Clinical mentorship of nurse initiated antiretroviral therapy in Khayelitsha, South Africa: a quality of care assessment.

To combat the AIDS epidemic and increase HIV treatment access, the South African government implemented a nurse-based, doctor-supported model of care that decentralizes administration of antiretroviral treatment (ART) for HIV positive patients through nurse initiated and managed ART. Médecins Sans Frontières (MSF) implemented a mentorship programme to ensure successful task-shifting, subsequently assessing the quality of clinical care provided by nurses

Mary Ann Cox Index: Royal Society Collection

Burton-Wood: in a series of letters, by a lady (Mrs. - Cox nee Wight), London (printed for the author by H.D.Steel) 1783, vol.11 (octovo vol, leather bound) Enclosed: note The book Burtonwood was written by the mother of Mary Ann Cox who ran the first coach from Hobart to Launceston. It was passed on to me by her grand-daughter Miss Dora Clerk of Malahide. I also am a grand-daughter of Mrs. Cox. Joan Harvey (John Edward Cox m. Mary Ann Halls V.D.L. 1821 J.E.C. started Hobart-Launceston coach) - (note - Mrs. Harvey's identification of the author of the volume was based on family tradition although not confirmed - no details are known of John Edward Cox's parents) Poems by C(harles) Best c 1847 - 1849 Includes poems to Miss Wilmot (Georgiana Wilmot, - Mrs. C. Butler) and Mary Wilmot. Enclosed: note by Joan Harvey Article on Mrs. Mary Ann Cox 1950. A pioneer career woman (on coach service between Hobart - Launceston) from "Woman's Day" Aug. 21, 1950 (news clipping) R.S. 14

Assays for Measuring C. difficile Toxin Activity and Inhibition in Mammalian Cells

Clostridium difficile infections (CDIs) are the leading cause of hospital-acquired infectious diarrhea. The symptoms of CDI are caused by two exotoxins, TcdA and TcdB, which are structurally and functionally highly homologous. Both toxins bind to specific receptors on mammalian cells, are internalized through endocytosis, translocate to the cytoplasm, and inactivate Rho-type GTPases via covalent glucosylation. This leads to downstream events that include morphological changes and disruption of epithelial tight junctions, release of pro-inflammatory mediators, and cell death. Assays used to assess the effects of toxins on cells have historically relied on evaluation of cell rounding or quantitation of ATP levels to estimate cell death—assays which can be qualitative and variable. In this chapter, several assays are described that robustly and quantitatively measure early and late toxin-dependent events in cells, including (i) toxin binding, (ii) Rac1 glucosylation, (iii) changes in cellular morphology (measured as dynamic mass redistribution), (iv) loss of epithelial integrity (measured as transepithelial electrical resistance), and (v) cell death (measured as total cellular protein using a colorimetric assay). The assays were validated using the highly specific monoclonal antitoxin antibodies, actoxumab and bezlotoxumab, which neutralize TcdA and TcdB, respectively

Effector memory differentiation increases detection of replication-competent HIV-l in resting CD4+ T cells from virally suppressed individuals.

Studies have demonstrated that intensive ART alone is not capable of eradicating HIV-1, as the virus rebounds within a few weeks upon treatment interruption. Viral rebound may be induced from several cellular subsets; however, the majority of proviral DNA has been found in antigen experienced resting CD4+ T cells. To achieve a cure for HIV-1, eradication strategies depend upon both understanding mechanisms that drive HIV-1 persistence as well as sensitive assays to measure the frequency of infected cells after therapeutic interventions. Assays such as the quantitative viral outgrowth assay (QVOA) measure HIV-1 persistence during ART by ex vivo activation of resting CD4+ T cells to induce latency reversal; however, recent studies have shown that only a fraction of replication-competent viruses are inducible by primary mitogen stimulation. Previous studies have shown a correlation between the acquisition of effector memory phenotype and HIV-1 latency reversal in quiescent CD4+ T cell subsets that harbor the reservoir. Here, we apply our mechanistic understanding that differentiation into effector memory CD4+ T cells more effectively promotes HIV-1 latency reversal to significantly improve proviral measurements in the QVOA, termed differentiation QVOA (dQVOA), which reveals a significantly higher frequency of the inducible HIV-1 replication-competent reservoir in resting CD4+ T cells

A Gpr120-selective agonist improves insulin resistance and chronic inflammation in obese mice.

