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

• Congestive Heart Failure

  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]

  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]

  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]

• Pain

  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]

  […] 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]

• Inflammation

  [symptoma.com] Entire Body System Inflammation However, inflammation suggestive of myocarditis could not be identified (Figures 2(b) and 2(c)). [hindawi.com] Thus RAGE and S100A12 pathway are broadly tied to inflammation and vascular disease. [symptoma.com]

  However, inflammation suggestive of myocarditis could not be identified (Figures 2(b) and 2(c)). [hindawi.com]

  Thus RAGE and S100A12 pathway are broadly tied to inflammation and vascular disease. [ncbi.nlm.nih.gov]

  Adenosine signaling suppresses TNAP expression and inhibits vascular inflammation and neointima formation. ABCC6 has been hypothesized, though not yet proven, to modulate adenosine transport. [circresearch.com]

• Short Stature

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

  Phenotype Short stature, deafness, conductive (in some patients), angioid retinal streaks (in some patients), coronary and generalized artery calcification, cardiac dysfunction, periarticular calcification, hypophosphatemic rickets, and pseudoxanthoma [iofbonehealth.org]

  [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]

• 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]

  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]

  A syndrome of widened medullary cavities of bone, aortic calcification, abnormal dentition, and muscular weakness (the Singleton-Merten syndrome). Radiology 1976 ;118: 389 – 395. Google Scholar ISI 5. Weens, HS, Marin, CA. [doi.org]

  At 4 months he had an episode of apparent weakness of his left arm for approximately 48 hr. There was no associated jerking or twitching, and the weakness completely resolved. [documents.tips]

• Respiratory 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, 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]

  Abstract BACKGROUND A baby girl developed respiratory distress immediately after birth and required supplemental oxygen. She was born at term via lower-segment cesarean section. [unboundmedicine.com]

• 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]

• 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]

  […] 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]

  […] 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]

• Failure to Thrive

  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]

  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]

  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]

  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]

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

• 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 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]

  [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]

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

  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]

  The infant’s subsequent course in NICU was complicated by recurrent abdominal distension, feeding intolerance, irritability, pyrexia and systemic hypertension. Oral Editronate Sodium (10 mg/kg/day, twice a day) was started on day 40. [bmcpediatr.biomedcentral.com]

• 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. [23] Abdominal ultrasound can reveal hepatosplenomegaly [en.wikipedia.org]

  […] 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]

• Hypertension

  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]

  At the age of 2 years the child is doing well but requires medical treatment for arterial hypertension. [doi.org]

• 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]

  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

  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]

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

  Striking cardiomegaly with calcifications of the great vessels were noted. Radiological examination showed global and bilateral calcifications of the brachial and femoral arterial network. [ashg.org]

• Cyanosis

  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]

  [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]

• 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]

• 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]

  Dystrophic calcification is also frequently noted in diseased tissue, such as chronic ulcers and granulomas as well as in benign and malignant neoplasms. [oncotarget.com]

  Surgery is indicated when lesions are painful, recurrently infected, ulcerated or when functional impairment occurs[149]. [wjgnet.com]

• 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. [business.itbusinessnet.com]

• 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. [ncbi.nlm.nih.gov]

  Antenatal detection of idiopathic arterial calcification with hydrops fetalis. J Ultrasound Med 2003;22:653-659. Nasrallah MK.Prenatal diagnosis of idiopathic infantile arterial calcification with hydrops fetalis. [ojhas.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]

  Some case reports described association with clinical features of PXE such as angioid streaks of the retina and papular skin lesions [2]; PXE is characterized by dystrophic calcification of soft tissues. [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]

  Fishman G, Miller-Hansen D, Jacobsen C, Singhal V, Alon U: Hearing impairment in familial X-linked hypophosphatemic rickets. Eur J Pediatr 2004;163:622-623. [karger.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]

• Stroke

  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]

  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]

  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]

  Infants with the disease are also at risk for stroke, heart attacks, and kidney failure early in life. The prevalence of GACI is estimated to be about 1 in 391,000. Most babies are diagnosed with GACI after they are born. [chop.edu]

• Irritability

  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]

  [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]

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]

[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]

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 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. [doi.org]

  The sonographic findings were fetal hydrops (hydrothorax, skin edema, ascites, pericardial effusion and polyhydramnion), echogenic great arteries and pathological Doppler findings. [ncbi.nlm.nih.gov]

  Internal examination revealed pleural and pericardial effusions and moderate splenomegaly. Striking cardiomegaly with calcifications of the great vessels were noted. [ashg.org]

  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]

• Ventricular Hypertrophy

  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]

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

  hypertrophy and multiple intracardiac as well as vascular calcifications [6] Idiopathic arterial calcification of infancy should be suspected when there is hyperechogenicity of vessel walls, evidence of polyhydramnios or a past history of early neonatal [en.wikipedia.org]

  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 or a past history of early neonatal [wikidoc.org]

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

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

Treatment with bisphosphonates, which are synthetic PP(i) analogues, has been proposed as a means of reducing arterial calcifications in GACI patients, but no formalized treatment approach exists. [ncbi.nlm.nih.gov]

Treatment of hypophosphatemic rickets involves calcitriol and oral phosphate supplements. It seems prudent to avoid the use of warfarin if possible. [orpha.net]

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]

Prognosis - Generalized arterial calcification of infancy-1 (GACI1) Not supplied. Treatment - Generalized arterial calcification of infancy-1 (GACI1) Not supplied. Resources - Generalized arterial calcification of infancy-1 (GACI1) Not supplied. [checkorphan.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]

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]

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]

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

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]

[…] 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]

[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]

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]

Prevention - Generalized arterial calcification of infancy-1 (GACI1) Not supplied. [checkorphan.org]

Recently, a study on animal model has described that bisphosphonate treatment may be beneficial by a dual effect for preventing ectopic soft tissue mineralization while correcting decreased bone mineralization in GACI caused by ENPP1 mutations. [iofbonehealth.org]

Alternatively, a lack of functioning MRP6 may impair the transport of a substance that would normally prevent mineralization, leading to the abnormal accumulation of calcium characteristic of GACI. [ghr.nlm.nih.gov]

ENPP1-Fc prevents mortality and vascular calcifications in rodent model of generalized arterial calcification of infancy. Nature Communications, 6. [mendeley.com]