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Background: Unretrievable foreign bodies are associated with high morbidity and mortality. While the majority of reported cases involve the venous circulation, intra-arterial foreign body displacement have the potential to migrate more distally with a higher risk for dissection and hemorrhagic complications during retrieval. As the number of intravascular procedures continues to increase, there is also likely to be a concomittant increase in the number of retrieval procedures, particular for fractured catheters and sheaths. Although snaring is frequently the traditional, 'go-to' method for retrieval, there are inherent risks of further dislodgement or fracture., Case Report: We describe a case that involves retrieval of a fractured sheath that originated in the common femoral artery but migrated into the popliteal artery. Different retrieval approaches were employed, however ultimately balloon assisted, over-the-wire retrieval was the successful approach., Conclusions: We anticipate that over-the-wire, inline-retrieval approaches will continue to grow in popularity and use, particularly with respect to manipulation within the arterial circulation.

Understanding the mechanisms for cellular aging is a fundamental question in biology. Normal red blood cells (RBCs) survive for approximately 100 days, and their survival is likely limited by functional decline secondary to cumulative damage to cell constituents, which may be reflected in altered metabolic capabilities. To investigate metabolic changes during in vivo RBC aging, labeled cell populations were purified at intervals and assessed for abundance of metabolic intermediates using mass spectrometry. A total of 167 metabolites were profiled and quantified from cell populations of defined ages. Older RBCs maintained ATP and redox charge states at the cost of altered activity of enzymatic pathways. Time-dependent changes were identified in metabolites related to maintenance of the redox state and membrane structure. These findings illuminate the differential metabolic pathway usage associated with normal cellular aging and identify potential biomarkers to determine average RBC age and rates of RBC turnover from a single blood sample., Competing Interests: The authors declare no competing interests., (© 2020 The Author(s).)

Prostate cancer is a major cause of death among men worldwide. Recent preclinical evidence implicates cannabinoids as powerful regulators of cell growth and differentiation, as well as potential anti-cancer agents. The aim of this review was to evaluate the effect of cannabinoids on in vivo prostate cancer models. The databases searched included PubMed, Embase, Scopus, and Web of Science from inception to August 2020. Articles reporting on the effect of cannabinoids on prostate cancer were deemed eligible. We identified six studies that were all found to be based on in vivo/xenograft animal models. Results: In PC3 and DU145 xenografts, WIN55,212-2 reduced cell proliferation in a dose-dependent manner. Furthermore, in LNCaP xenografts, WIN55,212-2 reduced cell proliferation by 66-69%. PM49, which is a synthetic cannabinoid quinone, was also found to result in a significant inhibition of tumor growth of up to 90% in xenograft models of LNCaP and 40% in xenograft models of PC3 cells, respectively. All studies have reported that the treatment of prostate cancers in in vivo/xenograft models with various cannabinoids decreased the size of the tumor, the outcomes of which depended on the dose and length of treatment. Within the limitation of these identified studies, cannabinoids were shown to reduce the size of prostate cancer tumors in animal models. However, further well-designed and controlled animal studies are warranted to confirm these findings.

Melanoma is the fourth most common type of cancer diagnosed in Australians after breast, prostate, and colorectal cancers. While there has been substantial progress in the treatment of cancer in general, malignant melanoma, in particular, is resistant to existing medical therapies requiring an urgent need to develop effective treatments with lesser side effects. Several studies have shown that "cannabinoids", the major compounds of the Cannabis sativa L. plant, can reduce cell proliferation and induce apoptosis in melanoma cells. Despite prohibited use of Cannabis in most parts of the world, in recent years there have been renewed interests in exploiting the beneficial health effects of the Cannabis plant-derived compounds. Therefore, the aim of this study was in the first instance to review the evidence from in vivo studies on the effects of cannabinoids on melanoma. Systematic searches were carried out in PubMed, Embase, Scopus, and ProQuest Central databases for relevant articles published from inception. From a total of 622 potential studies, six in vivo studies assessing the use of cannabinoids for treatment of melanoma were deemed eligible for the final analysis. The findings revealed cannabinoids, individually or combined, reduced tumor growth and promoted apoptosis and autophagy in melanoma cells. Further preclinical and animal studies are required to determine the underlying mechanisms of cannabinoids-mediated inhibition of cancer-signaling pathways. Well-structured, randomized clinical studies on cannabinoid use in melanoma patients would also be required prior to cannabinoids becoming a viable and recognized therapeutic option for melanoma treatment in patients.

Introduction: Dabigatran, a direct thrombin inhibitor, is 80% renally eliminated and demonstrates multi-compartmental pharmacokinetics. Idarucizumab is a monoclonal antibody that reverses dabigatran-induced anticoagulation and displays single compartment pharmacokinetics, with a smaller volume of distribution and shorter elimination half-life than dabigatran. These differences in pharmacokinetics mean that redistribution of dabigatran from peripheral compartments can occur after idarucizumab has been eliminated, resulting in rebound in the dabigatran plasma concentration and treatment failure. Clinical experience notes failure of a single idarucizumab 5 g dose to fully reverse coagulopathy in certain patients. Aims: To identify factors predisposing to an incomplete response to the standard idarucizumab 5 g dose. Methods: A systematic literature search in PubMed using terms "dabigatran" and "idarucizumab" covering 2015 to October 2019 identified 387 entries. Titles and abstracts were screened initially, followed by full text review and data extraction from 97 eligible articles. Data extracted included clinical information, dabigatran concentrations, coagulation results, idarucizumab dosage and patient outcomes. Pharmacokinetic simulations were conducted using a two-compartment model to predict the likelihood that acute or chronic kidney disease will contribute to an incomplete reversal of dabigatran-induced anticoagulation. Results: Of 240 published cases receiving idarucizumab, 33 reported dabigatran concentration rebound, within a median time of 22 h. From 231 cases reporting idarucizumab dose, 10 received repeated administration due to a rebound in dabigatran concentrations. Baseline dabigatran concentrations >228 ng/mL were more likely to experience a rebound post-idarucizumab to >30 ng/mL (detectable). For baseline dabigatran >488 ng/mL, the concentration rebounded to >75 ng/mL (therapeutic). The impact of kidney dysfunction on the effect of the recommended dose of idarucizumab: Idarucizumab is expected to neutralise a maximum plasma dabigatran concentration of 980 ng/mL, but most likely a lesser amount. Pharmacokinetic modelling suggests, for patients taking dabigatran 150 mg twice daily, an incomplete response to 5 g idarucizumab is predicted after approximately 72 h dosing when GFR less than 30 mL/min (25% of normal), and after 36 h with severely impaired renal function (GFR 6 mL/min; GFR 5% of normal). Acute dabigatran self-poisoning: Idarucizumab has neutralised dabigatran following deliberate self-poisoning with dabigatran in a limited number of cases, even in the absence of bleeding. There are insufficient data regarding the use of idarucizumab as part of standard supportive care in this context. Clinical use of idarucizumab in complex circumstances: The dilute thrombin time can be used to determine the dabigatran concentration, but other more standard coagulation assays are less precise. A normal aPTT largely excludes dabigatran. We suggest performing coagulation assays and dabigatran concentrations every 6 h for a minimum of 36 h after idarucizumab administration to detect a rebound in dabigatran. This is particularly necessary in patients with glomerular filtration rate <30 mL/min or those with a plasma dabigatran concentration exceeding approximately 500 ng/mL. If a rebound in dabigatran is noted, then repeat administration of idarucizumab 5 g can be considered for reversal of recurrent coagulopathy if clinically indicated. Conclusion: The use of idarucizumab for reversal of dabigatran is complex and requires consideration of clinical circumstances and laboratory investigations. Monitoring post-idarucizumab may be required in acute or chronic kidney disease to detect a rebound in dabigatran concentration and the need for additional doses of idarucizumab.

