Customisable 3D printed microfluidics for integrated analysis and optimisation

The formation of smart Lab-on-a-Chip (LOC) devices featuring integrated sensing optics is currently hindered by convoluted and expensive manufacturing procedures. In this work, a series of 3D-printed LOC devices were designed and manufactured via stereolithography (SL) in a matter of hours. The spectroscopic performance of a variety of optical fibre combinations were tested, and the optimum path length for performing Ultraviolet-visible (UV-vis) spectroscopy determined. The information gained in these trials was then used in a reaction optimisation for the formation of carvone semicarbazone. The production of high resolution surface channels (100–500 μm) means that these devices were capable of handling a wide range of concentrations (9 μM–38 mM), and are ideally suited to both analyte detection and process optimisation. This ability to tailor the chip design and its integrated features as a direct result of the reaction being assessed, at such a low time and cost penalty greatly increases the user's ability to optimise both their device and reaction. As a result of the information gained in this investigation, we are able to report the first instance of a 3D-printed LOC device with fully integrated, in-line monitoring capabilities via the use of embedded optical fibres capable of performing UV-vis spectroscopy directly inside micro channels

The politics of the teaching of reading

Historically, political debates have broken out over how to teach reading in primary schools and infant classrooms. These debates and “reading wars” have often resulted from public concerns and media reportage of a fall in reading standards. They also reflect the importance placed on learning to read by parents, teachers, employers, and politicians. Public and media-driven controversies over the teaching of reading have resulted in intense public and professional debates over which specific methods and materials to use with beginning readers and with children who have reading difficulties. Recently, such debates have led to a renewed emphasis on reading proficiency and “standardized” approaches to teaching reading and engaging with literacy. The universal acceptance of the importance of learning to read has also led to vested interests in specific methods, reading programmes, and early literacy assessments amongst professional, business, commercial, and parental lobbying groups. This article traces these debates and the resulting growing support for a quantitative reductionist approach to early-reading programmes

Beyond Bernoulli: Improving the Accuracy and Precision of Noninvasive Estimation of Peak Pressure Drops

Background: Transvalvular peak pressure drops are routinely assessed noninvasively by echocardiography using the Bernoulli principle. However, the Bernoulli principle relies on several approximations that may not be appropriate, including that the majority of the pressure drop is because of the spatial acceleration of the blood flow, and the ejection jet is a single streamline (single peak velocity value). Methods and Results: We assessed the accuracy of the Bernoulli principle to estimate the peak pressure drop at the aortic valve using 3-dimensional cardiovascular magnetic resonance flow data in 32 subjects. Reference pressure drops were computed from the flow field, accounting for the principles of physics (ie, the Navier–Stokes equations). Analysis of the pressure components confirmed that the spatial acceleration of the blood jet through the valve is most significant (accounting for 99% of the total drop in stenotic subjects). However, the Bernoulli formulation demonstrated a consistent overestimation of the transvalvular pressure (average of 54%, range 5%–136%) resulting from the use of a single peak velocity value, which neglects the velocity distribution across the aortic valve plane. This assumption was a source of uncontrolled variability. Conclusions: The application of the Bernoulli formulation results in a clinically significant overestimation of peak pressure drops because of approximation of blood flow as a single streamline. A corrected formulation that accounts for the cross-sectional profile of the blood flow is proposed and adapted to both cardiovascular magnetic resonance and echocardiographic data

National Survey of Patients’ Bill of Rights Statutes

BACKGROUND Despite vigorous national debate between 1999–2001 the federal patients' bill of rights (PBOR) was not enacted. However, states have enacted legislation and the Joint Commission defined an accreditation standard to present patients with their rights. Because such initiatives can be undermined by overly complex language, we surveyed the readability of hospital PBOR documents as well as texts mandated by state law. METHODS State Web sites and codes were searched to identify PBOR statutes for general patient populations. The rights addressed were compared with the 12 themes presented in the American Hospital Association's (AHA) PBOR text of 2002. In addition, we obtained PBOR texts from a sample of hospitals in each state. Readability was evaluated using Prose, a software program which reports an average of eight readability formulas RESULTS Of 23 states with a PBOR statute for the general public, all establish a grievance policy, four protect a private right of action, and one stipulates fines for violations. These laws address an average of 7.4 of the 12 AHA themes. Nine states' statutes specify PBOR text for distribution to patients. These documents have an average readability of 15th grade (range, 11.6, New York, to 17.0, Minnesota). PBOR documents from 240 US hospitals have an average readability of 14th grade (range, 8.2 to 17.0) CONCLUSIONS While the average U.S. adult reads at an 8th grade reading level, an advanced college reading level is routinely required to read PBOR documents. Patients are not likely to learn about their rights from documents they cannot read.Pfizer Clear Health Communication Initiativ

