EPO, re-introducing confusion

Posted on 4 July 2013 by Keith Barrington

I thought that routine erythropoietin (EPO) treatment of preterm infants had been thrown out of the window. It is well known that EPO levels are low in preterms after birth, which is part of the multifactorial pathophysiology of anaemia of prematurity. Previous studies, and systematic review have shown that you can reduce the volume of blood transfused, if you routinely supplement with EPO, but have no significant effect on other clinical outcomes, or on donor exposure. There is some indication, from the Cochrane review, that retinopathy, and severe retinopathy is increased by early use of routine EPO, when it is started in the first week of life. After the first week of life there is no apparent effect on RoP. Direct comparisons of early versus late EPO have been performed which also seem to show more RoP with early treatment and no substantial benefit.

This is one issue that the neonatal community have investigated rather well, I thought. The RCTs include about 5000 preterm babies, many of them are high quality, and we have focused on clinically important outcomes. Done and dusted.

Or maybe not.

Ohls RK, Christensen RD, Kamath-Rayne BD, Rosenberg A, Wiedmeier SE, Roohi M, Lacy CB, Lambert DK, Burnett JJ, Pruckler B et al: A Randomized, Masked, Placebo-Controlled Study of Darbepoetin Alfa in Preterm Infants. Pediatrics 2013, 132(1):e119-e127. Darbepoetin is a long acting EPO analogue. In this rather small trial, 102 infants of 500 to 1250 g birth weight were randomized into 3 different groups. Darbepoetin weekly, EPO 3 times a week or sham treatment. The infants receiving either EPO or Darbepoetin had fewer transfusions and were exposed to fewer donors (mean 0.7 or 0.8 versus 1.2, of course the means aren’t very meaningful, the median in the sham group was 1, interquartile range 0 to 2). There were no apparent differences in RoP, but I don’t quite understand the numbers, there appear to be more babies in the various subcategories of RoP than the total number in each group (example: 32 babies were treated with darbepoietin : 22 did not develop RoP, 10 with ≤ stage 2, and 2 > stage 2 who required intervention, which makes 34).  That is a minor point, much more importantly the study is grossly underpowered for RoP outcomes. The authors quite rightly point this out themselves, and note that further (and I would emphasize, much larger) studies are required. 

One could question what is the clinical importance of reducing donor exposure? Current rates of viral infection from transfusion are tiny, is avoiding transfusion altogether or reducing the total number of donors all that important?

More interesting are the possible neuroprotective effects of EPO (also apparently shared by Darbepoetin). The babies in this study were eligible up to 48 hours of age if they had not been transfused, and actually received the first dose at a mean of 51 hours. For brain protection that is probably a little too late.

The blood transfusion practices in this study were quite restrictive, but there were a lot of transfusion protocol violations (0.8 transfusions out of protocol per patient in the Darbepoetin group, compared to 1.2 total transfusions per patient, so 2/3 of the transfusions were outside of protocol). What should be the appropriate thresholds for transfusion requires further study. Maybe the transfusion threshold studies should come before we do further studies of darbepoetin, so we would know what the baseline should be.

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HIE: what’s next?

Posted on 28 June 2013 by Keith Barrington

Kapadia VS, Chalak LF, Dupont TL, Rollins NK, Brion LP, Wyckoff MH: Perinatal Asphyxia with Hyperoxemia within the First Hour of Life Is Associated with Moderate to Severe Hypoxic-Ischemic Encephalopathy. The Journal of pediatrics 2013.

If you are acidotic at birth, and then you become hyperoxic, it seems that you are more likely to have more severe encephalopathy than if hyperoxia is avoided. This is the kind of thing that you can only ever find from observational studies. No-one would suggest a prospective RCT; even though this kind of study is often criticized, this is a perfect example of why such things should, at least sometimes, be published.

Tagin M, Shah PS, Lee KS: Magnesium for newborns with hypoxic-ischemic encephalopathy: a systematic review and meta-analysis. J Perinatol 2013.

