Role of Calprotectin, IL-6, and CRP in Distinguishing Between Inflammatory Bowel Disease and Diarrhea Predominant Irritable Bowel Syndrome.

Background: The early establishment of prophylaxis and immediate administration of anticoagulant therapy upon the diagnosis of venous thromboembolism should be the treatment objectives in these patients. Objective: The study aimed to determine the optimal cut-off point of Calprotectin, IL-6 (interleukin-6), CRP (C reactive protein) to differentiate UC, IBS-D. Methods: A cross-sectional descriptive study of 335 individuals ≥15 years old was performed, including 31 healthy controls, 215 with IBS-D, 71 diagnosed with UC, and 18 diagnosed with CD. Receiver Operating Characteristics (ROC), sensitivity, specificity, and area under curve (AUC) were computed. Results: The results showed that the median value of calprotectin (IQR) in healthy participants was 20.0 (6.0 - 34.0) µg/g; 17,7 (8,7-38,9) µg/g in IBS-D group; 1710.0 (588 - 4260,0) µg/g in UC group; and 560.5 (177.8 - 1210.0) µg/g in CD group. Calprotectin concentration in IBD group including UC and CD was higher than IBS-D with p<0.05. The median value of CRP (range IQR) was 1,3 (0,9 - 2,3) mg/L in IBS-D group; 7.0 (2.4 -16.6) mg/L in UC group; and 10.1 (2.2 - 42.5) mg/L in CD group. CRP concentration in IBD group including UC and CD was higher than IBS-D with p<0.05. The median value of IL-6 (range IQR) was 2.3 (1.6 - 5.7) pg/mL in IBS-D group; 16.8 (9.4 - 47.0) pg/mL in UC group; and 9.4 (7.9 - 11.0) pg/mL in CD group. Calprotectin concentration in IBD group including UC and CD was higher than IBS-D with p<0.05. The optimal cut-off point of calprotectin that differentiated IBS-D from IBD was 110.5 µg/g, with sensitivity and specificity of 93.3% and 91.4%, respectively; of IL-6 was 7.2 pg/mL with sensitivity and specificity of 92.0% and 78.0%, respectively; of CRP of 2.4 mg/L had specific sensitivities of 83.3% and 86.0%, respectively. Conclusion: The Calprotectin immunoassay has the best value in discriminating between IBD and IBS-D.

Exploring Convolutional Neural Network Architectures for EEG Feature Extraction.

The main purpose of this paper is to provide information on how to create a convolutional neural network (CNN) for extracting features from EEG signals. Our task was to understand the primary aspects of creating and fine-tuning CNNs for various application scenarios. We considered the characteristics of EEG signals, coupled with an exploration of various signal processing and data preparation techniques. These techniques include noise reduction, filtering, encoding, decoding, and dimension reduction, among others. In addition, we conduct an in-depth analysis of well-known CNN architectures, categorizing them into four distinct groups: standard implementation, recurrent convolutional, decoder architecture, and combined architecture. This paper further offers a comprehensive evaluation of these architectures, covering accuracy metrics, hyperparameters, and an appendix that contains a table outlining the parameters of commonly used CNN architectures for feature extraction from EEG signals.

Annona glabra L. Seeds: An Agricultural Waste Biosorbent for the Eco-Friendly Removal of Methylene Blue.

The seeds of Annona glabra L., an invasive plant in Vietnam, were first employed as a new biosorbent for the adsorption of methylene blue (MB) from aqueous media. The characterizations of the material using FT-IR, SEM, nitrogen adsorption-desorption analysis, and point of zero charge reveals that it possesses a rough and irregular surface, various polar functional groups, and pHpzc of 5.5. Certain adsorption conditions including adsorbent dose, solution pH, contact time, and initial concentration of MB were found to affect adsorption efficiency. The kinetic data are well fitted with pseudo-second-order model with the adsorption rate of 0.002 g mg-1 min-1 and initial rate of 4.46 mg g-1 min-1. For the adsorption isotherm, three nonlinear models were used to analyze the experiment data, including Langmuir, Freundlich, and Temkin. The results indicate that the Langmuir model best describes the adsorption of Annona glabra L. seeds powder (AGSP) with a maximum adsorption capacity of 98.0 mg g-1. The investigation underpins the adsorption mechanism, whereby the electrostatic attraction between positively charged MB and negatively charged surface of AGSP is expected to be the predominant mechanism, together with hydrogen bonding and pi-pi interaction. These results make AGSP an interesting biosorbent concerning its environmental friendliness, cost-effectiveness, and relatively high dye adsorption capacity.

