Widespread adoption of rapid genomic testing in pediatric critical care requires robust clinical and laboratory pathways that provide equitable and consistent service across health care systems.
To ...prospectively evaluate the performance of a multicenter network for ultra-rapid genomic diagnosis in a public health care system.
Descriptive feasibility study of critically ill pediatric patients with suspected monogenic conditions treated at 12 Australian hospitals between March 2018 and February 2019, with data collected to May 2019. A formal implementation strategy emphasizing communication and feedback, standardized processes, coordination, distributed leadership, and collective learning was used to facilitate adoption.
Ultra-rapid exome sequencing.
The primary outcome was time from sample receipt to ultra-rapid exome sequencing report. The secondary outcomes were the molecular diagnostic yield, the change in clinical management after the ultra-rapid exome sequencing report, the time from hospital admission to the laboratory report, and the proportion of laboratory reports returned prior to death or hospital discharge.
The study population included 108 patients with a median age of 28 days (range, 0 days to 17 years); 34% were female; and 57% were from neonatal intensive care units, 33% were from pediatric intensive care units, and 9% were from other hospital wards. The mean time from sample receipt to ultra-rapid exome sequencing report was 3.3 days (95% CI, 3.2-3.5 days) and the median time was 3 days (range, 2-7 days). The mean time from hospital admission to ultra-rapid exome sequencing report was 17.5 days (95% CI, 14.6-21.1 days) and 93 reports (86%) were issued prior to death or hospital discharge. A molecular diagnosis was established in 55 patients (51%). Eleven diagnoses (20%) resulted from using the following approaches to augment standard exome sequencing analysis: mitochondrial genome sequencing analysis, exome sequencing-based copy number analysis, use of international databases to identify novel gene-disease associations, and additional phenotyping and RNA analysis. In 42 of 55 patients (76%) with a molecular diagnosis and 6 of 53 patients (11%) without a molecular diagnosis, the ultra-rapid exome sequencing result was considered as having influenced clinical management. Targeted treatments were initiated in 12 patients (11%), treatment was redirected toward palliative care in 14 patients (13%), and surveillance for specific complications was initiated in 19 patients (18%).
This study suggests feasibility of ultra-rapid genomic testing in critically ill pediatric patients with suspected monogenic conditions in the Australian public health care system. However, further research is needed to understand the clinical value of such testing, and the generalizability of the findings to other health care settings.
Objectives. To adapt and extend an existing typology of vaccine misinformation to classify the major topics of discussion across the total vaccine discourse on Twitter.
Methods. Using 1.8 million ...vaccine-relevant tweets compiled from 2014 to 2017, we adapted an existing typology to Twitter data, first in a manual content analysis and then using latent Dirichlet allocation (LDA) topic modeling to extract 100 topics from the data set.
Results. Manual annotation identified 22% of the data set as antivaccine, of which safety concerns and conspiracies were the most common themes. Seventeen percent of content was identified as provaccine, with roughly equal proportions of vaccine promotion, criticizing antivaccine beliefs, and vaccine safety and effectiveness. Of the 100 LDA topics, 48 contained provaccine sentiment and 28 contained antivaccine sentiment, with 9 containing both.
Conclusions. Our updated typology successfully combines manual annotation with machine-learning methods to estimate the distribution of vaccine arguments, with greater detail on the most distinctive topics of discussion. With this information, communication efforts can be developed to better promote vaccines and avoid amplifying antivaccine rhetoric on Twitter.
Integrated genomic analysis of 456 pancreatic ductal adenocarcinomas identified 32 recurrently mutated genes that aggregate into 10 pathways: KRAS, TGF-β, WNT, NOTCH, ROBO/SLIT signalling, G1/S ...transition, SWI-SNF, chromatin modification, DNA repair and RNA processing. Expression analysis defined 4 subtypes: (1) squamous; (2) pancreatic progenitor; (3) immunogenic; and (4) aberrantly differentiated endocrine exocrine (ADEX) that correlate with histopathological characteristics. Squamous tumours are enriched for TP53 and KDM6A mutations, upregulation of the TP63∆N transcriptional network, hypermethylation of pancreatic endodermal cell-fate determining genes and have a poor prognosis. Pancreatic progenitor tumours preferentially express genes involved in early pancreatic development (FOXA2/3, PDX1 and MNX1). ADEX tumours displayed upregulation of genes that regulate networks involved in KRAS activation, exocrine (NR5A2 and RBPJL), and endocrine differentiation (NEUROD1 and NKX2-2). Immunogenic tumours contained upregulated immune networks including pathways involved in acquired immune suppression. These data infer differences in the molecular evolution of pancreatic cancer subtypes and identify opportunities for therapeutic development.