If you develop HIE, does magnesium supplementation help? This systematic review suggests that maybe it does, but maybe it increases mortality; the numbers of babies really tested for this are tiny, so we can have almost no confidence in any statement about either benefit or risk. Magnesium therapy has also never been tested since we started cooling babies, so there is room for another study. This is something that could be tested in low resource countries, whereas xenon, which is much more sexy, will never be tried in those places.

Walsh BH, Boylan GB, Dempsey EM, Murray DM: Association of nucleated red blood cells and severity of encephalopathy in normothermic and hypothermic infants. Acta Paediatrica 2013, 102(2):e64-e67.

One of the ‘biomarkers’ of the severity of asphyxia is the count of nucleated RBCs. The more severely asphyxiated you are the more your bone marrow (in general terms) will be stimulated to release red cells which are are not yet mature. This article from the brain research group in Cork, Ireland shows that this ‘biomarker’ of the severity of brain injury is no longer reliable in infants treated with therapeutic hypothermia. It points out what I think should be a general rule, biomarkers may be unreliable if therapies change.

I understand the desire to find ‘biomarkers’ (what we used to call surrogate outcomes) we have to find ways to make clinical research easier and cheaper and produce results without waiting for years of follow up, but we have to be extremely careful before basing changes in clinical management on a demonstrated change in ‘biomarkers’ without proof that real clinically important outcomes are affected. Even when we think that a specific surrogate outcome is reliable, then it has often been demonstrated that things which improve the surrogate don’t necessarily improve the real, clinically important outcomes. We have been down this path before (we just didn’t call them ‘biomarkers’ before). Hypertension, for example, is reliably decreased by beta-blockers, but they have no effect on other clinically important outcomes, such as stroke.

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Intensive care for the extremely preterm infant requires intensive care, and working with Obstetricians

Posted on 23 June 2013 by Keith Barrington

Alleman BW, Bell EF, Li L, Dagle JM, Smith PB, Ambalavanan N, et al. Individual and Center-Level Factors Affecting Mortality Among Extremely Low Birth Weight Infants. Pediatrics. 2013. This paper from the NICHD network shows substantial variation in survival between network hospitals for babies weighing under 1 kg. Let’s focus on the group with the highest mortality, below 25 weeks gestation. The authors examined differences in the risk characteristics of the babies and found that there were some differences, but when correcting for these risk factors there remained major differences between hospitals. They then examined how actively the hospitals intervened for each infant. They created an intervention score which included 11 different interventions that might be needed in the first day of life, and another 4 which are usually used later on.

If we first look at individual components of that score we can see enormous variation in their use between hospitals. Tracheal intubation for example was used for between 24% and 94% of the extremely preterm infants. 10% to 63% of them were delivered by cesarean. The results of this study show that the infants who had more interventions had lower early mortality (in the first 12 hours of life) and lower overall mortality prior to discharge. It seems that the willingness to provide interventions around birth, and to provide intensive care after birth leads to more babies surviving. The intervention score is one way of looking at this of course, but the problem with the score is that some items are ways to improve survival (antenatal steroids, NICU admission) and some are responses to serious illness, such as high frequency ventilation. Which is like putting apples and oranges into an overall fruit score. Nevertheless it does show that if you want to provide intensive care to extremely preterm infants with the best chance of success, you should be prepared to do intensive care.

Ruth Guinsberg has done a lot of great work in Brazil, in this new study she and the Brazilian Neonatal Network published the results of first day survival of 23 to 26 week gestation infants.  (Guinsburg R, de Almeida MFB, Sadeck LDR, Marba STM, Rugolo LMSD, Luz JH, et al. Proactive management of extreme prematurity: disagreement between obstetricians and neonatologists. Journal of Perinatology. 2012;32(12):913-9)  They examined whether the infants had at least one dose of steroids at some point prior to delivery or whether they were delivered by cesarean. If either were present it was considered active obstetric intervention. Then then looked at whether there was active intervention after delivery. They found that babies who were actively treated in the NICU despite not having active obstetric intervention had 3 times higher mortality than when both obstetrics and neonatology provided active care. This study has some of the limitations of all data base studies, you don’t know why certain interventions were given in an individual case, and the characteristics of the cases were different at baseline, but it is suggestive, and makes a lot of common sense. If you are prepared to give intensive care to extremely preterm babies, then the obstetrics team needs to be on-side, and a joint approach is required, with decisions made by the parents with both teams of caregivers.

