Genetic overexpression of COMP-Ang1 impairs BM microenvironment and induces senescence of BM HSCs.

Abstract: Supplemental Angiopoietin 1 (Ang1) exerts its therapeutic potential on microvascular regression-associated diseases, and this potential is linked with the function of hematopoietic stem cells (HSCs). However, the underlying mechanisms of the effect of enhanced angiogenesis on the modulation of HSCs are not yet defined. Here, we generated transgenic mice expressing Cartilage Oligomeric Matrix Protein (COMP)-Ang1 in keratin 14-expressing cells. The mutant animals expressed excessive angiogenic characteristics in the skin and bone marrow (BM) along with redder skin with more numerous and branched vessels compared with their wild-type (WT) littermates. The mutants displayed reduced long bone formation and osteoclast activity than did WT littermates and had fewer CD150+CD48-Lineage-Sca-1+c-Kit+ (LSK) cells in the BM. The mutants also exhibited greater senescence-associated (SA) β-gal activity, p16INK4a protein expression, and superoxide anion levels in CD150+CD48-LSK cells in the BM. Furthermore, transplantation assay revealed that the mutant-derived LSK cells were inferior to the cells derived from WT littermate in inducing competitive repopulating capacity in the recipients. Collectively, our results demonstrate that persistent and prolonged administration of COMP-Ang1 by inducible transgenic expression mediates excessive angiogenesis in the body and impairs BM microenvironment, eventually leading to senescence of BM HSCs.

Kook|Sung-Ho|SH| Sim|Hyun-Jaung|HJ| Hwang|Jae-Won|JW| Baek|Young-Hyun|YH| Kim|Chun-Chu|CC| Lee|Jeong-Hoon|JH| Cho|Eui-Sic|ES| Lee|Jeong-Chae|JC|

D064236:Cartilage Oligomeric Matrix Protein

COMP-Ang1
Senescence
Hematopoietic stem cells
Angiogenesis
Bone marrow


Ventricular volume, white matter alterations and outcome of major depression and their relationship to endocrine parameters - A pilot study.

Abstract:
OBJECTIVES
Brain morphology and its relation to endocrine parameters were examined, in order to determine the link of these parameters to treatment outcome to psychopharmacological treatment in depressed patients.

METHODS
We examined the potentially predictive value of Magnetic Resonance Imaging (MRI) parameters related to mineralocorticoid receptor (MR) function on the treatment outcome of depression. 16 inpatients with a major depressive episode (MDE) were studied at baseline and 14 of them approximately six weeks later. Physiological biomarkers and 3-T-structural MRI based volume measures, using FreeSurfer 6.0 software, were determined.

RESULTS
Non-responders (<50% reduction of HAMD-21; n = 6) had a significantly smaller volume of the right anterior cingulate cortex, a significantly larger ventricle to brain ratio (VBR) and third ventricle volume, and smaller volumes of the central and central-anterior corpus callosum (CC) in comparison to responders (n = 7; all p ≤ 0.05). Correlational analysis (Spearman) demonstrated that larger ventricle volume was correlated to a worse treatment outcome, higher body mass index (BMI) and smaller CC segment volume, whereas the total CC volume was negatively correlated to the saliva aldosterone/cortisol concentration ratio (AC-ratio).

CONCLUSION
Large ventricular volume may be a predictive marker for worse treatment response to standard antidepressant treatment, potentially via compression of white matter structures. A mediating role of the previously identified markers BMI and the AC-ratio, is suggested.

Murck|Harald|H|0000-0003-4827-1945 Luerweg|Benjamin|B| Hahn|Johannes|J| Braunisch|Matthias|M| Jezova|Daniela|D| Zavorotnyy|Maxim|M|0000-0001-5215-2055 Konrad|Carsten|C| Jansen|Andreas|A| Kircher|Tilo|T|

D003337:Corpus Callosum
D003863:Depression
D003865:Depressive Disorder, Major
D006801:Humans
D010865:Pilot Projects
D066127:White Matter

ventricular volume
Depression
corpus callosum
brain imaging
choroid plexus


How broad are state physician health program descriptions of physician impairment?

Abstract:
BACKGROUND
Physician health program websites in 23 states provide many descriptions of possible physician impairment. This study sought to determine whether these descriptions are so broad that almost everyone might potentially be suspected of being impaired given these descriptions.

METHODS
The authors randomly selected 25 descriptions of impairment and then presented them anonymously online to members of the general population in full-time employment through Amazon's Mechanical Turk (N = 199). Half of the respondents randomly received a narrowly worded version, and half received a broadly worded version of the survey questions.

RESULTS
In the narrowly worded version of the survey, 70.9% of respondents endorsed at least one description of impairment, and 59.2% endorsed more than one. In the broadly phrased version, 96.9% endorsed at least one description, and 95.8% endorsed more than one. These respondents endorsed a median of 10 out of 25 (40%) descriptions.

CONCLUSIONS
These findings call into question whether these descriptions really identify persons with poor performance or who pose a high risk of substantial, imminent harm to self or others in the workplace. They also demonstrate the extent to which these descriptions could potentially be misapplied and brand almost anyone as impaired.

D006296:Health Services
D006801:Humans
D020407:Internet
D010815:Physician Impairment
D016730:Program Development
D011639:Public Opinion

Physician health program
Physician impairment
Addiction
Americans with Disabilities Act
Coercion
Discrimination
Physician suicide
Stigma
Substance use disorder
Well-being
Wellness


Matrix Metallopeptidase 14: A Candidate Prognostic Biomarker for Diffuse Large B-Cell Lymphoma.

Abstract:
Background
Matrix metallopeptidase 14 (MMP14) is an important gene in the regulation of T-cell function. However, the correlation between MMP14 expression, prognosis, and immune cell infiltration in diffuse large B-cell lymphoma (DLBCL) remains unclear.

Methods
We investigated the influence of MMP14 on clinical prognosis using data obtained from three Gene Expression Omnibus (GEO) database sets (GSE98588, GSE10846, and GSE4475). The expression of MMP14 was analyzed using the Gene Expression Profiling Interactive Analysis (GEPIA). The correlation between MMP14 and immune cell infiltration was investigated using the Cell-type Identification By Estimating Relative Subsets Of RNA Transcripts (CIBERSORT) and Tumor Immune Estimation Resource (TIMER) tools. In addition, the correlation between MMP14 expression and immune gene markers was analyzed by TIMER and GEPIA.

Results
MMP14 expression positively correlated with favorable progression-free survival (PFS; GSE98588, P = 0.02) and overall survival (OS; GSE98588, P = 0.003; GSE10846, P = 5.517e-05; and GSE4475, P = 9.85e-04). Moreover, MMP14 expression was higher in DLBCL tumors than in normal tissues. Regarding clinical characteristics, high MMP14 expression was found to be correlated with race. MMP14 expression was also correlated with immune cell infiltration and had a remarkable correlation with various immune marker sets. It was found that M0 macrophages were the immune cells most related to survival, decreasing with the increase in Ann Arbor clinical stage. The results especially showed that MMP14 was a prognostic biomarker and related to the macrophages M0.

Conclusion
The results suggest that MMP14 is a novel prognostic molecular marker for DLBCL and is related to the immune cell infiltration, especially related to the macrophages M0. Our study provides insights for understanding the potential roles of MMP14 in tumor immunology and its suitability as a prognosis biomarker in DLBCL.

Yin|Chengliang|C| Zhang|Junyan|J| Shen|Ming|M| Gu|Zhenyang|Z| Li|Yan|Y| Xue|Wanguo|W| Shi|Jinlong|J| Huang|Wenrong|W|

matrix metallopeptidase 14
biomarker
diffuse large B-cell lymphoma
prognosis
immune cell infiltration


On estimands and the analysis of adverse events in the presence of varying follow-up times within the benefit assessment of therapies.

Abstract: The analysis of adverse events (AEs) is a key component in the assessment of a drug's safety profile. Inappropriate analysis methods may result in misleading conclusions about a therapy's safety and consequently its benefit-risk ratio. The statistical analysis of AEs is complicated by the fact that the follow-up times can vary between the patients included in a clinical trial. This paper takes as its focus the analysis of AE data in the presence of varying follow-up times within the benefit assessment of therapeutic interventions. Instead of approaching this issue directly and solely from an analysis point of view, we first discuss what should be estimated in the context of safety data, leading to the concept of estimands. Although the current discussion on estimands is mainly related to efficacy evaluation, the concept is applicable to safety endpoints as well. Within the framework of estimands, we present statistical methods for analysing AEs with the focus being on the time to the occurrence of the first AE of a specific type. We give recommendations which estimators should be used for the estimands described. Furthermore, we state practical implications of the analysis of AEs in clinical trials and give an overview of examples across different indications. We also provide a review of current practices of health technology assessment (HTA) agencies with respect to the evaluation of safety data. Finally, we describe problems with meta-analyses of AE data and sketch possible solutions.

Unkel|Steffen|S|0000-0002-2083-0090 Amiri|Marjan|M| Benda|Norbert|N|0000-0001-5605-2414 Beyersmann|Jan|J| Knoerzer|Dietrich|D| Kupas|Katrin|K| Langer|Frank|F| Leverkus|Friedhelm|F| Loos|Anja|A| Ose|Claudia|C| Proctor|Tanja|T| Schmoor|Claudia|C| Schwenke|Carsten|C| Skipka|Guido|G| Unnebrink|Kristina|K| Voss|Florian|F| Friede|Tim|T|0000-0001-5347-7441

D064420:Drug-Related Side Effects and Adverse Reactions

estimands
adverse events
benefit assessment
clinical trials
safety data


Human papillomavirus persistence or clearance after infection in reproductive age. What is the status? Review of the literature and new data of a vaginal gel containing silicate dioxide, citric acid, and selenite.

Abstract: Cervical cancer, the third most common cancer in women, is caused in nearly all cases by a persistent infection with high-risk types of the human papillomavirus. Although human papillomavirus infections are 80%-90% transient and disappear spontaneously within 24 months, human papillomavirus infections that remain are at risk of developing cervical lesions. Different therapeutical approaches have been tested to promote the regression of low-grade lesions or prevent progression. They include the application of 5-fluorouracil, curcumin, imiquimod, interferons, Vitamin D, and others. Also, the effect of probiotics and vaginal therapy with carboxy-methyl-beta glucan was assessed. Review of the literature and presentation of the last study data are presented. Clearance of high-risk human papillomavirus seemed to be promoted by treatment with a new vaginal gel containing a highly disperse SiO2 and an anti-oxidative combination of citric acid and sodium. This gel showed, after 6 months, an improvement of cytological Pap findings (ASC-US, LSIL, ASC-H, or HSIL) in 80.9% of the participants. Similarly, there was a clearing of hr-human papillomavirus in 53% of cases after 3 months of gel administration. The percentage increased slightly in the non-treated control group from 78.3% at baseline to 83% after 3 months. The percentage of patients who were tested positive for p16/Ki67 reduced from 75% at baseline to 5.3% in the treatment group after 6 months, while the percentage decreased only slightly in the non-treated group (baseline: 91.5%; 6 months: 75.2%). The examined vaginal gel may support the healing of conspicuous cytological findings (ASC-US, LSIL, ASC-H, or HSIL) and clearance of hr-human papillomavirus positive results.

