Are routinely collected NHS administrative records suitable for endpoint identification in clinical trials? Evidence from the West of Scotland coronary prevention study

Background: Routinely collected electronic patient records are already widely used in epidemiological research. In this work we investigated the potential for using them to identify endpoints in clinical trials.<p></p> Methods: The events recorded in the West of Scotland Coronary Prevention Study (WOSCOPS), a large clinical trial of pravastatin in middle-aged hypercholesterolaemic men in the 1990s, were compared with those in the record-linked deaths and hospitalisations records routinely collected in Scotland.<p></p> Results: We matched 99% of fatal study events by date. We showed excellent matching (97%) of the causes of fatal endpoint events and good matching (.80% for first events) of the causes of nonfatal endpoint events with a slightly lower rate of mismatching of record linkage than study events (19% of first study myocardial infarctions (MI) and 4% of first record linkage MIs not matched as MI). We also investigated the matching of non-endpoint events and showed a good level of matching, with .78% of first stroke/TIA events being matched as stroke/TIA. The primary reasons for mismatches were record linkage data recording readmissions for procedures or previous events, differences between the diagnoses in the routinely collected data and the conclusions of the clinical trial expert adjudication committee, events occurring outside Scotland and therefore being missed by record linkage data, miscoding of cardiac events in hospitalisations data as ‘unspecified chest pain’, some general miscoding in the record linkage data and some record linkage errors.<p></p> Conclusions: We conclude that routinely collected data could be used for recording cardiovascular endpoints in clinical trials and would give very similar results to rigorously collected clinical trial data, in countries with unified health systems such as Scotland. The endpoint types would need to be carefully thought through and an expert endpoint adjudication committee should be involved.<p></p&gt

Incident venous thromboembolic events in the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER)

<p>Background: Venous thromboembolic events (VTE), including deep venous thrombosis and pulmonary embolism, are common in older age. It has been suggested that statins might reduce the risk of VTE however positive results from studies of middle aged subjects may not be generalisable to elderly people. We aimed to determine the effect of pravastatin on incident VTE in older people; we also studied the impact of clinical and plasma risk variables.</p> <p>Methods: This study was an analysis of incident VTE using data from the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER), a randomized, double-blind, placebo-controlled trial of pravastatin in men and women aged 70-82. Mean follow-up was 3.2 years. Risk for VTE was examined in non-warfarin treated pravastatin (n = 2834) and placebo (n = 2865) patients using a Cox's proportional hazard model, and the impact of other risk factors assessed in a multivariate forward stepwise regression analysis. Baseline clinical characteristics, blood biochemistry and hematology variables, plasma levels of lipids and lipoproteins, and plasma markers of inflammation and adiposity were compared. Plasma markers of thrombosis and hemostasis were assessed in a nested case (n = 48) control (n = 93) study where the cohort was those participants, not on warfarin, for whom data were available.</p> <p>Results: There were 28 definite cases (1.0%) of incident VTE in the pravastatin group recipients and 20 cases (0.70%) in placebo recipients. Pravastatin did not reduce VTE in PROSPER compared to placebo [unadjusted hazard ratio (95% confidence interval) 1.42 (0.80, 2.52) p = 0.23]. Higher body mass index (BMI) [1.09 (1.02, 1.15) p = 0.0075], country [Scotland vs Netherlands 4.26 (1.00, 18.21) p = 0.050 and Ireland vs Netherlands 6.16 (1.46, 26.00) p = 0.013], lower systolic blood pressure [1.35 (1.03, 1.75) p = 0.027] and lower baseline Mini Mental State Examination (MMSE) score [1.19 (1.01, 1.41) p = 0.034] were associated with an increased risk of VTE, however only BMI, country and systolic blood pressure remained significant on multivariate analysis. In a nested case control study of definite VTE, plasma Factor VIII levels were associated with VTE [1.52 (1.01, 2.28), p = 0.044]. However no other measure of thrombosis and haemostasis was associated with increased risk of VTE.</p> <p>Conclusions: Pravastatin does not prevent VTE in elderly people at risk of vascular disease. Blood markers of haemostasis and inflammation are not strongly predictive of VTE in older age however BMI, country and lower systolic blood pressure are independently associated with VTE risk.</p&gt

