To describe an extreme presentation of the chylomicronemia syndrome resulting in multiorgan system dysfunction. [ncbi.nlm.nih.gov]

Presently, the company is conducting an international multi-centre, randomised, double-blind, placebo-controlled Phase three study in patients with Familial Chylomicronemia Syndrome. i) Familial Chylomicronemia Syndrome with either Lipoprotein Lipase [medical-dictionary.thefreedictionary.com]

• Splenomegaly

  Although the patient had a positive history for recurrent episodes of pancreatitis the characteristic lesions of the hyperchylomicronemia syndrome, such as eruptive xanthomas and lipemia retinalis, were not present and splenomegaly could not be documented [ncbi.nlm.nih.gov]

  Hepatomegaly is common, and, if the plasma TG levels are very high, splenomegaly may also be seen. Organomegaly occurs as a result of TG uptake by macrophages, which become foam cells and may rapidly regress with a decrease in dietary fat intake. [clinicaladvisor.com]

  Eye fundus examination found lipemia retinalis, and abdominal palpation revealed hepatomegaly with no splenomegaly. [elsevier.es]

  Disease, diseased - see also Syndrome Bürger-Grütz E78.3 (essential familial hyperlipemia) chylomicron retention E78.3 Frederickson's hyperlipoproteinemia, type I and V E78.3 Hepatosplenomegaly R16.2 ICD-10-CM Diagnosis Code R16.2 Hepatomegaly with splenomegaly [icd10data.com]

• Inflammation

  Symptoms may start in infancy and include: Abdominal pain due to pancreatitis (inflammation of the pancreas). Symptoms of nerve damage, such as loss of feeling in the feet or legs, and memory loss. [medlineplus.gov]

  Symptoms Symptoms may start in infancy and include: Abdominal pain due to pancreatitis (inflammation of the pancreas). Symptoms of nerve damage, such as loss of feeling in the feet or legs, and memory loss. [ufhealth.org]

  The signs and symptoms of include: Failure to thrive in infancy Episodes of abdominal pain due to inflammation of the pancreas. [dovemed.com]

  Many experience pancreatitis, an acute recurrent inflammation of the pancreas, which causes debilitating pain and can be fatal. 6-8 Others develop eruptive xanthomas (fatty deposits on the skin) lipemia retinalis (milky appearance of retinal veins and [fcs.raredr.com]

• Fatigue

  Abdominal pain and fatigue were the two most commonly reported symptoms. The incidence and frequency of symptoms increased with age, according to most of the patients. [healio.com]

  Over the next 10 years, my symptoms including extreme fatigue, chronic diarrhea, joint pain and chronic headaches continued on a daily basis. [globalgenes.org]

  Those living with FCS can be at risk for severe recurrent abdominal pain and potentially fatal pancreatitis, as well as symptoms that can interfere with daily living, including fatigue, lack of energy (asthenia), impaired cognition, and numbness/tingling [fcs.raredr.com]

  Other signs and symptoms that patients with FCS may experience are: xanthomas (fatty deposits in the skin) lipemia retinalis (milky appearance of retinal veins and arteries) neurological symptoms (such as forgetfulness, fatigue, or/and memory loss) Due [fcsfocus.com]

• Weakness

  Neurologic deterioration is slow to absent and prolonged survival is possible, but the muscle weakness may be progressive in adulthood. Less commonly reported features include optic atrophy, brachydactyly, and cone epiphyses. [marinesco-sjogren.org]

  Muscle weakness is progressive, but life expectancy is near normal. Cause [ edit ] This section is empty. [en.wikipedia.org]

  People with FCS report fatigue, weakness, fear, worry, cognitive impairment such as impaired memory and difficulty concentrating. [pancreasfoundation.org]

  Physical symptoms: generalized abdominal pain, bloating, indigestion and lack of appetite as well as generalized weakness and fatigue. [ionispharma.com]

  The most common symptoms of this disease are: weakness fatigue bleeding from the gums or nose weight loss bruises skin lesions skin discoloration swollen glands If the amount of IgM in your body becomes severely high, you may experience additional symptoms [healthline.com]

• Amyloidosis

  There are an estimated 50,000 people with hATTR amyloidosis worldwide.4 Additional information on hATTR amyloidosis, including a full list of organizations supporting the hATTR amyloidosis community worldwide, is available at www.hattrchangethecourse.com [backpackhealth.com]

