The application of antimicrobial stewardship knowledge to nursing practice: A national survey of United Kingdom pre-registration nursing students.

AIM: To assess student nurses understanding and skills in the application of antimicrobial stewardship knowledge to practice. DESIGN: Quantitative. METHODS: Cross-sectional survey. RESULTS: Five hundred and twenty three student nurses responded across 23 UK universities. Although students felt prepared in competencies in infection prevention and control, patient-centred care and interprofessional collaborative practice, they felt less prepared in competencies in which microbiological knowledge, prescribing and its effect on antimicrobial stewardship is required. Problem-based learning, activities in the clinical setting and face-to-face teaching were identified as the preferred modes of education delivery. Those who had shared antimicrobial stewardship teaching with students from other professions reported the benefits to include a broader understanding of antimicrobial stewardship, an understanding of the roles of others in antimicrobial stewardship and improved interprofessional working. CONCLUSION: There are gaps in student nurses' knowledge of the basic sciences associated with the antimicrobial stewardship activities in which nurses are involved, and a need to strengthen knowledge in pre-registration nurse education programmes pertaining to antimicrobial management, specifically microbiology and antimicrobial regimes and effects on antimicrobial stewardship. Infection prevention and control, patient-centred care and interprofessional collaborative practice are areas of antimicrobial stewardship in which student nurses feel prepared. Interprofessional education would help nurses and other members of the antimicrobial stewardship team clarify the role nurses can play in antimicrobial stewardship and therefore maximize their contribution to antimicrobial stewardship and antimicrobial management. IMPLICATIONS FOR THE PROFESSION: There is a need to strengthen knowledge from the basic sciences, specifically pertaining to antimicrobial management, in pre-registration nurse education programmes. PATIENT OR PUBLIC CONTRIBUTION: No patient or public contribution. IMPACT: What Problem Did the Study Address? Nurses must protect health through understanding and applying antimicrobial stewardship knowledge and skills (Nursing and Midwifery Council 2018); however, there is no research available that has investigated nurses understanding and skills of the basic sciences associated with the antimicrobial stewardship activities in which they are involved. What Were the Main Findings? There are gaps in student nurses' knowledge of the basic sciences (specifically microbiology and prescribing) associated with the antimicrobial stewardship activities in which nurses are involved. Problem-based learning, and activities in the clinical setting, were reported as useful teaching methods, whereas online learning, was seen as less useful. Where and on Whom Will the Research Have an Impact? Pre-registration nurse education programmes. REPORTING METHOD: The relevant reporting method has been adhered to, that is, STROBE.

The global distribution of special needs dentistry across dental school curricula.

INTRODUCTION: Special needs dentistry (SND) is an emerging dental specialty, with ongoing developments in education and clinical practice focused towards the tailored management of individuals with special needs (SN). Patients with SN have a higher prevalence of oral diseases and unmet dental needs compared to the general population. Although inadequate training and experience in managing patients with SN has been highlighted as a significant barrier to accessing care, there is limited data about the extent of SND teaching at the entry-to-practice or higher levels. METHODS: This work is the first to map SND curricula globally, across 180 countries and 1265 dental schools. RESULTS: Although 74.62% of dental schools were found in developing economies, the distribution of programs that reported SND in their courses was highly skewed towards developed countries. In terms of advanced degrees, beyond basic entry-to-practice training, the USA delivered 60% of the SND programs, followed by Canada (15.56%), UK (13.33%), and Australia (8.89%). The term SND appeared in 33.95% of entry-to-practice level program curricula and was less commonly used in transitioning economies. Only 112 SND-specialized practitioners enter the workforce globally each year from developed economies, and all but three advanced degrees are found in G7 countries. CONCLUSION: By exploring the impact of economic status on its distribution, this paper highlighted the lack of SND representation in dental curricula, especially amongst programs in transitioning or developing economies. Education of both general dentists and specialists is critical as a collaborative effort is needed to manage the growing population of patients with SN.

A Screening Program for SARS-CoV-2 among University of Hawai'i at Manoa Residence Hall Students during the COVID-19 Pandemic.

