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Human parainfluenza virus 3 (PIV3) and respiratory syncytial virus (RSV) are major causative agents of serious respiratory tract illness in newborns and infants. Maternal vaccination could be a promising approach to provide immediate protection against severe PIV3 and RSV infection in young infants. Previously, we demonstrated that maternal immunization with a subunit vaccine consisting of the RSV fusion (F) protein formulated with TriAdj, an adjuvant consisting of poly(I:C), immune defense regulatory peptide and polyphosphazene, protects newborn lambs from RSV. In the present study we evaluated the protective efficacy of a novel bivalent RSV-PIV3 vaccine candidate, FRipScHN/TriAdj, as a maternal vaccine against PIV3 infection in a neonatal lamb model. This vaccine consists of the pre-fusion form of the RSV F protein linked to the haemagglutinin-neuraminidase (HN) of PIV3, formulated with TriAdj. First, we successfully established PIV3 infection in neonatal lambs. Lambs infected with human PIV3 showed gross pathology, bronchointerstitial pneumonia and viral replication in the lungs. Subsequently, ewes were immunized with FRipScHN/TriAdj. RSV FRipSc- and PIV3 HN-specific antibodies with virus-neutralizing activity were detected in both the serum and the colostrum of the vaccinated ewes. The newborn lambs had RSV- and PIV3- neutralizing antibodies in their serum, which demonstrates that maternal antibodies were transferred to the neonates. At three days of age, the newborn lambs received an intrapulmonary challenge with PIV3. The lung pathology and virus production were significantly reduced in lambs that had received PIV3-specific maternal antibodies compared to lambs born to non-vaccinated ewes. These results suggest that maternal vaccination with a bivalent FRipScHN/TriAdj vaccine might be an effective method to provide protection against both PIV3 and RSV in neonates.

Respiratory syncytial virus (RSV) is a significant cause of mortality and morbidity in infants, the elderly, immunocompromised individuals, and patients with congenital heart diseases. Despite extensive efforts, a vaccine against RSV is still not available. We have previously reported the development of a subunit vaccine (ΔF/TriAdj) composed of a truncated version of the fusion protein (ΔF) and a polymer-based combination adjuvant (TriAdj). We compared inflammatory responses of ΔF/TriAdj-vaccinated and unvaccinated mice following intranasal challenge with RSV. Rapid and early inflammatory responses were observed in lung samples from both groups but modulated in the vaccinated group 7 days after the viral challenge. The underlying mechanism of action of ΔF/TriAdj was further studied through LC-MS-based metabolomic profiling by using 12C- or 13C-dansyl labeling for the amine/phenol submetabolome. RSV infection predominantly affected the amino acid biosynthesis pathways and urea cycle, whereas ΔF/TriAdj modulated the concentrations of almost all of the altered metabolites. Tryptophan metabolites were significantly affected, including indole, l-kynurenine, xanthurenic acid, serotonin, 5-hydroxyindoleacetic acid, and 6-hydroxymelatonin. The results from the present study provide further mechanistic insights into the mode of action of this RSV vaccine candidate and have important implications in the design of metabolic therapeutic interventions.

Respiratory syncytial virus (RSV) is the leading cause of acute lower respiratory infections in young children. Although the disease may be severe in immunocompromised, young, and elderly people, there is currently no approved vaccine. We previously reported the development and immunological assessment of a novel intranasal vaccine formulation consisting of a truncated version of the RSV fusion protein (ΔF) combined with a three-component adjuvant (TriAdj). Now, we aim to investigate the mechanism of action of the ΔF/TriAdj formulation by searching for metabolic alterations caused by intranasal immunization and the RSV challenge. We carried out untargeted lipidomics and submetabolome profiling (carboxylic acids and amine/phenol-containing metabolites) of lung tissue from ΔF/TriAdj-immunized and nonimmunized, RSV-challenged mice. We observed significant changes of lipids involved in the lung surfactant layer for the nonimmunized animals compared to healthy controls but not for the immunized mice. Metabolic pathways involving the synthesis and regulation of amino acids and unsaturated fatty acids were also modulated by immunization and the RSV challenge. This study illustrates that lipidomic and metabolomic profiling could provide a more comprehensive understanding of the immunological and metabolic alterations caused by RSV and the modulation effected by the ΔF/TriAdj formulation.

Background The aim of this study was to describe barriers and facilitators for shared decision making (SDM) as experienced by older patients with multiple chronic conditions (MCCs), informal caregivers and health professionals. Methods A structured literature search was conducted with 5 databases. Two reviewers independently assessed studies for eligibility and performed a quality assessment. The results from the included studies were summarized using a predefined taxonomy. Results Our search yielded 3838 articles. Twenty-eight studies, listing 149 perceived barriers and 67 perceived facilitators for SDM, were included. Due to poor health and cognitive and/or physical impairments, older patients with MCCs participate less in SDM. Poor interpersonal skills of health professionals are perceived as hampering SDM, as do organizational barriers, such as pressure for time and high turnover of patients. However, among older patients with MCCs, SDM could be facilitated when patients share information about personal values, priorities and preferences, as well as information about quality of life and functional status. Informal caregivers may facilitate SDM by assisting patients with decision support, although informal caregivers can also complicate the SDM process, for example, when they have different views on treatment or the patient’s capability to be involved. Coordination of care when multiple health professionals are involved is perceived as important. Conclusions Although poor health is perceived as a barrier to participate in SDM, the personal experience of living with MCCs is considered valuable input in SDM. An explicit invitation to participate in SDM is important to older adults. Health professionals need a supporting organizational context and good communication skills to devise an individualized approach for patient care.

