To understand, monitor and compare the scope of food waste in hospital foodservices, it is essential to measure food waste using a standardised method. The aims of this systematic review were to (i) describe and critique the methodological features of waste audits used in hospital foodservice settings that measure aggregate food and food-related waste and (ii) develop a consensus tool for conducting a food waste audit in a hospital foodservice setting. Seven electronic databases were searched for peer reviewed literature, and 17 Google Advanced searches located grey literature that described food waste audit methods previously used or developed for hospital foodservices. Study selection and quality assessment occurred in duplicate. Data describing the audit method, its feasibility, and strengths and limitations were extracted and synthesised to develop a consensus tool. Eight peer reviewed and nine grey literature documents describing a variety of food waste audit methods were found. The most common practices were 2-week data collection (n=5), foodservice staff collecting data (n=6), measuring food waste only (n=11), measuring food waste at main meals (n=5) and using electronic scales to measure waste (n=12). A consensus tool was developed that proposes a method for preparing, conducting and analysing data from a food waste audit. This review used published evidence to develop the first ever food waste audit consensus tool for hospital foodservices to use and measure food and food-related waste. Future research is needed to apply and test this tool in practice. This review used published evidence to develop the first ever food waste audit consensus tool for hospital foodservices to use and measure food and food-related waste. Future research is needed to apply and test this tool in practice.While the integration of supramolecular principles in catalysis attracts increasing attention, a direct comparative assessment of the resulting systems catalysts to work out distinct characteristics is often difficult. Herein is reported how the broad responsiveness of ether cyclizations to diverse inputs promises to fill this gap. Cyclizations in the confined, π-basic and Brønsted acidic interior of supramolecular capsules, for instance, are found to excel with speed (exceeding general Brønsted acid and hydrogen-bonding catalysts by far) and selective violations of the Baldwin rules (as extreme as the so far unique pnictogen-bonding catalysts). The complementary cyclization on π-acidic aromatic surfaces remains unique with regard to autocatalysis, which is shown to be chemo- and diastereoselective with regard to product-like co-catalysts but, so far, not enantioselective. This study investigated the relationships between anatomical findings around the eustachian tube (ET) and eosinophilic otitis media (EOM) accompanied by eosinophilic chronic rhinosinusitis (ECRS). This study employed axial, coronal, sagittal and oblique computed tomography. Patients who underwent endoscopic sinus surgery at the Department of Otolaryngology, Toho University Medical Center Omori Hospital and were diagnosed with ECRS (106 patients) based on the Japanese Epidemiological Survey of Refractory Eosinophilic Chronic Rhinosinusitis study were included. Subsequently, the presence of EOM accompanied by ECRS in 212 ear sides was assessed, and preoperative sinus computed tomography was used to evaluate various anatomical findings, such as the development of the sphenoid sinus and mastoid cells at the apex of petrous bone, the angle and length of the ET, and the size of the tympanic orifice of the ET. The relationships between these anatomical findings and the presence of EOM were analyzed statistically. EOM accompanied by ECRS was associated with a high peripheral blood eosinophil count and bronchial asthma. Among anatomical factors, the absence of peri-ET cells or petrous apex cells, and a low angle and short length of the ET, were risk factors for the onset of EOM. Anatomical factors such as the absence of peri-eustachian cells or petrous apex cells, and low angle or short length of the ET, are risk factors for the onset of EOM along with ECRS. Assessment of these factors may help in preventing the future onset or aggravation of EOM. 4 Laryngoscope, 2021. 4 Laryngoscope, 2021.A recent elegant study published in this journal (Zerbini, Winnebeck & Merrow, J Pineal Res, e12723, 2021) reported data on weekly and seasonal changes in circadian timing, as assessed by the melatonin rhythm in dim light in a population that was exposed to a change from standard time to day light saving time. The authors highlight a one hour earlier timing of melatonin onset in summer compared with winter and a 20 minutes delay on work-free days compared with work days. The variations in the timing of the melatonin rhythm are reported in standard time and the authors imply that the data are consistent with synchronization to midday and that "we know that humans entrain to sun time." Here, we show that their extensive data are most parsimoniously explained by entrainment to local clock time and associated light exposure rather than "sun time," indexed by either dawn or midday.Natural feed additives application in rabbit nutrition can help to control and prevent digestive disturbances and improve gut health and immunity around the critical weaning period. While probiotics are frequently used in rabbits, in vivo administration of bacteriocins is often limited. Therefore, the present study evaluates the effect of enterocin EntM, durancin EntED26E/7 and their combination on serum biochemistry, phagocytic activity and jejunal morphometry of rabbits. https://www.selleckchem.com/products/caspofungin-acetate.html Eighty rabbits (aged 35 days, meat line M91, both sexes) were divided into experimental groups E (EntM; dose 50 µl/animal/day, activity 25,600 AU/ml), D (EntED26E/7; 50 µl/animal/day, 12,800 AU/ml), E + D (50 µl EntM + 50 µl EntED26E/7 /animal/day) and control group (C). Additives were administrated in drinking water for 21 days. Both enterocins positively influenced tested serum parameters, with emphasis on durancin EntED26E/7 administration, alone and/or in combination with EntM. Increased total proteins (E, D p less then 0.001), urea (D p less then 0.

