Summary
Morphoea, also known as localized scleroderma, is a debilitating fibrosing disorder of uncertain aetiology, affecting the skin and subcutaneous tissues. Paediatric‐onset disease is not ...uncommon and is associated with frequent relapses. The disease has complex pathogenetic mechanisms and multiple clinical subtypes, and affects children of all ages. Recent research has focused on elucidating the disease pathophysiology and identifying measures of disease activity. We performed a literature search on PubMed, MEDLINE and Google Scholar, using keywords such as ‘pediatric morphea’, ‘juvenile localised scleroderma’ and ‘juvenile systemic sclerosis’. Relevant studies, including randomized trials, reviews of standard current guidelines and original research articles, were selected, and results were analysed before being summarized. In the first of this two‐part review, we provide a bird’s‐eye view of the current literature concerning the epidemiology, aetiopathogenesis and clinical classification of paediatric morphoea; in Part 2, we review the diagnosis, markers of disease activity, management and natural history.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
IMPORTANCE: The efficacy and safety of endovascular thrombectomy (EVT) in patients with large ischemic cores remains unknown, to our knowledge. OBJECTIVE: To compare outcomes in patients with large ...ischemic cores treated with EVT and medical management vs medical management alone. DESIGN, SETTING, AND PARTICIPANTS: This prespecified analysis of the Optimizing Patient’s Selection for Endovascular Treatment in Acute Ischemic Stroke (SELECT) trial, a prospective cohort study of imaging selection that was conducted in 9 US comprehensive stroke centers, enrolled patients between January 2016 and February 2018, and followed them up for 90 days. Patients with moderate to severe stroke and anterior circulation large-vessel occlusion presenting up to 24 hours from the time they were last known to be well were eligible for the cohort. Of these, patients with large ischemic cores on computed tomography (CT) (Alberta Stroke Program Early CT Score <6) or CT perfusion scanning (a volume with a relative cerebral blood flow <30% of ≥50 cm3) were included in analyses. EXPOSURES: Endovascular thrombectomy with medical management (MM) or MM only. MAIN OUTCOMES AND MEASURES: Functional outcomes at 90 days per modified Rankin scale; safety outcomes (mortality, symptomatic intracerebral hemorrhage, and neurological worsening). RESULTS: A total of 105 patients with large ischemic cores on either CT or CT perfusion images were included: 71 with Alberta Stroke Program Early CT Scores of 5 or less (EVT, 37; MM, 34), 74 with cores of 50 cm3 or greater on CT perfusion images (EVT, 39; MM, 35), and 40 who had large cores on both CT and CT perfusion images (EVT, 14; MM, 26). The median (interquartile range) age was 66 (60-75) years; 45 patients (43%) were female. Nineteen of 62 patients (31%) who were treated with EVT achieved functional independence (modified Rankin Scale scores, 0-2) vs 6 of 43 patients (14%) treated with MM only (odds ratio OR, 3.27 95% CI, 1.11-9.62; P = .03). Also, EVT was associated with better functional outcomes (common OR, 2.12 95% CI, 1.05-4.31; P = .04), less infarct growth (44 vs 98 mL; P = .006), and smaller final infarct volume (97 vs 190 mL; P = .001) than MM. In the odds of functional independence, there was a 42% reduction per 10-cm3 increase in core volume (adjusted OR, 0.58 95% CI, 0.39-0.87; P = .007) and a 40% reduction per hour of treatment delay (adjusted OR, 0.60 95% CI, 0.36-0.99; P = .045). Of 10 patients who had EVT with core volumes greater than 100 cm3, none had a favorable outcome. CONCLUSIONS AND RELEVANCE: Although the odds of good outcomes for patients with large cores who receive EVT markedly decline with increasing core size and time to treatment, these data suggest potential benefits. Randomized clinical trials are needed.
