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Archive for the ‘Chronic Thromboembolic Pulmonary Hypertension (CTEPH) and Pulmonary Arterial Hypertension (PAH)’ Category


Mitralign and Corvia, Tewksbury, Mass – Investment and Acquisition by Edwards Lifesciences

 

Reporter: Aviva Lev-Ari, PhD, RN

 

Edwards LifesciencesEdwards Lifesciences (NYSE:EW) said today that it made a pair of strategic bets on the structural heart space, paying $35 million for the right to acquire Corvia Medical and paying an unspecified amount for some of mitral valve repair device maker Mitralign‘s assets.

Tewksbury, Mass.-based Corvia is developing an interatrial shunt to treat heart failure by creating a small opening between the left and right atria to lower blood pressure in the left atrium and lungs. The device has CE Mark approval in the European Union and a pivotal U.S trial aimed at winning a nod from the FDA is under way, Edwards said.

“We are extremely pleased to have the support of the global leader in patient-focused innovations for structural heart disease as we continue to advance this novel treatment for heart failure,” Corvia president & CEO George Fazio said in prepared remarks. “We are proud of our accomplishments to date and look forward to completing the pivotal study with the support of our global clinical investigators.”

The Irvine, Calif.-based company also said it bought “certain” Mitralign assets, including intellectual property and associated clinical and regulatory experience. Mitralign, also based in Tewksbury, is developing an annuloplasty system for treating functional mitral and tricuspid regurgitation.

Edwards said the transactions are not expected to affect its financial outlook for 2019.

SOURCE

https://www.massdevice.com/edwards-lifesciences-gets-in-on-corvia-mitralign/?spMailingID=1958&puid=370787

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Lesson 3 Cell Signaling & Motility: G Proteins, Signal Transduction: Curations and Articles of reference as supplemental information: #TUBiol3373

Curator: Stephen J. Williams, Ph.D.

Lesson 3 Powerpoint (click link below):

cell signaling and motility 3 finalissima sjw

Four papers to choose from for your February 11 group presentation:

Structural studies of G protein Coupled receptor

Shapiro-2009-Annals_of_the_New_York_Academy_of_Sciences

G protein as target in neurodegerative disease

fish technique

 

 

Today’s lesson 3 explains how extracellular signals are transduced (transmitted) into the cell through receptors to produce an agonist-driven event (effect).  This lesson focused on signal transduction from agonist through G proteins (GTPases), and eventually to the effectors of the signal transduction process.  Agonists such as small molecules like neurotransmitters, hormones, nitric oxide were discussed however later lectures will discuss more in detail the large growth factor signalings which occur through receptor tyrosine kinases and the Ras family of G proteins as well as mechanosignaling through Rho and Rac family of G proteins.

Transducers: The Heterotrimeric G Proteins (GTPases)

An excellent review of heterotrimeric G Proteins found in the brain is given by

Heterotrimeric G Proteins by Eric J Nestler and Ronald S Duman.

 

 

from Seven-Transmembrane receptors – Scientific Figure on ResearchGate. Available from: https://www.researchgate.net/figure/Examples-of-heterotrimeric-G-protein-effectors_tbl1_11180073 [accessed 4 Feb, 2019] and see references within

 

 

See below for the G Protein Cycle

 

 

 

 

 

 

 

 

<a href=”https://www.researchgate.net/figure/32-The-G-protein-cycle-In-the-absence-of-agonist-A-GPCRs-are-mainly-in-the-low_fig2_47933733″><img src=”https://www.researchgate.net/profile/Veli_Pekka_Jaakola/publication/47933733/figure/fig2/AS:669499451781133@1536632516635/32-The-G-protein-cycle-In-the-absence-of-agonist-A-GPCRs-are-mainly-in-the-low.ppm&#8221; alt=”.3.2: The G protein cycle. In the absence of agonist (A), GPCRs are mainly in the low affinity state (R). After agonist binding, the receptor is activated in the high affinity state (R*), and the agonist-GPCR-G protein complex is formed. GTP replaces GDP in Gα. After that the G protein dissociates into the Gα subunit and the Gβγ heterodimer, which then activate several effector proteins. The built-in GTPase activity of the Gα subunit cleaves the terminal phosphate group of GTP, and the GDP bound Gα subunit reassociates with Gβγ heterodimer. This results in the deactivation of both Gα and Gβγ. The G protein cycle returns to the basal state. RGS, regulator of G protein signalling.”/></a>