Background: During drilling of bone, which is common in clinical surgeries, heat generation increases local temperature in the drilling site. Transmission of excessive heat to the surrounding bone tissue can cause thermal osteonecrosis. Consequently, it may lead to failure of implants and fixation screws or delay in healing process. Using cooling is a method for limiting temperature elevation., Materials and Methods: In this study, through comparing three conditions of drilling without cooling, external cooling with normal saline, and external cooling with OpSite spray, the efficiency of OpSite as coolant is studied. In this regard, 2 drill bit diameters, 3 drilling speeds, and 3 drilling feed-rates are considered as drilling variables in the experiments., Results: For the whole experiments, while cooling with normal saline resulted in lower maximum temperatures than without cooling condition, OpSite had even better results and limited the temperature elevation during drilling of bone efficiently., Conclusion: OpSite spray, which has lower infection risks than normal saline on one hand and lower maximum temperature rise with all combinations of drilling parameters on the other hand, can be considered in clinical surgeries for cooling applications.

Objectives: Tracheostomy is a very common clinical intervention in critically ill adult patients. The indications for tracheostomy procedures in pediatric patients with complex conditions have increased dramatically in recent years, but there are currently no guidelines on the optimal timing of tracheostomy in pediatric patients undergoing prolonged ventilation., Data Sources: We performed a systematic search of the existing literature in MEDLINE via PubMed and Embase databases and the Cochrane Library to identify clinical trials, observational studies, and cohort studies that compare early and late tracheostomy in children. The date of the last search was August 27, 2018. Included articles were subjected to manual searching., Study Selection: Studies in mechanically ventilated children that compared early with late tracheostomy were included., Data Extraction: Data were extracted into a spreadsheet and copied into Review Manager 5.3 (The Cochrane Collaboration, Copenhagen, Denmark)., Data Synthesis: Data were meta-analyzed using an inverse variance, random effects model. Continuous outcomes were calculated as mean differences with 95% CIs, and dichotomous outcomes were calculated as Mantel-Haenszel risk ratios with 95% CIs. We included eight studies (10 study arms). These studies were all retrospective cohort studies. Early tracheostomy was associated with significant reductions in mortality, days on mechanical ventilation, and length of intensive care and total hospital stay, although the lack of randomized, controlled trials limits the validity of these findings. Although variance was imputed for some studies, these conclusions did not change after removing these studies from the analysis., Conclusions: In children on mechanical ventilation, early tracheostomy may improve important medical outcomes. However, our data demonstrate the urgent need for high-quality, randomized controlled trials in the pediatric population.

Background: Accidental ingestion or consumption of supra-therapeutic doses of methadone can result in neurological sequelae in humans. We aimed to determine the neurological deficits of methadone-poisoned patients admitted to a referral poisoning hospital using brain magnetic resonance (MR) and diffusion weighted (DW) imaging., Methods: In this retrospective study, brain MRIs of the patients admitted to our referral center due to methadone intoxication were reviewed. Methadone intoxication was confirmed based on history, congruent clinical presentation, and confirmatory urine analysis. Each patient had an MRI with Echo planar T1, T2, FLAIR, and DWI and apparent deficient coefficient (ADC) sequences without contrast media. Abnormalities were recorded and categorized based on their anatomic location and sequence., Results: Ten patients with abnormal MRI findings were identified. Eight had acute- and two had delayed-onset encephalopathy. Imaging findings included bilateral confluent or patchy T2 and FLAIR high signal intensity in cerebral white matter, cerebellar involvement, and bilateral occipito-parietal cortex diffusion restriction in DWI. Internal capsule involvement was identified in two patients while abnormality in globus pallidus and head of caudate nuclei were reported in another. Bilateral cerebral symmetrical confluent white matter signal abnormality with sparing of subcortical U-fibers on T2 and FLAIR sequences were observed in both patients with delayed-onset encephalopathy., Conclusions: Acute- and delayed-onset encephalopathies are two rare adverse events detected in methadone-intoxicated patients. Brain MRI findings can be helpful in detection of methadone-induced encephalopathy.

The health benefits of long-term dietary plant ingestion are well-established. However, literature on acute nutritional challenges is very limited. This study aimed to identify available evidence on transcriptomics responses to acute ingestion of plants or plant extracts and identify signature gene profiles that may serve as biomarkers of health status. We systematically searched electronic databases and extracted information based-on inclusion criteria such as human clinical studies, single plant-based nutrients and outcomes reported on acute transcriptome responses. A total of 11 studies reported on acute intake of plant dietary interventions. Four studies investigating natural oil extracts with three reporting on whole plants and two studies on natural plant-derived extracts. Gene expression was found to be associated with immune response (7 studies), inflammation (9 studies), metabolism (8 studies), cellular processes and cancer. The finding of this systematic review suggests that acute ingestion may significantly impact diverse physiological and pathological pathways including inflammatory, immune, cancer and oxidative stress pathways. Transcriptomics approach is proven to be an effective strategy in discovery of these anticipated mechanisms. Further studies are now required to validate and continue exploring the short-term health impact of dietary plants and their bioactive phytochemicals on gene expression and function.

Introduction: On entry into the clinical environment, nursing students are confronted with many challenges. It is a common problem throughout the world, including Iran. Although many studies have been conducted on the problems of nursing students in the clinical environment, limited information is available on nursing students' experiences of the clinical learning environment and the way they respond to these experiences. Identifying nursing students' experiences is essential to develop interventions to reduce challenges., Objective: This study aimed to explore nursing students' experiences in a clinical learning environment and the way they responded to these experiences., Design: The present study was conducted based on the qualitative research design of the grounded theory methodology., Setting: This study was conducted at schools of nursing in academic settings in Iran., Participants: The participants included 19 nursing students, 4 nursing instructors and 3 clinical nurses., Methods: The data were collected using semistructured interviews, field notes and observation, and were analysed using Strauss and Corbin's approach., Results: Students, as a result of the inadequacy of the educational environment, were faced with 'confusion of identity', stating this as their main concern. When confronted with this concern, they employed specific strategies, some of which prevented them from getting into unpleasant conditions. These strategies did not help students solve their problems and also prevented them from accepting their professional roles and responsibilities. Conversely, some other strategies led them to advanced professional development and enabled them to accept their role and the clinical environment., Conclusion: According to the results of this study, educational policymakers should focus on improving the clinical environment. Identifying professional models and increasing their influence on management, education and clinical education, as well as teaching positive and constructive strategies, will promote positive strategies in coping with inadequate educational contexts. This is necessary for the professional development of nursing students., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Concurrent advancements in imaging and genomic biomarkers have created opportunities to identify non-invasive imaging surrogates of molecular phenotypes. In order to develop such imaging surrogates radiomics and radiogenomics/imaging genomics will be necessary; there has been consistent progress in these fields for primary liver cancers. In this article we evaluate the current status of the field specifically with regards to hepatocellular carcinoma and intrahepatic cholangiocarcinoma, highlighting some of the up and coming results that were presented at the annual Radiological Society of North America Conference in 2017. There are an increasing number of studies in this area with a bias towards quantitative feature measurement, which is expected to benefit reproducibility of the findings and portends well for the future development of biomarkers for diagnosis, prognosis, and treatment response assessment. We review some of the advancements and look forward to some of the exciting future applications that are anticipated as the field develops.