  […] commercialize through its wholly owned subsidiary, Akcea Therapeutics, to treat patients with either familial chylomicronemia syndrome or familial partial lipodystrophy; and IONIS-TTRRx, a drug Ionis is developing with GSK to treat patients with TTR amyloidosis [medical-dictionary.thefreedictionary.com]

  […] drug Ionis is developing and, if approved, plans to commercialize through its wholly owned subsidiary, Akcea Therapeutics, to treat patients with FCS and FPL; IONIS-TTR Rx, a drug Ionis is developing with GSK to treat patients with all forms of TTR amyloidosis [newswire.ca]

  (NASDAQ: IONS) today announced that data from the NEURO-TTR open-label extension study and the clinical impact of TEGSEDI on patients living with hereditary transthyretin amyloidosis (hATTR) will be presented at the American College of Cardiology’s 68th [fintel.io]

• Coronary Atherosclerosis

  : Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: consensus statement of the European Atherosclerosis Society. [f1000research.com]

• Dyspnea

  The chylomicronemia syndrome is associated with marked hypertriglyceridemia (plasma triglyceride level above 2000 mg per dl), abdominal pain or pancreatitis, eruptive xanthomata, lipemia retinalis, dyspnea, mental aberrations, and other minor findings [ncbi.nlm.nih.gov]

  However, people with this syndrome, at the onset of symptoms usually have triglyceride elevations greater than 2000 mg/dL, or 22.6 mmol/L and provide a history of recurrent episodes of: abdominal pain, sometimes with nausea vomiting, or dyspnea – shortness [reducetriglycerides.com]

  Other presenting symptoms may include diarrhea, internal bleeding and dyspnea. LPL deficiency is unlikely to be associated with atherosclerosis but recurrent pancreatitis may be life-threatening. [clinicaladvisor.com]

  Recurrent episodes of ill-defined abdominal pain that may be accompanied by nausea and vomiting are the most common presenting symptom, but chest pain and dyspnea may sometimes occur. [emedicine.medscape.com]

• Yawning

  By Richard Klasco, M.D Photo Credit Ask Well Photo Credit Why Do We Yawn? Reading about yawning makes people yawn. You are probably yawning right now. By Roni Caryn Rabin Latest Search Latest Articles Search Articles 13844 results for sorted by [nytimes.com]

• Abdominal Pain

  Among all symptoms of FCS, abdominal pain and pancreatitis present the most significant short- and long-term risks to patients. 14-16, 34 Pancreatitis can cause debilitating, life-threatening pain and is often more severe in patients with extremely high [fcs.raredr.com]

  Symptoms reported by the patients with FCS were primarily gastrointestinal, including abdominal pain, bloating, constipation, diarrhea and nausea; pain-related, including back pain, referred pain and headache; and fever. [healio.com]

  The chylomicronemia syndrome is associated with marked hypertriglyceridemia (plasma triglyceride level above 2000 mg per dl), abdominal pain or pancreatitis, eruptive xanthomata, lipemia retinalis, dyspnea, mental aberrations, and other minor findings [ncbi.nlm.nih.gov]

  During the eighteen month treatment period, the patient was essentially symptom free thanks to the gene therapy, experiencing no abdominal pain or pancreatitis attacks. [patientworthy.com]

• Nausea

  Symptoms reported by the patients with FCS were primarily gastrointestinal, including abdominal pain, bloating, constipation, diarrhea and nausea; pain-related, including back pain, referred pain and headache; and fever. [healio.com]

  […] significant short- and long-term risks to patients. 14-16, 34 Pancreatitis can cause debilitating, life-threatening pain and is often more severe in patients with extremely high triglyceride levels. 17 Bouts of pancreatitis typically begin with extreme nausea [fcs.raredr.com]

  Patients with FCS typically present with multiple symptoms as a result of their extremely high triglyceride levels, including daily or weekly episodes of abdominal pain, nausea and vomiting; neurocognitive effects, such as brain fog, forgetfulness and [ionispharma.com]

  […] particles (chylomicrons) in blood and a corresponding increase of fatty substances called triglycerides The signs and symptoms associated with Familial Lipoprotein Lipase Deficiency include recurrent attacks of pancreatitis resulting in abdominal pain, nausea [dovemed.com]

