Outcomes from COVID-19 across the range of frailty: excess mortality in fitter older people

Purpose: Our aim was to quantify the mortality from COVID-19 and identify any interactions with frailty and other demographic factors. / Methods: Hospitalised patients aged ≥ 70 were included, comparing COVID-19 cases with non-COVID-19 controls admitted over the same period. Frailty was prospectively measured and mortality ascertained through linkage with national and local statutory reports. / Results: In 217 COVID-19 cases and 160 controls, older age and South Asian ethnicity, though not socioeconomic position, were associated with higher mortality. For frailty, differences in effect size were evident between cases (HR 1.02, 95% CI 0.93–1.12) and controls (HR 1.99, 95% CI 1.46–2.72), with an interaction term (HR 0.51, 95% CI 0.37–0.71) in multivariable models. / Conclusions: Our findings suggest that (1) frailty is not a good discriminator of prognosis in COVID-19 and (2) pathways to mortality may differ in fitter compared with frailer older patients

Minsky machines and algorithmic problems

This is a survey of using Minsky machines to study algorithmic problems in semigroups, groups and other algebraic systems.Comment: 19 page

Accumulation of plutonium in mammalian wildlife tissues: comparison of recent data with the ICRP distribution models

We examined the distribution of plutonium (Pu) in the tissues of mammalian wildlife to address the paucity of such data under environmental exposure conditions. Pu activity concentrations were measured in Macropus rufus (red kangaroo), Oryctolagus cuniculus (European rabbit), and Pseudomys hermannsburgensis (sandy inland mouse)inhabiting the relatively undisturbed, semi-arid conditions at the former Taranaki weapons test site at Maralinga, Australia. Of the absorbed Pu (distributed via circulatory and lymph systems) accumulation was foremost in bone (83% ±10% SD), followed by muscle (9% ±10%), liver (7% ±7%), kidneys (0.5% ±0.3%), and heart (0.4% ±0.4%). The bone values are higher than those reported in ICRP 19 and 48 (45-50% bone), while the liver values are lower than ICRP values (30-45% liver). The ICRP values were based on data dominated by relatively soluble forms of Pu, including prepared solutions and single-atom ions produced by decay following the volatilisation of uranium during nuclear detonation (fallout Pu, ICRP 1986). In contrast, the Maralinga data relates to low-soluble forms of Pu used in tests designed to simulate accidental release and dispersal. We measured Pu in lung, GI-tract and the skin and fur as distinct from the absorbed Pu in bone, liver, muscle, and kidneys. Compared with the mean absorbed activity concentrations, the results for lung tissues were higher by up to one order of magnitude, and those in the GI tract contents and the washed skin/fur were higher by more than two orders of magnitude. These elevated levels are consistent with the presence of low-soluble Pu, including particulate forms, which pass through, or adhere upon, certain organs, but are not readily absorbed into the bloodstream. This more transitory Pu can provide dose to the lung and GI tract organs, as well as provide potential transfer of contamination when consumed in predator-prey food chains, or during human foodstuff consumption. For example, activity concentrations in O. cuniculus edible samples prepared according to traditional aboriginal methods were more than two orders of magnitude higher than in muscle alone. The increase was due to inclusion of GI tract components and contents in the traditional method. Our results provide new insights into the sequestration of Pu in mammalian tissues under environmental exposure conditions. These results contrast with those related to the specific forms of Pu and exposure conditions upon which the ICRP models were based. However, they provide data relevant to the assessment of key environmental legacy waste sites, and of potential release scenarios for the low-soluble oxide forms in the growing worldwide inventory of Pu associated with power production

Enhancement of regression of cervical intraepithelial neoplasia II (moderate dysplasia) with topically applied all-trans-retinoic acid: a randomized trial.