D014622:Vaginal Creams, Foams, and Jellies

vaginal gel
Pap testing
human papillomavirus clearance
silicon dioxide


Isotope dilution LC-orbitrap-HRMS with automated sample preparation for the simultaneous quantification of 11 antimycotics in human serum.

Abstract:
INTRODUCTION
The aim of this project was to develop and validate an isotope-dilution liquid chromatography high resolution mass spectrometry (LC-HRMS) method for the quantification of the 11 most widely used systemic antimycotics and to study whether HRMS is a feasible alternative for therapeutic drug monitoring (TDM) when compared to tandem MS (MS/MS) technology.

METHODS
After protein precipitation, followed by automated online sample clean-up the analytes were separated within 4 min on a C18 column using an acetonitrile-water gradient. Eleven antimycotics, namely 5-flucytosine, amphotericin B, anidulafungin, fluconazole, isavuconazole, itraconazole, ketoconazole, micafungin, OH-itraconazole, posaconazole and voriconazole were finally quantified in full MS scan mode using positive electrospray ionization (ESI +) with a mass range fromm/z 110-1300 using HRMS. The method was comprehensively validated on the basis of the European Medicines Agengy (EMA) method validation protocol using commercially available IVD kit components.

RESULTS
Good linear relationship between peak area responses and drug concentrations (R2 > 0.995) and excellent selectivity were observed for all antimycotics in this study. Inaccuracy and imprecision of all quality controls were consistently below ± 12.6% and ± 8.1%, respectively. Quantification results were in agreement with an IVD LC-MS/MS method.

CONCLUSION
HRMS was shown to be suitable for TDM of small molecules when compared to tandem mass spectrometry. The novel HRMS method is quickly installed and may be a robust and reliable tool for routine TDM of antimycotics in clinical laboratories.

Schuster|Carina|C| Paal|Michael|M| Lindner|Johanna|J| Zoller|Michael|M| Liebchen|Uwe|U| Scharf|Christina|C| Vogeser|Michael|M|

D002851:Chromatography, High Pressure Liquid

High resolution mass spectrometry (HRMS)


Quality of life and cognitive and functional performance of octogenarians and nonagenarians undergoing hemodialysis.

Abstract:
OBJECTIVE
To evaluate the quality of life, cognitive and functional capacity of older adult patients undergoing hemodialysis who are 80 years of age or older and compare them to older adults without chronic kidney disease (CKD) treated at a geriatrics outpatient clinic.

METHOD
First, 103 older adult patients undergoing hemodialysis and 103 older adults without CKD matched by gender and age were evaluated. Cognitive aspects as evaluated by the mini mental state examination, the Boston Naming Test and verbal fluency were analyzed; comorbidities according to the Charlson's comorbidity index; social support through the Medical Outcomes Study scale; functional ability through the chair sit-to-stand and gait speed tests, as well as the basic activities of daily living (BADL) and instrumental activities of daily living (IADL) and quality of life according to the Kidney Disease Quality of Life Short Form (KDQOL SF-36) questionnaires.

RESULTS
The hemodialysis group had a higher rate of comorbidities (7.8 ± 2.4 vs. 5.8 ± 2.3, p < 0.001). In the multiple logistic regression analysis, the group undergoing hemodialysis presented a ninefold greater chance of dependence for IADL than controls, a 4.3 and 3.2 times greater chances for inadequacy on the gait speed and chair sit-to-stand tests, respectively, as well as a 4.4-fold higher risk of cognitive decline on the verbal fluency test.

CONCLUSION
Long-lived patients undergoing hemodialysis presented worse quality of life and functional and cognitive performance compared to long-term patients attended at the outpatient clinic, indicating that preventive and protective measures should be considered and implemented.

Quality of life
Older adults
Chronic kidney disease
Dialysis
Mental assessment
Physical evaluation
Renal replacement therapy


Preliminary study on Sina (Sina Intraoperative Neurosurgical Assist) APP assisted localization of supratentorial lesions by smart phone.

Abstract: This article is aimed at investigating the use of smart phone software Sina in the localization of supratentorial lesions, finding the error between Sina method and neuronavigation, and identifying the reliability of the new method. Neuronavigation and Sina measurement were used to locate the lesion in the patients whose lesion lengths are between 2 cm and 6 cm. The reference point was the center of the lesion. We found the error of Sina method is 13.6 ± 0.55 mm comparing with neuronavigation, so the Sina method still cannot replace the localization method of the neuronavigation system. However, in practical clinical work, with the help of the new method, the lesion can be located more precisely and easily.

Guo|Yu|Y| Xu|Shujun|S| Li|Xingang|X| Ma|Xiangyu|X|

Supratentorial lesions
Preoperative localization
Smart phone application


Synchronous Multifocal Canalicular Adenomas.

Abstract: Canalicular adenoma (CAD) is an uncommon benign tumor of minor salivary glands with predilection for the upper labial mucosa. An 80-year-old female presented with nine submucosal nodules of the upper labial mucosa and bilateral buccal mucosa. Histopathologic examination revealed multifocal circumscribed tumor islands with a tubular growth pattern within a loose hypocellular myxoid background stroma. Interconnecting rows of columnar tumor cells imparted a canalicular morphology. In addition to the characteristic histopathologic findings, a comprehensive immunohistochemical panel supported a final diagnosis of multifocal CAD. Synchronous multifocality in CAD is an infrequent finding and this sine qua non clinicopathologic correlation article exemplifies such a case.

Multifocal canalicular adenoma
Minor salivary glands
Benign salivary gland tumour


Pharmacovigilance network as an additional tool for the surveillance of antimicrobial resistance.

Abstract:
BACKGROUND
The WHO Programme for International Drug Monitoring (PIDM) is a large Pharmacovigilance network of countries sharing Adverse Drug Reaction (ADR) reports. Pharmacovigilance Experts have suggested that antimicrobial resistance (AMR) is an overlooked adverse event. We undertook this study to investigate the potential role of Pharmacovigilance databases in the surveillance of AMR.

METHODS
Using the AWaRe (Access, Watch and Reserve) list and the WHO Priority Pathogens List, we established a list of antimicrobials and carried out a VigiBase search via VigiAccess, looking for ADR reports with Preferred Terms (PTs) that contained AMR-relevant information. Identified Terms were matched with codes from the Medical Dictionary for Regulatory Activities (MedDRA Version 21.1).

RESULTS
Records on 86 drugs were retrieved with a total of 1 170 751 ADR reports submitted between 1968 and 2018. Seventeen PTs suggesting suspected resistance, ineffectiveness, inappropriate use, or medication error were used to code 15 250 reports. The most frequently used PTs were "Drug Ineffective" (45.6%), "Off label use" (9.5%) and "Pathogen Resistance" (8.9%). A group of six agents (Amoxicillin, Cefalotin, Ciprofloxacin, Clarithromycin, Levofloxacin and Daptomycin) accounted for 38% (n = 5806) of all 15 250 AMR-relevant ADR reports. The PTs most frequently used in 5806 reports were grouped in 4 categories: drug ineffectiveness (62.5%), resistance (19.2%), off-label use (12.1%) and prescription errors (6.2%).

CONCLUSION
Our findings suggest that Pharmacovigilance databases could serve as a tool in tracking antimicrobial use and resistance especially in settings where laboratory capacity is still in its development stages. National Pharmacovigilance centers could play a proactive role in stimulating the reporting of AMR-relevant ADRs which can serve as a basis for resistance suspicion alerts. Further studies focusing on the narrative and other clinical pharmacology details in ADR reports are required.

D016907:Adverse Drug Reaction Reporting Systems

Pharmacovigilance
antimicrobial resistance
adverse drug reaction
AWaRe
VigiBase
VigiAccess
MedDRA
antimicrobial use


Analysis of single-cell RNA sequencing data based on autoencoders.

Abstract:
BACKGROUND
Single-cell RNA sequencing (scRNA-Seq) experiments are gaining ground to study the molecular processes that drive normal development as well as the onset of different pathologies. Finding an effective and efficient low-dimensional representation of the data is one of the most important steps in the downstream analysis of scRNA-Seq data, as it could provide a better identification of known or putatively novel cell-types. Another step that still poses a challenge is the integration of different scRNA-Seq datasets. Though standard computational pipelines to gain knowledge from scRNA-Seq data exist, a further improvement could be achieved by means of machine learning approaches.

RESULTS
Autoencoders (AEs) have been effectively used to capture the non-linearities among gene interactions of scRNA-Seq data, so that the deployment of AE-based tools might represent the way forward in this context. We introduce here scAEspy, a unifying tool that embodies: (1) four of the most advanced AEs, (2) two novel AEs that we developed on purpose, (3) different loss functions. We show that scAEspy can be coupled with various batch-effect removal tools to integrate data by different scRNA-Seq platforms, in order to better identify the cell-types. We benchmarked scAEspy against the most used batch-effect removal tools, showing that our AE-based strategies outperform the existing solutions.

CONCLUSIONS
scAEspy is a user-friendly tool that enables using the most recent and promising AEs to analyse scRNA-Seq data by only setting up two user-defined parameters. Thanks to its modularity, scAEspy can be easily extended to accommodate new AEs to further improve the downstream analysis of scRNA-Seq data. Considering the relevant results we achieved, scAEspy can be considered as a starting point to build a more comprehensive toolkit designed to integrate multi single-cell omics.

Tangherloni|Andrea|A| Ricciuti|Federico|F| Besozzi|Daniela|D| Liò|Pietro|P| Cvejic|Ana|A|

D000069550:Machine Learning
D012313:RNA
D017423:Sequence Analysis, RNA
D059010:Single-Cell Analysis
D000073359:Whole Exome Sequencing

Autoencoders
scRNA-Seq
Batch correction
Clustering
Data integration
Dimensionality reduction


Cloning, differential tissue expression of a novel hcApo gene, and its correlation with total carotenoid content in purple and white inner-shell color pearl mussel Hyriopsis cumingii.

Abstract: As a molecular carrier and storage protein, apolipoprotein (Apo) mediates the intracellular uptake of lipids, proteins, vitamins and carotenoids. In this study, we identified a novel Apo gene, designated hcApo, from the freshwater pearl mussel Hyriopsis cumingii. The complete hcApo cDNA consists of 4104 nucleotides with an open reading frame encoding 1155 amino acid residues. The hcApo protein contains a conserved lipoprotein N-terminal domain (LPD-N) that is a characteristic of the large lipid transfer protein (LLTP) superfamily. The hcApo mRNA is constitutively expressed in a wide range of tissues with the highest expression level in the liver. Moreover, differential expression analysis revealed that the hcApo gene is more highly expressed in the liver, kidney, mantle and gill of purple line mussels compared to white line mussels. In situ hybridization investigations of the precise expression site of hcApo mRNA in the mantle showed that hcApo mRNA is specifically expressed in the outer epithelial cells of the middle fold and the inner epithelial cells of the outer fold of the mantle, as well as throughout the outer epithelium of the outer fold and ventral mantle. Another very important finding is that significantly positive correlation existed between the hcApo gene expression level and the total carotenoid content in purple line mussels. These findings may provide a better understanding of the roles of hcApo in the molecular mechanisms of shell formation and coloring of H. cumingii.

Li|Xilei|X| Bai|Zhiyi|Z| Luo|Hongrui|H| Liu|Yue|Y| Wang|Guiling|G| Li|Jiale|J|

Carotenoids
Inner-shell color
Hyriopsis cumingii
Apolipoprotein
Gene expression


Structural view of the yeast Dam1 complex, a ring-shaped molecular coupler for the dynamic microtubule end.

