Comparison of safety and efficacy of Netarsudil 0.02% and Bimatoprost 0.01% monotherapy and combination therapy in primary open-angle glaucoma and ocular hypertension.

PURPOSE: To study and compare the efficacy and safety profile of Rho-kinase inhibitor (netarsudil 0.02%) and prostaglandin analog (bimatoprost 0.01%) both as monotherapy and in combination. DESIGN: Prospective, randomized, monocentric, open-label clinical trial. METHODS: Patients ≥20 years of age with primary open-angle glaucoma or ocular hypertension (IOP >21 mmHg) were recruited and randomized to receive either netarsudil 0.02%, netarsudil 0.02% + bimatoprost 0.01%, or bimatoprost 0.01% once daily for a period of 12 weeks. IOP and side effects were documented at 4, 8, and 12 weeks. RESULTS: The mean treated IOP ranged 17.51-18.57 mmHg for netarsudil, 15.80-16.46 mmHg for bimatoprost, and 14.00-14.87 mmHg for the combination therapy group. The mean IOP reduction from baseline at 4, 8, and 12 weeks was found to be statistically significant ( P < 0.001) in all three groups. The safety profile of netarsudil/bimatoprost combination was consistent with each constituent individually. The only frequently observed ocular adverse event was conjunctival hyperemia, which was seen mostly in netarsudil and netarsudil + bimatoprost groups ( P < 0.001). CONCLUSION: The IOP-lowering effect of netarsudil 0.02% once daily is non-inferior to bimatoprost 0.01% in patients with POAG and ocular hypertension with acceptable ocular safety, and the combination therapy achieved a higher IOP-lowering effect. This group of medications can be a useful adjunct in patients on maximal therapy.

Recurrent solitary fibrous tumor of eyelid: A rare entity.

Orbital and adnexal solitary fibrous tumors (SFT) are rare entities. The clinico-radiological and histologic features overlap with those of other spindle cell variants, and hence the use of immunohistochemical stains helps in making an accurate diagnosis. Furthermore, a thorough surgical resection is imperative to prevent tumor recurrences. We report a rare case of SFT arising primarily from the eyelid with multiple recurrences.

Long-term outcomes of transcutaneous retrobulbar amphotericin B in COVID-19-associated mucormycosis.

Purpose: To describe the long-term outcomes of transcutaneous retrobulbar amphotericin B (TRAMB) in COVID-19-associated mucormycosis. Methods: In total, 18 cases of COVID-19-associated mucormycosis were reviewed. In addition to the recommended treatment protocol, all patients were to be given 3.5 mg/ml/day of TRAMB for five days. Results: Of the 18 patients, 2 presented with stage 3a disease, 13 had stage 3c disease, and 3 patients had central nervous system (CNS) involvement (stage 4a and 4c). In addition to planned retrobulbar doses, five patients were given more while two patients received fewer injections (i.e., <5). At the last mean follow-up of 34.67 (±8.88) weeks, 11 patients were in radiological regression and 4 had stable disease while 2 patients had to undergo exenteration; one mortality was observed because of disease progression. Clinical regression in terms of visual and ptosis improvement was seen in seven and nine patients, respectively. Conclusion: Rhino-orbito-cerebral mucormycosis is a serious condition which warrants an aggressive treatment strategy. In unprecedented situations witnessed recently, TRAMB turned out to be an effective and economical alternative. Though large randomized studies are needed to establish its efficacy, TRAMB still manages to halt progression and salvage the globe in significant number of patients, and hence its use should be encouraged on a case-to-case basis especially in developing countries with limited resources.

A Case of Neuroretinitis following Inactivated Virion COVID-19 Vaccination.

PURPOSE: We report a rare presentation of neuroretinitis following vaccination with inactivated virion vaccine (COVAXIN). METHODS: Interventional Case Report. OBSERVATION: A 14-year-old female presented with sudden unilateral vision loss 3 days following COVID-19 vaccination. The clinical and radiological evaluation was consistent with classical neuroretinitis; the serological and immunological workup was negative. The patient responded well to the pulse steroid therapy and regained complete vision. CONCLUSION: The COVID-19 vaccine related adverse ocular events are beginning to emerge slowly and thus warrants close monitoring of all such cases. Also, ophthalmologists should be encouraged to seek vaccination status of patients presenting with inflammatory ocular conditions.