 

From Citation: Review: A. M. Preininger, H. E. Hamm, G protein signaling: Insights from new structures. Sci. STKE2004, re3 (2004)

 

For a tutorial on G Protein coupled receptors (GPCR) see

https://www.khanacademy.org/test-prep/mcat/organ-systems/biosignaling/v/g-protein-coupled-receptors

 

 

 

cyclic AMP (cAMP) signaling to the effector Protein Kinase A (PKA)

from https://courses.washington.edu/conj/gprotein/cyclicamp.htm

Cyclic AMP is an important second messenger. It forms, as shown, when the membrane enzyme adenylyl cyclase is activated (as indicated, by the alpha subunit of a G protein).

 

The cyclic AMP then goes on the activate specific proteins. Some ion channels, for example, are gated by cyclic AMP. But an especially important protein activated by cyclic AMP is protein kinase A, which goes on the phosphorylate certain cellular proteins. The scheme below shows how cyclic AMP activates protein kinase A.

Additional information on Nitric Oxide as a Cellular Signal

Nitric oxide is actually a free radical and can react with other free radicals, resulting in a very short half life (only a few seconds) and so in the body is produced locally to its site of action (i.e. in endothelial cells surrounding the vascular smooth muscle, in nerve cells). In the late 1970s, Dr. Robert Furchgott observed that acetylcholine released a substance that produced vascular relaxation, but only when the endothelium was intact. This observation opened this field of research and eventually led to his receiving a Nobel prize. Initially, Furchgott called this substance endothelium-derived relaxing factor (EDRF), but by the mid-1980s he and others identified this substance as being NO.

Nitric oxide is produced from metabolism of endogenous substances like L-arginine, catalyzed by one of three isoforms of nitric oxide synthase (for link to a good article see here) or release from exogenous compounds like drugs used to treat angina pectoris like amyl nitrate or drugs used for hypertension such as sodium nitroprusside.

The following articles are a great reference to the chemistry, and physiological and pathological Roles of Nitric Oxide:

46. The Molecular Biology of Renal Disorders: Nitric Oxide – Part III

Curator and Author: Larry H Bernstein, MD, FACP

https://pharmaceuticalintelligence.com/2012/11/26/the-molecular-biology-of-renal-disorders/

47. Nitric Oxide Function in Coagulation – Part II

Curator and Author: Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2012/11/26/nitric-oxide-function-in-coagulation/

48. Nitric Oxide, Platelets, Endothelium and Hemostasis

Curator and Author: Larry H Bernstein, MD, FACP

https://pharmaceuticalintelligence.com/2012/11/08/nitric-oxide-platelets-endothelium-and-hemostasis/

49. Interaction of Nitric Oxide and Prostacyclin in Vascular Endothelium

Curator and Author: Larry H Bernstein, MD, FACP

https://pharmaceuticalintelligence.com/2012/09/14/interaction-of-nitric-oxide-and-prostacyclin-in-vascular-endothelium/

50. Nitric Oxide and Immune Responses: Part 1

Curator and Author:  Aviral Vatsa PhD, MBBS

https://pharmaceuticalintelligence.com/2012/10/18/nitric-oxide-and-immune-responses-part-1/

51. Nitric Oxide and Immune Responses: Part 2

Curator and Author:  Aviral Vatsa PhD, MBBS

https://pharmaceuticalintelligence.com/2012/10/28/nitric-oxide-and-immune-responses-part-2/

56. Nitric Oxide and iNOS have Key Roles in Kidney Diseases – Part II

Curator and Author: Larry H Bernstein, MD, FACP

https://pharmaceuticalintelligence.com/2012/11/26/nitric-oxide-and-inos-have-key-roles-in-kidney-diseases/

57. New Insights on Nitric Oxide donors – Part IV

Curator and Author: Larry H Bernstein, MD, FACP

https://pharmaceuticalintelligence.com/2012/11/26/new-insights-on-no-donors/

59. Nitric Oxide has a ubiquitous role in the regulation of glycolysis -with a concomitant influence on mitochondrial function