This large study found no increased risk of cardiovascular events in children and young adults using attention deficit–hyperactivity disorder (ADHD) drugs. Although the data are compatible with ...nearly a doubling of risk, the study was underpowered and the absolute event rate was quite low.
Medications that are used to treat attention deficit–hyperactivity disorder (ADHD) are prescribed for more than 2.7 million children in the United States each year
1
and have been considered to be relatively safe.
2
–
5
However, reports of adverse events from Canada and the United States that have included cases of sudden death, myocardial infarction, and stroke in conjunction with the use of these drugs have raised concern about their safety.
6
,
7
Although case reports from adverse-event reporting systems can be an important source for identifying medication safety signals, they cannot reliably quantify risk. Thus, there is a compelling need to obtain . . .
Abstract
Using the Keck Planet Imager and Characterizer, we obtained high-resolution (
R
∼ 35,000)
K
-band spectra of the four planets orbiting HR 8799. We clearly detected H
2
O and CO in the ...atmospheres of HR 8799 c, d, and e, and tentatively detected a combination of CO and H
2
O in b. These are the most challenging directly imaged exoplanets that have been observed at high spectral resolution to date when considering both their angular separations and flux ratios. We developed a forward-modeling framework that allows us to jointly fit the spectra of the planets and the diffracted starlight simultaneously in a likelihood-based approach and obtained posterior probabilities on their effective temperatures, surface gravities, radial velocities, and spins. We measured
v
sin
(
i
)
values of
10.1
−
2.7
+
2.8
km
s
−
1
for HR 8799 d and
15.0
−
2.6
+
2.3
km
s
−
1
for HR 8799 e, and placed an upper limit of <14 km s
−1
of HR 8799 c. Under two different assumptions of their obliquities, we found tentative evidence that rotation velocity is anticorrelated with companion mass, which could indicate that magnetic braking with a circumplanetary disk at early times is less efficient at spinning down lower-mass planets.
Objective
Pain sensitization is associated with pain severity in knee osteoarthritis (OA), but its cause in humans is not well understood. We examined whether inflammation, assessed as synovitis and ...effusion on magnetic resonance imaging (MRI), or mechanical load, assessed as bone marrow lesions (BMLs), was associated with sensitization in knee OA.
Methods
Subjects in the Multicenter Osteoarthritis Study, a National Institutes of Health–funded cohort of persons with or at risk of knee OA, underwent radiography and MRI of the knee, and standardized quantitative sensory testing (temporal summation and pressure pain threshold PPT) of the wrist and patellae at baseline and 2 years later. We examined the relation of synovitis, effusion, and BMLs to temporal summation and PPT cross‐sectionally and longitudinally.
Results
There were 1,111 subjects in the study sample (mean age 67 years, mean body mass index 30 kg/m2, 62% female). Synovitis was associated with a significant decrease in PPT at the patella (i.e., more sensitized) over 2 years (adjusted β −0.30 95% confidence interval (95% CI) −0.52, −0.08). Effusion was similarly associated with a decrease in PPT at the wrist (adjusted β −0.24 95% CI −0.41, −0.08) and with risk of incident temporal summation at the patella (adjusted OR 1.54 95% CI 1.01, 2.36). BMLs were not associated with either quantitative sensory testing measure.
Conclusion
Inflammation, as evidenced by synovitis or effusion, is associated with pain sensitization in knee OA. In contrast, BMLs do not appear to contribute to sensitization in knee OA. Early targeting of inflammation is a reasonable strategy to test for prevention of sensitization and through this, reduction of pain severity, in knee OA.