Sessile Pelvic Osteochondroma: A Rare Case That Required Abdominal Wall Reconstruction After Excision.

Osteochondroma are the most common benign tumours of the bone presenting in the young age group. Commonly found at the metaphysis of the long bones and mostly pedunculated; atypical locations and sessile appearances have also been described in literature. Due to the risk of conversion to malignant chondrosarcoma, the recommended treatment of these lesions is complete excision. We encountered a similar sessile growth in the pelvic region of a 21-year-old male with complaints of pain and swelling. After thorough investigation, excisional biopsy was performed and abdominal wall repair was reinforced with a polypropylene mesh. Careful evaluation, adequate investigations and meticulous surgical treatment can avoid potential problems in managing these tumours.

Management of Dental and Orthodontic Practice in the COVID-19 Scenario.

The coronavirus disease-2019 (COVID-19) pandemic due to the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has casted a deep impact on every aspect of the human life all over the world. The healthcare professionals dealing with the patients have been at the greatest risk of exposure. Dental practitioners fall among the highest risk practitioners because of their field of operation being around the oropharyngeal region of patients, as well as due to the risk of generation of aerosols during various dental procedures. There is a continuous urgent need of modifying the dental practice in accordance with the guidelines issued by the health authorities time to time. Meticulously planned approaches, and adequate precautions and modifications need to be introduced into dental practice. The field of orthodontics also demands a high level of practice modification in order to ensure proper infection control for patients, practitioners, and dental staff.

Ball tipped guide wire for broken nail removal: a case report.

A broken intramedullary nail is a well-known complication of non-union of femur shaft fractures. Numerous surgical techniques have been presented before in patients with non-union of long bone fractures. We report the surgical technique used to perform removal of the broken distal segment of a nail in a patient who achieved uneventful union after intramedullary nailing of closed femur shaft fracture. A ball-tipped guidewire was inserted through the broken segment of the femur nail. A pre-bend plain wire was then inserted. With the help of a vise-grip, both wires were twisted in order to make a secure handle between guidewires and a broken implant. With the help of a mallet upward-directed blows were applied to extract a broken segment of the nail. We found ball-tipped guidewire technique a useful and effective technique in removing the broken distal portion of the nail.

Role of receptor tyrosine kinases mediated signal transduction pathways in tumor growth and angiogenesis-New insight and futuristic vision.

In the past two decades, significant progress has been made in the past two decades towards the understanding of the basic mechanisms underlying cancer growth and angiogenesis. In this context, receptor tyrosine kinases (RTKs) play a pivotal role in cell proliferation, differentiation, growth, motility, invasion, and angiogenesis, all of which contribute to tumor growth and progression. Mutations in RTKs lead to abnormal signal transductions in several pathways such as Ras-Raf, MEK-MAPK, PI3K-AKT and mTOR pathways, affecting a wide range of biological functions including cell proliferation, survival, migration and vascular permeability. Increasing evidence demonstrates that multiple kinases are involved in angiogenesis including RTKs such as vascular endothelial growth factor, platelet derived growth factor, epidermal growth factor, insulin-like growth factor-1, macrophage colony-stimulating factor, nerve growth factor, fibroblast growth factor, Hepatocyte Growth factor, Tie 1 & 2, Tek, Flt-3, Flt-4 and Eph receptors. Overactivation of RTKs and its downstream regulation is implicated in tumor initiation and angiogenesis, representing one of the hallmarks of cancer. This review discusses the role of RTKs, PI3K, and mTOR, their involvement, and their implication in pro-oncogenic cellular processes and angiogenesis with effective approaches and newly approved drugs to inhibit their unrestrained action.

Incidence and recurrence of new-onset atrial fibrillation detected during hospitalization for non-cardiac surgery: a systematic review and meta-analysis.

