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ISCOMATRIXTM adjuvant is capable of inducing broad and potent humoral and cellular immune responses. The components are well defined and the manufacturing process is simple and robust. Many vaccines containing the ISCOMATRIXTM adjuvant have been tested in a range of animal models, including human and non-human primates. Strong antibody and T cell responses have been induced in these studies . The antibody response is often achieved with lesser amounts of antigen than other adjuvant systems and the maximal responses have also been reached more quickly. Both CD4+ and CD8+ T cell responses are induced with the cytotoxic T lymphocyte responses being very long lived. Additionally, ISCOMATRIXTM adjuvant can be used in vaccines for induction of mucosal immune responses. This review provides an overview of the immune responses that can be elicited using ISCOMATRIXTM vaccines and the current state of knowledge regarding the mechanism of action of this adjuvant. [Copyright &y& Elsevier]

Background: Palliative care evolution focuses on education and medication accessibility. As little as 12% of palliative care needs are met. Assessment of the domains of Palliative care and patients' and families' experience are essential in life-limiting conditions. The Lagos University Teaching Hospital (LUTH), have the National Cancer Centre without offering palliative care services., Aim: The aim was to examine pattern of admissions and needs assessment for palliative services among patients admitted into LUTH wards., Materials and Method: Responses were entered into a data sheet inputted into Epi info version 7.2. Descriptive characteristics of the participants were presented as frequencies and percentages for age, sex, pattern of disease, domains of Palliative care, Advance care Plan, Preparation for home care, death and Education about the illness and category of medical conditions (palliative and non-palliative conditions). Together for Short Lives (TfSL) tool was used to categorize respondents' conditions into Palliative and Non-palliative conditions. Chi-square test was used to determine association between independent variables (pattern of diagnoses, stage of disease, advanced care plan, preparation for home care/ death and education on illness) and dependent variables (category of medical condition). Chi-square test was also used to explore the association between specialty of the managing doctor (independent variable) and Advance care plan (dependent variable). The level of statistical significance was P-value < 0.05., Results: 80.6% of the respondents had palliative care conditions, 83.7% had family members as their caregiver while 13.2% of the participants had no caregiver and 65.9% had no advance care plan. There was no preparation for home care or death in 72.1%, 70.5% had education about their illness, and 68.2% were in the advanced stage of their disease. Participants attending the surgery non-trauma unit (51.6%) were more likely to have advance care plans. Adults were more likely to have palliative care conditions (79.8%) compared to children (20.2%), and was statistically significant., Conclusion: Majority of the participants need palliative care services but are unavailable and unmet and the most predominant condition was cancer. Majority had no advance care plan or preparation for home care or death despite having advanced stage of the disease. This survey emphasized the need for symptom management, communication and provision of support., (© 2024. The Author(s).)