Ensemble models based on radial basis function network for landslide susceptibility mapping.

Ensemble learning techniques have shown promise in improving the accuracy of landslide models by combining multiple models to achieve better predictive performance. In this study, several ensemble methods (Dagging, Bagging, and Decorate) and a radial basis function classifier (RBFC) were combined to predict landslide susceptibility in the Trung Khanh district of the Cao Bang Province, Vietnam. The ensemble models were developed using a geospatial database containing 45 historical landslides (1074 points) and thirteen influencing variables characterizing the topography, geology, land use/cover, and human activities of the study area. The performance of the models was evaluated based on the area under the receiver operating characteristic curve (AUC) and several other performance metrics, including positive predictive value (PPV), negative predictive value (NPV), sensitivity (SST), specificity (SPF), accuracy (ACC), and root mean square error (RMSE). The Bagging-RBFC model with PPV = 86%, NPV = 95%, SST = 95%, SPF = 87%, ACC = 91%, RMSE = 0.297, and AUC = 98% was found to be the most accurate model for the prediction of landslide susceptibility, followed by the Dagging-RBFC, Decorate-RBFC, and single RBFC models. The study demonstrates the efficacy of ensemble learning techniques in developing reliable landslide predictive models, which can ultimately save lives and reduce infrastructure damage in landslide-prone regions worldwide.

A Comparison of a Conventional Chemical Coagulant and a Natural Coagulant Derived from Cassia fistula Seeds for the Removal of Heavy Metal Ions.

Cassia fistula seed-derived coagulant has been reported to exhibit high coagulating-flocculating activity, environmental friendliness, and cost-effectiveness for the wastewater treatment, especially of textile wastewater. For heavy metal removal, however, research focusing on evaluating the feasibility of this material is still limited. Therefore, this study reports jar-test experiments in which the Zn2+ and Ni2+ removal efficiency of C. fistula coagulant was assessed. Moreover, a comparison of coagulation performance using a conventional chemical coagulant and the natural coagulant was performed. Characterization of the C. fistula seed-derived coagulant revealed the presence of important functional groups and fibrous networks with rough surfaces. A bench-scale study indicated that the coagulation performance of the two coagulants depends strongly on the initial concentration of metal ions, pH level, and coagulant dosage. The C. fistula seed-derived coagulant was found to possess higher removal efficiency than polyaluminum chloride. This natural coagulant removed over 80% of metal ions at the optimal conditions of pH 5.0, a metal ion concentration of 25 ppm, and a dosage of 0.8 and 1.6 g/L for Zn2+ and Ni2+, respectively. This study shows that C. fistula seed-derived coagulant is a potential alternative to chemical coagulants and could be developed to provide an environmentally friendly, economical, and efficient wastewater treatment.

VinDr-Mammo: A large-scale benchmark dataset for computer-aided diagnosis in full-field digital mammography.

Mammography, or breast X-ray imaging, is the most widely used imaging modality to detect cancer and other breast diseases. Recent studies have shown that deep learning-based computer-assisted detection and diagnosis (CADe/x) tools have been developed to support physicians and improve the accuracy of interpreting mammography. A number of large-scale mammography datasets from different populations with various associated annotations and clinical data have been introduced to study the potential of learning-based methods in the field of breast radiology. With the aim to develop more robust and more interpretable support systems in breast imaging, we introduce VinDr-Mammo, a Vietnamese dataset of digital mammography with breast-level assessment and extensive lesion-level annotations, enhancing the diversity of the publicly available mammography data. The dataset consists of 5,000 mammography exams, each of which has four standard views and is double read with disagreement (if any) being resolved by arbitration. The purpose of this dataset is to assess Breast Imaging Reporting and Data System (BI-RADS) and breast density at the individual breast level. In addition, the dataset also provides the category, location, and BI-RADS assessment of non-benign findings. We make VinDr-Mammo publicly available as a new imaging resource to promote advances in developing CADe/x tools for mammography interpretation.

