Assessing and monitoring intratumor heterogeneity in glioblastoma: how far has multimodal imaging come?

Glioblastoma demonstrates imaging features of intratumor heterogeneity that result from underlying heterogeneous biological properties. This stems from variations in cellular behavior that result from genetic mutations that either drive, or are driven by, heterogeneous microenvironment conditions. Among all imaging methods available, only T1-weighted contrast-enhancing and T2-weighted fluid-attenuated inversion recovery are used in standard clinical glioblastoma assessment and monitoring. Advanced imaging modalities are still considered emerging techniques as appropriate end points and robust methodologies are missing from clinical trials. Discovering how these images specifically relate to the underlying tumor biology may aid in improving quality of clinical trials and understanding the factors involved in regional responses to treatment, including variable drug uptake and effect of radiotherapy. Upon validation and standardization of emerging MR techniques, providing information based on the underlying tumor biology, these images may allow for clinical decision-making that is tailored to an individual's response to treatment.Stephen Price is funded by a Clinician Scientist Award from the National Institute for Health Research.This is the author accepted manuscript. The final version is available from Future Medicine via http://dx.doi.org/10.2217/cns.15.2

The phenotype of MEGF8-related Carpenter syndrome (CRPT2) is refined through the identification of eight new patients

Carpenter syndrome (CRPTS) is a rare autosomal recessive condition caused by biallelic variants in genes that encode negative regulators of hedgehog signalling (RAB23 [CRPT1] or, more rarely, MEGF8 [CRPT2]), and is characterised by craniosynostosis, polysyndactyly, and other congenital abnormalities. We describe a further six families comprising eight individuals with MEGF8-associated CRPT2, increasing the total number of reported cases to fifteen, and refine the phenotype of CRPT2 compared to CRPT1. The core features of craniosynostosis, polysyndactyly and (in males) cryptorchidism are almost universal in both CRPT1 and CRPT2. However, laterality defects are present in nearly half of those with MEGF8-associated CRPT2, but are rare in RAB23-associated CRPT1. Craniosynostosis in CRPT2 commonly involves a single midline suture in comparison to the multi-suture craniosynostosis characteristic of CRPT1. No patient to date has carried two MEGF8 gene alterations that are both predicted to lead to complete loss-of-function, suggesting that a variable degree of residual MEGF8 activity may be essential for viability and potentially contributing to variable phenotypic severity. These data refine the phenotypic spectrum of CRPT2 in comparison to CRPT1 and more than double the number of likely pathogenic MEGF8 variants in this rare disorder

Direct and indirect costs of acute diarrhea in children under five years of age in Indonesia: Health facilities and community survey

Background: Diarrhea remains a major cause of child morbidity and mortality in low- and middle-income countries. Reliable data on the economic burden of diarrhea is required to support the selection of appropriate health intervention programs. This study aimed to estimate the costs of acute diarrhea in children under five years of age in Indonesia, a large middle-income country with a substantial diarrheal burden. Methods: Direct medical cost data were extracted retrospectively for 1050 children under five years of age with acute diarrhea receiving inpatient care across 45 health facilities in seven Indonesian provinces during 2017–2020. Direct medical costs for children treated in outpatient settings were estimated by collecting unit costs associated with standard diarrhea case management in children. A structured interview of 240 caregivers of inpatients was also conducted retrospectively to estimate direct non-medical costs as well as indirect costs from caregiver income loss. Results: The weighted average direct medical cost for treatment of acute diarrhea as an inpatient and outpatient across health facility types was US$99.8 (SD±$56.8)(35% room costs, 29% professional fees, 26% medication costs, 10% diagnostic costs) and US$7.6 (SD±$4.3) (34% diagnostic costs, 28% medication costs, 27% professional fees, 10% registration fees), respectively. The average direct non-medical household cost for an acute diarrheal admission was US$4.90 and the indirect cost was US$9.90. Conclusion: There is a significant economic burden associated with acute diarrhea in children in Indonesia. This study, based on a wide variety of health care settings and geographical regions, provides data to inform the economic evaluation of rotavirus vaccines and other diarrheal prevention programs. Funding: This work was supported by a research grant from the Murdoch Children's Research Institute (MCRI) and PATH; and the Indonesian Technical Advisory Group on Immunization (ITAGI)