PURPOSE: This systematic review aimed to summarize reports of the incidence and long-term recurrence of new-onset atrial fibrillation (AF) associated with non-cardiac surgery. SOURCES: We searched CENTRAL, MEDLINE and EMBASE from inception to November 2019. We included studies that reported on the incidence of new-onset perioperative AF during hospitalization for non-cardiac surgery and/or AF recurrence in such patients following discharge. Reviewers screened articles and abstracted data independently and in duplicate. We assessed study quality by appraising methodology for collecting AF history, incident AF during hospitalization, and AF recurrence after discharge. PRINCIPAL FINDINGS: From 39,233 citations screened, 346 studies that enrolled a total of 5,829,758 patients met eligibility criteria. Only 27 studies used prospective, continuous inpatient electrocardiographic (ECG) monitoring to detect incident AF. Overall, the incidence of postoperative AF during hospitalization ranged from 0.004 to 50.3%, with a median [interquartile range] of 8.7 [3.8-15.0]%. Atrial fibrillation incidence varied with type of surgery. Prospective studies using continuous ECG monitoring reported significantly higher incidences of AF than those that did not (13.9% vs 1.9%, respectively; P < 0.001). A total of 13 studies (25,726 patients) with follow-up up to 5.4 years reported on AF recurrence following hospital discharge; only one study used a prospective systematic monitoring protocol. Recurrence rates ranged from 0 to 37.3%. CONCLUSIONS: Rates of AF incidence first detected following non-cardiac surgery and long-term AF recurrence vary markedly. Differences in the intensity of ECG monitoring and type of surgery may account for this variation. TRIAL REGISTRATION: PROSPERO (CRD42017068055); registered 1 September 2017.

RéSUMé: OBJECTIF: Cette revue systématique visait à résumer les comptes rendus sur l'incidence et la récurrence à long terme de la fibrillation auriculaire (FA) de novo associée à une chirurgie non cardiaque. SOURCES: Nous avons effectué des recherches dans les bases de données CENTRAL, MEDLINE et EMBASE de leur création à novembre 2019. Nous avons inclus les études ayant examiné l'incidence de nouvelle FA périopératoire pendant l'hospitalisation pour une chirurgie non cardiaque et/ou la récurrence de la FA chez de tels patients après leur congé. Les chercheurs ont passé en revue les articles et les données extraites de manière indépendante et en double. Nous avons estimé la qualité des études en évaluant la méthodologie de collecte des antécédents de FA, de l'incident de FA pendant l'hospitalisation et de la récurrence de FA après le congé. CONSTATATIONS PRINCIPALES: Sur les 39 233 citations examinées, 346 études portant sur un total de 5 829 758 patients ont répondu à nos critères d'admissibilité. Seulement 27 études ont utilisé un monitorage électrocardiographique (ECG) continu prospectif et des patients hospitalisés pour détecter les incidents de FA. Dans l'ensemble, l'incidence de FA postopératoire pendant l'hospitalisation allait de 0,004 à 50,3 %, avec une médiane [écart interquartile] de 8,7 [3,8-15,0] %. L'incidence de fibrillation auriculaire variait en fonction du type de chirurgie. Des études prospectives utilisant un monitorage continu par ECG ont fait état d'incidences significativement plus élevées de FA que celles sans monitorage continu (13,9 % vs 1,9 %, respectivement; P < 0,001). Au total, 13 études (25 726 patients) avec un suivi allant jusqu'à 5,4 ans ont rapporté leurs données sur la récurrence de FA après le congé de l'hôpital; seule une étude a utilisé un protocole de monitorage prospectif systématique. Les taux de récurrence allaient de 0 à 37,3 %. CONCLUSION: Les taux d'incidence de nouvelle FA détectés après une chirurgie non cardiaque et la récurrence à long terme de FA varient considérablement. Les différences du degré de monitorage par ECG et le type de chirurgie pourraient expliquer cette variation. ENREGISTREMENT DE L'éTUDE: PROSPERO (CRD42017068055); enregistrée le 1er septembre 2017.

Ergonomics among dentists in the states of Telangana and Andhra Pradesh.

