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Objectives: Studies of neurocognitively elite older adults, termed SuperAgers, have identified clinical predictors and neurobiological indicators of resilience against age-related neurocognitive decline. Despite rising rates of older persons living with HIV (PLWH), SuperAging (SA) in PLWH remains undefined. We aimed to establish neuropsychological criteria for SA in PLWH and examined clinically relevant correlates of SA. Methods: 734 PLWH and 123 HIV-uninfected participants between 50 and 64 years of age underwent neuropsychological and neuromedical evaluations. SA was defined as demographically corrected (i.e., sex, race/ethnicity, education) global neurocognitive performance within normal range for 25-year-olds. Remaining participants were labeled cognitively normal (CN) or impaired (CI) based on actual age. Chi-square and analysis of variance tests examined HIV group differences on neurocognitive status and demographics. Within PLWH, neurocognitive status differences were tested on HIV disease characteristics, medical comorbidities, and everyday functioning. Multinomial logistic regression explored independent predictors of neurocognitive status. Results: Neurocognitive status rates and demographic characteristics differed between PLWH (SA=17%; CN=38%; CI=45%) and HIV-uninfected participants (SA=35%; CN=55%; CI=11%). In PLWH, neurocognitive groups were comparable on demographic and HIV disease characteristics. Younger age, higher verbal IQ, absence of diabetes, fewer depressive symptoms, and lifetime cannabis use disorder increased likelihood of SA. SA reported increased independence in everyday functioning, employment, and health-related quality of life than non-SA. Conclusions: Despite combined neurological risk of aging and HIV, youthful neurocognitive performance is possible for older PLWH. SA relates to improved real-world functioning and may be better explained by cognitive reserve and maintenance of cardiometabolic and mental health than HIV disease severity. Future research investigating biomarker and lifestyle (e.g., physical activity) correlates of SA may help identify modifiable neuroprotective factors against HIV-related neurobiological aging. (JINS, 2019, 25, 507–519)
Although most hospitals report very high levels of hand hygiene compliance (HHC), the accuracy of these overtly observed rates is questionable due to the Hawthorne effect and other sources of bias. In the study, we aimed (1) to compare HHC rates estimated using the standard audit method of overt observation by a known observer and a new audit method that employed a rapid (<15 minutes) “secret shopper” method and (2) to pilot test a novel feedback tool.
Quality improvement project using a quasi-experimental stepped-wedge design.
This study was conducted in 5 acute-care hospitals (17 wards, 5 intensive care units) in the Midwestern United States.
Sites recruited a hand hygiene observer from outside the acute-care units to rapidly and covertly observe entry and exit HHC during the study period, October 2016–September 2017. After 3 months of observations, sites received a monthly feedback tool that communicated HHC information from the new audit method.
The absolute difference in HHC estimates between the standard and new audit methods was ~30%. No significant differences in HHC were detected between the baseline and feedback phases (OR, 0.92; 95% CI, 0.84–1.01), but the standard audit method had significantly higher estimates than the new audit method (OR, 9.83; 95% CI, 8.82–10.95).
HHC estimates obtained using the new audit method were substantially lower than estimates obtained using the standard audit method, suggesting that the rapid, secret-shopper method is less subject to bias. Providing feedback using HHC from the new audit method did not seem to impact HHC behaviors.
Brain tumor behavior is driven by aberrations in the genome and epigenome. Many of these changes, such as IDH mutations in diffuse low-grade glioma (DLGG), are common amongst the same class of tumour and can be incorporated into the diagnostic criteria. However, any given tumor may have other, less common genomic aberrations that are essential for its biological behavior and may inform on underlying aberrant cellular pathways, and potential therapeutic agents. Precision oncology is a genomics-based approach which profiles these alterations to better manage cancer patients and has established itself within the practice of oncology and is slowly making its way into neuro-oncology. The BC Cancer’s Personalized OncoGenomics (POG) program has profiled 16 adult tumours originating from the central nervous system using whole genome and transcriptome analysis (WGTA), for the first time, within a meaningful clinical timeframe/setting. As expected, primary genomic drivers were consistent with their respective diagnoses, though secondary drivers were found to be unique to each tumour. Although these analyses did not result in altered clinical management for these patients, primarily due to availability of drug or clinical trials, they highlight the heterogeneity of secondary drivers in cancers and provide clinicians with meaningful biological information. Lastly, the data generated by POG has highlighted the frequency and complexity of novel driver fusions which are predicted to behave similarly to canonical driver events in their respective tumours. The information available to clinicians through POG has provided paramount knowledge into the biology of each unique tumour.
