A Blended Intervention for Patients With Knee and Hip Osteoarthritis in the Physical Therapy Practice: Development and a Pilot Study.

BACKGROUND: Blended care, a combination of online and face-to-face care, is seen as a promising treatment option. However, actual use of blended interventions in practice is disappointing. OBJECTIVE: The objective of this study was two folded. The first aim was to develop a blended exercise therapy intervention for patients with knee and hip osteoarthritis that matches the values of the users and that can be implemented in the daily routine of physical therapists. The second aim was to investigate the feasibility through interviews and a pilot study. METHODS: In this paper, we employed the first 3 steps of the CeHRes road map to develop a blended intervention for patients with knee and hip osteoarthritis. We used interviews, a focus group and discussions with stakeholders to explore the needs, values, and requirements with respect to our to-be-developed blended intervention, which we called e-Exercise. The first version of e-Exercise was tested in a pilot study. Feasibility outcomes, including recruitment rates within each practice, website usage (assignments completed and website visits), and user satisfaction, were measured. In addition, therapists and patients from the pilot study were interviewed to investigate users' experiences. RESULTS: The study captured important information about stakeholders' needs and perspectives. Based on our findings, we created a first version and attuned the application's content, functionality, and structure. Patients and, to lesser extent, physical therapists were satisfied with the e-Exercise intervention. Eight patients were recruited by 8 physical therapists. Of the 8 patients, 6 completed more than 7 of 12 modules. CONCLUSIONS: This study outlines the development and feasibility of a blended exercise therapy intervention for patients with knee and hip osteoarthritis. E-Exercise offers an alternative approach in the physical therapy treatment of knee and hip osteoarthritis. This study provides valuable information to conduct a further trial to evaluate the (cost) effectiveness of e-Exercise compared to usual physical therapy. TRIAL REGISTRATION: Netherlands Trial Register Number: NTR4224; www.trialregister.nl/trialreg/admin/rctview.asp?TC=4224 (Archived by WebCite at http://www.webcitation.org/6fOK4lrTO).

Active patient participation in the development of an online intervention.

BACKGROUND: An important and challenging part of living with cancer relates to the repeated visits to the hospital. Since how patients cope between these post-diagnostic visits depends partly on the information and support received from their physician during the visits, it is important to make the most of them. Recent findings reinforce the importance of training not only the health care professionals in communication skills, but providing patients with support in communication as well. Delivering such supportive interventions online can have potential benefits in terms of accessibility, cost-effectiveness, and ability to tailor information to personal needs. However, problems with attrition (dropout, non-usage) during the test phase and poor uptake after implementation are frequently reported. The marginal level of engagement of the patient as end user seems to play a role in this. Therefore, recent research suggests integrating theory-based development methods with methods that promote involvement of the patient at an early stage. This paper describes a participatory protocol, used to let patients guide a theory-informed development process. OBJECTIVE: The objective of this project was to apply a bottom-up inspired procedure to develop a patient-centered intervention with corresponding evaluation and implementation plan. METHODS: The applied development protocol was based on the intervention mapping framework, combined with patient participatory methods that were inspired by the participation ladder and user-centred design methods. RESULTS: The applied protocol led to a self-directed online communication intervention aimed at helping patients gain control during their communications with health care professionals. It also led to an evaluation plan and an implementation plan. The protocol enabled the continuous involvement of patient research partners and the partial involvement of patient service users, which led to valuable insights and improvements. CONCLUSIONS: The applied protocol realized patient participation on different levels throughout the entire project. Early involvement, involvement on different levels, and flexibility in terms of planning and setup seem to be preconditions to creating a bottom-up inspired development procedure with (seriously ill) patients. Further research is necessary to find out if a more patient-centered approach improves the implementation and uptake of eHealth interventions. TRIAL REGISTRATION: Netherlands National Trial Register ID number: NTR3779; http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=3779 (Archived by WebCite at http://www.webcitation.org/6TdfALKxV).

High sensitive detection of carbohydrate binding proteins in an ELISA-solid phase assay based on multivalent glyconanoparticles.