BackgroundRetinoids enhance differentiation of most epithelial tissues. Epidemiologic studies have shown an inverse relationship between dietary intake or serum levels of vitamin A and the development of cervical dysplasia and/or cervical cancer. Pilot and phase I investigations demonstrated the feasibility of the local delivery of all-trans-retinoic acid (RA) to the cervix using a collagen sponge insert and cervical cap. A phase II trial produced a clinical complete response rate of 50%.PurposeThis randomized phase III trial was designed to determine whether topically applied RA reversed moderate cervical intraepithelial neoplasia (CIN) II or severe CIN.MethodsAnalyses were based on 301 women with CIN (moderate dysplasia, 151 women; severe dysplasia, 150 women), evaluated by serial colposcopy, Papanicolaou cytology, and cervical biopsy. Cervical caps with sponges containing either 1.0 mL of 0.372% beta-trans-RA or a placebo were inserted daily for 4 days when women entered the trial, and for 2 days at months 3 and 6. Patients receiving treatment and those receiving placebo were similar with respect to age, ethnicity, birth-control methods, histologic features of the endocervical biopsy specimen and koilocytotic atypia, and percentage of involvement of the cervix at study. Treatment effects were compared using Fisher's exact test and logistic regression methods. Side effects were recorded, and differences were compared using Fisher's exact test.ResultsRA increased the complete histologic regression rate of CIN II from 27% in the placebo group to 43% in the retinoic acid treatment group (P = .041). No treatment difference between the two arms was evident in the severe dysplasia group. More vaginal and vulvar side effects were seen in the patients receiving RA, but these effects were mild and reversible.ConclusionsA short course of locally applied RA can reverse CIN II, but not more advanced dysplasia, with acceptable local side effects.ImplicationsA derivative of vitamin A can reverse or suppress an epithelial preneoplasia, lending further support to the notion that chemoprevention of human cancer is feasible

Functional and cognitive outcomes after COVID-19 delirium

Purpose: To ascertain delirium prevalence and outcomes in COVID-19. / Methods: We conducted a point-prevalence study in a cohort of COVID-19 inpatients at University College Hospital. Delirium was defined by DSM-IV criteria. The primary outcome was all-cause mortality at 4 weeks; secondary outcomes were physical and cognitive function. / Results: In 71 patients (mean age 61, 75% men), 31 (42%) had delirium, of which only 12 (39%) had been recognised by the clinical team. At 4 weeks, 20 (28%) had died, 26 (36%) were interviewed by telephone and 21 (30%) remained as inpatients. Physical function was substantially worse in people after delirium − 50 out of 166 points (95% CI − 83 to − 17, p = 0.01). Mean cognitive scores at follow-up were similar and delirium was not associated with mortality in this sample. / Conclusions: Our findings indicate that delirium is common, yet under-recognised. Delirium is associated with functional impairments in the medium term

A Fast bipolar H2 outflow from IRAS 16342-3814: an old star reliving its youth

Some evolved stars in the pre-planetary nebula phase produce highly-collimated molecular outflows that resemble the accretion-driven jets and outflows from pre-main sequence stars. We show that IRAS 16342-3814 (the Water Fountain Nebula) is such an object and present K-band integral field spectroscopy revealing a fast (> 150 km/s) bipolar H2 outflow. The H2 emission is shock excited and may arise in fast-moving clumps, accelerated by the previously observed precessing jet. The total luminosity in H2 is 0.37 L$_{\odot}$ which is comparable with that of accretion-powered outflows from Class 0 protostars. We also detect CO overtone bandhead emission in the scattered continuum, indicating hot molecular gas close to the centre, a feature also observed in a number of protostars with active jets. It seems likely that the jet and outflow in IRAS 16342-3814 are powered by accretion onto a binary companion.Comment: Accepted for publication in Monthly Notices of the Royal Astronomical Societ

Bead-Droplet Reactor for High-Fidelity Solid-Phase Enzymatic DNA Synthesis

Solid-phase synthesis techniques underpin the synthesis of DNA, oligopeptides, oligosaccharides, and combinatorial libraries for drug discovery. State-of-the-art solid-phase synthesizers can produce oligonucleotides up to 200-300 nucleotides while using excess reagents. Accumulated errors over multiple reaction cycles prevent the synthesis of longer oligonucleotides for the genome scale engineering of synthetic biological systems. The sources of these errors in synthesis columns remains poorly understood. Here we show that bead-bead stacking significantly contributes to reaction errors in columns by analyzing enzymatic coupling of fluorescently labelled nucleotides onto the initiated beads along with porosity, particle tracking and diffusion calculations. To circumvent stacking, we introduce dielectrophoretic bead-droplet reactor (DBDR); a novel approach to synthesize on individual microbeads within microdroplets. Dielectrophoretic force overcomes the droplet-medium interfacial tension to encapsulate and eject individual beads from microdroplets in a droplet microfluidic device. Faster reagent diffusion in droplets, and non-uniform electric field induced enhancement in reagent concentration at its surface can improve reaction fidelities in DBDR. Fluorescence comparisons suggest around 3-fold enhancement of reaction fidelity compared to columns. DBDR can potentially enable the high-purity synthesis of arbitrarily long strands of DNA to meet the emerging demands in healthcare, environment, agriculture, materials, and computing

