Inertial Migration in a Pressure-Driven Channel Flow: Beyond the Segre-Silberberg Pinch.

We examine theoretically the inertial migration of a neutrally buoyant rigid sphere in pressure-driven channel flow, accounting for its finite size relative to the channel width (the confinement ratio). For sufficiently large channel Reynolds numbers (Re_{c}), a small but finite confinement ratio qualitatively alters the inertial lift velocity profiles obtained using a point-particle formulation. Finite size effects lead to new equilibria, in addition to the well-known Segre-Silberberg pinch locations. Consequently, a sphere can migrate to either the near-wall Segre-Silberberg equilibria, or the new stable equilibria located closer to the channel centerline, depending on Re_{c} and its initial position. Our findings are in accord with recent experiments and simulations, and have implications for passive sorting of particles based on size, shape, and other physical characteristics, in microfluidic applications.

Continuous Pathway between the Elasto-Inertial and Elastic Turbulent States in Viscoelastic Channel Flow.

Viscoelastic plane Poiseuille flow is shown to become linearly unstable in the absence of inertia, in the limit of high elasticities, for ultradilute polymer solutions. While inertialess elastic instabilities have been predicted for curvilinear shear flows, this is the first ever report of a purely elastic linear instability in a rectilinear shear flow. The novel instability continues up to a Reynolds number (Re) of O(1000), corresponding to the recently identified elasto-inertial turbulent state believed to underlie the maximum-drag-reduced regime. Thus, for highly elastic ultradilute polymer solutions, a single linearly unstable modal branch may underlie transition to elastic turbulence at zero Re and to elasto-inertial turbulence at moderate Re, implying the existence of continuous pathways connecting the turbulent states to each other and to the laminar base state.

Orientation Dynamics of Sedimenting Anisotropic Particles in Turbulence.

We examine the dynamics of small anisotropic particles (spheroids) sedimenting through homogeneous isotropic turbulence using direct numerical simulations and theory. The gravity-induced inertial torque acting on sub-Kolmogorov spheroids leads to pronouncedly non-Gaussian orientation distributions localized about the broadside-on (to gravity) orientation. Orientation distributions and average settling velocities are obtained over a wide range of spheroid aspect ratios, Stokes, and Froude numbers. Orientational moments from the simulations compare well with analytical predictions in the inertialess rapid-settling limit, with both exhibiting a nonmonotonic dependence on spheroid aspect ratio. Deviations arise at Stokes numbers of order unity due to a spatially inhomogeneous particle concentration field resulting from a preferential sweeping effect; as a consequence, the time-averaged particle settling velocities exceed the orientationally averaged estimates.

Enzyme intermediates captured "on the fly" by mix-and-inject serial crystallography.

BACKGROUND: Ever since the first atomic structure of an enzyme was solved, the discovery of the mechanism and dynamics of reactions catalyzed by biomolecules has been the key goal for the understanding of the molecular processes that drive life on earth. Despite a large number of successful methods for trapping reaction intermediates, the direct observation of an ongoing reaction has been possible only in rare and exceptional cases. RESULTS: Here, we demonstrate a general method for capturing enzyme catalysis "in action" by mix-and-inject serial crystallography (MISC). Specifically, we follow the catalytic reaction of the Mycobacterium tuberculosis ß-lactamase with the third-generation antibiotic ceftriaxone by time-resolved serial femtosecond crystallography. The results reveal, in near atomic detail, antibiotic cleavage and inactivation from 30 ms to 2 s. CONCLUSIONS: MISC is a versatile and generally applicable method to investigate reactions of biological macromolecules, some of which are of immense biological significance and might be, in addition, important targets for structure-based drug design. With megahertz X-ray pulse rates expected at the Linac Coherent Light Source II and the European X-ray free-electron laser, multiple, finely spaced time delays can be collected rapidly, allowing a comprehensive description of biomolecular reactions in terms of structure and kinetics from the same set of X-ray data.

Viscoelastic Pipe Flow is Linearly Unstable.

