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The impacts of interferon (IFN) signaling on COVID-19 pathology are multiple, with both protective and harmful effects being documented. We report here a multiomics investigation of systemic IFN signaling in hospitalized COVID-19 patients, defining the multiomics biosignatures associated with varying levels of 12 different type I, II, and III IFNs. The antiviral transcriptional response in circulating immune cells is strongly associated with a specific subset of IFNs, most prominently IFNA2 and IFNG. In contrast, proteomics signatures indicative of endothelial damage and platelet activation associate with high levels of IFNB1 and IFNA6. Seroconversion and time since hospitalization associate with a significant decrease in a specific subset of IFNs. Additionally, differential IFN subtype production is linked to distinct constellations of circulating myeloid and lymphoid immune cell types. Each IFN has a unique metabolic signature, with IFNG being the most associated with activation of the kynurenine pathway. IFNs also show differential relationships with clinical markers of poor prognosis and disease severity. For example, whereas IFNG has the strongest association with C-reactive protein and other immune markers of poor prognosis, IFNB1 associates with increased neutrophil to lymphocyte ratio, a marker of late severe disease. Altogether, these results reveal specialized IFN action in COVID-19, with potential diagnostic and therapeutic implications.
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Sangre/metabolismo , COVID-19/inmunología , Interferones/sangre , Proteoma , Transcriptoma , COVID-19/sangre , Estudios de Casos y Controles , Conjuntos de Datos como Asunto , Humanos , Pacientes InternosRESUMEN
OBJECTIVE: This observational study reports on the postnatal mortality and 30-month outcome of children who underwent fully percutaneous fetoscopic repair of myelomeningocele (MMC) at a single center in Giessen, Germany. METHODS: Between October 2010 and August 2014, a total of 72 patients underwent fully percutaneous fetoscopic MMC closure at 21 + 0 to 29 + 1 (mean, 23 + 5) weeks' gestation. Of these, 52 (72%) participated in this study; however, 30-month mortality data are available for all 72 children. Children were examined at four timepoints: shortly after birth and at 3 months, 12 months and 30 months of corrected age. The patients underwent age-specific standardized neurological examinations and assessment of leg movements and ambulation at all timepoints. Cognitive and motor development were assessed using the Bayley Scales of Infant Development, second edition (BSID-II), at 30 months. RESULTS: All 72 children survived the intrauterine procedure, however, four (5.6%) infants died postnatally (including two of the 52 comprising the study cohort). Of the 52 patients included in the study, 11.5% were delivered before the 30th week of gestation (mean, 33 + 1 weeks) and, of the survivors, 48.1% had ventriculoperitoneal shunt placement. Of the 50 infants that were alive at 30 months, independent ambulation, without orthosis, was feasible for 46%. At 30 months of follow-up, 46% of children presented with a functional level that was at least two segments better than the anatomical level of the lesion. At 30 months, 70% of the children presented with BSID-II psychomotor development index score of ≥ 70 and 80% with BSID-II mental development index score of ≥ 70. CONCLUSION: Intrauterine repair of MMC by percutaneous fetoscopy shows largely similar outcomes to those reported for open repair, with respect to mortality, prematurity, shunt-placement rates, motor and mental development and free ambulation. © 2020 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.
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Enfermedades Fetales/cirugía , Fetoscopía/mortalidad , Meningomielocele/cirugía , Preescolar , Fetoscopía/métodos , Estudios de Seguimiento , Humanos , Lactante , Recién Nacido , Recien Nacido Prematuro , Meningomielocele/embriología , Trastornos del Neurodesarrollo/prevención & control , Rendimiento Físico Funcional , Derivación Ventriculoperitoneal/métodosRESUMEN
According to the World Health Organization (WHO), tuberculosis is the leading cause of death attributed to a single microbial pathogen worldwide. In addition to the large number of patients affected by tuberculosis, the emergence of Mycobacterium tuberculosis drug-resistance is complicating tuberculosis control in many high-burden countries. During the past 5 years, the global number of patients identified with multidrug-resistant tuberculosis (MDR-TB), defined as bacillary resistance at least against rifampicin and isoniazid, the two most active drugs in a treatment regimen, has increased by more than 20% annually. Today we experience a historical peak in the number of patients affected by MDR-TB. The management of MDR-TB is characterized by delayed diagnosis, uncertainty of the extent of bacillary drug-resistance, imprecise standardized drug regimens and dosages, very long duration of therapy and high frequency of adverse events which all translate into a poor prognosis for many of the affected patients. Major scientific and technological advances in recent years provide new perspectives through treatment regimens tailor-made to individual needs. Where available, such personalized treatment has major implications on the treatment outcomes of patients with MDR-TB. The challenge now is to bring these adances to those patients that need them most.