• Vomiting

  […] short- and long-term risks to patients. 14-16, 34 Pancreatitis can cause debilitating, life-threatening pain and is often more severe in patients with extremely high triglyceride levels. 17 Bouts of pancreatitis typically begin with extreme nausea and vomiting [fcs.raredr.com]

  Because of sustained high TG levels, patients with FCS are also at risk of a painful condition called pancreatitis, which is inflammation of the pancreas Patients may also experience vomiting and diarrhea. [fcsfocus.com]

  […] the eyes appear “milky” Memory Loss or ‘foggy-headedness Depression or a sense of isolation Severe pain in the abdomen often including back pain Acute or chronic pancreatitis Xanthomas, fatty deposits in the skin Patients with FCS may also experience: Vomiting [hormone.org]

  Patients with FCS typically present with multiple symptoms as a result of their extremely high triglyceride levels, including daily or weekly episodes of abdominal pain, nausea and vomiting; neurocognitive effects, such as brain fog, forgetfulness and [ionispharma.com]

  […] chylomicrons) in blood and a corresponding increase of fatty substances called triglycerides The signs and symptoms associated with Familial Lipoprotein Lipase Deficiency include recurrent attacks of pancreatitis resulting in abdominal pain, nausea, vomiting [dovemed.com]

• Severe Abdominal Pain

  FCS is a genetic condition that causes a buildup of fats in the blood that can increase the risk of severe abdominal pain and potentially fatal attacks of pancreatitis. [prnewswire.com]

  After finishing a night shift at a local hospital, I woke up with severe abdominal pain. I thought I was going to die. I had experienced abdominal pain before, but this was different; the pain was so excruciating I was unable to walk. [globalgenes.org]

  Calculation of the number of hospitalizations for pancreatitis or severe abdominal pain was performed by questionnaire and by reviewing patient's medical charts. [frontiersin.org]

  Symptoms While severe abdominal pain is the most common symptom of FCS, the symptoms of FCS can be clinical, emotional and cognitive and may include (Brahm and Hegele, 2015; Davidson et al. 2017): abdominal pain (daily low-level to debilitating) nausea [pancreasfoundation.org]

  This was a global study of 66 patients, who had a confirmed loss-of-function (LOF) variant and documented LPL activity ≤ 20% normal with a documented history of pancreatitis or hospitalization for severe abdominal pain consistent with acute pancreatitis [eas-society.org]

• Heart Disease

  Certain conditions such as infection, parasites, tumors, anemias, toxic states, storage diseases, heart failure, congenital heart disease, and metabolic disturbances may all cause an enlarged liver. [mountsinai.org]

  Lipoprotein disorders and cardiovascular disease. In: Zipes DP, Libby P, Bonow RO, Mann DL, Tomaselli GF, Braunwald E, eds. Braunwald's Heart Disease: A Textbook of Cardiovascular Medicine. 11th ed. Philadelphia, PA: Elsevier; 2019:chap 48. [medlineplus.gov]

  Lipoprotein disorders and cardiovascular disease. In: Bonow RO, Mann DL, Zipes DP, Libby P, Braunwald E, eds. Braunwald's Heart Disease: A Textbook of Cardiovascular Medicine. 10th ed. Philadelphia, PA: Elsevier Saunders; 2015:chap 45. Robinson JG. [ufhealth.org]

  Is lipoprotein(a) an independent risk factor for ischemic heart disease in men? The Quebec cardiovascular study. JACC 1998; 31: 519-525. Tanaka K, Hayashi K. [lipidambulanz.charite.de]

  Cardiac Catheterization : A heart procedure used to diagnose heart disease. [webmd.com]

• Hepatosplenomegaly

  Chylomicronemia syndrome (CMS) is a rare disorder characterized by the presence of chylomicrons in the fasting state causing a milky appearance of plasma, eruptive xanthomas, and hepatosplenomegaly; an acute and potentially life threatening complication [ncbi.nlm.nih.gov]

  […] acute recurrent inflammation of the pancreas, which causes debilitating pain and can be fatal. 6-8 Others develop eruptive xanthomas (fatty deposits on the skin) lipemia retinalis (milky appearance of retinal veins and arteries), abdominal pain, and hepatosplenomegaly [fcs.raredr.com]

