“
“Since 2006, the National Oncologic PET Registry has collected prospective data on F-18-FDG PET performed for cancer indications in Medicare

beneficiaries under the coverage-with-evidence-development (CED) policy of the Centers for Medicare & Medicaid Services. In April 2009, coverage for PET performed to inform the initial treatment 3 strategy of most solid tumors was expanded by the Centers for Medicare & Medicaid Services, but they continued to require CED for subsequent treatment strategy evaluations for many cancers. Methods: For all years, we assessed National Oncologic PET Registry data for bladder, kidney, pancreas, prostate, stomach, small CYT387 ic50 cell lung, uterine, and all other cancers that required CED. We compared clinical profiles and changes in intended management by interval (before or after April 2009, designated as the 2006 and 2009 cohorts) for PET scans performed for restaging or suspected recurrence (2006, n = 30,911; 2009, n = 54,747) or for chemotherapy monitoring (2006, n = 10,234; 2009, n = 15,611). Results: There were slight differences between time periods but little difference by cancer type or patient age within a time period. For restaging or suspected recurrence, comparing the 2006 and 2009 cohorts, total change in intended

management for all cancer types was about 33% in those younger than 65 y and about selleck inhibitor 35% in those older than 65 y (range by cancer type, 31%-41%). The referring physician impression of disease extent (restaging) or prognosis (chemotherapy monitoring) after PET was similar between cohorts. In the 2009 cohort, PET for chemotherapy monitoring was associated with a 25% increase in plans to continue therapy and a complementary decline in plans to adjust therapy. The greatest management impact of PET was during chemotherapy monitoring in the 2009 cohort, where a post-PET prognosis judged to be worse than before PET was associated with a plan to discontinue that therapy

in 90% and to change to a different therapy in 65%. Conclusion: Our data demonstrate a similar impact of PET on planned management of cancer patients before and after the 2009 expansion of coverage. These results strongly suggest it is unlikely that new useful information will be obtained by extending the coverage of certain Selisistat order cancer types and indications only under CED. Future research on advanced imaging in the management of patients with cancer should focus on optimal sequencing and frequency of PET and other imaging modalities.”
“Sex differences in neural development are established via a number of cellular processes (i.e., migration, death and survival). One critical factor identified is the neonatal rise in testosterone (T) which activates gene transcription via androgen (AR) and, after aromatization to estradiol, estrogen receptors (ER alpha and beta). Recent evidence shows that AR and ERs interact with histone modifying enzymes.

\n\nConclusion-Activation of the EP3 receptor raises baseline blood pressure and contributes to Ang II dependent hypertension a least partially via enhancing Ca2+ sensitivity and intracellular calcium concentration in vascular smooth muscle cells. Selective targeting of the EP3 receptor may represent a potential therapeutic target for the 4 Treatment of hypertension. (Arterioscler Thromb Vasc Biol. 2012;32:3024-3032.)”
“SPIN90 is a key regulator of actin cytoskeletal organization. Using the BioGRID(beta) database (General Repository for Interaction Datasets), we identified IRSp53 as a binding partner of SPIN90, and confirmed the in vivo formation of a SPIN90-IRSp53 complex

mediated through direct association of the proline-rich domain (PRD) of

SPIN90 with the SH3 domain of IRSp53. SPIN90 and IRSp53 positively cooperated to mediate Rac click here activation, Navitoclax inhibitor and co-expression of SPIN90 and IRSp53 in COS-7 cells led to the complex formation of SPIN90-IRSp53 in the leading edge of cells. PDGF treatment induced strong colocalization of SPIN90 and IRSp53 at membrane protrusions. Within such PDGF-induced protrusions, knockdown of SPIN90 protein using siRNA significantly reduced lamellipodia-like protrusions as well as localization of IRSp53 at those sites. Finally, competitive inhibition of SPIN90-IRSp53 binding by SPIN90 PRD dramatically reduced ruffle formation, further suggesting that SPIN90 plays a key role in the formation of the membrane protrusions associated with cell motility. (C) 2009 Elsevier Inc. All rights reserved.”
“Most centres in Europe have not introduced