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ECMO: not dead yet

Posted on 20 June 2013 by Keith Barrington

There is a sort of a quadruple entendre in the title of this post: ECMO still exists; ECMO is needed if you are ‘not yet dead’ and have a chance of surviving; ECMO decreases mortality if you need it; but, unfortunately, using ECMO may sometimes just delay death. I haven’t written about ECMO before on this blog, even though I have been very involved at certain times in my past, the frequency of needing ECMO for neonatal respiratory disease has become vanishingly rare in my practice (I haven’t referred a meconium aspiration for ECMO in 5 years). ECMO for diaphragmatic hernias and for postoperative cardiogenic shock, however, is still sometimes life-saving. I have put together a number of very recent publications.

Tabbutt S, Ghanayem N, Ravishankar C, Sleeper LA, Cooper DS, Frank DU, et al. Risk factors for hospital morbidity and mortality after the Norwood procedure: A report from the Pediatric Heart Network Single Ventricle Reconstruction trial. J Thorac Cardiovasc Surg. 2012;144(4):882-95. Not surprisingly, if you need ECMO after a Norwood, then you are more likely to die. Of those in this large multicenter cohort of infants with hypoplastic left heart syndrome (n=nearly 600) who had post-op ECMO the transplant free survival at 12 months was only 26% compared to 75% if you didn’t need ECMO (and didn’t get CPR either). Still 26% compared to zer0… I guess it depends on your viewpoint, and your resources.

Another study in a similar vein (or should I say with a similar heart) is an analysis of ELSO registry data of over 700 babies who had a Norwood and then needed ECMO. The survival overall (to hospital discharge) was 31%. Sherwin ED, Gauvreau K, Scheurer MA, Rycus PT, Salvin JW, Almodovar MC, et al. Extracorporeal membrane oxygenation after stage 1 palliation for hypoplastic left heart syndrome. The Journal of Thoracic and Cardiovascular Surgery. 2012;144(6):1337-43. The authors note that complications of ECMO are a bad risk factor. The median duration of ECMO among survivors was very close to 72 hours. They show that there was an increased duration of ECMO among non-survivors, and that the Odds Ratio for mortality for every additional day of ECMO is 1.2. Useful information for counselling parents. They also note that there were 28 babies who went back on ECMO for a second time, after the first decannulation, only 1 survived. Probably if you re-satisfy criteria to go back on ECMO, unless there is a surgically correctable reason, you should not offer a second course of ECMO.

But what if you have congenital heart disease and a diaphragmatic hernia? Is ECMO a reasonable option? Dyamenahalli U, Morris M, Rycus P, Bhutta AT, Tweddell JS, Prodhan P. Short-Term Outcome of Neonates With Congenital Heart Disease and Diaphragmatic Hernia Treated With Extracorporeal Membrane Oxygenation. The Annals of Thoracic Surgery. 2013;95(4):1373-6 This report from the ELSO registry has surprisingly good outcomes, and some surprises in the results. For infants with a diaphragmatic hernia who needed ECMO, survival to hospital discharge for those who also had hypoplastic left heart syndrome and single-ventricle physiology was 55% (33 of 60), 48% (43 of 89) for ventricular septal defect, and 40% (24 of 60) for coarctation of the aorta patients. Which is  a little weird, infants who had the most severe heart disease had better survival than those with less severe heart disease. I can think of a couple of possible reasons for this. But if you need ECMO for your diaphragmatic hernia (CDH) a VSD is probably not very relevant; it just means that you have a really bad CDH. Whereas if you have a hypoplastic left heart, it is much easier to satisfy ECMO criteria, so you might have less pulmonary hypoplasia, and a better prognosis for short term survival. How you might do after the second stage of the hypoplastic left heart repair is not clear.