Abstract: In a dividing eukaryotic cell, proper chromosome segregation requires the dynamic yet persistent attachment of kinetochores to spindle microtubules. In the budding yeast Saccharomyces cerevisiae, this function is especially crucial because each kinetochore is attached to a single microtubule; consequently, loss of attachment could lead to unrecoverable chromosome loss. The highly specialized heterodecameric Dam1 protein complex achieves this coupling by assembling into a microtubule-encircling ring that glides near the end of the dynamic microtubule to mediate chromosome motion. In recent years, we have learned a great deal about the structural properties of the Dam1 heterodecamer, its mechanism of self-assembly into rings, and its tethering to the kinetochore by the elongated Ndc80 complex. The most remarkable progress has resulted from defining the fine structures of helical bundles within Dam1 heterodecamer. In this review, we critically analyze structural observations collected by diverse approaches with the goal of obtaining a unified view of Dam1 ring architecture. A considerable consistency between different studies supports a coherent model of the circular core of the Dam1 ring. However, there are persistent uncertainties about the composition of ring protrusions and flexible extensions, as well as their roles in mediating ring core assembly and interactions with the Ndc80 complex and microtubule.

Chromosome segregation
Disordered extensions
Electron microscopy
Kinetochore-microtubule interactions
Microtubule-end coupler


The Role of Topographic Collaterals in Predicting Functional Outcome after Thrombolysis in Anterior Circulation Ischemic Stroke.

Abstract:
BACKGROUND
The Alberta Stroke Program Early CT (ASPECTS) leptomeningeal collaterals score on CT-angiography helps in prognosticating functional outcome in acute ischemic stroke (AIS) patients treated with intravenous thrombolysis. We evaluated whether a simplified topological ASPECTS collaterals scoring could serve as a rapid biomarker for early prediction in thrombolyzed AIS patients.

METHODS
Consecutive patients from 2010 to 2014 with anterior circulation AIS treated with intravenous thrombolysis were included. The primary outcome was good functional outcome (modified Rankin scale score 0-1 at 3-months). Collaterals were scored according to the extent of contrast opacification in arteries distal to the acute occlusion. Prognostic value of individual ASPECTS leptomeningeal collateral regions was determined by multivariate logistic regression.

RESULTS
A total of 283 patients were included (mean National Institutes of Health Stroke Scale [NIHSS] score 19.0 ± 6.3 points). Using multivariate logistic regression, good M5 region (parietal)-collaterals (OR 2.62, 95%CI 1.215-5.682, P = .014), younger age (OR .97 per year, 95%CI .943-.990, P = .006), nondiabetics (OR .44, 95%CI .224-.889, P = .021), and lower NIHSS (OR .89 per point, 95%CI .842-.935, P < .001) were independently associated with good functional outcome. The receiver operating characteristic curve showed NIHSS as a good predictor of functional outcome (area under the curve .718, 95%CI .656-.780, P < .001). However, a better predictive value was achieved when M5 collateral score was added to the NIHSS (area under the curve .752, 95%CI .694-.809, P < .001).

CONCLUSIONS
Good collaterals in the M5 region are associated with good functional outcome. Addition of this simple neuroimaging tool to the pretreatment NIHSS may serve as a reliable biomarker for prognosis.

Tan|Benjamin Yong-Qiang|BY|
Kong|Wan-Yee|WY|
Ngiam|Jinghao Nicholas|JN|
Teoh|Hock-Luen|HL|
Sharma|Vijay K|VK|
Yeo|Leonard Leong-Litt|LL|


Yielding hydroxyl radicals in the Fenton-like reaction induced by manganese (II) oxidation determines Cd mobilization upon soil aeration in paddy soil systems.

Abstract: As a redox-sensitive element, manganese (Mn) plays a critical role in Cd mobilization, especially in paddy soil. In an anoxic environment, the precipitation of Mn(II)-hydroxides specifically favors Cd retention, while draining the paddy fields results in substantial remobilization of Cd. However, how the change in Mn redox states during the periodical transit of anoxic to oxic systems affects Cd mobility remains unclear. In this study, we demonstrate that the radical effect generated during the oxidation of Mn(II)-hydroxides exerts a significant effect on the oxidative dissolution of Cd during the aeration of paddy soils. The extractable Cd concentration decreased rapidly during the reduction phases but increased upon oxidation, while Cd availability produced the opposite effect with soil pe + pH and the extractable Mn concentration. Inhibiting the oxidation of Mn(II)-containing phases by microbes suppressed the production of hydroxyl free radicals (•OH) and Cd mobilization in the drainage phase. Analysis of X-ray absorption spectroscopy and sequential extraction demonstrated that the transformation from the Mn phase of Mn(II) to Mn(III/IV) determines Cd solubility. Altogether, the oxidization of Mn(II)-hydroxides was associated with the generation of significant amounts of •OH. The dissolution of Mn(II)- incorporating phases lead to a net release of Cd into soils during soil aeration.

Wang|Meng|M| Liu|Yongbing|Y| Shi|Huading|H| Li|Shanshan|S| Chen|Shibao|S|

Hydroxyl radical
Paddy soil
Fenton-like pathway
Manganese redox
Soil cadmium availability


Association between the FTO SNP rs9939609 and Metabolic Syndrome in Chilean Children.

Abstract:
BACKGROUND
The increasing prevalence of obesity in children has raised the incidence of Metabolic Syndrome (MetS) in this age group. Given the short- and long-term health impact of MetS, it is essential to prevent its onset by detecting its main triggers. Besides, genetic factors play an essential role in influencing which individuals within a population are most likely to develop obesity in response to a particular environment. In this regard, a common variation in the FTO gene is reproducibly associated with BMI and obesity from childhood and the genetic load has been linked to several cardiovascular risk factors, highlighting the FTO single nucleotide polymorphism (SNP) rs9939609. Therefore, this study aimed to establish the relationship between the FTO SNP rs9939609 and MetS.

METHODS
A cross-sectional study was carried out on 220 children from the Biobío region (Chile). MetS diagnosis was established through the modified Cook criteria, using prevalence ratios, COR curves, and linear regressions to determine its association with MetS and its components.

RESULTS
The prevalence of MetS was significantly increased among carriers of the risk allele (A): TT, 20.2%; TA, 25.4%; AA, 44.7% (p = 0.006). Also, the presence of A was associated with altered MetS-related variables.

CONCLUSIONS
The FTO SNP rs9939609 was associated with a raised prevalence of MetS among A allele carriers, and was higher in the homozygous genotype (AA).

D020022:Genetic Predisposition to Disease


How to Boost our Immune System Against Coronavirus Infection?

Abstract: New emerging viruses like coronavirus 2019 (COVID-19) infections are always frightening. We know little about their transmission, behaviors, clinical manifestations, and outcomes. There is no vaccine or therapeutic strategies to deal with these infections yet. In this situation, preventive measures may be promising. Hand hygiene is a very important issue in preventing viral infection; however, there are other entities that can enhance the immune response and help in infection prevention. Herein we review some measures for boosting the immune system.

Moazzen|Nasrin|N|
Imani|Bahareh|B|
Aelami|Mohammad Hassan|MH|
Motevali Haghi|Nasrin Sadat|NS|
Kianifar|Hamid Reza|HR|
Khoushkhui|Maryam|M|
Ahanchian|Hamid|H|


Retrodiscal approach of lumbar epidural block.

Abstract:
OBJECTIVE
To compare the technical strengths and weaknesses between retrodiscal (RD) and conventional subpedicular (SP) approaches of transforaminal epidural block (TF-EPB).

METHOD
Sixty-one patients with L5 radiculopathy who planned to undergo TF-EPB were consecutively enrolled as study subjects. Subjects were randomly assigned to one of two groups. For the RD approach, the positioning of the patient and the C-arm were similar to that for lumbar discography. We compared the pattern of dye spreads, the frequency of complications during the procedures, and the effect of the pain block 2 weeks after the procedure between the two groups.

RESULTS
For the RD group (n=24), the contrast dye diffused around the L5 and S1 nerve roots in 16 cases (67%), but it diffused around only the L5 root in 27 cases (73%) in the SP group (n=37) (p<0.05). Two weeks after the procedure, the visual analogue scale (VAS) decreased by the same amount in both groups (RD group: 3.1±1.6, SP group: 3.2±2.6). Symptoms of nerve root irritation occurred in 1 case of the RD group and in 10 cases of the SD group (p<0.05).

CONCLUSION
The RD approach was as efficient as the SP approach for temporary diagnostic relief and offered considerable advantages, such as lower nerve root irritation possible lower risk of vascular injection. Thus, it could be a useful technique when a herniated disc segment is stuck or when the foraminal stenosis is severe.

Kim|Chul|C|
Moon|Chang Jin|CJ|
Choi|Hee Eun|HE|
Park|Yongbum|Y|

Retrodiscal Lumbar Transforaminal Injection Spinal


Comparison between stair-climbing test and six-minute walk test after lung resection using video-assisted thoracoscopic surgery lobectomy.

Abstract: [Purpose] Currently, the six-minute walk distance (6MWD) is used to evaluate exercise capacity in people following lung resection for non-small cell lung cancer. However, it is unclear whether the 6MWD can detect changes in cardiorespiratory fitness induced by exercise training or lung resection. Conversely, the stair-climbing test is used frequently for the preoperative evaluation of lung resection candidates. It is considered a sensitive method for detecting changes associated with training, but is not used to evaluate exercise capacity after lung resection. The purpose of this study was to compare the stair-climbing test and the six-minute walk test (6MWT) after lung resection. [Subjects and Methods] Fourteen patients undergoing lung resection completed the stair-climbing test and the 6MWT preoperatively, and one month postoperatively. The postoperative values and the percentage change in the stair-climbing test and the 6MWT were evaluated. [Results] The stair-climbing test results showed a significant deterioration at one month after lung resection; however, a significant change in the 6MWD was not observed. [Conclusion] When compared with the 6MWT, the stair-climbing test was more sensitive in detecting lung resection-induced changes in cardiorespiratory fitness.

Kubori|Yohei|Y| Matsuki|Ryosuke|R| Hotta|Akira|A| Morisawa|Tomoyuki|T| Tamaki|Akira|A|

Six-minute walk distance
Exercise capacity
Lung cancer


EPR spectroscopy of multicomponent, multispin molecular system obtained by the photolysis of 2,4,6-triazido-3-cyano-5-fluoropyridine in solid argon.

Abstract: Complex multicomponent, multispin molecular system, consisting of a septet trinitrene, two quintet dinitrenes, and three triplet mononitrenes, was obtained by the photolysis of 2,4,6-triazido-3-cyano-5-fluoropyridine in solid argon. To identify these paramagnetic products, electron paramagnetic resonance spectroscopy in combination with line-shape spectral simulations and density functional theory calculations was used. The products of the photolysis was found to be triplet 2,4-diazido-3-cyano-5-fluoropyridyl-6-nitrene (DT  = 1.000 cm-1 , ET  = 0), triplet 2,4-diazido-3-cyano-5-fluoropyridyl-2-nitrene (DT  = 1.043 cm-1 , ET  = 0), triplet 2,6-diazido-3-cyano-5-fluoropyridyl-4-nitrene (DT  = 1.128 cm-1 , ET  = 0 cm-1 ), quintet 4-azido-3-cyano-5-fluoropyridyl-2,6-dinitrene (DQ  = 0.211 cm-1 , EQ  = 0.0532 cm-1 ), quintet 2-azido-3-cyano-5-fluoropyridyl-4,6-dinitrene (DQ  = 0.208 cm-1 , EQ  = 0.0386 cm-1 ), and septet 3-cyano-5-fluoropyridyl-2,4,6-trinitrene (DS  = -0.1017 cm-1 , ES  = -0.0042 cm-1 ) in a 38:4:7:22:14:4 ratio, respectively.