Objectives: This study reports on a yearlong sequence of three periodic, virtual trainings in primary palliative care for healthcare professionals across Nigeria. Our overall objective was to determine the impact of the full course on participants' attitudes, knowledge, skills and plans to implement and deliver palliative care in their local contexts., Methods: The curriculum for this programme was codeveloped by a team of USA and Nigerian palliative care professionals and delivered via three 3-day virtual sessions. Daily surveys, knowledge tests and end-of-training surveys were administered to participants electronically. Demographics, knowledge scores, confidence levels and self-reported achievement were analysed using descriptive statistics., Results: Pretraining and post-training knowledge scores showed significant improvement with average gains of 10.3 percentage points in training 1 (p<0.001) to 11.7 percentage points in training 2 (p=0.01). More than three-quarters of participants improved their test scores. Most participants (89.4%-100%) agreed that they had achieved the daily learning objectives across all trainings. Nearly 100% of participants reported that they felt more empowered as healthcare workers, more confident in their decision-making and more comfortable communicating with patients and other healthcare workers about palliative care., Conclusions: Healthcare workers in Nigeria demonstrated increased knowledge and confidence in providing palliative care as a result of an adapted virtual training programme. Further research is needed to (1) demonstrate feasibility for online trainings in similar resource-limited settings and (2) evaluate impact on patient-centred outcomes., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: With expanding neurosurgical options in epilepsy, it is important to characterise each options' risk for postoperative cognitive decline. Here, we characterise how patients' preoperative white matter (WM) networks relates to postoperative memory changes following different epilepsy surgeries., Methods: Eighty-nine patients with temporal lobe epilepsy with T1-weighted and diffusion-weighted imaging as well as preoperative and postoperative verbal memory scores (prose recall) underwent either anterior temporal lobectomy (ATL: n=38) or stereotactic laser amygdalohippocampotomy (SLAH; n=51). We computed laterality indices (ie, asymmetry) for volume of the hippocampus and fractional anisotropy (FA) of two deep WM tracts (uncinate fasciculus (UF) and inferior longitudinal fasciculus (ILF))., Results: Preoperatively, left-lateralised FA of the ILF was associated with higher prose recall (p<0.01). This pattern was not observed for the UF or hippocampus (ps>0.05). Postoperatively, right-lateralised FA of the UF was associated with less decline following left ATL (p<0.05) but not left SLAH (p>0.05), while right-lateralised hippocampal asymmetry was associated with less decline following both left ATL and SLAH (ps<0.05). After accounting for preoperative memory score, age of onset and hippocampal asymmetry, the association between UF and memory decline in left ATL remained significant (p<0.01)., Conclusions: Asymmetry of the hippocampus is an important predictor of risk for memory decline following both surgeries. However, asymmetry of UF integrity, which is only severed during ATL, is an important predictor of memory decline after ATL only. As surgical procedures and pre-surgical mapping evolve, understanding the role of frontal-temporal WM in memory networks could help to guide more targeted surgical approaches to mitigate cognitive decline., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Seven knowledge domains were originally defined for the learning health system (LHS) scientist. To assess proficiency in each of these domains, we developed and published an assessment tool for use by emerging LHS scientists and training programs. (LHS, October 2022). In mid-2022, the AHRQ adopted an eighth LHS knowledge domain, Equity and Justice. The addition of this eighth domain emphasizes the importance and centrality of equity in the LHS and improvement science. To extend our prior LHS competency assessment, we developed a proficiency assessment for the new equity and justice domain. Content experts and trainees iteratively defined, reviewed, and edited the assessment criteria. The items were developed by trainees and experts at one LHS training center with experience conducting research focused on healthcare inequities among marginalized populations. The proficiency assessment criteria for the Equity domain apply the same four levels of mastery: "no exposure," "foundational awareness," "emerging," and "proficient" as were used for original competencies. LHS training programs can use these proficiency criteria to monitor skills among emerging scientists across the eight domains, with particular attention to equity and justice., Competing Interests: One author (Patricia D. Franklin) receives funding from the Agency for Healthcare Research and Quality to lead a Learning Health System K12 training program. However, no authors have a conflict of interest with the work presented in this manuscript., (© 2023 The Authors. Learning Health Systems published by Wiley Periodicals LLC on behalf of University of Michigan.)

