Evaluating Osteoarthritis Management Programs: outcome domain recommendations from the OARSI Joint Effort Initiative.

OBJECTIVE: To develop sets of core and optional recommended domains for describing and evaluating Osteoarthritis Management Programs (OAMPs), with a focus on hip and knee Osteoarthritis (OA). DESIGN: We conducted a 3-round modified Delphi survey involving an international group of researchers, health professionals, health administrators and people with OA. In Round 1, participants ranked the importance of 75 outcome and descriptive domains in five categories: patient impacts, implementation outcomes, and characteristics of the OAMP and its participants and clinicians. Domains ranked as "important" or "essential" by ≥80% of participants were retained, and participants could suggest additional domains. In Round 2, participants rated their level of agreement that each domain was essential for evaluating OAMPs: 0 = strongly disagree to 10 = strongly agree. A domain was retained if ≥80% rated it ≥6. In Round 3, participants rated remaining domains using same scale as in Round 2; a domain was recommended as "core" if ≥80% of participants rated it ≥9 and as "optional" if ≥80% rated it ≥7. RESULTS: A total of 178 individuals from 26 countries participated; 85 completed all survey rounds. Only one domain, "ability to participate in daily activities", met criteria for a core domain; 25 domains met criteria for an optional recommendation: 8 Patient Impacts, 5 Implementation Outcomes, 5 Participant Characteristics, 3 OAMP Characteristics and 4 Clinician Characteristics. CONCLUSION: The ability of patients with OA to participate in daily activities should be evaluated in all OAMPs. Teams evaluating OAMPs should consider including domains from the optional recommended set, with representation from all five categories and based on stakeholder priorities in their local context.

Greater efficacy of a combination of conservative therapies for thumb base OA in individuals with lower radial subluxation - a pre-planned subgroup analysis of the COMBO trial.

OBJECTIVE: To investigate heterogeneous effects of a combination of conservative therapies compared with an education comparator for thumb base (TB) osteoarthritis (OA) according to clinically relevant characteristics. METHODS: Pre-planned subgroup analysis of the COMBO trial (n = 204) which compared a combination of education on self-management and ergonomic principles, a prefabricated neoprene splint, hand exercises, and diclofenac sodium gel, with education alone for radiographic and symptomatic TB OA. Primary outcomes were change in pain (visual analogue scale [VAS], 0-100 mm) and hand function (Functional Index for Hand Osteoarthritis questionnaire, 0-30) from baseline to week-6. Other outcomes were grip and tip-pinch strength and patient's global assessment (PGA) (VAS, 0-100 mm). Possible treatment effect modifiers were the presence of interphalangeal joint pain, erosive hand OA, radiographic thumb carpometacarpal joint subluxation (higher vs equal or lower than the sample mean), and baseline radiographic OA severity (Kellgren Lawrence grade). Linear regression models were fitted, adding interaction terms for each subgroup of interest. RESULTS: The treatment effects of the combined intervention at 6 weeks were greater in participants with lower joint subluxation compared with those with greater subluxation (pain -11.6 [95%CI -22.2, -9.9] and 2.6 [-5.5, 10.7], respectively, difference between the subluxation groups 14.2 units (95% CI 2.3, 26.1), p-value 0.02; and PGA -14.0 [-22.4, -5.5] and 1.5 [-6.2, 9.3), respectively, difference between the subluxation groups 15.5 units (95% CI 4.2, 26.8), p-value 0.03). There was no statistically significant heterogeneity for the other subgroups. CONCLUSION: A combination of conservative therapies may provide greater benefits over 6 weeks in individuals with lower joint subluxation, although the clinical relevance is uncertain given the wide confidence intervals. Treatment strategies may need to be customized for those with greater joint subluxation. TRIAL REGISTRATION NUMBER: ACTRN 12616000353493.

Efficacy and safety of a supplement combination on hand pain among people with symptomatic hand osteoarthritis an internet-based, randomised clinical trial the RADIANT study.