The University of Hawai'i at Manoa (UHM) created a COVID-19 pandemic team to collaborate, plan, and mitigate the spread of COVID-19 across the campus. The purpose of this study was to identify asymptomatic and pre-symptomatic cases of SARS-CoV-2 among unvaccinated UHM residence hall students during 3 distinct intervals (semesters) within the COVID-19 pandemic. Supervised self-administered nasal swab testing samples were collected from unvaccinated UHM residence hall students and sent to a clinical laboratory for COVID-19 RT-PCR testing to detect SARS-CoV-2. Positive cases were contacted and placed in isolation while contact tracing was initiated. The screening program performed 2219 tests on 725 unique persons with the identification of COVID-19 infections in 38 asymptomatic unvaccinated students and an additional 10 cases through contact tracing. A positive correlation existed between the screening program case numbers and the state of Hawai'i 7-day average positive cases as demonstrated with a Pearson coefficient of 0.79 and P<.001. The COVID-19 positivity rate was greater during Spring Semester 2022 compared to both Spring Semester 2021 (P<.001) and Fall Semester 2021 (P <.001). This program served as a component ofa larger strategy to mitigate the effects of the COVID-19 pandemic on the UHM campus. Additional benefits of the program included opportunities to increase COVID-19 awareness, enact health policy measures, evolve to meet changing pandemic demands, and maintain a safe UHM campus.

STAR-0215 is a Novel, Long-Acting Monoclonal Antibody Inhibitor of Plasma Kallikrein for the Potential Treatment of Hereditary Angioedema.

Hereditary angioedema (HAE) is a rare autosomal dominant disorder caused by a deficiency in functional C1 esterase inhibitor, a serpin family protein that blocks the activity of plasma kallikrein. Insufficient inhibition of plasma kallikrein results in the overproduction of bradykinin, a vasoactive inflammatory mediator that produces both pain and unpredictable swelling during HAE attacks, with potentially life-threatening consequences. We describe the generation of STAR-0215, a humanized IgG1 antibody with a long circulating half-life (t1/2) that potently inhibits plasma kallikrein activity, with a >1000-fold lower affinity for prekallikrein and no measurable inhibitory activity against other serine proteases. The high specificity and inhibitory effect of STAR-0215 is demonstrated through a unique allosteric mechanism involving N-terminal catalytic domain binding, destabilization of the activation domain, and reversion of the active site to the inactive zymogen state. The YTE (M252Y/S254T/T256E) modified fragment crystallizable (Fc) domain of STAR-0215 enhances pH-dependent neonatal Fc receptor binding, resulting in a prolonged t1/2 in vivo (∼34 days in cynomolgus monkeys) compared with antibodies without this modification. A single subcutaneous dose of STAR-0215 (≥100 mg) was predicted to be active in patients for 3 months or longer, based on simulations using a minimal physiologically based pharmacokinetic model. These data indicate that STAR-0215, a highly potent and specific antibody against plasma kallikrein with extended t1/2, is a potential agent for long-term preventative HAE therapy administered every 3 months or less frequently. SIGNIFICANCE STATEMENT: STAR-0215 is a YTE-modified immunoglobulin G1 monoclonal antibody with a novel binding mechanism that specifically and potently inhibits the enzymatic activity of plasma kallikrein and prevents the generation of bradykinin. It has been designed to be a long-lasting prophylactic treatment to prevent attacks of HAE and to decrease the burden of disease and the burden of treatment for people with HAE.

Exploring the psychological effects of sharps injuries sustained by healthcare workers.

Much of the research into sharps injuries sustained by healthcare workers focuses on prevalence and incidence and to a lesser extent the financial implications of such injuries. An under-researched area is the psychological effects of such injuries. This article reports the findings of a narrative literature review that aimed to synthesise the evidence on this subject. Electronic databases and the grey literature were searched with no date limits set and 27 articles were included in the review. Findings suggested that healthcare workers may experience a range of psychological issues following a sharps injury, including post-traumatic stress disorder, anxiety and depression. There was also evidence to suggest that the necessary psychological follow-up care is often inadequate, so improvements are required in this area. Further research is necessary to enhance understanding of the psychological effects of sharps injuries on healthcare workers and to ensure they receive appropriate support.