206±85×10 /L, respectively; P=0.010), and the rate of planned ICU admission (elective surgery) was higher in the worse hearing group (57.1% vs. 28.8%, respectively; p=0.011). Age, sex, and the use of furosemide did not have adversely affect hearing function. Low serum platelet count and planned admission appear to be risk factors for worse hearing. Age, sex, and the use of furosemide did not have adversely affect hearing function. Low serum platelet count and planned admission appear to be risk factors for worse hearing.The objective was to evaluate the pure-tone audiogram-based screening protocols in VS diagnostics. We retrospectively analyzed presenting symptoms, pure tone audiometry and MRI finding from 246 VS patients and 442 controls were collected to test screening protocols (AAO-HNS, AMCLASS-A/B, Charing Cross, Cueva, DOH, Nashville, Oxford, Rule3000, Schlauch, Seattle, Sunderland) for sensitivity and specificity. Results were pooled with data from five other studies, and analysis of sensitivity, specificity and positive likelihood ratio (LR+) for each protocol was performed. Our results show that protocols with significantly higher sensitivity (AMCLASS-A/B, Nashville) show also significantly lowest specificity, and tend to have low association (positive likelihood ratio, LR+) to the VS. The highest LR+ was found for protocols AAO-HNS, Rule3000 and Seattle. https://www.selleckchem.com/JNK.html In conclusions, knowing their properties, screening protocols are simple decision-making tools in VS diagnostic. To use the advantage of the highest sensitivity, protocols AMCLASS-A + B or Nashville can be of choice. For more reasonable approach, applying the protocols with high LR+ (AAO-HNS, Rule3000, Seattle) may reduce the overall number of MRI scans at expense of only few primarily undiagnosed VS. The video head impulse test (vHIT) is used as a measure of compensation yet it's stability in patients with vestibular pathology is unknown. 144 patients (n=72 female, mean 54.46±15.8 years) were grouped into one of three primary diagnoses (Peripheral, Central, or Mixed). Subjects were further categorized based on sex (male versus female), ear (left versus right; ipsilesional versus contralesional), age (six groups ranging from 19 to 84 years), and duration between visits (five groups, mean 191.46±SE 29.42 days, median 55.5 days). The gain of the VOR during passive head rotation was measured for each semicircular canal (horizontal, anterior, posterior). There was no difference in the VOR gain within any semicircular canal between the two visits (horizontal p=0.179; anterior p=0.628; posterior p=0.613). However, the VOR gain from the horizontal canals was higher than the vertical canals for each visit (p<0.001). Patients diagnosed with peripheral vestibular pathology had significantly lower (p≤0.001) horizontal semicircular canal gains at each visit. There was no difference in VOR gain between sex (p=0.215) or age groupings (p=0.331). Test-retest reliability of vHIT in patient subjects is good (ICC=0.801) and the VOR gain values across two separate visits were significant and positively correlated (r=0.67) regardless of sex, ear, age, or duration between visits. The vHIT is a stable measure of VOR gain over two different times across a variety of vestibular patients with no influence of age or sex. The vHIT is a stable measure of VOR gain over two different times across a variety of vestibular patients with no influence of age or sex. The goal of this study is to analyze the clinical view of patients with direction-fixed positional nystagmus (DFPN) following head-roll maneuver. Sixty patients with DFPN were reviewed retrospectively. Patients were categorized into 3 groups according to the direction of nystagmus based on rotation side. Associated problems were documented, and cumulative data were compared between groups. One-way analysis of variance (ANOVA test) was used for statistical analysis ( <0.05). Thirty-three patients (55%) had stronger nystagmus beating towards the direction of head-roll (Group-A). Three patients developed geotropic LC-BPPV. Fourteen patients had inner ear disease. Sixteen patients (27%) had stronger nystagmus beating against the direction of head roll (Group-B). Nine patients had inner ear disease. None of the patients tested with head-shaking had change of direction of nystagmus. Eleven patients (18%) had DFPN with equal velocity during right or left head-roll maneuver (Group-C). Of those, nine patient. Head-shaking testing is recommended to expose the lateral canal BPPV. But the incidence is low. Severe bleeding following cardiac surgery remains a troublesome complication, but to date, there is a lack of comprehensive predictive models for the risk of severe bleeding following off-pump coronary artery bypass grafting (OPCABG). This study aims to analyze relevant indicators of severe bleeding after isolated OPCABG and establish a corresponding risk assessment model. The clinical data of 584 patients who underwent OPCABG from January 2018 to April 2020 were retrospectively analyzed. We gathered the preoperative baseline data and postoperative data immediately after intensive care unit admission and used multifactor logistic regression to screen the potential predictors of severe bleeding, upon which we established a predictive model. Using the consistency index and calibration curve, decision curve, and clinical impact curve analysis, we evaluated the performance of the model. This study is the first to establish a risk assessment and prediction model for severe bleeding following isolated OPCABG.therefore worthy of further exploration and verification. To investigate the effects of sodium-glucose cotransporter 2 inhibitors (SGLT2i) on cardiovascular outcomes in elderly Chinese patients with comorbid coronary heart disease (CHD) and type 2 diabetes mellitus (T2DM). A retrospective cohort study was conducted on 501 elderly inpatients (≥ 60 years) with comorbid CHD/T2DM in Department of Cardiovascular Medicine and Endocrinology, Chinese PLA General Hospital from January 2018 to December 2019. These patients were divided into two groups according to the administration of SGLT2i. All the demographic characteristics and clinical data were collected. Cardiovascular outcomes, including all-cause mortality, major adverse cardiovascular events (MACE), and hospitalization for heart failure (HHF), were followed up. In the cohort, there were 167 patients in the SGLT2i group and 334 patients in the control group. In the efficacy analyses, the incidence of MACE was lower in the SGLT2i group than in the control group 3.6% . 9.3% ( = 0.022). A lower risk of MACE was observed in the SGLT2i group [hazard ratio (HR) = 0.