OBJECTIVE: The RADIANT study aimed to investigate the efficacy and safety of a complementary medicine supplement combination in people with hand osteoarthritis (HOA). METHOD: This was an internet-based, double-blind, randomised, placebo-controlled trial. Participants aged over 40 years with symptomatic HOA with radiographic confirmation (Kellgren Lawrence grade ≥ 2) throughout Australia were recruited and randomly assigned (1:1) to receive either a supplement combination composed of Boswellia serrata extract 250 mg/day, pine bark extract 100 mg/day, methylsulfonylmethane 1,500 mg/day and curcumin 168 mg/day or placebo for 12 weeks. The primary outcome was change in hand pain assessed using a visual analogue scale (VAS 0-100) from baseline to week 12. A range of secondary outcomes and additional measures were recorded. Adverse events were monitored weekly. RESULTS: One hundred and six participants were included with mean age 65.6 years and 81% were women. 45% of the participants were graded as KLG 4, 40% KLG three and 39 (37%) had erosive OA. There was no significant difference in pain VAS reduction between groups. The adjusted between group difference in means (95%CI) was 5.34 (-2.39 to 13.07). Five participants (10%) in the supplement combination group discontinued study treatment due to AE vs four participants (7%) in the placebo group. CONCLUSION: There were no significant differences in symptomatic relief between the two groups over 12 weeks. These findings do not support the use of the supplement combination for treating hand pain in people with HOA. REGISTRATION: Prospectively registered (Australian New Zealand Clinical Trials Registry ACTRN12619000835145, 31/05/2019).

Is the Patient Activation Measure a valid measure of osteoarthritis self-management attitudes and capabilities? Results of a Rasch analysis.

BACKGROUND: The Patient Activation Measure (PAM-13) was developed using Rasch analysis to assess knowledge, skills and confidence in the management of one's health. Previous studies report positive relationships between PAM-13 scores, self-management behaviours and longitudinal health outcomes in adults with chronic disease. There is little extant measurement property evidence for the use of PAM-13 in specific osteoarthritis (OA) populations. This study tested measurement properties of the PAM-13 in people living with hip and knee OA. METHODS: Item response frequency analysis was conducted. Rasch analysis evaluated the fit of the PAM-13 data to the Rasch model. Model-data fit was evaluated using infit and outfit statistics; person/item reliability and person separation indices were computed. Unidimensionality was evaluated using Principal Components Analysis of Rasch residuals and the data were assessed for item redundancy. Differential Item Functioning (DIF) examined bias in respondent subgroups and correlations tested relationships between PAM-13 and other patient-reported outcomes. RESULTS: Two-hundred-and-seventeen PAM-13 surveys were completed; there were no missing responses, floor or ceiling effects. Person and item reliability were acceptable (0.98 and 0.87 respectively) with good separation (person separation index 2.58). Unidimensionality was evaluated, with 49.4% of the variance explained by the first eigenvector. There was evidence of potential local response-dependence. The Rasch fit statistics were acceptable (except for item-2). There were some issues identified with targeting of the PAM-13 items to people with higher ability and the item difficulty order was different to that proposed in original cohorts. Significant DIF was identified for sex and educational level for a small number of items. PAM-13 scores were moderately correlated with depressive symptoms on the Depression Anxiety Stress Scale and Assessment of Quality of Life-6D. There were small correlations between PAM-13 and Knee injury and Osteoarthritis Outcome Score pain and activities of daily living scores. CONCLUSIONS: This study provides some evidence of adequate person and item reliability, unidimensionality, and construct validity to support the use of PAM-13 to measure patient activation in people living with hip and knee OA. Possible limitations regarding targeting, different item difficulty order, DIF and local response dependence should be investigated in future research.

Development of a core capability framework for qualified health professionals to optimise care for people with osteoarthritis: an OARSI initiative.