Investigating the incidence and type of sharps injuries within the nursing student population in the UK.

AIMS: To identify the incidence and type of sharps injuries within a UK nursing student population. BACKGROUND: Evidence suggests that nursing students sustain sharps injuries across the world, but there is a lack of data from the UK. Design: Questionnaire survey. METHODS: A survey was administered to a volunteer sample of nursing students (n=1015) in a university, following which the survey was distributed to nursing students nationwide using snowball sampling via social media. Datasets from 1015 nursing students were available for analysis. RESULTS: Sharps injuries were most likely to occur with glass ampoules, when preparing injections and to occur in the second year of the programme. Contributing factors to sharps injury were identified, with inexperience being the primary cause. Some nursing students reported psychological impacts after sustaining the sharps injury. CONCLUSION: Sharps injuries are common among nursing students, and can have many psychological consequences for an individual.

PGFinder, a novel analysis pipeline for the consistent, reproducible, and high-resolution structural analysis of bacterial peptidoglycans.

Many software solutions are available for proteomics and glycomics studies, but none are ideal for the structural analysis of peptidoglycan (PG), the essential and major component of bacterial cell envelopes. It icomprises glycan chains and peptide stems, both containing unusual amino acids and sugars. This has forced the field to rely on manual analysis approaches, which are time-consuming, labour-intensive, and prone to error. The lack of automated tools has hampered the ability to perform high-throughput analyses and prevented the adoption of a standard methodology. Here, we describe a novel tool called PGFinder for the analysis of PG structure and demonstrate that it represents a powerful tool to quantify PG fragments and discover novel structural features. Our analysis workflow, which relies on open-access tools, is a breakthrough towards a consistent and reproducible analysis of bacterial PGs. It represents a significant advance towards peptidoglycomics as a full-fledged discipline.

The experience and psychological impact of a sharps injury on a nursing student population in the UK.

AIMS: The aims of this study were to explore the experience and psychological impact of sustaining a sharps injury within a nursing student population in the UK. Design: A qualitative approach was taken, using two methods to gather data, namely a Twitter chat and interviews. METHODS: A Twitter chat was orchestrated to investigate the experiences of sharps injury with nursing students and registered nurses nationwide (n=71). Interviews were conducted with nursing students from a university in the UK who had sustained a sharps injury (n=12) to discover their experiences and the impact of the injury. Findings were then synthesised and examined. RESULTS: Some nursing students reported psychological impacts after sustaining the sharps injury, which affected both their professional and personal life. The qualitative findings were synthesised into eight themes. CONCLUSION: Sharps injuries can have many psychological impacts on the individual nursing student and necessary support should be available.

Disease-modifying effects of edasalonexent, an NF-κB inhibitor, in young boys with Duchenne muscular dystrophy: Results of the MoveDMD phase 2 and open label extension trial.

Chronic activation of NF-κB is a key driver of muscle degeneration and suppression of muscle regeneration in Duchenne muscular dystrophy. Edasalonexent (CAT-1004) is an orally-administered novel small molecule that covalently links two bioactive compounds (salicylic acid and docosahexaenoic acid) that inhibit NF-κB. This placebo-controlled, proof-of-concept phase 2 study with open-label extension in boys ≥4-<8 years old with any dystrophin mutation examined the effect of edasalonexent (67 or 100 mg/kg/day) compared to placebo or off-treatment control. Endpoints were safety/tolerability, change from baseline in MRI T2 relaxation time of lower leg muscles and functional assessment, as well as pharmacodynamics and biomarkers. Treatment was well-tolerated and the majority of adverse events were mild, and most commonly of the gastrointestinal system (primarily diarrhea). There were no serious adverse events in the edasalonexent groups. Edasalonexent 100 mg/kg was associated with slowing of disease progression and preservation of muscle function compared to an off-treatment control period, with decrease in levels of NF-κB-regulated genes and improvements in biomarkers of muscle health and inflammation. These results support investigating edasalonexent in future trials and have informed the design of the edasalonexent phase 3 clinical trial in boys with Duchenne.