Curator and Author: Larry H Bernstein, MD, FACP

https://pharmaceuticalintelligence.com/2012/09/16/nitric-oxide-has-a-ubiquitous-role-in-the-regulation-of-glycolysis-with-         a-concomitant-influence-on-mitochondrial-function/

Biochemistry of the Coagulation Cascade and Platelet Aggregation: Nitric Oxide: Platelets, Circulatory Disorders, and Coagulation Effects

Nitric Oxide Function in Coagulation – Part II

Nitric oxide is implicated in many pathologic processes as well.  Nitric oxide post translational modifications have been attributed to nitric oxide’s role in pathology however, although the general mechanism by which nitric oxide exerts its physiological effects is by stimulation of soluble guanylate cyclase to produce cGMP, these post translational modifications can act as a cellular signal as well.  For more information of NO pathologic effects and how NO induced post translational modifications can act as a cellular signal see the following:

Nitric Oxide Covalent Modifications: A Putative Therapeutic Target?

58. Crucial role of Nitric Oxide in Cancer

Curator and Author: Ritu Saxena, Ph.D.

https://pharmaceuticalintelligence.com/2012/10/16/crucial-role-of-nitric-oxide-in-cancer/

Note:  A more comprehensive ebook on Nitric Oxide and Disease Perspectives is found at

Cardiovascular Diseases, Volume One: Perspectives on Nitric Oxide in Disease Mechanisms

available on Kindle Store @ Amazon.com

http://www.amazon.com/dp/B00DINFFYC

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Hypertriglyceridemia: Evaluation and Treatment Guideline

Reporter and Curator: Dr. Sudipta Saha, Ph.D.

 

Severe and very severe hypertriglyceridemia increase the risk for pancreatitis, whereas mild or moderate hypertriglyceridemia may be a risk factor for cardiovascular disease. Individuals found to have any elevation of fasting triglycerides should be evaluated for secondary causes of hyperlipidemia including endocrine conditions and medications. Patients with primary hypertriglyceridemia must be assessed for other cardiovascular risk factors, such as central obesity, hypertension, abnormalities of glucose metabolism, and liver dysfunction. The aim of this study was to develop clinical practice guidelines on hypertriglyceridemia.

The diagnosis of hypertriglyceridemia should be based on fasting levels, that mild and moderate hypertriglyceridemia (triglycerides of 150–999 mg/dl) be diagnosed to aid in the evaluation of cardiovascular risk, and that severe and very severe hypertriglyceridemia (triglycerides of >1000 mg/dl) be considered a risk for pancreatitis. The patients with hypertriglyceridemia must be evaluated for secondary causes of hyperlipidemia and that subjects with primary hypertriglyceridemia be evaluated for family history of dyslipidemia and cardiovascular disease.

The treatment goal in patients with moderate hypertriglyceridemia should be a non-high-density lipoprotein cholesterol level in agreement with National Cholesterol Education Program Adult Treatment Panel guidelines. The initial treatment should be lifestyle therapy; a combination of diet modification, physical activity and drug therapy may also be considered. In patients with severe or very severe hypertriglyceridemia, a fibrate can be used as a first-line agent for reduction of triglycerides in patients at risk for triglyceride-induced pancreatitis.

Three drug classes (fibrates, niacin, n-3 fatty acids) alone or in combination with statins may be considered as treatment options in patients with moderate to severe triglyceride levels. Statins are not be used as monotherapy for severe or very severe hypertriglyceridemia. However, statins may be useful for the treatment of moderate hypertriglyceridemia when indicated to modify cardiovascular risk.

