Maxillary ostium preservation in ethmoidectomy.

The paranasal sinuses play a role in producing and storing nitric oxide (NO). NO is a powerful antiviral and antibacterial gas which may be involved in the non-specific immune defenses of the respiratory tract. Conducted by the inspiratory current at the alveolar-capillary membrane, it increases pulmonary venous blood oxygenation. NO is actively released in the form of independent boluses in the respiratory tract, thanks to a sphincter function that can be identified during ethmoidectomy under general anesthesia. Safeguarding paranasal sinus physiology necessarily involves conserving this ostial sphincter function, which is essential to the respiratory role of the paranasal sinuses. Although it has not yet been demonstrated that the destruction of this ostial function has measurable consequences for respiratory function, it makes sense to avoid systematic antrostomy and to preserve this ostial function whenever possible, depending on the clinical conditions. This technical note describes step-by-step how to conserve the maxillary ostium, in the example of radical ethmoidectomy with mucosal ablation for nasal polyposis (nasalization). It is illustrated by two videos. The discussion focuses on the respective indications for ostial preservation and middle meatotomy (antrostomy).

Critical review of diagnosis in rhinology and its therapeutical implications.

Diagnosis in rhinology is currently based on the concept of inflammation (chronic rhinosinusitis [CRS]) or the clinical concept of chronic nasal dysfunction (CND). The complementarity between these two approaches can be discussed by a critical review of the literature structured by the analysis of the fundamental and diagnostic bases and the therapeutic implications linked to each. The concept of CRS is based on the anatomical continuity of the nasal and sinus respiratory mucosa and molecular biology data, seeking to analyze the mechanisms of chronic inflammation and to identify proteins and biomarkers involved in the different supposed endotypes of chronic inflammation of this mucosa. The concept of CND seeks to analyze medical, instrumental or surgical diagnostic and therapeutic strategies, taking account of both inflammatory and non-inflammatory causes impacting the anatomy or physiology of each of the three noses (olfactory, respiratory and sinus) that make up the mid-face sinonasal organ of evolution-development (Evo-Devo) theory. Thus, the concept of CRS offers an endotypic approach, based on biological characterization of mucosal inflammation, while the concept of CND offers a compartmentalized phenotypic and pathophysiological approach to sinonasal diseases. The joint contribution of these two concepts in characterizing nasal functional pathology could in future improve the medical service provided to patients.

Minimal clinically important differences on the DyNaChron questionnaire after surgery.

OBJECTIVES: To determine minimal clinically important differences (MCIDs) for the DyNaChron chronic rhinosinusitis quality-of-life questionnaire. INTRODUCTION: MCIDs are the smallest changes in a quality-of-life score that are of clinical relevance for the patient. They allow treatment benefit to be estimated. MCIDs have not previously been determined for DyNaChron. MATERIAL AND METHODS: A single-center retrospective study analyzed DyNaChron questionnaires filled out between June 2016 and December 2021 by all patients consulting for chronic nasal dysfunction. Five hundred and thirteen of the 2390 patients were operated on for nasal polyposis (NP; n=282) or septo(rhino)plasty+inferior turbinoplasty (SPIT; n=231). Standard error of measurement was used to determine MCIDs. RESULTS: MCID for DyNaChron global score was 60 in NP and 58 in SPIT. MCIDs per symptom domain in NP and SPIT respectively were: 15 and 13 for nasal obstruction, 21 and 21 for anterior rhinorrhea, 20 and 19 for posterior rhinorrhea, and 17 and 17 for olfaction. In agreement with global MCID, 257 NPs (91%) and 149 SPITs (65%) showed clinical improvement. CONCLUSION: MCID helps assess response to treatment. In the DyNaChron questionnaire, MCIDs enable global and symptom-specific assessment of chronic nasal dysfunction and its impact on quality of life in a single patient or in groups.

Urban-rural disparities in acceptance of human papillomavirus vaccination among women in Can Tho, Vietnam.

