Introduction Physical disability represents a major burden to health and lifespan, particularly as the proportion of older adults within the United States is expected to grow. Prevention efforts for ...physical disability targets methods and strategies to decrease modifiable risk factors. Potential challenges for health professionals may exist in synthesizing and interpreting this broad spectrum of literature due to the discipline-specific nuance of language used, practice type or specialty, and lack of interdisciplinary resources. This scoping review will map and synthesize the literature across healthcare disciplines to identify modifiable risk factors and the evidence related to their ability to predict physical disability. We will also draw attention to the possibility of modifiable risk factors for physical disability being operationalized as pre-disability in order to strengthen primary and secondary prevention efforts. Methods A planned search strategy using physical disability terminology will be searched in English across MEDLINE, CINAHL, Health Source, PEDro, and REHABDATA by two reviewers in line with our review objectives and inclusion criteria. Eligibility for inclusion include peer-reviewed primary research published in the English language and have established a relationship between a person-level measurable characteristic that is modifiable by changes in lifestyle behaviors and any of the commonly accepted terms used to categorize or describe physical disability. Expected results Presentation of results will be using the PRISMA flowchart, with additional mapping and synthesis of evidence for modifiable risk factors for physical disability to clarify divergent terms used in classifying and measuring these factors and their potential for prediction of physical disability. Expected conclusion It is anticipated that this scoping review will identify and highlight a variety of modifiable risk factors for physical disability that may aid primary and secondary prevention efforts for health professionals.
Pediatric intracranial ependymoma has seen a recent exponential expansion of biological findings, rapidly dividing the diagnosis into several subgroups, each with specific molecular and clinical ...characteristics. While such subdivision may complicate clinical conclusions from historical trials, this knowledge also provides an opportunity for interrogating the major clinical and biological questions preventing near-term translation into effective therapy for children with ependymoma. In this article, we briefly review some of the most critical clinical questions facing both patient management and the construct of future trials in childhood ependymoma, as well as explore some of the current barriers to efficient translation of preclinical discovery to the clinic.
Human herpesvirus-6A and -6B (HHV-6) are betaherpesviruses that reach > 90% seroprevalence in the adult population. Unique among human herpesviruses, HHV-6 can integrate into the subtelomeric regions ...of human chromosomes; when this occurs in germ line cells it causes a condition called inherited chromosomally integrated HHV-6 (iciHHV-6). Only two complete genomes are available for replicating HHV-6B, leading to numerous conflicting annotations and little known about the global genomic diversity of this ubiquitous virus.
Using a custom capture panel for HHV-6B, we report complete genomes from 61 isolates of HHV-6B from active infections (20 from Japan, 35 from New York state, and 6 from Uganda), and 64 strains of iciHHV-6B (mostly from North America). HHV-6B sequence clustered by geography and illustrated extensive recombination. Multiple iciHHV-6B sequences from unrelated individuals across the United States were found to be completely identical, consistent with a founder effect. Several iciHHV-6B strains clustered with strains from recent active pediatric infection. Combining our genomic analysis with the first RNA-Seq and shotgun proteomics studies of HHV-6B, we completely reannotated the HHV-6B genome, altering annotations for more than 10% of existing genes, with multiple instances of novel splicing and genes that hitherto had gone unannotated.
Our results are consistent with a model of intermittent de novo integration of HHV-6B into host germline cells during active infection with a large contribution of founder effect in iciHHV-6B. Our data provide a significant advance in the genomic annotation of HHV-6B, which will contribute to the detection, diversity, and control of this virus.
The microtubule inhibitor vincristine is currently used to treat a variety of brain tumors, including low-grade glioma and anaplastic oligodendroglioma. Vincristine, however, does not penetrate well ...into brain tumor tissue, and moreover, it displays dose-limiting toxicities, including peripheral neuropathy. Mebendazole, a Food and Drug Administration-approved anthelmintic drug with a favorable safety profile, has recently been shown to display strong therapeutic efficacy in animal models of both glioma and medulloblastoma. Importantly, appropriate formulations of mebendazole yield therapeutically effective concentrations in the brain. Mebendazole has been shown to inhibit microtubule formation, but it is not known whether its potency against tumor cells is mediated by this inhibitory effect. To investigate this, we examined the effects of mebendazole on GL261 glioblastoma cell viability, microtubule polymerization and metaphase arrest, and found that the effective concentrations to inhibit these functions are very similar. In addition, using mebendazole as a seed for the National Cancer Institute (NCI) COMPARE program revealed that the top-scoring drugs were highly enriched in microtubule-targeting drugs. Taken together, these results indicate that the cell toxicity of mebendazole is indeed caused by inhibiting microtubule formation. We also compared the therapeutic efficacy of mebendazole and vincristine against GL261 orthotopic tumors. We found that mebendazole showed a significant increase in animal survival time, whereas vincristine, even at a dose close to its maximum tolerated dose, failed to show any efficacy. In conclusion, our results strongly support the clinical use of mebendazole as a replacement for vincristine for the treatment of brain tumors.
