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.

Susceptibility of youth to tobacco: a social ecological framework for prevention.

For most smokers, tobacco dependence begins in childhood or adolescence. This review summarizes the state of social science with respect to the prevention of tobacco use. Social ecology is introduced as a theoretical framework useful for organizing prevention approaches. In recent years, the field has shifted from approaches directed at individuals, towards appreciation of additional, more comprehensive social and environmental influences on initiation. These range from intra-individual factors (including physiological responses to nicotine and the psychology of use) to individual, interpersonal, organizational, community, and population factors affecting access and demand. This review highlights prevention approaches that address social and societal influences, from school programs that attempt to change susceptibility of individual youth to tobacco, to community projects, media campaigns, restrictive policies, and tobacco pricing. The most promising approaches are those designed with input based on extensive formative research including studies with youth, directed at multiple levels of the social ecology, and sustained over time with significant resources and ongoing, multi-sector inputs.

Nontraditional family romance.

Family stories lie at the heart of psychoanalytic developmental theory and psychoanalytic clinical technique, but whose family? Increasingly, lesbian and gay families, multiparent families, and single-parent families are relying on modern reproductive technologies to form families. The contemplation of these nontraditional families and the vicissitudes of contemporary reproduction lead to an unknowing of what families are, including the ways in which psychoanalysts configure the family within developmental theory. This article focuses on the stories that families tell in order to account for their formation--stories that include narratives about parental union, parental sexuality, and conception. The author addresses three constructs that inform family stories and that require rethinking in light of the category crises posed by and for the nontraditional family: (1) normative logic, (2) family reverie and the construction of a family romance, and (3) the primal scene. These constructs are examined in tandem with detailed clinical material taken from the psychotherapy of a seven-year-old boy and his two mothers.

In their own words: a model of healthy aging.

Many previous studies have assessed the aging process by measuring clinical and functional variables. To supplement that quantitative understanding, we asked older people what constitutes their health and contributes to it. Using grounded theory-type methods, we analyzed semi-structured interviews with 22 study subjects, who were randomly selected from among those whose reported perceived health differed from that predicted by a regression model constructed from data from a randomized trial of a primary care intervention. We focused on disparate cases to identify factors that best discriminate between more and less healthy aging. Interview questions targeted perceptions of health; well-being; valued abilities, activities, and relationships; social support; control; sense of coherence; and personal outlook. A model of healthy aging emerged. To these older people health meant going and doing something meaningful, which required four components: something worthwhile to do, balance between abilities and challenges, appropriate external resources, and personal attitudinal characteristics (e.g., positive attitude vs. "poor me"). By reframing healthy aging in older people's own terms, this model encourages interdisciplinary support of their desired goals and outcomes rather than only medical approaches to deficits and challenges.

Effect of organic cations on the renal tubular secretion of pseudoephedrine in the rat.

1. Pseudoephedrine is a weak organic base that undergoes renal tubular secretion. The aim of the present study was to assess whether two other commonly used weak organic bases (cimetidine and morphine) inhibit the renal tubular secretion of pseudoephedrine in the rat isolated perfused kidney. 2. A total of 12 perfusions were performed with four perfusions in each of three treatment groups. In the control group, pseudoephedrine was administered as a bolus dose of [14C]-pseudoephedrine and unlabelled pseudoephedrine to achieve an initial perfusate concentration of 0.4 microg/mL. For the treatment groups, pseudoephedrine was administered as above and cimetidine or morphine was added to the perfusion medium in increasing concentrations of 0.5-12.5 and 0.2-5.0 microg/mL, respectively. 3. The mean (+/-SD) fraction unbound of pseudoephedrine alone in perfusate was 0.866+/-0.014 and was not different (P> 0.05) in the presence of cimetidine or morphine. 4. In control experiments, the renal excretory clearance (CLR) of pseudoephedrine was three-fold greater than glomerular filtration rate (GFR), yielding a ratio consistently greater than unity, which indicates extensive net tubular secretion of pseudoephedrine. The CLR and total clearance of pseudoephedrine were similar, suggesting an absence of renal metabolism of pseudoephedrine. 5. The CLR/GFR ratio for pseudoephedrine was not affected by morphine, but was significantly reduced (P < 0.05) in the presence of cimetidine. 6. The results indicate that cimetidine inhibits the renal tubular secretion of pseudoephedrine.

Valproate for sleep consolidation in periodic limb movement disorder.

In this study, open-label valproate (VPA) was administered to patients as a treatment for periodic limb movement disorder (PLMD). Six patients aged 28 to 62 years with complaints of sleep disturbance and at least five periodic limb movements (PLMs) per hour of sleep underwent polysomnograms (PSGs) with and without low-dose VPA treatment (125-600 mg at bedtime). After a baseline PSG, patients received VPA therapy from 2 weeks to 14 months, until the time of the follow-up PSG on VPA (median, 5 months; mean, 6 months). All six patients experienced subjective improvement in daytime alertness. Sleep efficiency was improved from 76% to 88% (p = 0.003), stage 1 (light) sleep decreased from 26% to 13% (p = 0.04), stage 3 and 4 (deep) sleep increased from 19% to 30% (p = 0.01), and rapid eye movement sleep was unchanged. There was a trend toward a reduction in the number of PLMs per hour of sleep and in the percentage of arousals associated with PLMs. All of the patients continued taking VPA after the PSGs were completed. One patient discontinued VPA 1 month after completion of the last PSG because of short-term side effects, and one patient stopped VPA 22 months after the last PSG because of weight gain. Thus, these data indicate that VPA has a long-term beneficial effect on sleep consolidation in patients with PLMD.