Background: In Vietnam, cervical cancer is a significant public health concern for women. Unfortunately, despite the availability of the HPV vaccine, low vaccination rates persist. Objectives: This study investigates the discrepancy between urban and rural areas in the willingness to receive HPV vaccination with or without fees. Methods: A cross-sectional study was conducted on a sample of 648 women aged between 15 and 49, living in two urban and two rural Vietnamese districts of Can Tho, between May and December 2021. Results: The overall vaccination rate was 4%, with urban women having a higher rate of 4.9% compared to rural women at 3.1%. Among unvaccinated women, those from rural areas expressed a significantly higher desire to receive the free vaccine (91.4%) than urban women (84.4%). However, the intention to vaccinate declined when rural women and urban women were advised to pay the cost (63.4% and 57.1%, respectively). A strong correlation was found between a positive attitude and intention for vaccination, irrespective of its price or free availability. Education and access to information about the HPV vaccine were also identified as the most significant factors influencing the intention to vaccination among urban and rural women. Conclusion: The low HPV vaccination rates among women aged 15-49 living in both urban and rural regions of Vietnam are a notable public health concern. These outcomes emphasize the critical need for effective programs of vaccine laterization, as an introduction to the offer of affordable and accessible HPV vaccines for women in Can Tho, Vietnam.

Bioconjugation of COL1 protein on liquid-like solid surfaces to study tumor invasion dynamics.

Tumor invasion is likely driven by the product of intrinsic and extrinsic stresses, reduced intercellular adhesion, and reciprocal interactions between the cancer cells and the extracellular matrix (ECM). The ECM is a dynamic material system that is continuously evolving with the tumor microenvironment. Although it is widely reported that cancer cells degrade the ECM to create paths for migration using membrane-bound and soluble enzymes, other nonenzymatic mechanisms of invasion are less studied and not clearly understood. To explore tumor invasion that is independent of enzymatic degradation, we have created an open three-dimensional (3D) microchannel network using a novel bioconjugated liquid-like solid (LLS) medium to mimic both the tortuosity and the permeability of a loose capillary-like network. The LLS is made from an ensemble of soft granular microgels, which provides an accessible platform to investigate the 3D invasion of glioblastoma (GBM) tumor spheroids using in situ scanning confocal microscopy. The surface conjugation of the LLS microgels with type 1 collagen (COL1-LLS) enables cell adhesion and migration. In this model, invasive fronts of the GBM microtumor protruded into the proximal interstitial space and may have locally reorganized the surrounding COL1-LLS. Characterization of the invasive paths revealed a super-diffusive behavior of these fronts. Numerical simulations suggest that the interstitial space guided tumor invasion by restricting available paths, and this physical restriction is responsible for the super-diffusive behavior. This study also presents evidence that cancer cells utilize anchorage-dependent migration to explore their surroundings, and geometrical cues guide 3D tumor invasion along the accessible paths independent of proteolytic ability.

Chronic respiratory rhinitis: Toward endoscopic diagnosis of nasal allergy? An observational study.

OBJECTIVE: The study objective was to assess the functional, endoscopic and tomodensitometric semiology of a cohort of patients with chronic respiratory rhinitis (CRR). The concept of CRR is based on the anatomical, pathophysiological and semiological individualization of the respiratory nose within the sinonasal organ, in which three noses are distinguished by the parallel study of evolution and development in the "evo-devo" theory of the origins of the nose, anterior base of the skull and middle third of the face. MATERIAL AND METHOD: A single-center retrospective study included a cohort of 28 patients (16 men and 12 women, aged 19 to 69years) with CRR. The main objective was to describe symptoms clinically, endoscopically and on CT. The secondary objective was to compare clinical symptomatology and CT data between CRR and a control group of 31 patients with nasal polyposis (NP). The endoscopic semiology of CRR was analyzed consensually on video recordings using a pre-established grid. The DyNaChron self-administered questionnaire was used to compare symptom intensity and deterioration in quality of life. Olfaction was compared using the Sniffin' Sticks test. CT opacities were compared between CRR and NP on Lund-Mackay sinus score and a specific ethmoid opacities score. RESULTS: In CRR, endoscopy found a constant association of inflammatory or edematous signs in the inferior or middle turbinates with signs of hypersecretion. Ethmoid opacities in CRR were discrete and significantly smaller than in NP (P<0.0001), and were mainly located in the medial compartment in contact with the olfactory cleft (P<0.0001). Allergological assessment was positive in 17 of the 28 cases of CRR. Chronic nasal dysfunction was similar in CRR and NP, but olfactory impairment was significantly lower in CRR (P<0.0001). CONCLUSION: The CRR entity clinically resembles atopic central compartment disease. In both entities, endoscopy reveals inflammatory lesions restricted to the nasal cavities without significant ethmoid opacity on CT, an observation which seems to contradict the pathophysiological united airway concept.

