded. We observed longer patient trajectories in wave 2 than wave 1. Interpretation Our analyses illustrate the wide spectrum of disease trajectories as shown by differences in incidence, survival, and clinical pathways. We have provided a modular analytical framework that can be used to monitor the impact of the pandemic and generate evidence of clinical and policy relevance using multiple EHR sources. Funding British Heart Foundation Data Science Centre, led by Health Data Research UK.

We report a simple, scalable two-step method for direct-write laser fabrication of 3D, porous graphene-like carbon electrodes from polyimide films with integrated contact plugs to underlying metal layers (Au or Ni). Irradiation at high average CO2 laser power (30 W) and low scan speed (∼18 mm s)−1 leads to formation of ‘keyhole’ contact plugs through local ablation of polyimide (initial thickness 17 μm) and graphitization of the plug perimeter wall. Top-surface laser-induced graphene (LIG) electrodes are then formed and connected to the plug by raster patterning at lower laser power (3.7 W) and higher scan speed (200 mm s)−1. Sheet resistance data (71 ± 15 Ω sq.)−1 indicates formation of high-quality surface LIG, consistent with Raman data which yield sharp first- and second-order peaks. We have also demonstrated that high-quality LIG requires a minimum initial polyimide thickness. Capacitance data measured between surface LIG electrodes and the buried metal film indicate a polyimide layer of thickness ∼7 μm remaining following laser processing. By contrast, laser graphitization of polyimide of initial thickness ∼8 μm yielded devices with large sheet resistance (>1 kΩ sq.)−1. Raman data also indicated significant disorder. Plug contact resistance values were calculated from analysis of transfer line measurement data for single- and multi-plug test structures. Contacts to buried nickel layers yielded lower plug resistances (1-plug: 158 ± 7 Ω , 4-plug: 31 ± 14 Ω) compared to contacts to buried gold (1-plug: 346 ± 37 Ω , 4-plug: 52 ± 3 Ω). Further reductions are expected for multi-plug structures with increased areal density. Proof-of-concept mm-scale LIG electrochemical devices with local contact plugs yielded rapid electron transfer kinetics (rate constant k 0 ∼ 0.017 cm s−1), comparable to values measured for exposed Au films (k 0 ∼0.023 cm s)−1. Our results highlight the potential for integration of LIG-based sensor electrodes with semiconductor or roll-to-roll manufacturing.

Large-area synthesis is of great demand for the preparation of high-performance transition-metal-dichalcogenides (TMD) devices, however there are only limited reports to date of device operation on large-area TMDs. In this work we fabricate MoS2 devices based on Thermal Assisted Conversion (TAC) of metal layers, and characterize the thin-films with material analysis combined with electrical device parameter extraction. Specifically we report on temperature dependent parameter extraction for Ti/Au contacts to MoS2 thin-films to determine sheet resistance (Rsh), resistivity (ρ), and the activation energy (EA) of on-state current flow. For undoped MoS2, ρ was determined to be 191 Ω.cm at 25°C. The activation energy of the on-state current was found to be 0.18 eV, pointing to the presence of deep levels in MoS2.

We have demonstrated a proof of concept with affinity-based purification of sperm cells from mock forensic samples using SOMAmer™ reagents, DNA-based affinity reagents developed by SomaLogic, Inc. SOMAmer reagents were selected in vitro using whole-cell SELEX to bind specifically with intact, detergent-treated sperm cells. Successful separation of sperm from epithelial cells and their debris was demonstrated using buccal swabs with added semen. Primarily male DNA profiles were generated from sperm cells eluted from the types of cotton swabs typically used for rape kit evidence collection. The quality of sperm DNA isolated from samples purified using SOMAmers is comparable to existing commercially available differential extraction-based methods at higher sperm concentrations. This purification method is simple, offers relatively rapid (

When describing biogeochemical transfers, textbook authors have often overstated the role of soil while neglecting the role of carbon dioxide. Unfortunately, these errors align with naive biogeochemical intuitions. This article aims to increase awareness of the prevalence of such misconceptions and offers countermeasures. Avoiding these misconceptions becomes increasingly important as concerns over carbon emissions grow. In addition, because an accurate understanding of biogeochemical cycles can transform deeply held beliefs, successfully teaching this topic can have the collateral benefit of inspiring lasting interest in science.