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OBJECTIVE: To evaluate the need for postnatal neurosurgical intervention after fetoscopic patch coverage of spina bifida aperta (SBA). METHODS: This was a retrospective analysis of a cohort of 71 fetuses which underwent minimally invasive fetoscopic patch coverage of SBA between 21 + 0 and 29 + 1 weeks of gestation. Postnatal neurosurgical procedures were classified into two types: re-coverage of the SBA within the first 3 months following birth, and shunt placement as treatment of associated hydrocephalus within the first year. RESULTS: Location of the SBA was lumbosacral in 59 cases, lumbar in seven, thoracic in three and sacral in two. In total, 20/71 (28%) patients underwent early postnatal neurosurgical intervention by means of re-coverage of the SBA. This was performed because of cerebrospinal fluid leakage in seven (35%), adhesions with functional deterioration in three (15%), incomplete coverage in five (25%) and skin defect in five (25%) cases. Ventriculoperitoneal shunt placement within 1 year was required in 32 (45%) cases and was preceded by ventriculostomy in two. Three (4%) infants needed Chiari decompression surgery in the first 12 months following birth, because of syringomyelia or gait disturbance. CONCLUSIONS: Fetoscopic patch coverage of SBA may require postnatal re-coverage in some cases. In most cases, conservative wound treatment shows good results, without requiring neurosurgical intervention. The low 1-year-shunt rate is comparable to data of the Management of Myelomeningocele Study and lower compared with published data of patients with postnatal only coverage of SBA.
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Fetoscopía/efectos adversos , Feto/cirugía , Procedimientos Neuroquirúrgicos/métodos , Espina Bífida Quística/cirugía , Femenino , Fetoscopía/métodos , Edad Gestacional , Humanos , Hidrocefalia/etiología , Hidrocefalia/cirugía , Lactante , Recién Nacido , Región Lumbosacra/embriología , Región Lumbosacra/cirugía , Atención Posnatal/métodos , Embarazo , Reoperación/métodos , Estudios Retrospectivos , Espina Bífida Quística/complicaciones , Espina Bífida Quística/embriología , Derivación VentriculoperitonealRESUMEN
PURPOSE: The aim of the study was to describe the response of fetal lung vasculature to maternal hyperoxygenation (MH) in the case of prenatally diagnosed hypoplastic left heart (HLH) with intact or restrictive (IAS/RAS) and without restriction of the atrial septum. Furthermore, the ability of MH to differentiate between newborns with HLH who do not require immediate atrial septostomy and newborns who will undergo immediate left atrial septoplasty after birth was evaluated. MATERIALS AND METHODS: Cross-sectional prospective study of fetuses ≥â26 weeks of gestation with prenatally diagnosed HLH. Lung perfusion (LP) was qualitatively assessed by color Doppler interrogation and LP was quantitatively measured using the pulsatility index for veins (PIV). Measurements were performed both with the mother breathing room air (LPRA) and after receiving 100% oxygen for 10 minutes (LPMH). The oxygen test was defined as positive if MH led to an increase in lung perfusion and as negative if MH did not lead to an increase. RESULTS: A total number of 22 pregnancies with hypoplasia of the left heart structures were included. 6/20 cases presented with an intact or restrictive atrial septum (IAS/RAS). All of these fetuses presented with a reduced LPRA. MH led to an increase in LP in 2/6 cases. The overall 30-day-survival rate was 83.3% (5/6). In 14/20 fetuses an open septum was detected. 11 cases had a normal LPRA, and the LPRA was reduced in 3/14 fetuses. The overall 30-day-survival rate was 92.9% (13/14). CONCLUSION: MH might be a useful adjunct in the assessment of pulmonary vasculopathy in fetuses with HLH.
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Ecocardiografía Doppler en Color , Hiperoxia/diagnóstico por imagen , Hiperoxia/fisiopatología , Síndrome del Corazón Izquierdo Hipoplásico/diagnóstico por imagen , Síndrome del Corazón Izquierdo Hipoplásico/fisiopatología , Pulmón/irrigación sanguínea , Intercambio Materno-Fetal/fisiología , Ultrasonografía Prenatal , Tabique Interatrial/diagnóstico por imagen , Tabique Interatrial/fisiopatología , Estudios Transversales , Femenino , Humanos , Síndrome del Corazón Izquierdo Hipoplásico/mortalidad , Terapia por Inhalación de Oxígeno , Embarazo , Tercer Trimestre del Embarazo , Pronóstico , Estudios Prospectivos , Arteria Pulmonar/diagnóstico por imagen , Arteria Pulmonar/fisiopatología , Venas Pulmonares/diagnóstico por imagen , Venas Pulmonares/fisiopatología , Flujo Pulsátil/fisiología , Análisis de la Onda del Pulso , Valores de Referencia , Tasa de SupervivenciaRESUMEN
Culturing before DNA extraction represents a major time-consuming step in whole-genome sequencing of slow-growing bacteria, such as Mycobacterium tuberculosis. We report a workflow to extract DNA from frozen isolates without reculturing. Prepared libraries and sequence data were comparable with results from recultured aliquots of the same stocks.