OBJECTIVE: Develop a generic trans-disciplinary, skills-based capability framework for health professionals providing care for people with OA. DESIGN: e-Delphi survey. An international inter-professional Delphi Panel (researchers; clinicians; consumer representatives) considered a draft framework (adapted from elsewhere) of 131 specific capabilities mapped to 14 broader capability areas across four domains (A: person-centred approaches; B: assessment, investigation and diagnosis; C: management, interventions and prevention; D: service and professional development). Over three rounds, the Panel rated their agreement (Likert or numerical rating scales) on whether each specific capability in Domains B and C was essential (core) for all health professionals when providing care for all people with OA. Those achieving consensus (≥80% of Panel) rating of ≥ seven out of ten (Round 3) were retained. Generic domains (A and D) were included in the final framework and amended based on Panel comments. RESULTS: 173 people from 31 countries, spanning 18 disciplines and including 26 consumer representatives, participated. The final framework comprised 70 specific capabilities across 13 broad areas i) communication; ii) person-centred care; iii) history-taking; iv) physical assessment; v) investigations and diagnosis; vi) interventions and care planning; vii) prevention and lifestyle interventions; viii) self-management and behaviour change; ix) rehabilitative interventions; x) pharmacotherapy; xi) surgical interventions; xii) referrals and collaborative working; and xiii) evidence-based practice and service development). CONCLUSION: Experts agree that health professionals require an array of skills in person-centred approaches; assessment, investigation and diagnosis; management, interventions and prevention; and service and professional development to provide optimal care for people with OA.

Radial subluxation in relation to hand strength and radiographic severity in trapeziometacarpal osteoarthritis.

OBJECTIVE: Greater joint laxity and radial subluxation of the thumb metacarpal base have been shown to be risk factors for the development of trapeziometacarpal osteoarthritis in an asymptomatic and radiographically normal joint. Despite this, it is unknown whether joint laxity changes with disease progression from mild to severe osteoarthritis. This study aimed to investigate the relationship between joint laxity and osteoarthritis severity, using the trapeziometacarpal subluxation ratio as an indicator of joint laxity. METHOD: Baseline data were used from the first 100 participants included in the COMBO (Efficacy of combined conservative therapies on clinical outcomes in base of thumb OA) trial. All participants had bilateral posteroanterior (PA) and Eaton stress view hand radiographs, as well as grip and tip-pinch strength measurements. The PA view was used to assess Kellgren-Lawrence and Eaton grades, and the Eaton stress view was used to assess the trapeziometacarpal joint subluxation ratios. Generalised estimating equations were utilized to account for the fact that hand data are paired, and within-person measurements are therefore not independent. RESULTS: Lower radial subluxation ratios were associated with higher Kellgren-Lawrence grades (B-coefficient -0.302; p-value 0.027), and lower grip strength scores (B-coefficient 2.06; p-value 0.006). CONCLUSIONS: Radial subluxation ratios decreased with increasing disease severity, contrary to the progression from a normal joint to one with mild osteoarthritis, wherein higher joint laxity is a risk factor for disease. This may be explained by the mechanical stabilization provided by osteophytes and capsular changes in worsening osteoarthritis, as has been shown to be the case in the knee. TRIAL REGISTRATION NUMBER: ACTRN 12616000353493. LEVEL OF EVIDENCE: III.

Significance of informal (on-the-job) learning and leadership development in health systems: lessons from a district finance team in South Africa.