 

References:

 

https://www.medpagetoday.com/clinical-connection/cardio-endo/77242?xid=NL_CardioEndoConnection_2019-01-21

https://www.ncbi.nlm.nih.gov/pubmed/19307519

https://www.ncbi.nlm.nih.gov/pubmed/23009776

https://www.ncbi.nlm.nih.gov/pubmed/6827992

https://www.ncbi.nlm.nih.gov/pubmed/22463676

https://www.ncbi.nlm.nih.gov/pubmed/17635890

 

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Curation of selected topics and articles on Role of G-Protein Coupled Receptors in Chronic Disease as supplemental information for #TUBiol3373

Curator: Stephen J. Williams, PhD 

Below is a series of posts and articles related to the role of G protein coupled receptors (GPCR) in various chronic diseases.  This is only a cursory collection and by no means represents the complete extensive literature on pathogenesis related to G protein function or alteration thereof.  However it is important to note that, although we think of G protein signaling as rather short lived, quick, their chronic activation may lead to progression of various disease. As to whether disease onset, via GPCR, is a result of sustained signal, loss of desensitization mechanisms, or alterations of transduction systems is an area to be investigated.

From:

Molecular Pathogenesis of Progressive Lung Diseases

Author: Larry H. Bernstein, MD, FCAP

 

Chronic Obstructive Lung Disease (COPD)

Inflammatory and infectious factors are present in diseased airways that interact with G-protein coupled receptors (GPCRs), such as purinergic receptors and bradykinin (BK) receptors, to stimulate phospholipase C [PLC]. This is followed by the activation of inositol 1,4,5-trisphosphate (IP3)-dependent activation of IP3 channel receptors in the ER, which results in channel opening and release of stored Ca2+ into the cytoplasm. When ER Ca2+ stores are depleted a pathway for Ca2+ influx across the plasma membrane is activated. This has been referred to as “capacitative Ca2+ entry”, and “store-operated calcium entry” (3). In the next step PLC mediated Ca2+ i is mobilized as a result of GPCR activation by inflammatory mediators, which triggers cytokine production by Ca2+ i-dependent activation of the transcription factor nuclear factor kB (NF-kB) in airway epithelia.

 

 

 

In Alzheimer’s Disease

Important Lead in Alzheimer’s Disease Model

Larry H. Bernstein, MD, FCAP, Curator discusses findings from a research team at University of California at San Diego (UCSD) which the neuropeptide hormone corticotropin-releasing factor (CRF) as having an important role in the etiology of Alzheimer’s Disease (AD). CRF activates the CRF receptor (a G stimulatory receptor).  It was found inhibition of the CRF receptor prevented cognitive impairment in a mouse model of AD.  Furthermore researchers at the Flanders Interuniversity Institute for Biotechnology found the loss of a protein called G protein-coupled receptor 3 (GPR3) may lower the amyloid plaque aggregation, resulting in improved cognitive function.  Additionally inhibition of several G-protein coupled receptors alter amyloid precursor processing, providing a further mechanism of the role of GPCR in AD (see references in The role of G protein-coupled receptors in the pathology of Alzheimer’s disease by Amantha Thathiah and Bart De Strooper Nature Reviews Feb 2011; 12: 73-87 and read post).

 

In Cardiovascular and Thrombotic Disease

 

Adenosine Receptor Agonist Increases Plasma Homocysteine

 

and read related articles in curation on effects of hormones on the cardiovascular system at

Action of Hormones on the Circulation

 

In Cancer

A Curated History of the Science Behind the Ovarian Cancer β-Blocker Trial

 

Further curations and references of G proteins and chronic disease can be found at the Open Access journal https://pharmaceuticalintelligence.com using the search terms “GCPR” and “disease” in the Search box in the upper right of the home page.

 

 

 

 

 

 

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Inferior Vena Cava Filters: Device for Prevention of Pulmonary Embolism and Thrombosis

Reporter: Aviva Lev-Ari, PhD, RN

 

UPDATED on 7/18/2018

 

Original Investigation
Cardiology
July 13, 2018

Association of Inferior Vena Cava Filter Placement for Venous Thromboembolic Disease and a Contraindication to Anticoagulation With 30-Day Mortality

JAMA Network Open. 2018;1(3):e180452. doi:10.1001/jamanetworkopen.2018.0452
Key Points

Question  What is the association of inferior vena cava filter placement with 30-day mortality in patients with venous thromboembolic disease and a contraindication to anticoagulation?

Findings  In this cohort study, using 2 different statistical methods with adjustment for immortal time bias, inferior vena cava filter placement in patients with venous thromboembolic disease and a contraindication to anticoagulation was associated with an increased risk of 30-day mortality.