The Postdoc Academy: Succeeding as a Postdoc was designed to build postdocs' skills in career transition, career planning, collaborative research, resilience, and self-reflection. This study examined self-reported changes in five skills as learners progressed through the course. Data were collected from participants who responded to both pre- and post-surveys and engaged with the course learning activities. Results from repeated measures multivariate analysis of variance revealed that all of the self-reported perceptions of skills improved significantly upon completion of the course. Hierarchical regressions revealed that underrepresented minority learners had greater gains in their development of skills in career planning, resilience, and self-reflection. Qualitative analysis of learners' responses to learning activities found that postdocs perceived networking and mentor support as contributing factors to their skill advancement while tensions among multiple obligations and concerns of uncertainties were significant challenges to applying those skills., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Sun et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Presurgical evaluation of refractory epilepsy involves functional investigations to minimize postoperative deficit. Assessing language and memory is conventionally undertaken using Wada and fMRI, and occasionally supplemented by data from invasive intracranial electroencephalography, such as electrical stimulation, corticortical evoked potentials, mapping of high frequency activity and phase amplitude coupling. We describe the comparative and complementary role of these methods to inform surgical decision-making and functional prognostication. We used Wada paradigm to standardize testing across all modalities. Postoperative neuropsychological testing confirmed deficit predicted based on these methods., Competing Interests: Competing Interests The authors report no relevant competing interests., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Objective: Major obstacles to data harmonization in neuropsychology include lack of consensus about what constructs and tests are most important and invariant across healthy and clinical populations. This study addressed these challenges using data from the National Neuropsychology Network (NNN)., Method: Data were obtained from 5,000 NNN participants and Pearson standardization samples. Analyses included variables from four instruments: Wechsler Adult Intelligence Scale, 4th Edition (WAIS-IV); Wechsler Memory Scale, 4th Edition (WMS-IV); California Verbal Learning Test, 3rd Edition (CVLT3); and Delis-Kaplan Executive Function System (D-KEFS). We used confirmatory factor analysis to evaluate models suggested by prior work and examined fit statistics and measurement invariance across samples. We examined relations of factor scores to demographic and clinical characteristics., Results: For each instrument, we identified four first-order and one second-order factor. Optimal models in patients generally paralleled the best-fitting models in the standardization samples, including task-specific factors. Analysis of the NNN data prompted specification of a Recognition-Familiarity factor on the WMS-IV and an Inhibition-Switching factor on the D-KEFS. Analyses showed strong to strict factorial invariance across samples with expected differences in factor means and variances. The Recognition-Familiarity factor correlated with age more strongly in NNN than in the standardization sample., Conclusions: Factor models derived from healthy groups generally fit well in patients. NNN data helped identify novel Recognition-Familiarity and Inhibition-Switching factors that were also invariant across samples and may be clinically useful. The findings support efforts to identify evidence-based and optimally efficient measurements of neuropsychological constructs that are valid across groups. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Advancing biomedical research in low and middle income countries (LMICs) to expand the capacity for LMICs to integrate biomedical research into their health care systems and education has been the focus of many programs in global health over the past two decades. Central to the success of these programs is effective research mentoring, characterized by academic, career and psychosocial support through culturally appropriate practices. Research mentoring is a learned skill, developed through training, mutual discussions, practice and feedback. The majority of extant training programs are designed and delivered by US partners, so the next stage in building capacity is to train facilitators within the LMIC partner institutions to contextualize and advance mentoring specifically within their cultural and institutional norms by co-developing, delivering and evaluating semi-annual research mentoring training. To this end, we describe the development, delivery and outcome evaluation of a 5-week course in the art and skill of facilitation. Care was taken to explicitly distinguish between concepts of "teaching" and "facilitation," since "teaching" is closely connected to a transmission or banking model of education, which is characterized by "top-down," hierarchical relationship. The course discussed power and positionality, themes that resonate with partners in Nigeria and Tanzania. These themes provided unique entry into deeper conversations core to advancing mentoring practice away from the traditional dyadic power structure that remains from colonization. Evaluation findings indicate significant advances in awareness of differences between teaching and facilitating, increased confidence in facilitation skills, especially in the area of structured planning and organization, as well as improved communication and interpersonal skills. All respondents felt that students in Nigeria and Tanzania would respond well to the facilitation approach conveyed during the course and they found value in participating in the course as a cohort., Competing Interests: Conflict of interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Context: Palliative care awareness, education and practice vary widely across global health systems, especially throughout low- and middle-income countries such as Nigeria. Unfortunately, qualitative investigations into the context, experiences and challenges of Nigerian health care professionals providing palliative care in these settings are still underrepresented in the literature., Objectives: The aim of this study was to better understand the perceptions of palliative care providers in Nigeria., Methods: The authors conducted an online survey of health professionals caring for patients with palliative care and end of life needs. Survey participants were recruited via convenience sampling from a palliative care training program in Lagos, Nigeria., Results: 27 palliative care program participants (12 physicians, seven nurses, four pharmacists, two psychiatrists and two physiotherapists) responded to the two-question survey. 39 free text responses were collected and analyzed. A majority (33%, n = 13) of responses reported challenges associated with caring for patients with cancer. Suboptimal pain management was the second most common response type (18%, n = 7). Other significant responses included caring for patients with comorbidities (13%, n = 5), patients seeking spiritual care (8%, n = 3) and patients who were unable to afford standard treatment (5%, n = 2). Uncategorized responses (23%, n = 9) included experiences caring for patients with injuries sustained in military operations and COVID-19, among others., Conclusion: These results provide valuable insights into the palliative care experiences and challenges of an interdisciplinary set of health care practitioners providing palliative care in Nigeria. Further research is needed to elucidate the facilitators and barriers of delivering palliative care in similar settings., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Education and capacity building in palliative care are greatly needed in Nigeria. Currently, two institutions integrate palliative care into the undergraduate medical curriculum and no post graduate training exists. A team from the University of Lagos in Nigeria and Northwestern University in the US collaborated to design, implement, and evaluate a 12-hour virtual palliative care training program for Nigerian health professionals., Objective: This study investigated the impact of the first session of the training program on healthcare professionals' knowledge, skills, attitudes, and confidence in palliative care., Methods: The Education in Palliative and End-of-Life (EPEC) curriculum and the Kenya Hospices and Palliative Care Association (KEHPCA) curriculum were used as foundations for the program and adapted for the Nigerian context. Delivered online, the training focused on goals of palliative care, whole patient assessment, communication skills, pain management, psychosocial issues, palliative care in COVID, oncology, and HIV. A mixed-methods evaluation based on Kirkpatrick's evaluation framework was used and data were gathered from surveys and focus groups., Findings: Thirty-five health professionals completed the training. The training had a positive impact on knowledge, skills, and attitudes. Confidence in providing end-of-life care increased from 27.3% to 92.9% while confidence in prescribing medication to relieve symptoms at the end of life increased from 42.9% to 92.0%. Performance on multiple-choice knowledge tests increased by 10% (p < 0.01). All participants stated that they would recommend the program to a peer while 96.4% reported the program was relevant to the Nigerian context. Qualitative analysis suggested that the training would help participants provide more holistic care for patients, communicate better, and change how they interacted with families. Topics to be addressed in future training were identified., Conclusions: This virtual training can be an important element in palliative care capacity building in Nigeria and represents a model for global health collaboration., Competing Interests: The authors have no competing interests to declare., (Copyright: © 2022 The Author(s).)