Background Shared decision making (SDM) contributes to personalized decisions that fit the personal preferences of patients when choosing a treatment for a condition. However, older adults frequently face multiple chronic conditions (MCC). Therefore, implementing SDM requires special features. The aim of this paper is to describe the development of an intervention to improve SDM in older adults with MCC. Methods Following the Medical Research Council framework for developing complex interventions, the SDMMCC intervention was developed step-wise. Based on a literature review and empirical research in a co-creation process with end users, we developed training for geriatricians and a preparatory tool for older patients with MCC and informal caregivers. After assessing feasibility, the intervention was implemented in a pilot study (N = 108) in two outpatient geriatric clinics of an academic and a non-academic teaching hospital in Amsterdam, the Netherlands. Results Key elements of the training for geriatricians include developing skills to involve older adults with MCC and informal caregivers in SDM and following the six-step ‘Dynamic model for SDM with frail older patients’, as well as learning how to explore personal goals related to quality of life and how to form a partnership with the patient and the informal caregiver. Key elements of the preparatory tool for patients include an explicit invitation to participate in SDM, nomination that the patient’s own knowledge is valuable, invitation to form a partnership with the geriatrician, encouragement to share information about daily and social functioning and exploration of possible goals. Furthermore, the invitation of informal caregivers to share their concerns was also a key element. Conclusions Through a process of co-creation, both training for geriatricians and a preparatory tool for older adults and their informal caregivers were developed, tailored to the needs of the end users and based on the ‘Dynamic model of SDM with frail older patients’.

Objectives: For older persons with two or more chronic diseases (multiple chronic conditions) insight into what they perceive as important in their lives is essential when discussing preferences in the shared decision making process. The aims of this study were to 1) investigate the personal views on the ageing process communicated by older persons and 2) compare the personal views of older persons with and without multiple chronic conditions. Design: Using structured interviews participants were asked five questions about what they perceived as important in terms of ageing, worries, their future, healthy ageing and quality of life. Two independent researchers coded the data and performed content analyses. A stratified content analysis was performed to explore whether persons with and without multiple chronic conditions expressed different personal views with regard to the ageing process. Participants & setting: 547 community dwelling older persons aged 70 years and above. Results: The mean (SD) age was 78.9 (5.9) years, and 60.3% were female. Multiple chronic conditions were present in 72% of the study sample. There were no significant differences in demographic characteristics between persons with and without multiple chronic conditions . However persons with multiple chronic conditions more often had polypharmacy (43% vs 24%; p

Introduction This study explores clinicians’ views on and experiences with when, how, and by whom decisions about diagnostic testing for Alzheimer's disease are made and how test results are discussed with patients. Methods Following a preparatory focus group with 13 neurologists and geriatricians, we disseminated an online questionnaire among 200 memory clinic clinicians. Results Respondents were 95 neurologists and geriatricians (response rate 47.5%). Clinicians (74%) indicated that decisions about testing are made before the first encounter, yet they favored a shared decision-making approach. Patient involvement seems limited to receiving information. Clinicians with less tolerance for uncertainty preferred a bigger say in decisions (P < .05). Clinicians indicated to always communicate the diagnosis (94%), results of different tests (88%–96%), and risk of developing dementia (66%). Discussion Clinicians favor patient involvement in deciding about diagnostic testing, but conversations about decisions and test results can be improved and supported.

Respiratory syncytial virus (RSV) is the most common cause of respiratory tract infections in both children and elderly people. In this study we evaluated the short- and long-term protective efficacy of a single intranasal (IN) immunization with a RSV vaccine formulation consisting of a codon-optimized fusion (F) protein formulated with poly(I:C), an innate defense regulator peptide and a polyphosphazene (ΔF/TriAdj). This vaccine induced strong systemic and local immune responses, including RSV F-specific IgG1 and IgG2a, SIgA and virus neutralizing antibodies in mice. Furthermore, ΔF/TriAdj promoted production of IFN-γ-secreting T cells and RSV F85–93-specific CD8+ effector T cells. After RSV challenge, no virus was recovered from the lungs of the vaccinated mice. To evaluate the duration of immunity induced by a single IN vaccination, mice were again immunized once with ΔF/TriAdj and challenged with RSV five months later. High levels of IgG1, IgG2a and virus neutralizing antibodies were detected in the ΔF/TriAdj-vaccinated animals. Moreover, this vaccine formulation induced robust local SIgA production and IgA-secreting memory B cell development, and conferred complete protection against subsequent RSV challenge. In conclusion, a single IN vaccination with RSV ΔF protein formulated with TriAdj induced robust, long-term protective immune responses against RSV infection.

Background: As a result of advances in diagnostic testing in the field of Alzheimer disease (AD), patients are diagnosed in earlier stages of the disease, for example, in the stage of mild cognitive impairment (MCI). This poses novel challenges for a clinician during the diagnostic workup with regard to diagnostic testing itself, namely, which tests are to be performed, but also on how to engage patients in this decision and how to communicate test results. As a result, tools to support decision making and improve risk communication could be valuable for clinicians and patients. Objective: The aim of this study was to present the design, development, and testing of a Web-based tool for clinicians in a memory clinic setting and to ascertain whether this tool can (1) facilitate the interpretation of biomarker results in individual patients with MCI regarding their risk of progression to dementia, (2) support clinicians in communicating biomarker test results and risks to MCI patients and their caregivers, and (3) support clinicians in a process of shared decision making regarding the diagnostic workup of AD. Methods: A multiphase mixed-methods approach was used. Phase 1 consisted of a qualitative needs assessment among professionals, patients, and caregivers; phase 2, consisted of an iterative process of development and the design of the tool (ADappt); and phase 3 consisted of a quantitative and qualitative assessment of usability and acceptability of ADappt. Across these phases, co-creation was realized via a user-centered qualitative approach with clinicians, patients, and caregivers. Results: In phase 1, clinicians indicated the need for risk calculation tools and visual aids to communicate test results to patients. Patients and caregivers expressed their needs for more specific information on their risk for developing AD and related consequences. In phase 2, we developed the content and graphical design of ADappt encompassing 3 modules: a risk calculation tool, a risk communication tool including a summary sheet for patients and caregivers, and a conversation starter to support shared decision making regarding the diagnostic workup. In phase 3, ADappt was considered to be clear and user-friendly. Conclusions: Clinicians in a memory clinic setting can use ADappt, a Web-based tool, developed using multiphase design and co-creation, for support that includes an individually tailored interpretation of biomarker test results, communication of test results and risks to patients and their caregivers, and shared decision making on diagnostic testing.

