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            "en" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Discriminative ability of the model predictive of the occurrence of ibuprofen treatment efficacy in ductus arteriosus closure &#40;area under the receiver operating characteristic curve&#61;0&#46;782&#59; 95&#37; confidence interval 0&#46;624 to 0&#46;941&#41; in preterm newborns with gestational age between 23 and 32 weeks&#46;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a></p>"
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    "titulo" => "Ductus arteriosus&#58; The coming of age of a fetal vessel"
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    "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0070" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleDisplayedQuote" id="dsq0005"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">&#8220;<span class="elsevierStyleItalic">Nature&#39;s destruction of fetal structures that are superfluous in the adult seems to me something much greater than her original creation of those structures</span>&#8221;</p></span></p><p id="par0010" class="elsevierStylePara elsevierViewall">Galen of Pergamun &#40;AD 129-200&#41;</p><p id="par0015" class="elsevierStylePara elsevierViewall">The ductus arteriosus &#40;DA&#41; is a unique&#44; dynamic vascular structure functioning as a prenatal bypass between pulmonary artery and aorta&#46; Intimal thickening together with O<span class="elsevierStyleInf">2</span>-dependent constriction functionally closes the DA during the first hours after birth&#46; While in healthy term newborns&#44; the DA&#41; presents a spontaneous functional closure of almost 100&#37; within 72 hours of life&#44;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">1</span></a> in premature neonates&#44; the closure of the PDA may occur later or not at all&#46; It is influenced by several factors&#44; including gestational age &#40;GA&#41;&#44; prenatal corticosteroid administration&#44; hyaline membrane disease&#44; mechanical ventilation&#44; fluid intake in the first week of life&#44; infection and genetic factors&#46;<a class="elsevierStyleCrossRefs" href="#bib0060"><span class="elsevierStyleSup">2&#44;3</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">Persistent ductus arteriosus &#40;PDA&#41; is&#44; therefore&#44; a frequent occurrence in preterm infants requiring intensive care&#44; with an incidence inversely proportional to GA&#44; of around 30&#37; in extremely low birth weight newborns &#40;&#8804;28 weeks&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">3</span></a> On account of the hemodynamic changes that occur after birth&#44; PDA leads to shunting of the blood from the systemic to the pulmonary circulation&#46; The clinical and hemodynamic impact depends on the magnitude of the shunt and the compensation capacity of the preterm myocardium to maintain effective systemic blood flow&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">A large shunt volume through the PDA may cause a significant increase in pulmonary blood flow&#44; congestive heart failure &#40;HF&#41; and decreased systemic blood flow&#46; Pulmonary hyperperfusion may lead to pulmonary edema and hemorrhage&#44; which usually manifest itself by the second day of life&#44; respiratory deterioration&#44; increased need for mechanical ventilation and increased risk of bronchopulmonary dysplasia &#40;BPD&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">4</span></a> The phenomenon of systemic &#8220;circulatory steal&#8221; seems to be related to acidosis and systemic hypoperfusion and&#47;or hypotension&#44; which is more evident in the first hours of life and may put several organs at risk of ischemia&#46; Indeed&#44; several D&#246;ppler and NIRS studies have shown decreased cerebral&#44; coronary&#44; abdominal aorta&#44; superior mesenteric and renal blood flow in RNPT PDAs&#44; suggesting a potential role for the PDA in the pathogenesis of inotropic-resistant hypotension&#44; intraperiventricular hemorrhage&#44; periventricular leukomalacia&#44; cerebral palsy&#44; necrotizing enterocolitis&#44; and renal dysfunction&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">The hemodynamic changes resulting from the PDA and the epidemiological association of PDAs with increased morbidity and mortality in preterm infants<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">4</span></a> have meant that for decades PDAs have been considered a pathological condition requiring active closure therapy&#46; However&#44; and despite six decades of research&#44; there is still no conclusive evidence of a causal relationship between the hemodynamic changes resulting from PDA and neonatal morbidity and mortality&#44; or of the long-term benefit of the various strategies for PDA closure&#46; It is not clear whether the morbidity and mortality associated with PDA result from the volume of ductal shunt&#44; the adverse effects of treatment or are merely consequences of prematurity&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">The management of PDA in preterm infants consists of three different methods&#58; conservative management with supportive therapy alone&#44; pharmacologic closure&#44; and surgical ligation&#46;<a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">5&#44;6</span></a> Several pharmacological strategies have been tried&#44; mainly with cyclooxygenase &#40;COX&#41; inhibitors&#44; and more recently with paracetamol&#46; COX inhibitors&#44; such as indomethacin and ibuprofen&#44; work by reducing the production of prostaglandin&#46; Although these therapeutic strategies