Newtonian pipe flow is known to be linearly stable at all Reynolds numbers. We report, for the first time, a linear instability of pressure-driven pipe flow of a viscoelastic fluid, obeying the Oldroyd-B constitutive equation commonly used to model dilute polymer solutions. The instability is shown to exist at Reynolds numbers significantly lower than those at which transition to turbulence is typically observed for Newtonian pipe flow. Our results qualitatively explain experimental observations of transition to turbulence in pipe flow of dilute polymer solutions at flow rates where Newtonian turbulence is absent. The instability discussed here should form the first stage in a hitherto unexplored dynamical pathway to turbulence in polymer solutions. An analogous instability exists for plane Poiseuille flow.

Exploring the impact of workplace cyberbullying on trainee doctors.

OBJECTIVES: Workplace bullying is an occupational hazard for trainee doctors. However, little is known about their experiences of cyberbullying at work. This study examines the impact of cyberbullying among trainee doctors, and how attributions of blame for cyberbullying influence individual and work-related outcomes. METHODS: Doctors at over 6 months into training were asked to complete an online survey that included measures of cyberbullying, blame attribution, negative emotion, job satisfaction, interactional justice and mental strain. A total of 158 trainee doctors (104 women, 54 men) completed the survey. RESULTS: Overall, 73 (46.2%) respondents had experienced at least one act of cyberbullying. Cyberbullying adversely impacted on job satisfaction (ß = - 0.19; p < 0.05) and mental strain (ß = 0.22; p < 0.001), although attributions of blame for the cyberbullying influenced its impact and the path of mediation. Negative emotion mediated the relationship between self-blame for a cyber-bullying act and mental strain, whereas interactional injustice mediated the association between blaming the perpetrator and job dissatisfaction. CONCLUSIONS: Acts of cyberbullying had been experienced by nearly half of the sample during their training and were found to significantly relate to ill health and job dissatisfaction. The deleterious impact of cyberbullying can be addressed through both workplace policies, and training for trainee doctors and experienced medical professionals.

Time-resolved spectra from millivolt EELS data.

The millivolt energy resolution now obtainable in electron energy-loss spectra (EELS) on the latest monochromated scanning transmission electron microscope corresponds, via the uncertainty principle, to a time range of 414 fs (for 10 meV resolution), and a time resolution of 0.138 fs (for energy range of 30 eV). (Thus, the width of an EELS peak is inversely related to the lifetime of an excitation.) This compares favorably with the latest X-ray free electron lasers. The time evolution of a Drude-Lorentz oscillator may be obtained from an EELS using logarithmic deconvolution followed by Kramers-Kronig analysis to extract the frequency-dependent dielectric function, and a final Fourier transform from frequency to time domain. This time-dependent dielectric function was interpreted as the impulse response of electrons, phonons, or ions based on the Drude-Lorentz theory. The time evolution of electronic oscillators from ice and protein, extracted from low resolution experimental data, were compared. Using higher energy resolution data we have also extracted the time-resolved spectra from excitons in an alkali halide, BaF2. Despite the small scanning transmission electron microscope probe size, delocalization limits the spatial resolution to about 50 nm, which is, nevertheless, better than the millimeter resolution of infrared absorption spectroscopy or Raman spectroscopy.

Allopurinol and blood pressure variability following ischemic stroke and transient ischemic attack: a secondary analysis of XILO-FIST.

Blood Pressure Variability (BPV) is associated with cardiovascular risk and serum uric acid level. We investigated whether BPV was lowered by allopurinol and whether it was related to neuroimaging markers of cerebral small vessel disease (CSVD) and cognition. We used data from a randomised, double-blind, placebo-controlled trial of two years allopurinol treatment after recent ischemic stroke or transient ischemic attack. Visit-to-visit BPV was assessed using brachial blood pressure (BP) recordings. Short-term BPV was assessed using ambulatory BP monitoring (ABPM) performed at 4 weeks and 2 years. Brain MRI was performed at baseline and 2 years. BPV measures were compared between the allopurinol and placebo groups, and with CSVD and cognition. 409 participants (205 allopurinol; 204 placebo) were included in the visit-to-visit BPV analyses. There were no significant differences found between placebo and allopurinol groups for any measure of visit-to-visit BPV. 196 participants were included in analyses of short-term BPV at week 4. Two measures were reduced by allopurinol: the standard deviation (SD) of systolic BP (by 1.30 mmHg (95% confidence interval (CI) 0.18-2.42, p = 0.023)); and the average real variability (ARV) of systolic BP (by 1.31 mmHg (95% CI 0.31-2.32, p = 0.011)). There were no differences in other measures at week 4 or in any measure at 2 years, and BPV was not associated with CSVD or cognition. Allopurinol treatment did not affect visit-to-visit BPV in people with recent ischemic stroke or TIA. Two BPV measures were reduced at week 4 by allopurinol but not at 2 years.