EPR spectroscopy
photolysis
azides
high-spin states
matrix isolation
nitrenes


Bridging the Gap: From 2D Cell Culture to 3D Microengineered Extracellular Matrices.

Abstract: Historically the culture of mammalian cells in the laboratory has been performed on planar substrates with media cocktails that are optimized to maintain phenotype. However, it is becoming increasingly clear that much of biology discerned from 2D studies does not translate well to the 3D microenvironment. Over the last several decades, 2D and 3D microengineering approaches have been developed that better recapitulate the complex architecture and properties of in vivo tissue. Inspired by the infrastructure of the microelectronics industry, lithographic patterning approaches have taken center stage because of the ease in which cell-sized features can be engineered on surfaces and within a broad range of biocompatible materials. Patterning and templating techniques enable precise control over extracellular matrix properties including: composition, mechanics, geometry, cell-cell contact, and diffusion. In this review article we explore how the field of engineered extracellular matrices has evolved with the development of new hydrogel chemistry and the maturation of micro- and nano- fabrication. Guided by the spatiotemporal regulation of cell state in developing tissues, techniques for micropatterning in 2D, pseudo-3D systems, and patterning within 3D hydrogels will be discussed in the context of translating the information gained from 2D systems to synthetic engineered 3D tissues.

micropatterning
developmental engineering
in vitro morphogenesis
soft lithography
tissue engineering


Sunitinib dosing schedule 2/1 improves tolerability, efficacy, and health-related quality of life in Chinese patients with metastatic renal cell carcinoma.

Abstract:
PURPOSE
To assess the efficacy and tolerability of sunitinib dosing schedule of 2 weeks on and 1 week off (schedule 2/1) vs. the traditional schedule of 4 weeks on and 2 week off (schedule 4/2) and its influence on health-related quality of life (HRQoL) in Chinese patients with metastatic renal cell carcinoma (mRCC).

MATERIALS AND METHODS
A retrospective analysis of 108 patients with mRCC who were treated with sunitinib regimens (50mg daily) between January 2009 and July 2013 was undertaken. Overall, 3 groups of patients were studied according to the dosing schedule they received: schedule 4/2 (n = 50), transitional schedule 2/1 (T2/1; patients switched from schedule 4/2 to 2/1; n = 26), and initial schedule 2/1 (I2/1; n = 32). The tumor response, progression-free survival (PFS) time, adverse events, and HRQoL were assessed and compared among the groups.

RESULTS
The incidences of diarrhea, fatigue, hand-foot syndrome, and neutropenia induced by the treatment of sunitinib were all significantly less common with schedule I2/1 and T2/1 than with schedule 4/2 (P<0.05). Although there was no statistically significant difference in the tumor response among the 3 groups, the median PFS time was significantly longer with schedule I2/1 than with schedules T2/1 and 4/2 (11.2 vs. 9.4 and 9.5mo, respectively, P = 0.030), and HRQoL (as determined by 19-item Functional Assessment of Cancer Therapy Kidney Symptom Index scores) was better.

CONCLUSIONS
Treatment with sunitinib 50mg daily using a 2/1 dosing schedule can provide better tolerability and a longer PFS with better HRQoL in Chinese patients with mRCC than the traditional schedule 4/2.

Pan|Xiuwu|X| Huang|Hai|H| Huang|Yi|Y| Liu|Bing|B| Cui|Xingang|X| Gan|Sishun|S| Ye|Jianqing|J| Xu|Danfeng|D| Chen|Lu|L| Zhou|Qiwei|Q| Li|Lin|L| Hong|Yi|Y|

Sunitinib
Dosing schedules
Metastatic renal cell carcinoma
Tumor response
Adverse events
Quality-of-life


Efficacy of a nurse-led lipid-lowering secondary prevention intervention in patients hospitalized for ischemic heart disease: A pilot randomized controlled trial.

Abstract:
BACKGROUND AND AIMS
Lack of achievement of secondary prevention objectives in patients with ischaemic heart disease remains an unmet need in this patient population. We aimed at evaluating the six-month efficacy of an intensive lipid-lowering intervention, coordinated by nurses and implemented after hospital discharge, in patients hospitalized for an ischaemic heart disease event.

METHODS
Randomized controlled trial, in which a nurse-led intervention including periodic follow-up, serial lipid level controls, and subsequent optimization of lipid-lowering therapy, if appropriate, was compared with standard of care alone in terms of serum lipid-level control at six months after discharge.

RESULTS
The nurse-led intervention was associated with an improved management of low-density lipoprotein (LDL) cholesterol levels compared with standard of care alone: LDL cholesterol levels ⩽100 mg/dL were achieved in 97% participants in the intervention arm as compared with 67% in the usual care arm ( p value <0.001), the LDL cholesterol ⩽70 mg/dL target recommended by the 2016 European Society of Cardiology guidelines was achieved in 62% vs. 37% participants ( p value 0.047) and the LDL cholesterol reduction of ⩾50% recommended by the American College of Cardiology/American Heart Association in 2013 was achieved in 25.6% of participants in the intervention arm as compared with 2.6% in the usual care arm ( p value 0.007). The intervention was also associated with improved blood pressure control among individuals with hypertension.

CONCLUSIONS
Our findings highlight the opportunity that nurse-led, intensive, post-discharge follow-up plans may represent for achieving LDL cholesterol guideline-recommended management objectives in patients with ischaemic heart disease. These findings should be replicated in larger cohorts.

Ruiz-Bustillo|Sonia|S| Ivern|Consol|C| Badosa|Neus|N| Farre|Nuria|N| Marco|Esther|E| Bruguera|Jordi|J| Cladellas|Mercè|M| Enjuanes|Cristina|C| Cainzos-Achirica|Miguel|M| Marti-Almor|Julio|J| Comin-Colet|Josep|J|

secondary prevention
ischaemic heart disease
Nurse-led intervention
lipids
cholesterol
acute coronary syndrome
statins


Medication use by adolescents and adults with fragile X syndrome.

Abstract:
BACKGROUND
The behavioural challenges and medical conditions associated with fragile X syndrome (FXS) can lead to increased need for medications.

METHOD
This longitudinal study examined the use of prescription medications for psychotropic and non-psychotropic purposes by adolescents and adults with FXS drawn from a North American community sample (N = 105). Odds and probabilities of continuing or discontinuing medication were calculated. Predictors of medication use were calculated.

RESULTS
More than two-thirds took psychotropic medication, and about one-quarter took non-psychotropic medication. Over a 3-year period, those who initially took prescription medications were considerably more likely to remain on medications than to stop. Individuals with more autism symptoms, more behavioural problems, a mental health diagnosis, and greater family income were significantly more likely to use psychotropic medication 3 years later. Individuals who had more health problems, a mental health diagnosis, and were female were more likely to use non-psychotropic medication over this time period.

CONCLUSIONS
Findings highlight the elevated and ongoing use of medication by individuals with FXS. Implications for social and behavioural research on FXS are discussed.

Laxman|D J|DJ|0000-0002-5505-9806
Greenberg|J S|JS|
DaWalt|L S|LS|
Hong|J|J|
Aman|M G|MG|
Mailick|M|M|

adolescents and adults
fragile X syndrome
psychotropic medication
non-psychotropic medication


Ecological responses to forest age, habitat, and host vary by mycorrhizal type in boreal peatlands.

Abstract: Despite covering vast areas of boreal North America, the ecological factors structuring mycorrhizal fungal communities in peatland forests are relatively poorly understood. To assess how these communities vary by age (younger vs. mature), habitat (fen vs. bog), and host (conifer trees vs. ericaceous shrub), we sampled the roots of two canopy trees (Larix laricina and Picea mariana) and an ericaceous shrub (Ledum groenlandicum) at four sites in northern Minnesota, USA. To characterize the specific influence of host co-occurrence on mycorrhizal fungal community structure, we also conducted a greenhouse bioassay using the same three hosts. Root samples were assessed using Illumina-based high-throughput sequencing (HTS) of the ITS1 rRNA gene region. As expected, we found that the relative abundance of ectomycorrhizal fungi was high on both Larix and Picea, whereas ericoid mycorrhizal fungi had high relative abundance only on Ledum. Ericoid mycorrhizal fungal richness was significantly higher in mature forests, in bogs, and on Ledum hosts, while ectomycorrhizal fungal richness did not differ significantly across any of these three variables. In terms of community composition, ericoid mycorrhizal fungi were more strongly influenced by host while ectomycorrhizal fungi were more influenced by habitat. In the greenhouse bioassay, the presence of Ledum had consistently stronger effects on the composition of ectomycorrhizal, ericoid, and ericoid-ectomycorrhizal fungal communities than either Larix or Picea. Collectively, these results suggest that partitioning HTS-based datasets by mycorrhizal type in boreal peatland forests is important, as their responses to rapidly changing environmental conditions are not likely to be uniform.

Fen
Bog
Larix laricina
Picea mariana
Ledum groenlandicum
Mycorrhizal fungi
SPRUCE


Anillin regulates breast cancer cell migration, growth, and metastasis by non-canonical mechanisms involving control of cell stemness and differentiation.

Abstract:
BACKGROUND
Breast cancer metastasis is driven by a profound remodeling of the cytoskeleton that enables efficient cell migration and invasion. Anillin is a unique scaffolding protein regulating major cytoskeletal structures, such as actin filaments, microtubules, and septin polymers. It is markedly overexpressed in breast cancer, and high anillin expression is associated with poor prognosis. The aim of this study was to investigate the role of anillin in breast cancer cell migration, growth, and metastasis.

METHODS
CRISPR/Cas9 technology was used to deplete anillin in highly metastatic MDA-MB-231 and BT549 cells and to overexpress it in poorly invasive MCF10AneoT cells. The effects of anillin depletion and overexpression on breast cancer cell motility in vitro were examined by wound healing and Matrigel invasion assays. Assembly of the actin cytoskeleton and matrix adhesion were evaluated by immunofluorescence labeling and confocal microscopy. In vitro tumor development was monitored by soft agar growth assays, whereas cancer stem cells were examined using a mammosphere formation assay and flow cytometry. The effects of anillin knockout on tumor growth and metastasis in vivo were determined by injecting control and anillin-depleted breast cancer cells into NSG mice.

RESULTS
Loss-of-function and gain-of-function studies demonstrated that anillin is necessary and sufficient to accelerate migration, invasion, and anchorage-independent growth of breast cancer cells in vitro. Furthermore, loss of anillin markedly attenuated primary tumor growth and metastasis of breast cancer in vivo. In breast cancer cells, anillin was localized in the nucleus; however, knockout of this protein affected the cytoplasmic/cortical events, e.g., the organization of actin cytoskeleton and cell-matrix adhesions. Furthermore, we observed a global transcriptional reprogramming of anillin-depleted breast cancer cells that resulted in suppression of their stemness and induction of the mesenchymal to epithelial trans-differentiation. Such trans-differentiation was manifested by the upregulation of basal keratins along with the increased expression of E-cadherin and P-cadherin. Knockdown of E-cadherin restored the impaired migration and invasion of anillin-deficient breast cancer cells.