Competing Interests: Nazila Jamshidi was the editorial registrar for Australian Prescriber in 2018.

Metabolomic data is the youngest of the high-throughput data types; however, it is potentially one of the most informative, as it provides a direct, quantitative biochemical phenotype. There are a number of ways in which metabolomic data can be analyzed in systems biology; however, the thermodynamic and kinetic relevance of these data cannot be overstated. Genome-scale metabolic network reconstructions provide a natural context to incorporate metabolomic data in order to provide insight into the condition-specific kinetic characteristics of metabolic networks. Herein we discuss how metabolomic data can be incorporated into constraint-based models in a flexible framework that enables scaling from small pathways to cell-scale models, while being able to accommodate coarse-grained to more detailed, allosteric interactions, all using the well-known principle of mass action.

Aim: to describe trends in baclofen reports to Australia's largest Poisons Information Centre (PIC) and present a case series detailing severity of overdoses., Short Summary: PBS data demonstrates baclofen use is increasing in Australia, while calls to NSWPIC illustrate an increase in number of exposures associated with toxicity. Baclofen toxicity may require prolonged intensive care admission. To minimize harms associated, especially with off-label baclofen prescribing for AUD, prescribers should pay careful attention to psychiatric comorbidities, and closely monitor treatment and dispensing., Methods: this is a retrospective observational study of baclofen overdoses reported to New South Wales PIC (NSWPIC) from January 1 2004 to 31 December 2016. In addition, referrals to a metropolitan toxicology service relating to baclofen toxicity from 2014 to 2017 were analysed. The number of Pharmaceutical Benefit Scheme (PBS) claims for baclofen were also reviewed., Results: during the 13-year study period, 403 cases of baclofen toxicity were reported to NSWPIC. There was a 230% increase in annual exposures over this period, 71% of patients were symptomatic, with 77% requiring hospitalization. Coingestants were reported in 53%, with 57% being psychoactive medications (including alcohol). An increase in number of baclofen dispensing episodes was also noted. From the five cases of deliberate self-harm reported to the metropolitan toxicology service, three obtained baclofen for management of alcohol use disorder (AUD) and required prolonged treatment in the intensive care unit (ICU)., Conclusions: NSWPIC data shows an increase in number of calls regarding intentional baclofen exposures in parallel with increase the number of baclofen PBS claims. These closely parallel the increase in dispensing of baclofen since 2008. Case studies presented reinforce the severity of baclofen toxicity. Together, they demonstrate the potential risk of harm of baclofen prescribing, and the greater need for caution. Baclofen should be considered carefully in patients high risk of overdose or be used only in specialist services with close monitoring.

Background: Hyperkyphosis is a common postural defect with high prevalence in the 20 to 50 year old population. It appears to compromise proximal scapular stability. Grip and pinch strength are used to evaluate general upper extremity function., Objective: The aim of this study was to compare pinch and grip strength between young women with and without hyperkyphosis., Methods: Thirty young women (18-40 years old) with hyperkyphosis and 30 healthy women matched for age and body mass index participated in the study. Hyperkyphosis was confirmed by measuring the kyphosis angle with a flexible ruler. Grip strength was measured with the Waisa method and a dynamometer. Pinch strength was assessed with a pinch meter., Results: Grip (P= 0.03) and pinch strength (P= 0.04) were significantly lower in women with hyperkyphosis compared to the control group. Kyphosis angle correlated weakly with grip (r= 0.26) and pinch strength (r= 0.23)., Conclusions: Hyperkyphotic posture has led to decreased grip and pinch strength compared to people without hyperkyphosis.

Background and Aims: There is little information with regards to the efficacy of baclofen among alcohol patients concurrently receiving antidepressants (AD). The present study aimed to conduct a secondary analysis of the moderating role of antidepressants in the BacALD trial which evaluated the efficacy of baclofen to reduce alcohol consumption in alcohol dependent patients. Methods: Alcohol dependent patients ( N = 104) were treated for 12 weeks with 30 mg/day of baclofen (21 = AD and 15 = no AD), 75 mg baclofen (19 = AD and 16 = no AD) or placebo (17 = AD and 16 = no AD). Patients were included in the trial if they were concurrently receiving anti-depressants upon enrolment but were excluded if they commenced antidepressants 2 months prior to enrolment. Patients were also excluded in the case of concurrent psychotropic medications, active major mental disorder such as bipolar disorder, psychosis, or history of suicide attempt. Predefined primary outcomes included time to lapse (any drinking), relapse (>5 drinks per day in men and >4 in women). Other outcomes included drinks per drinking day, number of heavy drinking days, and percentage days abstinent and frequency of adverse events. Results: For the number of days to first lapse, there was a trend of significance for the interaction baclofen × AD (Log Rank: χ 2 = 2.98, P = 0.08, OR: 0.41, 95%CI: 0.15-1.12). For the number of days to relapse, there was a trend of significance for the interaction of baclofen × AD (Log Rank: χ 2 = 3.72, P = 0.05, OR: 3.40, 95%CI: 1.01-11.46). Placing significant baseline variables into the models as covariates (tobacco, ALD) weakened these interactions ( P 's > 0.15). There were no significant effects of ADs on the frequency of adverse events reported ( P 's > 0.19). Conclusion: Concurrent receipt of ADs commenced more than 2 months prior to baclofen treatment did not negatively impact on drinking outcomes. Future research examining the interaction between commencing ADs during baclofen treatment on alcohol dependent patients is required. Trial Registration: ClinicalTrials.gov, NCT01711125, https://clinicaltrials.gov/ct2/show/NCT01711125.

Purpose To determine the concordance and accuracy of imaging surrogates of immunohistochemical (IHC) markers and the molecular classification of breast cancer. Materials and Methods A total of 3050 patients from 17 public breast cancer data sets containing IHC marker receptor status (estrogen receptor/progesterone receptor/human epidermal growth factor receptor 2 [HER2]) and their molecular classification (basal-like, HER2-enriched, luminal A or B) were analyzed. Diagnostic accuracy and concordance as measured with the κ statistic were calculated between the IHC and molecular classifications. Simulations were performed to assess the relationship between accuracy of imaging-based IHC markers to predict molecular classification. A simulation was performed to examine effects of misclassification of molecular type on patient survival. Results Accuracies of intrinsic subtypes based on IHC subtype were 71.7% (luminal A), 53.7% (luminal B), 64.8% (HER2-enriched), and 81.7% (basal-like). The κ agreement was fair (κ = 0.36) for luminal A and HER2-enriched subtypes, good (κ = 0.65) for the basal-like subtype, and poor (κ = 0.09) for the luminal B subtypes. Introduction of image misclassification by simulation lowered image-true subtype accuracies and κ values. Simulation analysis showed that misclassification caused survival differences between luminal A and basal-like subtypes to decrease. Conclusion There is poor concordance between triple-receptor status and intrinsic molecular subtype in breast cancer, arguing against their use in the design of prognostic genomic-based image biomarkers. © RSNA, 2018 Online supplemental material is available for this article.

The purpose of this simulation study was to analyze the effect of variation in Knee-Ankle-Foot-Orthosis stiffness on the joint power and the energy cost of walking. The effect of contractile tissue was simulated using linear elastic spring and viscous dampers in knee and ankle joints. Then, joint angles, ground reaction force, were collected from Twenty chronic hemiparesis subjects (15 males and 5 females) and twenty control subjects (14 males and 6 females), and spring stiffness were considered as the inputs. In this new study, the generated muscle torques were optimized by changing the stiffness as the desired output in the mathematical model attained by the MATLAB SimMechanics toolbox. Finally, the simulated mathematical model was introduced as an appropriate substitute in obtaining the optimized stiffness with a more convenient and efficient designed orthosis.