Perceptions and behaviors of learner engagement with virtual educational platforms.

BACKGROUND: The COVID-19 pandemic has increased utilization of educational technology for surgical education. Our aim was to determine attitudes and behaviors of surgical education champions towards virtual educational platforms and learner engagement. METHODS: An electronic survey was distributed to all Association of Surgical Education members addressing i) methods of engagement in virtual learning ii) ways to improve engagement and iii) what influences engagement. Stratified analysis was used to evaluate differences in responses by age, gender, level of training and specialty. RESULTS: 154 ASE members completed the survey (13% response rate). 88% respondents accessed virtual learning events at home. Most (87%) had joined a virtual learning event and then participated in another activity. 1 in 5 who did this did so "always" or "often". Female respondents were more likely than males to join audio and then participate in another activity (62.3% v 37.7%, p = 0.04). CONCLUSIONS: Virtual platforms do not automatically translate into increased learner engagement. Careful design of educational strategies is essential to increase and maintain learner engagement when utilizing virtual surgical education.

Assessing learner engagement with virtual educational events: Development of the Virtual In-Class Engagement Measure (VIEM).

BACKGROUND: The COVID-19 pandemic has necessitated virtual education, but effects on learner engagement are unknown. We developed a virtual in-class engagement measure (VIEM) to assess learner engagement in online surgical education events. METHODS: Using the STROBE, an observer collected tool to document student engagement, as a template an ASE committee workgroup developed the VIEM. The VIEM had two parts: observer assessment and learner self-assessment of engagement. Trained observers collected engagement data from two institutions using the VIEM. Surgical attendings, fellows and residents were observed during virtual learning events. Educator attitudes towards online teaching were also assessed via survey. RESULTS: 22 events with 839 learners were observed. VIEM distinguished between sessions with low and high engagement. 20% of learners pretended to participate. Half of instructors were comfortable with virtual teaching, but only 1/3 believed was as effective as in-person. 2/3 of teachers believed video learners were more engaged than audio learners. CONCLUSIONS: Virtual platforms do not automatically translate into increased engagement. Standard tools such as VIEM may help with assessment of engagement during virtual education.

Simulation-based training in endoscopic endonasal surgery: Assessment of the cyrano simulator.

PURPOSE: Endoscopic endonasal surgery requires many skills: a learning program was developed with progressive steps, on a surgical simulator (Cyrano) designed to train junior surgeons in the acquisition of basic endoscopic surgery skills and to assess their progress. The main objective of this study was to establish the construct validity of these exercises and to refine objective criteria to establish students' level. MATERIAL AND METHODS: Thirty volunteers with varying experience in endoscopic endonasal surgery were blindly evaluated on 4 modules according to objective and subjective criteria. RESULTS: Ten beginner, 11 intermediate and 9 expert level participants were included. For each exercise, at least one criterion was discriminant for level of expertise. Weighted scores succeeded in discriminating groups. Interpretation of a single criterion must remain cautious and evaluation should rather rely on composite scores, which better reflect the participants' level. Useful criteria and their reference values are specific of each exercise. Face and content validity were rated at 3.92/5 and 4.59/5 respectively (5-level Likert scale). CONCLUSION: The construct/face/content validity of the proposed modules have been verified. Most of the modules tested here were physically not realistic, but they were all rated as highly relevant for surgical training by the participants.

The relationship between spontaneous cerebrospinal fluid leak and idiopathic intracranial hypertension.

Surgical treatment of spontaneous cerebrospinal fluid (CSF) leak is now performed by ENT surgeons, endonasal endoscopy being preferred to craniotomy as less invasive. However, it is often the symptom of underlying idiopathic intracranial hypertension, which lies outside the traditional sphere of ENT competence. Surgery is a necessary step, but should not obscure the need to treat the underlying pathology. This treatment is complex, and requires multidisciplinary team-work between otorhinolaryngologist, ophthalmologist, neurologist, neurosurgeon, radiologist, dietician, endocrinologist and psychotherapist. The present update details this multidisciplinary management to which the ENT surgeons must be attentive before and after spontaneous CSF leak repair.