CONCLUSION
Our study demonstrates that anillin plays essential roles in promoting breast cancer growth and metastatic dissemination in vitro and in vivo and unravels novel functions of anillin in regulating breast cancer stemness and differentiation.

Wang|Dongdong|D|
Naydenov|Nayden G|NG|
Dozmorov|Mikhail G|MG|
Koblinski|Jennifer E|JE|
Ivanov|Andrei I|AI|0000-0003-4823-209X

D023041:Xenograft Model Antitumor Assays

Invasion
Actin cytoskeleton
Stem cells
Keratins
E-cadherin
Actin-binding proteins


Comparison of Standardized Cytomegalovirus (CMV) Viral Load Thresholds in Whole Blood and Plasma of Solid Organ and Hematopoietic Stem Cell Transplant Recipients with CMV Infection and Disease.

Abstract:
BACKGROUND
Quantification of cytomegalovirus (CMV) deoxyribonucleic acid (DNA) has important diagnostic, prognostic, and therapeutic implications in the management of transplant recipients. We aimed to assess a viral load in plasma and whole blood that distinguishes CMV disease from asymptomatic infection in a cohort of solid organ and hematopoietic stem cell transplantation.

METHODS
We prospectively measured and compared CMV viral load in paired plasma and whole blood samples collected from transplant recipients with CMV infection and disease. Cytomegalovirus viral loads were determined by a commercially available US Food and Drug Administration-approved quantitative assay (COBAS AmpliPrep/COBAS TaqMan CMV Test [CAP/CTM CMV]) calibrated to the first World Health Organization International Standard for CMV DNA quantification.

RESULTS
Moderate agreement of CMV viral load was observed between plasma and whole blood, with 31% of samples having discordant findings, particularly among samples with low DNA levels. Among the subset of samples where both paired samples had quantifiable levels, we observed a systematic bias that reflected higher viral load in whole blood compared with plasma. Based on receiver operating curve analysis, an initial plasma CMV viral load threshold of 1700 IU/mL in solid organ transplant recipients (sensitivity 80%, specificity 74%) and 1350 IU/mL in allogeneic hematopoietic stem cell transplant recipients (sensitivity 87%, specificity 87%) distinguished CMV disease and asymptomatic infection.

CONCLUSIONS
This study identifies standardized viral load thresholds that distinguish CMV disease from asymptomatic infection using CAP/CTM CMV assay. We propose these thresholds as potential triggers to be evaluated in prospective studies of preemptive therapy. Plasma was better than whole blood for measuring viral load using the CAP/CTM CMV assay.

Dioverti|M Veronica|MV|
Lahr|Brian D|BD|
Germer|Jeffrey J|JJ|
Yao|Joseph D|JD|
Gartner|Michelle L|ML|
Razonable|Raymund R|RR|

cytomegalovirus
viral load
transplantation
CMV DNA


Sub-clinical orthostatic hypotension is associated with greater subjective memory impairment in older adults.

Abstract:
INTRODUCTION
Orthostatic blood pressure (BP) is a measure of cardiovascular autonomic function. Orthostatic BP dysregulation may lie on the causal pathway to dementia. Subjective memory impairment (SMI) is commonly reported by older people some of whom may progress to dementia. We hypothesised that sub-clinical orthostatic hypotension would be associated with SMI and explored these associations according to sex.

METHODS
Cross-sectional analysis of data from 4340 participants aged 50 and over collected during the first wave (2009-2011) of the cohort study, The Irish Longitudinal Study on Ageing. Subjective memory was rated according to a 5-point scale ranging from 'poor' to 'excellent'. BP was measured during orthostatic stress using continuous non-invasive beat-to-beat recording over 2 min.

RESULTS
2% reported 'poor' subjective memory, 12.3% 'fair' , 38% 'good', 33% 'very good' and 14.6% 'excellent'. After controlling for several potential confounding factors including cardiovascular risk, objective cognition, and depressive symptoms mean systolic orthostatic BP was lowest in those with poor subjective memory: 92.2 mmHg (CI95% = 87.1, 97.3) versus excellent 99.3 mmHg (CI95% = 97.4, 101.2); p = 0.011. Further adjustment for supine systolic BP suggested that men with poor subjective memory reached the lowest average systolic orthostatic BP and had the greatest impairment in systolic orthostatic BP stabilisation to baseline levels at 10 s post-stand (-6.64 mmHg; CI95% = -11.49, -1.79; p = 0.007).

CONCLUSIONS
Sub-clinical orthostatic hypotension is associated with SMI, and there are sex-specific relationships evident in this population-based cohort. Subtle cardiovascular autonomic dysfunction may represent a modifiable risk marker at an early stage of cognitive decline in older adults. Copyright © 2016 John Wiley & Sons, Ltd.

O'Hare|Celia|C|
McCrory|Cathal|C|
O'Connell|Matthew Dl|MD|
Kenny|Rose Anne|RA|

D000368:Aged
D000369:Aged, 80 and over
D000704:Analysis of Variance
D001794:Blood Pressure
D003430:Cross-Sectional Studies
D005260:Female
D006801:Humans
D007024:Hypotension, Orthostatic
D008137:Longitudinal Studies
D008297:Male
D008569:Memory Disorders
D008875:Middle Aged
D012044:Regression Analysis
D012737:Sex Factors

orthostatic hypotension
subjective memory
autonomic function


Health Risks Associated With Excessive Exposure to Solar Ultraviolet Radiation Among Outdoor Workers in South Africa: An Overview.

Abstract: Exposure of outdoor workers to high levels of solar ultraviolet radiation (UVR) poses significant, well-known health risks including skin cancer and eye diseases. In South Africa, little is known about how many workers are potentially overexposed to solar UVR and what the associated impacts on their health might be. In this overview, the geography and solar UVR environment in South Africa are considered, as well as the different outdoor occupational groups likely to be affected by excessive solar UVR exposure. Sunburn, pterygium, cataract, keratinocyte cancers, and melanoma are discussed in the context of outdoor workers. Few studies in South Africa have considered these health issues and the most effective ways to reduce solar UVR exposure for those working outside. Several countries have developed policies and guidelines to support sun safety in the workplace which include training and education, in addition to the provision of personal protective equipment and managerial support. Several gaps in occupational sun protection and workplace sun safety for South Africa are identified. Legislation needs to recognize solar UVR exposure as an occupational health hazard, with sun safety guidelines and training provided for employers and employees.

skin cancer
cataract
keratinocyte cancers
melanoma
employment
environmental health
personal sun safety
sun exposure


Representing causal knowledge in environmental policy interventions: Advantages and opportunities for qualitative influence diagram applications.

Abstract: This article develops and explores a methodology for using qualitative influence diagrams in environmental policy and management to support decision-making efforts that minimize risk and increase resiliency. Influence diagrams are representations of the conditional aspects of a problem domain. Their graphical properties are useful for structuring causal knowledge relevant to policy interventions and can be used to enhance inference and inclusivity of multiple viewpoints. Qualitative components of influence diagrams are beneficial tools for identifying and examining the interactions among the critical variables in complex policy development and implementation. Policy interventions on social-environmental systems can be intuitively diagrammed for representing knowledge of critical relationships among economic, environmental, and social attributes. Examples relevant to coastal resiliency issues in the US Gulf Coast region are developed to illustrate model structures for developing qualitative influence diagrams useful for clarifying important policy intervention issues and enhancing transparency in decision making. Integr Environ Assess Manag 2018;14:381-394. Published 2018. This article is a US Government work and is in the public domain in the USA.

Carriger|John F|JF|
Dyson|Brian E|BE|
Benson|William H|WH|

D003247:Conservation of Natural Resources

Causality
Influence diagrams
Coastal resiliency
Evidence-based policy
Watershed conservation practices


Attentional avoidance of fearful facial expressions following early life stress is associated with impaired social functioning.

Abstract:
BACKGROUND
Early life stress is associated with poorer social functioning. Attentional biases in response to threat-related cues, linked to both early experience and psychopathology, may explain this association. To date, however, no study has examined attentional biases to fearful facial expressions as a function of early life stress or examined these biases as a potential mediator of the relation between early life stress and social problems.

METHODS
In a sample of 154 children (ages 9-13 years) we examined the associations among interpersonal early life stressors (i.e., birth through age 6 years), attentional biases to emotional facial expressions using a dot-probe task, and social functioning on the Child Behavior Checklist.

RESULTS
High levels of early life stress were associated with both greater levels of social problems and an attentional bias away from fearful facial expressions, even after accounting for stressors occurring in later childhood. No biases were found for happy or sad facial expressions as a function of early life stress. Finally, attentional biases to fearful faces mediated the association between early life stress and social problems.

CONCLUSIONS
Attentional avoidance of fearful facial expressions, evidenced by a bias away from these stimuli, may be a developmental response to early adversity and link the experience of early life stress to poorer social functioning.

Humphreys|Kathryn L|KL|
Kircanski|Katharina|K|
Colich|Natalie L|NL|
Gotlib|Ian H|IH|

Early life stress
social problems
attentional bias
fearful faces


Association of exposure to benzene and smoking with oxidative damage to nucleic acids by means of biological monitoring of general population volunteers.

Abstract: In this study, the validation of liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) isotopic dilution method for the determination of benzene and nicotine metabolites in urine was carried out. Limit of detection are 0.026 μg/L for S-phenylmercapturic acid (SPMA), 0.55 μg/L for t,t-muconic acid (t,t-MA), and 12.41 μg/L for the cotinine, and the relative combined uncertainty was also calculated. The study involves 446 healthy volunteer residents since at least 10 years in an area of central Italy. SPMA resulted to be strongly correlated with cotinine (p = 0.75), its concentration in smokers (93) being about ten times than in non/ex-smokers (197/156), while the t,t-MA of smokers is about twice the non/ex-smokers value. A cutoff value for the definition of smoker is set at 100 μg/g creat. Oxidative stress was studied in smokers and non- and ex-smokers by means of the determination of the biomarkers 8-Oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodGuo), 8-Oxo-7,8-dihydroguanosine (8-oxoGuo), and 8-Oxo-7,8-dihydroguanine (8-oxoGua): no significant differences were found between smokers and non/ex-smokers, but when subjects are classified according to the cotinine cutoff value, a correlation in smokers' urinary 8-oxodGuo is found with SPMA and cotinine (p = 0.60 and p = 0.57). Results were confirmed by chemometric analysis that also identified the experimental variables most contributing the discrimination as cotinine and t,t-MA.


The Shc protein Rai enhances T-cell survival under hypoxia.