Several antimalarial drugs exist, but differences between life cycle stages among malaria species pose challenges for developing more effective therapies. To understand the diversity among stages and species, we reconstructed genome-scale metabolic models (GeMMs) of metabolism for five life cycle stages and five species of Plasmodium spanning the blood, transmission, and mosquito stages. The stage-specific models of Plasmodium falciparum uncovered stage-dependent changes in central carbon metabolism and predicted potential targets that could affect several life cycle stages. The species-specific models further highlight differences between experimental animal models and the human-infecting species. Comparisons between human- and rodent-infecting species revealed differences in thiamine (vitamin B1), choline, and pantothenate (vitamin B5) metabolism. Thus, we show that genome-scale analysis of multiple stages and species of Plasmodium can prioritize potential drug targets that could be both anti-malarials and transmission blocking agents, in addition to guiding translation from non-human experimental disease models.

The science and art of Genome scale metabolic network reconstructions have been explicitly documented in the literature for organisms across all the three kingdoms of life. Constraints-based models derived from such reconstructions have been used to assess metabolic phenotypes of their complex connections to genotype accurately. The problem of infectious disease is complex due to the multifactorial response of the host to the pathogen. Systems biology approaches and modeling allow one to study, understand, and predict emergent properties of such complex responses. The integration of the host and pathogen metabolic networks and the subsequent merger of their stoichiometric matrices is nontrivial and requires understanding of both pathogen and host metabolism and physiologies. The protocol here describes the detailed process of network and stoichiometric matrix merger using a salmonella-mouse macrophage model. The protocol also discusses the interfacial and objective functions required to actually embark on the analysis of host-pathogen interaction models.

Background: The traction bed is a noninvasive device for treating lower back pain caused by herniated intervertebral discs. In this study, we investigated the impact of the traction bed on the lower back as a means of increasing the disc height and creating a gap between facet joints., Methods: Computed tomography (CT) images were obtained from a female volunteer and a three-dimensional (3D) model was created using software package MIMICs 17.0. Afterwards, the 3D model was analyzed in an analytical software (Abaqus 6.14). The study was conducted under the following traction loads: 25%, 45%, 55%, and 85% of the whole body weight in different angles., Results: Results indicated that the loading angle in the L3-4 area had 36.8%, 57.4%, 55.32%, 49.8%, and 52.15% effect on the anterior longitudinal ligament, posterior longitudinal ligament, intertransverse ligament, interspinous ligament, and supraspinous ligament, respectively. The respective values for the L4-5 area were 32.3%, 10.6%, 53.4%, 56.58%, and 57.35%. Also, the body weight had 63.2%, 42.6%, 44.68%, 50.2%, and 47.85% effect on the anterior longitudinal ligament, posterior longitudinal ligament, intertransverse ligament, interspinous ligament, and supraspinous ligament, respectively. The respective values for the L4-5 area were 67.7%, 89.4%, 46.6%, 43.42% and 42.65%. The authenticity of results was checked by comparing with the experimental data., Conclusions: The results show that traction beds are highly effective for disc movement and lower back pain relief. Also, an optimal angle for traction can be obtained in a 3D model analysis using CT or magnetic resonance imaging images. The optimal angle would be different for different patients and thus should be determined based on the decreased height of the intervertebral disc, weight and height of patients., Competing Interests: CONFLICT OF INTEREST: No potential conflict of interest relevant to this article was reported.

Aim: To reduce post treatments of kyphoplasty, as a common treatment for osteoporotic vertebrae., Methods: This study suggests a new method for treating vertebrae by setting the hexagonal porous structure instead of the rigid bone cement mass in the kyphoplasty (KP). The KP procedure was performed on the fresh ovine vertebra of the level L1. Micro finite element modeling was performed based on micro computed tomography of ovine trabecular cube. The hexagonal porous structure was set on one cube instead of the bone cement mass. For the implant designing, two geometrical parameters were considered: Spacing diameter and thickness., Results: The results of micro finite element analyses indicated the improvement in the mechanical behavior of the vertebra treated by the hexagonal porous structures, as compared to those treated by vertebroplasty (VP) and KP under static loading. The improvement in the mechanical behavior of the vertebra, was observed as 54% decrease in the amount of maximum Von Misses stress (improvement of stress distribution), in trabecular cube with embedded hexagonal structure, as compared to VP and KP. This is comparable to the results of the experimental study already performed; it was shown that the improvement of mechanical behavior of the vertebra was observed as: 83% increase in the range of displacements before getting to the ultimate strength (increasing the toughness) after setting hexagonal pearls inside vertebrae. Both the material and geometry of implant influenced the amount of Von Mises stress in the structure., Conclusion: The new proposed method can be offered as a substitute for the KP. The implant geometry had a more obvious effect on the amount of Von Mises stress, as compared to the implant material., Competing Interests: Conflict-of-interest statement: To the best of our knowledge no conflict of interest exists.

The Warburg effect (WE), or aerobic glycolysis, is commonly recognized as a hallmark of cancer and has been extensively studied for potential anti-cancer therapeutics development. Beyond cancer, the WE plays an important role in many other cell types involved in immunity, angiogenesis, pluripotency, and infection by pathogens (e.g., malaria). Here, we review the WE in non-cancerous context as a "hallmark of rapid proliferation." We observe that the WE operates in rapidly dividing cells in normal and pathological states that are triggered by internal and external cues. Aerobic glycolysis is also the preferred metabolic program in the cases when robust transient responses are needed. We aim to draw attention to the potential of computational modeling approaches in systematic characterization of common metabolic features beyond the WE across physiological and pathological conditions. Identification of metabolic commonalities across various diseases may lead to successful repurposing of drugs and biomarkers.

Purpose To assess the underlying genomic variation of prostate gland microenvironments of patients with prostate adenocarcinoma in the context of colocalized multiparametric magnetic resonance (MR) imaging and histopathologic assessment of normal and abnormal regions by using whole-exome sequencing. Materials and Methods Six patients with prostate adenocarcinoma who underwent robotic prostatectomy with whole-mount preservation of the prostate were identified, which enabled spatial mapping between preoperative multiparametric MR imaging and the gland. Four regions of interest were identified within each gland, including regions found to be normal and abnormal via histopathologic analysis. Whole-exome DNA sequencing (>50 times coverage) was performed on each of these spatially targeted regions. Radiogenomic analysis of imaging and mutation data were performed with hierarchical clustering, phylogenetic analysis, and principal component analysis. Results Radiogenomic multiparametric MR imaging and whole-exome spatial characterization in six patients with prostate adenocarcinoma (three patients, Gleason score of 3 + 4; and three patients, Gleason score of 4 + 5) was performed across 23 spatially distinct regions. Hierarchical clustering separated histopathologic analysis-proven high-grade lesions from the normal regions, and this reflected concordance between multiparametric MR imaging and resultant histopathologic analysis in all patients. Seventy-seven mutations involving 29 cancer-associated genes across the 23 spatially distinct prostate samples were identified. There was no significant difference in mutation load in cancer-associated genes between regions that were proven to be normal via histopathologic analysis (34 mutations per sample ± 19), mildly suspicious via multiparametric MR imaging (37 mutations per sample ± 21), intermediately suspicious via multiparametric MR imaging (31 mutations per sample ± 15), and high-grade cancer (33 mutations per sample ± 18) (P = .30). Principal component analysis resolved samples from different patients and further classified samples (regardless of histopathologic status) from prostate glands with Gleason score 3 + 4 versus 4 + 5 samples. Conclusion Multiregion spatial multiparametric MR imaging and whole-exome radiogenomic analysis of prostate glands with adenocarcinoma shows a continuum of mutations across regions that were found via histologic analysis to be high grade and normal. © RSNA, 2017 Online supplemental material is available for this article.