Respiratory syncytial virus (RSV) is responsible for a large proportion of acute lower respiratory tract infections, specifically in children. Pneumonia virus of mice (PVM) causes similar lung pathology and clinical disease in rodents, and is therefore an appropriate model of RSV infection. Previously, we demonstrated that a single intranasal dose of P-I-P, a novel immunomodulator composed of the toll-like receptor 3 agonist poly(I:C), an innate defense regulator peptide and a polyphosphazene, confers protection in Balb/c mice for up to 3 days from lethal PVM-15 infection. In the present study a dual intranasal treatment with P-I-P was shown to extend the duration of the protection conferred by P-I-P from PVM-15 challenge. Balb/c mice treated twice with P-I-P showed higher survival rates and milder clinical signs when compared to animals that received a single P-I-P dose. While the mice treated with two consecutive doses of P-I-P experienced some weight loss, they all recovered. The dual P-I-P treatment mediated infiltration of several innate immune cells into the BALF and lung, including alveolar macrophages, neutrophils, and γδ T cells. Partial depletion of alveolar macrophages decreased survival rates and exacerbated clinical signs of mice subjected to the P-I-P dual treatment regime followed by PVM-15 challenge. This suggests that the alveolar macrophage is at least partially responsible for the protection elicited by this novel prophylactic treatment strategy.

Shared decision making (SDM) is increasingly considered as the best way to reach a treatment decision in a clinical environment. However, the use of SDM in practice can be obstructed by a number of factors, such as time constraints or lack of applicability due to patient characteristics. Our project, PrepDoc, explores how a Virtual Training Doctor (VTD) can help patients overcome some of these obstacles to experiencing effective SDM during doctor's visits. In this paper, we report on user studies conducted with 19 participants in Scotland aged 65+. The goal of these studies was to identify the reactions of this audience to the PrepDoc system, evaluate its suitability within Scotland, and elicit suggestions to improve it. Our findings revealed that the idea of empowering people to participate in SDM using a virtual agent was positively received by all participants. However, the reactions to how this idea was implemented in the PrepDoc system varied greatly across participants. Based on this, our paper outlines recommendations for enhancing the user experience with VTDs, accommodating individual differences of older adults, and accounting for the national context.

In shared decision making, the exploration of preferred personal health outcomes is important. Patient-reported outcome measures (PROMs) provide input for discussions between patients and healthcare professionals. The Older Persons and Informal Caregivers Survey Minimum DataSet (TOPICS-MDS) PROM is a multidimensional questionnaire on the physical and mental health and wellbeing of older adults. This study investigates how the TOPICS-MDS could be used in individual healthcare conversations. We explored views of older adults regarding 1) whether the health domains they want to discuss are included in the TOPICS-MDS and 2) the comprehensibility of the TOPICS-MDS for healthcare conversations with older adults. A three-round Delphi study was conducted. A total of 57 older adults participated in the study, the mean (SD) age was 71.5 (8.5) years, and 78.9% of the participants were female. The participants were divided into four panels based on educational level and cultural background. We used online questionnaires and focus groups. Consensus was pre-defined to be the point when ≥75% of the participants agreed that a domain was important or very important (scored on a 5-point Likert scale). The inter-expert agreement was computed for Round 1 and 3 with Kendall's W. Round 2 was a focus-group. Qualitative data were analyzed by content analysis. Older adults considered 'functional limitations', 'emotional wellbeing', 'social functioning' and 'quality of life' to be important domains of the TOPICS-MDS to discuss in healthcare conversations. The participants added 'coping with stress', 'dealing with health conditions and the effects on life' as extra domains for healthcare conversations. Challenges regarding the comprehensibility of the TOPICS-MDS included difficult words and lengthy or sensitive questions. Questions that included multiple topics were difficult to understand. The TOPICS-MDS covers the domains of life that older adults value as important to discuss with healthcare professionals, and two additional domains were identified. For older adults with a low level of education or a culturally diverse background, the TOPICS-MDS needs to be adjusted for comprehensibility.

Respiratory syncytial virus (RSV) is the leading cause of acute lower respiratory tract infections in infants and young children. There are no licensed RSV vaccines available, and the few treatment options for high-risk individuals are either extremely costly or cause severe side effects and toxicity. Immunomodulation mediated by a novel formulation consisting of the toll-like receptor 3 agonist poly(I:C), an innate defense regulator peptide and a polyphosphazene (P-I-P) was evaluated in the context of lethal infection with pneumonia virus of mice (PVM). Intranasal delivery of a single dose of P-I-P protected adult mice against PVM when given 24 h prior to challenge. These animals experienced minimal weight loss, no clinical disease, 100% survival, and reduced lung pathology. Similar clinical outcomes were observed in mice treated up to 3 days prior to infection. P-I-P pre-treatment induced early mRNA and protein expression of key chemokine and cytokine genes, reduced the recruitment of neutrophils and eosinophils, decreased virus titers in the lungs, and modulated the delayed exacerbated nature of PVM disease without any short-term side effects. On day 14 post-infection, P-I-P-treated mice were confirmed to be PVM-free. These results demonstrate the capacity of this formulation to prevent PVM and possibly other viral respiratory infections., Highlights • P-I-P pre-treatment, consisting of poly(I:C), IDR peptide and PCEP, was tested in the context of PVM infection in mice. • P-I-P confers complete protection against lethal PVM infection by reducing clinical signs and immunopathology. • P-I-P minimizes viral titers in the lungs reduces the influx of neutrophils and eosinophils into the tissue. • P-I-P induces early upregulation of genes involved in host defense without any observable adverse effects. • Survivor mice were PVM negative, suggesting that P-I-P mediates the successfully clearance of the virus in vivo.