Abstract: Hypoxia occurs in physiological and pathological conditions. T cells experience hypoxia in pathological and physiological conditions as well as in lymphoid organs. Indeed, hypoxia-inducible factor 1α (HIF-1α) affects T cell survival and functions. Rai, an Shc family protein member, exerts pro-survival effects in hypoxic neuroblastoma cells. Since Rai is also expressed in T cells, we here investigated its role in hypoxic T cells. In this work, hypoxia differently affected cell survival, proapoptotic, and metabolic programs in T cells, depending upon Rai expression. By using Jurkat cells stably expressing Rai and splenocytes from Rai-/- mice, we demonstrated that Rai promotes T cell survival and affects cell metabolism under hypoxia. Upon exposure to hypoxia, Jurkat T cells expressing Rai show (a) higher HIF-1α protein levels; (b) a decreased cell death and increased Akt/extracellular-signal-regulated kinase phosphorylation; (c) a decreased expression of proapoptotic markers, including caspase activities and poly(ADP-ribose) polymerase cleavage; (d) an increased glucose and lactate metabolism; (e) an increased activation of nuclear factor-kB pathway. The opposite effects were observed in hypoxic splenocytes from Rai-/- mice. Thus, Rai plays an important role in hypoxic signaling and may be relevant in the protection of T cells against hypoxia.

Criscuoli|Mattia|M|
Ulivieri|Cristina|C|
Filippi|Irene|I|
Monaci|Sara|S|
Guerrini|Giuditta|G|0000-0002-1446-0556
Crifò|Bianca|B|
De Tommaso|Domiziana|D|
Pelicci|Giuliana|G|
Baldari|Cosima T|CT|
Taylor|Cormac T|CT|
Carraro|Fabio|F|
Naldini|Antonella|A|0000-0002-9600-2486

D051795:Hypoxia-Inducible Factor 1, alpha Subunit

Shc protein
hypoxia
T cell
HIF-1α
cell survival


Combination Therapy for Neuropathic Pain: A Review of Recent Evidence.

Abstract: Pharmacological treatment is not very effective for neuropathic pain (NP). A progressive decrease in the estimated effect of NP drugs has been reported, giving rise to an increase in the use of the multimodal analgesic approach. We performed a new independent review to assess whether more and better-quality evidence has become available since the last systematic review. We evaluated the efficacy, tolerability, and safety of double-blinded randomized controlled trials involving only adult participants and comparing combination therapy (CT: ≥2 drugs) with a placebo and/or at least one other comparator with an NP indication. The primary outcome assessed was the proportion of participants reporting ≥50% pain reductions from baseline. The secondary outcome assessed was the proportion of drop-outs due to treatment-emergent adverse events. After removing duplicates, 2323 citations were screened, with 164 articles assessed for eligibility, from which 16 were included for qualitative analysis. From the latter, only five lasted for at least 12 weeks and only six complied with the required data for complete analysis. CT has been adopted for years without robust evidence. Efforts have been made to achieve better-quality evidence, but the quality has not improved over the years. In this regard, guidelines for NP should attempt to make recommendations about CT research, prioritizing which combinations to analyze.

combination therapy
neuropathic pain
randomized control trial
pharmacotherapy


Modeling U.S. monetary policy during the global financial crisis and lessons for Covid-19.

Abstract: The paper formulates the modeling of unconventional monetary policy and critically evaluates its effectiveness to address the Global Financial Crisis. We begin with certain principles guiding general scientific modeling and focus on Milton Friedman's 1968 Presidential Address that delineates the strengths and limitations of monetary policy to pursue certain goals. The modeling of monetary policy with its novelty of quantitative easing to target unusually high unemployment is evaluated by a Markov switching econometric model using monthly data for the period 2002-2015. We conclude by relating the lessons learned from unconventional monetary policy during the Global Financial Crisis to the recent bold initiatives of the Fed to mitigate the economic and financial impact of the Covid-19 pandemic on U.S. households and businesses.

Quantitative easing
Unemployment
10-Year treasury
Labor market
Modeling unconventional monetary policy
The Covid-19 pandemic and the Fed


Strigolactones Decrease Leaf Angle in Response to Nutrient Deficiencies in Rice.

Abstract: Strigolactones (SLs) are a class of plant hormones that are synthesized from β-carotene through sequential reactions catalyzed by DWARF (D) 27, D17, D10, and OsMORE AXILLARY GROWTH (MAX) 1 in rice (Oryza sativa L.). In rice, endogenous SL levels increase in response to deficiency of nitrogen, phosphate, or sulfate (-N, -P, or -S). Rice SL mutants show increased lamina joint (LJ) angle as well as dwarfism, delayed leaf senescence, and enhanced shoot branching. The LJ angle is an important trait that determines plant architecture. To evaluate the effect of endogenous SLs on LJ angle in rice, we measured LJ angle and analyzed the expression of SL-biosynthesis genes under macronutrient deficiencies. In the "Shiokari" background, LJ angle was significantly larger in SL mutants than in the wild-type (WT). In WT and SL-biosynthesis mutants, direct treatment with the SL synthetic analog GR24 decreased the LJ angle. In WT, deficiency of N, P, or S, but not of K, Ca, Mg, or Fe decreased LJ angle. In SL mutants, deficiency of N, P, or S had no such effect. We analyzed the time course of SL-related gene expression in the LJ of WT deficient in N, P, or S, and found that expression of SL-biosynthesis genes increased 2 or 3 days after the onset of deficiency. Expression levels of both the SL-biosynthesis and signaling genes was particularly strongly increased under -P. Rice cultivars "Nipponbare", "Norin 8", and "Kasalath" had larger LJ angle than "Shiokari", interestingly with no significant differences between WT and SL mutants. In "Nipponbare", endogenous SL levels increased and the LJ angle was decreased under -N and -P. These results indicate that SL levels increased in response to nutrient deficiencies, and that elevated endogenous SLs might negatively regulate leaf angle in rice.

Shindo|Masato|M| Yamamoto|Shu|S| Shimomura|Koichiro|K| Umehara|Mikihisa|M|

strigolactone
Oryza sativa
lamina joint
nitrogen deficiency
phosphate deficiency
sulfur deficiency


PI3K/SHIP2/PTEN pathway in cell polarity and hepatitis C virus pathogenesis.

Abstract: Hepatitis C virus (HCV) infects hepatocytes, polarized cells in the liver. Chronic HCV infection often leads to steatosis, fibrosis, cirrhosis and hepatocellular carcinoma, and it has been identified as the leading cause of liver transplantation worldwide. The HCV replication cycle is dependent on lipid metabolism and particularly an accumulation of lipid droplets in host cells. Phosphoinositides (PIs) are minor phospholipids enriched in different membranes and their levels are tightly regulated by specific PI kinases and phosphatases. PIs are implicated in a vast array of cellular responses that are central to morphogenesis, such as cytoskeletal changes, cytokinesis and the recruitment of downstream effectors to govern mechanisms involved in polarization and lumen formation. Important reviews of the literature identified phosphatidylinositol (PtdIns) 4-kinases, and their lipid products PtdIns(4)P, as critical regulators of the HCV life cycle. SH2-containing inositol polyphosphate 5-phosphatase (SHIP2), phosphoinositide 3-kinase (PI3K) and their lipid products PtdIns(3,4)P2 and PtdIns(3,4,5)P3, respectively, play an important role in the cell membrane and are key to the establishment of apicobasal polarity and lumen formation. In this review, we will focus on these new functions of PI3K and SHIP2, and their deregulation by HCV, causing a disruption of apicobasal polarity, actin organization and extracellular matrix assembly. Finally we will highlight the involvement of this pathway in the event of insulin resistance and nonalcoholic fatty liver disease related to HCV infection.


Direct heart shunt placement for CSF diversion: technical note.

Abstract: The authors report a complex case of an 18-year-old male with a history of hydrocephalus secondary to intraventricular hemorrhage of prematurity, with more than 30 previous shunt revisions, who presented to the authors' institution with shunt malfunction. After exhausting his peritoneal cavity and pleural space as possible distal sites of shunt placement, he underwent a direct heart shunt placement when it was discovered he had thrombosis of his subclavian vein precluding a standard wire-guided atrial cannulation. His course was complicated by postoperative distal catheter migration and repeat surgery for reimplantation of the shunt directly into the atrium. At the 16-month follow-up visit, the patient showed no symptoms of shunt malfunction or pericardial effusion. Imaging studies demonstrated a functioning shunt system. This is the second reported successful ventricle to direct heart shunt placement in an adult. The authors report on the technical aspects of the case and review the relevant literature.

Moses|Ziev B|ZB|
Ozpinar|Alp|A|
Abd-El-Barr|Muhammad M|MM|
Quinonez|Luis G|LG|
Emani|Sitaram M|SM|
Goumnerova|Liliana C|LC|

VATS = video-assisted thoracoscopic surgery


Colorimetric detection of bisphenol A based on unmodified aptamer and cationic polymer aggregated gold nanoparticles.

Abstract: In this study, a colorimetric method was exploited to detect bisphenol A (BPA) based on BPA-specific aptamer and cationic polymer-induced aggregation of gold nanoparticles (AuNPs). The principle of this assay is very classical. The aggregation of AuNPs was induced by the concentration of cationic polymer, which is controlled by specific recognition of aptamer with BPA and the reaction of aptamer and cationic polymer forming "duplex" structure. This method enables colorimetric detection of BPA with selectivity and a detection limit of 1.50 nM. In addition, this colorimetric method was successfully used to determine spiked BPA in tap water and river water samples.

Zhang|Dongwei|D| Yang|Jiayi|J| Ye|Jing|J| Xu|Lurong|L| Xu|Hanchu|H| Zhan|Shenshan|S| Xia|Bing|B| Wang|Lumei|L|

Bisphenol A
Cationic polymer
Gold nanoparticles
Biosensor
Colorimetry


Affective Disorders with Psychosis in Youth: An Update.

Abstract: Mood disorders, including major depression and mania, can present with psychotic features. In youth psychotic-like phenomena such as "seeing faces in the dark" or "hearing noises" are fairly common. Rates of lifetime psychotic symptoms are much higher than rates of psychosis during a "current" episode of mania or depression in youth. Psychotic phenomena can be mood congruent or incongruent. A detailed mental status examination and clinical history include questioning to ensure the informants understand the questions being asked. There are interviews that structure how questions are asked, and rating scales that help anchor severity and quality of the mood episode.

Psychosis
Depression
Mania
Bipolar
Mood congruent/incongruent


Video-based training to improve perceptual-cognitive decision-making performance of Australian football umpires.

Abstract: Decision-making is a central component of the in-game performance of Australian football umpires; however, current umpire training focuses largely on physiological development with decision-making skills development conducted via explicit lecture-style meetings with limited practice devoted to making actual decisions. Therefore, this study investigated the efficacy of a video-based training programme, aimed to provide a greater amount of contextualised visual experiences without explicit instruction, to improve decision-making skills of umpires. Australian football umpires (n = 52) were recruited from metropolitan and regional Division 1 competitions. Participants were randomly assigned to an intervention or control group and classified according to previous umpire game experience (i.e., experienced; less experienced). The intervention group completed a 12-week video-based decision-making training programme, with decision-making performance assessed at pre-training, and 1-week retention and 3-week retention periods. The control group did not complete any video-based training. Results indicated a significant Group (intervention; Control) × Test interaction (F(1, 100) = 3.98; P = 0.02, partial ῆ2 = 0.074), with follow-up pairwise comparisons indicating significant within-group differences over time for the intervention group. In addition, decision-making performance of the less experienced umpires in the intervention group significantly improved (F(2, 40) = 5.03, P = 0.01, partial ῆ2 = 0.201). Thus, video-based training programmes may be a viable adjunct to current training programmes to hasten decision-making development, especially for less experienced umpires.

Cognition
game officials
observation
perception
referees


How Telemedicine and Centralized Care Changed the Natural History of Retinoblastoma in a Developing Country: Analysis of 478 Patients.