In non-small-cell lung cancer (NSCLC), concurrent mutations in the oncogene KRAS and the tumour suppressor STK11 (also known as LKB1) encoding the kinase LKB1 result in aggressive tumours prone to ...metastasis but with liabilities arising from reprogrammed metabolism. We previously demonstrated perturbed nitrogen metabolism and addiction to an unconventional pathway of pyrimidine synthesis in KRAS/LKB1 co-mutant cancer cells. To gain broader insight into metabolic reprogramming in NSCLC, we analysed tumour metabolomes in a series of genetically engineered mouse models with oncogenic KRAS combined with mutations in LKB1 or p53. Metabolomics and gene expression profiling pointed towards activation of the hexosamine biosynthesis pathway (HBP), another nitrogen-related metabolic pathway, in both mouse and human KRAS/LKB1 co-mutant tumours. KRAS/LKB1 co-mutant cells contain high levels of HBP metabolites, higher flux through the HBP pathway and elevated dependence on the HBP enzyme glutamine-fructose-6-phosphate transaminase isomerizing 2 (GFPT2). GFPT2 inhibition selectively reduced KRAS/LKB1 co-mutant tumour cell growth in culture, xenografts and genetically modified mice. Our results define a new metabolic vulnerability in KRAS/LKB1 co-mutant tumours and provide a rationale for targeting GFPT2 in this aggressive NSCLC subtype.
Correction for 'How to stay out of trouble in RIXS calculations within equation-of-motion coupled-cluster damped response theory? Safe hitchhiking in the excitation manifold by means of core-valence ...separation' by Kaushik D. Nanda
et al.
,
Phys. Chem. Chem. Phys.
, 2020,
22
, 2629-2641, DOI:
10.1039/c9cp03688a
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In MR-only clinical workflow, replacing CT with MR image is of advantage for workflow efficiency and reduces radiation to the patient. To eliminate CT from the workflow, it is necessary to generate ...the information provided by CT via an MR image. We propose a method to generate accurate synthetic CT (sCT) from MRI to suit the radiation therapy (RT) workflow.
We present a machine learning method for sCT generation from zero-echo-time (ZTE) MRI aimed at structural and quantitative accuracies of the image, with a particular focus on the accurate bone value. We propose a loss function that favors a spatially sparse bone region. We harness the ability of the multi-task network to produce correlated outputs to enable localization of region of interest (RoI) via segmentation, emphasize regression of values within RoI and retain the overall accuracy.
We have included $54$ brain patient images in this study and tested sCT images against CT on a subset of $20$ cases. A pilot dose evaluation was performed on $9$ test cases to demonstrate the viability of sCT in RT planning. The average quantitative metrics produced by the proposed method over the test set were - (a) MAE of 70±8.6 HU; (b) PSNR of 29.4±2.8 dB; SSIM of 0.95±0.02; and (d) Dice coefficient 0.984±0.
We demonstrate that the proposed method generates sCT images that resemble real CT image and has a quantitative accuracy that suits RT dose planning application. We compare the dose calculation from the proposed sCT and the real CT in a radiation therapy treatment planning setup and show that sCT based planning falls within 0.5\% target dose error. The method presented here with an initial dose evaluation makes an encouraging precursor to a broader clinical evaluation of sCT based RT planning on different anatomical regions.