Respiratory syncytial virus (RSV) is the causative agent of serious upper and lower respiratory tract infections in newborns and infants. Protection from RSV is crucial for neonates, and maternal immunization is one approach that holds promise for providing immediate protection to young infants against severe RSV infection. We previously reported efficacy of a subunit vaccine consisting of the fusion (F) protein formulated with a novel adjuvant (ΔF/TriAdj) in neonates. The goal of the current study was to evaluate the ΔF/TriAdj as a maternal vaccine. Pregnant ewes were vaccinated intramuscularly with ΔF/TriAdj or PBS six weeks prior to lambing, and re-vaccinated four weeks later, which resulted in transfer of maternal antibodies (MatAbs) to the newborn lambs through the colostrum. Significantly higher levels of RSV ΔF-specific serum IgG were detected in vaccinated pregnant ewes and their lambs when compared to control animals, which revealed that MatAbs were passively transferred to the offspring. All newborn lambs were challenged with RSV at three days of age. After RSV challenge, virus production and lung pathology were significantly lower in lambs that had received passively transferred antibodies than in control animals. These results indicate that maternal immunization with ΔF/TriAdj might be an alternative, safe and effective approach to provide protection against RSV in newborn and young infants.

PurposeThis paper aims to examine how visual and haptic package design characteristics singularly and jointly affect consumers' brand impressions.Design/methodology/approachIntegrating and extending design perception with congruence and fluency theories, the paper presents three research propositions that are tested in three studies. Bottled water serves as an example category with data provided by professionals and consumers.FindingsStudy 1 identifies key types of holistic bimodal designs (Modern, Big Grip, Prototypical‐Small, Boxy Billboards, and Prototypical‐Large) based on brand visual and haptic factors. Study 2 relates these types to unique single‐modal brand impressions. Study 3 determines how consumers evaluate brands depending on the semantic congruence between haptics and visuals. Except for the excitement dimension, brand evaluations are more positive under conditions of high rather than low congruence.Research limitations/implicationsThe findings are obtained for a single category (bottled water) using experiments designed to highlight and focus consumer attention on the formation of impressions. The findings may thus not fully reflect consumer responses in actual retail purchase situations.Practical implicationsThe paper provides preliminary guidelines on how to utilize visual and haptic cues in the design of brand packages for stimulating desired consumer responses.Originality/valueThe work presented in this paper contributes to the literature on design‐based brand inferences and semantic congruence by integrating the visual with the haptic perspectives.

Introduction This study aims to assess patients' and caregivers' views on and experiences with (1) decisions about diagnostic testing for Alzheimer's disease (AD) and (2) receiving test results. Methods We conducted separate focus groups with patients from three hospitals who underwent diagnostic testing for AD ( N = 11) and their caregivers ( N = 11). Audio recordings were transcribed verbatim and analyzed using MaxQDA. Results Patients and caregivers preferred and perceived active involvement in decision making, but the decision to initiate diagnostic testing seems to be made before the clinician-patient encounter. Patients and caregivers indicate that decisions are driven by a strong need to explain the patient's symptoms. They missed information on why different diagnostic tests were used, what the results of these tests were, and to what extent these results were (ab)normal. Discussion The decision-making process around diagnostic testing for AD and the information provision before and after diagnostic testing could be improved.

Adjuvants are crucial components of vaccines. They significantly improve vaccine efficacy by modulating, enhancing, or extending the immune response and at the same time reducing the amount of antigen needed. In contrast to previously licensed adjuvants, current successful adjuvant formulations often consist of several molecules, that when combined, act synergistically by activating a variety of immune mechanisms. These “combination adjuvants” are already registered with several vaccines, both in humans and animals, and novel combination adjuvants are in the pipeline. With improved knowledge of the type of immune responses needed to successfully induce disease protection by vaccination, combination adjuvants are particularly suited to not only enhance, but also direct the immune responses desired to be either Th1-, Th2- or Th17-biased. Indeed, in view of the variety of disease and population targets for vaccine development, a panel of adjuvants will be needed to address different disease targets and populations. Here, we will review well-known and new combination adjuvants already licensed or currently in development—including ISCOMs, liposomes, Adjuvant Systems Montanides, and triple adjuvant combinations—and summarize their performance in preclinical and clinical trials. Several of these combination adjuvants are promising having promoted improved and balanced immune responses.

Shared decision making (SDM) contributes to personalised decisions that fit the personal preferences of patients. However, older adults frequently face multiple chronic conditions (MCC). Therefore, implementing SDM requires special features. The aim of this paper is to describe the development of an intervention to improve SDM in older adults with MCC. Following the Medical Research Council framework for developing complex interventions, the SDMMCC intervention was developed step-wise. Based on a literature review and empirical research we developed in a co-creation process with the end-users a training for geriatricians and a preparatory tool for older patients with MCC and informal caregivers. After assessing feasibility the intervention was implemented at two outpatient geriatric clinics in a pilot study (N=108). Key elements of the training for geriatricians include: developing skills how to involve older adults with MCC and informal caregivers in SDM and learning how to explore personal goals related to quality of life. Key elements of the preparatory tool for patients include: an explicit invitation to participate in SDM, nomination that the patient’s own knowledge is valuable, invitation to form a partnership with the geriatrician, encouragement to share information about daily and social functioning and exploration of possible goals. Furthermore, invitation of informal caregivers to share their concerns. Through a process of co-creation both a training for geriatricians and a preparatory tool for older adults and their informal caregivers were developed, tailored to the needs of the end-users and based on the ‘Dynamic model of SDM with frail older adults’.

