Cetuximab, an anti-EGFR monoclonal antibody used to treat head and neck cancer illustrates adverse effects from off-target binding. - 69.163.183.109. The FDA considered 1 case of intractable nausea and vomiting and 2 cases of facial swelling (both in individuals with previous cosmetic injections) as possibly associated with the vaccine. Hepatitis B vaccination and associated oral manifestations: A non-systematic review of literature and case reports. The COV-2093 trial evaluated the safety of subcutaneous injection involving 600mg of casirivimab and imdevimab and reported site reactions in 12% of casirivimab and imdevimab group (approximately 87 people) compared to 4% of placebo (approximately 9 people) [14]. Huang Y, Yang C, Xu XF, et al. All Rights Reserved. "The long-term side effects of COVID infection are a major concern. The diluent is 0.9% or 0.45% saline, and the solution is infused over 1h. Sotrovimab is a recombinant IgG1-kappa made of 2 identical light and 2 identical heavy chains. ), More recently, an even more rare side effect myocarditis, or inflammation of the heart muscle has been reported in people receiving Pfizer and Moderna COVID-19 vaccines. Early indications are that Delta infections bring more severe side effects than other forms of COVID, but that vaccines are still protective against Delta. In the case of the two mRNA COVID-19 vaccines, well over 90% of people immunized developed the protective adaptive immune response while fewer than 50% developed any side effects, and most were mild. N Engl J Med 2021;384(19):18241835. 2023 Springer Nature Switzerland AG. An analysis of 50,000 hospitalized patients with COVID who received convalescent plasma through the FDAs Early Access Program reported transfusion reactions (n=78), thromboembolic or thrombotic events (n=113, 75 judged unrelated), and cardiac events (n=677; 597 judged unrelated), mainly myocarditis and acute coronary syndrome [10]. Myocarditis following COVID-19 vaccination. Convalescent plasma has side effects like monoclonal antibodies, but with more infusion reactions and less efficacy. In 1976, a vaccine against swine flu that was widely distributed in the United States was identified in rare cases (approximatelyone in 100,000) as a cause of Guillain-Barr Syndrome, in which the immune system attacks the nerves. The action you just performed triggered the security solution. AusVaxSafety is tracking whether people experience side effects after COVID-19 vaccines. https://doi.org/10.1038/nrd.2017.243. 2020;28(5):91. https://doi.org/10.1038/s41541-020-00243-x. New services include a primary-care mental health team with a licensed psychiatrist and psychiatric nurse practitioner for telehealth appointments all hosted through HIPAA-compliant Zoom. FDA authorizes Pfizer-BioNTech COVID-19 vaccine for emergency use in children 5 through 11 years of age.
Covid vaccine side-effects: what are they, who gets them and why? An interim analysis of an ongoing double-blinded multicenter trial, COMET-ICE, found that non-hospitalized patients with COVID-19 who received a one-time infusion of 500mg sotrovimab were 85% relatively less likely (6% absolute risk reduction) to be hospitalized due to disease progression in the 29days following the infusion than those who received saline [16]. The Sputnik V vaccine also uses Ad26. HHS Vulnerability Disclosure, Help "We don't know why that is, how long these symptoms will last or if there are effective ways to treat them. UAB also encourages applications from individuals with disabilities and veterans. UAB - The University of Alabama at Birmingham, Vaccine side effects show up within weeks if at all, Our COVID vaccine experience during the past six months, survey of parents with children ages 12-15, in the New England Journal of Medicine here, British governments regulatory agency here, vaccines are still protective against Delta, My Health Rewards offers incentives for making healthy choices, Reduce stress with this quick, self-paced office ergonomics course, Check out the winners of the 2022 Wellness Week photo/video activity, Discover 12 outdoor oases hiding in plain sight, Find opportunities for mindfulness and health during Wellness Week Oct. 17-21, Wellscreens are back register for yours today, An infection prevention expert explains how to avoid COVID, flu and the next pandemic, Achieve mental clarity through mindfulness meditation this spring. That's why it's important to wait until after you've gotten the vaccine (and have started creating an inflammatory response already) to take pain medication. 