a rapid response team (RRT), partly because of concerns that data from other health-care systems may not be relevant. We tested whether patient characteristics and outcomes for deteriorating patients differ between two health-care systems separated by distance and culture.\n\nWe obtained data from 3,063 RRT calls: 815 calls at Karolinska University Hospital (Sweden) and Stattic 2,248 calls at Austin Hospital (Australia) and compared demographic and clinical data, as well as outcomes for patients reviewed by a RRT.\n\nAt Karolinska, 46.9% of patients were female compared with 45.1% at Austin. Mean age was 66.5 years versus 69.4 years. The unit of admission was surgical/medical in 49.1%/50.9% versus 48.8%/51.1% of patients, respectively. Overall, 56.7% versus 55.8% of the calls were out-of-hours (1700-0800 hours). There was a predominance of respiratory triggers at both centres and the “worried” criterion was frequently used in both hospitals (17.2% versus 14.4%) as a trigger for RRT activation. Overall, 30-day mortality was 27.7% versus 29.4% and allocation of Limitations of Medical Treatment (LOMT) orders was 34.2% versus 30.8%. The allocation of LOMT orders was influenced by the RRT in 14.4% versus 12.6% of cases.

\n\nMethods: A prospective, consecutive and comparative trial was conducted in 75 patients who underwent elective pulmonary resection for non small cell lung cancer.

This study compared two digitals devices with the current analogue version in 75 patients. The digital and analogue groups had 26, 24, and 25 patients, respectively.\n\nResults: Clinical population data were not statistically different between the groups. The withdrawal of the chest tube was Thopaz, 2.4 learn more days; Digivent, 3.3 days and PleurEvac, 4.5days. Patients and nurses were subjectively more comfortable with digital devices. Surgeons obtained more 123 objective information with digital devices. The safety mechanism

of the Thopaz was also subjectively better, and one patient was discharged home without complications after one week.\n\nConclusions: The digital and continuous measurement of air leak instead of the currently used static analogue systems reduced the chest tube withdrawal and hospital stay by more accurately and reproducibly measuring air leak. Intrapleural pressure curves from the Digivent may also help predict the optimal chest tube setting for each patient. The Thopaz alarm mechanism is very useful to prevent deficiencies in the mechanism and do not required wall suction. (C) 2010 AEC. Published by Elsevier Espana, S.L. All rights reserved.”
“Objectives To assess contraceptive find more knowledge, use of emergency contraception (EC) and the

motives of women seeking induced abortion.\n\nMethods A descriptive and cross-sectional study conducted at the T. C. Izmir Dr. Hayri Ekrem Ustundag Gynaecology and Maternity Hospital and the Izmir Ataturk Research and Teaching Hospital, Turkey. The research sample consisted of 440 women who requested an abortion between January and May 2010, and voluntarily agreed to participate.\n\nResults Sixty-two percent of the women became pregnant while using family planning (FP) methods. The contraceptive used by 42%% was the condom, and 45%% believed that they had become pregnant because of improper use of the contraceptive. Ninety-three percent had never used EC. Thirty-seven percent GW4869 wanted their pregnancy terminated because they did not want another child, whereas 26%% viewed induced abortion as a method of FP. Sixty-nine percent of the women received FP counselling from health professionals, and 80%% found the information provided adequate.\n\nConclusion The women assessed were insufficiently knowledgeable about FP in general and EC in particular. Many had become pregnant as a result of inaccurate information.”
“Chemical allergens bind directly, or after metabolic or abiotic activation, to endogenous proteins to become allergenic.

Follow-up examinations including clinical assessment and Doppler ultrasound imaging were performed at 3 months and every 6 months thereafter. Findings demonstrated bypass patency and healing of the 432 covered defect in all cases. Outcome in this initial series demonstrates the clinical feasibility of the new BF reconstruction technique, which allows revascularization and coverage of tissue defects using a one-piece anatomic unit.”
“The aim of this paper was to analyze

energy-related properties of forestry and agricultural wastes for energy production purposes, and to compare them with fossil fuels. The forestry wastes used were red cedar, Eucalyptus, and Pinus wood shavings. The agricultural wastes analyzed were rice husk, coffee wastes, sugar cane bagasse, maize harvesting wastes, and bamboo cellulose pulp. The forestry wastes presented more suitable properties for bioenergy production