Increased ST was significantly associated with developmental delay, in particular, in the domains of language acquisition and communication. In children aged ≥ 2 years, a delay in ≥ 3 domains was associated with ST (adjusted odds ratio [AOR] = 17.75, 95% CI 5.04-62.49, p less then 0.001), as was language delay (AOR = 52.92, 95% CI 12.33-227.21, p less then 0.001). In children aged less then 2 years, a delay in ≥ 2 domains was associated with ST (AOR = 16.79, 95% CI 2.26-124.4, p less then 0.001), as was language delay (AOR = 20.93, 95% CI 2.68-163.32, p less then 0.01). A very high prevalence of excessive ST was identified, with a significant association with developmental delay in children. There is an urgent need to include education on ST limits at the primary healthcare level.Herpes zoster, the result of varicella-zoster virus (VZV) reactivation, is frequently complicated by difficult-to-treat chronic pain states termed postherpetic neuralgia (PHN). While there are no animal models of VZV-induced pain following viral reactivation, subcutaneous VZV inoculation of the rat causes long-term nocifensive behaviors indicative of mechanical and thermal hypersensitivity. Previous studies using UV-inactivated VZV in the rat model suggest viral gene expression is required for the development of pain behaviors. However, it remains unclear if complete infection processes are needed for VZV to induce hypersensitivity in this host. To further assess how gene expression and replication contribute, we developed and characterized three replication-conditional VZV using a protein degron system to achieve drug-dependent stability of essential viral proteins. Each virus was then assessed for induction of hypersensitivity in rats under replication permissive and nonpermissive conditions. VZV with a degome abortively infected with VZV during reactivation and survive, but host signaling becomes altered in order to transmit ongoing pain.Although decreasing rates of cervical cancer in the U.S. are attributable to health policy, immigrant women, particularly Haitians, experience disproportionate disease burden related to delayed detection and treatment. However, risk prediction and dynamics of access remain largely underexplored and unresolved in this population. This study seeks to assess cervical cancer risk and access of unscreened Haitian women. Extracted and merged from two studies, this sample includes n = 346 at-risk Haitian women in South Florida, the largest U.S. enclave of Haitians (ages 30-65 and unscreened in the previous three years). Three approaches (logistic regression [LR]; classification and regression trees [CART]; and random forest [RF]) were employed to assess the association between screening history and sociodemographic variables. https://www.selleckchem.com/products/bi-2865.html LR results indicated women who reported US citizenship (OR = 3.22, 95% CI = 1.52-6.84), access to routine care (OR = 2.11, 95%CI = 1.04-4.30), and spent more years in the US (OR = 1.01, 95%CI = 1.00-1.03) were significantly more likely to report previous screening. CART results returned an accuracy of 0.75 with a tree initially splitting on women who were not citizens, then on 43 or fewer years in the U.S., and without access to routine care. RF model identified U.S. years, citizenship, and access to routine care as variables of highest importance indicated by greatest mean decreases in Gini index. The model was .79 accurate (95% CI = 0.74-0.84). This multi-pronged analysis identifies previously undocumented barriers to health screening for Haitian women. Recent US immigrants without citizenship or perceived access to routine care may be at higher risk for disease due to barriers in accessing U.S. health-systems.Natural disasters such as flooding and landslides are important unexpected events during the rainy season in Thailand, and how to direct action to avoid their impacts is the motivation behind this study. The differences between the means of natural rainfall datasets in different areas can be estimated using simultaneous confidence intervals (SCIs) for pairwise comparisons of the means of delta-lognormal distributions. Our proposed methods are based on a parametric bootstrap (PB), a fiducial generalized confidence interval (FGCI), the method of variance estimates recovery (MOVER), and Bayesian credible intervals based on mixed (BCI-M) and uniform (BCI-U) priors. Their coverage probabilities, lower and upper error probabilities, and relative average lengths were used to evaluate and compare their SCI performances through Monte Carlo simulation. The results show that BCI-U and PB work well in different situations, even with large differences in variances [Formula see text]. All of the methods were applied to estimate pairwise differences between the means of natural rainfall data from five areas in Thailand during the rainy season to determine their abilities to predict occurrences of flooding and landslides. We evaluated if flowcytometry, using Sysmex UF-5000, could improve diagnosis of urinary tract infections by rapid identification of culture negative and contaminated samples prior to culture plating, thus reducing culture plating workload and response time. We also evaluated if it is possible to reduce the response time for antibiotic susceptibility profiles using the bacteria information flag on Sysmex UF-5000 to differentiate between Gram positive and negative bacteria, followed by direct Antibiotic Susceptibility Testing (dAST) on the positive urine samples. One thousand urine samples were analyzed for bacteria, white blood cells and squamous cells by flowcytometry before culture plating. Results from flowcytometric analysis at different cut-off values were compared to results of culture plating. We evaluated dAST on 100 urine samples that were analyzed as positive by flowcytometry, containing either Gram positive or Gram negative bacteria. Using a cut-off value with bacterial count ≥100.000/mL and Wation between epithelial cells and contamination. Flowcytometry offers advantages for diagnosis of urinary tract infections. Screening for negative urine samples on the day of arrival reduces culture plating and workload, and results in shorter response time for the negative samples. The bacteria information flag predicts positive samples containing Gram negative bacteria for dAST with high accuracy, thus Antibiotic Susceptibility Profile can be reported the day after arrival. For the positive samples containing Gram negative bacteria the concordance was very good between dAST and Antibiotic Susceptibility Testing in routine. For positive samples containing Gram positive bacteria the results were not convincing. We did not find any correlation between epithelial cells and contamination.

Aim A new HPLC method with fluorescence detection has been developed and validated for the determination of levofloxacin, one of the fluoroquinolone class antibiotics, in breast milk. Materials & methods Chromatographic separation was carried out on a reversed phase C18 column with acetonitrile and 10 mM o-phosphoric acid (2575, v/v) mobile phase composition. Moxifloxacin was used as internal standard and the peaks were detected by fluorescence detection. Results & conclusion Calibration graph was found linearly within the range of 2.5-500 ng/ml. Limit of detection and limit of quantification were found to be 0.63 and 2.11 ng/ml, respectively. Mean absolute recovery was 96.18%. The developed method has been successfully applied to the determination of levofloxacin in human breast milk taken from two healthy volunteers.Aim To compare methods of quantifying serum hepcidin (based on MS and ELISA) and their ability to diagnose true iron deficiency anemia in critically ill patients. Materials & methods Serum hepcidin was measured in 119 critically ill patients included in the HEPCIDANE clinical trial, using either an ultra-sensitive ELISA kit (from DRG) or two different MS methods. Results The results show a good correlation between the different methods studied. The Bland-Altman analysis and the Kappa test for clinical groups show a good or very good agreement between the different tests. Conclusion ELISA or