2021;44(11):120914. https://www.cdc.gov/vaccines/covid-19/info-by-product/moderna/reactogenicity.html. Of those patients, 98% were male. Kishimoto T. Interleukin-6: from basic science to medicine40 years in immunology. Most cases (68.5%) occurred in women with 48.1% of total cases occurring in women ages 18 to 49. A new study has found that certain vaccine side effects are more common in people who have already . An open, non-randomised, phase 1/2 trial on the safety, tolerability, and immunogenicity of single-dose vaccine Sputnik Light for prevention of coronavirus infection in healthy adults. Serious adverse events occurred in 103 of 295 patients (34.9%) in the tocilizumab group and in 55 of 143 patients (38.5%) in the placebo group. This is particularly true of the mRNA vaccines. The 1st dose should give you some protection from 3 or 4 weeks after you've had it. University of Florida, 2018. British Dental Journal Adenovirus serotype 5 vaccine vectors trigger IL-27-dependent inhibitory CD4+ T cell responses that impair CD8+ T cell function. J Med Virol. April 14 is scheduled as a day off for the academic campus to rejuvenate. Methods: N Engl J Med. 2021;384(7):6439. Myocarditis with COVID-19 mRNA vaccines. Please include what you were doing when this page came up and the Cloudflare Ray ID found at the bottom of this page. We include case reports even though they cannot demonstrate causality, because they often provide the first description of severe toxicity. Avoid the most common mistakes and prepare your manuscript for journal Jiawen Deng, Kiyan Heybati, Shayan Heybati, Nour K. Younis, Rana O. Zareef, Mariam Arabi, Ramesh Nathan, Imad Shawa, Gregory Huhn, Malamatenia Lamprinou, Athanasios Sachinidis, Georgios Papazisis, Amit P. Ladani, Muruga Loganathan & Abhijeet Danve, Christina Chan, Sean T. Foster, Neil T. Wright, Journal of Medical Toxicology https://doi.org/10.1056/NEJMra2035343. This increase is less than the risk of developing myocarditis from COVID-19 (relative risk: 2 [95% CI, 1.442.65, vaccinated] vs 15 [95% CI, 11.0919.8, unvaccinated]) [86, 87]. Chary MA, Barbuto AF, Izadmehr S, Hayes BD, Burns MM. Fischer S, Cabrera-Fuentes HA, Noll T, Preissner KT.
Selected Adverse Events Reported after COVID-19 Vaccination | CDC Coronavirus (COVID-19) Vaccine and Drug Interactions - GoodRx Stress is unavoidable in this uncertain time. 2021;385(15):138292. Without integrating itself into the host DNA, the sequence is transcribed into mRNA and translated into the amino acid sequence for the S protein, which is subsequently expressed on the surface of host cells inducing an immune response [42].
COVID-19 Vaccine and Your Eyes - healthline.com The proportion of other solicited local and systemic adverse events were similar between the groups [41]. A similar association has been reported for the smallpox and influenza vaccines [88, 89]. 2022;9:951314. https://doi.org/10.3389/fcvm.2022.951314. The most frequent serious adverse events more frequent in the vaccine group were myocardial infarction (5 vs 3 cases), cholecystitis (3 vs 0 cases), and nephrolithiasis (3 vs 0 cases). These APCs then migrate to lymph nodes where they present (express on their cell surface) the S protein to B and T cells. Almost all of these cases occurred in the eight weeks after a person received the vaccine. There was heterogeneity in the acknowledgement of vaccine-related adverse events in North America compared with Europe. Disclaimer. CanSinBio is a DNA vaccine like Johnson & Johnson. In the larger Phase 2/3 SPECTRA trial, mild-to-moderate injection site pain was reported more by those who received the vaccine (n=6215) than the placebo (n=6104) after the first (35.7%; 287 of 803 vs 10.3%; 81 of 786) or second dose (26.9%; 189 of 702 vs 7.4%; 52 of 699). https://doi.org/10.1002/hep.31487. But the flu itself also can cause Guillain-Barr Syndrome; in fact, the syndrome occurs 17 times more frequently after natural flu infection than after vaccination. Macrophages secrete IL-6 when they detect an entity whose cell surface expresses pathogen associated molecular patterns [22, 23]. But because we have had so many people vaccinated, we actually have far more safety data than we have had for any other vaccine, and these COVID vaccines have an incredible safety track record. Myocarditis following immunization with mRNA COVID-19 vaccines in members of the US military. JAMA.