Improved detection of anti-carbohydrate antibodies is a need in clinical identification of biomarkers for cancer cells or pathogens. Here, we report a new ELISA approach for the detection of specific immunoglobulins (IgGs) against carbohydrates. Two nanometer gold glyconanoparticles bearing oligosaccharide epitopes of HIV or Streptococcus pneumoniae were used as antigens to coat ELISA-plates. A ~3,000-fold improved detection of specific IgGs in mice immunized against S. pneumoniae respect to the well known BSA-glycoconjugate ELISA was achieved. Moreover, these multivalent glyconanoparticles have been employed in solid phase assays to detect the carbohydrate-dependent binding of human dendritic cells and the lectin DC-SIGN. Multivalent glyconanoparticles in ELISA provide a versatile, easy and highly sensitive method to detect and quantify the binding of glycan to proteins and to facilitate the identification of biomarkers.

Gold nanoparticles as carriers for a synthetic Streptococcus pneumoniae type 14 conjugate vaccine.

AIMS: Coupling of capsular polysaccharides of pathogens to immunogenic protein carriers (conjugate vaccines) improves carbohydrate immune response. Our idea is to explore gold nanoclusters as carriers to prepare fully synthetic carbohydrate vaccines. MATERIALS & METHODS: Gold glyconanoparticles bearing a synthetic tetrasaccharide epitope related to the Streptococcus pneumoniae type 14 capsular polysaccharide (Pn14PS), the T-helper ovalbumin 323-339 peptide (OVA(323-339)), and D-glucose were prepared by a one-pot method. Their immunogenicity was tested in mice. Cytokine levels after spleen cell stimulation with OVA(323-339) were analyzed using a luminex-multiplex cytokine assay. The capacity of the evoked antibodies to promote the uptake of S. pneumoniae type 14 by leukocytes was assessed. RESULTS & DISCUSSION: Glyconanoparticles containing 45% of tetrasaccharide and 5% OVA(323-339) triggered specific anti-Pn14PS IgG antibodies. Cytokine levels confirmed that glyconanoparticles led to T-helper cell activation. The anti-saccharide antibodies promoted the phagocytosis of type 14 bacteria by human leukocytes, indicating the functionality of the antibodies. CONCLUSION: Gold nanoparticles have great potential as carriers for the development of a great diversity of fully synthetic carbohydrate-based vaccines.

The immune response to group B streptococcus type III capsular polysaccharide is directed to the -Glc-GlcNAc-Gal- backbone epitope.

The structures of the branched capsular polysaccharides of group B streptococcus type III (GBSIIIPS) and Streptococcus pneumoniae type 14 (Pn14PS) are identical apart from the (α2→3)-linked sialic acid in the side chains of GBSIIIPS. The present study tries to determine the minimal epitope in GBSIIIPS, using both a panel of anti-Pn14PS mouse sera and sera of humans vaccinated with either Pn14PS or GBSIIIPS. Type-specific Pn14PS antibodies that recognize the branched structure of Pn14PS have a low affinity for the native GBSIIIPS. Desialylation of GBSIIIPS results in dramatically higher affinity of anti-Pn14PS antibodies. Epitope specific anti-Pn14PS mouse antibodies and human sera of PCV7 vaccinees only recognized structures with the branching element -Glc-(Gal-)GlcNAc-, in particular -Gal-Glc-(Gal-)GlcNAc- in Pn14PS. On the other hand anti-GBSIIIPS human antibodies recognize predominantly the linear structure in the backbone of Pn14PS or GBSIIIPS, i.e., -Glc-GlcNAc-Gal-. This difference in antigenicity of Pn14PS and GBSIIIPS is in agreement with the difference in flexibility of the two polysaccharides caused by the presence or absence of sialic acid.

Antibody- and cell-mediated immune responses to a synthetic oligosaccharide conjugate vaccine after booster immunization.

Memory formation to CRM-neoglycoconjugate, a synthetic branched tetrasaccharide of Streptococcus pneumoniae type 14 polysaccharide (Pn14PS) that is conjugated to a CRM197 protein, was investigated using mice models. Mice were first immunized with the CRM-neoglycoconjugate and then boosted with either the same neoglycoconjugate or a native Pn14PS in order to investigate the effect of booster immunization. Boosting with the CRM-neoglycoconjugate resulted in increased levels of interleukin 5 (IL-5) in the serum on Day 1, followed by the appearance of high levels of specific anti-Pn14PS IgG antibodies on Day 7. Boosting with native Pn14PS resulted in neither IL-5 induction nor the generation of anti-Pn14PS IgG antibodies. In vitro (re)stimulation of spleen cells after booster injection with the neoglycoconjugate revealed the presence of IL-4 and IL-5. This was not seen in spleen cells obtained from mice boosted with the polysaccharide. When stimulated with heat-inactivated bacteria, however, the polysaccharide-boosted mice did have higher levels of IFN-γ and lower levels of IL-17 than both the CRM-neoglycoconjugate-boosted mice and the mock-immunized mice. In conclusion, neoglycoconjugate boosting is responsible for the activation of memory cells and the establishment of sustained immunity. Not only is a booster with native polysaccharide ineffective in inducing opsonic antibodies, but it also interferes with several immunoregulatory mechanisms.