Madderom MJ, Toussaint L, van der Cammen-van Zijp MHM, Gischler SJ, Wijnen RMH, Tibboel D, et al. Congenital diaphragmatic hernia with(out) ECMO: impaired development at 8 years. Archives of Disease in Childhood – Fetal and Neonatal Edition. 2012. This study was a very complete evaluation of 8 year old survivors of CDH repair. The children who needed ECMO in the neonatal period had lower IQ scores than those who survived without. Dutch children are obviously very intelligent, the CDH children who did not need ECMO had a mean IQ of 112. It must be all that cheese or more likely the raw herring ‘Hollandse nieuwe haring’, yum yum. Or maybe living below sea level with their higher PaO2 helps brain development, it certainly makes them tall. The CDH children who had needed ECMO didn’t do quite as well (mean IQ 91) and both groups had troubles with concentration, but overall their quality of life was really good.

If we look at the ELSO registry data for acute neurologic complications (Polito A, Barrett CS, Wypij D, Rycus PT, Netto R, Cogo PE, et al. Neurologic complications in neonates supported with extracorporeal membrane oxygenation. An analysis of ELSO registry data. Intensive care medicine. 2013:1-8) we find that they are common, occurring in about 20% of supported infants, and associated with increased mortality. As always in database information, we don’t know if that might be because the medical care changed as a result of the complication. Is the increased mortality because care was redirected after a complication?…

Madderom MJ, Reuser JJ, Utens EM, van Rosmalen J, Raets M, Govaert P, et al. Neurodevelopmental, educational and behavioral outcome at 8 years after neonatal ECMO: a nationwide multicenter study. Intensive care medicine. 2013:1-10.     135 Dutch babies required ECMO in a 5 year period. Eight years later the survivors are doing really well.   The mean IQ is 100 ( I know for a Dutch child that is probably rather low, but it still sounds quite good for the rest of the world). They did have some problems, with some attention difficulties, and a few more having learning disability that will probably require specific educational attention. But these outcomes are very encouraging, and in addition, they aren’t dead yet!

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Speech is developing even before the speech centers appear

Posted on 18 June 2013 by Keith Barrington

Someone who is more expert in this field than me could probably take apart that title, but the message of this article is that, even at 29 weeks gestation, , the preterm brain reacts differently to different phonemes (ba versus ga) and different voices (masculine versus feminine). That’s cool. Because at 29 weeks the neurons which will eventually form the centers involved in speech are still not at their final locations. The brain is still very immature at that point, and those parts of the brain that we usually expect to respond to speech have not been properly constituted. Language really is hard-wired into our brains.

Mahmoudzadeh M, Dehaene-Lambertz G, Fournier M, Kongolo G, Goudjil S, Dubois J, et al. Syllabic discrimination in premature human infants prior to complete formation of cortical layers. Proceedings of the National Academy of Sciences. 2013;110(12):4846-51.

If you take those preterm babies when they are adults, they seem to be processing language with different parts of the brain. Although their scores on standardized testing of language skills were the same as controls born at term, the preterm born adults were using pathways in their cerebellum to process language, but not the term born adults. Constable RT, Vohr BR, Scheinost D, Benjamin JR, Fulbright RK, Lacadie C, et al. A left cerebellar pathway mediates language in prematurely-born young adults. NeuroImage. 2013;64(0):371-8. This seems to me to be new evidence of the plasticity of the brain, which develops differently if you are born very preterm, the average gestation of the subjects was 28 weeks.

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We can stop routine suctioning at birth!

Posted on 17 June 2013 by Keith Barrington

I never understood why it was thought to be so important, (indeed by some essential) to stick some sort of suctioning device into the babies mouth, usually right back to the posterior pharyngeal wall, and suck out amniotic fluid. It was as if we thought that despite many millions of years of evolution, human beings were not capable of surviving unless someone sucked out their upper airways after birth. Most mammals do not have access to suction devices at birth, yet surprisingly most of them survive regardless. Fortunately Wally Carlo’s team (does he ever sleep?) have just shown that babies who only have their face wiped (which I guess is analogous to the facial licking that a lot of mammals do) have a clinical outcome that is just as good as babies who get induced vagal stimulation oropharyngeal suctioning by caregivers. We already know that routine suctioning increases bradycardia, now we know that it doesn’t have any routine advantages. Let’s stop. Kelleher J, Bhat R, Salas AA, Addis D, Mills EC, Mallick H, et al. Oronasopharyngeal suction versus wiping of the mouth and nose at birth: a randomised equivalency trial. The Lancet. 2013(0). Of note the current recommendations from several bodies have already abandoned routine suctioning in infants born at term with clear amniotic fluid, but that recommendation was based on very little data, this new trial gives a lot more force to that recommendation. I think we can move from not recommending routine suctioning, to recommending against it.

