There is growing evidence of poor mental health and quality of life among survivors of intensive care. However, it is not yet clear to what extent the trauma of life-threatening illness, associated ...drugs and treatments, or patients' psychological reactions during intensive care contribute to poor psychosocial outcomes. Our aim was to investigate the relative contributions of a broader set of risk factors and outcomes than had previously been considered in a single study.
A prospective cohort study of 157 mixed-diagnosis highest acuity patients was conducted in a large general intensive care unit (ICU). Data on four groups of risk factors (clinical, acute psychological, socio-demographic and chronic health) were collected during ICU admissions. Post-traumatic stress disorder (PTSD), depression, anxiety and quality of life were assessed using validated questionnaires at three months (n = 100). Multivariable analysis was used.
At follow-up, 55% of patients had psychological morbidity: 27.1% (95% CI: 18.3%, 35.9%) had probable PTSD; 46.3% (95% CI: 36.5%, 56.1%) probable depression, and 44.4% (95% CI: 34.6%, 54.2%) anxiety. The strongest clinical risk factor for PTSD was longer duration of sedation (regression coefficient = 0.69 points (95% CI: 0.12, 1.27) per day, scale = 0 to 51). There was a strong association between depression at three months and receiving benzodiazepines in the ICU (mean difference between groups = 6.73 points (95% CI: 1.42, 12.06), scale = 0 to 60). Use of inotropes or vasopressors was correlated with anxiety, and corticosteroids with better physical quality of life.
Strikingly high rates of psychological morbidity were found in this cohort of intensive care survivors. The study's key finding was that acute psychological reactions in the ICU were the strongest modifiable risk factors for developing mental illness in the future. The observation that use of different ICU drugs correlated with different psychological outcomes merits further investigation. These findings suggest that psychological interventions, along with pharmacological modifications, could help reduce poor outcomes, including PTSD, after intensive care.
The human genome expresses thousands of natural antisense transcripts (NAT) that can regulate epigenetic state, transcription, RNA stability or translation of their overlapping genes
. Here we ...describe MAPT-AS1, a brain-enriched NAT that is conserved in primates and contains an embedded mammalian-wide interspersed repeat (MIR), which represses tau translation by competing for ribosomal RNA pairing with the MAPT mRNA internal ribosome entry site
. MAPT encodes tau, a neuronal intrinsically disordered protein (IDP) that stabilizes axonal microtubules. Hyperphosphorylated, aggregation-prone tau forms the hallmark inclusions of tauopathies
. Mutations in MAPT cause familial frontotemporal dementia, and common variations forming the MAPT H1 haplotype are a significant risk factor in many tauopathies
and Parkinson's disease. Notably, expression of MAPT-AS1 or minimal essential sequences from MAPT-AS1 (including MIR) reduces-whereas silencing MAPT-AS1 expression increases-neuronal tau levels, and correlate with tau pathology in human brain. Moreover, we identified many additional NATs with embedded MIRs (MIR-NATs), which are overrepresented at coding genes linked to neurodegeneration and/or encoding IDPs, and confirmed MIR-NAT-mediated translational control of one such gene, PLCG1. These results demonstrate a key role for MAPT-AS1 in tauopathies and reveal a potentially broad contribution of MIR-NATs to the tightly controlled translation of IDPs
, with particular relevance for proteostasis in neurodegeneration.
A signature item that beleaguers most teachers is classroom management. Recognizing the futility of punitive classroom management within school discipline practices, Weinstein and colleagues forged ...culturally responsive classroom management (CRCM). While nearly 20 years of scholarship highlights the importance of teachers employing CRCM to reduce their reliance on punitive discipline approaches, which are disproportionally skewed against students of color, there exists a gap between educational research and educational policies concerning the use of CRCM in schools. We employed a critical policy analysis to determine the existence of CRCM in student code-of-conduct policies, across all 50 states. Our findings highlight an absence of CRCM in states’ policies, and limited support for the incorporation of CRCM in schools and school districts. Ultimately, an opportunity awaits stakeholders (teachers, school districts, education preparation programs, and policymakers) to reform educational policies and the tools teachers can employ to affirm and sustain students’ learning environments.
Purpose Survivors of childhood acute lymphoblastic leukemia (ALL) are at risk for neurocognitive deficits that are associated with treatment, individual, and environmental factors. This study ...examined the impact of different methotrexate (MTX) and corticosteroid treatment strategies on neurocognitive functioning in children with high-risk B-lineage ALL. Methods Participants were randomly assigned to receive high-dose MTX with leucovorin rescue or escalating dose MTX with PEG asparaginase without leucovorin rescue. Patients were also randomly assigned to corticosteroid therapy that included either dexamethasone or prednisone. A neurocognitive evaluation of intellectual functioning (IQ), working memory, and processing speed (PS) was conducted 8 to 24 months after treatment completion (n = 192). Results The method of MTX delivery and corticosteroid assignment were unrelated to differences in neurocognitive outcomes after controlling for ethnicity, race, age, gender, insurance status, and time off treatment; however, survivors who were age < 10 years at diagnosis (n = 89) had significantly lower estimated IQ ( P < .001) and PS scores ( P = .02) compared with participants age ≥ 10 years. In addition, participants who were covered by US public health insurance had estimated IQs that were significantly lower ( P < .001) than those with US private or military insurance. Conclusion Children with high-risk B-lineage ALL who were age < 10 years at diagnosis are at risk for deficits in IQ and PS in the absence of cranial radiation, regardless of MTX delivery or corticosteroid type. These data may serve as a basis for developing screening protocols to identify children who are at high risk for deficits so that early intervention can be initiated to mitigate the impact of therapy on neurocognitive outcomes.