AIM: This study is designed to evaluate the work-related musculoskeletal disorders among dentists in the states of Telangana and Andhra Pradesh. MATERIALS AND METHODS: This study was conducted to disclose the incidence, location, and intensity of musculoskeletal pain among dentists in the states of Telangana and Andhra Pradesh. A questionnaire study was designed. Six hundred and twenty-four dentists participated in the survey working in different centers of Telangana and Andhra Pradesh. Demographic information, type of professional practice, duration of working hours, posture of working, and the distance of travel from home to workplace were collected. This was related to whether a dentist is suffering from any musculoskeletal disorder. The location of pain, intensity of pain, and the preventive measure they employ in their daily life are noted. RESULTS: It was observed that oral and maxillofacial surgeons followed by general dentists were more prone to musculoskeletal disorders. Due to the lack of a well qualified/trained assistant in addition to lack of sophisticated equipment is resulting in professional induced musculoskeletal disorders among oral and maxillofacial Surgeons. General dentists who try to perform all the dental procedures by themselves without the support of specialists were more prone to musculoskeletal disorders. The majority of the participants have lower back pain with a visual analog scale score of 5. It was believed by most of the participants that a good physical exercise in the morning helps from preventing such professional-induced musculoskeletal disorders. CONCLUSION: Oral and maxillofacial surgeons, due to their unique work, are more prone to muscle imbalances, and hence ergonomic interventions are essential to maintain optimal health during the course of their professional career.

Nutritional support in chronic liver disease and cirrhotics.

The liver is a major organ and an essential component in maintaining an appropriate nutritional status in healthy individuals through metabolism of protein, carbohydrates, and fat. In individuals with chronic liver disease (CLD), along with a number of other essential functions that the liver serves, its role in nutrition maintenance is severely impaired. Common causes of CLD include hepatitis C, alcoholic liver disease, and non-alcoholic liver disease. Amongst this population, the most common manifestation of impaired nutritional maintenance is protein-calorie malnutrition. Aside from inherent abnormalities in metabolism, such as malabsorption and maldigestion, CLD can be associated with anorexia as well as increased metabolic requirements, all of which contribute to a state of malnutrition. Given the systemic implications and impact on prognosis of malnutrition, proper nutritional assessment is essential and can be achieved through a thorough history and physical, as well as biochemical investigations and anthropometry as needed. Following an appropriate assessment of a patient's nutritional status, an approach to management can be decided upon and is based on the extent of malnutrition which directly reflects the severity of disease. Management options can be grossly separated into enteral and parenteral nutrition. The former is usually sufficient in the form of oral supplements in less severe cases of malnutrition, but as the CLD worsens, parenteral nutrition becomes necessary. With appropriate assessment and early intervention, many of the complications of CLD can be avoided, and ultimately better outcomes can be achieved.

Approach to pseudomyxoma peritonei.

Pseudomyxoma peritonei (PMP) is a mucinous tumour of the appendix that spreads into the peritoneal cavity in the form of gelatinous deposits. The incidence of PMP is believed to be approximately 1-3 out of a million per year. Nonetheless, due to its indolent nature, it is usually discovered at an advanced stage and severely impacts quality of life. Curative treatment for PMP is complete cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC). An extensive literature review was conducted searching EMBASE, MEDLINE, PubMed, and Google Scholar databases for PMP in aims to delineate a clinical approach to diagnosis and treatment. Literature was limited to the years 2007-2018. We found the 5-year overall survival with CRS and HIPEC estimated to be between 23%-82% and rates of major complications as high as 24%. Therefore, it is important to appropriately stage and select patients that should undergo CRS with HIPEC. Modalities like MDCT radiological scores have been shown to have sensitivity and specificity of 94% and 81%, respectively, in being able to predict resectability and survival. Despite treatment, the disease often recurs. Tumor markers have significant potential for establishing prognosis pre-operatively, and this paper will review the most recent evidence in support of them.

Role of Whole-Spine Screening Magnetic Resonance Imaging Using Short Tau Inversion Recovery or Fat-Suppressed T2 Fast Spin Echo Sequences for Detecting Noncontiguous Multiple-Level Spinal Tuberculosis.