Timing and duration of bevacizumab treatment and survival in patients with recurrent ovarian, fallopian tube, and peritoneal cancer: a multi-institution study.

Bevacizumab has demonstrated significant benefit in recurrent ovarian, fallopian tube and peritoneal cancer (OC), but its optimal position within the sequence of systemic therapies remains controversial. Since rebound progression after bevacizumab has been observed in other cancers, and because bevacizumab is incorporated in several regimens used in the recurrent setting, the duration of treatment may impact survival. We sought to identify whether earlier bevacizumab exposure is associated with prolonged bevacizumab therapy and survival by conducting a multi-institution retrospective study of recurrent OC patients treated with bevacizumab from 2004-2014. Multivariate logistic regression identified factors associated with receiving more than six bevacizumab cycles. Overall survival by duration and ordinal sequence of bevacizumab therapy were evaluated using logrank testing and Cox regression. In total, 318 patients were identified. 89.1% had stage III or IV disease; 36% had primary platinum resistance; 40.5% received two or fewer prior chemotherapy regimens. Multivariate logistic regression demonstrated that primary platinum sensitivity (Odds Ratio (OR) 2.34, p = 0.001) or initiating bevacizumab at the first or second recurrence (OR 2.73, p < 0.001) were independently associated with receiving more than six cycles of bevacizumab. Receiving more cycles of bevacizumab was associated with improved overall survival whether measured from time of diagnosis (logrank p < 0.001), bevacizumab initiation (logrank p < 0.001), or bevacizumab discontinuation (logrank p = 0.017). Waiting one additional recurrence to initiate bevacizumab resulted in a 27% increased hazard of death (Hazard Ratio (HR) 1.27, p < 0.001) by multivariate analysis. In conclusion, patients with primary platinum sensitive disease who received fewer prior lines of chemotherapy were able to receive more cycles of bevacizumab, which was associated with improved overall survival. Survival worsened when bevacizumab was initiated later in the ordinal sequence of therapies.

Eumitrins I-K: three new xanthone dimers from the lichen Usnea baileyi.

In the continuing discovery and structure elucidation of natural xanthone dimers, which are still rarely reported in absolute configuration, three new xanthone dimers, eumitrins I-K (1-3) were isolated from the lichen Usnea baileyi, a rich source of natural xanthone dimers. Their structures were elucidated unambiguously by spectroscopic analyses, including high-resolution electrospray ionization mass spectrometry (HRESIMS), 1D and 2D nuclear magnetic resonance spectroscopy (1D and 2D NMR). The absolute configuration of all three compounds was established through DP4 probability and ECD calculation. All compounds revealed weak activity for their enzymatic inhibition against α-glucosidase and tyrosinase, as well as antibacterial activity.

Plastic surgery and adjuvant chemoradiotherapy in the management of advanced external auditory canal cancer.

Background: Carcinoma of the external auditory canal is a rare malignancy that originates in the external auditory canal and has a tendency to spread to adjacent structures such as the periorbital soft tissues, parotid gland, temporomandibular joint and mastoid. It is difficult to determine the primary tumour from the external ear canal or from adjacent structures. In addition, the lack of a unified classification system, along with the rarity of the disease, is a major obstacle in providing specific treatment guidelines for this disease. Case presentation: In this report, we describe a clinical case of a 59-year-old male patient who was admitted to the hospital because of ear pain and discharge from the outer ear canal with swelling in the right temporal region. The initial diagnosis is highly suggestive of an advanced external auditory canal malignancy with involvement of the parotid gland. The patient underwent surgery to remove the entire tumour, neck lymph nodes, followed by plastic surgery. The patient then received adjuvant chemoradiotherapy. There was no recurrence of cancer for 28 months, to date, after completing treatment. Conclusions: Extensive tumour resection combined with reconstruction and adjuvant chemoradiotherapy is a treatment strategy with good outcomes for patients with advanced squamous cell carcinoma of the external ear canal.

High prevalence of esophagitis in patients with severe ineffective esophageal motility: need for a new diagnostic cutoff.

