Usability of therapy controllers in elderly patients with deep brain stimulation

<p>Abstract</p> <p>Background</p> <p>Technical devices are becoming more prevalent in society and also in medical care. Older adults need more support to learn new technologies than younger subjects. So far, no research has been done on the usability of patient controllers in deep brain stimulation in an elderly population. The aim of the study was to investigate the factors influencing the performance of elderly DBS patients with respect to usability aspects of Medtronic Access therapy controllers.</p> <p>Methods</p> <p>Time, mistakes and frequency of use of the controller were compared in 41 elderly DBS patients who prior to the study had already owned a therapy controller for more than six years. One group (n = 20, mean age = 66.4 years) was watching an instructional video and then completed practical assignments on a model implantable pulse generator (IPG). The other group (n = 21, mean age = 65.9 years) completed the tasks without having seen the video before. Any errors that patients made were documented and also corrected so that all of them received hands-on training. After six months all patients were re-evaluated on the dummy IPG in order to compare the effects of hands-on alone vs. video-based training combined with hands-on.</p> <p>Results</p> <p>The group that had seen the video before significantly outperformed the control group at both assessments with respect to number of errors. Both groups performed faster after six months compared to baseline and tend to use the controller more often than at baseline.</p> <p>Conclusion</p> <p>Our results indicate that elderly DBS patients who have been using the controller for several years still have various difficulties in operating the device. However, we also showed that age-specific training may improve the performance in older adults. In general, the design of DBS patient controllers should focus on the specific needs of the end-users. But as changes to medical devices take a long time to be implemented, video instructions with age-specific content plus hands-on training may improve learning for older adults.</p

Accounting Problems Under the Excess Profits Tax

DNA vaccines based on subunits from pathogens have several advantages over other vaccine strategies. DNA vaccines can easily be modified, they show good safety profiles, are stable and inexpensive to produce, and the immune response can be focused to the antigen of interest. However, the immunogenicity of DNA vaccines which is generally quite low needs to be improved. Electroporation and co-delivery of genetically encoded immune adjuvants are two strategies aiming at increasing the efficacy of DNA vaccines. Here, we have examined whether targeting to antigen-presenting cells (APC) could increase the immune response to surface envelope glycoprotein (Env) gp120 from Human Immunodeficiency Virus type 1 (HIV- 1). To target APC, we utilized a homodimeric vaccine format denoted vaccibody, which enables covalent fusion of gp120 to molecules that can target APC. Two molecules were tested for their efficiency as targeting units: the antibody-derived single chain Fragment variable (scFv) specific for the major histocompatilibility complex (MHC) class II I-E molecules, and the CC chemokine ligand 3 (CCL3). The vaccines were delivered as DNA into muscle of mice with or without electroporation. Targeting of gp120 to MHC class II molecules induced antibodies that neutralized HIV-1 and that persisted for more than a year after one single immunization with electroporation. Targeting by CCL3 significantly increased the number of HIV-1 gp120-reactive CD8(+) T cells compared to non-targeted vaccines and gp120 delivered alone in the absence of electroporation. The data suggest that chemokines are promising molecular adjuvants because small amounts can attract immune cells and promote immune responses without advanced equipment such as electroporation.Funding Agencies|Research Council of Norway; Odd Fellow</p

Cost-effectiveness of rotavirus vaccination in the Netherlands; the results of a consensus model

Contains fulltext : 96770.pdf (publisher's version ) (Open Access)BACKGROUND: Each year rotavirus gastroenteritis results in thousands of paediatric hospitalisations and primary care visits in the Netherlands. While two vaccines against rotavirus are registered, routine immunisation of infants has not yet been implemented. Existing cost-effectiveness studies showed inconsistent results for these vaccines because of lack of consensus on the impact. We aimed to investigate which factors had a major impact on cost-effectiveness and were primarily responsible for the large differences in previously estimated cost-effectiveness ratios. METHODS: Based on updated data on health outcomes and cost estimates, we re-assessed the cost-effectiveness of routine paediatric rotavirus vaccination within the National Immunization Program for the Netherlands. Two consensus meetings were organised with national and international experts in the field to achieve consensus and resolve potential controversies. RESULTS: It was estimated that rotavirus vaccination in the Netherlands could avert 34,214 cases of rotavirus gastroenteritis in children aged less than 5 years. Notably, 2,779 hospitalisations were averted of which 315 were extensions of existing hospital stays due to nosocomial rotavirus infection. With a threshold varying from 20K euro - 50K euro per QALY and according to the base-case scenario, the full vaccination costs per child leading to cost-effectiveness was euro 57.76 -euro 77.71. Results were sensitive to the inclusion of potential vaccine induced herd protection, QALY losses and number of deaths associated with rotavirus gastroenteritis. CONCLUSIONS: Our economic analysis indicates that inclusion of rotavirus vaccination in the Dutch National Immunization Program might be cost-effective depending on the cost of the vaccine and the impact of rotavirus gastroenteritis on children's quality of life