Therapeutics potentiating microglial p21-Nrf2 axis can rescue neurodegeneration caused by neuroinflammation.

Neurodegenerative disorders are caused by progressive neuronal loss, and there is no complete treatment available yet. Neuroinflammation is a common feature across neurodegenerative disorders and implicated in the progression of neurodegeneration. Dysregulated activation of microglia causes neuroinflammation and has been highlighted as a treatment target in therapeutic strategies. Here, we identified novel therapeutic candidate ALGERNON2 (altered generation of neurons 2) and demonstrate that ALGERNON2 suppressed the production of proinflammatory cytokines and rescued neurodegeneration in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson's disease model. ALGERNON2 stabilized cyclinD1/p21 complex, leading to up-regulation of nuclear factor erythroid 2-related factor 2 (Nrf2), which contributes to antioxidative and anti-inflammatory responses. Notably, ALGERNON2 enhanced neuronal survival in other neuroinflammatory conditions such as the transplantation of induced pluripotent stem cell-derived dopaminergic neurons into murine brains. In conclusion, we present that the microglial potentiation of the p21-Nrf2 pathway can contribute to neuronal survival and provide novel therapeutic potential for neuroinflammation-triggered neurodegeneration.

Intestinal and non-intestinal nasal cavity adenocarcinoma: Impact of wood dust exposure.

The aim of the present study was to investigate the role of wood dust exposure in intestinal (ITAC) and non-intestinal type (non-ITAC) nasal adenocarcinoma, so as to improve understanding of the oncogenic mechanisms in the light of the recent literature and of evo-devo concepts. MATERIALS AND METHODS: All consecutive patients operated in our institution for nasal adenocarcinoma diagnosed on anatomopathology between May 2004 and February 2014 were included. Surgical specimens were examined twice by independent pathologists, blind to wood dust exposure status. Clinical and demographic data, including wood dust exposure, were collected for the two groups (ITAC and non-IATC). RESULTS: 90 patients (84 ITAC, 6 non-ITAC) were included. No non-ITAC patients had history of wood dust exposure, versus 83/84 cases (99%) in ITAC (mean exposure duration: 30±16 years; range 2-65 years). Only 12 ITAC patients (18%) were still exposed at diagnosis. ITAC may develop long after the end of wood dust exposure (up to 60 years). Eight patients (12%) had exposure durations of less than 5 years. Latency between onset of exposure and onset of disease did not decrease with exposure duration. CONCLUSION: Exposure to wood dust, even for short periods of time, incurs a risk of developing ITAC, usually after a long latency period. Any exposure requires lifetime follow-up, to ensure prompt treatment. Factors leading to the development of nasal ITAC and non-ITAC are probably different. The analogy with Barret's esophagus and esophageal adenocarcinoma may shed light on the oncogenesis of nasal ITAC.

Technical Note: Real-time image-guided adaptive radiotherapy of a rigid target for a prototype fixed beam radiotherapy system.

PURPOSE: Fixed beam radiotherapy systems utilize couch movement and rotation instead of gantry rotation in order to simplify linear accelerator design. We investigate the ability to deliver fixed beam treatments with the same level of clinical accuracy as conventional (rotating beam) treatments using real-time image guidance to maintain this accuracy in the presence of rigid target motion. METHODS: A prototype fixed beam radiotherapy system was built using a standard linac with the beam fixed in the vertical position and a computer controlled rotation stage that rotated a rigid phantom about the superior-inferior axis. Kilovoltage Intrafraction Monitoring (KIM) and real-time beam adaptation with MLC tracking was applied to a five-field IMRT treatment plan with motion introduced to the phantom. The same IMRT treatment was also delivered with real-time adaptation using the conventional rotating beam geometry. Film dosimetry was used to measure the dose delivered with a fixed beam compared to a rotating beam, as well as to compare treatments delivered with and without real-time adaptation. RESULTS: The dose distributions were found to be equivalent between the fixed beam and rotating beam geometry for real-time adaptive radiotherapy using KIM and MLC tracking beam adaptation. Gamma analysis on the films showed agreement >98% using a 2%/2 mm criteria with adaptation for static shifts and periodic motion. CONCLUSIONS: Fixed beam treatments with real-time beam adaptation are dosimetrically equivalent to conventional treatments with a rotating beam, even in the presence of rigid target motion. This suggests that, for a rigid target, the high clinical accuracy of real-time adaptive radiotherapy can be achieved with simpler beam geometry.