selleck screening library than the agricultural wastes. check details Desirable energetic properties were found for coffee wastes. The opposite was verified for rice husks. Among the biomass studied, coffee wastes presented the highest equivalent in fossil fuel volume and hence may lead to the highest decrease in CO2 emissions by fossil fuels used in Brazil for steam and heat production. The results suggests that CO2 benefits can be obtained if bioenergy is generated in the same locale where biomass is produced, avoiding CO2 cost of logistics and leading to greater end-use efficiency. The present work promotes the widespread use of different lignocellulosic wastes for bioenergy production and gives useful information for the planning and the control of power plants using biomass.”
“Erythrocytes have an environment of continuous pro-oxidant generation due to the presence of hemoglobin (Hb), which represents an additional and quantitatively significant source of superoxide (O-2(center dot-)) generation in biological systems. To counteract oxidative stress, erythrocytes have a self-sustaining antioxidant defense system. Thus, red blood cells uniquely function to protect Hb via a selective barrier

allowing gaseous and other ligand transport as well as providing antioxidant protection not only to themselves but also to other tissues and organs in the body. Sickle www.selleckchem.com/products/netarsudil-ar-13324.html hemoglobin molecules suffer repeated polymerization/depolymerization generating greater amounts of reactive oxygen species, which can lead to a cyclic cascade characterized by blood cell adhesion, hemolysis, vaso-occlusion, and ischemia-reperfusion injury. In other words, sickle cell disease is intimately linked to a pathophysiologic condition of multiple sources of pro-oxidant processes with consequent chronic and systemic oxidative stress. For this reason, newer therapeutic agents that can target oxidative stress may constitute a valuable means for preventing or delaying the development of organ complications. (C) 2013 Elsevier Inc. All rights reserved.

At the 1s exciton resonance, two peaks are identified in the absorption spectra, which are assigned to splitting of the exciton ground state into the triplet and singlet states. 2DFT spectra acquired for co-linear polarization of the excitation pulses feature an additional peak originating from coherent energy transfer between the singlet and triplet. At cross-linear polarization of the excitation pulses, the 2DFT spectra expose a new peak likely originating from bound biexcitons. The polarization dependent 2DFT spectra are well reproduced by simulations using the optical Bloch equations for a four level system, where many-body effects

are included phenomenologically. Although biexciton effects are thought to be strong in this material, only moderate contributions from bound biexciton

creation can be observed. The biexciton see more binding energy of similar to 2 meV was estimated from the separation of the FK228 order peaks in the 2DFT spectra. Temperature dependent absorption and 2DFT measurements, combined with “ab initio” theoretical calculations of the phonon spectra, indicate strong interaction with the A(1)’ phonon mode. Excitation density dependent 2DFT measurements reveal excitation induced dephasing and provide a lower limit for the homogeneous linewidth of the excitons in the present GaSe crystal. (C) 2015 AIP Publishing LLC.”
“A Summary This is the first reported study to describe local bone mineral density, assess parameters of fracture risk and report history of fractures in adolescents with motor difficulties. Motor difficulties evidenced by poor coordination in adolescence should be considered a new risk factor for below-average bone strength and structure and fracture risk. Introduction Adolescents with motor difficulties are characterised by poor coordination and low levels of physical

activity and fitness. It is possible these deficits translate into below-average bone strength and structure. The objectives GSK1838705A mouse of this study were to describe local bone mineral density (BMD), assess parameters of fracture risk (stress-strain index, SSI) and report history of fractures in this group. Methods Thirty-three adolescents (13 females), mean age of 14.3 (SD = 1.5) years, with motor difficulties underwent peripheral quantitative computed tomography (pQCT) measurements at proximal (66 %) and distal (4 %) sites of the non-dominant radius (R4 and R66) and tibia (T4 and T66). One sample t test was used to compare Z-scores for total BMD, trabecular density, cortical density and stress strain index (SSI) against standardized norms. Results Significant differences were present at R4 total density mean Z-score = -0.85 (SD = 0.7, p smaller than 0.001), R66 cortical density mean Z-score = -0.74 (SD = 1.97, p = 0.038), R66 SSI mean Z-score = -1.00 (SD = 1.08, p smaller than 0.001) and T66 SSI mean Z-score = -0.70 (SD = 1.15, p smaller than 0.001). There was a higher incidence of fractures (26.9 %) compared to the normal population (3-9 %).