Internet-based monitoring of influenza-like illness (ILI) in the general population of the Netherlands during the 2003–2004 influenza season

BACKGROUND: An internet-based survey of influenza-like illness (ILI) – the Great Influenza Survey or GIS – was launched in the Netherlands in the 2003–2004 influenza season. The aim of the present study was to validate the representativeness of the GIS population and to compare the GIS data with the official ILI data obtained by Dutch GPs participating in the Dutch Sentinel Practice Network. METHOD: Direct mailings to schools and universities, and repeated interviews on television and radio, and in newspapers were used to kindle the enthusiasm of a broad section of the public for GIS. Strict symptomatic criteria for ILI were formulated with the assistance of expert institutes and only participants who responded at least five times to weekly e-mails asking them about possible ILI symptoms were included in the survey. Validation of GIS was done at different levels: 1) some key demographic (age distribution) and public health statistics (prevalence of asthma and diabetes, and influenza vaccination rates) for the Dutch population were compared with corresponding figures calculated from GIS; 2) the ILI rates in GIS were compared with the ILI consultation rates reported by GPs participating in the Dutch Sentinel Practice Network. RESULTS: 13,300 persons (53% of total responders), replied at least five times to weekly e-mails and were included in the survey. As expected, there was a marked under-representation of the age groups 0–10 years and 81->90 years in the GIS population, although the similarities were remarkable for most other age groups, albeit that the age groups between 21 and 70 years were slightly overrepresented. There were striking similarities between GIS and the Dutch population with regard to the prevalence of asthma (6.4% vs. 6.9%) and the influenza vaccination rates, and to a lesser degree for diabetes (2.4% vs. 3.5%). The vaccination rates in patients with asthma or diabetes, and persons older than 65 years were 68%, 85%, and 85% respectively in GIS, while the corresponding percentages in the Dutch population were 73%, 85% and 87%. There was also a marked similarity between the seasonal course of ILI measured by GIS and the GPs. Although the ILI rate in GIS was about 10 times higher, the curves followed an almost similar pattern, with peak incidences occurring in the same week. CONCLUSION: The current study demonstrates that recruitment of a high number of persons willing to participate in on-line health surveillance is feasible. The information gathered proved to be reliable, as it paralleled the information obtained via an undisputed route. We believe that the interactive nature of GIS and the appealing subject were keys to its success

HER2-based recombinant immunogen to target DCs through FcγRs for cancer immunotherapy

Dendritic cell (DC)-based immunotherapy is an attractive approach to induce long lasting antitumor effector cells aiming to control cancer progression. DC targeting is a critical step in the design of DC vaccines in order to optimize delivery and processing of the antigen, and several receptors have been characterized for this purpose. In this study, we employed the FcγRs to target DCs both in vitro and in vivo. We designed a recombinant molecule (HER2-Fc) composed of the immunogenic sequence of the human tumor-associated antigen HER2 (aa 364–391) and the Fc domain of a human IgG1. In a mouse model, HER2-Fc cDNA vaccination activated significant T cell-mediated immune responses towards HER2 peptide epitopes as detected by IFN-γ ELIspot and induced longer tumor latency as compared to Ctrl-Fc-vaccinated control mice. Human in vitro studies indicated that the recombinant HER2-Fc immunogen efficiently targeted human DCs through the FcγRs resulting in protein cross-processing and in the activation of autologous HER2-specific CD8+ T cells from breast cancer patients

Non-participation in population-based disease prevention programs in general practice

<p>Abstract</p> <p>Background</p> <p>The number of people with a chronic disease will strongly increase in the next decades. Therefore, prevention of disease becomes increasingly important. The aim of this systematic review was to identify factors that negatively influence participation in population-based disease prevention programs in General Practice and to establish whether the program type is related to non-participation levels.</p> <p>Methods</p> <p>We conducted a systematic review in Pubmed, EMBASE, CINAHL and PsycINFO, covering 2000 through July 6th 2012, to identify publications including information about characteristics of non-participants or reasons for non-participation in population-based disease prevention programs in General Practice.</p> <p>Results</p> <p>A total of 24 original studies met our criteria, seven of which focused on vaccination, eleven on screening aimed at early detection of disease, and six on screening aimed at identifying high risk of a disease, targeting a variety of diseases and conditions. Lack of personal relevance of the program, younger age, higher social deprivation and former non-participation were related to actual non-participation. No differences were found in non-participation levels or factors related to non-participation between the three program types. The large variation in non-participation levels within the program types may be partly due to differences in recruitment strategies, with more active, personalized strategies resulting in higher participation levels compared to an invitation letter.</p> <p>Conclusions</p> <p>There is still much to be gained by tailoring strategies to improve participation in those who are less likely to do so, namely younger individuals, those living in a deprived area and former non-participants. Participation may increase by applying more active recruitment strategies.</p