Meaning  Randomized clinical trials are needed to define the role of inferior vena cava filter placement in patients with venous thromboembolic disease and a contraindication to anticoagulation.

 

Abstract

Importance  Despite the absence of data from randomized clinical trials, professional societies recommend inferior vena cava (IVC) filters for patients with venous thromboembolic disease (VTE) and a contraindication to anticoagulation therapy. Prior observational studies of IVC filters have suggested a mortality benefit associated with IVC filter insertion but have often failed to adjust for immortal time bias, which is the time before IVC filter insertion, during which death can only occur in the control group.

Objective  To determine the association of IVC filter placement with 30-day mortality after adjustment for immortal time bias.

Design, Setting, and Participants  This comparative effectiveness, retrospective cohort study used a population-based sample of hospitalized patients with VTE and a contraindication to anticoagulation using the State Inpatient Database and the State Emergency Department Database, part of the Healthcare Cost and Utilization Project of the Agency for Healthcare Research and Quality, from hospitals in California (January 1, 2005, to December 31, 2011), Florida (January 1, 2005, to December 31, 2013), and New York (January 1, 2005, to December 31, 2012). Data analysis was conducted from September 15, 2015, to March 14, 2018.

Exposure  Inferior vena cava filter placement.

Main Outcomes and Measures  Multivariable Cox proportional hazard models were constructed with IVC filters as a time-dependent variable that adjusts for immortal time bias. The Cox model was further adjusted using the propensity score as an adjustment variable.

Results  Of 126 030 patients with VTE, 61 281 (48.6%) were male and the mean (SD) age was 66.9 (16.6) years. In this cohort, 45 771 (36.3%) were treated with an IVC filter, whereas 80 259 (63.7%) did not receive a filter. In the Cox model with IVC filter status analyzed as a time-dependent variable to account for immortal time bias, IVC filter placement was associated with a significantly increased hazard ratio of 30-day mortality (1.18; 95% CI, 1.13-1.22; P < .001). When the propensity score was included in the Cox model, IVC filter placement remained associated with an increased hazard ratio of 30-day mortality (1.18; 95% CI, 1.13-1.22; P < .001).

Conclusions and Relevance  After adjustment for immortal time bias, IVC filter placement was associated with increased 30-day mortality in patients with VTE and a contraindication to anticoagulation. Randomized clinical trials are needed to determine the efficacy of IVC filter placement in patients with VTE and a contraindication to anticoagulation.

 

Requiem for Liberalizing Indications for Vena Caval Filters?

Samuel Z. Goldhaber

Guidelines

However, it is premature to hammer nails into the coffin and to gather as a medical community for a requiem that celebrates no indication for liberalizing indications for placing an IVC filter. Instead, we need to shift the focus of the questions that we investigate and pour resources into further randomized and observational trials of IVC filter insertion in special highrisk populations.

There remain important groups of patients who may benefit from IVC filters with reduction in PE and PE-associated mortality (Table 2). In some cases, tantalizing data suggest that these populations warrant filters. In other cases, we lack data to guide us. Patients with massive PE—accompanied by cardiogenic shock requiring vasopressors to support blood pressure—are desperately ill. They are clinically unstable. An additional PE under these circumstances can be the fatal blow. Data from the National Inpatient Sample and the International Cooperative PE Registry suggest that filters in these patients may be lifesaving.

Patients with severe PE who undergo acute surgical pulmonary embolectomy are vulnerable to recurrent PE, especially during the early postoperative period where full anticoagulation cannot be immediately implemented. I have had personal experience managing this type of patient where the embolectomy is successful but the patient dies of recurrent PE.19

Table 1. Generally Accepted Consensus Recommendations for IVC Filter Insertion in Patients With VTE

  • Major bleeding on full-dose anticoagulation
  • Major contraindication to full-dose anticoagulation
  • New-onset acute PE (especially recurrent PE) despite well-documented fulldose anticoagulation for an existing VTE

IVC indicates inferior vena caval; PE, pulmonary embolism; and VTE, venous thromboembolism.