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Neonatal Updates #35

Posted on 15 June 2013 by Keith Barrington

Huang SS, Septimus E, Kleinman K, Moody J, Hickok J, Avery TR, et al. Targeted versus Universal Decolonization to Prevent ICU Infection. New England Journal of Medicine. 2013;368(24):2255-65. A cluster randomized study in adults in intensive care. There were 3 groups. 1. Screening for MRSA and isolation of positive patients (which was the standard of care before the study). 2. Screening for MRSA and treatment of positive adults with intra-nasal mupirocin and cleaning them with chlorhexidine wipes, for a 5-day period. 3. No screening, just treating all admitted adults with mupirocin for 5 days and chlorhexidine wipes for the entire ICU stay. The primary outcome was MRSA positive cultures (which I think includes for example positive nasal cultures after the first screening culture), and secondary outcomes included all serious nosocomial infections, MRSA bacteremia and bacteremia from all organisms. Universal treatment and body washes reduced serious nosocomial infections much more than the other approaches, both MRSA septicemia and all cause septicemia, by about 44%. It is starting to look like these chlorhexidine impregnated washcloths really work to reduce serious nosocomial infections. We need more studies to see  in which babies it would be safe to do this (by examining absorption and toxicity in preterm and very preterm infants), and we need to restrict their use to the ICUs, to avoid the evolution of resistance, which will surely, eventually, happen if they are too widely used (in domestic animals for example!)

Bertini G, Elia S, Ceciarini F, Dani C. Reduction of catheter-related bloodstream infections in preterm infants by the use of catheters with the AgION antimicrobial system. Early Human Development. 2013;89(1):21-5. Another RCT for infection control, this time in newborn infants, 86 of whom were randomized to get an umbilical venous catheter that was impregnated with an antiseptic silver compound, or control. There was a substantial, and significant reduction in infection related to the catheter with the silver impregnated catheter, but the control rate was extraordinarily high, 22% of the control group had a catheter related infection, during a mean catheter duration of about 8 days. This will need to be tested in NICUs with much lower UVC infection rates, and we really need to be sure that the exposure to silver zeolite is safe.

Boss RD, Kinsman HI, Donohue PK. Health-related quality of life for infants in the neonatal intensive care unit. J Perinatol. 2012;32(12):901-6. This interesting piece is a review of publications of quality of life, the main thrust of the article is that we have no data about quality of life of babies while they are still in the NICU.  They refer to the article that Antoine Payot and I wrote about quality of life of former preterm infants (and infants with other chronic conditions) throughout life, and make a plea to establish quality of life scales for babies while they are still in the NICU. I found that an interesting idea that I had not really considered, we have ways of measuring pain, and several other scores which are peripherally related to QoL, but no agreed method for analyzing QoL during our NICU treatment, which may last months, and, unfortunately, for some babies is the only life they ever know.

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Hyperinsulinemic babies don’t neccesarily have high insulin??

Posted on 14 June 2013 by Keith Barrington

It has been known for some time that some SGA babies with hypoglycemia are hyperinsulinemic. As many as 20% of some small series have shown this phenomenon, they can be suspected because of the high glucose requirements, and confirmed, I thought, but measuring insulin concentrations during a hypoglycemia. I now find out that sometimes babies who have hyperinsulinemic hypoglycemia aren’t all hyperinsulinemic when they are hypoglycemic. (try saying that quickly after a glass of wine).

I have seen this in practice, a baby who needs a lot of sugar, is probably hyperinsulinemic but has low or undetectable insulin when hypoglycemic, I didn’t know previously how to interpret it, but it seems that it is not uncommon. I guess the insulin level is too high when the sugar is normal, but when they get hypoglycemic they are able to suppress insulin production to below the sensitivity of the lab tests.