MS show a satisfactory commutability to quantify serum hepcidin. This is of great importance for the determination of therapeutic strategies in iron deficiency.Aim Methadone exhibits significant variability in clinical response. This study explores the genetic influence of variable methadone pharmacokinetics. Methods This is a prospective study of methadone in children undergoing major surgery. CYP2B6 genotyping, plasma methadone and metabolite levels were obtained. Clinical outcomes include pain scores and postoperative nausea and vomiting (PONV). Results CYP2B6 poor metabolizers (*6/*6) had >twofold lower methadone metabolism compared with normal/rapid metabolizers. The incidence of PONV was 4.7× greater with CYP2B6 rs1038376 variant. AG/GG variants of rs2279343 SNP had 2.86-fold higher incidence of PONV compared with the wild variant (AA). Nominal associations between rs10500282, rs11882424, rs4803419 and pain scores were observed. Conclusion We have described novel associations between CYP2B6 genetic variants and perioperative methadone metabolism, and associations with pain scores and PONV.Dementia is a significant public health problem in the 21st century. Alzheimer's disease (AD) is an essential factor in dementia. Currently, the drugs used for the treatment of AD are mainly acetylcholine inhibitors (AChEIs). As an AChEI, donepezil (DP) can improve patients' cognitive ability with low side effects and has been accepted by most patients and doctors. https://www.selleckchem.com/products/6-diazo-5-oxo-l-norleucine.html For AD patients, the dosage regimen is also crucial due to aging and diseases. Although there are DP oral tablets on the market, there are still many problems to be solved. At present, more and more research is conducted to optimize the route of administration of DP to improve the self-administration of patients. The research fields of DP administration include oral administration, injection administration, intranasal administration, and transdermal administration. This Review is to present the development of different DP administrations and evaluates the advantages and limitations of those works, hoping to optimize the DP dosage regimen for AD patients.The development of three-dimensional (3D) micro-/nanostructures with multiscale hierarchy offers new potential for the improvement of the pristine textile properties. In this work, a polyester fabric coated with 3D hierarchically structured rutile TiO2 nanowires (THNWP) was fabricated by a facile hydrothermal strategy. The THNWP samples exhibit markedly improved photocatalytic activities and antibacterial properties owing to their 3D hierarchical architecture constructed by one-dimensional nanowire structures, good crystallinity, excellent light-harvesting capability, and fast electron-transfer rate. Furthermore, the unique 3D hierarchical nanostructures also combine with the monofilament to produce ternary-scale hierarchy, which endows the fabric surface with outstanding superamphiphobicity after further facile fluorination treatment. The supportive air-pockets trapped within the unique ternary-scale architectures are proved to be the crucial factor in the achievement of high liquid repellency, and the highest performing superamphiphobic surface is capable of repelling liquids down to a minimal surface tension of 23.4 mN m-1. We envision that our findings may possess great potential in the bottom-up design of high-performance textiles.Nontarget screening studies have recently revealed the accumulation of typically unmonitored organohalogen compounds (OHCs) in various marine animals, but information for terrestrial food chains is still lacking. This study investigated the accumulation profiles of known and unknown OHCs in the liver of representative wild bird specimens from Osaka, Japan using nontarget analysis based on two-dimensional gas chromatography-time-of-flight mass spectrometry. A large number of unmonitored OHCs were identified, including anthropogenic contaminants and marine halogenated natural products (HNPs), and their accumulation profiles were considered to be influenced by terrestrial and brackish water-based diets. Anthropogenic OHCs were highly accumulated in terrestrial predator species (peregrine falcon, hawks, and black kite), and some unmonitored highly chlorinated contaminants reached the levels of microgram per gram lipid in the liver, i.e., C10-/C15-based chlordane related compounds (CHLs) and their epoxides, dichlorodiphenyldichloroethylene (DDE) homologues, and polychlorinated terphenyls (PCTs). In contrast, HNPs were accumulated at higher levels in piscivorous birds (gray heron and common cormorant). Considering the enrichment of the unmonitored C10-/C15-based CHLs, PCTs, and DDE homologues relative to structurally similar persistent organic pollutants (POPs) in high trophic-level species such as raptors, further studies are needed to elucidate their environmental levels, behavior in terrestrial food chains, and ecotoxicological impacts.

e impedance sensing and the porcine ex vivo organ culture methods are powerful tools to discover differences in cancer cell migration and invasion. Taken together, our results indicate an inverse correlation between IL1RA expression and tumor cell invasive capacity and migration, suggesting that IL1RA plays a role in bladder carcinogenesis, while the exact mechanisms by which IL1RA influences tumor cells migration/invasion remain to be clarified in future studies. Furthermore, we confirmed that real-time impedance sensing and the porcine ex vivo organ culture methods are powerful tools to discover differences in cancer cell migration and invasion.The orthodontic miniscrew is driven into bone in a clockwise direction. Counter-clockwise rotational force applied to the implanted miniscrew can degrade the stability. The purpose of this three-dimensional finite element study was to figure out the effect of shifting the miniscrew head hole position from the long axis. Two miniscrew models were developed, one with the head hole at the long axis and the other with an eccentric hole position. One degree of counter-clockwise rotation was applied to both groups, and the maximum Von-Mises stress and moment was measured under various wire insertion angles from -60° to +60°. All Von-Mises stress and moments increased with an increase in rotational angle or wire insertion angle. The increasing slope of moment in the eccentric hole group was significantly higher than that in the centric hole group. Although the maximum Von-Mises stress was higher in the eccentric hole group, the distribution of stress was not very different from the centric hole group. As the positive wire insertion angles generated a higher moment under a counter-clockwise rotational force, it is recommended to place the head hole considering the implanting direction of the miniscrew. Clinically, multidirectional and higher forces can be applied to the miniscrew with an eccentric head hole position.Mesenchymal stem cells (MSCs) are self-renewal and capable of differentiating to various functional cell types, including osteocytes, adipocytes, myoblasts, and chondrocytes. They are, therefore, regarded as a potential source for stem cell therapy. Fisetin is a bioactive flavonoid known as an active antioxidant molecule that has been reported to inhibit cell growth in various cell types. Fisetin was shown to play a role in regulating osteogenic differentiation in animal-derived MSCs; however, its molecular mechanism is not well understood. We, therefore, studied the effect of fisetin on the biological properties of human MSCs derived from chorion tissue and its role in human osteogenesis using MSCs and osteoblast-like cells (SaOs-2) as a model. We found that fisetin inhibited proliferation, migration, and osteogenic differentiation of MSCs as well as human SaOs-2 cells. Fisetin could reduce Yes-associated protein (YAP) activity, which results in downregulation of osteogenic genes and upregulation of fibroblast genes. Further analysis using molecular docking and molecular dynamics simulations suggests that fisetin occupied the hydrophobic TEAD pocket preventing YAP from associating with TEA domain (TEAD). This finding supports the potential application of flavonoids like fisetin as a protein-protein interaction disruptor and also suggesting an implication of fisetin in regulating human osteogenesis.FLT3-mutated acute myeloid leukemia accounts for around 30% of acute myeloid leukemia (AML). The mutation carried a poor prognosis until the rise of tyrosine kinase inhibitors (TKIs). New potent and specific inhibitors have successfully altered the course of the disease, increasing the complete response rate and the survival of patients with FLT3-mutated AML. The aim of this article is to review all the current knowledge on these game-changing drugs as well as the unsolved issues raised by their use for fit and unfit FLT3-mutated AML patients. To this end, we analyzed the results of phase I, II, III clinical trials evaluating FLT3-TKI both in the first-line, relapse monotherapy or in combination referenced in the PubMed, the American Society of Hematology, the European Hematology Association, and the Clinicaltrials.gov databases, as well as basic science reports on TKI resistance from the same databases. The review follows a chronological presentation of the different trials that allowed the development of first- and second-generation TKI and ends with a review of the current lines of evidence on leukemic blasts resistance mechanisms that allow them to escape TKI.Glycosaminoglycans (GAGs) and proteoglycans (PGs) are major components of the glycocalyx. The secreted GAG and CD44 ligand hyaluronic acid (HA), and the cell surface PG syndecan-1 (Sdc-1) modulate the expression and activity of cytokines, chemokines, growth factors, and adhesion molecules, acting as critical regulators of tumor cell behavior. Here, we studied the effect of Sdc-1 siRNA depletion and HA treatment on hallmark processes of cancer in breast cancer cell lines of different levels of aggressiveness. We analyzed HA synthesis, and parameters relevant to tumor progression, including the stem cell phenotype, Wnt signaling constituents, cell cycle progression and apoptosis, and angiogenic markers in luminal MCF-7 and triple-negative MDA-MB-231 cells. Sdc-1 knockdown enhanced HAS-2 synthesis and HA binding in MCF-7, but not in MDA-MB-231 cells. Sdc-1-depleted MDA-MB-231 cells showed a reduced CD24-/CD44+ population. Furthermore, Sdc-1 depletion was associated with survival signals in both cell lines, affecting cell cycle progression and apoptosis evasion. These changes were linked to the altered expression of KLF4, MSI2, and miR-10b and differential changes in Erk, Akt, and PTEN signaling. We conclude that Sdc-1 knockdown differentially affects HA metabolism in luminal and triple-negative breast cancer model cell lines and impacts the stem phenotype, cell survival, and angiogenic factors.Direct in vivo evidence of altered metabotropic glutamate receptor-5 (mGluR5) availability in alcohol-related disorders is lacking. We performed [11C]ABP688 positron emission tomography (PET) and resting-state functional magnetic resonance imaging (rs-fMRI) in prolonged abstinent subjects with alcohol dependence to examine alterations of mGluR5 availability, and to investigate their functional significance relating to neural systems-level changes. Twelve prolonged abstinent male subjects with alcohol dependence (median abstinence duration six months) and ten healthy male controls underwent [11C]ABP688 PET imaging and 3-Tesla MRI. https://www.selleckchem.com/products/shikonin.html For mGluR5 availability, binding potential (BPND) was calculated using the simplified reference tissue model with cerebellar gray matter as the reference region. The initial region-of-interest (ROI)-based analysis yielded no significant group differences in mGluR5 availability. The voxel-based analysis revealed significantly lower [11C]ABP688 BPND in the middle temporal and inferior parietal cortices, and higher BPND in the superior temporal cortex in the alcohol dependence group compared with controls.

For , carriage prevalence was higher in the azithromycin arm for BM (13.8% versus 8.7%, 0.055) but not for VS or NPS. Prevalence of azithromycin resistant was higher in the azithromycin arm for BM (3.6% versus 1.0%, 0.050) and VS (1.5% versus 0% 0.057). Oral intrapartum azithromycin did not reduce carriage of and and was associated with an increase in the prevalence of azithromycin-resistant and isolates in BM and VS. Oral intrapartum azithromycin did not reduce carriage of E. coli and K. pneumoniae and was associated with an increase in the prevalence of azithromycin-resistant E. coli and K. pneumoniae isolates in BM and VS.Graphical Abstract.Graphical Abstract. To evaluate the current prevalence status of MRSA among dairy farms in England and Wales 5 years after a previous survey conducted in 2011-12. A convenience sample of 697 dairy farms in England and Wales was used for the study, conducted in 2017-18, testing bulk tank milk samples for the presence of MRSA using high salt broth enrichment and chromogenic MRSA agar selection. All putative MRSA isolates were screened by PCR for the presence of and genes and subjected to antimicrobial susceptibility testing using both the disc diffusion method and VITEK 2. MRSA isolates were also sequenced for genomic characterization. MRSA were detected on 4 out of 697 dairy farms in England and Wales (prevalence 0.57%, 95% CI 0.16%-1.46%). Three of the isolates were ST425 and one was ST4652 (in the CC130 lineage). Two MRSA were also isolated one ST5 and one ST398. These results indicate that there has been a substantial reduction in the prevalence of MRSA in England and Wales with a 72% reduction (2.15% to 0.57%) compared with a previous study. https://www.selleckchem.com/products/od36.html While the levels of MRSA remain very low the continued presence of ST398, a livestock-associated MRSA, suggests that this lineage is established in the UK. These results indicate that there has been a substantial reduction in the prevalence of mecC MRSA in England and Wales with a 72% reduction (2.15% to 0.57%) compared with a previous study. While the levels of mecA MRSA remain very low the continued presence of ST398, a livestock-associated MRSA, suggests that this lineage is established in the UK. Approximately 10% of people have an unverified penicillin allergy, with multiple personal and public health consequences. To assess the efficacy and safety of direct oral challenge, without prior skin testing, in this population. MEDLINE, EMBASE, CINAHL, the Cochrane Library and Google Scholar were searched from inception to 28 June 2020 (updated November 2020) to find published and unpublished studies that reported direct oral challenge for the purpose of removal of penicillin allergy labels. Population weighted mean was used to calculate the proportion of patients who developed an immediate or delayed reaction to direct oral challenge across the studies. Thirteen studies were included in the review, with a sample size of 1202 (range 7-328). Studies included inpatient and outpatient cohorts assessed as low risk for true allergy. In pooled analysis of all 13 studies there were 41/1202 (3.41%) mild immediate or delayed reactions to direct oral challenge. The population-weighted mean incidence of immedior patients, support antimicrobial stewardship, and minimize antimicrobial resistance.Graphical Abstract.Graphical Abstract.Graphical Abstract.Graphical Abstract. WHO's Global Action Plan on Antimicrobial Resistance includes as a priority to increase public education surrounding antibiotic use and resistance. Monitoring population-level antibiotic behaviours is crucial for informing intervention strategies, but data from a broad range of settings, particularly lower-resourced countries, are lacking. We measured public knowledge, attitudes and practices regarding antibiotics and antibiotic resistance in Cambodia, providing baseline information against which to monitor the progress of future interventions. Between September and October 2018, we conducted a household survey of knowledge, attitudes and practices related to antibiotic use in urban and rural populations of three Cambodian provinces Phnom Penh, Siem Reap and Prey Veng. Response