Introduction: Learning health systems (LHS) science is fundamentally a transdisciplinary field. To capture the breadth of the competencies of an LHS scientist, AHRQ and national experts defined a series of 42 competencies across seven domains that support success. Clinicians, researchers, and leaders who are new to the LHS field can identify and prioritize proficiency development among these domains. In addition, existing leaders and researchers will assemble teams of experts who together represent the LHS science domains. To serve LHS workforce development and proficiency assessment, the AHRQ-funded ACCELERAT K12 training program recruited domain experts and trainees to define and operationalize items to include in an LHS Competency Assessment to support emerging and existing LHS scientists in prioritizing and monitoring proficiency development., Methods: Sequential interviews with 18 experts iteratively defined skills and tasks to illustrate stage in proficiency, and its progression, for each of 42 competencies in the seven LHS expertise domains: systems science; research questions and standards of scientific evidence; research methods; informatics; ethics of research and implementation in health systems; improvement and implementation science; and engagement, leadership, and research management. An educational assessment expert and LHS scientist refined the assessment criteria at each stage to use parallel language across domains. Last, current trainees reviewed and pilot tested the assessment and the LHS Competency Assessment was further refined using their feedback. The assessment framework was informed by Bloom's revised taxonomy of educational objectives (Anderson and Krathwohl, A taxonomy for learning, teaching, and assessing: A revision of Bloom's taxonomy of educational objectives, 2001) where learning progresses from recalling, defining, understanding, and awareness at the lower levels of the taxonomy, to applying and adopting and finally to creating, designing, and critiquing at the upper levels of the taxonomy. We also developed assessment criteria that could be used for longer term assessment of direct performance. Van der Vleuten et al. (Best Pract Res Clin Obstetr Gynaecol. 2010;24(6):703-719) define longer term direct assessment methods as assessment that occurs over a period ranging from weeks to even years and involves multiple assessment methods and exposure to the learner's work over an extended period., Results: This experience report describes the content of the LHS Competency Assessment. For each domain and competency, the assessment lists examples of evidence to support expertise at each level of proficiency: no exposure; foundational (awareness/understanding); emerging (early application); and proficient (application with a high level of skill). Trainees begin with baseline standard assessment tables, where they can indicate no exposure or mark the foundational and emerging skills with which they have competence. For domains where foundational and emerging skills have been achieved, users can move on to assessment tables that list evidence of proficiency., Conclusion: The LHS Competency Assessment offers consistent, graded criteria across the seven LHS domains to guide trainees and mentors to evaluate progress from no experience to foundational knowledge, emerging proficiency, and proficiency. The assessment can also be used to design training and mentoring for those newly exposed to LHS science and for those with key expertise who wish to expand LHS expertise., (© 2022 The Authors. Learning Health Systems published by Wiley Periodicals LLC on behalf of University of Michigan.)