  The impact of FCS includes acute physical manifestations (eruptive xanthoma, lipemia retinalis, hepatosplenomegaly) and potentially life-threatening recurrent acute pancreatitis, which frequently leads to chronic pancreatitis,” Brown and colleagues wrote [healio.com]

  R16.2 ICD-10-CM Diagnosis Code R16.2 Hepatomegaly with splenomegaly, not elsewhere classified 2016 2017 2018 2019 Billable/Specific Code Applicable To Hepatosplenomegaly NOS hyperlipemic E78.3 (Bürger-Grütz type) Hyperchylomicronemia (familial) (primary [icd10data.com]

  The disease is usually detected in childhood based on repeated episodes of abdominal pain, recurrent attacks of pancreatitis, eruptive cutaneous xanthomatosis, and hepatosplenomegaly. [ommbid.mhmedical.com]

• Hepatomegaly

  An abdominal ultrasound examination confirmed hepatomegaly. [elsevier.es]

  An enlarged liver (hepatomegaly) is also common. Hepatomegaly is caused by the accumulation of fat in the liver (fatty liver or steatosis). [rarediseases.org]

  Hepatomegaly is enlargement of the liver beyond its normal size. [mountsinai.org]

  Cardiomegaly Debranching enzyme deficiency Cori disease clinical manifestations Hypotonia, hepatomegaly Shows limit dextrins accumulation Myophosphorilase deficiency Mcardle diseases manifestations - High glycogen in muscle - Muscle cramps - Myoglobinuria [quizlet.com]

  Hepatomegaly is common, and, if the plasma TG levels are very high, splenomegaly may also be seen. Organomegaly occurs as a result of TG uptake by macrophages, which become foam cells and may rapidly regress with a decrease in dietary fat intake. [clinicaladvisor.com]

• Lipemia Retinalis

  The chylomicronemia syndrome is associated with marked hypertriglyceridemia (plasma triglyceride level above 2000 mg per dl), abdominal pain or pancreatitis, eruptive xanthomata, lipemia retinalis, dyspnea, mental aberrations, and other minor findings [ncbi.nlm.nih.gov]

  Ophthalmological examination revealed lipemia retinalis. [omicsonline.org]

• Xanthoma

  Abstract A 25-year-old man who presented with eruptive xanthomas, hyperglycemia and hyperlipidemia was admitted to our hospital. [jstage.jst.go.jp]

  The xanthomas are the aggregates of chylomicrons that have become large enough to see on the exterior of the skin. [chylomicronemiasyndrome.wordpress.com]

  Chylomicronemia, when accompanied by eruptive xanthoma, lipemia retinalis, or abdominal symptoms, is referred to as the "chylomicronemia syndrome" and can cause acute pancreatitis. [ncbi.nlm.nih.gov]

  The disease leads to symptoms such as recurrent pancreatitis and fatty deposits in the skin (xanthomas). (See “Symptoms.”) The syndrome results in a marked elevation of chylomicrons and triglycerides. [chylomicronemiasyndrome.com]

• Sweating

  […] long-term risks to patients. 14-16, 34 Pancreatitis can cause debilitating, life-threatening pain and is often more severe in patients with extremely high triglyceride levels. 17 Bouts of pancreatitis typically begin with extreme nausea and vomiting, sweating [fcs.raredr.com]

  Pancreatitis can be associated with abdominal pain, chills, jaundice, weakness, sweating, vomiting, and weight loss. [rarediseases.org]

  […] recessive dissorders - hemophihlia a and b - g6pd deficiency - ornithine transcarbamylase deficiency - duchenne muscular distrophy Most lethal genetic disease in caucasians - Autosomal recesive - CFTR MUTATION Clinical manifestation Cystic fibrosis - salty sweat [quizlet.com]

• Irritability

  Pancreatitis symptoms are similar to those of heart attack, appendicitis, ulcers, irritable bowel syndrome, hiatal hernia, gallstones, and hepatitis. So accurate diagnosis is important.. [reducetriglycerides.com]

  It may include other signs such as anemia, jaundice, irritability, diarrhea, and pallor. These manifestations vary in time and severity. [lipidworld.biomedcentral.com]