Background: A new classification criterion for diagnosing ineffective esophageal motility (IEM) was proposed at the 2018 Stanford symposium, but limited data exists about the utility of this criterion. Methods: We conducted a cross-sectional study among 3826 patients treated at the Institute of Gastroenterology and Hepatology, Hanoi, Vietnam, between March 2018 and May 2020. Patients were classified as having normal motility, mild IEM, severe IEM, or absent contractility based on the Chicago classification version 3.0 and the new IEM criterion (severe IEM was defined as having >70% ineffective swallows). We examined the association between these 4 motility subgroups and the presence of erosive esophagitis and Barrett's esophagus, using multivariate logistic regression analysis. Results: The mean age of the study sample was 44.7 years and 66.3% were women. The prevalence of symptoms, hiatal hernia, and Helicobacter pylori-positive patients was similar in the 4 study groups. The 4-second integrated relaxation pressures and lower esophageal sphincter resting pressures were lower in patients with severe IEM and absent contractility. Severe IEM and absent contractility, but not mild IEM, were significantly associated with Los Angeles (LA) grade B-D esophagitis (relative risk ratio [RRR] for severe IEM 1.81, 95% confidence interval [CI] 1.17-2.80; and RRR for absent contractility 2.37, 95%CI 1.12-5.04). None of the hypomotility subgroups were associated with LA grade A esophagitis and Barrett's esophagus. Conclusions: Patients with severe IEM have a high prevalence of severe erosive esophagitis. These findings suggest the need for a more meaningful classification criterion for IEM.

VinDr-CXR: An open dataset of chest X-rays with radiologist's annotations.

Most of the existing chest X-ray datasets include labels from a list of findings without specifying their locations on the radiographs. This limits the development of machine learning algorithms for the detection and localization of chest abnormalities. In this work, we describe a dataset of more than 100,000 chest X-ray scans that were retrospectively collected from two major hospitals in Vietnam. Out of this raw data, we release 18,000 images that were manually annotated by a total of 17 experienced radiologists with 22 local labels of rectangles surrounding abnormalities and 6 global labels of suspected diseases. The released dataset is divided into a training set of 15,000 and a test set of 3,000. Each scan in the training set was independently labeled by 3 radiologists, while each scan in the test set was labeled by the consensus of 5 radiologists. We designed and built a labeling platform for DICOM images to facilitate these annotation procedures. All images are made publicly available in DICOM format along with the labels of both the training set and the test set.

A High-Quality Genome Assembly of Striped Catfish (Pangasianodon hypophthalmus) Based on Highly Accurate Long-Read HiFi Sequencing Data.

The HiFi sequencing technology yields highly accurate long-read data with accuracies greater than 99.9% that can be used to improve results for complex applications such as genome assembly. Our study presents a high-quality chromosome-scale genome assembly of striped catfish (Pangasianodon hypophthalmus), a commercially important species cultured mainly in Vietnam, integrating HiFi reads and Hi-C data. A 788.4 Mb genome containing 381 scaffolds with an N50 length of 21.8 Mb has been obtained from HiFi reads. These scaffolds have been further ordered and clustered into 30 chromosome groups, ranging from 1.4 to 57.6 Mb, based on Hi-C data. The present updated assembly has a contig N50 of 14.7 Mb, representing a 245-fold and 4.2-fold improvement over the previous Illumina and Illumina-Nanopore-Hi-C based version, respectively. In addition, the proportion of repeat elements and BUSCO genes identified in our genome is remarkably higher than in the two previously released striped catfish genomes. These results highlight the power of using HiFi reads to assemble the highly repetitive regions and to improve the quality of genome assembly. The updated, high-quality genome assembled in this work will provide a valuable genomic resource for future population genetics, conservation biology and selective breeding studies of striped catfish.

Salinity significantly affects intestinal microbiota and gene expression in striped catfish juveniles.