BACKGROUND: The district health system (DHS) has a critical role to play in the delivery of primary healthcare (PHC). Effective district management, particularly leadership is considered to be crucial element of the DHS. Internationally, the debate around developing leadership competencies such as motivation or empowerment of staff, managing relationships, being solution driven as well as fostering teamwork are argued to be possible through approaches such as formal and informal training. Despite growing multidisciplinary evidence in fields such as engineering, computer sciences and health sciences there remains little empirical evidence of these approaches, especially the informal approach. Findings are based on a broader doctoral thesis which explored district financial management; although the core focus of this paper draws attention to the significance of informal learning and its practical value in developing leadership competencies. METHODS: A qualitative case study was conducted in one district in the Gauteng province, South Africa. Purposive and snowballing techniques yielded a sample of 18 participants, primarily based at a district level. Primary data collected through in-depth interviews and observations (participant and non-participant) were analysed using thematic analysis. FINDINGS: Results indicate the sorts of complexities, particularly financial management challenges which staff face and draws attention to the use of two informal learning strategies-learning from others (how to communicate, delegate) and fostering team-based learning. Such strategies played a role in developing a cadre of leaders at a district level who displayed essential competencies such as motivating staff, and problem solving. CONCLUSIONS: It is crucial for health systems, especially those in financially constrained settings to find cost-effective ways to develop leadership competencies such as being solution driven or motivating and empowering staff. This study illustrates that it is possible to develop such competencies through creating and nurturing a learning environment (on-the-job training) which could be incorporated into everyday practice.

Instruments assessing attitudes toward or capability regarding self-management of osteoarthritis: a systematic review of measurement properties.

OBJECTIVE: To make a recommendation on the "best" instrument to assess attitudes toward and/or capabilities regarding self-management of osteoarthritis (OA) based on available measurement property evidence. METHODS: Electronic searches were performed in MEDLINE, EMBASE, CINAHL and PsychINFO (inception to 27 December 2016). Two reviewers independently rated measurement properties using the Consensus-based Standards for the selection of Health Measurement Instruments (COSMIN) 4-point scale. Best evidence synthesis was determined by considering COSMIN ratings for measurement property results and the level of evidence available for each measurement property of each instrument. RESULTS: Eight studies out of 5653 publications met the inclusion criteria, with eight instruments identified for evaluation: Multidimensional Health Locus of Control (MHLC), Perceived Behavioural Control (PBC), Patient Activation Measure (PAM), Educational Needs Assessment (ENAT), Stages of Change Questionnaire in Osteoarthritis (SCQOA), Effective Consumer Scale (EC-17) and Perceived Efficacy in Patient-Physician Interactions five item (PEPPI-5) and ten item scales. Measurement properties assessed for these instruments included internal consistency (k = 8), structural validity (k = 8), test-retest reliability (k = 2), measurement error (k = 1), hypothesis testing (k = 3) and cross-cultural validity (k = 3). No information was available for content validity, responsiveness or minimal important change (MIC)/minimal important difference (MID). The Dutch PEPPI-5 demonstrated the best measurement property evidence; strong evidence for internal consistency and structural validity but limited evidence for reliability and construct validity. CONCLUSION: Although PEPPI-5 was identified as having the best measurement properties, overall there is a poor level of evidence currently available concerning measurement properties of instruments to assess attitudes toward and/or capabilities regarding osteoarthritis self-management. Further well-designed studies investigating measurement properties of existing instruments are required.

Implementation and public acceptability: lessons from food irradiation and how they might apply to pathogen reduction in blood products.

BACKGROUND AND OBJECTIVES: The issues around food irradiation (FI) have both similarities and differences to pathogen reduction (PR) in blood products. We performed a systematic search of the FI literature to identify lessons that could help to inform the implementation of pathogen reduction technology for blood products. METHODS: A comprehensive literature search was performed in EMBASE. MEDLINE, PSYCHINFO, CINAL and Physiological Abstracts for articles related to FI that met predefined eligibility criteria. A coding scheme was developed by the investigators, and relevant information from the articles was coded using NVivo 9. Reports for each code were generated and summarized. RESULTS: One thousand two hundred and sixty-six articles were identified by the broad search, and 50 met the study eligibility criteria for inclusion. The implementation of FI was slow and has been met by significant controversy, sparked by concerns from the public and social groups about the acceptability of irradiated food. Numerous factors influenced public acceptability including: demographic factors; perceptions of safety and risk; endorsement of and trust in the FI industry and social institutions that serve as opinion leaders; knowledge and the provision of scientific information including benefits and cost; and the availability of choice. CONCLUSION: There are a number of lessons from the FI literature that may be generalizable to the implementation of PR of blood products. Based on findings from this study, six recommendations are made to facilitate public implementation of this new technology.