rates were respectively 79%, 86% and 86%. Among the 2005 participants, we found high levels of awareness of terms relating to antibiotics (86.5%) and antibiotic resistance; most participants also recognized that antibiotic resistance is a problem (58.4%). However, few understood that antibiotics are effective only against bacterial infections (1.2%). We also found province-specific differences in participants' sources of antibiotics and their sources of AMR-related information. In regression analyses, more favourable antibiotic practice scores were associated with higher knowledge (β = 0.18; 95% CI 0.14-0.22) and attitude (β = 0.16; 95% CI 0.11-0.22) scores, as well as trust in healthcare sources to obtain antibiotics and antibiotic information. This study highlights the importance of interventions and public communication on antibiotic use and resistance that is effectively targeted to the local context through trusted healthcare providers. This study highlights the importance of interventions and public communication on antibiotic use and resistance that is effectively targeted to the local context through trusted healthcare providers.These evidence-based guidelines are an updated version of those issued in 2008. They have been produced following a review of the published literature (2007-18) pertaining to the treatment of infections caused by MRSA. The guidelines update, where appropriate, previous recommendations, taking into account changes in the UK epidemiology of MRSA, ongoing national surveillance data and the efficacy of novel anti-staphylococcal agents licensed for use in the UK. Emerging therapies that have not been licensed for use in the UK at the time of the review have also been assessed. Outpatient parenteral antimicrobial therapy (OPAT) with vancomycin is a common treatment modality for certain Gram-positive infections. Data regarding the safety of various models of delivery are limited. To review outcomes of a nurse-led OPAT vancomycin monitoring service. This was a retrospective cohort study of consecutive patients referred to a nurse-led OPAT vancomycin clinic from December 2015 to March 2018. Patients were administered IV vancomycin in the home with active laboratory monitoring of vancomycin trough levels, renal function and complete blood count using an integrated electronic database linked with community laboratories (virtual vancomycin clinic, VVC). Monitoring was coordinated by nurses with physician approval of recommended dosing changes. Data were extracted from the electronic medical record. Demographics; clinical indication; microbial aetiology; culture source; antimicrobial regimen(s); serum creatinine and vancomycin trough values; initiation, discharge and completion dates; hospitalizations; adverse events; and outcomes were all evaluated.

805A>C [p.Asn269His]). Patients with NPS often develop nail, ocular, or orthopedic symptoms prior to nephrotic syndrome. Corneal leucoma may be a novel clinical presentation of NPS.Autosomal recessive (AR) DOCK8 deficiency is a well-known actinopathy, a combined primary immune deficiency with impaired actin polymerization that results in altered cell mobility and immune synapse. DOCK8-deficient patients present early in life with eczema, viral cutaneous infections, chronic mucocutaneous candidiasis, bacterial pneumonia, and abscesses, together with eosinophilia, thrombocytosis, lymphopenia, and variable dysgammaglobulinemia that usually includes Hyper-IgE. In fact, before its genetic etiology was known, patients were described as having a form of Hyper-IgE syndrome, a name now deprecated in favor of genetic defects. We describe a school-age male patient with a clinical picture suggestive of DOCK8 deficiency, except for high serum IgE or a family history early onset, failure to thrive, eczema, warts, condyloma, bronchiolitis, pneumonia, recurrent otitis media, bronchiectasis, candidiasis, leukocytosis, eosinophilia, high IgA, low IgG, and low CD4+ T cells. We were able to confirm the diagnosis through protein expression and whole-exome sequencing. We review the clinical, laboratory, and genetic features of 200 DOCK8-deficient patients; at least 4 other patients have had no elevated IgE, and about 40% do not have Hyper-IgE (above 1,000 IU/mL). Despite this, the constellation of signs, symptoms, and findings allow the suspicion of DOCK8 deficiency and other actinopathies.Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific liver disease. The maternal symptoms are characterized by skin pruritus and elevated bile acids, causing several adverse outcomes for fetuses, including an increased risk of preterm birth, meconium-stained amniotic fluid, neonatal depression, respiratory distress syndrome, and stillbirth. Genetic, hormonal, immunological, and environmental factors contribute to the pathogenesis of ICP, and the estrogen-bile acid axis is thought to play a dominant role. The advances in the past 10 years uncover more details of this axis. Moreover, dysregulation of extracellular matrix and oxygen supply, organelle dysfunction, and epigenetic changes are also found to cause ICP, illuminating more potential drug targets for interfering with. Here, we summarize the molecular pathogenesis of ICP with an emphasis on the advancement in the past 10 years, aiming to give an updated full view of this field. Shoulder pain is the third most common type of musculoskeletal disorder and rotator cuff (RC) tendinopathy is the most frequent diagnosis. Ultrasound is the most preferable guidance tool for diagnostic and interventional purposes. The aim of this study is to compare the effectiveness of the prolotherapy injection with corticosteroid injection in patients with RC dysfunction. Thirty to sixty-five-year-old patients with chronic RC disease were divided into two groups. Ultrasound-guided dextrose prolotherapy of supraspinatus tendon was done for one group and ultrasound-guided corticosteroid injection in the subacromial bursa was done for the other groups. Visual analog scale (VAS) and Shoulder Pain and Disability Index (SPADI) were evaluated for both groups at baseline, 3 and 12 weeks after injections. Thirty-three patients were included in the result. Both the groups showed significant improvement in VAS and SPADI scores in 3 and 12 weeks after injections compared with preinjection times with no difference between two groups neither in 3 weeks nor in 12 weeks after injections. Both ultrasound-guided dextrose prolotherapy and CS injections are effective in the management of RC-related shoulder pain in both short-term and long-term with neither being superior to the other. Therefore, prolotherapy may be a safe alternative therapy instead of corticosteroid injection due to lack of its side effects. Both ultrasound-guided dextrose prolotherapy and CS injections are effective in the management of RC-related shoulder pain in both short-term and long-term with neither being superior to the other. Therefore, prolotherapy may be a safe alternative therapy instead of corticosteroid injection due to lack of its side effects. Sleep disorder is one of the most common problems in cancer patients involved in chemotherapy stages, which is caused by the side effects of anticancer drugs and the exacerbation of mental disorders. The aim of this study was to evaluate the effectiveness of sleep health education on sleep quality of cancer patients during chemotherapy stages. In this clinical trial, 70 cancer patients were selected in the chemotherapy phase and divided into two groups of 35. In the intervention group, two 60-min training sessions on sleep hygiene were educated, solutions of coping with the exacerbation of sleep disturbances were determined, and routine care was provided in the control group. Patients were evaluated for sleep disorders before and 1 and 3 weeks after the intervention by the Pittsburgh questionnaire and then the effect of this intervention compared between the two groups. The mean score of sleep medication consumption in the intervention group was not significantly different between the three times ( = 0.59), but the mean score of total sleep quality disorder and its other dimensions was significantly