Human herpesvirus (HHV) 6 is thought to remain clinically latent in most individuals after primary infection and to reactivate to cause disease in persons with severe immunosuppression. In allogeneic ...hematopoietic stem cell transplant recipients, reactivation of HHV-6 species B is a considerable cause of morbidity and mortality. HHV-6B reactivation is the most frequent cause of infectious meningoencephalitis in this setting and has been associated with a variety of other complications such as graft rejection and acute graft versus host disease. This has inspired efforts to develop HHV-6-targeted immunotherapies. Basic knowledge of HHV-6-specific adaptive immunity is crucial for these endeavors, but remains incomplete. Many studies have focused on specific HHV-6 antigens extrapolated from research on human cytomegalovirus, a genetically related betaherpesvirus. Challenges to the study of HHV-6-specific T-cell immunity include the very low frequency of HHV-6-specific memory T cells in chronically infected humans, the large genome size of HHV-6, and the lack of an animal model. This review will focus on emerging techniques and methodological improvements that are beginning to overcome these barriers. Population-prevalent antigens are now becoming clear for the CD4+ T-cell response, while definition and ranking of CD8+ T-cell antigens and epitopes is at an earlier stage. This review will discuss current knowledge of the T-cell response to HHV-6, new research approaches, and translation to clinical practice.
Structure reflects a variety of practices teachers use with the intent to guide students' behavior and increase academic success. A research synthesis was conducted on the role of classroom structure ...in the academic engagement, disengagement, competence beliefs, and achievement of preschool through high school students. A meta-analysis of 191 samples from 165 correlational studies revealed statistically significant correlations with achievement (.11), engagement (.28), and competence beliefs (.22), and a statistically non-significant relationship with disengagement (-.08). A meta-analysis of 71 samples from 46 structure intervention studies revealed a positive statistically significant average effect (g) on achievement (0.33), engagement (0.46), and disengagement (-0.34), but a statistically non-significant effect for competence beliefs (0.26). Consistent with a dual process model of engagement, associations were stronger for engagement than disengagement. Results related to variation suggested some universality, particularly across grade levels, and underscored the importance of emphasizing anticipatory strategies, minimizing the controlling aspects of structure, and considering the broader context, including the country context, income background of students, or whether structure is paired with other psychological supports. Methodological features also explained variation, highlighting the importance of using methods that center teachers' and students' experiences and align with the nature of the focal outcome.
Packed school lunch consumption remains a sparsely studied aspect of childhood nutrition. Most American research focuses on in-school meals provided through the National School Lunch Program (NSLP). ...The wide variety of available in-home packed lunches are usually nutritionally inferior compared to the highly regulated in-school meals. The purpose of this study was to examine the consumption of home-packed lunches in a sample of elementary-grade children. Through weighing packed school lunches in a 3rd grade class, mean caloric intake was recorded at 67.3% (32.7% plate waste) of solid foods, while sugar-sweetened beverage intake reported a 94.6% intake. This study reported no significant consumption change in the macronutrient ratio. Intake showed significantly reduced levels of calories, sodium, cholesterol, and fiber from the home-packed lunches (
< 0.05). The packed school lunch consumption rates for this class were similar to those reported for the regulated in-school (hot) lunches. Calories, sodium, and cholesterol intake are within childhood meal recommendations. What is encouraging is that the children were not "filling up" on more processed foods at the expense of nutrient dense foods. Of concern is that these meals still fall short on several parameters, especially low fruit/vegetable intake and high simple sugar consumption. Overall, intake moved in a healthier direction compared to the meals packed from home.