STUDY DESIGN: Retrospective review. PURPOSE: The purpose of the present study was to evaluate the role of whole-spine screening using short tau inversion recovery (STIR) or fat-suppressed T2W fast spin echo (FSE) sequences in patients with spinal tuberculosis (TB). OVERVIEW OF LITERATURE: The identification of noncontiguous multiple-level spinal tuberculosis (NMLST), symptomatic or not, is important because of its management implications. Most centers do not perform routine whole-spine magnetic resonance imaging (MRI), and the reported incidence of NMLST varies from 1.1% to 74.1%. METHODS: We completed a retrospective review of clinical and radiographic data of 365 patients with spinal TB who presented at Jawaharlal Nehru Medical College, Aligarh over 5 years. The final analysis included 187 patients who full filled the inclusion criteria, consisting of availability of whole-spine MRI and confirmation of vertebral TB. Diagnosis of NMLST was considered when other vertebral lesions were identified in addition to the primary vertebral disease, with the lesions separated by at least one normal spinal segment. The primary site was defined as the site for which the patient had been referred for MRI. RESULTS: NMLST was identified in 47 of 187 patients investigated using whole-spine MRI. The incidence was 25.1%, which was higher than that in earlier reports where whole-spine MRI was not routinely performed. The lumbar spine was involved in 37 patients, thoracic spine in 25, cervical spine in 16, and sacrum in five patients. Combined lumbar spine and thoracic spine involvement was observed in 19 patients. Thirteen patients had lumbar and cervical spine involvement, nine had thoracic and cervical spine involvement, four had combined lumbar and sacral spine involvement, and the remaining two had thoracic and sacral spine involvement. CONCLUSIONS: Tubercular spondylitis may affect the spine at multiple noncontiguous sites with the majority of additional affected sites remaining asymptomatic. Routine whole-spine MRI using all recommended sequences is not cost-effective and hence not feasible. Therefore, we recommend whole-spine screening using STIR or fat-suppressed T2W FSE sequences in all patients with suspected spinal TB. This screening is cost-effective compared with full-protocol MRI and detects additional cases of NMLST over conventional practice.

Power generation and pollutants removal from landfill leachate in microbial fuel cell: Variation and influence of anodic microbiomes.

MFC was studied using young and old landfill leachate substrate to remove pollutants and produce renewable energy coupled with study of anodic microbiomes. The power output of 96.8mWm-2 with COD removal of 90.0±1.2% was achieved at 60% young leachate in batch mode, which decreased to 75mWm-2 having 55.5% COD abatement in continuous mode employing 100% young leachate. Power production using simulated wastewater without organic source proved that ammonium could also serve as fuel in MFC. The high ammonium dosage increased the overall system performance but beyond a certain limit, the inhibitory effect intensified. Nitrogen removal (66.0±3.3% NH4+-N and 86.0±0.1% NO2--N) occurred obeying different removal pathways. Sequencing analyses revealed that anammox bacteria (2%), denitrifying bacteria (5%) and electrogenic bacteria (15%) were in abundance of the microbial community in the anode. This technology can be promising for leachate treatment and power production however certain constraints still exist in pilot scale experiments.

Tear film and ocular surface dysfunction in diabetes mellitus in an Indian population.

PURPOSE: Ophthalmic complications in diabetes such as retinopathy, cataract, and infections have been extensively studied. Recently, attention has been drawn toward ocular surface changes in diabetes mellitus (DM). This study has been carried out to investigate the tear film and ocular surface abnormalities in type II DM patients. MATERIALS AND METHODS: A total of 83 participants (130 eyes) were enrolled: 53 diabetics (80 eyes) and 30 healthy controls (50 eyes). Of the 53 diabetics, 24 patients (42 eyes) had some diabetic retinopathy. The tear film and ocular surface were evaluated using Schirmer test, tear film break-up time (TBUT), keratoepitheliopathy score (KES), Rose Bengal Staining (RBS) test, and conjunctival impression cytology. RESULTS: When compared with the healthy controls, diabetics showed significantly reduced Schirmer, TBUT measurements and the higher grades of KES and RBS test (P < 0.001). Impression cytology analysis showed goblet cell loss and conjunctival squamous metaplasia in diabetics. CONCLUSION: Tear film abnormality is a significant feature of diabetic ocular surface diseases. These abnormalities are likely on account of poor quality and function of tears, combined with the subnormal ocular surface. Therefore, all diabetic patients especially those with evidence of retinopathy changes should undergo routine early examination and follow-up of tear function and ocular surface parameters.

A Standardized Ultrasound Scoring System for Preoperative Prediction of Difficult Laparoscopic Cholecystectomy.