Is there sufficient 'sink' in current bioaccessibility determinations of organic pollutants in soils?

Bioaccessibility tests can be used to improve contaminated land risk assessments. For organic pollutants a 'sink' is required within these tests to better mimic their desorption under the physiological conditions prevailing in the intestinal tract, where a steep diffusion gradient for the removal of organic pollutants from the soil matrix would exist. This is currently ignored in most PBET systems. By combining the CEPBET bioaccessibility test with an infinite sink, the removal of PAH from spiked solutions was monitored. Less than 10% of spiked PAH remained in the stomach media after 1 h, 10% by 4 h in the small intestine compartment and c.15% after 16 h in the colon. The addition of the infinite sink increased bioaccessibility estimates for field soils by a factor of 1.2-2.8, confirming its importance for robust PBET tests. TOC or BC were not the only factors controlling desorption of the PAH from the soils.

Incidence and predictors of contracture after spinal cord injury--a prospective cohort study.

STUDY DESIGN: Prospective cohort study. OBJECTIVES: To determine incidence of contracture and develop prediction models to identify patients susceptible to contracture after spinal cord injury. SETTING: Two Sydney spinal cord injury units. METHODS: A total of 92 consecutive patients with acute spinal cord injury were assessed within 35 days of injury and 1 year later. Incidence of contracture at 1 year was measured in all major appendicular joints by categorizing range of motion on a 4-point scale (0-no contracture to 3-severe contracture), and in the wrist, elbow, hip and ankle by measuring range of motion at standardized torque. Multivariate models were developed to predict contracture at 1 year using age, neurological status, spasticity, pain and limb fracture recorded at the time of injury. RESULTS: At 1 year, 66% of participants developed at least one contracture (defined as ≥1 point deterioration on the 4-point scale). Incidence of contracture at each joint was: shoulder 43%, elbow and forearm 33%, wrist and hand 41%, hip 32%, knee 11% and ankle 40%. Incidence of contracture determined by standardized torque measures of range (defined as loss of ≥10 degrees) was: elbow 27%, wrist 26%, hip 23% and ankle 25%. Prediction models were statistically significant but lacked sufficient predictive accuracy to be clinically useful (R(2)≤31%). CONCLUSION: The incidence of contracture in major joints 1 year after spinal cord injury ranges from 11-43%. The ankle, wrist and shoulder are most commonly affected. It is difficult to accurately predict those susceptible to contracture soon after injury.

Protection afforded against aerosol challenge by systemic immunisation with inactivated Francisella tularensis live vaccine strain (LVS).

BALB/c mice were immunised with inactivated Francisella tularensis live vaccine strain (LVS) and the level of protection afforded against aerosol challenge with virulent strains of F. tularensis ascertained. Intramuscular (IM) injection of inactivated LVS with an aluminium-hydroxide-based adjuvant-stimulated IgG1-biased LVS-specific antibody responses and afforded no protection against aerosol challenge with subspecies holarctica (strain HN63). Conversely, IM injection of inactivated LVS adjuvanted with preformed immune-stimulating complexes (ISCOMS) admixed with immunostimulatory CpG oligonucleotides afforded robust protection against aerosol-initiated infection with HN63. However, despite a significantly extended time-to-death relative to naïve controls, the majority of mice immunised with the most potent vaccine formulation were not protected against a low-dose aerosol challenge with subspecies tularensis (strain Schu S4). These data indicate that parenterally administered non-living vaccines can be used for effective immunisation against aerosol challenges with subspecies holarctica, although not high virulence strains of F. tularensis.

Immunisation against plague by transcutaneous and intradermal application of subunit antigens.