Substance-dependent individuals have been shown to display increased P3 amplitudes in response to substance-related stimuli. The P3 component of the event-related potential (ERP) has been associated with ‘motivated attention’ for substance cues. Enhanced processing of substance cues has not been unequivocally demonstrated in alcohol-dependent patients. The main goal of the present study was to further investigate electrophysiological processing of alcohol and non-alcohol (soft drink) cues in alcohol-dependent patients and controls. In addition, it was examined whether groups differed in the processing of positive emotional cues. Results showed that alcohol-dependent patients did not respond with more enlarged P3 amplitudes to alcohol cues than soft drink cues. At fronto-central sites they even showed reduced alcohol cue-elicited P3 amplitudes as compared to controls. These results are in line with results from studies using behavioral measures of cognitive processing and might be explained by the use of avoidance strategies, i.e., patients' effort to remain abstinent or control their alcohol use. There were no differences between groups regarding the processing of positive cues. Interpretations and implications of the findings are discussed.

Vascular dysfunction is an important pathophysiologic manifestation of sickle cell disease (SCD), a condition that increases risk of pulmonary hypertension and stroke. We hypothesized that infrared (IR) imaging would detect changes in cutaneous blood flow reflective of vascular function. We performed IR imaging and conventional strain gauge plethysmography in twenty-five adults with SCD at baseline and during intra-arterial infusions of an endothelium-dependent vasodilator acetylcholine (ACh), an endothelium-independent vasodilator sodium nitroprusside (SNP), and a NOS inhibitor L-NMMA. Skin temperature measured by IR imaging increased in a dose-dependent manner to graded infusions of ACh (+1.1° C, p < 0.0001) and SNP (+0.9° C, p < 0.0001), and correlated with dose-dependent increases in forearm blood flow (ACh: +19.9 mL/min/100mL, p < 0.0001; rs = 0.57, p = 0.003; SNP: +8.6 mL/min/100mL, p < 0.0001; r = 0.70, p = 0.0002). Although IR measurement of skin temperature accurately reflected agonist-induced increases in blood flow, it was less sensitive to decreases in blood flow caused by NOS inhibition. Baseline forearm skin temperature measured by IR imaging correlated significantly with baseline forearm blood flow (31.8±0.2° C, 6.0±0.4 mL/min/100mL; r = 0.58, p = 0.003), and appeared to represent a novel biomarker of vascular function. It predicted a blunted blood flow response to SNP (r = −0.61, p = 0.002), and was independently associated with a marker of pulmonary artery pressure, as well as hemoglobin level, diastolic blood pressure, homocysteine, and cholesterol (R2 = 0.84, p < 0.0001 for the model). IR imaging of agonist-stimulated cutaneous blood flow represents a less cumbersome alternative to plethysmography methodology. Measurement of baseline skin temperature by IR imaging may be a useful new marker of vascular risk in adults with SCD.

WHIM syndrome is a rare congenital immunodeficiency disorder characterized by warts, hypogammaglobulinemia, infections, and myelokathexis (neutropenia because of impaired egress from the BM); most patients also have severe panleukopenia. Because WHIM syndrome is caused by mutations in the chemokine receptor CXCR4 that result in increased agonist-dependent signaling, we hypothesized that the CXCR4 antagonist plerixafor (Mozobil [Genyzme Corporation], AMD3100), might be an effective treatment. To test this, we enrolled 3 unrelated adult patients with the most common WHIM mutation, CXCR4R334X, in a phase 1 dose-escalation study. Plerixafor increased absolute lymphocyte, monocyte, and neutrophil counts in blood to normal without significant side effects in all 3 patients. Peak responses occurred at 3-12 hours after injection and waned by 24 hours after injection which tracked the drug's pharmacokinetics. All 3 cell types increased in a dose-dependent manner with the rank order of responsiveness absolute lymphocyte > monocyte > neutrophil. These data provide the first pharmacologic evidence that panleukopenia in WHIM syndrome is caused by CXCL12-CXCR4 signaling-dependent leukocyte sequestration, and support continued study of plerixafor as mechanism-based therapy in this disease. This study is registered at http://www.clinicaltrials.gov as NCT00967785.

Aims and objectives. This study examined the feasibility of nursing falls prevention advice and factors influencing feasibility. Background. The frequency and seriousness of falls in hospitalised patients are underestimated, and such falls should be preventable because of the presence of professionals. A best practice-based falls prevention advice was developed to decrease the incidence of secondary falls and the incidence of primary falls in the long term and to increase the knowledge of nurses about falls prevention and the seriousness of falls. Design. A descriptive, explorative study. Methods. Feasibility of the advice for 30 patients was assessed 82 times (theoretically, three times per patient) by observation and by interviewing nurses, patients and their families. Results. The falls prevention advice was used in 48% of the assessments. There was a difference in use between interventions. Interventions that required more knowledge, communication and extra activities were implemented the least. The absence of materials and knowledge about falls prevention were important determinants of the non-implementation of certain interventions. Conclusion. Before falls prevention advice is implemented, it is important to educate nurses about falls, communication skills and implementation of the advice. Relevance to clinical practice. The falls prevention advice might help nurses to prevent falls and increase their knowledge about falls prevention.

Adjuvants are critical components of many vaccines. The majority of existing vaccines contain a single adjuvant. Owing to their inherent limitations, no single adjuvant is capable of inducing all the protective immune responses required in the many different vaccines. Consequently, investigators are exploring the potential of using formulations with multiple adjuvants in a vaccine. An emerging paradigm is that careful selection of adjuvant combinations can result in complementary and even synergistic enhancement of immune responses to vaccines. This approach is promising and presents tremendous opportunities for vaccinologists to tailor immune responses to specific vaccines. In this article, adjuvant combinations at different stages of development will be reviewed.