“
“Background: High-mobility group AT-hook 2 (HMGA2) protein acts as an oncofoetal transcriptional regulator. In mesenchymal tissues, its expression can be induced by a variety of growth factors such as fibroblast growth factor-1 (FGF1) and platelet-derived growth factor-BB (PDGF-BB) as well as by foetal bovine serum (FBS), thus enhancing proliferation. Materials and Methods: To examine these effects in epithelial malignancies, we used the PC-3 prostate cancer cell line for assaying proliferation

and HMGA2 expression in Selleckchem Napabucasin response to incubation with growth factors and FBS. The HMGA2 locus was investigated by fluorescence in situ hybridisation (FISH) for loss, amplification or re-arrangement. Results: PC-3 is a cell line that

moderately overexpresses HMGA2. None of the growth factors nor FBS caused significantly increased expression of HMGA2. In contrast, a significantly augmented proliferation rate was observed when applying FGF1 or PDGF-BB for 12 h. Conclusion: HMGA2 is expressed independently of external stimuli, whereas proliferation stimulated by growth factors is independent of further elevated HMGA2 expression.”
“Since its use as a model to study metazoan parasite culture and in vitro development, the plerocercoid of the tapeworm, Ligula intestinalis, has served as a useful scientific tool to study a range of biological factors, particularly within its fish intermediate host. From the extensive long-term ecological studies on the interactions between the parasite

and cyprinid hosts, to the recent advances made using molecular HKI-272 price G418 chemical structure technology on parasite diversity and speciation, studies on the parasite have, over the last 60 years, led to significant advances in knowledge on host-parasite interactions. The parasite has served as a useful model to study pollution, immunology and parasite ecology and genetics, as well has being the archetypal endocrine disruptor.”
“Nonisothermal densification in 8% yttria doped zirconia (8YSZ) particulate matter of 250 nm median particle size was studied under 215 V/cm dc electric field and 9 degrees C/min heating rate, using time-resolved in-situ high temperature energy dispersive x-ray diffractometry with a polychromatic 200 keV synchrotron probe. Densification occurred in the 876-905 degrees C range, which resulted in 97% of the theoretical density. No local melting at particle-particle contacts was observed in scanning electron micrographs, implying densification was due to solid state mass transport processes. The maximum current draw at 905 degrees C was 3 A, corresponding to instantaneous absorbed power density of 570 W/cm(3). Densification of 8YSZ was accompanied by anomalous elastic volume expansions of the unit cell by 0.45% and 2.80% at 847 degrees C and 905 degrees C, respectively.

Significance: Alternative splicing plays a fundamental role in regulating functionality upon T cell activation. The noncanonical nuclear factor B (ncNFB) pathway regulates the expression of chemokines required for secondary lymphoid organ formation and thus plays a pivotal role in adaptive immunity. Whereas ncNFB signaling has been well described in stromal cells and B cells, its role and regulation in T cells remain largely unexplored. ncNFB activity MAPK inhibitor critically depends on the upstream NFB-inducing kinase (NIK). NIK expression is negatively regulated by the full-length isoform of TNF receptor-associated factor 3 (Traf3) as formation of a NIK-Traf3-Traf2

complex targets NIK for degradation. Here we show that T cell-specific and activation-dependent alternative splicing generates a Traf3 isoform lacking exon 8 (Traf3DE8) that, in contrast to the

full-length protein, activates ncNFB signaling. Traf3DE8 disrupts the NIK-Traf3-Traf2 complex and allows accumulation of NIK to initiate ncNFB signaling in activated T cells. ncNFB activity results in expression of several chemokines, among them B cell chemoattractant (CxCL13), both in a model T cell line and in primary human CD4(+) T cells. Because CxCL13 plays an important role in B cell migration and activation, our data suggest an involvement and provide a mechanistic basis for Traf3 alternative splicing and ncNFB activation in Selleck Rabusertib contributing to T cell-dependent adaptive immunity.”
“The aim of this study was to estimate the prognostic factors for the outcomes of chronic myeloid leukemia (CML) patients receiving allogeneic stem cell transplantation (SCT) in chronic phase (CP) in the era of tyrosine kinase inhibitors (TKIs). Ninety-seven patients who underwent allogeneic SCT in CP were analyzed. Forty-seven were TKI-naive

