Evaluation of a vaccine passport to improve vaccine coverage in people living with HIV.

An increased risk of vaccine-preventable infections (VPIs) is seen in people living with HIV (PLWH), and current vaccine coverage and immunity is variable. Vaccine passports have the potential to improve vaccine coverage. The objective was to assess how successful a vaccine passport was in improving vaccine coverage in PLWH. Baseline immunity to VPIs was established in PLWH attending a single HIV clinic and vaccinations required were determined based on the BHIVA Vaccination Guidelines (2015). The passport was completed and the PLWH informed about additional vaccines they should obtain from primary care. After 6-9 months the passport was reviewed including confirmation if vaccines were given. PLWH satisfaction with the system was evaluated by a survey. Seventy-three PLWH provided sufficient data for analysis. At baseline significant proportions of PLWH were not immune/unvaccinated to the main VPIs, especially human papillomavirus, pneumococcus and measles. After the passport was applied immunity improved significantly (56% overall, p < 0.01) for most VPIs; however, full coverage was not achieved. The system was popular with PLWH. The passport was successful in increasing vaccination coverage although full or near-full coverage was not achieved. A more successful service would probably be achieved by commissioning English HIV clinics to provide all vaccines.

Adjunctive screening devices for oral lesions: their use by Canadian Dental Hygienists and the need for knowledge translation.

Screening for oral cancer and other mucosal conditions is a knowledge-to-action objective that should be easy: there is supportive evidence, it is fast and non-invasive, and the oral cavity is easy to visualize. However, over 60% of oral cancers are diagnosed late, when treatment is complex and prognosis poor. Adjunctive screening devices (ASDs), e.g. toluidine blue (TB), fluorescence visualization (FV), chemiluminescence (CL) and brush biopsies, were designed to assess risk of oral lesions or aid in identification and localization of oral premalignant and malignant lesions. Little is known on how clinicians feel about using ASDs. OBJECTIVES: To evaluate use and level of comfort in using ASDs for oral cancer screening among dental hygienists. METHODS: Online email survey of a stratified random sample of nearly 3000 dental hygienists from four Canadian provinces. RESULTS: A total of 369 hygienists responded about ASDs. Ninety-three (25%) had used an ASD. Use was associated with six or more continuing education (CE) courses per year (P = 0.030), having a CE course in oral pathology within the last 3 years (P = 0.003) and having a screening protocol (P = 0.008). The most commonly used ASD is FV, which was the tool hygienists felt most comfortable using. Few used brush biopsies. Older graduates were more comfortable using TB (P = 0.014) and CL (0.033). CONCLUSION: Current evidence and education through CE appears to bolster knowledge translation efforts for hygienists to become more comfortable in the use of ASDs. ASDs with minimal supporting evidence and not specifically targeted to hygienists, such as the brush biopsies, are not well utilized.

Mucosal delivery of human papillomavirus pseudovirus-encapsidated plasmids improves the potency of DNA vaccination.

Mucosal immunization may be important for protection against pathogens whose transmission and pathogenesis target the mucosal tissue. The capsid proteins of human papillomavirus (HPV) confer tropism for the basal epithelium and can encapsidate DNA during self-assembly to form pseudovirions (PsVs). Therefore, we produced mucosal vaccine vectors by HPV PsV encapsidation of DNA plasmids expressing an experimental antigen derived from the M and M2 proteins of respiratory syncytial virus (RSV). Intravaginal (IVag) delivery elicited local and systemic M-M2-specific CD8+ T-cell and antibody responses in mice that were comparable to an approximately 10,000-fold higher dose of naked DNA. A single HPV PsV IVag immunization primed for M-M2-specific-IgA in nasal and vaginal secretions. Based on light emission and immunofluorescent microscopy, immunization with HPV PsV-encapsidated luciferase- and red fluorescent protein (RFP)-expressing plasmids resulted in transient antigen expression (<5 days), which was restricted to the vaginal epithelium. HPV PsV encapsidation of plasmid DNA is a novel strategy for mucosal immunization that could provide new vaccine options for selected mucosal pathogens.

Molecular structures and interactions in the yeast kinetochore.