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Understanding how bacteria interact with surfaces with micrometer and/or sub-micrometer roughness is critical for developing antibiofouling and bactericidal topographies. A primary ...research focus in this field has been replicating and emulating bioinspired nanostructures on various substrates to investigate their mechanobactericidal potential. Yet, reports on polymer substrates, especially with very high aspect ratios, have been rare, despite their widespread use in our daily lives. Specifically, the role of a decrease in stiffness with an increase in the aspect ratio of nanostructures may be consequential for the mechanobactericidal mechanism, which is biophysical in nature. Therefore, this work reports on generating bioinspired high aspect ratio nanostructures on poly(ethylene terephthalate) (PET) surfaces to study and elucidate their antibacterial and antibiofouling properties. Biomimetic nanotopographies with variable aspect ratios were generated via maskless dry etching of PET in oxygen plasma. It was found that both high and low-aspect ratio structures effectively neutralized Gram-negative bacterial contamination by imparting damage to their membranes but were unable to inactivate Gram-positive cells. Notably, the clustering of the soft, flexible tall nanopillars resulted in cooperative stiffening, as revealed by the nanomechanical behavior of the nanostructures and validated with the help of finite element simulations. Moreover, external capillary forces augmented the killing efficiency by enhancing the strain on the bacterial cell wall. Finally, experimental and computational investigation of the durability of the nanostructured surfaces showed that the structures were robust enough to withstand forces encountered in daily life. Our results demonstrate the potential of the single-step dry etching method for the fabrication of mechanobactericidal topographies and their potential in a wide variety of applications to minimize bacterial colonization of soft substrates like polymers.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Innumerable personages are associated with susceptibility to the COVID-19 pandemic viral infection evolution, which has globally overblown the healthcare facilities. Following the emergence of ...respiratory syndrome coronavirus, 2019- nCoV delineates as a third major emergence of a novel coronavirus. β-coronavirus having suspected origin from bat comprehend congestion of the respiratory system, indicating a worldwide life threat to around 235 million asthma patients’ existents as per WHO records. This review aims to investigate the risk constituents involved in virus-induced asthma, its management and prevention, origin, and transmission of coronavirus, including the relationship between different CoV infections. This review culminated the role of cytokines and chemokines and others found in COVID19 patients, which could directly or indirectly affect the smooth muscle contractility reasoned to promote asthma severity, but this still remains unknown. The research highlights how essential it is to regularly wash your hands and clean surfaces that are touched by your hands in order to prevent illness. Some pre-clinical data suggests the preferred use of a PDE4 inhibitor like Roflumilast in case of uncontrolled virus-induced asthma exacerbations. Although there is a lack of particular asthma management so far, that is why the rectification of the consequences can only be done by taking supportive treatment.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
1 Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, Nebraska; and 2 Department of Pharmacology, Midwestern University, Downers Grove, Illinois
Submitted ...17 October 2007
; accepted in final form 26 March 2008
Exercise training (ExT) normalizes the increased sympathetic outflow in heart failure (HF), but the mechanisms are not known. We hypothesized that ExT would normalize the augmented glutamatergic mechanisms mediated by N -methyl- D -aspartic acid (NMDA) receptors within the paraventricular nucleus (PVN) that occur with HF. Four groups of rats were used: 1 ) sham-operated (Sham) sedentary (Sed), 2 ) Sham ExT, 3 ) HF Sed, and 4 ) HF ExT. HF was induced by left coronary artery ligation, and ExT consisted of 3 wk of treadmill running. In -chloralose-urethane-anesthetized rats, the increase in renal sympathetic nerve activity in response to the highest dose of NMDA (200 pmol) injected into the PVN in the HF Sed group was approximately twice that of the Sham Sed group. In the HF ExT group the response was not different from the Sham Sed and Sham ExT groups. Relative NMDA NR1 receptor subunit mRNA expression was 63% higher in the HF Sed group compared with the Sham Sed group but in the HF ExT group was not different from the Sham Sed and Sham ExT groups. NR1 receptor subunit protein expression was increased 87% in the HF Sed group compared with the Sham Sed group but in the HF ExT group was not significantly different from the Sham Sed and Sham ExT groups. Thus one mechanism by which ExT alleviates elevated sympathetic outflow in HF may be through normalization of glutamatergic mechanisms within the PVN.
paraventricular nucleus; N -methyl- D -aspartic acid receptors; sympathetic nerve activity
Address for reprint requests and other correspondence: K. P. Patel, Dept. of Cellular and Integrative Physiology, Univ. of Nebraska Medical Center, 985850 Nebraska Medical Center, Omaha, NE 68198-5850 (e-mail: kpatel{at}unmc.edu )
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