Retrospective review of all gastric cancer surgeries from 2005 to 2009 ( = 2,588) revealed 53 patients (2.0%) who developed anastomotic leakage and were treated conservatively. EN was performed via a nasointestinal tube inserted using a guidewire under X-ray

fluoroscopy. Clinical outcomes and complications following EN were compared with those in patients treated with PN (historical control group). The severity of complications was evaluated according to the Clavien-Dindo classification.

Fifty patients were included in the final this website analysis (three patients died): 29 patients managed by EN and 21 managed by PN. There were no significant differences in clinical outcomes and the frequency of total complications between the two groups; however, there were fewer tube/catheter-related complications in the EN compared with the PN group (1 vs. 7, respectively; < 0.01). There was one epistaxis (3.4%; grade I) in the EN group and seven catheter infections (33.3%; grade II) in the PN group. The risk of grade II or higher complications was greater in the PN than the EN group (11 vs. 4, respectively; < 0.01), with the greatest difference seen in the incidence of catheter infections. On days 7, 10, and 15 after diagnosis of leakage, the white Mdivi1 blood cell count and C-reactive protein levels were higher in the PN than in the EN group. The PN group required prolonged intravenous antibiotic infusion ( < 0.01).

Nasointestinal

tube insertion with EN can be performed safely for patients with anastomotic leakage. A major advantage of EN is fewer infectious complications. Because EN was not inferior to PN in terms of clinical outcome, we recommended that it is used in patients with anastomotic leakage after gastric cancer surgery.”
“OBJECTIVES: Laser lead extraction is a challenging procedure, especially in patients with old or multiple pacemaker (PM) or implantable cardioverter defibrillator (ICD) leads. The mechanical force is a leading cause of

complications during the extraction procedure. Use of new laser sheaths, which deliver a rate of 80 pulses per second, may probably reduce intraoperative adverse events by reduction of extraction force.

METHODS: selleck chemicals llc Between January 2012 and April 2013, 76 PM and ICD leads were treated in 38 patients using GlideLight 80 Hz laser sheaths. Indications for lead removals were pocket infection (42.1%), septicaemia or endocarditis (23.7%), lead dysfunction (31.6%) and upgrade from PM to ICD (2.6%). Data on procedural success rates, intra-and postoperative outcomes, as well as 30-day mortality were collected into a database and analysed retrospectively.

RESULTS: The mean patient age was 62.0 +/- 17.7 years (range 18-83), and 73.7% were male. The mean time from initial lead implantation was 96.0 +/- 58.3 months (range 24-288). Thirty-seven (48.7%) PM and 39 (51.3%) ICD leads had to be extracted. The mean procedural time was 68.3 +/- 27.3 min (range 35-115).

95 (1.59-5.48). The latter tendency remained strong until 1965. Among non-allergics, the increase in surgery probability by age cohort showed the same tendency, but the relationship was less strong than for those with allergy.

Conclusions: Despite a twofold increase in recurrent OM and OM surgery from 1925 to 1945, the proportion of OM and OM surgery have been stable since 1945. Our findings suggest a shift in clinical practice, most likely

indicating a change in surgery from acute infections to otitis media with effusion (OME). (C) 2010 Elsevier FG-4592 mw Ireland Ltd. All rights reserved.”
“Background: Our study was designed to (1) investigate the risk factors associated with cervical or trochanteric hip fractures; and (2) identify the risk factors for increased mortality in the elderly population sustaining hip fractures, after adjusting the miscellaneous

baseline prefracture conditions.

Methods: Two hundred seventeen elder patients with first-time, low-trauma hip fractures were enrolled. The follow-up time ranged from 35 months to 56 months. Potential risk factors for hip fracture types included (1) the 77 items on the self-reported questionnaire; (2) the body height, weight, and body mass index; (3) tests Ferrostatin-1 datasheet of coordination, handgrip strength, and peak expiratory flow rate; and (4) the bone mineral density variables. GTFN ratio was defined as the bone mineral density ratio between the greater trochanter and the femoral neck. Multivariate logistic regression and Cox regression models were used for analysis. The population attributable risk proportion of death to each significant factor was estimated.