Glaucoma Rose Plot Analysis: detecting early structural progression using angular histograms

Purpose To evaluate the novel Rose Plot Analysis (RPA) in the analysis and presentation of glaucoma structural progression data. Design Case-control image analysis study using retrospective retinal imaging series. Subjects Subjects with open-angle glaucoma with at least 5 registered spectral-domain OCT scans. Methods Glaucoma RPA was developed, combining a novel application of angular histograms and dynamic cluster analysis of circumpapillary retinal nerve fiber layer (cRNFL) OCT data. Rose Plot Analysis plots were created for each eye and each visit. Significant clusters of progression were indicated in red. Three masked clinicians categorized all RPA plots (progressing, not progressing), in addition to measuring the significant RPA area. A masked OCT series assessment with linear regression of averaged global and sectoral cRNFL thicknesses was conducted as the clinical imaging standard. Main Outcome Measures Interobserver agreement was compared between RPA and the clinical imaging standard. Discriminative ability was assessed using receiver-operating characteristic curves. The time to detection of progression was compared using a Kaplan–Meier survival analysis, and the agreement of RPA with the clinical imaging standard was calculated. Results Seven hundred fourty-three scans from 98 eyes were included. Interobserver agreement was significantly greater when categorizing RPA (κ, 0.86; 95% confidence interval [CI], 0.81–0.91) compared with OCT image series (κ, 0.66; 95% CI, 0.54–0.77). The discriminative power of RPA to differentiate between eyes that were progressing and not progressing (area under the curve [AUC], 0.97; 95% CI, 0.92–1.00) was greater than that of global cRNFL thickness (AUC, 0.71; 95% CI, 0.59–0.82; P < 0.0001) and equivalent to that of sectoral cRNFL regression (AUC, 0.97; 95% CI, 0.92–1.00). A Kaplan–Meier survival analysis showed that progression was detected 8.7 months sooner by RPA than by global cRNFL linear regression (P < 0.0001) in progressing eyes but was not sooner than with sectoral cRNFL (P = 0.06). Rose Plot Analysis showed substantial agreement with the presence of significant thinning on sectoral cRNFL linear regression (κ, 0.715; 95% CI, 0.578–0.853). Conclusions Rose Plot Analysis has been shown to provide accurate and intuitive, at-a-glance data analysis and presentation that improve interobserver agreement and may aid early diagnosis of glaucomatous disease progression

Annexins in glaucoma

Glaucoma is one of the leading causes of irreversible visual loss, which has been estimated to affect 3.5% of those over 40 years old and projected to affect a total of 112 million people by 2040. Such a dramatic increase in affected patients demonstrates the need for continual improvement in the way we diagnose and treat this condition. Annexin A5 is a 36 kDa protein that is ubiquitously expressed in humans and is studied as an indicator of apoptosis in several fields. This molecule has a high calcium-dependent affinity for phosphatidylserine, a cell membrane phospholipid externalized to the outer cell membrane in early apoptosis. The DARC (Detection of Apoptosing Retinal Cells) project uses fluorescently-labelled annexin A5 to assess glaucomatous degeneration, the inherent process of which is the apoptosis of retinal ganglion cells. Furthermore, this project has conducted investigation of the retinal apoptosis in the neurodegenerative conditions of the eye and brain. In this present study, we summarized the use of annexin A5 as a marker of apoptosis in the eye. We also relayed the progress of the DARC project, developing real-time imaging of retinal ganglion cell apoptosis in vivo from the experimental models of disease and identifying mechanisms underlying neurodegeneration and its treatments, which has been applied to the first human clinical trials. DARC has potential as a biomarker in neurodegeneration, especially in the research of novel treatments, and could be a useful tool for the diagnosis and monitoring of glaucoma