Personalized medicine promises individualized disease prediction and treatment. The convergence of machine learning (ML) and available multimodal data is key moving forward. We build upon previous ...work to deliver multimodal predictions of Parkinson's disease (PD) risk and systematically develop a model using GenoML, an automated ML package, to make improved multi-omic predictions of PD, validated in an external cohort. We investigated top features, constructed hypothesis-free disease-relevant networks, and investigated drug-gene interactions. We performed automated ML on multimodal data from the Parkinson's progression marker initiative (PPMI). After selecting the best performing algorithm, all PPMI data was used to tune the selected model. The model was validated in the Parkinson's Disease Biomarker Program (PDBP) dataset. Our initial model showed an area under the curve (AUC) of 89.72% for the diagnosis of PD. The tuned model was then tested for validation on external data (PDBP, AUC 85.03%). Optimizing thresholds for classification increased the diagnosis prediction accuracy and other metrics. Finally, networks were built to identify gene communities specific to PD. Combining data modalities outperforms the single biomarker paradigm. UPSIT and PRS contributed most to the predictive power of the model, but the accuracy of these are supplemented by many smaller effect transcripts and risk SNPs. Our model is best suited to identifying large groups of individuals to monitor within a health registry or biobank to prioritize for further testing. This approach allows complex predictive models to be reproducible and accessible to the community, with the package, code, and results publicly available.
Abstract Dementia with Lewy bodies (DLB) is the second most common neurodegenerative dementia after Alzheimer
'
s disease. Although an increasing number of genetic factors have been connected to this ...debilitating condition, the proportion of cases that can be attributed to distinct genetic defects is unknown. To provide a comprehensive analysis of the frequency and spectrum of pathogenic missense mutations and coding risk variants in nine genes previously implicated in DLB, we performed exome sequencing in 111 pathologically confirmed DLB patients. All patients were Caucasian individuals from North America. Allele frequencies of identified missense mutations were compared to 222 control exomes. Remarkably, ~ 25% of cases were found to carry a pathogenic mutation or risk variant in APP , GBA or PSEN1 , highlighting that genetic defects play a central role in the pathogenesis of this common neurodegenerative disorder. In total, 13% of our cohort carried a pathogenic mutation in GBA , 10% of cases carried a risk variant or mutation in PSEN1 , and 2% were found to carry an APP mutation. The APOE ε4 risk allele was significantly overrepresented in DLB patients ( p -value < 0.001). Our results conclusively show that mutations in GBA , PSEN1 , and APP are common in DLB and consideration should be given to offer genetic testing to patients diagnosed with Lewy body dementia.
To test whether the synucleinopathies Parkinson's disease and multiple system atrophy (MSA) share a common genetic etiology, we performed a candidate single nucleotide polymorphism (SNP) association ...study of the 384 most associated SNPs in a genome‐wide association study of Parkinson's disease in 413 MSA cases and 3,974 control subjects. The 10 most significant SNPs were then replicated in additional 108 MSA cases and 537 controls. SNPs at the SNCA locus were significantly associated with risk for increased risk for the development of MSA (combined p = 5.5 × 1012; odds ratio 6.2). Ann Neurol 2009;65:610–614
We performed a genome-wide association study (GWAS) in 1,713 individuals of European ancestry with Parkinson's disease (PD) and 3,978 controls. After replication in 3,361 cases and 4,573 controls, we ...observed two strong association signals, one in the gene encoding α-synuclein (SNCA; rs2736990, OR = 1.23, P = 2.24 × 10−16) and another at the MAPT locus (rs393152, OR = 0.77, P = 1.95 × 10−16). We exchanged data with colleagues performing a GWAS in Japanese PD cases. Association to PD at SNCA was replicated in the Japanese GWAS, confirming this as a major risk locus across populations. We replicated the effect of a new locus detected in the Japanese cohort (PARK16, rs823128, OR = 0.66, P = 7.29 × 10−8) and provide supporting evidence that common variation around LRRK2 modulates risk for PD (rs1491923, OR = 1.14, P = 1.55 × 10−5). These data demonstrate an unequivocal role for common genetic variants in the etiology of typical PD and suggest population-specific genetic heterogeneity in this disease.
This article presents improvements of large-signal RF power performance at Ka -band of gallium nitride high electron mobility transistors (HEMTs) utilizing a scandium aluminum nitride barrier. Three ...samples were fabricated and measured having different passivation schemes, including gallium nitride, silicon nitride, and aluminum gallium nitride. The pinning of the Fermi level against the valence band reduced the gain and output power density of the gallium nitride passivated device, resulting in 4.5 W/mm at a drain bias of 32 V. With silicon nitride alone as the passivation, dc/RF dispersion was reduced, and gain increased significantly, boosting the output power for this device to 8.0 W/mm at 28 V, though at the cost of a reduced breakdown voltage. Adding an epitaxial aluminum gallium nitride passivating layer increased the maximum bias voltage that the devices can operate at compared to devices with the silicon nitride passivation. When biased at 40 V, the output power of the devices reached 10.8 W/mm at 30 GHz. These devices show the importance of the passivation design to large-signal RF performance in scandium aluminum nitride-based HEMTs and will help guide further improvements.
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