different between the three time points ( < 0.05). Least significant difference test showed that the mean total score of sleep quality disorder and its dimensions except using sleep medication 1 week after the intervention was significantly less than before the intervention and 3 weeks after the intervention <1 week after the intervention in the intervention group ( < 0.05). Sleep health education for cancer patients involved in chemotherapy can significantly have a positive effect on improving their sleep quality. Sleep health education for cancer patients involved in chemotherapy can significantly have a positive effect on improving their sleep quality.Respiratory infections like influenza infections have been found to increase the risk of coronary artery disease and precipitate cardiac failure. However, Indian data is lacking. A retrospective observational study was done to describe patients with influenza infection who had concomitant heart failure (HF) requiring admission over 5 years (January 2013-December 2017). A total of 93 influenza cases were hospitalised during this time, of which 14 (15%) also had features of HF. Among them, the types of influenza infection were AH1N1 (6,43%), BH1N1 (4,29%), AH3N2 (3,21%) with one patient having both strains. Two-thirds of the HF were new onset (10, 71%), whereas rest were due to acute worsening of pre-existing HF (4, 29%). Ten (64.3%) of the patients had HF with reduced ejection fraction (HFrEF). The average hospital stay was 10 days with 2 (14%) deaths. https://www.selleckchem.com/products/blu-554.html The peak of influenza in August and September preceded the peak admission for HF. A total of 15% of influenza admissions have concomitant HF. They are predominantly due to influenza A H1N1 (43%), influenza A H3N2 (21%) and influenza B (29%).

To ensure effective implementation of future initiatives, deeper organisational-level change, requiring buy-in from all levels of management and staff, may be needed to shift organisational culture and associated social norms. Hypertension and periodontal diseases share several risk factors. Inflammation biomarkers in saliva are related to hypertension and periodontal disease. The aim of this study was to explore the role of the salivary inflammatory biomarkers in the treatment effectiveness of patients with hypertension and periodontal disease. This observational study enrolled 160 subjects diagnosed with periodontitis, 40 of which had a history of hypertension. All subjects had completed scaling and root planning therapeutic procedures within four weeks. The clinical periodontal parameters (i.e., bleeding on probing, plaque control record (PCR), and probing depth (PD)) were evaluated before and after the treatment. Pro-inflammatory markers were determined using a commercial kit. The recovery rate (PD 4-9 mm) in non-hypertensive subjects was significantly higher than in hypertensive subjects (60.47% vs. 52.60%, respectively; = 0.04). All clinical parameters, excluding PCR, positively correlated with salivary IL-1β at baseline and after completing treatment. Our results showed that increased salivary IL-1β levels were positively associated with decreased PCR (β = -27.65 and = 0.05) and PD recovery rate (β = -17.05 and = 0.02) in hypertensive subjects. The present study sheds important light on the clinical use of salivary pro-inflammatory cytokines as valuable biomarkers for predicting the treatment effectiveness of patients suffering from hypertension and periodontitis. The present study sheds important light on the clinical use of salivary pro-inflammatory cytokines as valuable biomarkers for predicting the treatment effectiveness of patients suffering from hypertension and periodontitis.The health benefits of physical activity (PA) are well recognized, and PA levels vary in different populations. https://www.selleckchem.com/products/sant-1.html The study aimed to investigate PA levels and associated sociodemographic factors among people with hypertension in a rural area in Bangladesh. Baseline data were part of a cluster randomized controlled trial of 307 adults aged 30-75 years to study the effectiveness of PA and lifestyle changes in lowering blood pressure. The outcome variables were PA at work, commuter, recreation, metabolic equivalent task (MET)-minute per week and sitting time. Total 68 (22.1%) people participated in vigorous-intensity activity, 23 (7.5%) participated in moderate-intensity sports. Overall, 83% of people were physically active more than 600 MET-min. Women (OR 2.95, 95% CI, 1.36-6.39) compared to men, and people with no education (OR 4.47, 95% CI, 1.62-12.33) compared to people with secondary school certificates or above were less physically active. Of total PA, 63% were work-related, and 1% were recreation-related for women, and these figures were 55% and 3% for men. The study reports that vigorous-intensity PA is low, and recreation time is minimal. Routine PA, especially for women and people with low education levels, should be encouraged to increase PA to manage hypertension.Optical monitors have proven their versatility into the studies of air quality in the workplace and indoor environments. The current study aimed to perform a screening of the indoor environment regarding the presence of various fractions of particulate matter (PM) and the specific thermal microclimate in a classroom occupied with students in March 2019 (before COVID-19 pandemic) and in March 2021 (during pandemic) at Valahia University Campus, Targoviste, Romania. The objectives were to assess the potential exposure of students and academic personnel to PM and to observe the performances of various sensors and monitors (particle counter, PM monitors, and indoor microclimate sensors). PM1 ranged between 29 and 41 μg m-3 and PM10 ranged between 30 and 42 μg m-3. It was observed that the particles belonged mostly to fine and submicrometric fractions in acceptable thermal environments according to the PPD and PMV indices. The particle counter recorded preponderantly 0.3, 0.5, and 1.0 micron categories. The average acute dose rate was estimated as 6.58 × 10-4 mg/kg-day (CV = 14.3%) for the 20-40 years range. Wearing masks may influence the indoor microclimate and PM levels but additional experiments should be performed at a finer scale.Through a statistical survey of 760 front-line medical staff during the COVID-19 epidemic, this study attempts to explore the relationships between relational capital, psychological security, post-traumatic growth and the meaning of work. Data analysis verifies that trust, reciprocity, and identification can promote post-traumatic growth by enhancing the individual's psychological security. A high level of work meaning can enhance the role of trust, reciprocity and identification in promoting psychological security. Work meaning has a moderated mediating effect when trust and reciprocity affect post-traumatic growth through psychological security, but no moderated mediating effect is found when identification affects post-traumatic growth through psychological security.Sexual victimization is a major public health, judicial, and societal concern worldwide. Nationally representative and comparable studies are still lacking. We applied a broad definition of sexual violence, including hands-off and hands-on victimization, and behaviorally specific questions to assess sexual victimization. Lifetime and 12-month prevalence estimates were obtained that are representative of the Belgian general population aged 16 to 69 with regard to sex and age. These estimates indicate that 64% experienced some form of sexual victimization in their lives, and 44% experienced some form of sexual victimization in the past 12 months. Logistic regression analysis revealed significant associations for sex, age, sexual orientation, the number of sexual partners, and the financial situation with sexual victimization. Furthermore, our data show that mental health is significantly worse in persons with a history of prior sexual victimization. Prevalence estimates for all forms of sexual victimization are presented and compared to other national and international studies on sexual victimization.