Glioblastomas (GBMs) account for nearly half of all primary malignant brain tumours, and current therapies are often only marginally effective. Our understanding of the underlying biology of these tumours and the development of new therapies have been complicated in part by widespread inter- and intratumoural heterogeneity. To characterize this heterogeneity, we performed regional subsampling of primary glioblastomas and derived organoids from these tissue samples. We then performed single-cell RNA-sequencing (scRNA-seq) on these primary regional subsamples and 1-3 matched organoids per sample. We have profiled samples from six tumour sets to date and have obtained sequencing data for 21,234 primary tissue cells and 14,742 organoid cells. While the most apparent differences in gene expression appear to be between individual tumours, we were also able to identify similar cellular subpopulations across tissue samples and across organoids. Importantly, organoids derived from the same tissue sample appeared to be composed of similar cellular subpopulations and were highly comparable to each other, indicating that replicate organoids faithfully represent the original tumour tissue. Overall, our scRNA-seq approach will help evaluate the utility of tumour-derived organoids as model systems for GBM and will aid in identifying cellular subpopulations defined by gene expression patterns, both in primary GBM regional subsamples and their associated organoids. These analyses will allow for the characterization of clonal or subclonal populations that are likely to respond to different therapeutic approaches and may also uncover novel therapeutic targets previously unrevealed through bulk analyses.
Objectives: Human immunodeficiency virus (HIV) disproportionately affects Hispanics/Latinos in the United States, yet little is known about neurocognitive impairment (NCI) in this group. We compared the rates of NCI in large well-characterized samples of HIV-infected (HIV+) Latinos and (non-Latino) Whites, and examined HIV-associated NCI among subgroups of Latinos. Methods: Participants included English-speaking HIV+ adults assessed at six U.S. medical centers (194 Latinos, 600 Whites). For overall group, age: M=42.65 years, SD=8.93; 86% male; education: M=13.17, SD=2.73; 54% had acquired immunodeficiency syndrome. NCI was assessed with a comprehensive test battery with normative corrections for age, education and gender. Covariates examined included HIV-disease characteristics, comorbidities, and genetic ancestry. Results: Compared with Whites, Latinos had higher rates of global NCI (42% vs. 54%), and domain NCI in executive function, learning, recall, working memory, and processing speed. Latinos also fared worse than Whites on current and historical HIV-disease characteristics, and nadir CD4 partially mediated ethnic differences in NCI. Yet, Latinos continued to have more global NCI [odds ratio (OR)=1.59; 95% confidence interval (CI)=1.13–2.23; p<.01] after adjusting for significant covariates. Higher rates of global NCI were observed with Puerto Rican (n=60; 71%) versus Mexican (n=79, 44%) origin/descent; this disparity persisted in models adjusting for significant covariates (OR=2.40; CI=1.11–5.29; p=.03). Conclusions: HIV+ Latinos, especially of Puerto Rican (vs. Mexican) origin/descent had increased rates of NCI compared with Whites. Differences in rates of NCI were not completely explained by worse HIV-disease characteristics, neurocognitive comorbidities, or genetic ancestry. Future studies should explore culturally relevant psychosocial, biomedical, and genetic factors that might explain these disparities and inform the development of targeted interventions. (JINS, 2018, 24, 163–175)
Background: Oligodendroglioma (ODG), a molecularly defined subtype of glioma, is a treatment responsive, slow growing tumour strongly associated with IDH mutation and 1p19q co-deletion. Mutations in Capicua (CIC), located on chromosome 19q, have been found in up to 70% of IDH mutated, 1p19q co-deleted ODGs; suggesting that loss or altered function of CIC may be crucially associated with ODG’s unique biology. CIC and ATXN1L have previously been implicated in neurodegeneration, however, this interaction has not been studied in cancer. Methods: Transcriptome profiling of CIC knockout HEK293 cell lines generated using CRISPR was performed using microarray. CIC and ATXN1L interaction was confirmed using immunoprecipitation and immunofluorescence. Transcript and protein changes of CIC targets were tested using RT-qPCR and Western blot following ATXN1L siRNA knockdown. Results: Transcriptomic profiling of CIC knockout cell lines resulted in a list of candidate CIC target genes validated against clinical samples. Immunoprecipitation and immunofluorescence confirmed CIC and ATXN1L interaction. Derepression of candidate CIC targets at transcript and protein levels was seen upon siRNA knockdown of ATXN1L. Conclusions: The interaction between CIC and ATXN1L is necessary for the repression of CIC target genes, including known oncogenes. Further research into the relationship between CIC and ATXN1L may lead potentially novel avenues of therapeutic approaches for less favorable gliomas.
