[en.wikipedia.org] [symptoma.com] Case presentation The clinical presentation was characterized by a severe early-onset of hypertension refractory to multiple therapy. [symptoma.com]

They can present in the uterus with decreased fetal activity, increased fluid around the fetus (polyhydramnios); after birth they present with blush color to the skin (cyanosis), heart failure, high blood pressure, fast breathing, swelling, distended [nicklauschildrens.org]

Case presentation The clinical presentation was characterized by a severe early-onset of hypertension refractory to multiple therapy. [go.gale.com]

Of these, 48% of cases presented in utero or at birth with hydrops fetalis, maternal hydramnios, heart failure, or respiratory distress and 52% present later, at a median age of 3 months, with sudden onset of fever, vomiting, irritability, or respiratory [ncbi.nlm.nih.gov]

• Pain

  […] bone pain, bowed femora, and short stature. [symptoma.com]

  Beyond six months, the mortality rate significantly decreases among survivors, who may later develop ARHR2, characterized clinically by short stature, bone deformities and pain. [bone-abstracts.org]

  […] the child uses for pain, e.g., ouch, hurt. • Ask the child to give examples of pain (to identify the child’s understanding and use of words Chest Wall Pain: Costochondritis. [apotechsrl.it]

  At first, she began having pain in her hands and was initially diagnosed with arthritis. However, test results were negative. She was sent home with no answers. Over the years, the pain intensified and traveled to her lower extremities. [medicalbag.com]

  He was receiving EHDP, 200 mg/day orally, and had odynodysphagia, diffuse opioid-controlled pain, plagiocephaly, facial dysmorphism, joint calcifications, contractures, and was wheelchair bound. [ncbi.nlm.nih.gov]

• Congestive Heart Failure

  [webmd.com] Congestive Heart Failure [symptoma.com] Entire Body System Congestive Heart Failure [orpha.net] Entire Body System Congestive Heart Failure Affected infants are usually diagnosed before birth or in the neonatal period with symptoms of congestive [symptoma.com]

  More on Hypophosphatemic rickets » Congestive heart failure : Congestive Heart Failure occurs when the heart cannot pump adequately to send the blood around the body. [familydiagnosis.com]

  Affected infants are usually diagnosed before birth or in the neonatal period with symptoms of congestive heart failure. Therapy with bisphosphonate has been used to treat the condition, but with inconsistent results. [ncbi.nlm.nih.gov]

  Three new patients are reported who presented with congestive heart failure. The visualization of faint vascular calcifications in the extra-thoracic soft tissues presented an opportunity to establish the diagnosis radiologically. [doi.org]

• Short Stature

  [jultrasoundmed.org] Short Stature As a consequence, GACI patients develop severe rachitic complications such as short stature and skeletal deformities. [symptoma.com]

  Beyond six months, the mortality rate significantly decreases among survivors, who may later develop ARHR2, characterized clinically by short stature, bone deformities and pain. [bone-abstracts.org]

  As a consequence, GACI patients develop severe rachitic complications such as short stature and skeletal deformities. [ncbi.nlm.nih.gov]

  ARHR2 is characterized by short stature, dental caries, and bone deformities, and biochemically by hypophosphatemia, hyperphosphaturia and elevated plasma alkaline phosphatase. The disease frequency is unknown. [clinicaltrials.gov]

• Weakness

  [rareguru.com] Weakness At one hour of age, he was noted to be pale, hypoperfused, with weak pulses, a hyperdynamic precordium and a grade IV/VI pansystolic murmur. The rest of his examination was normal. [symptoma.com]

  In the adult phase, in addition to continuing vascular and organ calcification, ENPP1 deficiency manifests as osteomalacia, which leads to severe bone pain, fatigue, muscle weakness, and risk of recurring bone fractures. [inozyme.com]

  Symptoms of a stroke include sudden weakness, confusion, or dizziness, along with vision and speech impairment. [share.upmc.com]

  At one hour of age, he was noted to be pale, hypoperfused, with weak pulses, a hyperdynamic precordium and a grade IV/VI pansystolic murmur. The rest of his examination was normal. A chest X-ray showed massive cardiomegaly and pulmonary oedema. [bmcpediatr.biomedcentral.com]