In February 2020, the World Health Organization announced an ‘infodemic’ -- a deluge of both accurate and inaccurate health information -- that accompanied the global pandemic of COVID-19 as a major ...challenge to effective health communication. We assessed content from the most active vaccine accounts on Twitter to understand how existing online communities contributed to the ‘infodemic’ during the early stages of the pandemic. While we expected vaccine opponents to share misleading information about COVID-19, we also found vaccine proponents were not immune to spreading less reliable claims. In both groups, the single largest topic of discussion consisted of narratives comparing COVID-19 to other diseases like seasonal influenza, often downplaying the severity of the novel coronavirus. When considering the scope of the ‘infodemic,’ researchers and health communicators must move beyond focusing on known bad actors and the most egregious types of misinformation to scrutinize the full spectrum of information -- from both reliable and unreliable sources -- that the public is likely to encounter online.
Second homes - the cottage, the summer house, the bach - are an important part of the tourism and leisure lifestyles of many people in the developed world. Second homes are therefore an integral ...component of tourism experiences in rural and peripheral areas. Yet, despite their significance not only for tourism but also for rural communities and the rural economy, relatively little research has been undertaken on the topic until recent times. This volume represents the first major international analysis and review of second homes for over 25 years. It will provide a significant resource for those interested in changing patterns of tourism and leisure behaviour as well as the use of the countryside and peripheral areas. The book describes the economic, social and environmental impacts of second homes as well as their planning implications and places such discussions within the context of contemporary human mobility. The volume represents essential reading for those interested in rural regional development processes and the development of new rural leisure landscapes.
Basal-like and triple negative breast cancer (TNBC) share common molecular features, poor prognosis and a propensity for metastasis to the brain. Amplification of epidermal growth factor receptor ...(EGFR) occurs in ~50% of basal-like breast cancer, and mutations in the epidermal growth factor receptor (EGFR) have been reported in up to ~ 10% of Asian TNBC patients. In non-small cell lung cancer several different mutations in the EGFR tyrosine kinase domain confer sensitivity to receptor tyrosine kinase inhibitors, but the tumourigenic potential of EGFR mutations in breast cells and their potential for targeted therapy is unknown.
Constructs containing wild type, G719S or E746-A750 deletion mutant forms of EGFR were transfected into the MCF10A breast cells and their tumorigenic derivative, MCF10CA1a. The effects of EGFR over-expression and mutation on proliferation, migration, invasion, response to gefitinib, and tumour formation in vivo was investigated. Copy number analysis and whole exome sequencing of the MCF10A and MCF10CA1a cell lines were also performed.
Mutant EGFR increased MCF10A and MCF10CA1a proliferation and MCF10A gefitinib sensitivity. The EGFR-E746-A750 deletion increased MCF10CA1a cell migration and invasion, and greatly increased MCF10CA1a xenograft tumour formation and growth. Compared to MCF10A cells, MCF10CA1a cells exhibited large regions of gain on chromosomes 3 and 9, deletion on chromosome 7, and mutations in many genes implicated in cancer.
Mutant EGFR enhances the oncogenic properties of MCF10A cell line, and increases sensitivity to gefitinib. Although the addition of EGFR E746-A750 renders the MCF10CA1a cells more tumourigenic in vivo it is not accompanied by increased gefitinib sensitivity, perhaps due to additional mutations, including the PIK3CA H1047R mutation, that the MCF10CA1a cell line has acquired. Screening TNBC/basal-like breast cancer for EGFR mutations may prove useful for directing therapy but, as in non-small cell lung cancer, accompanying mutations in PIK3CA may confer gefitinib resistance.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Sensors are becoming ubiquitous in everyday life, generating data at an unprecedented rate and scale. However, models that assess impacts of human activities on environmental and human health, have ...typically been developed in contexts where data scarcity is the norm. Models are essential tools to understand processes, identify relationships, associations and causality, formalize stakeholder mental models, and to quantify the effects of prevention and interventions. They can help to explain data, as well as inform the deployment and location of sensors by identifying hotspots and areas of interest where data collection may achieve the best results. We identify a paradigm shift in how the integration of models and sensors can contribute to harnessing ‘Big Data’ and, more importantly, make the vital step from ‘Big Data’ to ‘Big Information’. In this paper, we illustrate current developments and identify key research needs using human and environmental health challenges as an example.
•Sensors and models play vital roles in harnessing ‘Big Data’ to extract information.•Data analytics can help to diminish monitoring burden and support locating sensors.•Exploring ‘Big Data’ is essential to detect universal associations across space and time.•Ethical challenges and issues of standards and harmonisation need to be addressed.•Citizen science needs robust sensors and models to crowd-source and interpret data.
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