It is well known that the ω-3 fatty acids (ω-3-FAs; also known as n-3 fatty acids) can exert potent anti-inflammatory effects. Commonly consumed as fish products, dietary supplements and pharmaceuticals, ω-3-FAs have a number of health benefits ascribed to them, including reduced plasma triglyceride levels, amelioration of atherosclerosis and increased insulin sensitivity. We reported that Gpr120 is the functional receptor for these fatty acids and that ω-3-FAs produce robust anti-inflammatory, insulin-sensitizing effects, both in vivo and in vitro, in a Gpr120-dependent manner. Indeed, genetic variants that predispose to obesity and diabetes have been described in the gene encoding GPR120 in humans (FFAR4). However, the amount of fish oils that would have to be consumed to sustain chronic agonism of Gpr120 is too high to be practical, and, thus, a high-affinity small-molecule Gpr120 agonist would be of potential clinical benefit. Accordingly, Gpr120 is a widely studied drug discovery target within the pharmaceutical industry. Gpr40 is another lipid-sensing G protein-coupled receptor, and it has been difficult to identify compounds with a high degree of selectivity for Gpr120 over Gpr40 (ref. 11). Here we report that a selective high-affinity, orally available, small-molecule Gpr120 agonist (cpdA) exerts potent anti-inflammatory effects on macrophages in vitro and in obese mice in vivo. Gpr120 agonist treatment of high-fat diet-fed obese mice causes improved glucose tolerance, decreased hyperinsulinemia, increased insulin sensitivity and decreased hepatic steatosis. This suggests that Gpr120 agonists could become new insulin-sensitizing drugs for the treatment of type 2 diabetes and other human insulin-resistant states in the future

A selective and potent CXCR3 antagonist SCH 546738 attenuates the development of autoimmune diseases and delays graft rejection

<p>Abstract</p> <p>Background</p> <p>The CXCR3 receptor and its three interferon-inducible ligands (CXCL9, CXCL10 and CXCL11) have been implicated as playing a central role in directing a Th1 inflammatory response. Recent studies strongly support that the CXCR3 receptor is a very attractive therapeutic target for treating autoimmune diseases, such as rheumatoid arthritis, multiple sclerosis and psoriasis, and to prevent transplant rejection. We describe here the in vitro and in vivo pharmacological characterizations of a novel and potent small molecule CXCR3 antagonist, SCH 546738.</p> <p>Results</p> <p>In this study, we evaluated in vitro pharmacological properties of SCH 546738 by radioligand receptor binding and human activated T cell chemotaxis assays. In vivo efficacy of SCH 546738 was determined by mouse collagen-induced arthritis, rat and mouse experimental autoimmune encephalomyelitis, and rat cardiac transplantation models. We show that SCH 546738 binds to human CXCR3 with a high affinity of 0.4 nM. In addition, SCH 546738 displaces radiolabeled CXCL10 and CXCL11 from human CXCR3 with IC₅₀ranging from 0.8 to 2.2 nM in a non-competitive manner. SCH 546738 potently and specifically inhibits CXCR3-mediated chemotaxis in human activated T cells with IC₉₀about 10 nM. SCH 546738 attenuates the disease development in mouse collagen-induced arthritis model. SCH 546738 also significantly reduces disease severity in rat and mouse experimental autoimmune encephalomyelitis models. Furthermore, SCH 546738 alone achieves dose-dependent prolongation of rat cardiac allograft survival. Most significantly, SCH 546738 in combination with CsA supports permanent engraftment.</p> <p>Conclusions</p> <p>SCH 546738 is a novel, potent and non-competitive small molecule CXCR3 antagonist. It is efficacious in multiple preclinical disease models. These results demonstrate that therapy with CXCR3 antagonists may serve as a new strategy for treatment of autoimmune diseases, including rheumatoid arthritis and multiple sclerosis, and to prevent transplant rejection.</p

Delays in Leniency Application: Is There Really a Race to the Enforcer's Door?

This paper studies cartels’ strategic behavior in delaying leniency applications, a take-up decision that has been ignored in the previous literature. Using European Commission decisions issued over a 16-year span, we show, contrary to common beliefs and the existing literature, that conspirators often apply for leniency long after a cartel collapses. We estimate hazard and probit models to study the determinants of leniency-application delays. Statistical tests find that delays are symmetrically affected by antitrust policies and macroeconomic fluctuations. Our results shed light on the design of enforcement programs against cartels and other forms of conspiracy

Acceleration of dormant storage effects to address the reliability of silicon surface micromachined Micro-Electro-Mechanical Systems (MEMS).