• Plethora

  [gaciglobal.org] Plethora [bmcpediatr.biomedcentral.com] Plethora Chest radiography showed cardiomegaly and pulmonary plethora. Electrocardiography showed left ventricular hypertrophy and strain pattern. [symptoma.com]

  Chest radiography showed cardiomegaly and pulmonary plethora. Electrocardiography showed left ventricular hypertrophy and strain pattern. [doi.org]

  Extramedullary hematopoiesis of liver [9] Hypertrophy of myocardium Bright and hyper-reflective myocardium[10] Periarticular calcifications in the wrists, ears, shoulders, ankles and hip[11][12] Heart usually looks structurally normal Cardiomegaly and pulmonary plethora [wikidoc.org]

  These factors may be broadly categorized into two major causes, namely, an elevated calcium blood level (hypercalcemia) and tissue injury, both of which may be triggered by a plethora of conditions. [news-medical.net]

• Respiratory Distress

  Distress Distress Of these, 48% of cases presented in utero or at birth with hydrops fetalis, maternal hydramnios, heart failure, or respiratory distress and 52% present later, at a median age of 3 months, with sudden onset of fever, vomiting, irritability [symptoma.com]

  Of these, 48% of cases presented in utero or at birth with hydrops fetalis, maternal hydramnios, heart failure, or respiratory distress and 52% present later, at a median age of 3 months, with sudden onset of fever, vomiting, irritability, or respiratory [ncbi.nlm.nih.gov]

  Early-onset disease presents variably with fetal distress, heart failure, polyhydramnios, hypertension, respiratory distress, hydrops fetalis, edema, visceral effusions, cyanosis, cardiomegaly, and ascites. [orpha.net]

• Tachypnea

  [acc.org] Tachypnea [apotechsrl.it] Tachypnea [symptoma.com] Tachypnea [bone-abstracts.org] Tachypnea […] months of life or in utero. [2] Decreased fetal activity Gestation with an antenatal diagnosis of hydrops fetalis [6] [7] Polyhydramnios Low biophysical [symptoma.com]

  […] or in utero.[2] History and Symptoms Decreased fetal activity Gestation with an antenatal diagnosis of hydrops fetalis[3][4] Polyhydramnios Low biophysical profile Marked cyanosis Edema[5] Severe hypertension[6] No or fade pulses Refusal of feeds[7] Tachypnea [wikidoc.org]

  She had tachycardia (heart rate 180/min), tachypnea (respiratory rate 80/min) with normal blood pressure and required supplemental oxygen. Peripheral pulses were not palpable. Systemic examination was normal. [pediatriconcall.com]

  […] months of life or in utero. [2] Decreased fetal activity Gestation with an antenatal diagnosis of hydrops fetalis [6] [7] Polyhydramnios Low biophysical profile Marked cyanosis Edema [8] Severe hypertension [9] No or fade pulses Refusal of feeds [10] Tachypnea [en.wikipedia.org]

• Dyspnea

  [rareguru.com] Dyspnea [orpha.net] Dyspnea [unboundmedicine.com] Dyspnea In GACI probands, initial symptoms included dyspnea (62%) and cyanosis (16%); 73% were ventilated. [symptoma.com]

  In GACI probands, initial symptoms included dyspnea (62%) and cyanosis (16%); 73% were ventilated. [bone-abstracts.org]

  Initially, she had dyspnea consistent with New York Heart Association (NYHA) Functional Classification class II (light limitation of physical activity with ordinary physical activity resulting in fatigue, palpitation, dyspnea) which progressed to class [cureus.com]

  Color compare parasternal short axis view demonstrating origin of the right coronary artery from the left sinus of Valsalva in a 16-year-old female presenting with exertional chest pain and dyspnea. [acc.org]

• Vomiting

  [gaciglobal.org] Vomiting [orpha.net] [orpha.net] Vomiting Of these, 48% of cases presented in utero or at birth with hydrops fetalis, maternal hydramnios, heart failure, or respiratory distress and 52% present later, at a median age of 3 months, with [symptoma.com]

  Of these, 48% of cases presented in utero or at birth with hydrops fetalis, maternal hydramnios, heart failure, or respiratory distress and 52% present later, at a median age of 3 months, with sudden onset of fever, vomiting, irritability, or respiratory [ncbi.nlm.nih.gov]