have proved effective in closing the DA&#44; especially if started early&#44; there is no evidence of benefits from the various therapeutic strategies on long-term neonatal morbidity&#44; especially BPD&#44; retinopathy of prematurity &#40;ROP&#41;&#44; neurosensory deficit&#44; death and combined results of death or BPD and death or neurosensory deficit&#46; The exception to this being the significant reduction in severe HIPV and severe pulmonary hemorrhage in the first week of life with prophylactic indomethacin&#44; and the significant reduction of NEC with prophylactic surgical ligation&#46;<a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">5&#8211;8</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">On the other hand&#44; in clinical practice&#44; not all PDAs respond to the different pharmacological treatments&#44; and not without being associated with significant adverse effects&#44; such as increased ventilation days and supplemental oxygen and increased risk of BPD with indomethacin&#44; ibuprofen and prophylactic surgical closure&#59; increased risk of gastrointestinal perforation&#44; especially with the association of indomethacin or ibuprofen with perinatal corticosteroids&#59; increased gastrointestinal bleeding with ibuprofen&#59; renal adverse effects with early indomethacin and ibuprofen and ROP&#44; neurodevelopmental impairment&#44; left vocal cord paralysis&#44; diaphragmatic paresis or eventration&#44; chylothorax and scoliosis&#44; with surgical closure&#46; These aspects&#44; associated with the possibility of spontaneous closure of the DA&#44; have led many centers in recent years to advocate a less aggressive approach to PDA&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">Although the evidence suggests that routine treatment for DA closure has no demonstrable long-term benefit&#44; the perception that large shunts may put some preterm infants at risk of pulmonary edema and hemorrhage&#44; congestive HF&#44; and systemic hypoperfusion has led to a growing trend toward an individualized therapeutic approach&#44; which considers the individual variability of the new-born&#46; Hence&#44; the active treatment for PDA closure is suggested for newborns who may benefit most from treatment&#44; i&#46;e&#46;&#44; the most premature&#44; without prenatal corticoids&#44; with severe respiratory disease&#44; ventilated&#44; with spontaneous DA constriction failure and a &#8220;growing&#8221; or &#8220;pulsatile&#8221; ductal flow pattern in the first hours of life&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">It is therefore not surprising that several groups have dedicated their efforts to the search for markers to identify patients who are more likely to respond to pharmacologic treatment&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">9</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">In this issue of the journal&#44; Santos et al&#46;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">10</span></a> present the results of an eight-year retrospective observational study&#44; which included all preterm infants with a GA between 23 and 32 weeks with a diagnosis of PDA&#44; admitted to the Neonatology Department of a large Portuguese Hospital Center&#46; Their aim was to identify predictive factors of response to medical treatment&#44; to enable better stratification of the provision of care to preterm newborns with hemodynamically significant PDA&#46; The closure rate with ibuprofen was within the margins reported by previous studies&#44; with approximately 62&#37; responding to one cycle of treatment and 80&#37; after a second cycle&#46; Not surprisingly&#44; statistically significant differences were identified for the type of delivery &#40;eutocic&#41;&#44; GA&#44; the mean weight and length &#40;more premature&#44; smaller&#44; and lighter&#41;&#44; the mean platelet count &#40;and need for platelet transfusion&#41;&#44; need for invasive mechanical ventilation&#44; the treatment with diuretics &#40;furosemide&#41;&#46; These variables were all associated with a worse response to ibuprofen treatment&#46; A logistic regression model was developed that considered the effect of the variables GA&#44; type of delivery and need for diuretic treatment and transfusion on response to ibuprofen therapy&#44; with a positive predictive value of 89&#37; and a negative predictive value of 88&#46;8&#37;&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">These results&#44; although relevant for the personalized approach to these patients&#44; should be seen in the light of the limitations inherent to its retrospective nature&#44; and of having been carried out at only one center&#44; with a small sample &#40;81 preterm infants&#41;&#46; These data emphasize the need to define a personalized approach to preterm infants with hemodynamically significant PDA&#44; to improve the individual approach to this very vulnerable group of patients&#44; helping to identify a subgroup in whom active pharmacologic closure treatment is more likely to be beneficial&#46; This would prevent unnecessary exposure to drugs and considering surgical ligation early during therapy&#46; Further studies will be needed in order to improve the predictive model&#46;</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Conflicts of interest</span><p id="par0065" class="elsevierStylePara elsevierViewall">The author has no conflicts of interest to declare&#46;</p></span></span>"
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Ductus arteriosus: The coming of age of a fetal vessel
Canal arterial: o amadurecimento de um vaso fetal
Sérgio Matoso Laranjoa,b