Results: Risk factors for trochanteric fractures include a GTFN ratio <= 0.81, being male, and an age >80 years. Risk factors for higher mortality after hip fracture included trochanteric fracture, body mass index <= 20 (kg/m(2)), poor self-assessed health status, peak expiratory flow rate <=

215 (L/min), being male, illiteracy, and coordination abnormality, in the declining order of population attributable risk proportion. Trochanteric fractures had a significantly higher cumulative mortality at 36 months, 48 months, and 60 months than cervical fractures.

Conclusions: The novel GTFN ratio was associated with hip fracture sites. Clinically, cervical and trochanteric fractures Alpelisib clinical trial represent different disease entities because of the difference in their mortality rates.”
“Background Insecticide-treated nets (ITNs) and indoor residual spraying (IRS) are highly effective tools for controlling malaria transmission in Africa because the most important vectors, from the Anopheles gambiae complex and the A. funestus group, usually prefer biting humans indoors at night.

Methods Matched surveys of mosquito and human behaviour from six rural sites in Burkina Faso, Tanzania, Zambia, and Kenya, with ITN use ranging from 0.2% to 82.

Data from the

cohort were used to examine the ability of the CRIS-CAT to predict key one year outcomes. Data from the CRIS-CAT administration study were used to calculate ICC (2,1) minimum detectable change (MDC), and average number of items used during CAT administration.

Results: Reliability scores for all scales were above 0.75, but decreased at both Selleckchem Talazoparib ends of the score continuum. CRIS-CAT scores were correlated with concurrent validity indicators and differed significantly between the three Veteran groups (P < .001). The odds of having any Emergency Room visits were reduced for Veterans with better CRIS-CAT scores (Extent, Perceived Satisfaction respectively: OR = 0.94, 0.93, 0.95; P < .05). CRIS-CAT scores were predictive of SF-12 physical and mental health related quality of life scores at the 1 year follow-up. Scales had ICCs >0.9. MDCs were 5.9, 6.2, and 3.6, respectively for Extent, Perceived and Satisfaction subscales. Number of items (mn, SD) administered at Visit 1 were 14.6 (3.8) 10.9 (2.7) and 10.4 (1.7) respectively for Extent, Perceived and Satisfaction subscales.

Conclusion: The CRIS-CAT demonstrated sound measurement properties including INCB024360 solubility dmso reliability, construct, known group and predictive validity, and it was administered with minimal respondent burden. These findings support the use

of this measure in assessing community reintegration.”
“Sleep and its disorders are increasingly becoming important in our sleep deprived society. Sleep is intricately connected to various hormonal and metabolic processes in the body and is important in maintaining metabolic homeostasis. Research shows that sleep deprivation and sleep disorders may have profound metabolic and cardiovascular implications. Sleep deprivation, sleep disordered breathing, and circadian misalignment are believed to cause metabolic dysregulation through myriad pathways involving sympathetic overstimulation, hormonal imbalance, and VX-809 subclinical inflammation. This paper reviews sleep and metabolism, and how sleep deprivation and sleep disorders

may be altering human metabolism.”
“Background: Population based studies are important for prevalence, incidence and association studies, but their external validity might be threatened by decreasing participation rates. The 50 807 participants in the third survey of the HUNT Study (HUNT3, 2006-08), represented 54% of the invited, necessitating a nonparticipation study.

Methods: Questionnaire data from HUNT3 were compared with data collected from several sources: a short questionnaire to nonparticipants, anonymous data on specific diagnoses and prescribed medication extracted from randomly selected general practices, registry data from Statistics Norway on socioeconomic factors and mortality, and from the Norwegian Prescription Database on drug consumption.

8 [3.5-4.3]). Standardised mortality ratio (SMR) was higher for type 1 compared with type 2 diabetic patients (4.5 [3.8-5.3] vs 3.5 [3.1-4.0], p = 0.032). For cardiovascular and non-cardiovascular deaths SMRs were 5.6 (95% CI 4.8-6.6) and 2.7 (2.3-3.1) and did not differ according to type of diabetes. SMRs for all-cause and cardiovascular mortality were significantly higher in women compared with men in type 1 (p <0.05 and p <0.01) and type 2 diabetes (p <0.001 and p <0.01). In both types of diabetes, SMRs

significantly decreased during the last two decades R406 inhibitor (p for trend 0.004 and 0.002).