Massive Open Online Courses (MOOCs) have gained traction as resources for professional development. This article presents the method that we used to evaluate a professional development MOOC for postdoctoral trainees that was created by a university consortium in the US. Most approaches to evaluating MOOCs focus on analysis of participation, outcomes from course assignments, self-reported learning outcomes, course completion and user pathways through the online content or clickstream data. Few published evaluations describe in detail how learning happens within online courses and the anticipated medium and longer term cognitive and behavioral outcomes on participants. This work aims to guide those who are designing, implementing and evaluating MOOCs through applying theories of change to focus evaluation on the process of learning. This approach can be used as a complement to traditional approaches for evaluating MOOCs. We described how we worked with the MOOC team building the content to develop a theory of change for each module (or lesson) within the MOOC and used the theory of change to guide evaluation of short and medium term participant cognitive, affective and attitudinal, and behavioral outcomes. Finally, we share lessons learned and suggestions for implementing theories of change in both the design and evaluation phases of MOOC development., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The purpose of this study was to describe the home fire safety quality improvement model designed to aid organizations in achieving institutional program goals. The home fire safety model was developed from community-based participatory research (CBPR) applying training-the-trainer methods and is illustrated by an institutional case study. The model is applicable to other types of organizations to improve home fire safety in vulnerable populations. Utilizing the education model leaves trained employees with guided experience to build upon, adapt, and modify the home fire safety intervention to more effectively serve their clientele, promote safety, and meet organizational objectives., (Copyright © 2016 Elsevier Ltd and ISBI. All rights reserved.)

In children under 1 year of age, the proportion of unintentional burns increases with infant age and mobility. Infants are not able to avoid burns and are dependent on parental or adult help. Treatment of burns in young children is expensive in terms of the life-long costs. The purpose of this study was to examine changes in home fire safety (HFS) knowledge and practices over time for parents of newborn children and expecting parents. HFS knowledge of 103 parents was assessed at baseline, immediately after watching a DVD on HFS (recall), and at 2-week follow-up (retention). In addition, the United States Fire Administration (USFA)/Federal Emergency Management Agency (FEMA) Home Safety Checklist which examines HFS practices in the homes was administered. Seventy percent of the participants were Caucasian, 65% were married, and 81% were first-time parents. HFS knowledge increased significantly from baseline to recall (45±12% vs. 87±17% correct responses, p<0.0001), but declined to 75±18% correct at retention. That is, an individual's baseline scores nearly doubled at recall (42±11% change in baseline score), but only increased by 67% at retention (30±15% change in baseline score). For a subsample of parents who completed the USFA Checklist (n=22), the mean percentage of advocated practices followed was 71±11% (range: 40-89%). Using DVDs was an effective educational modality for increasing HFS knowledge. This addressed an important problem of decreasing burns in infants through increasing parent knowledge and HFS practices using a short, inexpensive DVD., (Copyright © 2015 Elsevier Ltd and ISBI. All rights reserved.)