Numerical study of nonlinear heat transfer from a wavy surface to a high permeability medium with pseudo-spectral and smoothed particle methods

Motivated by petro-chemical geological systems, we consider the natural convection boundary layer flow from a vertical isothermal wavy surface adjacent to a saturated non-Darcian high permeability porous medium. High permeability is considered to represent geologically sparsely packed porous media. Both Darcian drag and Forchheimer inertial drag terms are included in the velocity boundary layer equation. A high permeability medium is considered. We employ a sinusoidal relation for the wavy surface. Using a set of transformations, the momentum and heat conservation equations are converted from an (x, y) coordinate system to an (x,η) dimensionless system. The two-point boundary value problem is then solved numerically with a pseudo-spectral method based on combining the Bellman–Kalaba quasi linearization method with the Chebyschev spectral collocation technique (SQLM). The SQLM computations are demonstrated to achieve excellent correlation with smoothed particle hydrodynamic (SPH) Lagrangian solutions. We study the effect of Darcy number (Da), Forchheimer number (Fs), amplitude wavelength (A) and Prandtl number (Pr) on the velocity and temperature distributions in the regime. Local Nusselt number is also computed for selected cases. The study finds important applications in petroleum engineering and also energy systems exploiting porous media and undulating (wavy) surface geometry. The SQLM algorithm is shown to be exceptionally robust and achieves fast convergence and excellent accuracy in nonlinear heat transfer simulations

Correction : Transcriptome analysis of pigeon milk production - role of cornification and triglyceride synthesis genes