Conclusions: Patients with type 1 and type 2 diabetes had an increased long-term mortality compared with the general Swiss population. Excess mortality was higher in type 1 compared with type 2 diabetes and in women compared with men for both types of diabetes, but steadily

decreased over the last two decades.”
“Study Design. Prospective longitudinal cohort.

Objective. To evaluate the efficacy of hydroxyapatite (HA) grafts in combination with cervical plates in terms of fusion, restoration, and maintenance of cervical lordosis and to compare clinical and radiologic outcomes of patients who experienced graft breakage with patients who did not.

Summary of Background Data. The most common complication related to the use of HA graft for cervical anterior fusion is graft breakage. However, the implication of graft breakage in terms of loss of graft height, cervical alignment, plate migration, and clinical outcomes has not been adequately evaluated.

Methodology. A prospective study of 40 patients who underwent anterior cervical PU-H71 in vivo fusion in which HA graft and plate systems were used. Clinical and radiologic assessments were made 1 month after surgery and again at the final follow-up.

Results.

At the final follow-up evaluation, 80% of patients had an excellent clinical outcome, 15% had a good outcome, and 5% had a fair outcome based on Odom’s classification. All patients achieved lordotic alignment in the immediate EPZ015666 in vitro postoperative period. Graft breakage was observed in 25% of cases. Patients who experienced HA block breakage have 21 times more chance to have intervertebral height loss greater than 2 mm, 4.9 times more likely to undergo loss of cervical alignment exceeding 3, and 12.4 times more likely to present migration of the plates when compared to patients who had normal HA grafts.

Conclusion. Despite the positive clinical results observed in this study, breakage of HA grafts was a common complication occurring in 25% of patients. Graft breakage was associated with strut height loss of more than 2 mm, loss of cervical alignment exceeding 3 and a higher rate of plate migration. These changes related to the HA graft breakage demonstrate the necessity to continue searching for better grafting methods to perform cervical interbody fusion.

Arterial stiffness was assessed by a TensioClinic arteriograph, a recently validated technique. Brachial arterial FMD and ccIMT were determined

using high-resolution ultrasonography. Autoimmune patients exerted impaired FMD (3.7 +/- 3.8%), increased ccIMT (0.7 +/- 0.2 mm), AIx (1.2 +/- 32.2%), and PWV (9.7 +/- 2.4 m/s) in comparison to control subjects (FMD = 8.4 +/- 4.0%; ccIMT = 0.6 +/- 0.1 mm; Aix = -41.1 +/- 22.5%; PWV = 8.0 +/- 1.5 m/s; p < 0.05). We found a significant negative correlation of FMD with AIx (R = -0.64; p < 0.0001) and PWV (R = -0.37; p = 0.00014). There were significant positive correlations between mTOR inhibitor ccIMT and AIx (R = 0.34; p = 0.0009), ccIMT and PWV (R = 0.44; p < 0.0001), as well as AIx and PWV (R = 0.47; p < 0.0001).

AIx, PWV, and ccIMT positively correlated and FMD negatively correlated with the age of the autoimmune patients. Arterial stiffness indicated by increased AIx and PWV may be strongly associated with endothelial dysfunction and overt atherosclerosis in patients with autoimmune diseases. Assessment of arterial stiffness, FMD, and ccIMT are reproducible and reliable noninvasive techniques for the complex assessment of vascular abnormalities in patients at high risk.”
“The PD-1/PD-L1 signaling pathway effects of Ni dopants and O vacancies on the electronic structure and magnetic properties of Ni-doped SnO2 are studied using the first-principles density functional calculation. Both of generalized

gradient approximation (GGA (and GGA+U calculations show that substitutional Ni atoms at Sn sites cannot induce magnetic moment in Ni-doped SnO2 without O vacancy. O vacancies prefer to locate near Ni atoms and induce the magnetic moments at Ni atom and its nearest O atoms. Moreover, O vacancies in a chain connecting two Ni atoms of large distance can lead to a long-range ferromagnetic (FM (coupling between the two Ni atoms. The strength of coupling calculated by GGA+U is about triple that calculated by GGA. The spin density distribution shows that the long-range BX-795 FM coupling between two Ni atoms can be explained in terms of the bound magnetic polaron model. (C) 2010 American Institute of Physics. [doi: 10.1063/1.3428473]“
“This work deals with development, characterization, and performance of an electro-conductive fabric prepared by in situ polymerization of thiophene onto polyester. An attempt was made to optimize the polymerization process to achieve highest level of electro-conductivity of this fabric. The essential characteristics of this electro-conductive fabric were examined and its electromagnetic shielding performance was evaluated. Polythiophene powder was also synthesized and analyzed. (C) 2010 Wiley Periodicals, Inc.