at the time of transplant, and 50 received TKI(s) treatment before transplantation. After a median follow-up of 115.8 months, the GSK923295 4-year overall survival and event-free survival were 80.4 and 58.8%, respectively. Multivariate analysis showed that there were no differences in survival outcomes based on prior TKI therapy. Older age was a prognostic factor for higher treatmentrelated mortality (TRM), and the type of graft source and younger age were associated with relapse, but prior TKI therapy and disease status at the time of transplant were not associated with either TRM or relapse. Additionally, a major molecular response at 1 month and an MR4.5 at 3 months were important predictors of favorable long-term outcomes. This study demonstrates the prognostic factors for the outcomes of allogeneic SCT in CP CML and shows that survival outcomes were not affected by the administration of long-term multi-TKI treatment prior to transplantation.”
“Superficial fungal infections are widespread, regardless of age and gender, in populations all around the world and may affect the skin and skin appendages.

We provide evidence to support a possible hypothesis which could explain much of the

conflicting clinical and experimental evidence.”
“Multivariate regression is increasingly used to study the relation between fMRI spatial activation patterns and experimental stimuli or behavioral ratings. With linear models, informative brain locations are identified by mapping the model coefficients. This is a central aspect in neuroimaging, as it provides the sought-after link between the activity of neuronal populations and subject’s perception, cognition or behavior. Here, we show that mapping of informative brain locations using multivariate linear regression (MLR) may lead to incorrect conclusions and interpretations. buy Daporinad MLR algorithms for high dimensional data are designed to deal with targets (stimuli or behavioral ratings, in fMRI) separately, and the predictive map of a model integrates information deriving from both neural activity patterns and experimental design. Not accounting explicitly for the presence of other targets whose associated activity spatially overlaps with the one of interest may lead to predictive maps of troublesome interpretation. We propose a new model that can correctly identify the spatial patterns associated with a target while achieving good generalization. For each target, the training is based

on an augmented dataset, which includes all remaining targets. www.selleckchem.com/products/wnt-c59-c59.html The estimation on such datasets produces both maps and interaction coefficients, which are then used to generalize. The proposed formulation is independent of the regression algorithm employed. We validate this model on simulated fMRI data and on a publicly available dataset. Results indicate that our method achieves high spatial sensitivity and good generalization and that it helps disentangle specific neural effects from interaction with predictive maps associated with other targets. Hum Brain Mapp 35:2163-2177, 2014. (c) 2013 Wiley Periodicals, Inc.”
“Objectives: 1) Evaluate the effects

of monopolar cautery on cochlear implant devices. 2) Determine whether voltage fluctuations within the cochlear implant adversely affect the Y-27632 cochlear implant devices Study Design: Two Med-El cochlear implants modified to record voltage difference from the apical and proximal electrodes were implanted into an unembalmed, fresh cadaver. Cautery was applied to the ipsilateral pectoralis major muscle and ipsilateral temporalis muscle at bipolar, monopolar coagulation, and monopolar cut settings of 50 W. The intensity in each modality setting was increased by increments of 10 W to a maximum of 100 W. Integrity testing was performed before, during, and after each cautery setting. Voltage fluctuations were measured during cautery, and maximal voltage changes for each setting were noted. After explantation, devices were returned to the manufacturer for in-depth failure analysis to evaluate for any damage to the devices.

Taken together, our study demonstrates that LEN plus RTX provides a synergistically therapeutic effect on MCL cells by enhancing PLX4032 molecular weight apoptosis and RTX-dependent NK cell-mediated cytotoxicity and may be an optimal combination

in the clinical trial of relapsed or refractory MCL. Am. J. Hematol. 84:553-559, 2009. (C) 2009 Wiley-Liss, Inc.”
“Thrombocytopenia caused by rapid platelet consumption contributes to the severe thrombocytopenia of Wiskott-Aldrich syndrome (WAS) and to the milder thrombocytopenia seen in murine WAS. We show that rapid clearance of mIn-labeled murine WASP(-) platelets correlates with enhanced splenic uptake. Using platelets labeled with a pH-sensitive fluorescent marker (pHrodo), we quantify normal platelet uptake by red pulp macrophages (RPMs), and demonstrate