Control of the high-k/III-V interface by deposition of thin (~1-2 nm) interface control layers (ICLs) of Al2O3 or MgO, as part of an overall bi-layer structure with a high-k metal oxide MO2 (M = Hf|Zr), is explored. An Al2O3 or MgO ICL is deposited on unpassivated InxGa1-xAs (x = 0|0.53) substrates prior to MO2 gate oxide deposition, forming a Pd/high-k/ICL/III-V gate stack. The aim of a bi-layer structure is to enable continued device scaling using a high-k MO2 oxide while improving the high-k/III-V interface quality and interfacial band structure, with an Al2O3 or MgO ICL. Metal-oxide-semiconductor capacitor (MOSCAP) devices with an Al2O3 ICL on p-GaAs display significantly reduced leakage current density, and reduced frequency dispersion of accumulation capacitance when compared to a no-ICL device, indicating an improved high-k/III-V band structure and interface quality, respectively. Further studies on ZrO2/Al2O3/In0.53Ga0.47As devices find a reduced defect response with a post-metal forming gas anneal.

Titanates exhibit electronic properties highly desirable for field effect transistors such as very high permittivity and ferroelectricity. However, the difficulty of chemically etching titanates hinders their commercial use in device manufacturing. Here, the authors report the selective area in finestra growth of highly crystalline BaTiO3 (BTO) within photolithographically defined openings of a sacrificial SiO2 layer on a Ge (001) wafer by molecular beam epitaxy. After the BaTiO3 deposition, the sacrificial SiO2 can be etched away, revealing isolated nanoscale gate stacks circumventing the need to etch the titanate thin film. Reflection high-energy electron diffraction in conjunction with scanning electron microscopy is carried out to confirm the crystallinity of the samples. X-ray diffraction is performed to determine the out-of-plane lattice constant and crystal quality of the BTO film. Electrical measurements are performed on electrically isolated Pt/BaTiO3/SrTiO3/Ge capacitor devices.Titanates exhibit electronic properties highly desirable for field effect transistors such as very high permittivity and ferroelectricity. However, the difficulty of chemically etching titanates hinders their commercial use in device manufacturing. Here, the authors report the selective area in finestra growth of highly crystalline BaTiO3 (BTO) within photolithographically defined openings of a sacrificial SiO2 layer on a Ge (001) wafer by molecular beam epitaxy. After the BaTiO3 deposition, the sacrificial SiO2 can be etched away, revealing isolated nanoscale gate stacks circumventing the need to etch the titanate thin film. Reflection high-energy electron diffraction in conjunction with scanning electron microscopy is carried out to confirm the crystallinity of the samples. X-ray diffraction is performed to determine the out-of-plane lattice constant and crystal quality of the BTO film. Electrical measurements are performed on electrically isolated Pt/BaTiO3/SrTiO3/Ge capacitor devices.

The post-breakdown (BD) current-voltage (I-V) characteristics in MgO/Si and MgO/InP stacks with metal gate were investigated. We show that both stacks exhibit the soft and hard BD conduction modes and that the magnitude of the post-BD currents depends statistically on the substrate material, being larger in the case of the InP samples. This is contrary to what happens with the current in the fresh devices, which irrespective of the InP surface treatment, is larger for the Si samples. A comparative analysis of the post-BD conduction characteristics and direct evidences of the localized thermal effects on the metal gate electrode of both structures are presented.

