Disposition and metabolism of cabotegravir: a comparison of biotransformation and excretion between different species and routes of administration in humans.

1. Cabotegravir [(3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6-hydroxy-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide] is an HIV-1 integrase inhibitor under development as a tablet for both oral lead-in therapy and long-acting (LA) injectable for intramuscular dosing. 2. Metabolism, pharmacokinetics and excretion were investigated in healthy human subjects who received either a single oral dose (28.2 mg) of [(14)C]cabotegravir in a mass balance study, or LA formulations of unlabeled cabotegravir (200-800 mg), intramuscularly or subcutaneously, in a separate study. Metabolism, distribution and excretion of [(14)C]cabotegravir were also investigated in mice, rats and monkeys. 3. Recovery of radioactivity in humans represented a mean total of 85.3% of the dose, including 26.8% in the urine. The mean apparent terminal phase half-life was similar for both cabotegravir and radioactivity, 39 h compared to 41 h. 4. Following oral, intramuscular and subcutaneous administration, cabotegravir was the major component in plasma and the glucuronic acid conjugate (M1) represented the predominant component in urine. Cabotegravir was present in bile along with its major metabolite (M1). 5. The primary metabolite of [(14)C]cabotegravir in mouse, rat and monkey was the same as that in human. In vitro phenotyping experiments demonstrated that cabotegravir was metabolized by UDP-glucuronosyltransferase (UGT) 1A1 and UGT1A9.

Phylogeographic Dynamics of H9N2 Avian Influenza Viruses in Tunisia.

Avian influenza virus subtype H9N2 is endemic in commercial poultry in Tunisia. This subtype affects poultry and wild birds in Tunisia and poses a potential zoonotic risk. Tunisian H9N2 strains carry, in their hemagglutinins, the human-like marker 226 L that is most influential in avian-to-human viral transmission. For a better understanding of how ecological aspects of the H9N2 virus and its circulation in poultry, migratory birds and environment shapes the spread of the dissemination of H9N2 in Tunisia, herein, we investigate the epidemiological, evolutionary and zoonotic potential of seven H9N2 poultry isolates and sequence their whole genome. Phylogeographic and phylodymanic analysis were used to examine viral spread within and among wild birds, poultry and environment at geographical scales. Genetic evolution results showed that the eight gene sequences of Tunisian H9N2 AIV were characterized by molecular markers involved with virulence and mammalian infections. The geographical distribution of avian influenza virus appears as a network interconnecting countries in Europe, Asia, North Africa and West Africa. The spatiotemporal dynamics analysis showed that the H9N2 virus was transmitted from Tunisia to neighboring countries notably Libya and Algeria. Interestingly, this study also revealed, for the first time, that there was a virus transmission between Tunisia and Morocco. Bayesian analysis showed exchanges between H9N2 strains of Tunisia and those of the Middle Eastern countries, analysis of host traits showed that duck, wild birds and environment were ancestry related to chicken. The subtypes phylodynamic showed that PB1 segment was under multiple inter-subtype reassortment events with H10N7, H12N5, H5N2 and H6N1 and that PB2 was also a subject of inter-subtype reassortment with H10N4.

Phylogenetic analysis and assessment of the pathogenic potential of the first H9N2 avian influenza viruses isolated from wild birds and Lagoon water in Tunisia.

H9N2 avian influenza virus (AIV) has been isolated from various species of wild birds and domestic poultry worldwide. It has been reported since the late 1990s, that H9N2 AIV has infected humans as reported in some Asian and North African countries. This subtype has already been circulating and constituting a serious threat to the poultry industry in Tunisia back in 2009. To investigate zoonotic potential and pathogenicity of H9N2 AIV in chickens and mice in Tunisia, five strains have been isolated during the period from 2014 to 2018. Samples were withdrawn from several wild bird species and environment (Lagoon water) of Maamoura and Korba Lagoons as well as Kuriat Island. Phylogenetic analyzes demonstrated that the isolated H9N2 strains belonged to the G1-like sublineage and were close to AIV H9N2 poultry viruses from North Africa, West Africa and the Middle East. All strains carried in their hemagglutinin the residue 226 L, which is an important marker for avian-to-human viral transmission. The hemagglutinin cleavage site has several motifs: PSKSSR/G, PARSSR/G and HARSSR/G. The neuraminidase showed S372A and R403W substitutions that have been previously detected in H3N2 and H2N2 viruses that were reported in human pandemics. Many mutations associated with mammalian infections have been detected in internal proteins. Pathogenicity evaluation in chickens showed that GF/14 replicates effectively in the lungs, tracheas, spleens, kidneys and brains and that it was transmitted among contact chickens. However, GHG/18 replicates poorly in chickens and has not an efficient transmission in contact chickens. GF/14 and GHG/18 could not kill mice though they replicated in their respiratory tract and caused a significant body weight loss (p < 0.05). This study highlights the importance of H9N2 AIV monitoring in both migratory birds and the environment to prevent virus transmission to humans.

Breast disease diagnostic ability of nurse practitioners and surgeons.