Olfactory cleft dilatation.

The surgical technique of olfactory cleft dilatation consists in transmucosal lateral fracture-dislocation of the lateral wall of each olfactory cleft (i.e., of the turbinate wall of the ethmoid, composed, from anterior to posterior, of the middle, superior and supreme turbinates), in order to get access to the recess hosting the human olfactory mucosa and to the roof of the olfactory cleft (i.e., cribriform plate), with minimal trauma to the mucosa. Olfactory cleft dilatation is indicated for dysosmia secondary to constitutional stenosis of the olfactory clefts due to abnormal development of the ethmoid. Constitutional stenosis of the olfactory clefts should be differentiated from inflammatory obstruction and other diseases of the olfactory clefts, and especially from respiratory epithelial adenomatoid hamartoma, which enlarges the olfactory clefts and must be treated by resection. The technique of olfactory cleft dilatation is illustrated by three surgical cases. There was clear improvement in dysosmia in all three cases, without any complications. The place of constitutional olfactory cleft stenosis needs still to be defined in both diagnosis and treatment of dysosmia.

Updating nasalisation: From concept to technique and results.

Nasalisation is a surgical technique proposed for the treatment of nasal polyposis in 1995. The technique as initially described was based on large opening of the maxillary, sphenoidal and frontal ostia and resection of the middle turbinates, with the aim of resecting the mucosa of the lateral masses of the ethmoid as completely and safely as possible. Recent findings on the evolution and development of the nose and sinuses and sinus physiology allow both the concept and the technique of nasalisation to be updated. According to evo-devo theory, the ethmoid is not a paranasal sinus but the skull-base bone housing the olfactory mucosa. In humans, the olfactory mucosa can be distinguished as functional in the upper recess of both olfactory clefts and vestigial in the rest of the ethmoid bone. Nasal polyposis presents clinically as a specific disease of the vestigial olfactory mucosa of the human ethmoid (and not as a particular kind of chronic rhinosinusitis). The aim of surgery for nasal polyposis is thus maximal resection of the vestigial olfactory mucosa, conserving olfactory function as long as possible. By the production, storage and bolus release of nitric oxide thanks to the sphincter function of the paranasal (maxillary, sphenoidal and frontal) sinus ostia, the paranasal sinuses perform a respiratory function that should be conserved as much as possible. The nasalisation technique has been modified in order for the vestigial olfactory mucosa to be completely resected while sparing the sinus ostia. Middle turbinate surgery still needs to be evaluated: resection is a step toward maximal removal of vestigial olfactory mucosa, while conservation could ensure olfactory cleft integrity. Thus, updating the concept of nasalisation enables the nasalisation technique to be integrated in the evo-devo concept of rhinology.

Nasal polyposis (or chronic olfactory rhinitis).

The concept of chronic rhinosinusitis with or without polyps is founded on the structural and functional unicity of the pituitary mucosa and its united response to environmental aggression by allergens, viruses, bacteria, pollution, etc. The present review sets this concept against the evo-devo three-nose theory, in which nasal polyposis is distinguished as specific to the olfactory nose and in particular to the non-olfactory mucosa of the ethmoid, which is considered to be not a sinus but rather the skull-base bone harboring the olfactory mucosa. The evo-devo approach enables simple and precise positive diagnosis of nasal polyposis and its various clinical forms, improves differential diagnosis by distinguishing chronic diseases of the respiratory nose and those of the paranasal sinuses, hypothesizes an autoimmune origin specifically aimed at olfactory system auto-antigens, and supports the surgical concept of nasalization against that of functional sinus and ostiomeatal-complex surgery. The ventilation function of the sinuses seems minor compared to their production, storage and active release of nitric oxide (NO) serving to oxygenate arterial blood in the pulmonary alveoli. This respiratory function of the paranasal sinuses may indeed be their most important. NO trapped in the ethmoidal spaces also accounts for certain radiographic aspects associated with nasal polyposis.

Chronic respiratory rhinitis.