Orthogonal Comparison of Analytical Methods by Theoretical Reconstruction from Bottom-up Assay Data.

In the never-ending endeavor to produce stable and efficacious protein therapeutics, biopharmaceutical companies often employ numerous analytical techniques to characterize and quantify a drug candidate's stability. Mass spectrometry, due to the information-rich data it produces, is commonly used in its numerous configurations to ascertain chemical and structural stability. At issue is the comparison of the various configurations utilized, that is, comparing bottom-up methods such as proteolytic digest followed by reversed phase LC-MS with intact LC-MS methods. Similar issues also arise when using capillary isoelectric focusing to see how charge variants change over time, that is, monitoring the progression of charge altering modifications like deamidation. To this end, site-specific degradations as quantified from bottom-up methods like peptide mapping can be used to build reconstructions of both theoretical intact mass spectra as well as theoretical electropherograms. The result can then be superimposed over the experimental data to qualitatively, and perhaps quantitatively, evaluate differences. In theory, if both experimental bottom-up data and intact data are accurate, the theoretical reconstruction produced from the bottom-up data should perfectly overlay with that of the experimental data. Valuable secondary information can also be ascertained from reconstructions, such as whether modifications are stochastic, as well as a detailed view of all possible combinations of modifications and their quantities used in the reconstruction. This comparison is also useful in determining unknown mass differences in deconvoluted intact protein spectra that may be a result of multiple modifications in combination. The comparison of data from alternate sources provides a holistic and more comprehensive view of the molecule under study.

The lysosomal endopeptidases Cathepsin D and L are selective and effective proteases for the middle-down characterization of antibodies.

Mass spectrometry is gaining momentum as a method of choice to de novo sequence antibodies (Abs). Adequate sequence coverage of the hypervariable regions remains one of the toughest identification challenges by either bottom-up or top-down workflows. Methods that efficiently generate mid-size Ab fragments would further facilitate top-down MS and decrease data complexity. Here, we explore the proteases Cathepsins L and D for forming protein fragments from three IgG1s, one IgG2, and one bispecific, knob-and-hole IgG1. We demonstrate that high-resolution native MS provides a sensitive method for the detection of clipping sites. Both Cathepsins produced multiple, albeit specific cleavages. The Abs were cleaved immediately after the CDR3 region, yielding ~ 12 kDa fragments, that is, ideal sequencing-sized. Cathepsin D, but not Cathepsin L, also cleaved directly below the Ab hinge, releasing the F(ab')2. When constrained by the different disulfide bonds found in the IgG2 subtype or by the tertiary structure of the hole-containing bispecific IgG1, the hinge region digest product was not produced. The Cathepsin L and Cathepsin D clipping motifs were related to sequences of neutral amino acids and the tertiary structure of the Ab. A single pot (L + D) digestion protocol was optimized to achieve 100% efficiency. Nine protein fragments, corresponding to the VL, VH, CL, CH1, CH2, CH3, CL + CH1, and F(ab')2, constituted ~ 70% of the summed intensities of all deconvolved proteolytic products. Cleavage sites were confirmed by the Edman degradation and validated with top-down sequencing. The described work offers a complementary method for middle-down analysis that may be applied to top-down Ab sequencing. ENZYMES: Cathepsin L-EC 3.4.22.15, Cathepsin D-EC 3.4.23.5.

Identification of critical chemical modifications and paratope mapping by size exclusion chromatography of stressed antibody-target complexes.

Therapeutic proteins including antibodies and Fc-fusion proteins undergo a large number of chemical modifications during cell culture, purification, storage and in human circulation. They are also exposed to harsh conditions during stress studies, including elevated temperature, extremes of pH, forced oxidation, physiological pH, UV light to assess the possible degradation pathways and suitability of methods for detecting them. Some of these modifications are located on residues in binding regions, leading to loss of binding and potency and classified as critical quality attributes. Currently, criticality of modifications is assessed by a laborious process of collecting antibody fractions from the soft chromatography techniques ion exchange and hydrophobic interaction chromatography and characterizing the fractions one-by-one for potency and chemical modifications. Here, we describe a method for large-scale, parallel identification of all critical chemical modifications in one experiment. In the first step, the antibody is stressed by one or several stress methods. It is then mixed with target protein and separated by size-exclusion chromatography (SEC) on bound antibody-target complex and unbound antibody. Peptide mapping of fractions and statistical analysis are performed to identify modifications on amino acid residues that affect binding. To identify the modifications leading to slight decreases in binding, competitive SEC of antibody and antigen mixtures was developed and described in a companion study by Shi et al, where target protein is provided at lower level, below the stoichiometry. The newly described method was successfully correlated to crystallography for assessing criticality of chemical modifications and paratope mapping. It is more sensitive to low-level modifications, better streamlined and platform ready.