The electrical and physical properties of La2O3 based NiSi/High-k/Si structures formed by electron beam evaporation, in-situ amorphous silicon capping and ex-situ NiSi formation are presented for the (100) and (110)Si substrate orientations. The silicon substrate orientation, (100) or (110), does not affect leakage current density or the maximum accumulation capacitance, but does have an impact on interface state densities. The interface states exhibit the electrical signature of Pbo centres for the (100)Si orientation and can be annealed in a H2/N2 ambient. The samples exhibit negligible hysteresis (

The authors report on the structural and electrical properties of TiN/Al2O3/TiN metal–insulator–metal (MIM) capacitor structures in submicron three-dimensional (3D) trench geometries with an aspect ratio of ∼30. A simplified process route was employed where the three layers for the MIM stack were deposited using atomic layer deposition (ALD) in a single run at a process temperature of 250 °C. The TiN top and bottom electrodes were deposited via plasma-enhanced ALD using a tetrakis(dimethylamino)titanium precursor. 3D trench devices yielded capacitance densities of 36 fF/μm2 and quality factors >65 at low frequency (200 Hz), with low leakage current densities (

The great auricular nerve (GAN) originates from the cervical plexus at the levels of C2 and C3, supplying sensation to the skin overlying the lower aspect of the pinna and angle of the mandible. The GAN can be injured during many procedures in the head and neck, resulting in a significant negative impact on the patient's quality of life. There are no reliable anatomic studies of GAN in the area where it is most likely to get injured.To determine the GAN relationship to the posterior border of the platysma and the external jugular vein (EJV).Patients undergoing neck dissections were included in the study. Measurements were taken between the posterior border of the platysma relative to the nearest edge of the EJV and the GAN. The distance between the GAN and the EJV was also noted.The posterior borders of the platysma and EJV are found, on average, 0.08 cm away from each other, and the free edge of the platysma was most often posterior to the EJV. The distance from the platysma to the GAN was, on average, 0.60 cm. The distance between the EJV and the GAN was 1.17 cm.We have added a safe, reliable, and surgically relevant technique to the head and neck surgeon's armamentarium for identifying the GAN and avoiding attendant injury with long-term debilitating neurologic sequelae.

Any base change at position 530 introduced into Escherichia coli on a multicopy plasmid leads to cell death [Powers & Noller (1990) Proc. Natl. Acad. Sci. U.S.A. 87, 1042-1046]. It was suggested that these mutants cannot carry out chain elongation. To define more precisely the function of base 530, we have studied ribosomes in which G530 was mutated to U530. In vivo, U530 16S rRNA was incorporated into 30S subunits and could combine with 50S to make 70S ribosomes. 16S rRNA in vitro transcripts containing U530 were assembled into 30S ribosomes, and their activity was tested in defined steps of protein synthesis. Mutant 30S ribosomes were as active as wild-type in poly(U)-dependent poly(Phe) synthesis, P- and A-site tRNA binding, and 30S initiation complex formation. 30S initiation complexes, in the presence of 50S, could react with puromycin like the wild-type. The rate, extent, and position of cross-linking of AcVal-tRNA in the P site to 16S RNA were identical in mutant and wild-type ribosomes. Although there appeared to be no defect in 70S initiation complex formation or in direct A-site binding of Phe-tRNA dependent on poly(U), U530 30S ribosomes were nevertheless defective in carrying out synthesis of fMet-Val dipeptide using natural mRNA. Mutant 30S ribosomes were also refractory to streptomycin-induced misreading although no misreading was observed in its absence.(ABSTRACT TRUNCATED AT 250 WORDS)