Older adults are more likely to experience problems that contribute to an increase in burn-related morbidity and mortality. The purpose of the current study was to determine if the educational home fire safety (HFS) intervention was an effective method of improving HFS knowledge over time in two groups of urban older adults, home bound and community-based. HFS knowledge of 110 urban older adults was assessed at baseline, immediately after watching a HFS DVD (recall), and at 2-week follow-up (retention). The United States Fire Administration Home Safety Checklist which examines HFS practices in the home was also administered. HFS knowledge scores significantly increased over time for both groups (p<0.0001), but no significant differences existed between the two groups over time (p=0.183). In addition, HFS knowledge scores were significantly impacted by the number of chronic illnesses, number of independent activities of daily living, and income. The findings from this study suggest the educational HFS intervention was effective in increasing urban older adults' HFS knowledge over time. Lowering the burns morbidity and mortality in the older adult population is an important public health concern that needs to be addressed through tailored prevention and education strategies., (Copyright © 2015 Elsevier Ltd and ISBI. All rights reserved.)

Background: Parents of children with special needs are vigilant as their child may have difficulty independently escaping a burning home. The purpose of this study was to evaluate if providing home fire safety information via a digital video disc (DVD) increases families' knowledge, behavior and ability regarding home fire safety., Methods: A school based classroom intervention (using a home fire safety DVD) was provided to parents (n=40) of children with and without special needs to improve home fire safety knowledge, behavior and ability. In addition, parents seen at the Kentucky Commission for Children with Special Health Care Needs clinics (n=47) received the same intervention in cohorts of 1-2 children. For both groups, knowledge, and behavior were measured before and after intervention. Repeated measures ANOVA were used to test for differences between groups and over time. Significance was set at p<0.05., Results: No difference in scores between pre- and post-test scores existed between groups (with special needs vs. without special needs, or classroom vs. individualized instruction). However, some differences were noted for some individual survey questions during post-hoc comparisons. Having a smoke alarm in the home (90% vs. 95%, p=0.029) and having a smoke alarm outside of where everyone sleeps (75% vs. 95%, p=0.005) increased over time and was retained. Having a fire escape plan increased at post intervention (58% vs. 79%, p=0.033), but returned to pre levels at follow-up (58%). Perceived knowledge (7.7 vs. 9.3, p<0.001) and ability (8.7 vs. 9.1, p=0.069) increased over time., Implication for Practice: Parents of children with special needs had a significant increase in knowledge and behavior over those parents of children without special needs. They also perceived having a high fire safety ability. Many of the post-test questions/behaviors (e.g., capable of exiting home during a fire, etc.) were reported at 100%. The intervention was well received, but may not necessarily be needed. Focus for home fire safety may need to look at younger children and smaller families. Parents of special needs children may have had frequent interaction with health care professionals., (Copyright © 2013 Elsevier Ltd and ISBI. All rights reserved.)