“
“Introduction: The phase III TITAN trial evaluated the use of darunavir with low-dose ritonavir (DRV/r)

600/100 mg twice daily (bid) compared with lopinavir with low-dose ritonavir (LPV/r) in treatment-experienced, lopinavir-naive patients. This study estimates the cost effectiveness of DRV/r from a US societal perspective when compared with LPV/r in treatment-experienced patients with a profile similar to those TITAN patients who had one or more International AIDS Society – USA (IAS-USA) primary protease inhibitor (PI) resistance-associated mutations (RAMs) at baseline. This NMS-E628 population had less advanced HIV disease and a broader range of previous PI exposure/failure (0-2 PIs) at enrolment than those in the darunavir phase IIb POWER trials.

Methods: An existing Markov model containing

six health states defined by CD4 cell count range (>500, 351-500, 201-350, 101-200, 51-100 and 0-50 cells/mm(3)) and an absorbing state of death was adapted. Baseline demographics, CD4 cell count distribution and antiretroviral https://www.selleckchem.com/products/geneticin-g418-sulfate.html drug usage, virological response (at week 24), and immunological response estimates and matching transition probabilities were based on data collected directly from the one or more IAS-USA PI mutation subpopulation during the first 48 weeks of the TITAN trial, as well as from published literature. Patients were assumed to switch to a regimen containing tipranavir plus an optimized background regimen after treatment failure. For each CD4 cell count range

or health state, the utility values, HIV and non-HIV-related mortality rates, and non-antiretroviral-related VE 822 cost of HIV care estimates were derived from published literature. Unit costs were derived from official local sources. A lifetime horizon was taken in the base-case analysis.

Results: The base-case analysis predicted discounted quality-adjusted survival gains of 0.493 quality-adjusted life-years (QALYs) for DRV/r compared with LPV/r, resulting in an incremental cost-effectiveness ratio (ICER) of US$23 057 per QALY gained over a lifetime horizon. Probabilistic sensitivity analysis indicated a 0.754 probability of an ICER below the threshold of US$50 000 per QALY gained. DRV/r remained cost effective over all parameter ranges tested in extensive one-way sensitivity analyses and variability analyses, which examined the impact of input parameter uncertainty and changes in model assumptions and treatment patterns, respectively. Shortening the model time horizon had the largest impact on the ICER, reducing it most notably to US$4919 with a 10-year time horizon.

Methods: We retrospectively compared results of completely portal robot lobectomy with 4 arms (CPRL-4) against propensity-matched controls and results after technical changes to CPRL-4.

Results: In 14 months, 168 patients underwent robotic pulmonary resection: 7 had metastatic pleural disease, 13 had conversion to open procedures, and 148 had completion robotically (106 lobectomies, 26 wedge resections, 16 segmentectomies). All

patients underwent R0 resection and removal of all visible lymph nodes (median of 5 N2, 3 N1 nodal stations, 17 lymph nodes). The 106 patients who underwent CPRL-4 were compared with 318 propensity-matched patients selleck chemicals who underwent lobectomy by rib- and nerve-sparing thoracotomy. The robotic group had reduced morbidity (27% vs 38%; P = .05), lower mortality (0% vs 3.1%; P = .11), improved PCI-32765 ic50 mental quality of life (53 vs 40; P < .001), and shorter hospital stay (2.0 vs 4.0 days; P = .02). Results of CPRL-4 after technical modifications led to reductions in median operative time (3.7 vs 1.9 hours; P < .001) and conversion (12/62 vs 1/106; P < .001). Technical improvements were

addition of fourth robotic arm for retraction, vessel loop to guide the stapler, tumor removal above the diaphragm, and carbon dioxide insufflation.