PURPOSE: Laparoscopic cholecystectomy (LC) has become the treatment of choice for cholelithiasis. Still some patients required conversion to open cholecystectomy (OC). Our aim was to develop a standardized Ultrasound based scoring system for preoperative prediction of difficult LC. METHODS AND MATERIALS: Ultrasound findings of 300 patients who underwent LC were reviewed retrospectively. Four parameters (time taken, biliary leakage, duct or arterial injury, and conversion) were analyzed to classify LC as easy or difficult. The following ultrasound findings were analyzed: GB wall thickness, pericholecystic collection, distended GB, impacted stones, multiple stones, CBD diameter and liver size. Out of seven parameters, four were statistically significant in our study. A score of 2 was assigned for the presence of each significant finding and a score of 1 was assigned for the remaining parameters to a total score of 11. A cut-off value of 5 was taken to predict easy and difficult LC. RESULTS: 66 out of 83 cases of difficult LC and 199 out of 217 cases of easy LC were correctly predicted on the basis of scoring system. A score of >5 had sensitivity 80.7% and specificity 91.7% for correctly identifying difficult LC. Prediction came true in 78.8% difficult and 92.6% easy cases. US findings of GB wall thickness, distended GB, impacted stones and dilated CBD were found statistically significant. CONCLUSION: This indigenous scoring system is effective in predicting conversion risk of LC to OC. Patients having high risk may be informed and scheduled appropriately and decision to convert to OC in case of anticipated difficulty may be taken earlier.

Extreme Ophthalmomyiasis externa with simultaneous facial and scalp involvement.

BACKGROUND: Ophthalmomyiasis is a rare entity seen mainly in immunocompromised host with neglected wounds under poor hygienic conditions. CASE: We report a case of extreme ophthalmomyiasis with extensive facial and scalp involvement in an old rural inhabitant following evisceration. CONCLUSION: Proper wound care and personal hygiene are of paramount importance for good wound healing.

Delleman Oorthuys syndrome.

Oculocerebrocutaneous or Delleman syndrome is a rare congenital syndrome characterized by microphthalmia/anophthalmia with or without orbital cysts, focal skin defects, intracranial cysts and skin appendages. We here report a case of 1-year-old male child with periocular skin tags, lid colobomas, and dermal hypoplasia. The patient had delayed developmental milestones and history of tonic-clonic seizures. Magnetic resonance imaging of the head revealed a large arachnoid cyst, aplastic cerebellar vermis and polymicrographic pattern of the cerebral cortex. A complex cyst of spleen was also noted on abdominal ultrasonography. Orbital cysts depending on the size can be excised or left alone. Neuroimaging evaluation of patients with congenital orbital cysts and skin appendages is emphasized for early and appropriate management.

Managment of superficial infantile capillary hemangiomas with topical timolol maleate solution.

Capillary hemangioma is the most common benign tumor of eyelids and orbit in children. Recently, a topical beta blocker has been reported as an effective treatment for superficial capillary hemangiomas. We present a case report of two children having large capillary hemangiomas who responded well to topical treatment by 0.5% timolol maleate solution. After 12 months of treatment, the lesion has significantly reduced in size, thickness, and color in both cases. Thus, we conclude that long-term use of topical 0.5% timolol maleate solution is safe and effective in treating superficial capillary hemangiomas.

Trend over time; a structural review of articles published in Journal of Pakistan Medical Association from 1953-2009.

OBJECTIVE: To review the articles published in the Journal of Pakistan Medical Association from 1953 to 2009 and to assess the components of each article by a pretested proforma containing a checklist of items based on modified 'Strengthening the Reporting of Observational Studies in Epidemiology' statement. METHODS: The retrospective study was conducted at the office of the Journal of Pakistan Medical Association, Karachi, from February to November 2010. A checklist of items in the modified 'Strengthening the Reporting of Observational Studies in Epidemiology' statement was made after discussion among the authors of the study to finally include a revised checklist of 45 items instead of the checklist of 22 items of the statement. A total sample size of 370 was calculated. Simple randomisation was done for selection of articles from each year. For each article, major and minor items were documented. Data was fed into SPSS version 15. RESULTS: The scientific quality of reporting of most of the components of Introduction, Results and Discussion sections have improved progressively with time (p < 0.001) whereas most components of Methodology have remained consistent. CONCLUSION: A change in trend over time was observed over the study period in major and minor items of the articles in the Journal, showing improved reporting of various sub-components of articles.The modified 'Strengthening the Reporting of Observational Studies in Epidemiology' statement provides a checklist that may be used to improve the quality of articles.