Children with special needs are at a higher risk for the devastating effects caused by a burn injury (eg, pain, appearance, and mobility changes); however, little is known about their burn prevention (BP) needs. The purpose of this project was to determine the BP needs, preferred method of parent education, and the actions of parents and professionals caring for children with and without disabilities. A novel instrument measuring fire-safety education needs, priorities, preferred method of education, and BP actions was administered to a total of 150 parents and professionals caring for children with physical limitations (n = 41), vision impairment (n = 80), and controls (n = 29). Differences in each outcome variable among the groups were tested using χ tests for categorical variables. There was no difference in ranking between parents and professionals or among groups (disability, vision impaired, and control) in preferred BP safety areas (P > .05); however, there was a difference in their preferred method for education (P < .001) among the groups (disability, vision impaired, and control). In addition, there were differences in preferences of methods of education for classroom, DVD, and home inspection between parents and professionals (P < .05). Our results suggest that type of education method preferred may need to be tailored differently by group. These findings are preliminary and further research in this area is indicated. Information from this project will be used to develop and test a community-based intervention within a large metropolitan area in north central Kentucky.

It is thought that the development of vaccines for the treatment of infectious diseases and cancer is likely to be achieved in the coming decades. This is partially due to a better understanding of the regulatory networks connecting innate with adaptive immune responses. The innate immune response is triggered by the recognition of conserved pathogen-associated molecular patterns by germ line-coded pattern recognition receptors. Several families of pattern recognition receptors have been characterized, including Toll-like receptors and nucleotide-binding domain receptors. The identification of their ligands has driven the development of novel adjuvants many of which have been tested in vaccine clinical trials. Here, the authors review recent preclinical data and clinical trial results supporting the view that combinations of adjuvants are the way forward in vaccine design. Multiadjuvanted vaccines can stimulate the broad and robust protective immune responses required to fight chronic infectious diseases and cancer.

For the induction of robust humoral and cellular immune responses, a strong rationale exists to use vaccine-adjuvant combinations possessing both immune modulatory and enhanced delivery capabilities. Herein, we evaluated the combination of 2 different adjuvants, a TLR9 agonist, composed of synthetic oligodeoxynucleotides (ODN) containing immunostimulatory CpG motifs (CpG), and ISCOMATRIX adjuvant (ISCOMATRIX), composed of saponin, phospholipid, and cholesterol, which possesses both immunostimulatory and delivery properties. While both individual adjuvants have been shown effective in numerous preclinical and clinical studies, it is likely that for optimal adjuvant activity a combined adjuvant approach will be necessary. Herein, using three different antigens, namely, hepatitis B surface antigen (HBsAg), ovalbumin (OVA), and influenza A haemagglutinin antigen (HA), we show in mice that some adjuvant effects of CpG and ISCOMATRIX are further enhanced if they are used in combination. In particular, with all three antigens, IFN-γ levels were greatly increased with the CpG/ISCOMATRIX combination. The ability of the CpG/ISCOMATRIX combination to induce antitumor responses when administered with OVA following administration to mice of a highly metastatic OVA-secreting tumor cell line (B16-OVA melanoma) was also demonstrated. Thus the CpG/ISCOMATRIX combination may prove to be a valuable tool in the development of novel or improved vaccines.

Subunit vaccines composed of recombinant or purified antigens have a good safety record but are poorly immunogenic and require adjuvants to activate innate immunity and facilitate antigen specific immune response. Of the many adjuvant formulations that are under development, very few are licensed mainly due to concerns about adverse side effects. The goal of our study was to develop in vitro assays that could predict toxicity of adjuvants in vivo. Pro-inflammatory cytokines IL-β, IL-6, TNF-α, and IL-8 were measured in human primary monocytes and the monocytoid cell line, MonoMac 6 (MM6), activated with a panel of TLR agonists or with adjuvants. A 0.5 EU/ml dose of Standard for endotoxin (previously shown to provide a margin between pyrogenic and non-pyrogenic substances in rabbits) was used as a comparator to establish a "safety threshold". FSL-1, Pam3CSK4, flagellin, and R848 TLR agonists but not Alum, MF59, Poly I:C, or MPL adjuvants induced cytokines in MM6 cells above the safety threshold. To confirm the predictive value of the in vitro assays, FSL-1 and flagellin were injected intramuscularly into New Zealand White (NZW) rabbits. Both TLR agonists induced fever within 6-8h post-injection followed 24-48 h later by increased C reactive protein (CRP). Importantly, an early peak in plasma prostaglandin E2 (PGE(2)) levels preceded rise in body temperature. In vitro production of PGE(2) in monocytes and MM6 cells was found following treatments with various TLR agonists but not with alum, MF59, MPL, or Poly I:C adjuvants. Together, our studies demonstrated a strong correlation between production of pro-inflammatory cytokines above a "safety threshold" and production of PGE(2)in vitro and an increase in body temperature in rabbits. The developed human cell based assays could provide an important tool for early screening of new molecular moieties and adjuvant formulations and may assist in selection of safer products., (Published by Elsevier Ltd.)