The clinical distinction of chronic respiratory rhinitis appears to confirm the evo-devo theory of the three noses. The authors report two cases of advanced allergic rhinitis, in which chronic inflammation had induced a violaceous colour of the mucosa of the respiratory nose and a whitish polypoid appearance of the free edge of the middle turbinate. Nose and paranasal sinus CT scan revealed, beyond the virtual nasal cavities observed on nasal endoscopy and CT imaging, normal radiolucency or only minor opacities of the ethmoid (i.e. olfactory nose) and paranasal sinuses that could not explain the severity of the chronic nasal dysfunction. The hypothesis of non-allergic chronic respiratory rhinitis is developed according to these two observations. The differential diagnosis between chronic respiratory rhinitis and dysfunction of the cavernous plexuses of the respiratory nose is discussed. A precise diagnosis appears to be a prerequisite for appropriate and effective management. Surgery of the respiratory nose can associate septoplasty to inferior turbinoplasty, but must be preceded and combined with medical treatment adapted to the underlying inflammatory process.

[Covering of Finger-Tissue Loss by Local Flaps in Hanoi, Vietnam]. / Recouvrement des pertes de substance de la pulpe des doigts par des lambeaux locaux à Hanoï, Vietnam.

The accidental loss of fingertip soft tissues, which may expose tendons and bones, is a common injury in emergency departments. If these lesions are poorly treated, they can impair fine motor skills and tactile sensitivity of the fingertips. The study was conducted on 30 patients (24 males and 6 females) with 32 soft tissue defects of the fingertip treated in emergency plastic surgery with local pedicled flap at the Plastic Surgery Department of Saint Paul Hospital Hanoi from 01/2016 to 06/2017. The most common cause of injury (21/30) was occupational accidents. At the time of the accident, 12 patients did not have personal protective equipment (PPE). Among 18 patients who had one, eight had incomplete equipment. Of 32 implanted skin flaps, 31 survived completely without necrosis or infection, only one being affected by epidermolysis. Postoperative evaluation showed excellent motor skills for 31/32 fingers and a sensitivity restoration at S4 level for 27/32. Workplace accident is the main cause of fingers soft tissue defects. Covering the fingers soft tissue defects with local pedicled flap in emergency preserves the fine motor function and the delicated tactile sensation of the fingers.

Une étude sur les pertes de substance accidentelles de la pulpe des doigts et leur recouvrement par lambeaux locaux a été réalisée dans le service de chirurgie reconstructive de l'hôpital Saint Paul de Hanoï de janvier 2016 à juin 2017. Elle a concerné 30 patients, 24 hommes et 6 femmes. La cause la plus fréquente était l'accident de travail, soit 21/30 cas. Au moment de l'accident, 12 patients ne disposaient pas d'équipement de protection individuelle (EPI). Sur les 18 patients qui en possédaient, 8 avaient un équipement incomplet. Sur 32 lambeaux mis en place, 31 ont survécu complètement sans nécrose, ni infection, et un a subi une épidermolyse. Trente et un des 32 doigts opérés ont conservé une fonction motrice de bonne qualité et 27 ont récupéré une sensibilité de niveau S4. Le traitement en urgence des pertes de substance de la pulpe des doigts par des lambeaux locaux permet de préserver la fonction motrice fine et la sensibilité des pulpes des doigts.

Endoscopic surgery of the olfactory cleft.

The olfactory cleft is the specific site of development of many tumours (respiratory epithelial adenomatoid hamartoma, intestinal-type adenocarcinoma, neuroblastoma, inverted papilloma, glomangiopericytoma, etc.) and is also the site of CSF rhinorrhoea via the cribriform plate (cribri-rhinorrhoea). Olfactory cleft surgery must therefore be considered to be a specific type of surgery, complementary to ethmoidal labyrinth surgery and anterior skull base surgery. Olfactory cleft tumours can be resected according to five different surgical procedures: olfactory cleft mucosal resection, partial resection of the olfactory cleft, total resection of the olfactory cleft, unilateral endoscopic anterior skull base resection, and bilateral endoscopic anterior skull base resection. The diagnosis and closure of cribri-rhinorrhoea (i.e. documented CSF rhinorrhoea, demonstrated to arise from the cribriform plate during endoscopic examination of the olfactory cleft under general anaesthesia in a patient with no localizing signs on imaging) completes this range of treatment options.