  Mutilation, irritability R- Retardation T- Dystonia Processes before mRNA leaves nucleus - Capping - Splicing - poly A mRNA translation regulation and degradation Also storage Enzymes that reverts oxidative stress - Superoxide dismutase - Glutathione [quizlet.com]

• Vertigo

  These symptoms frequently occur as a result of hyperviscosity and include: vision changes, including blurry vision and vision loss headaches dizziness or vertigo changes in mental status Waldenstrom’s disease develops when your body overproduces IgM antibodies [healthline.com]

  […] deficiency in USA Retinal pigments Differentiation of epithelial cells into specialized cells - Night blindness - keratomalacya - Dry skin Vitamin A uses and toxicity - Used to treat acne and promyelocitic leukemia - toxicity causes nausea, vomiting, vertigo [quizlet.com]

• Tingling

  Those living with FCS can be at risk for severe recurrent abdominal pain and potentially fatal pancreatitis, as well as symptoms that can interfere with daily living, including fatigue, lack of energy (asthenia), impaired cognition, and numbness/tingling [fcs.raredr.com]

• Peripheral Neuropathy

  neuropathy - Dermatitis - Anemia - Carboxylation enzymes ex. [quizlet.com]

• Asthenia

  Those living with FCS can be at risk for severe recurrent abdominal pain and potentially fatal pancreatitis, as well as symptoms that can interfere with daily living, including fatigue, lack of energy (asthenia), impaired cognition, and numbness/tingling [fcs.raredr.com]

A thorough history, physical examination, and laboratory workup failed to identify a clear etiology of the extremely abnormal blood lipid level, prompting genetic investigation to identify the genetic cause of the milky serum. [lipidworld.biomedcentral.com]

See Workup for more detail. [emedicine.medscape.com]

• Enlargement of the Liver

  […] of the liver or spleen). 9,10 Patients are also often fatigued, lack energy, have impaired cognition, and develop numbness/tingling that can affect their ability to handle many daily responsibilities. [fcs.raredr.com]

  Hepatomegaly is enlargement of the liver beyond its normal size. [mountsinai.org]

  In addition to my symptoms, they might have recognized that I had an enlarged spleen and liver. They could have helped me to access any available treatments. And I would at least have had an answer sooner. [globalgenes.org]

  Clinically, FCS is associated with pancreatitis, eruptive xanthoma, lipaemia retinalis, abdominal pain, and/or abnormal enlargement of the liver and/or spleen, which together confer a substantial morbidity burden on patients. 2 There is currently no treatment [eas-society.org]

• Hypertriglyceridemia

  The marked hypertriglyceridemia is usually due to the interaction of a common familial form of hypertriglyceridemia and a common acquired form of hypertriglyceridemia secondary to another disease, drug, or alcohol. [ncbi.nlm.nih.gov]

  His hypertriglyceridemia had been poorly controlled, because of medication noncompliance. He did not use any medication for his severe hypertriglyceridemia since one year. The patient did not smoke or consume alcohol. [omicsonline.org]

• Pancreatic Necrosis

  […] tryglyceride levels (≥1000 mg/dL) 17 : 60% required intensive care 50% had pancreatic necrosis as identified via contrast CT-scan findings 48% developed persistent organ failure 8% died In patients with FCS, episodes of abdominal pain and pancreatitis [fcs.raredr.com]

  Patients with extremely high levels of triglycerides may have a more severe course of pancreatitis, leading to worse outcomes including longer hospital stays, a higher rate of pancreatic necrosis, more frequent persistent organ failure, and higher rates [pancreasfoundation.org]

The organization will also work to support research targeting new treatments and a cure for FCS. "FCS is a rare genetic disease which can have devastating effects on its victims. [prnewswire.com]

In the study, there were no treatment-related liver adverse events, including no increases in liver fat. There were no treatment-related renal adverse events. [newswire.ca]

After two years of treatment with ciprofibrate, the patient had not experienced new episodes of abdominal pain or new eruptive xanthomas. [elsevier.es]

Affected individuals should talk to their physician and medical team about their specific case, associated symptoms, and overall prognosis. [rarediseases.org]

Therefore, the prognosis of individuals with chylomicronemia syndrome is not so bleak after all. They can lead a relatively normal life, and to be honest, with a healthier diet than many people without the disease. [chylomicronemiasyndrome.wordpress.com]