Objective: The purpose of this study was to evaluate the reliability and quality of radiomic features in glioblastoma multiforme (GBM) derived from tumor volumes obtained with semi-automated tumor segmentation software., Materials and Methods: MR images of 45 GBM patients (29 males, 16 females) were downloaded from The Cancer Imaging Archive, in which post-contrast T1-weighted imaging and fluid-attenuated inversion recovery MR sequences were used. Two raters independently segmented the tumors using two semi-automated segmentation tools (TumorPrism3D and 3D Slicer). Regions of interest corresponding to contrast-enhancing lesion, necrotic portions, and non-enhancing T2 high signal intensity component were segmented for each tumor. A total of 180 imaging features were extracted, and their quality was evaluated in terms of stability, normalized dynamic range (NDR), and redundancy, using intra-class correlation coefficients, cluster consensus, and Rand Statistic., Results: Our study results showed that most of the radiomic features in GBM were highly stable. Over 90% of 180 features showed good stability (intra-class correlation coefficient [ICC] ≥ 0.8), whereas only 7 features were of poor stability (ICC < 0.5). Most first order statistics and morphometric features showed moderate-to-high NDR (4 > NDR ≥1), while above 35% of the texture features showed poor NDR (< 1). Features were shown to cluster into only 5 groups, indicating that they were highly redundant., Conclusion: The use of semi-automated software tools provided sufficiently reliable tumor segmentation and feature stability; thus helping to overcome the inherent inter-rater and intra-rater variability of user intervention. However, certain aspects of feature quality, including NDR and redundancy, need to be assessed for determination of representative signature features before further development of radiomics.

Diabetes and its associated complications are realized as one of the most challenging medical conditions threatening more than 29 million people only in the USA. The forecasts suggest a suffering of more than half a billion worldwide by 2030. Amid all diabetic complications, diabetic foot ulcer (DFU) has attracted much scientific investigations to lead to a better management of this disease. In this paper, a system thinking methodology is adopted to investigate the dynamic nature of the ulceration. The causal loop diagram as a tool is utilized to illustrate the well-researched relations and interrelations between causes of the DFU. The result of clustering causality evaluation suggests a vicious loop that relates external trauma to callus. Consequently a hypothesis is presented which localizes development of foot ulceration considering distribution of normal and shear stress. It specifies that normal and tangential forces, as the main representatives of external trauma, play the most important role in foot ulceration. The evaluation of this hypothesis suggests the significance of the information related to both normal and shear stress for managing DFU. The results also discusses how these two react on different locations on foot such as metatarsal head, heel and hallux. The findings of this study can facilitate tackling the complexity of DFU problem and looking for constructive mitigation measures. Moreover they lead to developing a more promising methodology for managing DFU including better prognosis, designing prosthesis and insoles for DFU and patient caring recommendations., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Purpose To identify the variables and factors that affect the quantity and quality of nucleic acid yields from imaging-guided core needle biopsy. Materials and Methods This study was approved by the institutional review board and compliant with HIPAA. The authors prospectively obtained 232 biopsy specimens from 74 patients (177 ex vivo biopsy samples from surgically resected masses were obtained from 49 patients and 55 in vivo lung biopsy samples from computed tomographic [CT]-guided lung biopsies were obtained from 25 patients) and quantitatively measured DNA and RNA yields with respect to needle gauge, number of needle passes, and percentage of the needle core. RNA quality was also assessed. Significance of correlations among variables was assessed with analysis of variance followed by linear regression. Conditional probabilities were calculated for projected sample yields. Results The total nucleic acid yield increased with an increase in the number of needle passes or a decrease in needle gauge (two-way analysis of variance, P < .0001 for both). However, contrary to calculated differences in volume yields, the effect of needle gauge was markedly greater than the number of passes. For example, the use of an 18-gauge versus a 20-gauge biopsy needle resulted in a 4.8-5.7 times greater yield, whereas a double versus a single pass resulted in a 2.4-2.8 times greater yield for 18- versus 20-gauge needles, respectively. Ninety-eight of 184 samples (53%) had an RNA integrity number of at least 7 (out of a possible score of 10). Conclusion With regard to optimizing nucleic acid yields in CT-guided lung core needle biopsies used for genomic analysis, there should be a preference for using lower gauge needles over higher gauge needles with more passes. © RSNA, 2016 Online supplemental material is available for this article. An earlier incorrect version of this article appeared online. This article was corrected on October 21, 2016.

Background: Implant loosening may occur after dental implant placement as a result of the mechanical conditions created around the implant. In this research, the effect of bone drilling conditions on the magnitude of stress created in newly-formed bone around the implant, after placement, was investigated using FEA analysis., Method: The simulations performed in this study were based on the three-dimensional (3D) shape of the created cavities, extracted from the drilled cortical bone of the jaws. With this aim, a dental implant model was placed in the jaw and a shell of the 3D bone cavity remained as a newly-formed cortical bone after implant placement. Then, a load was exerted on the implant model and the value of stress created on the newly-formed bone was obtained. Overall, eight combined models were used in all the eight drilling and loading simulations. The examined variables were rotational speed of drill bit, its feed rate and head angle. Also, an animal test was performed to investigate the accuracy of the simulation results., Results: The results of this study showed that the amount of principal stress was the least (16.7MPa) for a newly-formed cortical bone whose cavity was created under drilling condition at the same head angle and feed rate of the drill bit with a rotational speed of 400rpm. The same results were obtained for the head angle and feed rate of a drill bit of 70° and 1.5mm/s, respectively., Conclusions: Drilling conditions have effect on the stress created in a newly-formed cortical bone after dental implant loading., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Malignant transformation is often accompanied by significant metabolic changes. To identify drivers underlying these changes, we calculated metabolic flux states for the NCI60 cell line collection and correlated the variance between metabolic states of these lines with their other properties. The analysis revealed a remarkably consistent structure underlying high flux metabolism. The three primary uptake pathways, glucose, glutamine and serine, are each characterized by three features: (1) metabolite uptake sufficient for the stoichiometric requirement to sustain observed growth, (2) overflow metabolism, which scales with excess nutrient uptake over the basal growth requirement, and (3) redox production, which also scales with nutrient uptake but greatly exceeds the requirement for growth. We discovered that resistance to chemotherapeutic drugs in these lines broadly correlates with the amount of glucose uptake. These results support an interpretation of the Warburg effect and glutamine addiction as features of a growth state that provides resistance to metabolic stress through excess redox and energy production. Furthermore, overflow metabolism observed may indicate that mitochondrial catabolic capacity is a key constraint setting an upper limit on the rate of cofactor production possible. These results provide a greater context within which the metabolic alterations in cancer can be understood.

Objectives: Students of medical sciences are exposed to many emotional and mental problems. In light of the importance of sleep quality in learning and liveliness, this study was conducted to examine the relationship between psychological variables (stress, anxiety, and depression) and sleep quality of students., Design: This research is a cross-sectional analytical study, where all students studying at Fasa University of Medical Sciences in 2012-2013 year were selected. To examine the students' stress, anxiety, and depression values, the standardized 21-item DASS-21 was used, and to examine their sleep quality, Pittsburgh Sleep Quality Index (PSQI) was used., Results: The results of the study demonstrated that 73% of the students have moderate and severe stress, and 46.4% of them have PSQ scores ≥ 5. The students' mean sleep quality score was 4.65 ± 2.37, and their stress score was 8.09 ± 5.14. A statistically significant relationship was found between the students' stress levels and sleep quality ( P < 0.001)., Conclusion: The high stress levels decrease students' sleep quality. High stress levels and also the significant relationship between stress value and decrease in students' sleep quality call for more attention to and care for students' emotional and mental issues and timely proper interference on the part of authorities.