a Serviço de Cardiologia Pediátrica, Hospital de Santa Marta, Centro de Referência de Cardiopatias Congénitas, Centro Hospitalar e Universitário de Lisboa Central, Lisboa, Portugal
b Comprehensive Health Research Center, Universidade NOVA de Lisboa, Lisboa, Portugal
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            "en" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Discriminative ability of the model predictive of the occurrence of ibuprofen treatment efficacy in ductus arteriosus closure &#40;area under the receiver operating characteristic curve&#61;0&#46;782&#59; 95&#37; confidence interval 0&#46;624 to 0&#46;941&#41; in preterm newborns with gestational age between 23 and 32 weeks&#46;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a></p>"
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    "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0070" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleDisplayedQuote" id="dsq0005"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">&#8220;<span class="elsevierStyleItalic">Nature&#39;s destruction of fetal structures that are superfluous in the adult seems to me something much greater than her original creation of those structures</span>&#8221;</p></span></p><p id="par0010" class="elsevierStylePara elsevierViewall">Galen of Pergamun &#40;AD 129-200&#41;</p><p id="par0015" class="elsevierStylePara elsevierViewall">The ductus arteriosus &#40;DA&#41; is a unique&#44; dynamic vascular structure functioning as a prenatal bypass between pulmonary artery and aorta&#46; Intimal thickening together with O<span class="elsevierStyleInf">2</span>-dependent constriction functionally closes the DA during the first hours after birth&#46; While in healthy term newborns&#44; the DA&#41; presents a spontaneous functional closure of almost 100&#37; within 72 hours of life&#44;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">1</span></a> in premature neonates&#44; the closure of the PDA may occur later or not at all&#46; It is influenced by several factors&#44; including gestational age &#40;GA&#41;&#44; prenatal corticosteroid administration&#44; hyaline membrane disease&#44; mechanical ventilation&#44; fluid intake in the first week of life&#44; infection and genetic factors&#46;<a class="elsevierStyleCrossRefs" href="#bib0060"><span class="elsevierStyleSup">2&#44;3</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">Persistent ductus arteriosus &#40;PDA&#41; is&#44; therefore&#44; a frequent occurrence in preterm infants requiring intensive care&#44; with an incidence inversely proportional to GA&#44; of around 30&#37; in extremely low birth weight newborns &#40;&#8804;28 weeks&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">3</span></a> On account of the hemodynamic changes that occur after birth&#44; PDA leads to shunting of the blood from the systemic to the pulmonary circulation&#46; The clinical and hemodynamic impact depends on the magnitude of the shunt and the compensation capacity of the preterm myocardium to maintain effective systemic blood flow&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">A large shunt volume through the PDA may cause a significant increase in pulmonary blood flow&#44; congestive heart failure &#40;HF&#41; and decreased systemic blood flow&#46; Pulmonary hyperperfusion may lead to pulmonary edema and hemorrhage&#44; which usually manifest itself by the second day of life&#44; respiratory deterioration&#44; increased need for mechanical ventilation and increased risk of bronchopulmonary dysplasia &#40;BPD&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">4</span></a> The phenomenon of systemic &#8220;circulatory steal&#8221; seems to be related to acidosis and systemic hypoperfusion and&#47;or hypotension&#44; which is more evident in the first hours of life and may put several organs at risk of ischemia&#46; Indeed&#44; several D&#246;ppler and NIRS studies have shown decreased cerebral&#44; coronary&#44; abdominal aorta&#44; superior mesenteric and renal blood flow in RNPT PDAs&#44; suggesting a potential role for the PDA in the pathogenesis of inotropic-resistant hypotension&#44; intraperiventricular hemorrhage&#44; periventricular leukomalacia&#44; cerebral palsy&#44; necrotizing enterocolitis&#44; and renal dysfunction&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">The hemodynamic changes resulting from the PDA and the epidemiological association of PDAs with increased morbidity and mortality in preterm infants<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">4</span></a> have meant that for decades PDAs have been considered a pathological condition requiring active closure therapy&#46; However&#44; and despite six decades of research&#44; there is still no conclusive evidence of a causal relationship between the hemodynamic changes resulting from PDA and neonatal morbidity and mortality&#44; or of the long-term benefit of the various strategies for PDA closure&#46; It is not clear whether the morbidity and mortality associated with PDA result from the volume of ductal shunt&#44; the adverse effects of treatment or are merely consequences of prematurity&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">The management of PDA in preterm infants consists of three different methods&#58; conservative management with supportive therapy alone&#44; pharmacologic closure&#44; and surgical ligation&#46;<a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">5&#44;6</span></a> Several pharmacological strategies have been tried&#44; mainly with cyclooxygenase &#40;COX&#41; inhibitors&#44; and more recently with paracetamol&#46; COX inhibitors&#44; such