Abstract:
PURPOSE
To evaluate the efficacy of integrating a telemedicine-based twinning partnership and centralized care for retinoblastoma on survival and eye salvage.

DESIGN
Four hundred seventy-eight retinoblastoma patients treated at a tertiary referral cancer center (King Hussein Cancer Centre [KHCC]) from 2003 through 2019.

PARTICIPANTS
Four hundred seventy-eight retinoblastoma patients treated at KHCC after implementing a telemedicine-based program with St. Jude Children's Research Hospital.

METHODS
We reviewed the outcomes of retinoblastoma patients who were treated at KHCC after implementing a telemedicine-based eye salvage program with St. Jude Children's Research Hospital, and we compared that with outcomes for retinoblastoma patients who were treated before implementing a telemedicine-based retinoblastoma service at KHCC.

MAIN OUTCOME MEASURES
We analyzed patient demographics, clinical characteristics, treatments received, consultation type and duration, and long-term patient outcomes before and after implementing the twinning program.

RESULTS
Over 17 years, 813 eyes from 478 children with retinoblastoma were treated at KHCC. Three hundred thirty-five patients (70%) had bilateral disease. Six patients (4%) with unilateral disease and 66 patients (20%) with bilateral disease had a family history of retinoblastoma. After the twinning program was established in 2003, the mortality rate decreased from 38% to 5% (P < 0.0001), and the overall eye salvage rate increased from 4% to 61% (98% for group A, 93% for group B, 81% for group C, and 48% for group D; P < 0.0001). Initially, all cases were discussed via telemedicine, but as knowledge transfer increased, the proportion of cases that required discussion decreased to less than 3% 10 years later. Similarly, treatment changes based on consultations decreased from 70% to 7% after 10 years. Both survival and eye-salvage rates were comparable at the early and later stages of implementing the twinning program. At a median follow-up of 120 months, 5% of patients had died of metastases or secondary neoplasms, 81% were alive, and 14% were lost to follow-up.

CONCLUSIONS
Centralization of care at a single center in developing countries can achieve patient outcomes comparable with those of developed countries via twinning and telemedicine. This benefit can extend to a large region because two thirds of patients treated at KHCC were non-Jordanians.

Yousef|Yacoub A|YA|
Al-Nawaiseh|Ibrahim|I|
Mehyar|Mustafa|M|
Sultan|Iyad|I|
Al-Hussaini|Maysa|M|
Jaradat|Imad|I|
Mohammad|Mona|M|
AlJabari|Reem|R|
Abu-Yaghi|Nakhleh|N|
Rodriguez-Galindo|Carlos|C|
Qaddoumi|Ibrahim|I|
Wilson|Matthew|M|


The Persistence of Self-injurious and Aggressive Behavior in Males with Fragile X Syndrome Over 8 Years: A Longitudinal Study of Prevalence and Predictive Risk Markers.

Abstract: Self-injurious and aggressive behaviors are common in fragile X syndrome (FXS). However, little is known about the persistence of these behaviors and associated risk markers. We established the prevalence and persistence of self-injurious and aggressive behaviors over eight years in males with FXS, and associations with risk markers. Results showed 77% and 69% persistence rates for self-injurious and aggressive behavior, respectively. Baseline levels of repetitive behavior predicted persistent self-injurious behavior. Chronological age, impulsivity and overactivity were associated with persistent aggressive behavior but only impulsivity predicted persistence. This is the first study to document the persistence of self-injurious and aggressive behavior in FXS over the medium to long term and to identify behavioral risk markers that might facilitate targeted early intervention.

Crawford|Hayley|H| Karakatsani|Efthalia|E| Singla|Gursharan|G| Oliver|Chris|C|

Aggression
Fragile X syndrome
Risk markers
Repetitive behavior
Self-injurious behavior
Impulsivity
Early intervention
Autism
Challenging behavior


A case report of adult cerebellar high-grade glioma with H3.1 K27M mutation: a rare example of an H3 K27M mutant cerebellar tumor.

Abstract: Diffuse midline glioma, H3 K27M mutant, is newly recognized as a distinct category, which usually arises in the brain stem, thalamus or spinal cord of children, and young adults. The oncogenic H3 K27M mutation involves H3.3 (encoded by H3F3A) or H3.1 (encoded by HIST1H3B/HIST1H3C), and the incidence of each mutation differs among the primary sites. Recently, several papers have reported that cerebellar high-grade gliomas in both children and adults also harbor H3 K27 mutation. With the exception of one pediatric case, all of the cases carried the mutation in H3.3. We herein present the case of an adult cerebellar high-grade astrocytic tumor with H3.1 K27M mutation in a 45-year-old man, which also involvedTP53 mutation and was immunonegative for ATRX. Some groups have reported that H3.3 and H3.1 K27M mutations define subgroups of diffuse intrinsic pontine gliomas (DIPGs) with different phenotypes as well as genetic alterations. On comparing the findings of the present case, particularly TP53 mutation status and ATRX expression, to the findings of the previous studies on DIPGs, our case seems unusual among the H3.1 K27M mutant subgroup. Further studies are needed to clarify the exact frequency, clinicopathological characteristics, and genomic alterations of cerebellar gliomas harboring H3 K27M mutation.


Bicruciate-retaining total knee arthroplasty reproduces in vivo kinematics of normal knees to a lower extent than unicompartmental knee arthroplasty.

Abstract:
PURPOSE
This study aimed to clarify the natural knee kinematics provided by bicruciate-retaining total knee arthroplasty (BCR-TKA) compared with those of unicompartmental knee arthroplasty (UKA) and normal knees.

METHODS
Volunteers and patients who had undergone UKA and BCR-TKA with anatomical articular surface performed squatting motion under fluoroscopy. To estimate the knee's spatial position and orientation, a two-dimensional/three-dimensional registration technique was used. The rotation angle and anteroposterior translation of the medial and lateral sides of the femur relative to the tibia in each flexion angle were directly evaluated using the same local coordinate system and their differences amongst the three groups were analysed using two-way analysis of variance and Bonferroni post hoc pairwise comparison.

RESULTS
From 0° to 10° of flexion, the femoral external rotation angle of BCR-TKA knees was significantly greater than that of normal and UKA knees and the medial side of BCR-TKA knees was significantly more anteriorly located than that of normal and UKA knees. From 40° to 50° of flexion, the medial side of UKA knees was significantly more posteriorly located than that of normal and BCR-TKA knees. From 30° to 120° of flexion, the lateral side of BCR-TKA knees was significantly more anteriorly located than that of normal and UKA knees.

CONCLUSION
The in vivo kinematics of BCR-TKA knees reproduces those of normal knees to a lower extent than those of UKA knees. Thus, BCR-TKA with anatomical articular surface reproduces in vivo kinematics of normal knees to a lower extent than UKA.

LEVEL OF EVIDENCE
III.


A novel germline BRCA2 mutation in a Chinese patient with prostate cancer sensitive to platinum chemotherapy: a case report.

Abstract:
BACKGROUND
Germline BRCA2 mutation is associated with an aggressive prostate cancer phenotype and indicates higher risk for hereditary cancer. Recently, numerous studies have attempted to identify the genomic landscape of prostate cancer to better understand the genomic drivers of this disease and look for the molecular targets to guide treatment selection.

CASE PRESENTATION
We report a 67-year-old patient diagnosed with prostate cancer who experienced rapid disease progression after androgen deprivation therapy and subsequent docetaxel treatment. The patient had a strong family history of malignancy as his mother was diagnosed with breast cancer and his father was died of lung cancer. Next generation sequencing demonstrated a novel pathogenic germline BRCA2 mutation (p.Gly2181Glufs*10) in the patient. His mother with breast cancer and his son were found to have the same BRCA2 mutation. The patient experienced impressive and durable responses to carboplatin treatment.

CONCLUSIONS
This case demonstrated that the carboplatin could have a dramatic antitumor effect on patients with prostate cancer with germline BRCA2 mutations and family history will help to ensure that patients and their families can be provided with proper genetic counseling.

Jiang|Lijuan|L| Bai|Zunguang|Z| Zhu|Shoulun|S| Zhao|Tingting|T| Yang|Yining|Y| Li|Zhiyong|Z| Chen|Dong|D| Wu|Zhiming|Z| Wang|Yanjun|Y| Zhou|Fangjian|F| Li|Yonghong|Y|

BRCA2
Prostate cancer
Platinum chemotherapy
Family history


The NADPH oxidase NOX4 inhibits hepatocyte proliferation and liver cancer progression.

Abstract: The NADPH oxidase NOX4 has emerged as an important source of reactive oxygen species in signal transduction, playing roles in physiological and pathological processes. NOX4 mediates transforming growth factor-β-induced intracellular signals that provoke liver fibrosis, and preclinical assays have suggested NOX4 inhibitors as useful tools to ameliorate this process. However, the potential consequences of sustained treatment of liver cells with NOX4 inhibitors are yet unknown. The aim of this work was to analyze whether NOX4 plays a role in regulating liver cell growth either under physiological conditions or during tumorigenesis. In vitro assays proved that stable knockdown of NOX4 expression in human liver tumor cells increased cell proliferation, which correlated with a higher percentage of cells in S/G2/M phases of the cell cycle, downregulation of p21(CIP1/WAF1), increase in cyclin D1 protein levels, and nuclear localization of β-catenin. Silencing of NOX4 in untransformed human and mouse hepatocytes also increased their in vitro proliferative capacity. In vivo analysis in mice revealed that NOX4 expression was downregulated under physiological proliferative situations of the liver, such as regeneration after partial hepatectomy, as well as during pathological proliferative conditions, such as diethylnitrosamine-induced hepatocarcinogenesis. Xenograft experiments in athymic mice indicated that NOX4 silencing conferred an advantage to human hepatocarcinoma cells, resulting in earlier onset of tumor formation and increase in tumor size. Interestingly, immunochemical analyses of NOX4 expression in human liver tumor cell lines and tissues revealed decreased NOX4 protein levels in liver tumorigenesis. Overall, results described here strongly suggest that NOX4 would play a growth-inhibitory role in liver cells.

Crosas-Molist|Eva|E| Bertran|Esther|E| Sancho|Patricia|P| López-Luque|Judit|J| Fernando|Joan|J| Sánchez|Aránzazu|A| Fernández|Margarita|M| Navarro|Estanis|E| Fabregat|Isabel|I|

D015972:Gene Expression Regulation, Neoplastic

NADPH oxidase
NOX4
Hepatocyte proliferation
Liver cancer
Reactive oxygen species
Hepatocarcinogenesis
Free radicals
Hepatocellular carcinoma
Liver regeneration


Evaluations of Lifestyle, Dietary, and Pharmacologic Treatments for Pediatric Nonalcoholic Fatty Liver Disease: A Systematic Review.

Abstract:
BACKGROUND & AIMS
There are no approved treatments for pediatric nonalcoholic fatty liver disease (NAFLD) and there is a lack of consensus on the best outcome measure for randomized controlled trials. We performed a systematic review of treatments tested for pediatric NAFLD, the degree of heterogeneity in trial design, and endpoints analyzed in these studies.

METHODS
We searched publication databases and clinical trial registries through January 7, 2018 for randomized controlled trials (published and underway) of children (<18 years) with NAFLD. We assessed improvements in histologic features, radiologic and biochemical markers of reduced fibrosis, metabolic syndrome parameters, and adverse events. The quality of the trials was assessed using a modified version of the Cochrane risk of bias tool.