Kinetochores are the elaborate protein assemblies that attach chromosomes to spindle microtubules in mitosis and meiosis. The kinetochores of point-centromere yeast appear to represent an elementary module, which repeats a number of times in kinetochores assembled on regional centromeres. Structural analyses of the discrete protein subcomplexes that make up the budding-yeast kinetochore have begun to reveal principles of kinetochore architecture and to uncover molecular mechanisms underlying functions such as transmission of tension and establishment and maintenance of bipolar attachment. The centromeric DNA is probably wrapped into a compact organization, not only by a conserved, centromeric nucleosome, but also by interactions among various other DNA-bound kinetochore components. The rod-like, heterotetrameric Ndc80 complex, roughly 600 Å long, appears to extend from the DNA-proximal assembly to the plus end of a microtubule, to which one end of the complex is known to bind. Ongoing structural studies will clarify the roles of a number of other well-defined complexes.

Developing locally based research capacity in Uganda.

AIM: To describe an educational project to enhance local research capacity within Hospice Africa Uganda, a Uganda-wide community-based palliative care organization. BACKGROUND: This project emerged from a British Council Higher Education Links Scheme involving stakeholder British and Ugandan higher education institutions. The paper describes the project in relation to the remit of the British Council, the Ugandan context and the specifics of this exploratory project. The aim of the project was to build on the pre-existing local research capacity. FINDINGS: The lessons learnt and the participatory approach adopted for meeting the challenges of teaching/learning that emerged from this project are described in relation to the local interprofessional, organizational, socio-economic and socio-cultural contexts. CONCLUSION: Local knowledge gained through participatory engagement and collaborative working within Uganda is relevant and useful for current and future UK-Ugandan higher education partnerships.

Long-term profile changes in extraction and nonextraction patients.

INTRODUCTION: The purpose of this investigation was to determine the long-term differences in soft tissue profile changes between extraction and nonextraction patients who had been treated to the same incisor position and lip line. METHODS: Twenty extraction and 20 matched nonextraction patients, with posttreatment and long-term follow-up (average 15 years) records, were selected from a single private orthodontic practice. Posttreatment and long-term follow-up profile photos of the patients' nose, lip, and chin areas were evaluated by 105 orthodontists and 225 laypeople, who indicated their preferences and the amount of change they perceived among the 40 profiles. The patients had similar dental protrusion, soft tissue profile measurements, and ages at the posttreatment observation. RESULTS: No significant cephalometric differences between the extraction and nonextraction groups were found at long-term follow-up; both groups showed similar long-term changes. Significant (P < .05) differences were found between males and females at long-term follow-up; male lips became relatively more retrusive, and their profiles became flatter. Significant (P < .05) changes in the profiles were also perceived over time, but there was no relationship between the amount of change perceived and profile changes measured cephalometrically. There were also no significant (P < .05) differences in preferences between orthodontists and laypeople, between extraction and nonextraction patients, or between males and females. CONCLUSIONS: If extraction and nonextraction patients are treated to the same incisor position and lip line, the treatment modality does not affect long-term soft tissue profile changes. Furthermore, the amounts of change perceived by either orthodontists or laypeople were not related to the amount of change measured cephalometrically.

A comparison of physiological responses and rating of perceived exertion in two modes of aerobic exercise in men and women over 50 years of age.

OBJECTIVES: To compare the physiological responses and ratings of perceived exertion to aerobic dance and walking sessions completed at a self selected pace. METHODS: Six women and six men with a sample mean (SD) age of 68 (7) years completed aerobic dance and walking sessions in random order. A treadmill test was performed by each subject from which peak oxygen uptake (.VO(2)) and maximum heart rates (HRmax) were determined. During the aerobic dance and walking sessions, heart rate and .VO(2) were measured continuously throughout. Rate of perceived exertion (RPE) was measured every three minutes throughout the session. RESULTS: The sample means (SD) for %peak .VO(2) were 67 (17)% for the aerobic dance sessions and 52 (10)% for the walking sessions, and the %HRmax sample means (SD) were 74 (12)% for the aerobic dance sessions and 60(8)% for walking sessions. The sample mean (SD) RPE for the aerobic dance sessions was 11(2), and for the walking sessions it was 10(2). CONCLUSIONS: %peak .VO(2), %HRmax, and RPE were significantly higher for aerobic dance than for walking. However, both the aerobic dance and walking sessions were of adequate intensity to improve aerobic fitness in most subjects. Further investigation into the relation between RPE and %peak .VO(2) in a field setting over representative exercise time periods would be useful.