A genome-wide association study of hepatitis B vaccine response in an Indonesian population reveals multiple independent risk variants in the HLA region.

We performed a two-stage genome-wide association study (GWAS) of antibody titer in 3614 hepatitis B vaccine recipients from Indonesia's Riau Archipelago, leading to the identification of at least three independent signals within the human leukocyte antigen (HLA) complex. These appear to implicate HLA-DR [rs3135363; P= 6.53 × 10(-22); odds ratio (OR) = 1.53, 95% confidence interval (CI) = 1.35-1.74]; HLA-DP, previously associated with the risk of chronic hepatitis B infection (rs9277535; P= 2.91 × 10(-12); OR = 0.72, 95% CI = 0.63-0.81); and a gene rich HLA Class III interval (rs9267665; P = 1.24 × 10(-17); OR = 2.05, CI = 1.64-2.57). The substantial overlap of these variants and those identified by GWAS of chronic hepatitis B infection confirms vaccine response as a model for infection, while suggesting that the vaccine is least effective in those most at risk of lifelong infection, following exposure to the virus.

Codelivery of adjuvants at the primary immunization site is essential for evoking a robust immune response to neoglycoconjugates.

A series of nonformulated adjuvants, i.e. Quil-A, MPL, DDA, CpG and Alum were codelivered with a synthetic branched tetrasaccharide fragment corresponding to Streptococcus pneumoniae type 14 polysaccharide (Pn14PS) conjugated to CRM(197) in order to investigate antibody- and cell-mediated immune responses in a mouse model. The first immunization was performed intracutaneously in the presence of adjuvants. Booster injections which were given without adjuvant dramatically enhanced and expanded the immune response from IgM to IgG1 and other IgG subclasses. Codelivery of the neoglycoconjugate with CpG or Alum had no additional effect over vaccine in saline, and elicited mainly IgG1 antibodies against Pn14PS. CpG even has a modest suppressive effect on the antibody response. Codelivery of the neoglycoconjugate with Quil-A, MPL, DDA alone or in combination resulted in both IgG1, IgG2a, IgG2b and IgG3 antibodies. Quil-A alone or in combination with MPL induced systemic IL-5 and IL-6 6h after primary immunization. This adjuvant combination also increased CD4/CD8 T cells ratio in lymph nodes and peripheral blood on day 1 after immunization. Seven days later, the ratios in blood and lymph nodes had returned to normal. In conclusion, codelivery of Quil-A alone or in combination with MPL had the most dramatic effect on antibody- and cell-mediated immune response to neoglycoconjugate of Pn14PS.

Identification of the smallest structure capable of evoking opsonophagocytic antibodies against Streptococcus pneumoniae type 14.

Synthetic overlapping oligosaccharide fragments of Streptococcus pneumoniae serotype 14 capsular polysaccharide (Pn14PS), [6)-[beta-D-Galp-(1-->4)-]beta-D-GlcpNAc-(1-->3)-beta-D-Galp-(1-->4)-beta-D-Glcp-(1-->](n), were conjugated to CRM(197) protein and injected into mice to determine the smallest immunogenic structure. The resulting antibodies were then tested for Pn14PS specificity and for their capacity to promote the phagocytosis of S. pneumoniae type 14 bacteria. Earlier studies have reported that the oligosaccharide corresponding to one structural repeating unit of Pn14PS, i.e., Gal-Glc-(Gal-)GlcNAc, induces a specific antibody response to Pn14PS. The broader study described here, which evaluated 16 oligosaccharides, showed that the branched trisaccharide element Glc-(Gal-)GlcNAc is essential in inducing Pn14PS-specific antibodies and that the neighboring galactose unit at the nonreducing end contributes clearly to the immunogenicity of the epitope. Only the oligosaccharide conjugates that produce antibodies recognizing Pn14PS were capable of promoting the phagocytosis of S. pneumoniae type 14. In conclusion, the branched tetrasaccharide Gal-Glc-(Gal-)GlcNAc may be a serious candidate for a synthetic oligosaccharide conjugate vaccine against infections caused by S. pneumoniae type 14.