  Presentation of late-onset disease variably includes respiratory distress, cyanosis, feeding difficulties, congestive heart failure, vomiting, irritability, failure to thrive, fever, hypertension, and edema. [orpha.net]

• Failure to Thrive

  […] to Thrive [orpha.net] In some babies, feeding problems, irritability and failure to thrive are the presenting features. [symptoma.com]

  Idiopathic infantile arterial calcification was diagnosed in a 2 week old infant with failure to thrive associated with neurological, renal and cardiac signs. Therapy with diphosphonate resulted in a complete resolution of vascular calcifications. [ncbi.nlm.nih.gov]

  The features associated with ACI typically include heart failure, high blood pressure (hypertension), and failure to thrive. These features vary, with each infant being differently affected by the severity of their symptoms. [checkorphan.org]

  Abstract Idiopathic infantile arterial calcification was diagnosed in a 2 week old infant with failure to thrive associated with neurological, renal and cardiac signs. [doi.org]

• Abdominal Distension

  Distension Distension [en.wikipedia.org] [en.wikipedia.org] The infant’s subsequent course in NICU was complicated by recurrent abdominal distension, feeding intolerance, irritability, pyrexia and systemic hypertension. [symptoma.com]

  distension General arterial rigidity[8] Cardiac failure (most common clinical finding) Strain pattern Dilated and hypertrophied ventricles Extramedullary hematopoiesis of liver [9] Hypertrophy of myocardium Bright and hyper-reflective myocardium[10] [wikidoc.org]

  distension General arterial rigidity [11] Cardiac failure (most common clinical finding) Strain pattern Cause [ edit ] GACI is inherited in an autosomal recessive pattern. [en.wikipedia.org]

• Hepatosplenomegaly

  [en.wikipedia.org] Liver, Gall & Pancreas Hepatosplenomegaly [bmcpediatr.biomedcentral.com] Liver, Gall & Pancreas Hepatosplenomegaly […] clinical features including microcephaly, intracranial calcifications, rash, intrauterine growth restriction, jaundice [symptoma.com]

  […] calcification involving aorta, carotid, cerebral, renal, mesenteric and cardiac arteries Echo-dense aortic annulus, ascending aorta, transverse arch, descending aorta, main pulmonary artery, and coronary arteries unusually.[13] Abdominal ultrasound can reveal hepatosplenomegaly [wikidoc.org]

  Although each of the congenital intrauterine infections has distinct clinical manifestations and sequelae, some of them do share certain clinical features including microcephaly, intracranial calcifications, rash, intrauterine growth restriction, jaundice, hepatosplenomegaly [hindawi.com]

  The absence of jugular turgor and hepatosplenomegaly were evaluated and fluids were administered through intraosseous tibial as anti-shock rescue; however, the non-invasive blood pressure remains invaluable. [pediatrics.imedpub.com]

• Hypertension

  [en.wikipedia.org] [en.wikipedia.org] Anti-hypertensive therapy is warranted for hypertension. [orpha.net] At the age of 2 years the child is doing well but requires medical treatment for arterial hypertension. [symptoma.com]

  Case presentation The clinical presentation was characterized by a severe early-onset of hypertension refractory to multiple therapy. [go.gale.com]

  The clinical presentation was characterized by a severe early-onset of hypertension refractory to multiple therapy. [ncbi.nlm.nih.gov]

  Standard anti-hypertensive therapy is warranted for hypertension. Aspirin therapy is warranted in those with severe coronary stenosis who are at increased risk for coronary thrombosis. Anti-hypertensive therapy is warranted for hypertension. [orpha.net]

• Heart Failure

  We report the case of a 32-week-old infant with hydrops fetalis and heart failure who died at 4 days of age. [ncbi.nlm.nih.gov]

  We report the case of a 4-year-old Italian child submitted to heart transplant, at 18 months old, for end-stage heart failure due to extensive myocardial infarction of the left ventricle and diffuse coronary calcifications. [moh-it.pure.elsevier.com]

• Cyanosis

  [contact.org.uk] Cyanosis [chop.edu] Cyanosis There are 2 types: Central cyanosis and Acrocyanosis. [nicklauschildrens.org] There are 2 types: Central cyanosis and Acrocyanosis. [symptoma.com]