 

Table 2. Special Populations Where Benefits of IVC Filter Insertion May Outweigh Risks

  • Massive PE or high-risk submassive PE
  • Surgical pulmonary embolectomy
  • Cancer patients with VTE or at high risk of VTE with concomitant high risk of bleeding if anticoagulated
  • Surgical patients (especially during preoperative evaluation) at high risk of VTE with concomitant high risk of bleeding if anticoagulated

IVC indicates inferior vena caval; PE, pulmonary embolism; and VTE, venous thromboembolism.

http://dx.doi.org/10.1161/CIRCULATIONAHA.116.022730

References

1. Stein PD, Matta F, Hull RD. Increasing use of vena cava filters for prevention of pulmonary embolism. Am J Med. 2011;124:655–661. doi:10.1016/j.amjmed.2011.02.021.

2. Jia Z, Wu A, Tam M, Spain J, McKinney JM, Wang W. Caval penetration by inferior vena cava filters: a systematic literature review of clinical significance and management. Circulation. 2015;132:944–952. doi: 10.1161/ CIRCULATIONAHA.115.016468

3. Owens CA, Bui JT, Knuttinen MG, Gaba RC, Carrillo TC, Hoefling N, Layden-Almer JE. Intracardiac migration of inferior vena cava filters: review of published data. Chest. 2009;136:877–887. doi: 10.1378/ chest.09-0153.

4. Nicholson W, Nicholson WJ, Tolerico P, Taylor B, Solomon S, Schryver T, McCullum K, Goldberg H, Mills J, Schuler B, Shears L, Siddoway L, Agarwal N, Tuohy C. Prevalence of fracture and fragment embolization of Bard retrievable vena cava filters and clinical implications including cardiac perforation and tamponade. Arch Intern Med. 2010;170:1827–1831. doi: 10.1001/archinternmed.2010.316.

5. Angel LF, Tapson V, Galgon RE, Restrepo MI, Kaufman J. Systematic review of the use of retrievable inferior vena cava filters. J Vasc Interv Radiol. 2011;22:1522–1530.e3. doi: 10.1016/j.jvir.2011.08.024.

19. Aklog L, Williams CS, Byrne JG, Goldhaber SZ. Acute pulmonary embolectomy: a contemporary approach. Circulation. 2002;105:1416–1419.

Other related articles published in this Open Access Online Scientific Journal include the follwoing:

 

Xarelto (Rivaroxaban): Anticoagulant Therapy gains FDA New Indications and Risk Reduction for: (DVT) and (PE), while in use for Atrial fibrillation increase in Gastrointestinal (GI) Bleeding Reported

https://pharmaceuticalintelligence.com/2012/11/04/xarelto-rivaroxaban-anticoagulant-therapy-gains-fda-new-indications-and-risk-reduction-for-dvt-and-pe-while-in-use-for-atrial-fibrillation-increase-in-gastrointestinal-gi-bleeding-reported/

Venous Thromboembolism (VTE): Blood Clots in Leg and Lungs – No. 3 Cardiovascular Killer Globally – Is Leading Cause of Premature Death and Disability in Hospitals

https://pharmaceuticalintelligence.com/2014/10/13/venous-thromboembolism-vte-blood-clots-in-leg-and-lungs-no-3-cardiovascular-killer-globally-is-leading-cause-of-premature-death-and-disability-in-hospitals/

The Relation between Coagulation and Cancer affects Supportive Treatments

https://pharmaceuticalintelligence.com/2015/10/19/the-relation-between-coagulation-and-cancer-affects-supportive-treatments/

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Cleveland Clinic research finds that chronic kidney disease is widely prevalent in patients with pulmonary hypertension, and that lower levels of kidney function are associated with an increased risk of death.

Sourced through Scoop.it from: consultqd.clevelandclinic.org

See on Scoop.itCardiovascular Disease: PHARMACO-THERAPY

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https://www.youtube.com/v/SFbCh2wYSxQ?fs=1&hl=fr_FR

In this video from the ATRIUM Cardiology Collaborative, Brent Reed provides an overview of the pathophysiology of pulmonary arterial hypertension.

Sourced through Scoop.it from: www.youtube.com

See on Scoop.itCardiovascular Disease: PHARMACO-THERAPY

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