Durability of tobacco control efforts in the 22 Community Intervention Trial for Smoking Cessation (COMMIT) communities 2 years after the end of intervention.

Funding organizations increasingly want to know that successful interventions are continued after the end of a research project. Assessments of durability are rare and where done do not include the comparison communities. In this study we ascertain what tobacco control activities continued in intervention communities involved in the Community Intervention Trial for Smoking Cessation (COMMIT), a randomized, controlled community trial aimed at adult smokers, and also assessed level of tobacco control activities in the comparison communities. A mailed survey of key informants including paid staff and community volunteers in the 22 COMMIT communities was conducted. Approximately 79% of key informants responded to the survey. Although there was evidence that tobacco control activities were continuing in the intervention communities, there was an equal amount of tobacco control effort in the comparison communities. Within the specific tobacco control intervention areas, only the youth area showed more activity in intervention communities than comparison communities. We conclude that despite a positive trial outcome, differential durability was not achieved. More work needs to be done to assist communities in maintaining proven intervention activities. More study of methods to measure durability is also needed.

Kinetics and dynamics of lorazepam during and after continuous intravenous infusion.

OBJECTIVE: To evaluate the kinetics and dynamics of lorazepam during administration as a bolus plus an infusion, using electroencephalography as a pharmacodynamic end point. METHODS: Nine volunteers received a 2-mg bolus loading dose of lorazepam, coincident with the start of a 2 microg/kg/hr zero-order infusion. The infusion was stopped after 4 hrs. Plasma lorazepam concentrations and electroencephalographic activity in the 13- to 30-Hz range were monitored for 24 hrs. RESULTS: The bolus-plus-infusion scheme rapidly produced plasma lorazepam concentrations that were close to those predicted to be achieved at true steady state. Mean kinetic values for lorazepam were as follows: volume of distribution, 126 L; elimination half-life, 13.8 hrs; and clearance, 109 mL/min. Electroencephalographic effects were maximal 0.5 hr after the loading dose, were maintained essentially constant during infusion, and then declined in parallel with plasma concentrations after the infusion was terminated. There was no evidence of tolerance. Plots of pharmacodynamic electroencephalographic effect vs. plasma lorazepam concentration demonstrated counterclockwise hysteresis, consistent with an effect-site equilibration delay. This was incorporated into a kinetic-dynamic model in which hypothetical effect-site concentration was related to pharmacodynamic electroencephalographic effect via the sigmoid Emax model. The analysis yielded the following mean estimates: maximum electroencephalographic effect, 12.7% over baseline; 50% effective concentration, 13.1 ng/mL; and effect-site equilibration half-life, 8.8 mins. CONCLUSION: Despite the delay in effect onset, continuous infusion of lorazepam, preceded by a bolus loading dose, produces a relatively constant sedative effect on the central nervous system, which can be utilized in the context of critical care medicine.

Explaining infant feeding style of low-income black women.

Unstructured interviews were conducted with 10 low-income black women to explore infant feeding style. Formula-feeding with early introduction of cereal in the bottle was the most common pattern used by mothers in the first 3 months. By 6 months, formula-fed infants had a complex diet of a variety of foods. Half the women intended to breast-feed, but only one exclusively breast-fed. Beliefs about healthy infants and crying influenced feeding. There was a lack of knowledge about and support for breast-feeding in these women's environment. Support and advice about infant feeding from the health care system were uneven.

Problems in the interpretation of HIV-1 viral load assays using commercial reagents.

During routine monitoring of human immunodeficiency virus (HIV) viral load, two problems arose. First, a number of patients, the majority being African, were found to have low viral loads by the Chiron branched-chain DNA assay in conjunction with low CD4(+) cell numbers. In order to determine whether this was due to failure of the branched-chain DNA assay to detect non-B subtypes of HIV, selected samples were subtyped and HIV RNA quantified by branched-chain DNA, NASBA, and the Roche Monitor RT-PCR assay. Twenty-eight (97%) of 29 Africans were infected with a non-B subtype of HIV and 15 (93.7%) of 16 non-Africans with subtype B. Twenty-three samples had a low viral load by branched-chain DNA, which was confirmed by the NASBA and RT-PCR assays. All three assays detected B and non-B subtypes with similar efficiency; NASBA failed to detect HIV RNA in a small number of non-B samples. Discrepancies between viral load and CD4(+) cell numbers did not appear therefore to be related to subtype. Second, while quantification of HIV RNA was being conducted using version 2 of the branched-chain DNA assay (lower detection limit 500 HIV RNA copies/ml) the manufacturers had developed a more sensitive assay and a comparative evaluation was therefore conducted. In approximately 30% of samples the viral load was up to 10 times higher with the more sensitive assay. These experiences emphasise the importance of close collaboration between the clinic and the laboratory.

Potential risk of cross-infection during peripheral-venous access by contamination of tourniquets.

We found that a high proportion of reusable tourniquets are contaminated with blood and bacterial pathogens. Their use contravenes hospital cross-infection control protocols and we therefore recommend the use of disposable tourniquets.