Comments on D-branes in Kazama-Suzuki models and Landau-Ginzburg theories

We study D-branes in Kazama-Suzuki models by means of the boundary state description. We can identify the boundary states of Kazama-Suzuki models with the solitons in N=2 Landau-Ginzburg theories. We also propose a geometrical interpretation of the boundary states in Kazama-Suzuki models.Comment: 28 pages, 2 figure

Naturally Rehearsing Passwords

We introduce quantitative usability and security models to guide the design of password management schemes --- systematic strategies to help users create and remember multiple passwords. In the same way that security proofs in cryptography are based on complexity-theoretic assumptions (e.g., hardness of factoring and discrete logarithm), we quantify usability by introducing usability assumptions. In particular, password management relies on assumptions about human memory, e.g., that a user who follows a particular rehearsal schedule will successfully maintain the corresponding memory. These assumptions are informed by research in cognitive science and validated through empirical studies. Given rehearsal requirements and a user's visitation schedule for each account, we use the total number of extra rehearsals that the user would have to do to remember all of his passwords as a measure of the usability of the password scheme. Our usability model leads us to a key observation: password reuse benefits users not only by reducing the number of passwords that the user has to memorize, but more importantly by increasing the natural rehearsal rate for each password. We also present a security model which accounts for the complexity of password management with multiple accounts and associated threats, including online, offline, and plaintext password leak attacks. Observing that current password management schemes are either insecure or unusable, we present Shared Cues--- a new scheme in which the underlying secret is strategically shared across accounts to ensure that most rehearsal requirements are satisfied naturally while simultaneously providing strong security. The construction uses the Chinese Remainder Theorem to achieve these competing goals

Spin dynamics and exchange interactions in CuO measured by neutron scattering

The magnetic properties of CuO encompass several contemporary themes in condensed matter physics, including quantum magnetism, magnetic frustration, magnetically-induced ferroelectricity and orbital currents. Here we report polarized and unpolarized neutron inelastic scattering measurements which provide a comprehensive map of the cooperative spin dynamics in the low temperature antiferromagnetic (AFM) phase of CuO throughout much of the Brillouin zone. At high energies ($E \gtrsim 100$\,meV) the spectrum displays continuum features consistent with the des Cloizeax--Pearson dispersion for an ideal $S=\frac{1}{2}$ Heisenberg AFM chain. At lower energies the spectrum becomes more three-dimensional, and we find that a linear spin-wave model for a Heisenberg AFM provides a very good description of the data, allowing for an accurate determination of the relevant exchange constants in an effective spin Hamiltonian for CuO. In the high temperature helicoidal phase, there are features in the measured low-energy spectrum that we could not reproduce with a spin-only model. We discuss how these might be associated with the magnetically-induced multiferroic behavior observed in this phase

D-branes on a Deformation of SU(2)

We discuss D-branes on a line of conformal field theories connected by an exact marginal deformation. The line contains an SU(2) WZW model and two mutually T-dual SU(2)/U(1) cosets times a free boson. We find the D-branes preserving a U(1) isometry, an F-flux quantization condition and conformal invariance. Away from the SU(2) point a U(1) times U(1) symmetry is broken to U(1) times Z_k, i.e. continuous rotations of branes are accompanied by rotations along the branes. Requiring decoupling of the cosets from the free boson at the endpoints of the deformation breaks the continuous rotation of branes to Z_k. At the SU(2) point the full U(1) times U(1) symmetry is restored. This suggests the occurrence of phase transitions for branes at angles in the coset model, at a semiclassical level. We also discuss briefly the orientifold planes along the deformation line.Comment: 19 pages, latex, 5 figures, references adde

Assessment of dispersion of airborne particles of oral/nasal fluid by high flow nasal cannula therapy

