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On March 11, 2020, the World Health Organization declared an outbreak of a new viral entity, coronavirus 2019 (COVID-19), to be a worldwide pandemic. The characteristics of this virus, as well as its short- and long-term implications, are not yet well understood. The objective of the current paper was to provide a critical review of the emerging literature on COVID-19 and its implications for neurological, neuropsychiatric, and cognitive functioning.
A critical review of recently published empirical research, case studies, and reviews pertaining to central nervous system (CNS) complications of COVID-19 was conducted by searching PubMed, PubMed Central, Google Scholar, and bioRxiv.
After considering the available literature, areas thought to be most pertinent to clinical and research neuropsychologists, including CNS manifestations, neurologic symptoms/syndromes, neuroimaging, and potential long-term implications of COVID-19 infection, were reviewed.
Once thought to be merely a respiratory virus, the scientific and medical communities have realized COVID-19 to have broader effects on renal, vascular, and neurological body systems. The question of cognitive deficits is not yet well studied, but neuropsychologists will undoubtedly play an important role in the years to come.
Our objective was to compare patterns of dental antibiotic prescribing in Australia, England, and North America (United States and British Columbia, Canada).
Population-level analysis of antibiotic prescription.
Outpatient prescribing by dentists in 2017.
Patients receiving an antibiotic dispensed by an outpatient pharmacy.
Prescription-based rates adjusted by population were compared overall and by antibiotic class. Contingency tables assessed differences in the proportion of antibiotic class by country.
In 2017, dentists in the United States had the highest antibiotic prescribing rate per 1,000 population and Australia had the lowest rate. The penicillin class, particularly amoxicillin, was the most frequently prescribed for all countries. The second most common agents prescribed were clindamycin in the United States and British Columbia (Canada) and metronidazole in Australia and England. Broad-spectrum agents, amoxicillin-clavulanic acid, and azithromycin were the highest in Australia and the United States, respectively.
Extreme differences exist in antibiotics prescribed by dentists in Australia, England, the United States, and British Columbia. The United States had twice the antibiotic prescription rate of Australia and the most frequently prescribed antibiotic in the US was clindamycin. Significant opportunities exist for the global dental community to update their prescribing behavior relating to second-line agents for penicillin allergic patients and to contribute to international efforts addressing antibiotic resistance. Patient safety improvements will result from optimizing dental antibiotic prescribing, especially for antibiotics associated with resistance (broad-spectrum agents) or C. difficile (clindamycin). Dental antibiotic stewardship programs are urgently needed worldwide.
Residual depressive symptoms are generally documented as a risk factor for recurrence. In the absence of a specific instrument for the assessment of residual symptoms, a new 25-item Depression Residual Symptom Scale (DRSS) was elaborated and tested for recurrence prediction over a 1-year follow-up.
Sampling and methods
Fifty-nine patients in remission after a major depressive episode (MDE) were recruited in two centres. They were assessed with the DRSS and the Montgomery-Asberg Depression Rating Scale (MADRS) at inclusion and followed for 1 year according to a seminaturalistic design. The DRSS included specific depressive symptoms and subjective symptoms of vulnerability, lack of return to usual self and premorbid level of functioning.
Severity of residual symptoms was not significantly associated with increased risk of recurrence. However, DRSS score was significantly higher among patients with three or more episodes than one to two episodes. Number of previous episodes and treatment interruption were not identified as significant predictors of recurrence.
The proposed instrument is not predictive of depressive recurrence, but is sensitive to increased perception of vulnerability associated with consecutive episodes. Limitations include small sample size, seminaturalistic design (no standardisation of treatment) and content of the instrument.
Frascati international research criteria for HIV-associated neurocognitive disorders (HAND) are controversial; some investigators have argued that Frascati criteria are too liberal, resulting in a high false positive rate. Meyer et al. recommended more conservative revisions to HAND criteria, including exploring other commonly used methodologies for neurocognitive impairment (NCI) in HIV including the global deficit score (GDS). This study compares NCI classifications by Frascati, Meyer, and GDS methods, in relation to neuroimaging markers of brain integrity in HIV.
Two hundred forty-one people living with HIV (PLWH) without current substance use disorder or severe (confounding) comorbid conditions underwent comprehensive neurocognitive testing and brain structural magnetic resonance imaging and magnetic resonance spectroscopy. Participants were classified using Frascati criteria versus Meyer criteria: concordant unimpaired [Frascati(Un)/Meyer(Un)], concordant impaired [Frascati(Imp)/Meyer(Imp)], or discordant [Frascati(Imp)/Meyer(Un)] which were impaired via Frascati criteria but unimpaired via Meyer criteria. To investigate the GDS versus Meyer criteria, the same groupings were utilized using GDS criteria instead of Frascati criteria.
When examining Frascati versus Meyer criteria, discordant Frascati(Imp)/Meyer(Un) individuals had less cortical gray matter, greater sulcal cerebrospinal fluid volume, and greater evidence of neuroinflammation (i.e., choline) than concordant Frascati(Un)/Meyer(Un) individuals. GDS versus Meyer comparisons indicated that discordant GDS(Imp)/Meyer(Un) individuals had less cortical gray matter and lower levels of energy metabolism (i.e., creatine) than concordant GDS(Un)/Meyer(Un) individuals. In both sets of analyses, the discordant group did not differ from the concordant impaired group on any neuroimaging measure.
The Meyer criteria failed to capture a substantial portion of PLWH with brain abnormalities. These findings support continued use of Frascati or GDS criteria to detect HIV-associated CNS dysfunction.
We describe the case of an 11-month-old girl with a rare cerebellar glioblastoma driven by a NACC2-NTRK2 (Nucleus Accumbens Associated Protein 2-Neurotrophic Receptor Tyrosine Kinase 2) fusion. Initial workup of our case demonstrated homozygous CDKN2A deletion, but immunohistochemistry for other driver mutations, including IDH1 R132H, BRAF V600E, and H3F3A K27M were negative, and ATRX was retained. Tissue was subsequently submitted for personalized oncogenomic analysis, including whole genome and whole transcriptome sequencing, which demonstrated an activating NTRK2 fusion, as well as high PD-L1 expression, which was subsequently confirmed by immunohistochemistry. Furthermore, H3 and IDH demonstrated wildtype status. These findings suggested the possibility of treatment with either NTRK- or immune checkpoint- inhibitors through active clinical trials. Ultimately, the family pursued standard treatment that involved Head Start III chemotherapy and proton radiotherapy. Notably, at most recent follow upapproximately two years from initial diagnosis, the patient is in disease remission and thriving, suggesting favorable biology despite histologic malignancy. This case illustrates the value of personalized oncogenomics, as the molecular profiling revealed two actionable changes that would not have been apparent through routine diagnostics. NTRK fusions are known oncogenic drivers in a range of cancer types, but this is the first report of a NACC2-NTRK2 fusion in a glioblastoma.
This presentation will enable the learner to:
1. Explore the current molecular landscape of pediatric high grade gliomas
2. Recognize the value of personalized oncogenomic analysis, particularly in rare and/or aggressive tumors
3. Discuss the current status of NTRK inhibitor clinical trials
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.
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.
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.
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.
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.