as indomethacin and ibuprofen&#44; work by reducing the production of prostaglandin&#46; Although these therapeutic strategies have proved effective in closing the DA&#44; especially if started early&#44; there is no evidence of benefits from the various therapeutic strategies on long-term neonatal morbidity&#44; especially BPD&#44; retinopathy of prematurity &#40;ROP&#41;&#44; neurosensory deficit&#44; death and combined results of death or BPD and death or neurosensory deficit&#46; The exception to this being the significant reduction in severe HIPV and severe pulmonary hemorrhage in the first week of life with prophylactic indomethacin&#44; and the significant reduction of NEC with prophylactic surgical ligation&#46;<a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">5&#8211;8</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">On the other hand&#44; in clinical practice&#44; not all PDAs respond to the different pharmacological treatments&#44; and not without being associated with significant adverse effects&#44; such as increased ventilation days and supplemental oxygen and increased risk of BPD with indomethacin&#44; ibuprofen and prophylactic surgical closure&#59; increased risk of gastrointestinal perforation&#44; especially with the association of indomethacin or ibuprofen with perinatal corticosteroids&#59; increased gastrointestinal bleeding with ibuprofen&#59; renal adverse effects with early indomethacin and ibuprofen and ROP&#44; neurodevelopmental impairment&#44; left vocal cord paralysis&#44; diaphragmatic paresis or eventration&#44; chylothorax and scoliosis&#44; with surgical closure&#46; These aspects&#44; associated with the possibility of spontaneous closure of the DA&#44; have led many centers in recent years to advocate a less aggressive approach to PDA&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">Although the evidence suggests that routine treatment for DA closure has no demonstrable long-term benefit&#44; the perception that large shunts may put some preterm infants at risk of pulmonary edema and hemorrhage&#44; congestive HF&#44; and systemic hypoperfusion has led to a growing trend toward an individualized therapeutic approach&#44; which considers the individual variability of the new-born&#46; Hence&#44; the active treatment for PDA closure is suggested for newborns who may benefit most from treatment&#44; i&#46;e&#46;&#44; the most premature&#44; without prenatal corticoids&#44; with severe respiratory disease&#44; ventilated&#44; with spontaneous DA constriction failure and a &#8220;growing&#8221; or &#8220;pulsatile&#8221; ductal flow pattern in the first hours of life&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">It is therefore not surprising that several groups have dedicated their efforts to the search for markers to identify patients who are more likely to respond to pharmacologic treatment&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">9</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">In this issue of the journal&#44; Santos et al&#46;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">10</span></a> present the results of an eight-year retrospective observational study&#44; which included all preterm infants with a GA between 23 and 32 weeks with a diagnosis of PDA&#44; admitted to the Neonatology Department of a large Portuguese Hospital Center&#46; Their aim was to identify predictive factors of response to medical treatment&#44; to enable better stratification of the provision of care to preterm newborns with hemodynamically significant PDA&#46; The closure rate with ibuprofen was within the margins reported by previous studies&#44; with approximately 62&#37; responding to one cycle of treatment and 80&#37; after a second cycle&#46; Not surprisingly&#44; statistically significant differences were identified for the type of delivery &#40;eutocic&#41;&#44; GA&#44; the mean weight and length &#40;more premature&#44; smaller&#44; and lighter&#41;&#44; the mean platelet count &#40;and need for platelet transfusion&#41;&#44; need for invasive mechanical ventilation&#44; the treatment with diuretics &#40;furosemide&#41;&#46; These variables were all associated with a worse response to ibuprofen treatment&#46; A logistic regression model was developed that considered the effect of the variables GA&#44; type of delivery and need for diuretic treatment and transfusion on response to ibuprofen therapy&#44; with a positive predictive value of 89&#37; and a negative predictive value of 88&#46;8&#37;&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">These results&#44; although relevant for the personalized approach to these patients&#44; should be seen in the light of the limitations inherent to its retrospective nature&#44; and of having been carried out at only one center&#44; with a small sample &#40;81 preterm infants&#41;&#46; These data emphasize the need to define a personalized approach to preterm infants with hemodynamically significant PDA&#44; to improve the individual approach to this very vulnerable group of patients&#44; helping to identify a subgroup in whom active pharmacologic closure treatment is more likely to be beneficial&#46; This would prevent unnecessary exposure to drugs and considering surgical ligation early during therapy&#46; Further studies will be needed in order to improve the predictive model&#46;</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Conflicts of interest</span><p id="par0065" class="elsevierStylePara elsevierViewall">The author has no conflicts of interest to declare&#46;</p></span></span>"
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