Over the past 100 years, animal infectious disease research has played a crucial role in the development of human vaccines. In fact, many of today’s vaccines are based on utilizing animal pathogens, either in the form of an attenuated vaccine or as a vaccine vector. Vaccine development has become increasingly complex with chronic and newly emerging diseases, a demand for therapeutic vaccines for noninfectious diseases, extended vaccine in the neonate and the elderly, and increasing concerns regarding vaccine safety. Furthermore, the evaluation of quantity and quality of immune responses and the ability to efficiently translate the results of basic research into the clinic are critical to ensure that vaccines meet their therapeutic potential. Here, we review the importance of animal models for developing and testing novel human vaccines, discuss the limitations of existing animal models in knowledge translation, and summarize the needs and criteria for future animal models. We argue that efficient translation of basic vaccine research to clinical therapies will depend upon the availability of appropriate animal models to address each of the questions which arise during vaccine development.

The pneumonia virus of mice (PVM) model is used to study respiratory syncytial virus (RSV) pathogenesis. The outcome of PVM infection varies in different inbred mouse strains, BALB/c being highly susceptible and C57BL/6 more resistant. As the disease symptoms induced by RSV infection can become more severe as people age, we examined the primary and secondary immune responses to infection with PVM in aged BALB/c and C57BL/6 mice. Based on clinical parameters, aged C57BL/6 mice displayed less severe disease than young adult mice when infected with 3000pfu of PVM-15, while BALB/c mice were equally susceptible at both ages showing significant weight loss and high levels of virus replication. Furthermore, after primary infection the CD4(+) T cell numbers in the lungs were higher in young adult mice, while the CD8(+) T cell numbers were comparable in both age groups and strains. When either C57BL/6 or BALB/c mice were infected with PVM as young adults and then re-infected as aged mice, they were protected from clinical disease, while virus replication was reduced. In contrast to mice with a primary PVM-infection, re-infected mice did not have infiltration of neutrophils or inflammatory mediators in the lung. BALB/c mice had higher virus neutralizing antibody levels in the serum and lung than C57BL/6 mice upon re-infection. Re-infection with PVM led to significant influx of effector CD4(+) T cells into the lungs when compared to aged mice with a primary infection, while this cell population was decreased in the lung draining lymph nodes in both mouse strains. After re-infection the effector CD8(+) T cell population was also decreased in the lung draining lymph nodes in both mouse strain when compared to aged mice after primary infection. However, the central memory CD4(+) and CD8(+) T cells were significantly enhanced in numbers in the lungs and draining lymph nodes of both mouse strains after re-infection, and these numbers were higher for C57BL/6 mice.

Respiratory syncytial virus (RSV) causes severe respiratory illness in infants. There are no licensed vaccines to prevent RSV infection. The neonate receives short-term protection from maternally derived antibodies, which, however, can also interfere with the active response to vaccination. A RSV vaccine consisting of a truncated version of the fusion protein formulated with polyI:C, innate defense regulator peptide and polyphosphazene (ΔF/TriAdj), was evaluated in two to three week-old lambs. When delivered intrapulmonary, ΔF/TriAdj elicited IgA production in the lung in addition to a robust systemic response similar to that induced by intramuscular immunization. To investigate potential interference by maternal antibodies, pregnant ewes were vaccinated with ΔF/TriAdj. Lambs born to RSV F-immune or non-immune ewes were then given three vaccinations with ΔF/TriAdj at 3 days, 4 weeks and 8 weeks post-birth. Lambs immunized intramuscularly with ΔF/TriAdj vaccine developed high-affinity ΔF-specific serum IgG and virus neutralizing antibodies, and displayed an increase in the frequency of IFN-γ-secreting cells by in vitro restimulated peripheral blood mononuclear cells. Maternal antibodies did not interfere with the development of an immune response to ΔF/TriAdj in the newborn lambs. These results indicate that immunization of neonates with ΔF/TriAdj is effective even in the face of maternal antibodies.

Summary Dendritic cells (DCs) play an important role in the induction of the primary immune response to infection. DCs may express the tryptophan-catabolizing enzyme indolamine2,3-dioxygenase (IDO), which is an inducer of immune tolerance. Because there is evidence that chronic hepatitis C virus (HCV) infection leads to functional impairment of certain DC populations, we analysed IDO expression in DCs and monocytes from chronically infected and recovered HCV patients. The IDO1 and -2 expression was increased significantly in the monocytes of chronic HCV patients but, interestingly, not in those from recovered patients. The myeloid DCs from chronically infected HCV patients also showed enhanced IDO1 expression, while no change in either IDO1 or -2 was found for plasmacytoid DCs. Up-regulation of IDO1 gene expression was confirmed by the presence of enhanced kynurenine/tryptophan ratios in the plasma from chronic HCV patients. Increased IDO1 and -2 expression was also observed in monocytes from healthy donors infected with an adapted mutant of the HCV JFH-1 strain ex vivo, confirming a direct effect of HCV infection. These changes in IDO expression could be prevented by treatment with the IDO inhibitor 1-methyl tryptophan (1-mT). Furthermore, maturation of monocyte-derived DCs from chronically infected HCV patients, as well as well as monocyte-derived DCs infected ex vivo with HCV, was impaired, but this was reversed by 1-mT treatment. This suggests that IDO inhibitors may be used to treat chronic HCV patients in vivo, in conjunction with current therapies, or to activate DCs from patients ex vivo, such that they can be administered back as a DC-based therapeutic vaccine.