  Reviewed by: Jack Wolfsdorf, MD, FAAP This page was last updated on: December 18, 2020 05:03 PM Learn more about Cyanosis A bluish tinge of the lips, tongue, nail beds or skin is called cyanosis. There are 2 types: Central cyanosis and Acrocyanosis. [nicklauschildrens.org]

  Early-onset disease presents variably with fetal distress, heart failure, polyhydramnios, hypertension, respiratory distress, hydrops fetalis, edema, visceral effusions, cyanosis, cardiomegaly, and ascites. [orpha.net]

• Cardiomegaly

  A chest X-ray showed massive cardiomegaly and pulmonary oedema. [symptoma.com]

  Case Presentation A multigravida with previous two normal issues was referred at 36 weeks of gestation, as the screening ultrasound revealed cardiomegaly. [austinpublishinggroup.com]

  At autopsy the infant was found to have cardiomegaly, myocardial infarctions and multifocal calcifications of the aorta and arteries in the lungs, heart, thyroid, spleen, and testis. [ncbi.nlm.nih.gov]

• Weak Pulse

  [bmcpediatr.biomedcentral.com] Weak Pulse At one hour of age, he was noted to be pale, hypoperfused, with weak pulses, a hyperdynamic precordium and a grade IV/VI pansystolic murmur. The rest of his examination was normal. [symptoma.com]

  At one hour of age, he was noted to be pale, hypoperfused, with weak pulses, a hyperdynamic precordium and a grade IV/VI pansystolic murmur. The rest of his examination was normal. A chest X-ray showed massive cardiomegaly and pulmonary oedema. [bmcpediatr.biomedcentral.com]

• Hearing Impairment

  [en.wikipedia.org] Ears Hearing Impairment [ojhas.org] Ears Hearing Impairment [doi.org] Ears Hearing Impairment Fishman G, Miller-Hansen D, Jacobsen C, Singhal V, Alon U: Hearing impairment in familial X-linked hypophosphatemic rickets. [symptoma.com]

  Davies M, Kane R, Valentine J: Impaired hearing in X-linked hypophosphataemic (vitamin-D-resistant) osteomalacia. Ann Intern Med 1984;100:230-232. [karger.com]

• Ulcer

  [symptoma.com] Skin Ulcer Infants with GACI may suffer from gastrointestinal complications such as ulcerating inflammation of the wall of the small intestine or obstruction due to stenosis. [symptoma.com]

  Infants with GACI may suffer from gastrointestinal complications such as ulcerating inflammation of the wall of the small intestine or obstruction due to stenosis. [gaciglobal.org]

• Angioid Streaks of the Retina

  Also, many PXE characteristics, including angioid streaks of the retina and peau d’orange skin lesions might frequently be overlooked in the clinical examinations of GACI patients. [frontiersin.org]

• Hydrops Fetalis

  [oncotarget.com] Fetus Hydrops Fetalis [doi.org] Fetus Hydrops Fetalis We report the case of a 32-week-old infant with hydrops fetalis and heart failure who died at 4 days of age. [symptoma.com]

  Conclusion: GACI might be one of the possible etiologies of hydrops fetalis. [thieme-connect.com]

  We report the case of a 32-week-old infant with hydrops fetalis and heart failure who died at 4 days of age. [ncbi.nlm.nih.gov]

• Bone Pain

  Rickets leads to severe skeletal deformities, short stature, severe bone pain, and an increased risk of bone fractures. [inozyme.com]

  bone pain, bowed femora, and short stature. [symptoma.com]

  ARHR2 manifests in the post-infancy stage and causes rickets, weakened bones, repeated bone fractures, skeletal deformities, short stature, muscle weakness, fatigue, and bone pain. [globenewswire.com]

• Kidney Failure

  The initial indication of GACI is high blood pressure or kidney failure. Physicians may order X-rays for newborns with these conditions to look for calcification in arteries. [chop.edu]

  [symptoma.com] Urogenital Kidney Failure [karger.com] Urogenital Kidney Failure The initial indication of GACI is high blood pressure or kidney failure. [symptoma.com]

  […] abdomen and and kidney failure. [nicklauschildrens.org]

• Stroke

  The cause of death is frequently myocardial infarction or stroke, and hypertension and congestive heart failure are common in fetuses and infants with GACI. [clinicaltrials.gov]