Tulsi, also known as holy basil, is indigenous to the Indian continent and highly revered for its medicinal uses within the Ayurvedic and Siddha medical systems. Many in vitro, animal and human studies attest to tulsi having multiple therapeutic actions including adaptogenic, antimicrobial, anti-inflammatory, cardioprotective, and immunomodulatory effects, yet to date there are no systematic reviews of human research on tulsi's clinical efficacy and safety. We conducted a comprehensive literature review of human studies that reported on a clinical outcome after ingestion of tulsi. We searched for studies published in books, theses, conference proceedings, and electronic databases including Cochrane Library, Google Scholar, Embase, Medline, PubMed, Science Direct, and Indian Medical databases. A total of 24 studies were identified that reported therapeutic effects on metabolic disorders, cardiovascular disease, immunity, and neurocognition. All studies reported favourable clinical outcomes with no studies reporting any significant adverse events. The reviewed studies reinforce traditional uses and suggest tulsi is an effective treatment for lifestyle-related chronic diseases including diabetes, metabolic syndrome, and psychological stress. Further studies are required to explore mechanisms of action, clarify the dosage and dose form, and determine the populations most likely to benefit from tulsi's therapeutic effects.

There has been a recent interest in the broader physiological importance of multispecific "drug" transporters of the SLC and ABC transporter families. Here, a novel multi-tiered systems biology approach was used to predict metabolites and signaling molecules potentially affected by the in vivo deletion of organic anion transporter 1 (Oat1, Slc22a6, originally NKT), a major kidney-expressed drug transporter. Validation of some predictions in wet-lab assays, together with re-evaluation of existing transport and knock-out metabolomics data, generated an experimentally validated, confidence ranked set of OAT1-interacting endogenous compounds enabling construction of an "OAT1-centered metabolic interaction network." Pathway and enrichment analysis indicated an important role for OAT1 in metabolism involving: the TCA cycle, tryptophan and other amino acids, fatty acids, prostaglandins, cyclic nucleotides, odorants, polyamines, and vitamins. The partly validated reconstructed network is also consistent with a major role for OAT1 in modulating metabolic and signaling pathways involving uric acid, gut microbiome products, and so-called uremic toxins accumulating in chronic kidney disease. Together, the findings are compatible with the hypothesized role of drug transporters in remote inter-organ and inter-organismal communication: The Remote Sensing and Signaling Hypothesis (Nigam, S. K. (2015) Nat. Rev. Drug Disc. 14, 29). The fact that OAT1 can affect many systemic biological pathways suggests that drug-metabolite interactions need to be considered beyond simple competition for the drug transporter itself and may explain aspects of drug-induced metabolic syndrome. Our approach should provide novel mechanistic insights into the role of OAT1 and other drug transporters implicated in metabolic diseases like gout, diabetes, and chronic kidney disease., (© 2016 by The American Society for Biochemistry and Molecular Biology, Inc.)

Objectives: To characterize a radiogenomic risk score (RRS), a previously defined biomarker, and to evaluate its potential for stratifying radiological progression-free survival (rPFS) in patients with metastatic renal cell carcinoma (mRCC) undergoing pre-surgical treatment with bevacizumab., Methodology: In this IRB-approved study, prospective imaging analysis of the RRS was performed on phase II clinical trial data of mRCC patients (n = 41) evaluating whether patient stratification according to the RRS resulted in groups more or less likely to have a rPFS to pre-surgical bevacizumab prior to cytoreductive nephrectomy. Survival times of RRS subgroups were analyzed using Kaplan-Meier survival analysis., Results: The RRS is enriched in diverse molecular processes including drug response, stress response, protein kinase regulation, and signal transduction pathways (P < 0.05). The RRS successfully stratified rPFS to bevacizumab based on pre-treatment computed tomography imaging with a median progression-free survival of 6 versus >25 months (P = 0.005) and overall survival of 25 versus >37 months in the high and low RRS groups (P = 0.03), respectively. Conventional prognostic predictors including the Motzer and Heng criteria were not predictive in this cohort (P > 0.05)., Conclusions: The RRS stratifies rPFS to bevacizumab in patients from a phase II clinical trial with mRCC undergoing cytoreductive nephrectomy and pre-surgical bevacizumab., Key Points: • The RRS SOMA stratifies patient outcomes in a phase II clinical trial. • RRS stratifies subjects into prognostic groups in a discrete or continuous fashion. • RRS is biologically enriched in diverse processes including drug response programs.

Dysregulated epithelial to mesenchymal transition (EMT) in cancer cells endows invasive and metastatic properties upon cancer cells that favor successful colonization of distal target organs and therefore play a critical role in transforming early-stage carcinomas into invasive malignancies. EMT has also been associated with tumor recurrence and drug resistance and cancer stem cell initiation. Therefore, better understanding of the mechanisms behind EMT could ultimately contribute to the development of novel prognostic approaches and individualized therapies that specifically target EMT processes. As an effort to characterize the central transcriptome changes during EMT, we have developed a Transforming growth factor (TGF)-beta-based in vitro EMT model and used it to profile EMT-related gene transcriptional changes in two different cell lines, a non-small cell lung cancer cell line H358, and a breast cell line MCF10a. After 7 days of TGF-beta/Oncostatin M (OSM) treatment, changes in cell morphology to a mesenchymal phenotype were observed as well as concordant EMT-associated changes in mRNA and protein expression. Further, increased motility was noted and flow cytometry confirmed enrichment in cancer stem cell-like populations. Microarray-based differential expression analysis identified an EMT-associated gene expression signature which was confirmed by RT-qPCR and which significantly overlapped with a previously published EMT core signature. Finally, two novel EMT-regulating transcription factors, IRF5 and LMCD1, were identified and independently validated., (© 2016 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Purpose To investigate whether non-small cell lung cancer (NSCLC) tumors that express high normalized maximum standardized uptake value (SUVmax) are associated with a more epithelial-mesenchymal transition (EMT)-like phenotype. Materials and Methods In this institutional review board-approved study, a public NSCLC data set that contained fluorine 18 ((18)F) fluoro-2-deoxyglucose positron emission tomography (PET) and messenger RNA expression profile data (n = 26) was obtained, and patients were categorized on the basis of measured normalized SUVmax values. Significance analysis of microarrays was then used to create a radiogenomic signature. The prognostic ability of this signature was assessed in a second independent data set that consisted of clinical and messenger RNA expression data (n = 166). Signature concordance with EMT was evaluated by means of validation in a publicly available cell line data set. Finally, by establishing an in vitro EMT lung cancer cell line model, an attempt was made to substantiate the radiogenomic signature with quantitative polymerase chain reaction, and functional assays were performed, including Western blot, cell migration, glucose transporter, and hexokinase assays (paired t test), as well as pharmacologic assays against chemotherapeutic agents (half-maximal effective concentration). Results Differential expression analysis yielded a 14-gene radiogenomic signature (P < .05, false discovery rate [FDR] < 0.20), which was confirmed to have differences in disease-specific survival (log-rank test, P = .01). This signature also significantly overlapped with published EMT cell line gene expression data (P < .05, FDR < 0.20). Finally, an EMT cell line model was established, and cells that had undergone EMT differentially expressed this signature and had significantly different EMT protein expression (P < .05, FDR < 0.20), cell migration, glucose uptake, and hexokinase activity (paired t test, P < .05). Cells that had undergone EMT also had enhanced chemotherapeutic resistance, with a higher half-maximal effective concentration than that of cells that had not undergone EMT (P < .05). Conclusion Integrative radiogenomic analysis demonstrates an association between increased normalized (18)F fluoro-2-deoxyglucose PET SUVmax, outcome, and EMT in NSCLC. (©) RSNA, 2016 Online supplemental material is available for this article.