Qualification of microsystems for weapon applications is critically dependent on our ability to build confidence in their performance, by predicting the evolution of their behavior over time in the stockpile. The objective of this work was to accelerate aging mechanisms operative in surface micromachined silicon microelectromechanical systems (MEMS) with contacting surfaces that are stored for many years prior to use, to determine the effects of aging on reliability, and relate those effects to changes in the behavior of interfaces. Hence the main focus was on 'dormant' storage effects on the reliability of devices having mechanical contacts, the first time they must move. A large number ({approx}1000) of modules containing prototype devices and diagnostic structures were packaged using the best available processes for simple electromechanical devices. The packaging processes evolved during the project to better protect surfaces from exposure to contaminants and water vapor. Packages were subjected to accelerated aging and stress tests to explore dormancy and operational environment effects on reliability and performance. Functional tests and quantitative measurements of adhesion and friction demonstrated that the main failure mechanism during dormant storage is change in adhesion and friction, precipitated by loss of the fluorinated monolayer applied after fabrication. The data indicate that damage to the monolayer can occur at water vapor concentrations as low as 500 ppm inside the package. The most common type of failure was attributed to surfaces that were in direct contact during aging. The application of quantitative methods for monolayer lubricant analysis showed that even though the coverage of vapor-deposited monolayers is generally very uniform, even on hidden surfaces, locations of intimate contact can be significantly depleted in initial concentration of lubricating molecules. These areas represent defects in the film prone to adsorption of water or contaminants that can cause movable structures to adhere. These analysis methods also indicated significant variability in the coverage of lubricating molecules from one coating process to another, even for identical processing conditions. The variability was due to residual molecules left in the deposition chamber after incomplete cleaning. The coating process was modified to result in improved uniformity and total coverage. Still, a direct correlation was found between the resulting static friction behavior of MEMS interfaces, and the absolute monolayer coverage. While experimental results indicated that many devices would fail to start after aging, the modeling approach used here predicted that all the devices should start. Adhesion modeling based upon values of adhesion energy from cantilever beams is therefore inadequate. Material deposition that bridged gaps was observed in some devices, and potentially inhibits start-up more than the adhesion model indicates. Advances were made in our ability to model MEMS devices, but additional combined experimental-modeling studies will be needed to advance the work to a point of providing predictive capability. The methodology developed here should prove useful in future assessments of device aging, however. Namely, it consisted of measuring interface properties, determining how they change with time, developing a model of device behavior incorporating interface behavior, and then using the age-aware interface behavior model to predict device function

Temporal Trends in the Characteristics of Children at Antiretroviral Therapy Initiation in Southern Africa: The IeDEA-SA Collaboration

BackgroundSince 2005, increasing numbers of children have started antiretroviral therapy (ART) in sub-Saharan Africa and, in recent years, WHO and country treatment guidelines have recommended ART initiation for all infants and very young children, and at higher CD4 thresholds for older children. We examined temporal changes in patient and regimen characteristics at ART start using data from 12 cohorts in 4 countries participating in the IeDEA-SA collaboration.Methodology/Principal FindingsData from 30,300 ART-naïve children aged <16 years at ART initiation who started therapy between 2005 and 2010 were analysed. We examined changes in median values for continuous variables using the Cuzick's test for trend over time. We also examined changes in the proportions of patients with particular disease severity characteristics (expressed as a binary variable e.g. WHO Stage III/IV vs I/II) using logistic regression. Between 2005 and 2010 the number of children starting ART each year increased and median age declined from 63 months (2006) to 56 months (2010). Both the proportion of children <1 year and ≥10 years of age increased from 12 to 19% and 18 to 22% respectively. Children had less severe disease at ART initiation in later years with significant declines in the percentage with severe immunosuppression (81 to 63%), WHO Stage III/IV disease (75 to 62%), severe anemia (12 to 7%) and weight-for-age z-score<−3 (31 to 28%). Similar results were seen when restricting to infants with significant declines in the proportion with severe immunodeficiency (98 to 82%) and Stage III/IV disease (81 to 63%). First-line regimen use followed country guidelines.Conclusions/SignificanceBetween 2005 and 2010 increasing numbers of children have initiated ART with a decline in disease severity at start of therapy. However, even in 2010, a substantial number of infants and children started ART with advanced disease. These results highlight the importance of efforts to improve access to HIV diagnostic testing and ART in children

When to Start Antiretroviral Therapy in Children Aged 2–5 Years: A Collaborative Causal Modelling Analysis of Cohort Studies from Southern Africa

There is limited evidence on the optimal timing of antiretroviral therapy (ART) initiation in children 2–5 y of age. We conducted a causal modelling analysis using the International Epidemiologic Databases to Evaluate AIDS–Southern Africa (IeDEA-SA) collaborative dataset to determine the difference in mortality when starting ART in children aged 2–5 y immediately (irrespective of CD4 criteria), as recommended in the World Health Organization (WHO) 2013 guidelines, compared to deferring to lower CD4 thresholds, for example, the WHO 2010 recommended threshold of CD4 count <750 cells/mm3 or CD4 percentage (CD4%) <25%