In the present study, juvenile striped catfish (Pangasianodon hypophthalmus), a freshwater fish species, have been chronically exposed to a salinity gradient from freshwater to 20 psu (practical salinity unit) and were sampled at the beginning (D20) and the end (D34) of exposure. The results revealed that the intestinal microbial profile of striped catfish reared in freshwater conditions were dominated by the phyla Bacteroidetes, Firmicutes, Proteobacteria, and Verrucomicrobia. Alpha diversity measures (observed OTUs (operational taxonomic units), Shannon and Faith's PD (phylogenetic diversity)) showed a decreasing pattern as the salinities increased, except for the phylogenetic diversity at D34, which was showing an opposite trend. Furthermore, the beta diversity between groups was significantly different. Vibrio and Akkermansia genera were affected differentially with increasing salinity, the former being increased while the latter was decreased. The genus Sulfurospirillium was found predominantly in fish submitted to salinity treatments. Regarding the host response, the fish intestine likely contributed to osmoregulation by modifying the expression of osmoregulatory genes such as nka1a, nka1b, slc12a1, slc12a2, cftr, and aqp1, especially in fish exposed to 15 and 20 psu. The expression of heat shock proteins (hsp) hsp60, hsp70, and hsp90 was significantly increased in fish reared in 15 and 20 psu. On the other hand, the expression of pattern recognition receptors (PRRs) were inhibited in fish exposed to 20 psu at D20. In conclusion, the fish intestinal microbiota was significantly disrupted in salinities higher than 10 psu and these effects were proportional to the exposure time. In addition, the modifications of intestinal gene expression related to ion exchange and stressful responses may help the fish to adapt hyperosmotic environment. KEY POINTS: • It is the first study to provide detailed information on the gut microbiota of fish using the amplicon sequencing method. • Salinity environment significantly modified the intestinal microbiota of striped catfish. • Intestinal responses may help the fish adapt to hyperosmotic environment.

Fear of disasters within the risk communication network of foreign students in Japan amid the COVID-19 pandemic crisis: A cohort design.

The main objective of this study is to examine the role of risk communication during the COVID-19 crisis, which is often neglected in studies investigating the outbreak of the pandemic. The study is based on survey data from a group of international (non-Japanese) students in Japan and the theoretical foundation of fear appeal theory. The results, which are based on the panel data structure, show that individually, (1) the act of seeking out others to discuss risks in depth in the current pandemic context or (2) the observed adoption of advocated precautionary health behaviours is not necessarily a good indicator of mental management, but (3) the combined effect of (1) and (2) unexpectedly suggests a conciliatory effect on the fear of disasters. Moreover, this evidence-based finding (3) suggests that a reciprocal relationship exists between threat and efficacy in terms of mediating fear under the framework and theory of fear appeals, indirectly challenging the fear control response proposition of the extended parallel process model. Our empirical findings emphasize the role of risk discourse and information sharing combined with preventive health behaviours adopted within a community in the context of global health crises.

A New Look and Convergence Rate of Federated Multitask Learning With Laplacian Regularization.

Non-independent and identically distributed (non-IID) data distribution among clients is considered as the key factor that degrades the performance of federated learning (FL). Several approaches to handle non-IID data, such as personalized FL and federated multitask learning (FMTL), are of great interest to research communities. In this work, first, we formulate the FMTL problem using Laplacian regularization to explicitly leverage the relationships among the models of clients for multitask learning. Then, we introduce a new view of the FMTL problem, which, for the first time, shows that the formulated FMTL problem can be used for conventional FL and personalized FL. We also propose two algorithms and decentrali-zed () to solve the formulated FMTL problem in communication-centralized and decentralized schemes, respectively. Theoretically, we prove that the convergence rates of both algorithms achieve linear speedup for strongly convex and sublinear speedup of order 1/2 for nonconvex objectives. Experimentally, we show that our algorithms outperform the conventional algorithm FedAvg, FedProx, SCAFFOLD, and AFL in FL settings, MOCHA in FMTL settings, as well as pFedMe and Per-FedAvg in personalized FL settings.

Clinical Patterns and Risk Factors for Pneumonia Caused by Atypical Bacteria in Vietnamese Children.

OBJECTIVE: To investigate clinical characteristics and risk factors for atypical community-acquired pneumonia (CAP) in children. METHODS: Multiplex polymerase chain reaction and specific IgM determination were used to detect atypical bacteria in 661 hospitalized children aged 1-15 years with CAP. Clinical and epidemiological patterns were compared between typical and atypical CAP. RESULTS: Children in atypical CAP group manifested significantly lower rates of wheezing, bronchial rales, and interstitial pneumonia and showed higher rates of asthma history, headache, chest pain, and lobar pneumonia . Age group, season of disease onset, asthma history, duration of symptom onset to hospital admission, and radiological findings were the significant risk factors for atypical CAP on multivariate logistic regression analysis. CONCLUSIONS: The clinical characteristics and risk factors can be used to identify a child at high risk of atypical CAP.