Stanley, D ORCiD: 0000-0001-7019-4726Background The pigeon crop is specially adapted to produce milk that is fed to newly hatched young. The process of pigeon milk production begins when the germinal cell layer of the crop rapidly proliferates in response to prolactin, which results in a mass of epithelial cells that are sloughed from the crop and regurgitated to the young. We proposed that the evolution of pigeon milk built upon the ability of avian keratinocytes to accumulate intracellular neutral lipids during the cornification of the epidermis. However, this cornification process in the pigeon crop has not been characterised. Results We identified the epidermal differentiation complex in the draft pigeon genome scaffold and found that, like the chicken, it contained beta-keratin genes. These beta-keratin genes can be classified, based on sequence similarity, into several clusters including feather, scale and claw keratins. The cornified cells of the pigeon crop express several cornification-associated genes including cornulin, S100-A9 and A16-like, transglutaminase 6-like and the pigeon ‘lactating’ crop-specific annexin cp35. Beta-keratins play an important role in ‘lactating’ crop, with several claw and scale keratins up-regulated. Additionally, transglutaminase 5 and differential splice variants of transglutaminase 4 are up-regulated along with S100-A10. Conclusions This study of global gene expression in the crop has expanded our knowledge of pigeon milk production, in particular, the mechanism of cornification and lipid production. It is a highly specialised process that utilises the normal keratinocyte cellular processes to produce a targeted nutrient solution for the young at a very high turnover. Background Pigeon lactation was first noted in the literature in 1786 when John Hunter described pigeon milk as being like “..granulated white curd” [1]. This curd-like substance is produced in the crop of male and female pigeons and regurgitated to the young. Like the mammary gland, the pigeon crop undergoes significant changes to the tissue structure during lactation. Several histological studies have characterised these changes and determined that pigeon milk consists of desquamated, sloughed crop epithelial cells [2, 3]. The process of pigeon milk production begins when the germinal cell layer of the crop rapidly proliferates in response to prolactin [4, 5], and this results in a convoluted, highly folded epithelial structure that then coalesces as it out-grows the vasculature, to form the nutritive cell layer that is sloughed off to produce the milk. This nutritive cell layer contains lipid-filled vacuoles [2, 3, 5, 6]. The lipid content of pigeon milk consists mainly of triglycerides, along with phospholipids, cholesterol, free fatty acids, cholesterol esters and diglycerides [7]. The triglyceride content decreases across the lactation period, from 81.2% of total lipid at day one, to 62.7% at day 19, whereas the other lipids increase, which suggests the cellular lipid content decreases towards the end of the lactation period, but the cell membrane-associated lipids remain constant [7]. Several studies have investigated the differences in gene expression between ‘lactating’ pigeon crop tissue and non-‘lactating’ crop tissue [6, 8, 9]. Nearly three decades ago, Horseman and Pukac were the first to identify that mRNA species differ in response to prolactin injection in the crop [8]. Specifically, they identified and characterised gene expression and protein translation of the prolactin-responsive mRNA anxI cp35 and the non-prolactin-responsive isoform, anxI cp37 [9, 10]. In addition, a recent global gene expression study in our laboratory [6] showed that genes encoding products involved in triglyceride synthesis and tissue signalling were up-regulated in the ‘lactating’ crop. We proposed that the evolution of the processes that result in the production of pigeon milk has built upon the more general ability of avian keratinocytes to accumulate intracellular neutral lipids during the cornification of the epidermis [11] in order to produce a nutritive substance for their young [6]. The mechanism of avian epidermal cornification and lipid accumulation is not well-characterised. However, studies have shown that antibodies against mammalian cornification proteins, which are relatively well-characterised, can cross-react with avian and reptilian species [12, 13], which suggests similarities in cornification proteins amongst vertebrate species. Cultured chicken keratinocytes have been shown to express beta-keratins (feather, scale and claw keratins), alpha-keratins (type I and II cytokeratins) and the cornified envelope precursor genes envoplakin and periplakin, as well as accumulating neutral lipids [11]. Mammalian keratinocytes differ from avian keratinocytes in that they are unable to accumulate intracellular neutral lipids [11], and can express alpha-keratins (cytokeratins) but not beta-keratins, which expanded from early archosaurians [14]. There are many cornification-associated proteins characterised from mammalian epidermal tissues. The proteins that form the cornified envelope include keratins, S100 proteins, small proline-rich proteins (SPRRs), late cornified envelope (LCE) proteins, annexins, involucrin, loricrin, filaggrin, desmoplakin, envoplakin, periplakin, trichohyalin, cystatin A, elafin and repetin [15]. Trans-glutaminase enzymes, some of which require cleavage by proteases and an increase in intracellular calcium concentration to become active, cross-link the cornified envelope proteins to form a ceramide lipid-coated protective barrier to the epidermis [16]. Many of the cornified envelope genes are present in the “epidermal differentiation complex” (EDC) which was first identified on chromosome 1q21 in humans [17]. Interestingly, the EDC region has been identified in an avian species (chicken), and is linked to the genes for beta-keratins, but lacks the LCE proteins [18]. Here we present an analysis of the pigeon crop transcriptome to show that pigeon milk production involves a specialised cornification process and de novo synthesis of lipids that accumulate intracellularly

The Therapeutic Evaluation of Steroids in IgA Nephropathy Global (TESTING) Study: Trial Design and Baseline Characteristics