Assessment of antibody response elicited by a 7-valent pneumococcal conjugate vaccine in pediatric human immunodeficiency virus infection.

We investigated antibody responses against pneumococci of serotypes 6B, 14, and 23F in 56 children and adolescents with perinatal human immunodeficiency virus (HIV) infection who were vaccinated with 7-valent pneumococcal conjugate vaccine. Overall immune responses differed greatly between serotypes. Correlation coefficients between immunoglobulin G (IgG) measured by enzyme-linked immunosorbent assay (ELISA) and functional antibodies measured by a flow cytometry opsonophagocytosis assay (OPA) varied with serotype and time points studied. After 3 months of administering a second PCV7 dose we got the highest correlation (with significant r values of 0.754, 0.414, and 0.593 for serotypes 6B, 14, and 23F, respectively) but no significant increase in IgG concentration and OPA titers compared to the first dose. We defined a responder to a serotype included in the vaccine with two criteria: frequency of at least twofold OPA and ELISA increases for each serotype and frequency of conversion from negative to positive OPA levels. Responders varied from 43.9% to 46.3%, 28.5% to 50.0%, and 38.0% to 50.0% for serotypes 6B, 14, and 23F, respectively, depending on the response criterion. The present research highlights the importance of demonstrating vaccine immunogenicity with suitable immunological endpoints in immunocompromised patients and also the need to define how much antibody is required for protection from different serotypes, since immunogenicity differed significantly between serotypes.

Short-chain oligosaccharide protein conjugates as experimental pneumococcal vaccines.

Streptococcus pneumoniae remains a major cause of acute respiratory infections worldwide and is responsible for approximately 1 million childhood deaths each year. Despite the widespread use of antibiotics, the mortality and morbidity of pneumococcal disease remains high. Therefore, effective vaccines to prevent pneumococcal disease are needed. Bacterial vaccine development in general follows a similar track starting from large, rather crude vaccines (whole live, attenuated pathogen) towards smaller, better defined subunit vaccines. Ultimately, this track leads to the development and evaluation of minimal, highly defined subunit vaccines, based on a collection of single protective epitopes. This mini-review deals with capsular saccharide based vaccines. After a short overview of the development of pneumococcal vaccines from the 23 - valent polysaccharide vaccines to polysaccharide-protein conjugate vaccines, it focuses on the vaccine potential of synthetic oligosaccharides, conjugated to carrier proteins.

Th1-directing adjuvants increase the immunogenicity of oligosaccharide-protein conjugate vaccines related to Streptococcus pneumoniae type 3.

Oligosaccharide (OS)-protein conjugates are promising candidate vaccines against encapsulated bacteria, such as Haemophilus influenzae, Neisseria meningitidis, and Streptococcus pneumoniae. Although the effects of several variables such as OS chain length and protein carrier have been studied, little is known about the influence of adjuvants on the immunogenicity of OS-protein conjugates. In this study, a minimal protective trisaccharide epitope of Streptococcus pneumoniae type 3 conjugated to the cross-reacting material of diphtheria toxin was used for immunization of BALB/c mice in the presence of different adjuvants. Subsequently, half of the mice received a booster immunization with conjugate alone. Independent of the use and type of adjuvant, all mice produced long-lasting anti-polysaccharide type 3 (PS3) antibody levels, which provided full protection against challenge with pneumococcal type 3 bacteria. All adjuvants tested increased the anti-PS3 antibody levels and opsonic capacities as measured by an enzyme-linked immunosorbent assay and an in vitro phagocytosis assay. The use of QuilA or a combination of the adjuvants CpG and dimethyl dioctadecyl ammonium bromide resulted in the highest phagocytic capacities and the highest levels of Th1-related immunoglobulin G (IgG) subclasses. Phagocytic capacity correlated strongly with Th1-associated IgG2a and IgG2b levels, to a lesser extent with Th2-associated IgG1 levels, and weakly with thiocyanate elution as a measure of avidity. Thus, the improved immunogenicity of OS-protein conjugates was most pronounced for Th1-directing adjuvants.