In these circumstances other indications of hyperinsulinism, such as very low free fatty acids, low beta-hydroxybutyrate, or an exaggerated glucose response to glucagon can confirm the diagnosis. (Hoe FM, Thornton PS, Wanner LA, Steinkrauss L, Simmons RA, Stanley CA: Clinical features and insulin regulation in infants with a syndrome of prolonged neonatal hyperinsulinism. The Journal of pediatrics 2006, 148(2):207-212.)

This new publication (Arya VB, Flanagan SE, Kumaran A, Shield JP, Ellard S, Hussain K, Kapoor RR: Clinical and molecular characterisation of hyperinsulinaemic hypoglycaemia in infants born small-for-gestational age. Archives of Disease in Childhood – Fetal and Neonatal Edition 2013.) examined whether there were abnormalities in the genes regulating insulin secretion, genes that may be abnormal in the permanent types of hyperinsulinemic hypoglycemia. There weren’t.

In these SGA babies with the condition it is transient, although it may last some months, and the new publication lets you know that a) these babies respond well to diazoxide, and b) when you can get the diazoxide dose below 5 mg/kg/day you can safely stop it.

So we need to measure these other indicators of hyperinsulinism if a hypoglycemic baby who needs a high glucose infusion rate needs further diagnostic testing.

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Xrays may not be innocuous

Posted on 13 June 2013 by Keith Barrington

This worrying article from Australia of a matched database study shows a significant increase in cancer risk with a CT scan performed during childhood or adolescence, (Mathews JD, Forsythe AV, Brady Z, Butler MW, Goergen SK, Byrnes GB, Giles GG, Wallace AB, Anderson PR, Guiver TA et al: Cancer risk in 680 000 people exposed to computed tomography scans in childhood or adolescence: data linkage study of 11 million Australians. BMJ 2013, 346(may21 1):f2360-f2360.) The increase in incidence is about 24% over the population baseline risk, which is not huge for a relatively infrequent group of diseases, but the follow up of the population was just under 10 years on average, so it might increase as time goes on. That’s about 10 cancers per 100,000 patient years at risk, so don’t panic yet!

Premature babies have a lot of radiographs, and get exposed to a lot of radiation. Donadieu J, Zeghnoun A, Roudier C, Maccia C, Pirard P, Andre C, Adamsbaum C, Kalifa G, Legmann P, Jarreau P-H: Cumulative effective doses delivered by radiographs to preterm infants in a neonatal intensive care unit. Pediatrics 2006, 117(3):882-888. But most of them are way below what you get from a CT scan, even if you add up all the radiation during their entire stay. A few get to quite high levels however, and some of them do end up with a CT scan. Need to consider carefully each time before a CT scan if the very small increase in risk of cancer is worth the clinical information that we will get.

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When she died there was a hailstorm, it was as if the Angels cried.

Posted on 11 June 2013 by Keith Barrington

Evy Kristine (the little girl that Siri Berg, her mother, wrote about) has a website, with a page in English. The title of this post is taken from one of the two very moving poems you can find there written by her elder brother. You can also find a link to a youtube video that the family made, and to other resources.

One of those resources recounts a much more positive interaction with the medical system, showing that we can sometimes get it right. Daniel’s book recounts a prenatal diagnosis of trisomy 13, and multiple interactions with helpful compassionate people who were willing to listen to the family’s wishes, to offer a range of possible approaches, and to support them in the decisions that they made. Daniel lived just 32 hours.

It sounds as if many of them had read John Carey’s article from last year, or maybe (as that isn’t possible) they were just caring people. Dr Carey’s article ‘‘Carey JC: Perspectives on the care and management of infants with trisomy 18 and trisomy 13: Striving for balance. Current Opinion in Pediatrics 2012, 24(6):672-678” is a review of the literature, and ends with recommendations, which I quote in a shortened form from the abstract:

The author recommends a balanced approach to counseling families of the newborn with trisomy 18 and 13 at the time of diagnosis. The counseling process should include presentation of accurate survival figures, avoidance of language that assumes outcome, communication of developmental outcome that does not presuppose perception of quality of life, and respect for the family’s choice, whether it be comfort care or intervention.

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