Coronavirus (COVID-19) Update: FDA Authorizes First Oral Antiviral for Headlines wont help you lose weight. 2007;104(15):638893. Vaccine COVID-19 Monitoring Readiness protocol; The AESI list changes based on the evolving safety profile of vaccines. Kannemeier C, Shibamiya A, Nakazawa F, Trusheim H, et al. https://doi.org/10.1016/j.jacc.2003.11.053. These might include swelling, pain, redness, an itchy rash, and other mild forms of . Lancet. After DNA vaccines, those aged 3050 are very slightly more likely to have thrombotic disease. A double-blind randomized placebo-controlled trial of 10,128 participants in Turkey reported adverse events in 1259 (18.9%) participants in the vaccine group (n=6646) and 603 (16.9%) in the placebo group (n=3470) with no fatalities or grade 4 adverse events. 2021;46(2):2707. Accessed 14 May 2022. A 90 percent decrease in risk of infections, and 94 percent effectiveness against hospitalization for the Pfizer and Moderna vaccines is fantastic, he said. (The majority of 285 cases reviewed by the CDC were mild.). The U.S. Centers for Disease Control and Prevention (CDC) lists common COVID-19 vaccine side effects as pain, swelling or redness at the injection site; fatigue; headaches; muscle pain; chills . 2021;6(10):12026. The concern is that pre-treating with pain medications that reduce fevers and inflammation (like acetaminophen and ibuprofen) could dampen your immune system's response to the vaccine. 2021;93(10):60276029. That data is already in, and it is overwhelming. -, Polack FP, Thomas SJ, Kitchin N, et al. MeSH (Compare this with the 60,000 children infected with polio in the United States in 1952, and themore than 3,000 childrenwho died from the disease in the United States that year.) Granados Villalpando JM, Romero Tapia SJ, Baeza Flores GDC, Ble Castillo JL, Juarez Rojop IE, Lopez Junco FI, Olvera Hernndez V, Quiroz Gomez S, Ruiz Quiones JA, Guzmn Priego CG. Out of 15 patients (93% male) hospitalized with myocarditis within 30days of receiving the Pfizer-BioNTech vaccine, 100% had chest pain and elevation in troponins. The site is secure. https://doi.org/10.4110/in.2015.15.2.51. Most reported myocarditis cases resolved either spontaneously or with the standard interventions for myocarditis. Applying a cool, wet cloth to the spot on your arm where the shot was given can help with some of the pain, according to the CDC. This past year, more than 4,700 employees activated their My Health Rewards account, and more than 3,600 logged enough healthy behaviors to receive a payout of $50 or more. White spots on your tongue can be a sign of Covid or a vaccine side effect, says expert WHITE spots on the tongue - it's usually nothing serious. A: COVID-19 vaccines can cause mild side effects, such as pain, redness or swelling where the shot was given, fever, fatigue, headache, chills and muscle or joint pain. Infusion reactions were most commonly pyrexia, chills, dizziness, and dyspnea. Radiology. https://doi.org/10.1038/s41375-021-01264-8. Custers J, Kim D, Leyssen M, Gurwith M, et al. https://doi.org/10.1007/s00441-014-1850-8. Accessed 26 Feb 2022. Headaches 2%. IL-6 binding to IL-6R promotes the transcription of acute phase proteins, T cell differentiation, and antibody production. Accessed 22 Mar 2022, National Center for Immunization and Respiratory Diseases (U.S.).Division of Viral Diseases, Moderna COVID-19 Vaccine (also known as Spikevax) Overview and Safety. Common COVID-19 vaccine side effects include: Redness or soreness at injection site. The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Mevorach D, Anis E, Cedar N, Bromberg M, et al. Of the four vaccines made in China, CoronoVac and Sinopharm are the most common, followed by CanSinBio and another produced jointly by Anhui Zhifei Longcom Biopharmaceutical and the Chinese Academy of Sciences. mRNA vaccines are not infectious and carry no risk of insertional mutagenesis [58]. It is not clear how COVID variants such as the highly infectious Delta mutation first seen in India may affect patients. https://doi.org/10.1056/NEJMoa2109730. 