Developing ecosystem service indicators: experiences and lessons learned from sub-global assessments and other initiatives

People depend upon ecosystems to supply a range of services necessary for their survival and well-being. Ecosystem service indicators are critical for knowing whether or not these essential services are being maintained and used in a sustainable manner, thus enabling policy makers to identify the policies and other interventions needed to better manage them. As a result, ecosystem service indicators are of increasing interest and importance to governmental and inter-governmental processes, including amongst others the Convention on Biological Diversity (CBD) and the Aichi Targets contained within its strategic plan for 2011-2020, as well as the emerging Intergovernmental Platform on Biodiversity and Ecosystem Services (IPBES). Despite this growing demand, assessing ecosystem service status and trends and developing robust indicators is o!en hindered by a lack of information and data, resulting in few available indicators. In response, the United Nations Environment Programme World Conservation Monitoring Centre (UNEP-WCMC), together with a wide range of international partners and supported by the Swedish International Biodiversity Programme (SwedBio)*, undertook a project to take stock of the key lessons that have been learnt in developing and using ecosystem service indicators in a range of assessment contexts. The project examined the methodologies, metrics and data sources employed in delivering ecosystem service indicators, so as to inform future indicator development. This report presents the principal results of this project

Angler Perception and Population Dynamics of the Northern Snakehead (Channa argus) in the Potomac River & Tributaries

Our research sought to address the extent to which the northern snakehead (Channa argus), an invasive fish species, represents a threat to the Potomac River ecosystem. The first goal of our research was to survey the perceptions and opinions of recreational anglers on the effects of the snakehead population in the Potomac River ecosystem. To determine angler perceptions, we created and administered 113 surveys from June – September 2014 at recreational boat ramps along the Potomac River. Our surveys were designed to expand information collected during previous surveys conducted by the U.S. Fish and Wildlife Service. Our results indicated recreational anglers perceive that abundances and catch rates of target species, specifically largemouth bass, have declined since snakehead became established in the river. The second goal of our research was to determine the genetic diversity and potential of the snakehead population to expand in the Potomac River. We hypothesized that the effective genetic population size would be much less than the census size of the snakehead population in the Potomac River. We collected tissue samples (fin clippings) from 79 snakehead collected in a recreational tournament held between Fort Washington and Wilson’s Landing, MD on the Potomac River and from electrofishing sampling conducted by the Maryland Department of Natural Resources in Pomonkey Creek, a tributary of the Potomac River. DNA was extracted from the tissue samples and scored for 12 microsatellite markers, which had previously been identified for Potomac River snakehead. Microsatellite allele frequency data were recorded and analyzed in the software programs GenAlEx and NeEstimator to estimate heterozygosity and effective genetic population size. Resampling simulations indicated that the number of microsatellites and the number of fish analyzed provided sufficient precision. Simulations indicated that the effective population size estimate would expect to stabilize for samples > 70 individual snakehead. Based on a sample of 79 fish scored for 12 microsatellites, we calculated an Ne of 15.3 individuals. This is substantially smaller than both the sample size and estimated population size. We conclude that genetic diversity in the snakehead population in the Potomac River is low because the population has yet to recover from a genetic bottleneck associated with a founder effect due to their recent introduction into the system

APOE ε2 resilience for Alzheimer’s disease is mediated by plasma lipid species: Analysis of three independent cohort studies

Introduction The apolipoprotein E (APOE) genotype is the strongest genetic risk factor for late-onset Alzheimer\u27s disease. However, its effect on lipid metabolic pathways, and their mediating effect on disease risk, is poorly understood. Methods We performed lipidomic analysis on three independent cohorts (the Australian Imaging, Biomarkers and Lifestyle [AIBL] flagship study, n = 1087; the Alzheimer\u27s Disease Neuroimaging Initiative [ADNI] 1 study, n = 819; and the Busselton Health Study [BHS], n = 4384), and we defined associations between APOE ε2 and ε4 and 569 plasma/serum lipid species. Mediation analysis defined the proportion of the treatment effect of the APOE genotype mediated by plasma/serum lipid species. Results A total of 237 and 104 lipid species were associated with APOE ε2 and ε4, respectively. Of these 68 (ε2) and 24 (ε4) were associated with prevalent Alzheimer\u27s disease. Individual lipid species or lipidomic models of APOE genotypes mediated up to 30% and 10% of APOE ε2 and ε4 treatment effect, respectively. Discussion Plasma lipid species mediate the treatment effect of APOE genotypes on Alzheimer\u27s disease and as such represent a potential therapeutic target