INTRODUCTION: Despite optimal current care, up to 30% of individuals suffering from immunoglobulin A nephropathy (IgAN) will develop kidney failure requiring dialysis or kidney transplantation. The Therapeutic Evaluation of STeroids in IgA Nephropathy Global (TESTING) study was designed to assess the benefits and risks of steroids in people with IgAN. We report the trial design as well as the baseline characteristics of study participants. METHODS: It is an investigator-initiated, multicenter, double-blind, placebo-controlled, randomized trial of individuals with kidney biopsy-confirmed IgAN, proteinuria ≥1 g/day, and an estimated GFR of 20-120 mL/min/1.73 m2, following at least 3 months of standard of care including maximum labelled (or tolerated) dose of renin-angiotensin system blockade. The original study design randomized participants 1:1 to oral methylprednisolone (0.6-0.8 mg/kg/day, maximum 48 mg/day) for 2 months, with subsequent weaning by 8 mg/day/month over 6-8 months, or matching placebo. The intervention was modified in 2016 (due to an excess of serious infection) to low-dose methylprednisolone (0.4 mg/kg/day, maximum 32 mg/day) for 2 months, followed by weaning by 4 mg/day/month over 6-9 months, or matching placebo. Participants recruited after 2016 also received prophylaxis against Pneumocystis jirovecii pneumonia during the first 12 weeks of treatment. RESULTS: The study recruitment period extended from May 2012 to November 2019. By the time the excess of serious infections was observed, 262 participants had been randomized to the original full-dose treatment algorithm, and an interim analysis was reported in 2016. Subsequently, 241 additional participants were randomized to a revised low-dose protocol, for a total of 503 participants from China (373), India (78), Canada (24), Australia (18), and Malaysia (10). The mean age of randomized participants was 38, 39% were female, mean eGFR at randomization was 62.7 mL/min/1.73 m2, and mean 24-h urine protein 2.54 g. The primary endpoint is a composite of 40% eGFR decline from baseline or kidney failure (dialysis, transplantation, or death due to kidney disease), and participants will be followed until the primary outcome has been observed in at least 160 randomized participants. Analyses will also be made across predefined subgroups. Effects on eGFR slope and albuminuria will also be assessed overall, as well as by the steroid dosing regimen. CONCLUSIONS: The TESTING study (combined full and low dose) will define the benefits of corticosteroid use on major kidney outcomes, as well as the risks of therapy, and provide data on the relative effects of different doses, in individuals with high-risk IgAN

Impact of COVID-19 on UK stress echocardiography practice: insights from the EVAREST sites.

Healthcare delivery is being transformed by COVID-19 to reduce transmission risk but continued delivery of routine clinical tests is essential. Stress echocardiography is one of the most widely used cardiac tests in the NHS. We assessed the impact of the first (W1) and second (W2) waves of the pandemic on ability to deliver stress echocardiography. Clinical echocardiography teams in 31 NHS hospitals participating in the EVAREST study were asked in July and November 2020 to complete a survey on the structure and delivery of stress echocardiography as well as impact on patients and staff. Results were compared to stress echocardiography activity in the same centre during January 2020. 24 and 19 NHS hospitals completed the survey in July and November, respectively. A 55% reduction in the number of studies performed was reported in W1, recovering to exceed pre-COVID rates in W2. The major change was in mode of stress delivery. 70% of sites stopped their exercise stress service in W1, compared to 19% in W2. In those still using exercise during W1, 50% were wearing FFP3/N95 masks, falling to 38% in W2. There was also significant variability in patient screening practices with 7 different pre-screening questionnaires used in W1 and 6 in W2. Stress echocardiography delivery restarted effectively after COVID-19 with adaptations to reduce transmission that means activity has been able to continue, and exceed, pre-COVID-19 levels during the second wave. Further standardisation of protocols for patient screening and PPE may help further improve consistency of practice within the UK

Loss of flight promotes beetle diversification

The evolution of flight is a key innovation that may enable the extreme diversification of insects. Nonetheless, many species-rich, winged insect groups contain flightless lineages. The loss of flight may promote allopatric differentiation due to limited dispersal power and may result in a high speciation rate in the flightless lineage. Here we show that loss of flight accelerates allopatric speciation using carrion beetles (Coleoptera: Silphidae). We demonstrate that flightless species retain higher genetic differentiation among populations and comprise a higher number of genetically distinct lineages than flight-capable species, and that the speciation rate with the flightless state is twice that with the flight-capable state. Moreover, a meta-analysis of 51 beetle species from 15 families reveals higher genetic differentiation among populations in flightless compared with flight-capable species. In beetles, which represent almost one-fourth of all described species, repeated evolution of flightlessness may have contributed to their steady diversification since the Mesozoic era