2022 Oct;11(10):5879-5886. doi: 10.4103/jfmpc.jfmpc_205_22. After your vaccine, you're supposed to wait for 15 minutes before leaving the place where you got vaccinated (or 30 minutes if you have a history of anaphylaxis) to be observed for reactions or serious side effects. Live-attenuated measles virus (MV) vaccines are safe and effective, and high coverage in two-dose regimens has successfully interrupted endemic transmission in large geographic areas. https://doi.org/10.1101/2021.05.07.21256652, Sadoff J, Le Gars M, Shukarev G, Heerwegh D, et al. Evid Based Dent. But as Professor Diane Tucker, Ph.D., explains, you can take control and make the most of this historic opportunity. In November 2020, the infusion or subcutaneous injection of casirivimab and imdevimab received EUA from the FDA for non-hospitalized COVID-19 patients over the age of 12 with immunosuppression or at high risk for disease progression, or for post exposure prophylaxis for immunosuppressed or unvaccinated patients at high risk for progression to severe disease. Vaccines, given in one- or two-shot doses, are very different from medicines that people take every day, potentially for years. Symptomatic acute myocarditis in 7 adolescents after Pfizer-BioNTech COVID-19 vaccination. Stop by anytime from 11 a.m.-noon for 15-minute group walk-alongs; start times will be staggered, and social distancing will be enforced. Possible adverse effects to mRNA vaccines include the generation of autoantibodies, adverse reactions to adjuvants, or diluents, and induction of type I interferon responses. https://doi.org/10.1016/S0140-6736(22)00055-1. https://doi.org/10.1007/s40264-021-01104-9. Safety and efficacy of the BNT162b2 mRNA Covid19 vaccine. Four patients with SARS-CoV-2 on mechanical ventilation and vasopressors were able to be extubated and weaned off pressors after receiving two infusions of 700mg leronlimab two weeks apart and IL-6 levels decreased, but these patients also received hydroxychloroquine, zinc, tocilizumab, remdesivir, and azithromycin [20]. According to Public Health England, most side-effects from two Covid vaccines - Pfizer/BioNTech and Oxford/AstraZeneca - are mild and short-lived. Serious adverse events were reported by 199 patients (1.4%) in the ZF2001 group and 264 patients (1.8%) in the placebo group. JAMA. 81.7.11.205
Global COVID-19 vaccine summary: Side effects - Medical News Today An analysis of self-reports from 3236 Iranian healthcare workers in Mazandaran, Iran, who were vaccinated with Sputnik V (mean age 39.32, 61.2% women) reported pain (56.9%), fatigue (50.9%), body pain (43.9%), headache (35.7%), fever (32.9%), joint pain (30.3%), chills (29.8%), and drowsiness (20.3%) as the most common side effects [114]. Fact sheet for health care providers emergency use authorisation (EUA) of bamlanivimab and etesevimab authorized use treatment. Accessed 18 Jan 2022, U.S. Food and Drug Administration. Free financial counseling from UAB and other employee training resources offer a step-by-step guide to savings success. 2021;384(3):22937. Parasitism is a close relationship between species, where one organism, the parasite, lives on or inside another organism, the host, causing it some harm, and is adapted structurally to this way of life. 2021;21(2):18192. We believe that awareness of these orofacial manifestations will improve recognition, management and reporting of vaccine-related adverse effects.