  Generalized arterial calcification of infancy (GACI) is an autosomal recessive disorder characterized by congenital calcification of large- and medium-sized arteries, associated with early myocardial infarction, heart failure, and stroke, and premature [ncbi.nlm.nih.gov]

  Eventually, you might develop symptoms of peripheral artery disease (PAD) or stroke. The most common PAD symptom is pain or cramping in your leg muscles when walking or climbing stairs. If plaque is dislodged, it can cause a stroke. [share.upmc.com]

  As a result of the cardiovascular problems associated with GACI, individuals with this condition often do not survive past infancy, with death typically caused by a heart attack or stroke. [rarediseases.oscar.ncsu.edu]

  The cause of death is frequently myocardial infarction or stroke. GACI is strongly associated with inactivating mutations in ectonucleotide pyrophosphate/ phosphodiesterase 1 (ENPP1). [patientwing.com]

• Irritability

  [chop.edu] Neurologic Irritability [chop.edu] Neurologic Irritability vomiting, irritability, or respiratory [ncbi.nlm.nih.gov] Presentation of late-onset disease variably includes respiratory distress, cyanosis, feeding difficulties, congestive heart [symptoma.com]

  Of these, 48% of cases presented in utero or at birth with hydrops fetalis, maternal hydramnios, heart failure, or respiratory distress and 52% present later, at a median age of 3 months, with sudden onset of fever, vomiting, irritability, or respiratory [ncbi.nlm.nih.gov]

  Presentation of late-onset disease variably includes respiratory distress, cyanosis, feeding difficulties, congestive heart failure, vomiting, irritability, failure to thrive, fever, hypertension, and edema. [orpha.net]

  The drug was given for a total of 65 days and then stopped after the appearance of severe thrombocytopenia; other side effects included sporadic hyperthermia and irritability. [doi.org]

[doi.org] Workup The infant died at the age of 7 weeks of cardiac failure and the parents were referred to Molecular Biology and Cytogenetic lab for further workup. [symptoma.com]

The infant died at the age of 7 weeks of cardiac failure and the parents were referred to Molecular Biology and Cytogenetic lab for further workup. [jcdronline.org]

Initial working diagnosis included congenital infection; however, patients remained without a definitive diagnosis despite extensive workup. Consequently, we investigated a potential genetic etiology. [meta.org]

Laboratory workup was significant for a low serum phosphorus; elevated parathyroid hormone (PTH); elevated 1,25(OH)2D; and reduced renal tubular reabsorption of phosphorus, or TRP. [mayoclinic.org]

Our workup revealed normal CBC, electrolyte, metabolic screening, lipid profile and negative blood culture growth. [avensonline.org]

• Pericardial Effusion

  The sonographic examination performed at 28 weeks' gestation revealed scalp edema, severe skin edema, bilateral hydrocele, ascites, and pleural and pericardial effusion. [avesis.istanbul.edu.tr]

  Targeted ultrasonography revealed moderate cardiomegaly and pericardial effusion in the fetus (Figure 1). There were no structural abnormality of the heart on fetal ECHO. [austinpublishinggroup.com]

  [symptoma.com] X-Ray Pericardial Effusion The fetal and postnatal echocardiographic features were a large pericardial effusion, thickened pulmonary and aortic valves, poor pulsation of the descending aorta, and calcification of the great vessels. [symptoma.com]

  Antenatally there was presence of pericardial effusion leading to hydrops and polyhydramnios. [pediatriconcall.com]

  Table 1: Reported cases of IIAC with pericardial effusion. [avensonline.org]

• Ventricular Hypertrophy

  [austinpublishinggroup.com] Hypertrophy Ventricular Hypertrophy Electrocardiography showed left ventricular hypertrophy and strain pattern. [symptoma.com]

  Electrocardiography showed left ventricular hypertrophy and strain pattern. Echocardiography showed a dilated and hypertrophied left ventricle, with bright and hyper-reflective myocardium (fig 1). Fractional shortening was 12.5%. [doi.org]

  […] function, however mild concentric ventricular hypertrophy and multiple intracardiac as well as vascular calcifications[3] Idiopathic arterial calcification of infancy should be suspected when there is hyperechogenicity of vessel walls, evidence ofpolyhydramnios [wikidoc.org]

  hypertrophy, and VSD [10]. [cureus.com]