We have investigated immunological responses in BALB/c mice following transcutaneous (TC) delivery of fraction 1 (F1) and V subunits from Yersinia pestis in conjunction with an enterotoxin-derived adjuvant (cholera toxin, CT). It was found that two or more TC applications of F1 and V subunits (admixed with cholera toxin) served to elicit significant levels of anti-F1 and V antibodies in the serum of immunised mice. IL-6 secretion from cultured splenocytes derived from immunised mice indicated that a single TC application of F1 and V subunits (admixed with cholera toxin) conferred a cell-mediated response. As compared with intranasal or direct intradermal injection of F1 and V, the numbers of F1/V-specific antibody-forming cells in the spleens of animals immunised by TC application of F1 and V (admixed with CT) was relatively low. It was noted that TC application of F1 and V admixed with CT was very effective for priming responses that were boosted by intranasal or intradermal routes. Similarly, it was found that TC application of F1 and V admixed with CT could be used to efficiently boost pre-existing responses engendered by intradermal injection or intranasal instillation of F1 and V. In order to assess if TC application of F1 and V admixed with CT could protect experimental animals from plague, immunised mice were injected with a virulent strain of Y. pestis. It was found that two TC applications of F1 and V admixed with CT conferred only limited protection against 10(2) MLDs. However, three TC applications of F1 and V admixed with CT conferred solid protection against 10(2) MLDs. Hence we have shown, for the first time, that TC application of F1 and V admixed with CT can protect animals against challenge with a virulent strain of plague causing bacteria. These data suggest that transcutaneous immunisation may be a simple and non-invasive method for immunising individuals against plague.

Linking perceptions of neighbourhood to health in Hamilton, Canada.

STUDY OBJECTIVE: To investigate the association between perceptions of neighbourhood physical and social characteristics and three health outcomes (self assessed health status, chronic conditions, and emotional distress). DESIGN: Cross sectional survey data analysed in small neighbourhoods. SETTING: Hamilton, Ontario, Canada, a medium sized industrial city, located at the western end of Lake Ontario (population at the time of the study about 380 000). PARTICIPANTS: Random sample of 1504 adults aged 18 years and older residing in four contrasting neighbourhoods. MAIN RESULTS: Significant differences across the four neighbourhoods are apparent in self assessed health status and emotional distress, but not in chronic conditions. Neighbourhoods with lower SES reported poorer health and more emotional distress. Perceptions of the physical environment dominated social concerns in all neighbourhoods. For all three health outcomes, individual risk factors followed expectations, with measures of poverty, age, and lifestyle all significantly associated with poor health outcomes. Physical environmental problems were positively and significantly associated with poor physical and emotional health. Specifically, people reporting they dislike aspects of their neighbourhood's physical environment are 1.5 times more likely to report chronic health conditions (OR 1.56, 95% CI 1.19 to 2.05), while those reporting physical likes with their neighbourhood are less likely to report fair/poor health (OR 0.50, 95% CI 0.28 to 0.90) or emotional distress (OR 0.45, 95% CI 0.26 to 0.80). CONCLUSIONS: These results demonstrate the importance of neighbourhood perceptions as a determinant of health, as well as conventional factors such as low income, lifestyle, and age. The dominance of physical environmental concerns may have arisen from the industrial nature of Hamilton, but this result merits further investigation.

Localization performance of unilateral cochlear implant users for speech, tones and noise.

Bilateral cochlear implants aim to improve sound localization compared to monaural implants, among other potential benefits. Monaural cochlear implants should not support localization in the horizontal plane as there are no interaural level and time difference cues available, although some previous studies have suggested limited capability. As background to other studies of bilateral implantation, the localization abilities of 18 monaural cochlear implantees were investigated experimentally in an anechoic chamber, using various sound stimuli with different amounts of temporal information. The effects of head movement and reverberation were also investigated. Localization performance was found to be close to chance for all stimuli. It is confirmed that monaural cochlear implants are unable to support useful auditory sound localization, even when head movements are allowed.

Environmental influences on healthcare expenditures: an exploratory analysis from Ontario, Canada.