Composition Live, attenuated measles, mumps, rubella, and varicella vaccines 7 to 8 times as much vaccine virus as monovalent varicella vaccine Efficacy Inferred from that of MMR vaccine and varicella vaccine on . -, Kaur SP, Gupta V. COVID19 vaccine: a comprehensive status report. Accessibility 2021;31(14):345976. https://stacks.cdc.gov/view/cdc/114179. Efficacy and safety of the mRNA1273 SARSCoV2 vaccine. Bookshelf https://doi.org/10.1016/j.jconrel.2021.03.043. The most common adverse events reported 7days after the first or booster vaccine were fever (62 patients, 48%), fatigue (40 patients, 31%), and headache (46 patients, 35%) [107]. https://doi.org/10.1038/s41577-021-00542-x. Part of Springer Nature. Our description of substances and their effects is not exhaustive and presents our knowledge as of June 2022. 3. https://doi.org/10.1161/CIRCULATIONAHA.121.055891. B Well UAB helps students easily access resources on mobile devices and build a self-care plan that encourages healthy habits. https://doi.org/10.1016/S1473-3099(21)00751-9. ", The long-term side effects of COVID infection are a major concern. While the majority of those who have been vaccinated have had no adverse reactions after getting their vaccine, some have experienced side-effects which include body aches, headaches and fever . 2021;384(20):19641965. The UAB Employee Assistance and Counseling Center will be eligible for up to 15 free counseling sessions and 15 free life-coaching sessions per calendar year, an increase from 12 per year in response to an increase in mental health and wellness needs during the COVID-19 pandemic. Correspondence to "This is particularly true of the mRNA vaccines. The Johnson & Johnson vaccine has an emergency use authorization by the FDA. Try these experiments instead. One of the most unusual and serious side-effects of the COVID-19 vaccine jab, which has been reported from various corners is Blood clotting. But because we have had so many people vaccinated, we actually have far more safety data than we have had for any other vaccine, and these COVID vaccines have an incredible safety track record. Available at. JAMA Netw Open. That is the most troubling unknown for me.. The most common side effects of the COVID-19 vaccines include: redness, pain, or. According to the CDC, the side effects of the Covid vaccine should go away in a few days. FDA grants Dupixent (dupilumab) Breakthrough Therapy designation for eosinophilic esophagitis * Designation based on positive results from Part A of pivotal Phase 3 trial * Dupixent is the first and only biologic to show positive and clinically-meaningful Phase 3 results in patients 12 years and older with eosinophilic esophagitis (EoE) * There are currently no FDA-approved treatments for . The https:// ensures that you are connecting to the quantifying the efficacy of 5 COVID vaccines reported that SinoPharm was 68% effective, but many participants mixed and matched vaccines and adverse events were not recorded [105]. Khubchandani J, Sharma S, Price JH, Wiblishauser MJ, et al. Women reported more adverse events than men (P<0.001), more AEs occurred after the first dose than the second dose (P<0.001), and the number of AEs decreased with age (P<0.001). Get your workspace set up right and learn the risks of cumulative trauma with UABs online Office Ergonomics Awareness Course. All confirmed cases occurred in females, with 90% having a previous history of allergies and 90% occurring within 30min of vaccine administration [83]. These were rare and included acute peripheral facial paralysis (Bell's palsy), facial swelling, and swelling of the lips, face or tongue associated with anaphylaxis. MAbs. The cases were mostly reported two weeks after injection and mostly in men age 50 and older. https://doi.org/10.1016/S0140-6736(21)00241-5. Anaesthesia, surgery, and life-threatening allergic reactions: epidemiology and clinical features of perioperative anaphylaxis in the 6th National Audit Project (NAP6). Fields virology: emerging viruses. Like CoronaVac, the SinoPharm vaccine is an inactivated virus harvested from Vero cells inoculated with a specific strain of SARS CoV-2. https://stacks.cdc.gov/view/cdc/115700. Neither publication presented data on adverse events. Safety and immunotoxicity assessment of immunomodulatory monoclonal antibodies.
Immediately after the infusion, 2 patients who received the combination and 1 who received saline reported rash, itchiness, and facial flushing with no change in vital signs. Unlike many medications, which are taken daily, vaccines are generally one-and-done. https://www.fda.gov/news-events/press-announcements/fda-takes-key-action-fight-against-covid-19-issuing-emergency-use-authorization-first-covid-19. ECG changes were seen in 87% of patients with ST elevations being the most common finding. https://doi.org/10.1056/NEJMc2105869, Niesen MJM, Pawlowski C, O'Horo JC, Challener DW, et al. In: Howley PM, Knipe DM, editors. Hum Vaccin Immunother. Accessed 22 Mar 2020.
Nurse Shares COVID Vaccine Side Effects from Trial Any risk is frightening, especially for a parent. Dai L, Gao L, Tao L, Hadinegoro SR, et al.