To investigate the function of base 792 of 16S rRNA in 30S ribosomes of Escherichia coli, the wild-type (adenine) residue was changed to guanine, cytosine, or uracil by oligonucleotide-directed mutagenesis. Each base change conferred a unique phenotype on the cells. Cells containing plasmid pKK3535 with G792 or T792 showed no difference in generation time in LB broth containing ampicillin, whereas cells with C792 exhibited a 20% increase in generation time in this medium. To study the effect on cell growth of a homogeneous population of mutant ribosomes, the mutations were cloned into the 16S rRNA gene on pKK3535 carrying a spectinomycin-resistance marker (thymine at position 1192), and the cells were grown with spectinomycin. Cells containing G792 or C792 showed 16% and 56% increases in generation time, respectively, and a concomitant decrease in 35S assimilation into proteins. Cells with T792 did not grow in spectinomycin-containing medium. Maxicell analyses indicated decreasing ability to form 70S ribosomes from 30S subunits containing guanine, cytosine, or uracil at position 792 in 16S rRNA. It appeared that C792-containing 30S ribosomes had lost the ability to bind initiation factor 3.

Novel integrated sensors will be required for future detection platforms for the measurement of fluorescence and luminescence. The current trend towards integration of optical detectors and the broad advances in optical emitting dyes and proteins will be combined in robust, low-cost, point-of-use, diagnostic equipment. To this end we are experimenting with an integrated optical hybrid sensing device which will combine a flip-chipped, array of solid-state single photon counting detectors with surface mount passive quench circuits on a conventional glass substrate. This flip-chipped arrangement both 1) increases the speed of response of the detector and 2) increases the robustness and ease of integration and reduces single photon detector handling requirements. The potential of integrated solid-state photon detectors will be demonstrated for the real-time quantitative detection of luciferase, a light emitting protein expression reporter molecule. A 15μm solid-state Geiger-mode avalanche photodiode (APD) operating in single photon counting mode will be compared with a standard photomultiplier tube (PMT) for luciferase luminescence detection. Detection levels of 2×10 6 and 1×10 7 enzyme molecules will be demonstrated for PMT and Geiger-mode APD respectively. The size of the Geiger-mode APD active area will be shown to be the limiting factor in luciferase signal detection for non-integrated applications. A simple geometric model will show that detection limits of 1×10 4 are achievable in integrated sensing platforms using room temperature operated single photon counting detectors.

Therapeutic and diagnostic applications have been envisioned for aptamers, a class of oligonucleotide ligands that bind their target molecules with high affinity and specificity (Gold, J. Biol. Chem. 270, 13581-13584, 1995). To identify parameters that are important for the in vivo activity of aptamers acting on intravascular targets, we have studied binding characteristics in vitro, pharmacokinetic parameters in Sprague-Dawley rats, and inhibitory activity in a SCID mouse/human lymphocyte model of lymphocyte trafficking for both 2'F pyrimidine 2'OH purine RNA and ssDNA anti-human L-selectin aptamers. The data indicate that aptamers with low nanomolar affinity are suitable candidates for use as in vivo reagents and that nonspecific binding to vascular cells is not an issue for efficacy. As is often observed for other reagents, plasma clearance is biphasic. Both the distribution phase and the clearance rate strongly affect in vivo activity. Pharmacokinetic parameters and in vivo activity are significantly improved by conjugating aptamers to a carrier molecule, such as polyethylene glycol (PEG). Most active in vivo is 1d40, a 2'F pyrimidine 2'OH purine aptamer conjugated to 40 kDa PEG. At a dose of 5.4 nmol/kg body weight, its duration of effect (time to 50% inhibition) is 11.2 hours, and at 1 mg or 90 nmol/kg, its plasma clearance rate (CL) is 0.4 ml/min/kg. Its ED50 is estimated to be 80 pmol/kg in preinjection dose-response experiments, compared with 4 pmol/kg for the dimeric anti-L-selectin antibody DREG56. Further improvement of in vivo activity is expected from nucleotide modifications that increase resistance to nuclease digestion for aptamers where mass is not rate limiting for clearance. Because the relationship of clearance to conjugate molecular weight (MW) is not the same for all aptamers, it is advisable to determine the relationship at the outset of in vivo studies. In summary, the data suggest that properly formulated aptamers have the capacity to be effective therapeutic agents against intravascular targets.