  Echocardiography demonstrated left ventricular hypertrophy with good function (fractional shortening 40%). He was normotensive. X-radiographs of chest and abdomen were normal. [documents.tips]

Treatment with bisphosphonates is ongoing, but is planned to be discontinued at 3 years of age. The child has remained healthy and developmentally normal. [go.gale.com]

Despite treatment with disodium etidronate both children died. [doi.org]

Both the GACI and ARHR2 phenotypes are potentially fatal or associated with severe morbidity, with no FDA-approved drugs or proven treatments. [clinicaltrials.gov]

"Generalized arterial calcification of infancy: Treatment with bisphosphonates". [wikidoc.org]

Generalized Arterial Calcification of Infancy: Treatment With Bisphosphonates. Nat Clin Pract Endocrinol Metab. 2009;5(3):167-72. PubMed PMID: 19229237. TY - JOUR T1 - Generalized arterial calcification of infancy: treatment with bisphosphonates. [unboundmedicine.com]

Prognosis Prognosis is poor; most infants die from myocardial infarction within the first year of life, with the greatest number of deaths occurring within the first six months. [orpha.net]

The prognosis is extremely poor, with 85% of affected infants dying within the first 6 months of life. [ncbi.nlm.nih.gov]

Abstract Idiopathic infantile arterial calcification (IIAC) is a rare disease of unknown etiology, which causes wide-spread arterial calcification and usually leads to early death from coronary arterial occlusion. [doi.org]

Idiopathic infantile arterial calcification is a disorder of unknown etiology manifested by widespread arterial calcification. This usually leads to early death from coronary artery occlusion. [ncbi.nlm.nih.gov]

[doi.org] Epidemiology Summary Epidemiology Approximately 300 cases have been reported worldwide in the medical literature. [symptoma.com]

Summary Epidemiology Approximately 300 cases have been reported worldwide in the medical literature. The prevalence is unknown; however, based on carrier frequency of the recognized pathogenic variants, the frequency of 1/566,000 has been suggested. [orpha.net]

Epidemiology Approximately 300 cases have been reported worldwide in the medical literature. The prevalence is unknown; however, based on carrier frequency of the recognized pathogenic variants, the frequency of 1/566,000 has been suggested. [rareguru.com]

[symptoma.com] It can therefore be hypothesized that the pathophysiology of ENPP1 and ABCC6 related disorders is based on common downstream mechanisms. [symptoma.com]

Unusual features in this disease include ultrasonographic prenatal diagnosis in the second two siblings and ultrastructural studies of the third patient that might shed light on the pathophysiologic characteristics of this disease. [jamanetwork.com]

It can therefore be hypothesized that the pathophysiology of ENPP1 and ABCC6 related disorders is based on common downstream mechanisms. [frontiersin.org]

Pseudoxanthoma Elasticum: a clinical pathophysiological and genetic update including 11 novel ABCC6 mutations. J Med Genet 2005; 42:881-892 [PubMed] 12. OMIM: An online catalog of human genes and genetic disorders [Electronic resource]. [journal.nephrolog.ru]

[…] biochemistry of nutrition 180 Nutritional disorders and their management 200 Clinical biochemistry of the gastrointestinal tract 214 Assessment of hepatic function and investigation of jaundice 231 Acute and chronic liver disease 250 Glucose metabolism and the pathophysiology [books.google.com]

ENPP1-Fc prevents mortality and vascular calcifications in rodent model of generalized arterial calcification of infancy. Nature Communications, 6. https://doi.org/10.1038/ncomms10006 [mendeley.com]

Here we demonstrate that subcutaneous administration of an ENPP1-Fc fusion protein prevents the mortality, vascular calcifications and sequela of disease in animal models of GACI, and is accompanied by a complete clinical and biomarker response. [ncbi.nlm.nih.gov]

ABCC6 prevents ectopic mineralization seen in pseudoxanthoma elasticum by inducing cellular nucleotide release. Proc Natl Acad Sci U S A. 2013;110(50):20206–11. [springermedizin.de]

[ncbi.nlm.nih.gov] Prevention - Generalized arterial calcification of infancy-1 (GACI1) Not supplied. [symptoma.com]

The treatment is usually given to manage signs and symptoms, and any complication that develops How can Arterial Calcification of Infancy be Prevented? Arterial Calcification of Infancy may not be preventable, since it is a genetic disorder. [dovemed.com]