Long COVID: Long-Term Effects of COVID-19 - Hopkins Medicine Early treatment for Covid-19 with SARS-CoV-2 neutralizing antibody sotrovimab. Clinical characteristics and outcomes of coronavirus disease 2019 patients who received compassionate-use leronlimab. Association of myocarditis with BNT162b2 messenger RNA COVID-19 vaccine in a case series of children. J Clin Pharmacol. 2020;383:26032615. We all have seen billboards and TV infomercials from law firms seeking people harmed by diet drugs or acid-reflux medicines for class-action lawsuits. 2021;385(23):21409. People have had varying reactions to the COVID-19 shot, which experts say is normal. They also have idiosyncratic side effects and variable and varying efficacy, reflecting their specificity for certain S protein sequences. https://doi.org/10.1038/d41586-021-01813-2. Radiology. Use the Previous and Next buttons to navigate the slides or the slide controller buttons at the end to navigate through each slide. To date, no clinical trials have been performed. 2021;384(22):2092101.
Reported orofacial adverse effects of COVID-19 vaccines: The - PubMed The Johnson & Johnson vaccine has been associated with thrombosis with thrombocytopenia syndrome (TTS) and Guillain-Barr syndrome (GBS). https://doi.org/10.4161/mabs.1.2.7909, ACTIV-3/Therapeutics for Inpatients with COVID-19 (TICO) Study Group. In the absence of direct evidence, we expect drugs of a similar class to have similar toxicity. Further complicating comparison, Moderna was authorized later than Pfizer leading to possible confounding by the varying inflammatory effects of different SARS-CoV-2 variants. Most adverse events are mild and include soreness at the site of injection or a slight fever.
Oral side effects of COVID-19 vaccine - Nature J Infect Dis. Circulation. Fact sheet for healthcare providers: emergency use authorization for actemra (tocilizumab).
Large study of COVID vaccine side effects in Sweden - News-Medical.net No children who received the combination therapy died or were hospitalized during treatment. The trigger for anaphylaxis after administration of the Pfizer-BioNTech or Moderna mRNA vaccines is not yet clear. 406 were considered non-serious (0.005% of bivalent COVID-19 doses administered) and 112 (0.0014% of bivalent COVID-19 doses administered) were considered serious. Vxart's Covid vaccine is in a small tablet and can be shipped and stored at room temperature, unlike Pfizer and Moderna's vaccines. 1;5(4):e227038. Thank you for visiting nature.com. Afrifa-Anane GF, Larbi RT, Addo B, Agyekum MW, Kyei-Arthur F, Appiah M, Agyemang CO, Sakada IG. https://doi.org/10.1001/jamacardio.2021.2833. 2022 Nov;28 Suppl 2:2639-2640. doi: 10.1111/odi.14361. Division of Medical Toxicology, Department of Emergency Medicine, Boston Childrens Hospital, Boston, MA, USA, Michael Chary,Alexander F. Barbuto,Eduardo Fleischer&Michele M. Burns, Regional Center for Poison Control and Prevention Serving Massachusetts and Rhode Island, Boston, MA, USA, Michael Chary,Alexander F. Barbuto&Michele M. Burns, Department of Emergency Medicine, Weill Cornell Medical College, New York, NY, USA, Department of Emergency Medicine, New York Presbyterian Queens, Flushing, NY, New York, USA, Department of Emergency Medicine, Carl R. Darnall Army Medical Center, Fort Hood, TX, USA, Division of Hematology and Medical Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA, Department of Emergency Medicine, Brigham and Womens Hospital, Boston, MA, USA, You can also search for this author in Smallpox vaccination and myopericarditis: a clinical review. Google Scholar. But the flu itself also can cause Guillain-Barr Syndrome; in fact, the syndrome occurs17 times more frequentlyafter natural flu infection than after vaccination. Individuals who receive a bivalent COVID-19 vaccine may experience side effects commonly reported by individuals who receive authorized or approved monovalent mRNA COVID-19 vaccines.. UAB leadership expert Jean Ann Larson, Ed.D., explains how to take control, whether you are managing colleagues or your kids' fears. Yes, you can take OTC pain meds after getting the Covid vaccine, says CDC plus other tips for dealing with side effects. Engler RJ, Nelson MR, Collins LC Jr, Spooner C, et al. Nature. Abi Zeid Daou C, Natout MA, El Hadi N. Biphasic anaphylaxis after exposure to the first dose of Pfizer-BioNTech COVID-19 mRNA vaccine. And decades of vaccine history plus data from more than a billion people who have received COVID vaccines since December 2020 both provide powerful proof that there is little chance that any new dangers will emerge from COVID vaccines.