Xanthine oxidase inhibition and white matter hyperintensity progression following ischaemic stroke and transient ischaemic attack (XILO-FIST): a multicentre, double-blinded, randomised, placebo-controlled trial.

Background: People who experience an ischaemic stroke are at risk of recurrent vascular events, progression of cerebrovascular disease, and cognitive decline. We assessed whether allopurinol, a xanthine oxidase inhibitor, reduced white matter hyperintensity (WMH) progression and blood pressure (BP) following ischaemic stroke or transient ischaemic attack (TIA). Methods: In this multicentre, prospective, randomised, double-blinded, placebo-controlled trial conducted in 22 stroke units in the United Kingdom, we randomly assigned participants within 30-days of ischaemic stroke or TIA to receive oral allopurinol 300 mg twice daily or placebo for 104 weeks. All participants had brain MRI performed at baseline and week 104 and ambulatory blood pressure monitoring at baseline, week 4 and week 104. The primary outcome was the WMH Rotterdam Progression Score (RPS) at week 104. Analyses were by intention to treat. Participants who received at least one dose of allopurinol or placebo were included in the safety analysis. This trial is registered with ClinicalTrials.gov, NCT02122718. Findings: Between 25th May 2015 and the 29th November 2018, 464 participants were enrolled (232 per group). A total of 372 (189 with placebo and 183 with allopurinol) attended for week 104 MRI and were included in analysis of the primary outcome. The RPS at week 104 was 1.3 (SD 1.8) with allopurinol and 1.5 (SD 1.9) with placebo (between group difference -0.17, 95% CI -0.52 to 0.17, p = 0.33). Serious adverse events were reported in 73 (32%) participants with allopurinol and in 64 (28%) with placebo. There was one potentially treatment related death in the allopurinol group. Interpretation: Allopurinol use did not reduce WMH progression in people with recent ischaemic stroke or TIA and is unlikely to reduce the risk of stroke in unselected people. Funding: The British Heart Foundation and the UK Stroke Association.

Two-fluid kinetic theory for dilute polymer solutions.

We provide a Boltzmann-type kinetic description for dilute polymer solutions based on two-fluid theory. This Boltzmann-type description uses a quasiequilibrium based relaxation mechanism to model collisions between a polymer dumbbell and a solvent molecule. The model reproduces the desired macroscopic equations for the polymer-solvent mixture. The proposed kinetic scheme leads to a numerical algorithm which is along the lines of the lattice Boltzmann method. Finally, the algorithm is applied to describe the evolution of a perturbed Kolmogorov flow profile, whereby we recover the major elastic effect exhibited by a polymer solution, specifically, the suppression of the original inertial instability.

Arterial and venous thrombotic stroke after ChAdOx1 nCoV-19 vaccine.

Vaccine-induced thrombosis with thrombocytopenia (VITT) is a recently-described condition associated with arterial and venous thrombosis following vaccination with the ChAdOx1 nCoV-19 (AstraZeneca) vaccine. This report describes two cases of stroke caused by arterial and venous thromboses presenting within 28 days of receiving the AstraZeneca vaccine. The patients were otherwise young and healthy with minimal risk factors for thrombosis yet developed a rapid, ultimately fatal neurological deterioration.The patients were significantly thrombocytopenic with disproportionately raised D-dimers, both of which are widely reported in this condition. Both cases had measurable immunoglobulin G platelet factor-4 antibodies detected via enzyme-linked immunosorbent assay, similar to those described in heparin-induced thrombocytopenia.These cases illustrate that physicians should be especially mindful of VITT in the context of evolving evidence on treatment and in view of the potentially rapid and catastrophic neurological deterioration, leading to fatality despite best supportive care.

Early Identification, Intervention and Management of Post-stroke Spasticity: Expert Consensus Recommendations.