Multiple Binding Sites for Fatty Acids on the Potassium Channel KcsA

Interactions of fatty acids with the potassium channel KcsA were studied using Trp fluorescence quenching and electron paramagnetic resonance (EPR) techniques. The brominated analogue of oleic acid was shown to bind to annular sites on KcsA and to the nonannular sites at each protein-protein interface in the homotetrameric structure with binding constants relative to dioleoylphosphatidylcholine of 0.67 ± 0.04 and 0.87 ± 0.08, respectively. Mutation of the two Arg residues close to the nonannular binding sites had no effect on fatty acid binding. EPR studies with a spin-labeled analogue of stearic acid detected a high-affinity binding site for the fatty acid with strong immobilization. Fluorescence quenching studies with the spin-labeled analogue showed that the binding site detected in the EPR experiments could not be one of the annular or nonannular binding sites. Instead, it is proposed that the EPR studies detect binding to the central hydrophobic cavity of the channel, with a binding constant in the range of ~0.1-1 ?M

Comprehensive genetic analysis of the human lipidome identifies loci associated with lipid homeostasis with links to coronary artery disease

We integrated lipidomics and genomics to unravel the genetic architecture of lipid metabolism and identify genetic variants associated with lipid species putatively in the mechanistic pathway for coronary artery disease (CAD). We quantified 596 lipid species in serum from 4,492 individuals from the Busselton Health Study. The discovery GWAS identified 3,361 independent lipid-loci associations, involving 667 genomic regions (479 previously unreported), with validation in two independent cohorts. A meta-analysis revealed an additional 70 independent genomic regions associated with lipid species. We identified 134 lipid endophenotypes for CAD associated with 186 genomic loci. Associations between independent lipid-loci with coronary atherosclerosis were assessed in ∼ 456,000 individuals from the UK Biobank. Of the 53 lipid-loci that showed evidence of association (P \u3c 1 × 10−3), 43 loci were associated with at least one lipid endophenotype. These findings illustrate the value of integrative biology to investigate the aetiology of atherosclerosis and CAD, with implications for other complex diseases

A study protocol of a randomised controlled trial incorporating a health economic analysis to investigate if additional allied health services for rehabilitation reduce length of stay without compromising patient outcomes

Background Reducing patient length of stay is a high priority for health service providers. Preliminary information suggests additional Saturday rehabilitation services could reduce the time a patient stays in hospital by three days. This large trial will examine if providing additional physiotherapy and occupational therapy services on a Saturday reduces health care costs, and improves the health of hospital inpatients receiving rehabilitation compared to the usual Monday to Friday service. We will also investigate the cost effectiveness and patient outcomes of such a service. Methods/Design A randomised controlled trial will evaluate the effect of providing additional physiotherapy and occupational therapy for rehabilitation. Seven hundred and twelve patients receiving inpatient rehabilitation at two metropolitan sites will be randomly allocated to the intervention group or control group. The control group will receive usual care physiotherapy and occupational therapy from Monday to Friday while the intervention group will receive the same amount of rehabilitation as the control group Monday to Friday plus a full physiotherapy and occupational therapy service on Saturday. The primary outcomes will be patient length of stay, quality of life (EuroQol questionnaire), the Functional Independence Measure (FIM), and health utilization and cost data. Secondary outcomes will assess clinical outcomes relevant to the goals of therapy: the 10 metre walk test, the timed up and go test, the Personal Care Participation Assessment and Resource Tool (PC PART), and the modified motor assessment scale. Blinded assessors will assess outcomes at admission and discharge, and follow up data on quality of life, function and health care costs will be collected at 6 and 12 months after discharge. Between group differences will be analysed with analysis of covariance using baseline measures as the covariate. A health economic analysis will be carried out alongside the randomised controlled trial. Discussion This paper outlines the study protocol for the first fully powered randomised controlled trial incorporating a health economic analysis to establish if additional Saturday allied health services for rehabilitation inpatients reduces length of stay without compromising discharge outcomes. If successful, this trial will have substantial health benefits for the patients and for organizations delivering rehabilitation services