Sequencing and analysis of the mitochondrial genome of Pennahia anea (Bloch, 1793) (Perciformes: Sciaenidae).

Donkey croaker, Pennahia anea (Bloch, 1793) is a commercially important croaker in the Indo-Pacific region. In this study, we sequenced and analyzed the mitogenome of P. anea. The nearly complete mitochondrial genome of P. anea is 15,694 bp in size. It contained 13 protein-coding genes (PCGs), 2 rRNA genes, and 22 tRNA genes. The sequence had the A-T content of 55.4% and GC content of 44.6%. All 13 PCGs used ATG codon for initiation, while TAA codon was the most common for termination. Phylogenetic analysis demonstrated that P. anea is located within the genus Pennahia. This study provides additional data for the understanding of the phylogeny of the family Sciaenidae.

Improving antibiotic prescribing for community-acquired pneumonia in a provincial hospital in Northern Vietnam.

OBJECTIVES: To test the effectiveness of a quality improvement programme to promote adherence to national quality standards (QS) for patients hospitalized with community-acquired pneumonia (CAP), exploring the factors that hindered improvements in clinical practice. METHODS: An improvement bundle aligned to the QS was deployed using plan-do-study-act methodology in a 600 bed hospital in northern Vietnam from July 2018 to April 2019. Proposed care improvements included CURB65 score guided hospitalization, timely diagnosis and inpatient antibiotic treatment review to limit the spectrum and duration of IV antibiotic use. Interviews with medical staff were conducted to better understand the barriers for QS implementation. RESULTS: The study found that improvements were made in CURB65 score documentation and radiology results available within 4 h (P < 0.05). There were no significant changes in the other elements of the QS studied. We documented institutional barriers relating to the health reimbursement mechanism and staff cultural barriers relating to acceptance and belief as significant impediments to implementation of the standards. CONCLUSIONS: Interventions led to some process changes, but these were not utilized by clinicians to improve patient management. Institutional and behavioural barriers documented may inhibit wider national uptake of the QS. National system changes with longer term support and investment to address local behavioural barriers are likely to be crucial for future improvements in the management of CAP, and potentially other hospitalized conditions, in Vietnam.

A Two-Stage Data Association Approach for 3D Multi-Object Tracking.

Multi-Object Tracking (MOT) is an integral part of any autonomous driving pipelines because it produces trajectories of other moving objects in the scene and predicts their future motion. Thanks to the recent advances in 3D object detection enabled by deep learning, track-by-detection has become the dominant paradigm in 3D MOT. In this paradigm, a MOT system is essentially made of an object detector and a data association algorithm which establishes track-to-detection correspondence. While 3D object detection has been actively researched, association algorithms for 3D MOT has settled at bipartite matching formulated as a Linear Assignment Problem (LAP) and solved by the Hungarian algorithm. In this paper, we adapt a two-stage data association method which was successfully applied to image-based tracking to the 3D setting, thus providing an alternative for data association for 3D MOT. Our method outperforms the baseline using one-stage bipartite matching for data association by achieving 0.587 Average Multi-Object Tracking Accuracy (AMOTA) in NuScenes validation set and 0.365 AMOTA (at level 2) in Waymo test set.

LC-MS/MS Method for Rapid Quantification of Progesterone in Rabbit Plasma and Its Application in a Pharmacokinetic Study of the Transdermal Formulation.

A rapid and effective method using QuEChERS-based sample preparation procedure and liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis has been developed and validated to determine progesterone in rabbit plasma. The analyte was extracted from plasma by acetonitrile with phase partitioning by a mixture of magnesium sulfate and sodium chloride. The supernatant was then directly injected into LC-MS/MS in a positive electrospray ionization mode and quantified using progesterone-d9 as the internal standard. The method linearity was in the range from 1 ng/mL (LOQ) to 200 ng/mL. Method recovery was from 86.0% to 103%, and repeatability was lower than 5.5%. The plasma sample was stable for 12 weeks stored at 18 ± 2°C. This method was applied to quantify progesterone in rabbit plasma in a pharmacokinetic study of two transdermal formulations: a reference drug and a eutectic-hydrogel system. The data indicate that the eutectic-hydrogel system's bioavailability was 1.5 times better than that of the reference drug, and the transdermal system is a potential drug delivery system for progesterone.