The many faces of Ras: recognition of small GTP-binding proteins.

The structures of over 30 complexes of Ras superfamily small GTP-binding proteins bound to diverse protein partners have been reported. Comparison of these complexes using the sequences of the small GTP-binding proteins to align the contact sites shows that virtually all surface positions make contacts with at least one partner protein. Rather than highlighting a single consensus binding site, these comparisons illustrate the remarkable diversity of contacts of Ras superfamily members. Here, a new analysis technique, the interface array, is introduced to quantify patterns of surface contacts. The interface array shows that small GTP-binding proteins are recognized in at least nine distinct ways. Remarkably, binding partners with similar functions, including those with distinct folds, recognize small GTP-binding proteins in similar ways. These classes of shared surface contacts support the occurrence of both divergent and convergent evolutionary processes and suggest that specific effector functions require particular protein-protein contacts.

Tailoring the substrate specificity of the beta-glycosidase from the thermophilic archaeon Sulfolobus solfataricus.

The substrate specificity of the thermophilic beta-glycosidase (lacS) from the archaeon Sulfolobus solfataricus (SSbetaG), a member of the glycohydrolase family 1, has been analysed at a molecular level using predictions from known protein sequences and structures and through site-directed mutagenesis. Three critical residues were identified and mutated to create catalysts with altered and broadened specificities for use in glycoside synthesis. The wild-type (WT) and mutated sequences were expressed as recombinant fusion proteins in Escherichia coli, with an added His(6)-tag to allow one-step chromatographic purification. Consistent with side-chain orientation towards OH-6, the single Met439-->Cys mutation enhances D-xylosidase specificity 4.7-fold and decreases D-fucosidase activity 2-fold without greatly altering its activity towards other D-glycoside substrates. Glu432-->Cys and Trp433-->Cys mutations directed towards OH-4 and -3, respectively, more dramatically impair glucose (Glc), galactose (Gal), fucose specificity than for other glycosides, resulting in two glycosidases with greatly broadened substrate specificities. These include the first examples of stereospecificity tailoring in glycosidases (e.g. WT-->W433C, k(cat)/K(M) (Gal):k(cat)/K(M) (mannose (Man))=29.4:1-->1.2:1). The robustness and high utility of these broad specificity SSbetaG mutants in parallel synthesis were demonstrated by the formation of libraries of beta-glycosides of Glc, Gal, xylose, Man in one-pot preparations at 50 degrees C in the presence of organic solvents, that could not be performed by SSbetaG-WT.

Relative contribution of CYP3A to amitriptyline clearance in humans: in vitro and in vivo studies.

The relative contribution of cytochrome P450 3A (CYP3A) to the oral clearance of amitriptyline in humans has been assessed using a combination of in vitro approaches together with a clinical pharmacokinetic interaction study using the CYP3A-selective inhibitor ketoconazole. Lymphoblast-expressed CYPs were used to study amitriptyline N-demethylation and E-10 hydroxylation in vitro. The relative activity factor (RAF) approach was used to predict the relative contribution of each CYP isoform to the net hepatic intrinsic clearance (sum of N-demethylation and E-10 hydroxylation). Assuming no extrahepatic metabolism, the model-predicted contribution of CYP3A to net intrinsic clearance should equal the fractional decrement in apparent oral clearance of amitriptyline upon complete inhibition of the enzyme. This hypothesis was tested in a clinical study of amitriptyline (50 mg, p.o.) with ketoconazole (three 200 mg doses spaced 12 hours apart) in 8 healthy volunteers. The RAF approach predicted CYP2C19 to be the dominant contributor (34%), with a mean 21% contribution of CYP3A (range: 8%-42% in a panel of 12 human livers). The mean apparent oral clearance of amitriptyline in 8 human volunteers was decreased from 2791 ml/min in the control condition to 2069 ml/min with ketoconazole. The average 21% decrement (range: 2%-40%) was identical to the mean value predicted in vitro using the RAF approach. The central nervous system (CNS) sedative effects of amitriptyline were slightly greater when ketoconazole was coadministered, but the differences were not statistically significant. In conclusion, CYP3A plays a relatively minor role in amitriptyline clearance in vivo, which is consistent with in vitro predictions using the RAF approach.