RESULTS
Our final analysis included 21 randomized controlled trials, comprising 1307 participants (mean age, 12.6 years; 63% male; mean duration of intervention, 8 months). Most studies evaluated weight loss with lifestyle intervention (n=8), oral polyunsaturated fatty acid treatment (PUFAs, n=6), or oral antioxidant treatment (n=7). Biomarkers of NAFLD decreased with weight loss, but most studies did not include histologic data. Trials of antioxidants were heterogeneous; some reported reduced histologic features of steatohepatitis with no effect on triglycerides or insulin resistance. PUFAs and probiotics reduced radiologic markers of steatosis, insulin resistance, and levels of triglycerides. Only 38% of the trials had biopsy-proven NAFLD as an inclusion criterion. There was heterogeneity in trial primary endpoints; 10 studies (48%) used levels of aminotransferases or ultrasonography findings as a primary endpoint and only 3 trials (14%) used histologic features as the primary endpoint. We identified 13 randomized controlled trials that are underway in children with NAFLD. None of the protocols include collection of liver biopsies; 9 trials (69%) will use magnetic resonance imaging quantification of steatosis as a primary outcome.

CONCLUSIONS
In a systematic review of published and active randomized controlled trials of children with NAFLD, we found a large amount of heterogeneity in study endpoints and inclusion criteria. Few trials included histologic analyses. Antioxidants appear to reduce some features of steatohepatitis. Effects of treatment with lifestyle modification, PUFAs, or probiotics have not been validated with histologic analysis. Trials that are underway quantify steatosis magnetic resonance imaging-outcomes are anticipated.

Mann|Jake Peter|JP|
Tang|George Yizhou|GY|
Nobili|Valerio|V|
Armstrong|Matthew James|MJ|

D065626:Non-alcoholic Fatty Liver Disease

Clinical Trial Design
MRI
NASH
Progression
Response


Mixed-Methods Study on Caregiver Strain, Quality of Life, and Perceived Health.

Abstract:
BACKGROUND
Caring for someone with dementia is associated with negative and positive experiences. There is little evidence based on large datasets.

OBJECTIVE
To present data around the experience of caring for someone with dementia, to identify support (emotional and practical) needs, and inform future service provision.

METHODS
A mixed-methods study embedded in the Promoting Activity, Independence and Stability in Early Dementia (PrAISED) Randomized Controlled Trial. We administered questionnaires on strain, quality of life (QoL), and perceived health to 301 caregivers and assessment of cognitive performance, depression, anxiety, and disability in activities of daily living to 301 participants with dementia. Data were analyzed through descriptive and modelling statistics. A subsample of 20 patient-caregiver dyads were qualitatively interviewed. Data around caregivers' experience of providing care were extrapolated and analyzed through inductive thematic analysis.

RESULTS
There were significant negative associations between caregiver strain and QoL (p < 0.01) and between caregiver age and QoL (p < 0.01), and significant positive associations between caregiver strain and disability (p < 0.01), cognitive impairment (p < 0.01), depression (p < 0.05), and anxiety of the person with dementia (p < 0.05). Older caregivers reported a lack of support, reinforced by their reluctance to seek help. All caregivers reported contradictory emotions associated with caring and accumulation of strain over time.

CONCLUSION
While there is recognition that it is essential to support caregivers, dedicated intervention programs, and support strategies to respond to the needs of older caregivers are still needed.

Di Lorito|Claudio|C|
Bosco|Alessandro|A|
Godfrey|Maureen|M|
Dunlop|Marianne|M|
Lock|Juliette|J|
Pollock|Kristian|K|
Harwood|Rowan H|RH|
van der Wardt|Veronika|V|

Caregiver
quality of life
dementia
randomized controlled trial
caregiver exhaustion


Effects of glargine insulin on glycemic control in patients with diabetes mellitus type II undergoing off-pump coronary artery bypass graft.

Abstract:
Background
The prevalence of diabetes mellitus in patients requiring coronary artery bypass grafting (CABG) is noticeably high (20%-30%). These patients have inferior perioperative outcome, reduced long-term survival, and high risk of recurrent episodes of angina. To improve perioperative outcome surgical unit defined satisfactory glycemic control is desired during this period. Hence, the aim of our study is to compare the efficacy of glargine insulin combination with continuous human insulin infusion for perioperative glycemic control in patients with diabetes undergoing CABG.

Materials and Methods
Fifty Patients, who were posted for off-pump CABG with diabetes mellitus type II, were randomized in two group, Group I normal saline + human insulin infusion during the perioperative period, Group II (glargine group): Glargine + human insulin infusion during perioperative period.

Results
During surgery and in the postoperative period, random blood sugar and human insulin requirement are significantly higher in control group than glargine group. Other infection, step-up antibiotics, intensive care unit (ICU) stay, and hospital stay were significantly higher in control groups in postoperative period.

Conclusion
Our study results suggest that glargine effectively manages blood glucose level with significantly greater control over postoperative morbidity.

Gandhi|Hemang|H| Sarvaia|Alpesh|A| Malhotra|Amber|A| Acharya|Himanshu|H| Shah|Komal|K| Rajavat|Jeevraj|J|

D047549:Coronary Artery Bypass, Off-Pump

off-pump coronary artery bypass grafting


Factors influencing the use by radiation therapists of cancer symptom guides: a mixed-methods study.

Abstract:
Background
Radiation therapists play an important role in helping patients to safely manage and triage potentially life-threatening symptoms. The purpose of the present study was to assess factors influencing the use by radiation therapists of evidence-informed symptom practice guides for patients experiencing cancer treatment-related symptoms.

Methods
In a mixed-methods descriptive study guided by the Knowledge-to-Action framework, interviews and a barriers survey were conducted. Two independent reviewers conducted a content analysis of interview transcripts. Barriers survey data were analyzed using frequency distributions and univariate descriptive statistics. Open-ended data from the surveys underwent content analysis and were triangulated with interview findings.

Results
Of 90 radiation therapists approached, 58 completed the survey (64%), and 14 were interviewed. Of the 98% who reported providing symptom management to patients undergoing radiation treatment, 53% used evidence-informed practice guidelines. Radiation therapists had moderate moral norms (4.6 of 7) and beliefs about the consequences of using costars (pan-Canadian Oncology Symptom Triage and Remote Support) practice guides (4.8), but neutral intention (3.4) and beliefs about their own capabilities (3.9). Environmental barriers included lack of time (2.0), lack of access (2.5), and neutral organizational support (3.0). Radiation therapists identified a need for training (5.5). Common unique barriers to practice guide use were lack of time during radiation treatments, unclear fit with scope of practice, disparate focus on site-specific symptoms, and lack of medication knowledge.

Conclusions
The symptom practice guides were perceived by the radiation therapists to benefit patients, enhance their own knowledge of symptom management, and promote consistent practice. Additional work is required to identify the scope of practice of radiation therapists within the interprofessional team.

Ludwig|C|C| Renaud|J|J| Barbera|L|L| Carley|M|M| Henry|C|C| Jolicoeur|L|L| Kuziemsky|C|C| Patry|A|A| Stacey|D|D|

radiation therapists
Symptom management
clinical practice guidelines
radiographers


High-Energy (>10 MeV) Oxygen and Sulfur Ions Observed at Jupiter From Pulse Width Measurements of the JEDI Sensors.

Abstract: The Jovian polar regions produce X-rays that are characteristic of very energetic oxygen and sulfur that become highly charged on precipitating into Jupiter's upper atmosphere. Juno has traversed the polar regions above where these energetic ions are expected to be precipitating revealing a complex composition and energy structure. Energetic ions are likely to drive the characteristic X-rays observed at Jupiter (Haggerty et al., 2017, https://doi.org/10.1002/2017GL072866; Houston et al., 2018, https://doi.org/10.1002/2017JA024872; Kharchenko et al., 2006, https://doi.org/10.1029/2006GL026039). Motivated by the science of X-ray generation, we describe here Juno Jupiter Energetic Particle Detector Instrument (JEDI) measurements of ions above 1 MeV and demonstrate the capability of measuring oxygen and sulfur ions with energies up to 100 MeV. We detail the process of retrieving ion fluxes from pulse width data on instruments like JEDI (called "puck's"; Clark, Cohen, et al., 2016, https://doi.org/10.1002/2017GL074366; Clark, Mauk, et al., 2016, https://doi.org/10.1002/2015JA022257; Mauk et al., 2013, https://doi.org/10.1007/s11214-013-0025-3) as well as details on retrieving very energetic particles (>20 MeV) above which the pulse width also saturates.

Jupiter
Juno
energetic particles
Io
X‐ray
aurora


Venovenous extracorporeal membrane oxygenation for acute respiratory distress syndrome due to an acute type B aortic dissection: a case report.

Abstract: Acute type B aortic dissection is sometimes complicated by acute respiratory failure requiring mechanical ventilation. Herein, we describe our experience in a rare acute type B aortic dissection-associated respiratory failure case culminating in acute respiratory distress syndrome. The patient was a 45-year-old man admitted with a complaint of sudden chest pain radiating to his back. On computed tomography, an acute type B aortic dissection was diagnosed. He had no dyspnea on admission, but his respiratory function subsequently deteriorated, and severe acute respiratory distress syndrome was diagnosed on Day 4. Venovenous extracorporeal membrane oxygenation with anticoagulation plus continuous renal replacement therapy for oliguria improved the oxygenation, and the patient was weaned from the extracorporeal membrane oxygenation on Day 8. This patient fully recovered without worsening the aortic dissection, using venovenous extracorporeal membrane oxygenation with anticoagulation plus a continuous renal replacement therapy.


Determination of non-neuronal acetylcholine in human peripheral blood mononuclear cells by use of hydrophilic interaction ultra-performance liquid chromatography-tandem mass spectrometry.

Abstract:
BACKGROUND
Cholinergic components in non-neuronal tissues and cells are proposed as important in maintaining cellular proliferation and immune homeostasis. However, direct quantification of non-neuronal acetylcholine (ACh) in cells has been inefficient. Therefore, we developed a stable method for determination of intracellular ACh.

METHODS
We used ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) with Waters CORTECS chromatographic columns to measure the intracellular ACh in human peripheral blood mononuclear cells (PBMCs). The presence of ACh was validated by RT-qPCR of mRNAs of cholinergic components.

RESULTS
This method successfully separated ACh from iso-ACh with highly sensitive precursor/product ion transitions and allowed a faster chromatography run time within 3.5min. The detection limit of intracellular ACh was 0.005ng/10(6) PBMCs. Intra-assay and inter-assay coefficient variations were all <7.0%. Mean recoveries in the samples were between 93.20% and 104.73%. Here, intracellular ACh was stable under multiple storage conditions, partly attributable to mutually stable relationships among cholinergic components. This method was successfully applied in a stroke study and revealed activation of the stroke-induced cholinergic anti-inflammatory pathway.

CONCLUSIONS
This method allows direct determination of intracellular ACh in various tissues. Evidences of cholinergic activity linking both the nervous system and non-neuronal system can be profiled by assessing ACh.

Zhang|Chao|C| Xia|Yiping|Y| Jiang|Wei|W| Wang|Chunyang|C| Han|Bin|B| Hao|Junwei|J|

D057927:Hydrophobic and Hydrophilic Interactions

Acetylcholine
Stroke
Immune cells
Inflammation