Therefore, the fluorescence nanoplatform, Fe3+/poly(NIPAM-AAm)-PNPs-COOH, was successfully used to detect endogenous hydrogen sulfide in living A549 cells.Selective membrane-based separation of light isotopes is considered to be possible based on the quantum phenomena. In this regard, the role of two mass-dependent effects, quantum tunneling and zero-point energy (ZPE), is realized to be consequential for selective separation of helium isotopes using appropriate membranes. In the present study, the efficiency of two analogous nanoporous membranes, graphenylene (GP) and inorganic graphenylene (IGP), for gas phase separation of 3He and 4He has been theoretically investigated. Since the performance of the studied membranes is extremely influenced by the close competition between both quantum tunneling and zero-point energy (ZPE) effects, high precision in the calculations is required to provide more realistic theoretical predictions. The current study attempts to provide such predictions by applying domain-based local pair natural orbital coupled cluster theory (DLPNO-CCSD) to obtain the accurate helium-pore interaction potential, based on which the tunneling rates, as well as the exact (anharmonic) bound levels for the vibration of helium in the pore plane, are calculated. From the analysis of the obtained results, the performance of the GP and IGP nanopores has been investigated in both kinetic competition and steady-state conditions in the temperature range of 10-200 K. The results of this study indicate that harmonic oscillator approximation significantly overestimates the efficiency of the studied nanopores for helium isotope separation. Based on our accurate calculations, both GP and IGP nanopores provide almost similar selectivities in kinetic competition conditions (Stot4/3 ≈ 3 at T = 50 K); however, the predicted permeance for GP (10-8 mol m-2 s-1 bar-1) is about 100 times higher than that predicted for IGP under the same conditions. Under steady-state conditions, IGP has been shown to be more efficient than GP, since it provides acceptable values of separation factor at higher temperatures.Prodrug strategy especially in the field of chemotherapy of cancers possesses significant advantages reducing the side toxicity of anticancer drugs. However, high-efficiency delivery and in situ activation of prodrugs for tumor growth suppression are still a great challenge. Herein, we report rationally engineered pH-responsive endosomolytic polymeric micelles for the delivery of an oxidation-activable prodrug into the cytoplasm of cancer cells and amplification of intracellular oxidative stress for further prodrug activation. The prepared block copolymers consist of a poly(ethylene glycol) (PEG) block and a segment grafted by endosomolytic moieties and acetal linkage-connected cinnamaldehyde groups. The amphiphilic diblock copolymers can self-assemble to form micelles in water for loading the oxidation-activable phenylboronic pinacol ester-caged camptothecin prodrug (ProCPT). The obtained micelles can release free cinnamaldehyde under acidic conditions in tumor tissues and endo/lysosomes followed by efficient endosomal escape, which further induces enhancement of intracellular reactive oxygen species (ROS) to activate the prodrugs. Simultaneously, intracellular glutathione (GSH) can be reduced by quinone methide that was produced during prodrug activation. The ProCPT-loaded micelles can finally achieve efficient tumor accumulation and retention as well as effective tumor growth inhibition. More importantly, hematological and pathological analysis of toxicity reveals that the ProCPT-loaded micelles do not cause obvious toxic side effects toward important organs of mice. https://www.selleckchem.com/products/Rolipram.html A positive immunomodulatory microenvironment in tumor tissue and serum can be detected after treatment with ProCPT-loaded micelles. Therefore, the endosomolytic ProCPT-loaded micelles exert synergistic therapeutic effects toward tumors through amplification of intracellular oxidative stress and activation of the prodrugs.The formation of C-aryl bonds has been the focus of intensive research over the last decades for the construction of complex molecules from simple, readily available feedstocks. Traditionally, these strategies involve the coupling of organohalides (I, Br, Cl) with organometallic reagents (Mg, Zn, B, Si, Sn,…) such as Kumada-Corriu, Negishi, Suzuki-Miyaura, Hiyama and Sonogashira cross-couplings. More recently, alternative methods have provided access to these products by reactions with less reactive C-Het (F, O, S, N) and C-C bonds. Compared to traditional methods, the direct cleavage and arylation of these chemical bonds, the essential link in accessible feedstocks, has become increasingly important from the viewpoint of step-economy and functional-group compatibility. This comprehensive review aims to outline the development and advances of this topic, which was organized into (1) C-F bond arylation, (2) C-O bond arylation, (3) C-S bond arylation, (4) C-N bond arylation, and (5) C-C bond arylation. Substantial attention has been paid to the strategies and mechanistic investigations. We hope that this review can trigger chemists to discover more efficient methodologies to access arylation products by cleavage of these C-Het and C-C bonds.A polarity-sensitive fluorescence probe AMN was developed to demonstrate the role of autophagy inhibitory drugs in the process of leather residue-induced neuroinflammation, promoting the knowledge of the relationship between autophagy and neuroinflammation. AMN showed a turn-on fluorescent signal in the process of autophagy inhibition via two-photon confocal imaging, which is different from the current popular autophagy probes. Therefore, AMN can offer high-sensitive imaging analysis of the autophagy inhibition process to better understand the role of autophagy in the process of neuroinflammation. The model of scrap leather-induced neuroinflammation using PC12 cells demonstrated that neuroinflammation can induce autophagy by releasing reactive oxygen species (ROS), and autophagy can alleviate neuroinflammation significantly via ROS scavenging.