Vaccine delivery by penetratin: mechanism of antigen presentation by dendritic cells

Cell-penetrating peptides (CPP) or membrane-translocating peptides such as penetratin from Antennapedia homeodomain or TAT from human immunodeficiency virus are useful vectors for the delivery of protein antigens or their cytotoxic (Tc) or helper (Th) T cell epitopes to antigen-presenting cells. Mice immunized with CPP containing immunogens elicit antigen-specific Tc and/or Th responses and could be protected from tumor challenges. In the present paper, we investigate the mechanism of class I and class II antigen presentation of ovalbumin covalently linked to penetratin (AntpOVA) by bone marrow-derived dendritic cells with the use of biochemical inhibitors of various pathways of antigen processing and presentation. Results from our study suggested that uptake of AntpOVA is via a combination of energy-independent (membrane fusion) and energy-dependent pathways (endocytosis). Once internalized by either mechanism, multiple tap-dependent or independent antigen presentation pathways are accessed while not completely dependent on proteasomal processing but involving proteolytic trimming in the ER and Golgi compartments. Our study provides an understanding on the mechanism of antigen presentation mediated by CPP and leads to greater insights into future development of vaccine formulations

A Ligand Peptide Motif Selected from a Cancer Patient Is a Receptor-Interacting Site within Human Interleukin-11

Interleukin-11 (IL-11) is a pleiotropic cytokine approved by the FDA against chemotherapy-induced thrombocytopenia. From a combinatorial selection in a cancer patient, we isolated an IL-11-like peptide mapping to domain I of the IL-11 (sequence CGRRAGGSC). Although this motif has ligand attributes, it is not within the previously characterized interacting sites. Here we design and validate in-tandem binding assays, site-directed mutagenesis and NMR spectroscopy to show (i) the peptide mimics a receptor-binding site within IL-11, (ii) the binding of CGRRAGGSC to the IL-11Rα is functionally relevant, (iii) Arg4 and Ser8 are the key residues mediating the interaction, and (iv) the IL-11-like motif induces cell proliferation through STAT3 activation. These structural and functional results uncover an as yet unrecognized receptor-binding site in human IL-11. Given that IL-11Rα has been proposed as a target in human cancer, our results provide clues for the rational design of targeted drugs

Human Cytomegalovirus Entry into Dendritic Cells Occurs via a Macropinocytosis-Like Pathway in a pH-Independent and Cholesterol-Dependent Manner

Human cytomegalovirus (HCMV) is a ubiquitous herpesvirus that is able to infect fibroblastic, epithelial, endothelial and hematopoietic cells. Over the past ten years, several groups have provided direct evidence that dendritic cells (DCs) fully support the HCMV lytic cycle. We previously demonstrated that the C-type lectin dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN) has a prominent role in the docking of HCMV on monocyte-derived DCs (MDDCs). The DC-SIGN/HCMV interaction was demonstrated to be a crucial and early event that substantially enhanced infection in trans, i.e., from one CMV-bearing cell to another non-infected cell (or trans-infection), and rendered susceptible cells fully permissive to HCMV infection. Nevertheless, nothing is yet known about how HCMV enters MDDCs. In this study, we demonstrated that VHL/E HCMV virions (an endothelio/dendrotropic strain) are first internalized into MDDCs by a macropinocytosis-like process in an actin- and cholesterol-dependent, but pH-independent, manner. We observed the accumulation of virions in large uncoated vesicles with endosomal features, and the virions remained as intact particles that retained infectious potential for several hours. This trans-infection property was specific to MDDCs because monocyte-derived macrophages or monocytes from the same donor were unable to allow the accumulation of and the subsequent transmission of the virus. Together, these data allowed us to delineate the early mechanisms of the internalization and entry of an endothelio/dendrotropic HCMV strain into human MDDCs and to propose that DCs can serve as a "Trojan horse" to convey CMV from entry sites to other locations that may favor the occurrence of either latency or acute infection