Background/Aim. Clinical learning is a main part of nursing education. Students' exposure to clinical learning environment is one of the most important factors affecting the teaching-learning process in clinical settings. Identifying challenges of nursing students in the clinical learning environment could improve training and enhance the quality of its planning and promotion of the students. We aimed to explore Iranian nursing students' challenges in the clinical learning environment. Materials and Methods. This is a qualitative study using the content analysis approach. The participants consisted of seventeen nursing students and three nursing instructors. The participants were selected through purposive sampling method and attended semistructured interviews and focus groups. Results. Three themes emerged after data analysis, including ineffective communications, inadequate readiness, and emotional reactions. Conclusion. Nursing students in Iran are faced with many challenges in the clinical learning environment. All challenges identified in this study affected the students' learning in clinical setting. Therefore, we recommend that the instructors prepare students with a specific focus on their communication and psychological needs.

Parasitic diseases caused by protozoan pathogens lead to hundreds of thousands of deaths per year in addition to substantial suffering and socioeconomic decline for millions of people worldwide. The lack of effective vaccines coupled with the widespread emergence of drug-resistant parasites necessitates that the research community take an active role in understanding host-parasite infection biology in order to develop improved therapeutics. Recent advances in next-generation sequencing and the rapid development of publicly accessible genomic databases for many human pathogens have facilitated the application of systems biology to the study of host-parasite interactions. Over the past decade, these technologies have led to the discovery of many important biological processes governing parasitic disease. The integration and interpretation of high-throughput -omic data will undoubtedly generate extraordinary insight into host-parasite interaction networks essential to navigate the intricacies of these complex systems. As systems analysis continues to build the foundation for our understanding of host-parasite biology, this will provide the framework necessary to drive drug discovery research forward and accelerate the development of new antiparasitic therapies., (© 2015 The Authors. WIREs Systems Biology and Medicine published by Wiley Periodicals, Inc.)

Understanding individual variation is fundamental to personalized medicine. Yet interpreting complex phenotype data, such as multi-compartment metabolomic profiles, in the context of genotype data for an individual is complicated by interactions within and between cells and remains an unresolved challenge. Here, we constructed multi-omic, data-driven, personalized whole-cell kinetic models of erythrocyte metabolism for 24 healthy individuals based on fasting-state plasma and erythrocyte metabolomics and whole-genome genotyping. We show that personalized kinetic rate constants, rather than metabolite levels, better represent the genotype. Additionally, changes in erythrocyte dynamics between individuals occur on timescales of circulation, suggesting detected differences play a role in physiology. Finally, we use the models to identify individuals at risk for a drug side effect (ribavirin-induced anemia) and how genetic variation (inosine triphosphatase deficiency) may protect against this side effect. This study demonstrates the feasibility of personalized kinetic models, and we anticipate their use will accelerate discoveries in characterizing individual metabolic variation., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Constraint-based models have become popular methods for systems biology as they enable the integration of complex, disparate datasets in a biologically cohesive framework that also supports the description of biological processes in terms of basic physicochemical constraints and relationships. The scope, scale, and application of genome scale models have grown from single cell bacteria to multi-cellular interaction modeling; host-pathogen modeling represents one of these examples at the current horizon of constraint-based methods. There are now a small number of examples of host-pathogen constraint-based models in the literature, however there has not yet been a definitive description of the methodology required for the functional integration of genome scale models in order to generate simulation capable host-pathogen models. Herein we outline a systematic procedure to produce functional host-pathogen models, highlighting steps which require debugging and iterative revisions in order to successfully build a functional model. The construction of such models will enable the exploration of host-pathogen interactions by leveraging the growing wealth of omic data in order to better understand mechanism of infection and identify novel therapeutic strategies.

Purpose: To evaluate the feasibility of constructing radiogenomic-based surrogates of molecular assays (SOMAs) in patients with clear-cell renal cell carcinoma (CCRCC) by using data extracted from a single computed tomographic (CT) image., Materials and Methods: In this institutional review board approved study, gene expression profile data and contrast material-enhanced CT images from 70 patients with CCRCC in a training set were independently assessed by two radiologists for a set of predefined imaging features. A SOMA for a previously validated CCRCC-specific supervised principal component (SPC) risk score prognostic gene signature was constructed and termed the radiogenomic risk score (RRS). It uses the microarray data and a 28-trait image array to evaluate each CT image with multiple regression of gene expression analysis. The predictive power of the RRS SOMA was then prospectively validated in an independent dataset to confirm its relationship to the SPC gene signature (n = 70) and determination of patient outcome (n = 77). Data were analyzed by using multivariate linear regression-based methods and Cox regression modeling, and significance was assessed with receiver operator characteristic curves and Kaplan-Meier survival analysis., Results: Our SOMA faithfully represents the tissue-based molecular assay it models. The RRS scaled with the SPC gene signature (R = 0.57, P < .001, classification accuracy 70.1%, P < .001) and predicted disease-specific survival (log rank P < .001). Independent validation confirmed the relationship between the RRS and the SPC gene signature (R = 0.45, P < .001, classification accuracy 68.6%, P < .001) and disease-specific survival (log-rank P < .001) and that it was independent of stage, grade, and performance status (multivariate Cox model P < .05, log-rank P < .001)., Conclusion: A SOMA for the CCRCC-specific SPC prognostic gene signature that is predictive of disease-specific survival and independent of stage was constructed and validated, confirming that SOMA construction is feasible., ((©) RSNA, 2015 Online supplemental material is available for this article. An earlier incorrect version of this article appeared online. This article was corrected on August 24, 2015.)

URAT1 (slc22a12) was identified as the transporter responsible for renal reabsorption of the medically important compound, uric acid. However, subsequent studies have indicated that other transporters make contributions to this process, and that URAT1 transports other organic anions besides urate (including several in common with the closely related multi-specific renal organic anion transporters, OAT1 (slc22a6) and OAT3 (slc22a8)). These findings raise the possibility that urate transport is not the sole physiological function of URAT1. We previously characterized mice null for the murine ortholog of URAT1 (mURAT1; previously cloned as RST), finding a relatively modest decrement in urate reabsorptive capacity. Nevertheless, there were shifts in the plasma and urinary concentrations of multiple small molecules, suggesting significant metabolic changes in the knockouts. Although these molecules remain unidentified, here we have computationally delineated the biochemical networks consistent with transcriptomic data from the null mice. These analyses suggest alterations in the handling of not only urate but also other putative URAT1 substrates comprising intermediates in nucleotide, carbohydrate, and steroid metabolism. Moreover, the analyses indicate changes in multiple other pathways, including those relating to the metabolism of glycosaminoglycans, methionine, and coenzyme A, possibly reflecting downstream effects of URAT1 loss. Taken together with the available substrate and metabolomic data for the other OATs, our findings suggest that the transport and biochemical functions of URAT1 overlap those of OAT1 and OAT3, and could contribute to our understanding of the relationship between uric acid and the various metabolic disorders to which it has been linked.