Combined methazolamide and theophylline improves oxygen saturation but not exercise performance or altitude illness in acute hypobaric hypoxia.

NEW FINDINGS: What is the central question of this study? Does the combination of methazolamide and theophylline reduce symptoms of acute mountain sickness (AMS) and improve aerobic performance in acute hypobaric hypoxia? What is the main finding and its importance? The oral combination of methazolamide (100 BID) and theophylline (300 BID) improved arterial oxygen saturation but did not reduce symptoms of AMS and impaired aerobic performance. We do not recommend this combination of drugs for prophylaxis against the acute negative effects of hypobaric hypoxia. ABSTRACT: A limited number of small studies have suggested that methazolamide and theophylline can independently reduce symptoms of acute mountain sickness (AMS) and, if taken together, can improve aerobic exercise performance in normobaric hypoxia. We performed a randomized, double-blind, placebo-controlled, cross-over study to determine if the combination of oral methazolamide and theophylline could provide prophylaxis against AMS and improve aerobic performance in hypobaric hypoxia (∼4875 m). Volunteers with histories of AMS were screened at low altitude (1650 m) and started combined methazolamide (100 mg BID) and theophylline (300 mg BID) treatment, or placebo, 72 h prior to decompression. Baseline AMS (Lake Louise Questionnaire), blood (haemoglobin, haematocrit), cognitive function, ventilatory and pulse oximetry ( SpO2 ) measures were assessed at low altitude and repeated between 4 and 10 h of exposure to hypobaric hypoxia (PB  = 425 mmHg). Aerobic exercise performance was assessed during a 12.5 km cycling time trial (TT) after 4 h of hypobaric hypoxia. Subjects repeated all experimental procedures after a 3-week washout period. Differences between drug and placebo trials were evaluated using repeated measures ANOVA (α = 0.05). The drugs improved resting SpO2 by ∼4% (P < 0.01), but did not affect the incidence or severity of AMS or cognitive function scores relative to placebo. Subjects' performance on the 12.5 km TT was ∼3% worse when taking the drugs (P < 0.01). The combination of methazolamide and theophylline in the prescribed dosages is not recommended for use at high altitude as it appears to have no measurable effect on AMS and can impair aerobic performance.

Conductance-Based Interface Detection for Multi-Phase Pipe Flow.

Sediment and flow depth monitoring in sewers is important for informing flow models and for predicting and mitigating against sewer blockage formation and surcharge. In this study, a novel sensor based on conductance measurement has been developed and tested under a laboratory environment and validated by a finite-element model. The relative conductance is measured between pairs of adjacent electrodes to provide a conductance profile along the sensor length. A piecewise linear relationship between conductance and electrode length was derived and the interface positions between sediment, water, and air can be determined from the profile. The results demonstrated that the root mean square error of the model and the measured interface level are within 1.4% and 2.6% of sensor's measurement range. An error distribution of interface height shows that all anticipated errors are within the resolution of the electrode length increments. Furthermore, it was found that the conductivity of the measured medium is proportional to the gradient of the linear relationship of conductance and electrode length. It could therefore prove a valuable new tool for the accurate quantification of sediment and flow levels in sewer conduits, coastal environments, drainage systems for transport networks, and other industrial or academic applications.

Optimal Use of Titanium Dioxide Colourant to Enable Water Surfaces to Be Measured by Kinect Sensors.