Conclusions: The newly refined CPRL-4 is safe and yields an R0 resection with complete lymph node removal. It has lower morbidity, mortality, shorter hospital stay, and better quality of life than rib- and nerve-sparing thoracotomy. Technical advances are possible to shorten and improve the operation. (J Thorac Cardiovasc Surg 2011; 142: 740-6)”
“The localization of stilbene synthase (STS) (EC 2.3.1.95) in grape berry (Vitis vinifera L.) was investigated during fruit development. The berries were collected at 2, 4, 7, 11, and 15 weeks postflowering from the cultivar Nebbiolo during the 2005 and 2006 growing seasons. High-performance liquid chromatography analysis showed that berries accumulated cis- and

trans-isomers of resveratrol mainly in the exocarp throughout fruit development. Immunodetection Rigosertib clinical trial of STS protein was performed on berry extracts and sections with an antibody specifically developed against recombinant grape STS1. In agreement with resveratrol presence, STS was found in berry exocarp tissues during all stages of fruit development. The labeled epidermal cells were few and were randomly distributed, whereas nearly all the outer hypodermis cells were STS-positive. The STS signal decreased gradually from exocarp to mesocarp, where the protein was detected only occasionally. At the subcellular level, STS was found predominantly within vesicles (of varying size), along the plasma membrane and in the cell wall, suggesting protein secretion in the apoplast compartment.

Most of the neuronal migration is completed by midgestation. The second part of the gestation corresponds to the development of the connectivity and sulcation, of the maturation of the oligodendrocytic lineage and of the microglia, and of the

vascular bed in the parenchyma beyond the germinal matrix.

In this paper, the main processes of the developmental anatomy of the premature brain are reviewed, and are correlated with the findings in a prospective series of 105 premature infants born between 24 and 32 weeks of gestation, and serially examined with MR imaging at birth, at term-equivalent age, at 2 years, and at 4 years. Special emphasis was placed (1) on the intraventricular hemorrhage because of the resulting destruction of the germinal matrix and its NF-��B inhibitor impact on the late cellular production, (2) on the periventricular venous hemorrhagic infarction because of the selective destruction of the intermediate zone which is associated, and (3) on the apparently perivenous punctate

lesions of the white matter because they involve the intermediate zone also, because they have no Defactinib convincing explanation yet, and because the microglia seems to be associated with their pathogenesis.

These deep venous injuries appear to preserve the subplate zone, which is likely to be a significant element to consider in the perspective of the neurodevelopmental outcome.”
“The formation of viable angiosperm seeds involves the co-ordinated growth and development of three genetically distinct organisms, the maternally derived seed coat and the zygotic embryo and endosperm. The

physical relationships of these tissues are initially established during the specification and differentiation of the female gametophyte within the tissues of the developing ovule. The molecular programmes implicated in both ovule and seed development EPZ015666 cost involve elements of globally important pathways (such as auxin signalling), as well as ovule- and seed-specific pathways. Recurrent themes, such as the precisely controlled death of specific cell types and the regulation of cell-cell communication and nutrition by the selective establishment of symplastic and apoplastic barriers, appear to play key roles in both pre- and post-fertilization seed development. Much of post-fertilization seed growth occurs during a key developmental window shortly after fertilization and involves the dramatic expansion of the young endosperm, constrained by surrounding maternal tissues. The complex tissue-specific regulation of carbohydrate metabolism in specific seed compartments has been shown to provide a driving force for this early seed expansion. The embryo, which is arguably the most important component of the seed, appears to be only minimally involved in early seed development.

Results: The results of diurnal rhythmicity revealed a trend showing marginally lower evening cortisol for the TS group. By contrast, the TS group had higher cortisol levels in response to the stressor. There were strong, negative correlations between evening cortisol and tic severity as well as diurnal cortisol and anxiety.

Conclusions: The children with TS showed increased cortisol in response to the MRI environment, supporting a model of enhanced HPA responsivity. The lower evening cortisol may be the result of chronic daily stress. Alternatively, the negative associations between cortisol

and reported anxiety and tics may reflect biologically based anxiolytic properties of tic expression. AZD9291 Taken together, the results clearly Barasertib implicate involvement of the HPA axis in the neuropathology of TS. (c) 2008 Elsevier Ltd. All rights reserved.”
“Cytokinesis, the final stage of the cell division cycle, requires the proper placement, assembly and contraction of an actomyosin-based contractile ring. Conserved sets of cytokinesis proteins and pathways have now been identified and characterized functionally. Additionally, fluorescent