its enhancement after in vivo opsonization of platelets. The spleens of WASP(-) mice contain an increased number of RPM, and rapid clearance of WASP(-) platelets in WASP(-) mice in turn generates an increased number of pHrodo(+) splenic RPMs. To separately assess the platelet intrinsic and recipient-dependent functions involved in the clearance and splenic phagocyte uptake of WASP(-) platelets, we performed “crossed” pHrodo(+) platelet injection studies (wild type [WT] to WASP(-), WASP(-) to WT). We show that an extrinsic effect of recipient WASP deficiency CP-868596 mouse on the clearance of WASP(-) platelets correlates with increased platelet SB203580 order uptake by RPMs. An intrinsic effect of platelet WASP deficiency on platelet clearance does not, however, correlate with increased total uptake by WT or WASP(-) RPMs. In contrast to other published findings, we find no evidence of a baseline or antibody-induced increase in phosphatidyl serine exposure on WASP(-) platelets. Our findings suggest that an increased number of RPMs in WASP(-) mice contributes significantly to the increased platelet consumption rate in WASP(-) mice. This might explain the consistent efficacy of splenectomy in murine and clinical

WAS. Published by Elsevier Inc. on behalf of ISEH – Society for Hematology and Stem Cells.”
“One of the first studies on the energy metabolism of a tumour was carried out, in 1922, in the laboratory of Otto Warburg. He established that cancer cells exhibited a specific metabolic pattern, characterized by a shift from respiration to fermentation, which has been later named the Warburg effect. Considerable work has been done since then, deepening our understanding of the process, with consequences for diagnosis and therapy. This review presents facts and perspectives on the Warburg effect for the 21st century. (C) 2010 Elsevier Inc. All rights reserved.”
“EphA2 kinase regulates cell shape, adhesion, and motility and is frequently overexpressed in several cancers, including melanoma, prostate, breast, and colon cancers and lung carcinoma.

The aim of this study is to evaluate whether levobupivacaine has vasoconstrictive effects on the basilar

artery in rabbits. Material and methods: Thirty male New Zealand white rabbits were divided randomly into three groups of ten rabbits each: group 1 (control); group 2 (0.125% levobupivacaine); group 3 (0.25% levobupivacaine). The cisterna magna was punctured as described below, then 1 ml of saline or 0.125% or 0.25% levobupivacaine was injected into the cisterna magna in 10 min by an infusion pump in groups 1, 2 and 3 respectively. All animals were euthanized by perfusion-fixation 30 min after the procedure. The luminal area and the size of the cross-sectional area for each basilar artery were measured. Results: Both 0.125% and 0.25% levobupivacaine infusion caused significant vasoconstriction. Protein Tyrosine Kinase inhibitor Vasoconstriction was more significant for the

0.125% concentration. Conclusions: The results of this study indicated that both 0.125% and 0.25% concentrations of levobupivacaine caused significant vasoconstriction of the basilar artery when administered into the subarachnoid space. This CDK inhibitors in clinical trials may constitute proof that subarachnoid administration of levobupivacaine may diminish the spinal cord blood flow, causing ischemia.”
“Chronic obstructive pulmonary disease (COPD) is an inflammatory lung disorder with complex pathological features and largely unknown etiology. The identification of biomarkers for this disease could

aid the development of methods to facilitate earlier diagnosis, the classification of disease subtypes, and provide a means to define therapeutic response. To identify gene expression biomarkers, we completed expression profiling of RNA derived from the lung tissue of 56 subjects with varying degrees of airflow obstruction using the Affymetrix U133 Plus 2.0 array. We applied multiple, independent analytical methods to define biomarkers for either discrete or quantitative disease phenotypes. Analysis of differential expression between cases (n = 15) and controls (n = 18) identified a set of 65 discrete biomarkers. Correlation of gene expression with quantitative measures of airflow obstruction (FEV(1)%predicted or FEV(1)/FVC) https://www.selleckchem.com/products/nct-501.html identified a set of 220 biomarkers. Biomarker genes were enriched in functions related to DNA binding and regulation of transcription. We used this group of biomarkers to predict disease in an unrelated data set, generated from patients with severe emphysema, with 97% accuracy. Our data contribute to the understanding of gene expression changes occurring in the lung tissue of patients with obstructive lung disease and provide additional insight into potential mechanisms involved in the disease process. Furthermore, we present the first gene expression biomarker for COPD validated in an independent data set.”
“Background: The C282Y mutation of the hemochromatosis (HFE)-gene increases body iron status.