Dendritic cells (DCs) are multifunctional cells that are pivotal in immune defense. As such they have been explored as vaccine carriers, largely in cancer immunotherapy and against some infectious diseases including HIV and viral hepatitis. However, while the use of DCs as vaccine carrier has shown some promise in cancer immunotherapy, this approach is laborious and is subject to strict quality control, which makes it expensive. Furthermore, in some individuals chronically infected with HIV, HCV and/or HBV the numbers of circulating DCs are reduced and/or their functions impaired. In vivo expansion and mobilization of DCs with Flt3L in combination with antigen and/or adjuvant targeting to critical DC receptors may be a more effective approach to control viral replication in chronically infected HIV, HBV and/or HCV patients than current DC immunotherapy approaches.

Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome is a rare immunodeficiency disorder caused by gain-of-function mutations in the G protein-coupled chemokine receptor CXCR4. The CXCR4 antagonist plerixafor, which is approved by the US Food and Drug Administration (FDA) for stem cell mobilization in cancer and administered for that indication at 0.24 mg/kg, has been shown in short-term (1- to 2-week) phase 1 dose-escalation studies to correct neutropenia and other cytopenias in WHIM syndrome. However, long-term safety and long-term hematologic and clinical efficacy data are lacking. Here we report results from the first long-term clinical trial of plerixafor in any disease, in which 3 adults with WHIM syndrome self-injected 0.01 to 0.02 mg/kg (4% to 8% of the FDA-approved dose) subcutaneously twice daily for 6 months. Circulating leukocytes were durably increased throughout the trial in all patients, and this was associated with fewer infections and improvement in warts in combination with imiquimod; however, immunoglobulin levels and specific vaccine responses were not fully restored. No drug-associated side effects were observed. These results provide preliminary evidence for the safety and clinical efficacy of long-term, low-dose plerixafor in WHIM syndrome and support its continued study as mechanism-based therapy in this disease. The ClinicalTrials.gov identifier for this study is NCT00967785.

Polynucleotide immunization has captured the imagination of numerous researchers and commercial companies around the world as a novel approach for inducing immunity in animals. Clearly, the ‘proof-of-principle’ has been demonstrated both in rodents and various animal species. However, to date, no commercial veterinary vaccine has been developed, or to our knowledge, is in the licensing phase. The present review summarizes the types of pathogens and host species for which polynucleotide immunization has been tried. We have tried to identify possible barriers to commercialization of this technology and areas that need attention if this promising technology is ever to become a reality in the commercial arena.

The ALICE experiment, which is being installed at the Large Hadron Collider at CERN, is designed to operate in a high-track density environment which is typical of relativistic heavy ions physics. This paper reports the main characteristics of the Inner Tracking System (ITS) of ALICE and describes the Silicon Strip Detector, which forms the two outermost layers of the ITS.

The two outermost layers of the ALICE Inner Tracking System consist of 1698 double-sided silicon microstrip modules, which form the Silicon Strip Detector (SSD). The SSD modules offer several novelties, which include the use of TAB-bonding technique for the connection of the front-end electronic via thin aluminium-polyimide cables. The module as well as its parts will be described and the assembling procedure illustrated.

The Silicon Strip Detector (SSD) forms the two outermost layers of the Inner Tracking System (ITS) of ALICE. The SSD detector consists of 1698 double-sided silicon microstrip modules. The electrical connection between silicon sensor and front-end electronics is made via TAB-bonded aluminium polyimide cables (chip-cables). The module assembly is challenging because of the module geometry and the use of chip-cables. This article describes the assembly procedure and the test protocol used.

Through bound apolipoprotein A-I (apoA-I), high-density lipoprotein cholesterol (HDL-C) activates endothelial nitric oxide synthase, inducing vasodilation. Because patients with sickle cell disease (SCD) have low apoA-I and endothelial dysfunction, we conducted a randomized, double-blinded, placebo-controlled trial to test whether extended-release niacin (niacin-ER) increases apoA-I-containing HDL-C and improves vascular function in SCD. Twenty-seven patients with SCD with levels of HDL-C39 mg/dl or apoA-I99 mg/dl were randomized to 12 weeks of niacin-ER, increased in 500-mg increments to a maximum of 1,500 mg/day, or placebo. The primary outcome was the absolute change in HDL-C level after 12 weeks, with endothelial function assessed before and at the end of treatment. Niacin-ER-treated patients trended to greater increase in HDL-C level compared with placebo treatment at 12 weeks (5.1 ± 7.7 vs 0.9 ± 3.8 mg/dl, 1-tailed p = 0.07), associated with significantly greater improvements in the ratios of low-density lipoprotein to HDL-C levels (1.24 vs 1.95, p = 0.003) and apolipoprotein B to apoA-I levels (0.46 vs 0.58, p = 0.03) compared with placebo-treated patients. No improvements were detected in 3 independent vascular physiology assays of endothelial function. Thus, the relatively small changes in HDL-C levels achieved by the dose of niacin-ER used in our study are not associated with improved vascular function in patients with SCD with initially low levels of apoA-I or HDL-C.

The practice of immunization of animals and humans has been carried out for centuries and is generally accepted as the most cost effective and sustainable method of infectious disease control. Over the past 20 years there have been significant changes in our ability to produce antigens by conventional extraction and purification, recombinant DNA and synthesis. However, many of these products need to be combined with carrier molecules to generate optimal immune responses. This review covers selected topics in the development of carrier technologies for use in the veterinary vaccine field, including glycoconjugate and peptide vaccines, microparticle and nanoparticle formulations, and finally virus-like particles. © 2012.