The ISCOMATRIX adjuvant has antigen delivery and presentation properties as well as immunomodulatory capabilities, which combine to provide enhanced and accelerated immune responses. The responses are broad, including a range of subclasses of antibodies as well as CD4(+) and CD8(+) T-cells. A range of ISCOMATRIX vaccines (ISCOMATRIX adjuvant combined with antigen) have now been tested in clinical trials and have been shown to be generally safe and well tolerated as well as immunogenic, generating both antibody (Ab) and T-cell responses. The mechanisms by which ISCOMATRIX adjuvant facilitates its immune effects are the scope of significant study and indicate that ISCOMATRIX adjuvant (i) rapidly traffics antigen into the cytosol of multiple dendritic cell subsets, (ii) induces the induction of an array of cytokines and chemokines and (iii) links the innate and adaptive immune responses in vivo in a Toll-like-receptor-independent but MyD88-dependent manner. These data highlight the clinical utility of ISCOMATRIX adjuvant in the development of prophylactic and therapeutic vaccines for infectious disease.

Generating a cytotoxic CD8(+) T-cell response that can eradicate malignant cells is the primary objective of cancer vaccine strategies. In this study we have characterized the innate and adaptive immune response to the ISCOMATRIX adjuvant, and the ability of vaccine antigens formulated with this adjuvant to promote antitumor immunity. ISCOMATRIX adjuvant led to a rapid innate immune cell response at the injection site, followed by the activation of natural killer and dendritic cells (DC) in regional draining lymph nodes. Strikingly, major histocompatibility complex (MHC) class I cross-presentation by CD8α(+) and CD8α(-) DCs was enhanced by up to 100-fold when antigen was formulated with ISCOMATRIX adjuvant. These coordinated features enabled efficient CD8(+) T-cell cross-priming, which exhibited prophylactic and therapeutic tumoricidal activity. The therapeutic efficacy of an ISCOMATRIX vaccine was further improved when co-administered with an anti-CD40 agonist antibody, suggesting that ISCOMATRIX-based vaccines may combine favorably with other immune modifiers in clinical development to treat cancer. Finally, we identified a requirement for the myeloid differentiation primary response gene 88 (MyD88) adapter protein for both innate and adaptive immune responses to ISCOMATRIX vaccines in vivo. Taken together, our findings support the utility of the ISCOMATRIX adjuvant for use in the development of novel vaccines, particularly those requiring strong CD8(+) T-cell immune responses, such as therapeutic cancer vaccines.

In a prior study of epilepsy and atmospheric pressure, we were able to show a small association between changes in atmospheric pressure and increased seizure frequency in consecutive patients with epilepsy undergoing video telemetry. In this study, we used a larger data set of similar patients undergoing telemetry at another Seattle institution, and examined the possible impact of atmospheric pressure (AP) changes on seizure onset in subtypes of seizures (focal, generalized, and nonepileptic). Comparisons were made between AP score at time of seizure onset and AP score at selected time ranges prior to the event (hour of seizure and 3, 6, and 24 hours prior) and a random sample of AP scores collected over similar time frames using nonparametric testing with correction for multiple comparisons. We could find no evidence to suggest atmospheric pressure changes made seizure occurrence more likely in any of the seizure groups across any of the time periods.