Recent studies have sought to use Microsoft Kinect sensors to measure water surface shape in steady flows or transient flow processes. They have typically employed a white colourant, usually titanium dioxide (TiO2), in order to make the surface opaque and visible to the infrared-based sensors. However, the ability of Kinect Version 1 (KV1) and Kinect Version 2 (KV2) sensors to measure the deformation of ostensibly smooth reflective surfaces has never been compared, with most previous studies using a V1 sensor with no justification. Furthermore, the TiO2 has so far been used liberally and indeterminately, with no consideration as to the type of TiO2 to use, the optimal proportion to use or the effect it may have on the very fluid properties being measured. This paper examines the use of anatase TiO2 with two generations of the Microsoft Kinect sensor. Assessing their performance for an ideal flat surface, it is shown that surface data obtained using the V2 sensor is substantially more reliable. Further, the minimum quantity of colourant to enable reliable surface recognition is discovered (0.01% by mass). A stability test shows that the colourant has a strong tendency to settle over time, meaning the fluid must remain well mixed, having serious implications for studies with low Reynolds number or transient processes such as dam breaks. Furthermore, the effect of TiO2 concentration on fluid properties is examined. It is shown that previous studies using concentrations in excess of 1% may have significantly affected the viscosity and surface tension, and thus the surface behaviour being measured. It is therefore recommended that future studies employ the V2 sensor with an anatase TiO2 concentration of 0.01%, and that the effects of TiO2 on the fluid properties are properly quantified before any TiO2-Kinect-derived dataset can be of practical use, for example, in validation of numerical models or in physical models of hydrodynamic processes.

Metabolism of bioconjugate therapeutics: why, when, and how?

Bioconjugation of therapeutic agents has been used as a selective drug delivery platform for many therapeutic areas. Bioconjugates are prepared by the covalent linkage of active compounds (small or large molecule) to a carrier molecule (lipids, proteins, peptides, carbohydrates, and polymers) through a chemical linker. The linkage of the active component to a carrier molecule enhances the therapeutic window through a targeted delivery and by reducing toxicity. Bioconjugates also possess improved pharmacokinetic properties such as a long half-life, increased stability, and cleavage by intracellular enzymes/environment. However, premature cleavage of the bioconjugates and the resulting metabolites/catabolites may produce undesirable toxic effects and, hence, it is critical to understand cleavage mechanisms, metabolism of bioconjugates, and translatability to human in the discovery stages. This article provides a comprehensive overview of linker cleavage pathways and catabolism/metabolism of antibody-drug conjugates, glycoconjugates, polymer-drug conjugates, lipid-drug conjugates, folate-targeted small molecule-drug conjugates, and drug-drug conjugates.

Phase 1 Study of Edasalonexent (CAT-1004), an Oral NF-κB Inhibitor, in Pediatric Patients with Duchenne Muscular Dystrophy.

BACKGROUND: Edasalonexent is an orally administered small molecule designed to inhibit NF-κB, which is activated from infancy in Duchenne muscular dystrophy and is central to causing muscle damage and preventing muscle regeneration. OBJECTIVE: Evaluate the safety, tolerability, pharmacokinetics and exploratory pharmacodynamics of three doses of edasalonexent in ambulatory males ≥4 to <8 years of age with genetically confirmed Duchenne muscular dystrophy. METHODS: This was a 1-week, open-label, multiple-dose study with 3 sequential ascending doses (33, 67 and 100 mg/kg/day) of edasalonexent administered under different dietary conditions to 17 males with a mean age of 5.5 years. RESULTS: All doses of edasalonexent were well tolerated, with no serious adverse events, no drug discontinuations and no dose reductions. The majority of adverse events were mild, and the most common adverse events were gastrointestinal (primarily diarrhea). Edasalonexent was rapidly absorbed with peak levels observed 2-6 hours after dosing and exposures appeared to increase nearly proportionally to dose for the 2 lower and all 3 doses under low-fat and high-fat meal conditions, respectively. Only minor plasma accumulation of edasalonexent was observed with 7 days of dosing. After treatment with edasalonexent for 7 days, levels of NF-κB-regulated genes and serum proteins were decreased. CONCLUSIONS: This first report of edasalonexent oral administration for one week in male pediatric patients with Duchenne muscular dystrophy showed that treatment was well tolerated and inhibited NF-kB pathways.