Abstract
We sought to determine whether donor-derived human herpesvirus (HHV) 6B–specific CD4+ T-cell abundance is correlated with HHV-6B detection after allogeneic hematopoietic cell ...transplantation. We identified 33 patients who received HLA-matched, non–T-cell–depleted, myeloablative allogeneic hematopoietic cell transplantation and underwent weekly plasma polymerase chain reaction testing for HHV-6B for 100 days thereafter. We tested donor peripheral blood mononuclear cells for HHV-6B–specific CD4+ T cells. Patients with HHV-6B detection above the median peak viral load (200 copies/mL) received approximately 10-fold fewer donor-derived total or HHV-6B–specific CD4+ T cells than those with peak HHV-6B detection at ≤200 copies/mL or with no HHV-6B detection. These data suggest the importance of donor-derived immunity for controlling HHV-6B reactivation.
We demonstrated that a higher number of donor-derived total and human herpesvirus (HHV) 6B–specific CD4+ T cells may reduce the risk for higher-level HHV-6B detection after allogeneic hematopoietic cell transplantation.
Human herpesvirus 6 (HHV-6) and cytomegalovirus (CMV) are population-prevalent betaherpesviruses with intermittent lytic replication that can be pathogenic in immunocompromised hosts. Elucidation of ...the adaptive immune response is valuable for understanding pathogenesis and designing novel treatments. Knowledge of T-cell antigens has reached the genome-wide level for CMV and other human herpesviruses, but study of HHV-6 is at an earlier stage. Using rare-cell enrichment combined with an HLA-agnostic, proteome-wide approach, we queried HHV-6B-specific CD4 T cells from 18 healthy donors with each known HHV-6B protein. We detected a low abundance of HHV-6-specific CD4 T cells in blood; however, the within-person CD4 T-cell response is quite broad: the median number of open reading frame (ORF) products recognized was nine per person. Overall, the data expand the number of documented HHV-6B CD4 T-cell antigens from approximately 11 to 60. Epitopes in the proteins encoded by U14, U90, and U95 were mapped with synthetic peptides, and HLA restriction was defined for some responses. Intriguingly, CD4 T-cell antigens newly described in this report are among the most population prevalent, including U73, U72, U95, and U30. Our results indicate that selection of HHV-6B ORFs for immunotherapy should consider this expanded panel of HHV-6B antigens.
Human herpesvirus 6 is highly prevalent and maintains chronic infection in immunocompetent individuals, with the potential to replicate widely in settings of immunosuppression, leading to clinical disease. Antiviral compounds may be ineffective and/or pose dose-limiting toxicity, and therefore, immune-based therapies have garnered increased interest in recent years. Attempts at addressing this unmet medical need begin with understanding the cellular response to HHV-6 at the individual and population levels. The present study provides a comprehensive assessment of HHV-6-specific T-cell responses that may inform the development of cell-based therapies directed at this virus.
Abstract
2-hydroxyoleic acid (2-OHOA) is the first potential anti-cancer drug to act by modification of cell membrane lipid content. The agent is a derivative of oleic acid, a naturally occurring ...component of olive oil. Through its unique mechanism of activating sphingomyelin synthase 1, 2-OHOA targets the membrane lipid composition of cancer cells. These lipid changes alter membrane-dependent signaling cascades, such as the Ras/MAPK pathway, that promote tumor cell proliferation. A comprehensive pre-clinical program has characterized the safety and effects of 2-OHOA across a host of animal models. A European phase I/IIa trial of 2-OHOA in adult patients has shown initial promising results with five refractory high-grade glioma patients demonstrating objective clinical benefit by RANO criteria for six or more months. The drug has been very well-tolerated in adult patients with minimal toxicity. This phase I study is the first pediatric investigation of 2-OHOA and focuses on the treatment of relapsed/refractory pediatric central nervous system (CNS) tumors. The trial consists of a dose-escalation phase in up to 18 patients using a standard “3 + 3” design, followed by an expanded safety cohort of up to 10 patients treated at the maximum tolerated dose to confirm the recommended phase II dose. Due to the promising clinical results in adult neuro-oncology patients and the widespread involvement of the Ras/MAPK pathway and other membrane-dependent signaling cascades in the development of pediatric malignancies, we hypothesize that 2-OHOA may be a safe and effective treatment for pediatric patients with several types of advanced CNS tumors.
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