Background Nasal High Flow (NHF) therapy delivers flows of heated humidified gases up to 60 LPM (litres per minute) via a nasal cannula. Particles of oral/nasal fluid released by patients undergoing NHF therapy may pose a cross-infection risk, which is a potential concern for treating COVID-19 patients. Methods Liquid particles within the exhaled breath of healthy participants were measured with two protocols: (1) high speed camera imaging and counting exhaled particles under high magnification (6 participants) and (2) measuring the deposition of a chemical marker (riboflavin-5-monophosphate) at a distance of 100 and 500 mm on filter papers through which air was drawn (10 participants). The filter papers were assayed with HPLC. Breathing conditions tested included quiet (resting) breathing and vigorous breathing (which here means nasal snorting, voluntary coughing and voluntary sneezing). Unsupported (natural) breathing and NHF at 30 and 60 LPM were compared. Results Imaging: During quiet breathing, no particles were recorded with unsupported breathing or 30 LPM NHF (detection limit for single particles 33 μm). Particles were detected from 2 of 6 participants at 60 LPM quiet breathing at approximately 10% of the rate caused by unsupported vigorous breathing. Unsupported vigorous breathing released the greatest numbers of particles. Vigorous breathing with NHF at 60 LPM, released half the number of particles compared to vigorous breathing without NHF. Chemical marker tests: No oral/nasal fluid was detected in quiet breathing without NHF (detection limit 0.28 μL/m3). In quiet breathing with NHF at 60 LPM, small quantities were detected in 4 out of 29 quiet breathing tests, not exceeding 17 μL/m3. Vigorous breathing released 200–1000 times more fluid than the quiet breathing with NHF. The quantities detected in vigorous breathing were similar whether using NHF or not. Conclusion During quiet breathing, 60 LPM NHF therapy may cause oral/nasal fluid to be released as particles, at levels of tens of μL per cubic metre of air. Vigorous breathing (snort, cough or sneeze) releases 200 to 1000 times more oral/nasal fluid than quiet breathing (p < 0.001 with both imaging and chemical marker methods). During vigorous breathing, 60 LPM NHF therapy caused no statistically significant difference in the quantity of oral/nasal fluid released compared to unsupported breathing. NHF use does not increase the risk of dispersing infectious aerosols above the risk of unsupported vigorous breathing. Standard infection prevention and control measures should apply when dealing with a patient who has an acute respiratory infection, independent of which, if any, respiratory support is being used

Dental management considerations for the patient with an acquired coagulopathy. Part 1: Coagulopathies from systemic disease

Current teaching suggests that many patients are at risk for prolonged bleeding during and following invasive dental procedures, due to an acquired coagulopathy from systemic disease and/or from medications. However, treatment standards for these patients often are the result of long-standing dogma with little or no scientific basis. The medical history is critical for the identification of patients potentially at risk for prolonged bleeding from dental treatment. Some time-honoured laboratory tests have little or no use in community dental practice. Loss of functioning hepatic, renal, or bone marrow tissue predisposes to acquired coagulopathies through different mechanisms, but the relationship to oral haemostasis is poorly understood. Given the lack of established, science-based standards, proper dental management requires an understanding of certain principles of pathophysiology for these medical conditions and a few standard laboratory tests. Making changes in anticoagulant drug regimens are often unwarranted and/or expensive, and can put patients at far greater risk for morbidity and mortality than the unlikely outcome of postoperative bleeding. It should be recognised that prolonged bleeding is a rare event following invasive dental procedures, and therefore the vast majority of patients with suspected acquired coagulopathies are best managed in the community practice setting

Integration of Machine Learning and Mechanistic Models Accurately Predicts Variation in Cell Density of Glioblastoma Using Multiparametric MRI

Glioblastoma (GBM) is a heterogeneous and lethal brain cancer. These tumors are followed using magnetic resonance imaging (MRI), which is unable to precisely identify tumor cell invasion, impairing effective surgery and radiation planning. We present a novel hybrid model, based on multiparametric intensities, which combines machine learning (ML) with a mechanistic model of tumor growth to provide spatially resolved tumor cell density predictions. The ML component is an imaging data-driven graph-based semi-supervised learning model and we use the Proliferation-Invasion (PI) mechanistic tumor growth model. We thus refer to the hybrid model as the ML-PI model. The hybrid model was trained using 82 image-localized biopsies from 18 primary GBM patients with pre-operative MRI using a leave-one-patient-out cross validation framework. A Relief algorithm was developed to quantify relative contributions from the data sources. The ML-PI model statistically significantly outperformed (p \u3c 0.001) both individual models, ML and PI, achieving a mean absolute predicted error (MAPE) of 0.106 ± 0.125 versus 0.199 ± 0.186 (ML) and 0.227 ± 0.215 (PI), respectively. Associated Pearson correlation coefficients for ML-PI, ML, and PI were 0.838, 0.518, and 0.437, respectively. The Relief algorithm showed the PI model had the greatest contribution to the result, emphasizing the importance of the hybrid model in achieving the high accuracy