Best available science still supports an ancient common origin of Devils Hole and Devils Hole pupfish.

The age of DHP and how pupfish colonized Devils Hole have always been a topic of interest. Recently, two different publications (Martin, Crawford, Turner, & Simons, & Saglam et al., ) tackled this issue using genomic data sets and demographic models but came to widely different conclusions. In their comment, Martin and Höhne () argue that our results (Saglam et al., ) were misleading because we used inappropriate calibration information and biased a priori assumptions. They then re-analysed our data using a "biologically informed" mutation rate prior and concluded that our data support a much younger age of DHP (12.6 kya) as opposed to 60 kya reported in our study. Below we will summarize why their arguments do not hold up and explore some of the inconsistencies between their claims and what was actually presented in our study. Furthermore, we will demonstrate their re-analyses provide no new information compared to what was presented in our original manuscript and reinforce our estimate of a 60 kya divergence of DHP as outweighing competing hypotheses.

SPH modelling of depth-limited turbulent open channel flows over rough boundaries.

A numerical model based on the smoothed particle hydrodynamics method is developed to simulate depth-limited turbulent open channel flows over hydraulically rough beds. The 2D Lagrangian form of the Navier-Stokes equations is solved, in which a drag-based formulation is used based on an effective roughness zone near the bed to account for the roughness effect of bed spheres and an improved sub-particle-scale model is applied to account for the effect of turbulence. The sub-particle-scale model is constructed based on the mixing-length assumption rather than the standard Smagorinsky approach to compute the eddy-viscosity. A robust in/out-flow boundary technique is also proposed to achieve stable uniform flow conditions at the inlet and outlet boundaries where the flow characteristics are unknown. The model is applied to simulate uniform open channel flows over a rough bed composed of regular spheres and validated by experimental velocity data. To investigate the influence of the bed roughness on different flow conditions, data from 12 experimental tests with different bed slopes and uniform water depths are simulated, and a good agreement has been observed between the model and experimental results of the streamwise velocity and turbulent shear stress. This shows that both the roughness effect and flow turbulence should be addressed in order to simulate the correct mechanisms of turbulent flow over a rough bed boundary and that the presented smoothed particle hydrodynamics model accomplishes this successfully.

CAT-2003: A novel sterol regulatory element-binding protein inhibitor that reduces steatohepatitis, plasma lipids, and atherosclerosis in apolipoprotein E*3-Leiden mice.

CAT-2003 is a novel conjugate of eicosapentaenoic acid (EPA) and niacin designed to be hydrolyzed by fatty acid amide hydrolase to release EPA inside cells at the endoplasmic reticulum. In cultured liver cells, CAT-2003 blocked the maturation of sterol regulatory element-binding protein (SREBP)-1 and SREBP-2 proteins and decreased the expression of multiple SREBP target genes, including HMGCR and PCSK9. Consistent with proprotein convertase subtilisin/kexin type 9 (PCSK9) reduction, both low-density lipoprotein receptor protein at the cell surface and low-density lipoprotein particle uptake were increased. In apolipoprotein E*3-Leiden mice fed a cholesterol-containing western diet, CAT-2003 decreased hepatic inflammation and steatosis as evidenced by fewer inflammatory cell aggregates in histopathologic sections, decreased nuclear factor kappa B activity in liver lysates, reduced inflammatory gene expression, reduced intrahepatic cholesteryl ester and triglyceride levels, and decreased liver mass. Plasma PCSK9 was reduced and hepatic low-density lipoprotein receptor protein expression was increased; plasma cholesterol and triglyceride levels were lowered. Aortic root segments showed reduction of several atherosclerotic markers, including lesion size, number, and severity. CAT-2003, when dosed in combination with atorvastatin, further lowered plasma cholesterol levels and decreased hepatic expression of SREBP target genes. Conclusion: SREBP inhibition is a promising new strategy for the prevention and treatment of diseases associated with abnormal lipid metabolism, such as atherosclerosis and nonalcoholic steatohepatitis. (Hepatology Communications 2017;1:311-325).