Somatic mutations in the Capicua (CIC) gene were first identified in Type I low-grade gliomas (LGGs), which are characterized by 1p/19q co-deletions and IDH mutations. They are found at frequencies of ~50-70% in this glioma subtype, and have since been identified in ~40% of stomach adenocarcinomas (STADs) of the microsatellite instability (MSI) subtype; however, the role of these somatic mutations in malignancy has yet to be established. In Drosophila, CIC functions as a transcriptional repressor whose activity is inhibited upon activation of the mitogen-activated protein kinase (MAPK) signalling pathway. Though mammalian CIC appears to retain these functions, only three of its target genes have been established in human cells: ETV1, ETV4, and ETV5 (ETV1/4/5). To further probe CIC’s transcriptional network, we developed CIC knockout cell lines and performed transcriptomic and proteiomic analyses in these and in control cell lines expressing wild type CIC, identifying a total of 582 differentially expressed genes. We also used RNA-seq data from The Cancer Genome Atlas (TCGA) for Type I LGGs and STADs to perform additional differential expression analyses between CIC-deficient and CIC-expressing samples. Though gene-level overlap was limited between the three contexts, we found that CIC appears to regulate the expression of genes involved in cell-cell adhesion, metabolism, and developmental processes in all three contexts. These results shed light on the pathological role of CIC mutations and may help explain why these have been associated with poorer outcome within Type I LGGs.
Preterm birth and epicardial fat thickness (EFT) constitute novel risk factors for the onset of future adverse cardiovascular events. In total, 30 ex-extremely low birth weight (ex-ELBW) subjects (10 males, 20 females, aged 17–28) were enrolled and compared with 30 healthy peers. EFT was significantly higher (8.7±0.7 mm v. 5.6±0.9 mm; P<0.001) in ex-ELBW than in controls and was correlated with birth weight (r=−0.47, P=0.0009), gestational age (r=−0.39, P=0.03) and cardiac left ventricular mass (r=0.51, P=0.004). When excluding the influence of body mass index, birth weight was the sole remaining determinant of EFT, irrespective of gestational age (r=−0.37, P=0.04). The same findings when excluding the possible influence of blood pressure values on the cardiac structures (r=−0.40, P=0.028). In conclusion, EFT is significantly higher in former preterm subjects and is likewise associated with an increase in left ventricular mass. In view of the acknowledged correlation between the latter and an increased incidence of cardiovascular diseases, EFT appears to be an easy-to-measure tool capable of predicting the likely development of future adverse cardiovascular events in these subjects.
Like earth and planetary scientists, most children are curious about the world, the solar system and the rest of the universe. However, for various reasons primary schools emphasise language and calculus rather than natural sciences. When science is taught, examination systems often favour knowledge of the ‘right’ answer over the process of investigation and logical reasoning towards that answer. In order to continue to spark children's curiosity and their motivation to learn and discover, science education hubs at universities and science museums could collaborate more with schools and teachers, and are beginning to do so. The objective of this position paper is to report on recent experiences in earth and planetary science education for pupils in primary and secondary education, to provide examples and inspiration for scientists. We report three examples of initiation and consolidation of science education in primary schools in the Netherlands: (1) a focus on asking questions and seeking information to reason towards the answer, initiated with a classroom game, Expedition Mundus, (2) bringing pupils and teachers together outside their school in the science museum to gain confidence and self-efficacy, and (3) having children ask their own questions and do their own research guided by the empirical cycle, for example on experimentation on sandbox scale models of channels and crater lake deltas as found on Mars. The focus on other planets, fictitious and real, stimulates pupils to ask questions about planet Earth. Finally, we argue that involvement of more scientists in science education would not only benefit primary and secondary schools and future students but also university education and science communication with society.
This article investigates how information from cotton yield monitors influences the perceptions of within-field yield variability of cotton producers. Using yield distribution modeling techniques and survey data from cotton producers in 11 southeastern states, we find that cotton farmers who responded to the survey tend to underestimate within-field yield variability (by approximately 5-18%) when not using site-specific yield monitor information. Results further indicate that surveyed cotton farmers who responded to a specific question about yield monitors place a value of approximately $20/acre/year (on average) on the additional information about within-field yield variability that the yield monitor technology provides.