AIM: This paper is a report of a study to compare history-taking and breast and axillary examination skills of nurse practitioners and surgeons. BACKGROUND: In the United Kingdom, patients referred by their general practitioners with suspected breast cancer should be seen within 2 weeks by a specialist. As a result of the European Working Time Directive there has been a reduction in junior doctors' working hours within the European Union. This makes such targets harder to achieve and risks delays in patient assessment and diagnosis. Trained nurse practitioners can perform an important role in assessing new patients in breast clinics to ensure that they are seen expeditiously. Nurse practitioners' competence assessing patients with breast disease needs to be objectively demonstrated. METHODS: Between 1st March 2007 and 31st March 2008 patients referred to a symptomatic breast disease clinic were seen by a single nurse practitioner and a single consultant surgeon. Findings were recorded on a standardised pro forma and compared using one-way analysis of variance. FINDINGS: Assessments were recorded for 128 patients. No abnormality was found in 41% of patients but nine (7%) had breast cancer. There was no evidence of a statistically significant mismatch in scoring between the nurse practitioner and consultant surgeon. Thirty-seven lumps were identified in 35 patients. There was no difference in mammography requests from the nurse practitioner and surgeon. CONCLUSION: The diagnostic accuracy of a nurse practitioner compares favourably with that of a consultant surgeon.

Laboratory and clinical studies of cancer chemoprevention by antioxidants in berries.

Reactive oxygen species (ROS) are a major cause of cellular injury in an increasing number of diseases, including cancer. Most ROS are created in the cell through normal cellular metabolism. They can be produced by environmental insults such as ultraviolet light and toxic chemicals, as well as by the inflammatory process. Interception of ROS or limiting their cellular effects is a major role of antioxidants. Due to their content of phenolic and flavonoid compounds, berries exhibit high antioxidant potential, exceeding that of many other foodstuffs. Through their ability to scavenge ROS and reduce oxidative DNA damage, stimulate antioxidant enzymes, inhibit carcinogen-induced DNA adduct formation and enhance DNA repair, berry compounds have been shown to inhibit mutagenesis and cancer initiation. Berry constituents also influence cellular processes associated with cancer progression including signaling pathways associated with cell proliferation, differentiation, apoptosis and angiogenesis. This review article summarizes laboratory and human studies, demonstrating the protective effects of berries and berry constituents on oxidative and other cellular processes leading to cancer development.

Overview of the National Health Educator Competencies Update Project, 1998-2004.

The National Health Educator Competencies Update Project (CUP), conducted during 1998-2004, addressed what health educators currently do in practice, the degree to which the role definition of the entry-level health educator is still up-to-date, and the validation of advanced-level competencies. A 19-page questionnaire was sent to a representative sample of health educators in recognized practice settings in all states and the District of Columbia. A total of 4,030 health educators participated in the research (70.6% adjusted response rate) resulting in the largest national data set of its kind, with 1.6 million data points. The model derived from the research was hierarchical (7 areas of responsibility, 35 competencies, and 163 subcompetencies), with three levels of practice (Entry, Advanced 1, and Advanced 2) differentiated by degrees earned and years of experience. The findings affect professional preparation, credentialing, and professional development.

Glial promoter selectivity following AAV-delivery to the immature brain.

Recombinant adeno-associated virus (AAV) vectors are versatile tools for gene transfer to the central nervous system (CNS) and proof-of-concept studies in adult rodents have shown that the use of cell type-specific promoters is sufficient to target AAV-mediated transgene expression to glia. However, neurological disorders caused by glial pathology usually have an early onset. Therefore, modelling and treatment of these conditions require expanding the concept of targeted glial transgene expression by promoter selectivity for gene delivery to the immature CNS. Here, we have investigated the AAV-mediated green fluorescent protein (GFP) expression driven by the myelin basic protein (MBP) or glial fibrillary acidic protein (GFAP) promoters in the developing mouse brain. Generally, the extent of transgene expression after infusion at immature stages was widespread and higher than in adults. The GFAP promoter-driven GFP expression was found to be highly specific for astrocytes following vector infusion to the brain of neonates and adults. In contrast, the selectivity of the MBP promoter for oligodendrocytes was poor following neonatal AAV delivery, but excellent after vector injection at postnatal day 10. To extend these findings obtained in naïve mice to a disease model, we performed P10 infusions of AAV-MBP-GFP in aspartoacylase (ASPA)-deficient mouse mutants presenting with early onset oligodendrocyte pathology. Spread of GFP expression and selectivity for oligodendrocytes in ASPA-mutants was comparable with our observations in normal animals. Our data suggest that direct AAV infusion to the developing postnatal brain, utilising cellular promoters, results in targeted and long-term transgene expression in glia. This approach will be relevant for disease modelling and gene therapy for the treatment of glial pathology.

Development and selection of edited B cells in B6.56R mice.

Tolerance to dsDNA is broken in mice with a high-affinity anti-DNA H chain transgene, 56R, on the C57BL/6 background (B6.56R). B6.56R produce more anti-dsDNA Abs than BALBc.56R. To investigate how anti-DNA Abs are regulated on the B6 background, phenotypic and genetic studies were performed. B6.56R have reduced numbers of B cells and phenotypically altered B cell subsets, including relative increases in the proportions of IgM-negative bone marrow B cells, cells with a marginal zone phenotype, and cells with a transitional T3 phenotype. The peripheral B cell repertoire in B6.56R is restricted: most B cells express the 56R H chain and use a similar, limited subset of editor L chains. DNA binding is more common in B6.56R because the repertoire is shifted toward L chains that are more permissive for DNA binding. H chain editing is also observed and is increased in spontaneous as compared with LPS hybridomas. A subset of spontaneous hybridomas appears to lack H chain expression.