Stroke patients with spasticity usually require long-lasting care and interventions but frequently report that outpatient and community treatment is limited, reflecting a significant unmet need in health and social care provision. Rehabilitation and spasticity management services are essential for patient recovery, with improvements in both activity and participation reducing the burden on patients, family and society. Current clinical guidance provides scope for improvements in both post-stroke management and spasticity prevention. However, access to specialist services can be limited and the patient journey does not always match national recommendations. Identification of spasticity and its predictors and lack of subsequent referral to rehabilitation or specialist spasticity services are key issues in the management of post-stroke spasticity. Implementation of a traffic light classification system prioritises patients at an increased risk of spasticity and promotes early and consistent management across the spectrum of primary and secondary care. The proposed system is based on clinical evidence, expert consensus and recent clinical guidelines. It provides simple and straightforward criteria for management, multidisciplinary consultation and referral to specialist spasticity services, with patients allocated by monitoring requirements and a low (green/periodic monitoring), medium (amber/routine referral) or high risk (red/urgent referral) of spasticity.

Evaluation of stroke thrombectomy including patients where IV thrombolysis is contraindicated or has failed: a randomized trial of two novel thrombectomy devices.

BACKGROUND: Study was a PROBE design phase II randomized controlled trial (RCT). We assessed trial feasibility and technical efficacy and safety of two novel thrombectomy devices - ERIC (a retriever device) and SOFIA (a distal access catheter) - used alone or in combination depending on operator preference. METHODS: Four UK neuroscience centers enrolled adults with proximal large artery occlusion (LAO) stroke on imaging where arterial puncture was achievable within 5.5 hours (8.5 hours for posterior circulation) of symptom onset; National Institutes of Health Stroke Scale (NIHSS) ≥6 with limited ischemic change on CT imaging. Randomization was 2:1 into intervention arm (ERIC and/or SOFIA). Patients and core lab were blinded to allocation. Primary outcome was independent core lab adjudication of reperfusion (modified Thrombolysis in Cerebral Infarction (mTICI) scale). Secondary outcomes were modified Rankin score (mRS) at 90 and 365 days (independence and shift analysis), 30-day mortality, symptomatic intracranial hemorrhage (sICH), procedural complications and NIHSS change. RESULTS: Sixty-six patients were enrolled. TICI 2B/3 reperfusion was achieved in 72% in intervention compared with 90% in control arm on intention to treat (ITT) analysis (P=0.2) and 78% compared with 86% on per protocol analysis (P=0.7). Functional independence at 90 days was 40% (intervention) compared with 43% (control) on ITT analysis (P=1.0). sICH rates were low at 0% and 5%, respectively (P=0.3). The 30-day mortality was 9% intervention compared with 14% control (P=0.7). CONCLUSIONS: Study indicated feasibility of a phase II RCT trial approach for assessing new thrombectomy devices. In a broad LAO stroke population ERIC and SOFIA were not statistically different from control devices. Larger trials are needed.

High-viscosity injector-based pink-beam serial crystallography of microcrystals at a synchrotron radiation source.

Since the first successful serial crystallography (SX) experiment at a synchrotron radiation source, the popularity of this approach has continued to grow showing that third-generation synchrotrons can be viable alternatives to scarce X-ray free-electron laser sources. Synchrotron radiation flux may be increased ∼100 times by a moderate increase in the bandwidth ('pink beam' conditions) at some cost to data analysis complexity. Here, we report the first high-viscosity injector-based pink-beam SX experiments. The structures of proteinase K (PK) and A2A adenosine receptor (A2AAR) were determined to resolutions of 1.8 and 4.2 Šusing 4 and 24 consecutive 100 ps X-ray pulse exposures, respectively. Strong PK data were processed using existing Laue approaches, while weaker A2AAR data required an alternative data-processing strategy. This demonstration of the feasibility presents new opportunities for time-resolved experiments with microcrystals to study structural changes in real time at pink-beam synchrotron beamlines worldwide.

Direct Structural and Chemical Characterization of the Photolytic Intermediates of Methylcobalamin Using Time-Resolved X-ray Absorption Spectroscopy.