Outlook (Prognosis) A fat-free diet can reduce symptoms dramatically. Possible Complications When untreated, the excess chylomicrons may lead to bouts of pancreatitis. This condition can be very painful and even life threatening. [ufhealth.org]

Abstract Hypertriglyderidemia is responsible for up to 10% of cases of pancreatitis, appearing as the third most common etiology. [galiciaclinica.info]

Other etiologic factors were excluded, including mutations in the PRSS1, SPINK1, and CFTR gene. Although both brothers had recurrent acute pancreatitis and the same LPL genotype, CP became evident in only one patient. [journals.lww.com]

Clinical and biochemical features of different molecular etiologies of familial chylomicronemia. J Clin Lipidol 2018; 12: 920-7. [ Links ] 36. Otokozawa S, Ai M, Diffenderfer M, et al. [scielo.org.ar]

Hegele Hypertriglyceridemia: its etiology, effects and treatment [4] N. Chokshi, S.D. Blumenschein, Z. Ahmad, A. Garg Genotype–phenotype relationships in patients with type I hyperlipoproteinemia [5] T. Gotoda, K. Shirai, T. Ohta, J. Kobayashi, S. [elsevier.es]

In our cases, genetic investigation could help to identify the etiology of infants with milky serum for the heterogeneity of FCS in the young group. [lipidworld.biomedcentral.com]

[…] treated with it commercially. [7] A total of 31 patients were treated with Glybera, most for free in clinical trials before the drug was taken off the market. [8] Incidence [ edit ] The disorder affects about 1 out of 1,000,000 people; [9] however, epidemiological [en.wikipedia.org]

[…] patients with type 2 diabetes found no effect of combination therapy with fenofibrate and a statin on the primary endpoint of fatal cardiovascular events, nonfatal MI or nonfatal stroke (HR 0.92; 95% CI 0.79-1.08; p=0.32). 40 After reviewing evidence from epidemiological [cmecorner.com]

In epidemiologic and interventional studies, hypertriglyceridemia is a risk factor for coronary artery disease (CAD). [emedicine.medscape.com]

JPN guidelines for the management of acute pancreatitis: Epidemiology, etiology, natural history, and outcome predictors in acute pancreatitis. J Hepatobiliary Pancreat Surg 2006;13(1):10-24. Kumar J, Wierzbicki AS. Images in clinical medicine. [nanbyou.or.jp]

: Lipoprotein (a): molecular and epidemiologic basis about its role in cardiovascular diseases. Revista Latinoamericana de Hipertensión. 2008; 3 (4): 113–122. Reference Source 46. [f1000research.com]

This review discusses the chylomicronemia syndrome presenting the pathophysiologic characteristics of triglyceride and chylomicrons metabolism, diagnosis, prevalence and treatment. [ncbi.nlm.nih.gov]

Purpose/Learning Objectives: Upon successful completion of this educational activity, participants should be better able to: Assess the burden of FCS, its pathophysiology, and the importance of early diagnosis and treatment. [healio.com]

[…] hypercholesterolemia genetic mutations familial hypercholesterolaemia gene mutations familial cancer gene mutations familial frontotemporal dementia mutations familial gastric cancer mutations Lesson on Familial Hypercholesterolemia: Genetic Basis, Pathophysiology [web.shadidphotography.com]

Given the importance of apoC-III in lipid metabolism and its pathophysiological role in CVD and other metabolic disorders, it was an obvious target for therapeutic intervention. [dicardiology.com]

Pathophysiology of hypertriglyceridemia. Biochim Biophys Acta. 2012 May. 1821(5):826-32. [Medline]. [emedicine.medscape.com]

Presented at: American Society for Preventive Cardiology Congress on Atherosclerotic Cardiovascular Disease Prevention; Sept. 16-18, 2016; Boca Raton, Fla. [healio.com]

Therapy that successfully lowers plasma triglyceride levels is associated with clearing of the symptoms and signs of the chylomicronemia syndrome and prevention of its recurrence. [ncbi.nlm.nih.gov]

Prevention There is no way to prevent someone from inheriting this syndrome. Images References Genest J, Libby P. Lipoprotein disorders and cardiovascular disease. In: Bonow RO, Mann DL, Zipes DP, Libby P, Braunwald E, eds. [ufhealth.org]