STUDY OBJECTIVE: This paper explores the relation between healthcare expenditures (HCEs) and environmental variables in Ontario, Canada. DESIGN: The authors used a sequential two stage regression model to control for variables that may influence HCEs and for the possibility of endogenous relations. The analysis relies on cross sectional ecological data from the 49 counties of Ontario. MAIN RESULTS: The results show that, after control for other variables that may influence health expenditures, both total toxic pollution output and per capita municipal environmental expenditures have significant associations with health expenditures. Counties with higher pollution output tend to have higher per capita HCEs, while those that spend more on defending environmental quality have lower expenditures on health care. CONCLUSIONS: The implications of our findings are twofold. Firstly, sound investments in public health and environmental protection have external benefits in the form of reduced HCEs. Combined with the other benefits such as recreational values, investments in environmental protection probably yield net social benefits. Secondly, health policy that excludes consideration of environmental quality may eventually result in increased expenditures. These results suggest a need to broaden the cost containment debate to ensure environmental determinants of health receive attention as potential complements to conventional cost control policies.

Stimulation of spleen cells in vitro by nanospheric particles containing antigen.

Activation of cells, in primary culture, by nanospheres containing antigen has been investigated. Single cell suspensions of spleen cells from primed and nai;ve animals were cocultured with escalating quantities of soluble tetanus toxoid (TT) or TT encapsulated within nanospheres fabricated from poly(lactide-co-glycolide) (PLGA). Concomitantly, spleen cells were also cultured in the presence of 'empty' PLGA nanospheres that contained no TT. Nanospheres loaded with antigen were found to elicit increased proliferation of splenocytes from preimmunised mice in comparison to free antigen during coculture at equivalent doses of immunogen (at low and intermediate doses). Interestingly, cellular proliferation was abolished if B-cells were removed from the splenocyte cultures. Production of IFN-gamma and IL-6 was increased, for formulated as compared to free antigen, in microcultures from both nai;ve and pre-immunised animals. Secretion of IFN-gamma or IL-6 was not observed when primed or nai;ve spleen cells were stimulated with 'empty' polymeric spheres. Some unspecific cytotoxicity was detected if cells were cocultured with high concentrations of PLGA particles, although toxic effects were not seen at concentrations where maximum levels of cytokine secretion and cellular proliferation were recorded. These cell culture data indicate that, at least in this in vitro model, nanoparticulate TT is able to elicit cytokine production that is probably consistent with increased stimulation. This mechanism is likely to be distinct from non-specific effects caused by components of the delivery vehicle itself.

Immunological aspects of polymer microsphere vaccine delivery systems.

In vitro studies using dendritic cells have identified that microencapsulated antigens are taken up and processed differently as compared with soluble proteins, and these findings have been reviewed. Similarly, in vivo, it is evident that microencapsulated materials have different properties in terms of uptake and trafficking. Intranasal (IN) instillation of encapsulated protective antigen resulted in a significant increase in the percentage of activated CD4+ and B-cells in the spleens of immunised mice, whereas IN instillation of soluble antigen failed to do so. This corroborates earlier findings concerning the uptake and trafficking of microparticles following bronchopulmonary administration. These data support the tenet that microencapsulation serves to modify the uptake, trafficking and processing of antigens.

Protection against plague following immunisation with microencapsulated V antigen is reduced by co-encapsulation with IFN-gamma or IL-4, but not IL-6.

We have investigated intranasal delivery of novel vaccines for plague, based on poly-L-lactide (PLLA) microencapsulated recombinant V antigen (rV) of Yersinia pestis. Microspheres containing rV alone or co-encapsulated with the cytokines IFN-gamma, IL-4 or IL-6 were administered in a two-dose regimen and antibody responses and protective efficacy were monitored. All treatment groups stimulated high rV-specific antibody titres in serum, predominantly of the IgG1 isotype, which were maintained over several months. There was evidence of both IgG and IgA responses in lung samples from all groups. Formulations based on rV antigen alone or rV co-encapsulated with IL-6 provided complete protection against systemic challenge with Y. pestis strain GB; however protective efficacy was impaired by co-encapsulating either IFN-gamma or IL-4 with rV.