Oligonucleotide ligands that bind a protein or a small molecule of interest are readily isolated by in vitro selection and amplification of rare sequences from combinatorial libraries of sequence-randomized oligonucleotides (Gold et al., 1995). Classic systematic evolution of ligands by exponential enrichment (SELEX) protocols are affinity based (Tuerk and Gold, 1990), but because many problems and applications require antagonists, protocols for selecting inhibitors are both desirable and valuable. A widely applicable approach for isolating inhibitors is competitive elution with a molecule that binds the targeted molecule's active or binding site. We have used this approach to isolate antagonists of wheat germ agglutinin (WGA) from a library of 2'NH2-pyrimidine, 2'OH-purine oligonucleotides by elution with N N' N"-triacetylchitotriose, (GlcNAc)3. The highest affinity aptamers have equilibrium dissociation constants of 1 nM-20 nM for WGA, a 10(3)-10(4)-fold improvement relative to (GlcNAc)3, and unlike the carbohydrate, are highly specific. In addition to competing for binding with (GlcNAc)3, aptamers inhibit WGA-mediated agglutination of sheep erythrocytes, demonstrating that they are able to compete with natural ligands presented on the surfaces of cells. These results illustrate the feasibility of isolating high-affinity, high-specificity antagonists by competitive elution with low molecular weight, relatively low-affinity, and low-specificity small molecules.

A family of sequence-related 2'-aminopyrimidine, 2'-hydroxylpurine aptamers, developed by oligonucleotide-based combinatorial chemistry, SELEX (systematic evolution of ligand by exponential enrichment) technology, binds human nonpancreatic secretory phospholipase A2 (hnps-PLA2) with nanomolar affinities and inhibits enzymatic activity. Aptamer 15, derived from the family, binds hnps-PLA2 with a Kd equal to 1.7 +/- 0.2 nM and, in a standard chromogenic assay of enzymatic activity, inhibits hnps-PLA2 with an IC50 of 4 nM, at a mole fraction of substrate concentration of 4 x 10(-6) and a calculated Ki of 0.14 nM. Aptamer 15 is selective for hnps-PLA2, having a 25- and 2500-fold lower affinity, respectively, for the unrelated proteins human neutrophil elastase and human IgG. Contractions of guinea pig lung pleural strips induced by hnps-PLA2 are abolished by 0.3 microM aptamer 15, whereas contractions induced by arachidonic acid are not altered. The structure that is essential for binding and inhibition appears to be a 40-base hairpin/loop motif with an asymmetrical internal loop. The affinity and activity of the aptamers demonstrate the ability of the SELEX process to isolate antagonists of nonnucleic-acid-binding proteins from vast oligonucleotide combinatorial libraries.

The selectins are calcium-dependent C-type lectins that recognize complex anionic carbohydrate ligands, initiating many cell-cell interactions in the vascular system. Selectin blockade shows therapeutic promise in a variety of inflammatory and postischemic pathologies. However, the available oligosaccharide ligand mimetics have low affinities and show cross-reaction among the three selectins, precluding efficient and specific blockade. The SELEX (systematic evolution of ligands by exponential enrichment) process uses combinatorial chemistry and in vitro selection to yield high affinity oligonucleotides with unexpected binding specificities. Nuclease-stabilized randomized oligonucleotides subjected to SELEX against recombinant L-selectin yielded calcium-dependent antagonists with approximately 10(5) higher affinity than the conventional oligosaccharide ligand sialyl LewisX. Most of the isolated ligands shared a common consensus sequence. Unlike sialyl LewisX, these antagonists show little binding to E- or P-selectin. Moreover, they show calcium-dependent binding to native L-selectin on peripheral blood lymphocytes and block L-selectin-dependent interactions with the natural ligands on high endothelial venules.

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