The risk of Bovine Leukemia Virus (BLV) transmission by rectal examination was determined over 22 months in a commercial dairy herd. All 167 BLV seronegative cattle, of breeding age or greater, were divided randomly into two groups and identified by neck-chain color. In the treatment group, routine rectal palpation occurred after a BLV infected animal and without a change of sleeve, while in the other group, palpation occurred in a similar manner with the exception that sleeves were changed between animals. When BLV seronegative cattle in either group were palpated after BLV infected cattle, the event and identification of the cattle involved were recorded. Serologic testing was performed eight times during the 22 month study to determine the number of animals that became infected following a palpation (an event). Thirty-one animals seroconverted during the study; 24 in the treatment (no sleeve change) group and seven in the sleeve change group. Sixteen of the animals in the treatment group that seroconverted had been palpated prior to their seroconversion. A hazard ratio (relative risk) for BLV seroconversion was determined between the two groups. Cows palpated with no sleeve change had a 2.8-fold increase in risk (confidence interval 1.1–6.8) of BLV infection. The increased risk of BLV infection associated with rectal palpation may have been affected by the presence of some highly infectious cows in the herd. This study confirms that rectal palpation without a change of sleeve may be a significant risk factor in some herds, and if efforts are made to decrease the spread of BLV in a herd, the potential for rectal sleeve transmission must be considered.

Item does not contain fulltext PURPOSE: To confirm the safety and compare the efficacy of intravitreal pegaptanib sodium 0.3 mg versus sham injections in subjects with diabetic macular edema (DME) involving the center of the macula associated with vision loss not due to ischemia. DESIGN: Randomized (1:1), sham-controlled, multicenter, parallel-group trial. PARTICIPANTS: Subjects with DME. INTERVENTION: Subjects received pegaptanib 0.3 mg or sham injections every 6 weeks in year 1 (total = 9 injections) and could receive focal/grid photocoagulation beginning at week 18. During year 2, subjects received injections as often as every 6 weeks per prespecified criteria. MAIN OUTCOME MEASURES: The primary efficacy endpoint was the proportion gaining >/= 10 letters of visual acuity (VA) from baseline to year 1. Safety was monitored throughout. RESULTS: In all, 260 (pegaptanib, n = 133; sham, n = 127) and 207 (pegaptanib, n = 107; sham, n = 100) subjects were included in years 1 and 2 intent-to-treat analyses, respectively. A total of 49 of the 133 (36.8%) subjects from the pegaptanib group and 25 of the 127 (19.7%) from the sham group experienced a VA improvement of >/= 10 letters at week 54 compared with baseline (odds ratio [OR], 2.38; 95% confidence interval, 1.32-4.30; P = 0.0047). For pegaptanib-treated subjects, change in mean VA from baseline by visit was superior (P

Older, more vulnerable individuals are increasingly often described in the literature as being frail. Because frailty is often perceived as being undesirable and associated with high health risks, it is important to establish how we can predict, recognize, and treat frailty. Frailty is predisposed by advancing age in combination with physiological deterioration, especially a loss of muscle mass and bone density. Although the symptoms of frailty are diverse, the most common symptoms are a deterioration of activities of daily living (ADL), mobility, nutritional status, cognition, and endurance. The consequences of frailty are institutionalization, morbidity, and mortality. The main determinants of frailty are limitations in ADL, weight loss, diminished mobility or patterns of activity, lowered serum cholesterol level, and sensitivity to change. There is no gold standard for the measurement of frailty, and often studies use a combination of instruments. Although a couple of multidimensional instruments have been developed to measure frailty in its totality, the reliability and validity of these instruments have yet to be established. Successful interventions against frailty include increasing muscle strength through training and individualized recommendations made on the basis of an extensive geriatric assessment.

The prevention of infectious diseases of animals by vaccination has been routinely practiced for decades and has proved to be one of the most cost-effective methods of disease control. However, since the pioneering work of Pasteur in the 1880s, the composition of veterinary vaccines has changed very little from a conceptual perspective and this has, in turn, limited their application in areas such as the control of chronic infectious diseases. New technologies in the areas of vaccine formulation and delivery as well as our increased knowledge of disease pathogenesis and the host responses associated with protection from disease offer promising alternatives for vaccine formulation as well as targets for the prevention of bacterial disease. These new vaccines have the potential to lessen our reliance on antibiotics for disease control, but will only reach their full potential when used in combination with other intervention strategies.

This paper presents a comparative study of four different approaches to automatic age and gender classification using seven classes on a telephony speech task and also compares the results with human performance on the same data. The automatic approaches compared are based on (1) a parallel phone recognizer, derived from an automatic language identification system; (2) a system using dynamic Bayesian networks to combine several prosodic features; (3) a system based solely on linear prediction analysis; and (4) Gaussian mixture models based on MFCCs for separate recognition of age and gender. On average, the parallel phone recognizer performs as well as Human listeners do, while loosing performance on short utterances. The system based on prosodic features however shows very little dependence on the length of the utterance.

Respiratory syncytial virus is the most important cause of lower respiratory tract infection in infants and young children. RSV clinical disease varies from rhinitis and otitis media to bronchiolitis and pneumonia. An increased incidence of asthma later in life has been associated with the more severe lower respiratory tract infections. Despite its importance as a pathogen, there is no licensed vaccine against RSV. This is due to a number of factors complicating the development of an effective and safe vaccine. The immunity to natural RSV infection is incomplete as re-infections occur in all age groups, which makes it challenging to design a protective vaccine. Second, the primary target population is the newborn infant, which has a relatively immature immune system and maternal antibodies that can interfere with vaccination. Finally, some vaccines have resulted in a predisposition for exacerbated pulmonary disease in infants, which was attributed to an imbalanced Th2-biased immune response, although the exact cause has not been elucidated. This makes it difficult to proceed with vaccine testing in infants. It is likely that an effective and safe vaccine needs to elicit a balanced immune response, including RSV-specific neutralising antibodies, CD8 T-cells, Th1/Th2 CD4 T-cells and preferably secretory IgA. Subunit vaccines formulated with appropriate adjuvants may be adequate for previously exposed individuals. However, intranasally delivered genetically engineered attenuated or vectored vaccines are currently most promising for newborns, as they are expected to induce a balanced immune response similar to that elicited to natural infection and not be subject to interference from maternal antibodies. Maternal vaccination may be the optimal strategy to protect the very young infants.