protein fusion technology enables quantitative high-resolution imaging of protein dynamics in living cells. For these reasons, the study of cytokinesis is now ripe for quantitative, systems-level approaches. Here, we review our current understanding of the molecular mechanisms of contractile ring dynamics in the model organism Schizosaccharomyces pombe (fission yeast), focusing on recent examples that illustrate a synergistic integration of quantitative experimental data with computational modeling. A picture of a highly dynamic and integrated system consisting of overlapping networks is beginning to emerge, the detailed nature of which remains to be elucidated.”
“Multiple system atrophy (MSA) is a sporadic neurodegenerative disorder. Its histopathological features include glial cytoplasmic

inclusions that contain a-synuclein as the main component. Recently, multiple lines of evidence have suggested a role for lysosomes in the pathogenesis of many neurodegenerative diseases. To elucidate whether lysosomes are also implicated in the pathology of MSA, we carried out an immunohistochemical study using antibodies against lysosomal proteins in the brains of patients with MSA and in control brains. A robust Lactose synthase increase in the expression and an alteration in the morphology and distribution of lysosomal-protein-positive structures were observed in MSA brains. Double immunohistochemistry demonstrated that lysosomal markers did not colocalize mainly with glial cytoplasmic inclusions, but colocalized with a microglial marker. These immunohistochemical signatures suggest that lysosomes are activated in microglia during the disease process, and play a pivotal role in the pathology of MSA. NeuroReport 23: 270-276 (C) 2012 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.

We induced morphine withdrawal by injecting naloxone to rats that self-administer morphine and evaluated the effects of acupuncture and/or GABA receptor antagonists on their withdrawal symptoms. Acupuncture at

HT7, but not at the control point LI5, significantly decreased symptoms of morphine withdrawal. HT7 inhibition of the withdrawal syndrome was blocked by pretreatment with either the GABA(A) receptor antagonist bicuculline or the GABA(B) antagonist SCH 50911. These findings suggest that the effects of acupuncture on suppression of morphine withdrawal syndrome are mediated, at least in part, through GABA receptors. Ulixertinib in vitro (C) 2011 Elsevier Ireland Ltd. All rights reserved.”
“Novel protein kinase Cs (nPKCs) contain an N-terminal C2 domain that cannot bind to calcium. We have previously shown that the Aplysia novel PKC Apl II’s C2 domain inhibits binding

of diacylglycerol PF-573228 manufacturer (DAG) to the C1 domain and that this inhibition is removed by phosphatidic acid (PA) binding to the C1b domain. Another model for C2 domain regulation of nPKCs suggests that the C2 domain binds to receptors for activated C kinase (RACKS) to assist in kinase translocation and activation. In the present study, we examined how a pharmacological peptide derived from RACK-binding site in the vertebrate novel PKCE regulates translocation of PKC Apl II from the cytosol to the plasma membrane. We found that a C2 domain-derived inhibitor peptide inhibited PKC Apl II translocation. This inhibition was removed by R273H mutation in the C1b domain and by phosphatidic acid, which can both remove C2-domain mediated inhibition suggesting that the peptide can regulate C1-C2 domain interactions. (C) 2011 Elsevier Ireland

Ltd. All rights reserved.”
“Defect of hypoxanthine phosphoribosyl transferase (HPRT) causes Lesch-Nyhan disease (LND), but the link between HPRT deficiency and the self-injurious behavior of LND is unknown. In a ARN-509 previous study (Pinto et al., J. Neurochem. 72 (2005) 1579-1586) we reported on a decrease in nucleotidase activity in membranes of several HPRT(-) cell lines and fibroblasts from LND patients. Since nucleotidases are involved in ATP-induced signal transduction, in the present study, we tested the hypothesis that P2X and P2Y receptor-mediated signal transduction is impaired in HPRT deficiency. As model we studied rat B103 neuroblastoma cells. Compared to control cells, in HPRT- cells, NTP and NDP-induced Ca(2+) influx across the membrane and Ca(2+) mobilization from intracellular stores were impaired. Both P2X and P2Y receptors were involved in the responses. Quantitative real-time PCR revealed reduced expression of receptors P2X(3), P2X(5), P2Y(2), P2Y(4), P2Y(12), P2Y(13) and P2Y(14) in HPRT deficiency.