Purpose: To perform a radiogenomic analysis of women with breast cancer to study the multiscale relationships among quantitative computer vision-extracted dynamic contrast material-enhanced (DCE) magnetic resonance (MR) imaging phenotypes, early metastasis, and long noncoding RNA (lncRNA) expression determined by means of high-resolution next-generation RNA sequencing., Materials and Methods: In this institutional review board-approved study, an automated image analysis platform extracted 47 computational quantitative features from DCE MR imaging data in a training set (n = 19) to screen for MR imaging biomarkers indicative of poor metastasis-free survival (MFS). The lncRNA molecular landscape of the candidate feature was defined by using an RNA sequencing-specific negative binomial distribution differential expression analysis. Then, this radiogenomic biomarker was applied prospectively to a validation set (n = 42) to allow prediction of MFS and lncRNA expression by using quantitative polymerase chain reaction analysis., Results: The quantitative MR imaging feature, enhancing rim fraction score, was predictive of MFS in the training set (P = .007). RNA sequencing analysis yielded an average of 55.7 × 10(6) reads per sample and identified 14 880 lncRNAs from a background of 189 883 transcripts per sample. Radiogenomic analysis allowed identification of three previously uncharacterized and five named lncRNAs significantly associated with high enhancing rim fraction, including Homeobox transcript antisense intergenic RNA (HOTAIR) (P < .05), a known predictor of poor MFS in patients with breast cancer. Independent validation confirmed the association of the enhancing rim fraction phenotype with both MFS (P = .002) and expression of four of the top five differentially expressed lncRNAs (P < .05), including HOTAIR., Conclusion: The enhancing rim fraction score, a quantitative DCE MR imaging lncRNA radiogenomic biomarker, is associated with early metastasis and expression of the known predictor of metastatic progression, HOTAIR., ((©) RSNA)

Recently there has not been a systematic, objective assessment of the metabolic capabilities of the human platelet. A manually curated, functionally tested, and validated biochemical reaction network of platelet metabolism, iAT-PLT-636, was reconstructed using 33 proteomic datasets and 354 literature references. The network contains enzymes mapping to 403 diseases and 231 FDA approved drugs, alluding to an expansive scope of biochemical transformations that may affect or be affected by disease processes in multiple organ systems. The effect of aspirin (ASA) resistance on platelet metabolism was evaluated using constraint-based modeling, which revealed a redirection of glycolytic, fatty acid, and nucleotide metabolism reaction fluxes in order to accommodate eicosanoid synthesis and reactive oxygen species stress. These results were confirmed with independent proteomic data. The construction and availability of iAT-PLT-636 should stimulate further data-driven, systems analysis of platelet metabolism towards the understanding of pathophysiological conditions including, but not strictly limited to, coagulopathies.

Background: Stability during standing is achieved by a complex process which involves the performance of various systems. Using a force plate for analysing the stability for a period of one minute has been reported exclusively by many investigators. Most of people stand for a long period of time when chatting with somebody, doing a job and when waiting in a queue. However nobody has analysed the stability during quiet standing for a prolonged standing (5 minutes)., Objective: The main aim of this research study was to analyse the performance of the subjects regarding stability for a period of 5 minutes., Method: A group of 40 normal subjects from the staff and students of Rehabilitation Faculty of Isfahan University of Medical Sciences were recruited in this research project. They were asked to stand on the force plate (Kistler) for a period of 5 minutes. They were instructed to look straight ahead and with their head erect and their arms at their sides in a comfortable position. The excursions of the COP sway in both planes were measured for all 20 seconds periods of data collection., Results: The results of this research study showed that stability analysing based on the sway of the COP, while the test was collected for one minute, is not recommended. There is a significant difference between the excursions of the COP during the first to fifth minutes. The stability of the subject was optimum in the third and fourth minutes of standing., Conclusion: Using the COP sway, based on the first minute of standing, is neither a good representative of the more stable position nor the unstable position. It is recommended to discuss the stability of subjects based on their ability to return from an unstable position to a more stable position.

Purpose: To perform a multilevel radiogenomics study to elucidate the glioblastoma multiforme (GBM) magnetic resonance (MR) imaging radiogenomic signatures resulting from changes in messenger RNA (mRNA) expression and DNA copy number variation (CNV)., Materials and Methods: Radiogenomic analysis was performed at MR imaging in 23 patients with GBM in this retrospective institutional review board-approved HIPAA-compliant study. Six MR imaging features-contrast enhancement, necrosis, contrast-to-necrosis ratio, infiltrative versus edematous T2 abnormality, mass effect, and subventricular zone (SVZ) involvement-were independently evaluated and correlated with matched genomic profiles (global mRNA expression and DNA copy number profiles) in a significant manner that also accounted for multiple hypothesis testing by using gene set enrichment analysis (GSEA), resampling statistics, and analysis of variance to gain further insight into the radiogenomic signatures in patients with GBM., Results: GSEA was used to identify various oncogenic pathways with MR imaging features. Correlations between 34 gene loci were identified that showed concordant variations in gene dose and mRNA expression, resulting in an MR imaging, mRNA, and CNV radiogenomic association map for GBM. A few of the identified gene-to-trait associations include association of the contrast-to-necrosis ratio with KLK3 and RUNX3; association of SVZ involvement with Ras oncogene family members, such as RAP2A, and the metabolic enzyme TYMS; and association of vasogenic edema with the oncogene FOXP1 and PIK3IP1, which is a member of the PI3K signaling network., Conclusion: Construction of an MR imaging, mRNA, and CNV radiogenomic association map has led to identification of MR traits that are associated with some known high-grade glioma biomarkers and association with genomic biomarkers that have been identified for other malignancies but not GBM. Thus, the traits and genes identified on this map highlight new candidate radiogenomic biomarkers for further evaluation in future studies.

Multispecific drug transporters of the solute carrier and ATP-binding cassette families are highly conserved through evolution, but their true physiologic role remains unclear. Analyses of the organic anion transporter 3 (OAT3; encoded by Slc22a8/Oat3, originally Roct) knockout mouse have confirmed its critical role in the renal handling of common drugs (e.g., antibiotics, antivirals, diuretics) and toxins. Previous targeted metabolomics of the knockout of the closely related Oat1 have demonstrated a central metabolic role, but the same approach with Oat3 failed to reveal a similar set of endogenous substrates. Nevertheless, the Oat3 knockout is the only Oat described so far with a physiologically significant phenotype, suggesting the disturbance of metabolic or signaling pathways. Here we analyzed global gene expression in Oat3 knockout tissue, which implicated OAT3 in phase I and phase II metabolism (drug metabolizing enzymes or DMEs), as well as signaling pathways. Metabolic reconstruction with the recently developed "mouse Recon1" supported the involvement of Oat3 in the aforementioned pathways. Untargeted metabolomics were used to determine whether the predicted metabolic alterations could be confirmed. Many significant changes were observed; several metabolites were tested for direct interaction with mOAT3, whereas others were supported by published data. Oat3 thus appears critical for the handling of phase I (hydroxylation) and phase II (glucuronidation) metabolites. Oat3 also plays a role in bioenergetic pathways (e.g., the tricarboxylic acid cycle), as well as those involving vitamins (e.g., folate), steroids, prostaglandins, gut microbiome products, uremic toxins, cyclic nucleotides, amino acids, glycans, and possibly hyaluronic acid. The data seemingly consistent with the Remote Sensing and Signaling Hypothesis (Ahn and Nigam, 2009; Wu et al., 2011), also suggests that Oat3 is essential for the handling of dietary flavonoids and antioxidants.