Immobilization by vitrification is one potential disposition option for a
portion of the United States' excess plutonium inventory. Research has been
performed at the Savannah River Site (SRS) to determine the optimum
composition of a lanthanide borosilicate frit for the vitrification of
plutonium using a Plackett-Burman design and simplex algorithm as a
statistical tool. This technique uses various response variables to rank and
optimize a composition. The variables used in this study correspond to
homogeneity, durability, actinide solubility and devitrification after
The optimized frit composition was determined using a constant
ThO2 loading of 20 wt%. No noticeable trends were followed
with respect to the individual components which may indicate a relatively
robust system able to accommodate variations in the feed.
Batches containing various loadings of ThO2 were melted to
determine if actinide solubility was improved in the optimized composition
compared to that of a similar lanthanide borosilicate glass. No noticeable
improvement in ThO2 solubility was realized as a result of using
this optimization technique.
Immobilization by vitrification is one potential disposition option for a
portion of the United States’ excess plutonium inventory. Research has been
performed to determine the glass forming region of a frit, plutonium and
rare earth system. The frit contains mainly oxides of aluminum, silicon and
boron; small amounts of ZrO2 and SrO are also included. The rare
earth elements provide a flux to the glass during processing. The rare
earths are also added as neutron absorbers (to prohibit criticality) in the
final vitreous product.
This report will show the compositional region, using Th as a Pu surrogate,
that should be targeted in future studies for maximum Pu solubility in the
lanthanide borosilicate glass system. Durability data and process variables
will also be provided.
The hydration thermodynamic approach to the prediction of glass durability
was originally applied to nuclear waste glasses by Jantzen and Plodinec.
This approach is useful for control of the production of nuclear waste
glasses. However, improvements are necessary if the approach is to be
extended to different glasses, particularly those with higher alkali metal
concentrations. This is of special significance for vitrification of the
salt wastes at Hanford. Various methods for improving the predictive power
of the approach have been examined. Combining a more accurate representation
of the alkali metal species in the glass with a more rigorous thermodynamic
approach is a promising avenue to improved predictive power.
Two LaBS glasses containing 9.5 wt.% (#1) and 5.0 wt.% PuO2 (#2) were prepared by melting in Pt ampoules at 1500 C and examined by scanning electron microscopy with energy dispersive X-ray spectroscopy. The bulk of sample #1, both as-prepared and stored for 3 yrs, was amorphous with homogeneous PuO2 distribution. Sample #2, especially after storage for 2-3 yrs, was partly devitrified primarily in the near-surface area. As followed from X-ray elemental maps, the vitreous phase was enriched with Al and Si whereas larger elongated and smaller dendrite crystals strongly enriched with rare earths (La, Nd, Gd) and Si and minor amounts of Hf may be attributed to britholite. A minor concentration of Pu was also observed in this phase. Moreover, relatively minor amounts of white regular crystals with high PuO2 and lower HfO2 contents were observed in the samples and are probably associated with PuO2 and a PuO2-HfO2 cubic solid solution phase. Nevertheless, even in devitrified areas of the samples, the majority of the Pu remained in the vitreous phase where it was homogeneously distributed.
Three types of HIV-associated neurocognitive disorders (HAND) exist that are distinguished by presence and severity of impairment in cognitive and everyday functioning. Although well-validated neurocognitive measures exist, determining impairment in everyday functioning remains a challenge. We aim to determine whether Self-Report measures of everyday functioning are as effective in characterizing HAND as Performance-Based measures. We assessed 674 HIV-infected participants with a comprehensive neurocognitive battery; 233 met criteria for a HAND diagnosis by having at least mild neurocognitive impairment. Functional decline was measured via Self-Report and Performance-Based measures. HAND diagnoses were determined according to published criteria using three approaches to assess functional decline: (1) Self-Report measures only, (2) Performance-Based measures only, and (3) Dual-method combining Self-Report and Performance-Based measures. The Dual-method classified the most symptomatic HAND, compared to either singular method. Singular method classifications were 76% concordant with each other. Participants classified as Performance-Based functionally impaired were more likely to be unemployed and more immunosuppressed, whereas those classified as Self-Report functionally impaired had more depressive symptoms. Multimodal methods of assessing everyday functioning facilitate detection of symptomatic HAND. Singular Performance-Based classifications were associated with objective functional and disease-related factors; reliance on Self-Report classifications may be biased by depressive symptoms. (JINS, 2012, 18, 79–88)