Cobalt-carbon bond cleavage is crucial to most natural and synthetic applications of the cobalamin class of compounds, and here we present the first direct electronic and geometric structural characteristics of intermediates formed following photoexcitation of methylcobalamin (MeCbl) using time-resolved X-ray absorption spectroscopy (XAS). We catch transients corresponding to two intermediates, in the hundreds of picoseconds and a few microseconds. Highlights of the picosecond intermediate, which is reduced in comparison to the ground state, are elongation of the upper axial Co-C bond and relaxation of the corrin ring. This is not so with the recombining photocleaved products captured at a few microseconds, where the Co-C bond almost (yet not entirely) reverts to its ground state configuration and a substantially elongated lower axial Co-NIm bond is observed. The reduced cobalt site here confirms formation of methyl radical as the photoproduct.

Knowledge and Risk Perceptions of Occupational Infections Among Health-care Workers in Malaysia.

Health-care workers are at risk of exposure to occupational infections with subsequent risk of contracting diseases, disability, and even death. A systematic collection of occupational disease data is useful for monitoring current trends in work situations and disease exposures; however, these data are usually limited due to under-reporting. The objective of this study was to review literature related to knowledge, risk perceptions, and practices regarding occupational exposures to infectious diseases in Malaysian health-care settings, in particular regarding blood-borne infections, universal precautions, use of personal protective equipment, and clinical waste management. The data are useful for determining improvements in knowledge and risk perceptions among health-care workers with developments of health policies and essential interventions for prevention and control of occupational diseases.

Serial millisecond crystallography of membrane and soluble protein microcrystals using synchrotron radiation.

Crystal structure determination of biological macromolecules using the novel technique of serial femtosecond crystallography (SFX) is severely limited by the scarcity of X-ray free-electron laser (XFEL) sources. However, recent and future upgrades render microfocus beamlines at synchrotron-radiation sources suitable for room-temperature serial crystallography data collection also. Owing to the longer exposure times that are needed at synchrotrons, serial data collection is termed serial millisecond crystallography (SMX). As a result, the number of SMX experiments is growing rapidly, with a dozen experiments reported so far. Here, the first high-viscosity injector-based SMX experiments carried out at a US synchrotron source, the Advanced Photon Source (APS), are reported. Microcrystals (5-20 µm) of a wide variety of proteins, including lysozyme, thaumatin, phycocyanin, the human A2A adenosine receptor (A2AAR), the soluble fragment of the membrane lipoprotein Flpp3 and proteinase K, were screened. Crystals suspended in lipidic cubic phase (LCP) or a high-molecular-weight poly(ethylene oxide) (PEO; molecular weight 8 000 000) were delivered to the beam using a high-viscosity injector. In-house data-reduction (hit-finding) software developed at APS as well as the SFX data-reduction and analysis software suites Cheetah and CrystFEL enabled efficient on-site SMX data monitoring, reduction and processing. Complete data sets were collected for A2AAR, phycocyanin, Flpp3, proteinase K and lysozyme, and the structures of A2AAR, phycocyanin, proteinase K and lysozyme were determined at 3.2, 3.1, 2.65 and 2.05 Šresolution, respectively. The data demonstrate the feasibility of serial millisecond crystallography from 5-20 µm crystals using a high-viscosity injector at APS. The resolution of the crystal structures obtained in this study was dictated by the current flux density and crystal size, but upcoming developments in beamline optics and the planned APS-U upgrade will increase the intensity by two orders of magnitude. These developments will enable structure determination from smaller and/or weakly diffracting microcrystals.

Glipizide matrix transdermal systems for diabetes mellitus: preparation, in vitro and preclinical studies.

The aim of the present investigation was to prepare glipizide matrix transdermal systems using the combinations of ethyl cellulose/polyvinylpyrrolidone and Eudragit RL-100/Eudragit RS-100. The systems were evaluated for various in vitro (drug content, drug permeation, scanning electron microscopy and drug-polymer interactions) and in vivo (acute and long-term hypoglycemic activity, biochemical and histopathological studies, skin irritation and pharmacokinetic studies in mice) parameters. Drug content of the patches was found to be more than 98%. Variations in drug permeation profiles were observed among various formulations. The scanning electron microscopy of the patches showed the formation of pores on the surface after in vitro permeation studies. The drug-polymer interaction results suggested no interaction between drug and polymers. The in vivo results revealed that the patches successfully prevented the severe hypoglycemia in the initial hours and they were also effective on chronic application. The transdermal route exhibited negligible skin irritation and produced better improvement with all the tested in vivo parameters compared to oral administration.