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ADN Bacteriano/aislamiento & purificación , Congelación , Mycobacterium tuberculosis/genética , Preservación Biológica , Genoma Bacteriano , Humanos , Análisis de Secuencia de ADNRESUMEN
Multiple gestation is associated with an increased risk for adverse pregnancy outcome. Monochorionic twins are at risk for complications specific to these pregnancies, such as twin-twin transfusion syndrome (TTTS) or twin reverse arterial perfusion (TRAP) sequence. In this article we give an overview on prenatal diagnosis, treatment and outcome of twin pregnancies complicated by TTTS and TRAP sequence.
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Transfusión Feto-Fetal/diagnóstico , Transfusión Feto-Fetal/terapia , Embarazo Gemelar , Diagnóstico Prenatal/métodos , Femenino , Humanos , Embarazo , Gemelos MonocigóticosRESUMEN
OBJECTIVES: To analyze the current technical approach of percutaneous minimal-access fetoscopic closure of spina bifida aperta (SBA) and provide an overview of its development in ovine and human fetuses. METHODS: Minimal-access percutaneous fetoscopic closure of SBA was performed at the German Center for Fetal Surgery & Minimal-access Therapy (DZFT) in 51 human fetuses at 21.0-29.1 weeks of gestation (mean age, 23.7 weeks). Various parameters of surgical relevance for the success and safety of the procedure and the early perioperative outcome were analyzed retrospectively. In addition, information from the early clinical cases was examined to determine how this shaped development of the approach. RESULTS: Percutaneous minimal-access fetoscopic closure of SBA was performed with a high rate of technical success, regardless of placental or fetal position. All fetuses survived surgery, but there was one very early preterm delivery 1 week after the procedure and this neonate died immediately, from early postoperative chorioamnionitis. Of the 50 surviving fetuses, 44 (88%) were delivered at or beyond 30 weeks and 25 (50%) at or beyond 34 weeks of gestation. There was one neonatal death from an uinsuspected case of trisomy 13 and two infant deaths from Chiari-II malformation. CONCLUSIONS: Following an adequate learning curve, minimal-access fetoscopic surgery for fetal spina bifida can be performed with a high rate of technical success, regardless of placental position.
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Fetoscopía/métodos , Espina Bífida Quística/cirugía , Adulto , Femenino , Edad Gestacional , Humanos , Edad Materna , Meningomielocele/cirugía , Embarazo , Resultado del Embarazo , Estudios Retrospectivos , Ultrasonografía Intervencional , Ultrasonografía Prenatal , Técnicas de Cierre de Heridas , Adulto JovenRESUMEN
OBJECTIVE: To assess maternal morbidity and outcome in women undergoing minimal-access fetoscopic surgery for spina bifida aperta. METHODS: This was a retrospective study of 51 women undergoing minimal-access fetoscopic surgery to improve postnatal neurological outcome of spina bifida aperta, at a mean gestational age of 24 weeks, at our center between July 2010 and June 2013. We analyzed various perioperative complications of surgery, namely: maternal and fetal death, need for maternal blood transfusion, placental abruption, pulmonary edema, spontaneous labor, oligohydramnios, chorioamnionitis, chorioamniotic membrane separation, duration of hospitalization, amniotic fluid leakage, gestational age at delivery and status of hysterotomy site. RESULTS: In none of the 51 women was there maternal demise, spontaneous labor, placental abruption or a need for maternal blood transfusion in the perioperative period. Chorioamniotic membrane separation occurred in one patient, mild pulmonary edema occurred in one and oligohydramnios occurred in seven. All fetuses survived surgery, but there was one very early preterm delivery 1 week after the procedure and this neonate died immediately, from early postoperative chorioamnionitis. Amniotic fluid leakage occurred in 43 patients, at a mean gestational age of 29.7 (range, 22.6-37.3) weeks; two of these patients developed chorioamnionitis. Duration of maternal hospitalization after surgery was 7.2 (range, 4-12) days. Mean gestational age at delivery was 33 (range, 24.6-38.1) weeks. All abdominal and uterine trocar insertion sites healed well. CONCLUSION: Minimal-access fetoscopic surgery for spina bifida aperta is apparently safe for most maternal patients. Despite the common occurrence of amniotic leakage, the majority of women deliver beyond 32 weeks of gestation.
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Fetoscopía/métodos , Atención Prenatal/métodos , Espina Bífida Quística/cirugía , Adulto , Anestesia Obstétrica/métodos , Protocolos Clínicos , Consejo , Femenino , Edad Gestacional , Humanos , Tiempo de Internación , Atención Perioperativa/métodos , Embarazo , Cuidados Preoperatorios/métodos , Derivación y Consulta , Estudios Retrospectivos , Adulto JovenRESUMEN
OBJECTIVE: The outlook for newborns with hypoplastic left heart (HLH) has substantially improved over the last decade. However, differences in outcome among various anatomical subgroups have been described. We aimed to describe the incidence of ventriculocoronary communications and endocardial fibroelastosis in HLH and the possible implication on hospital survival (30âd). METHODS: We retrospectively reviewed our medical records, still frames and video loops of 72 fetuses with HLH and critical aortic valve stenosis and evolving HLH from 2008â-â2013. The presence of VCAC and EFE were systematically assessed. Outcome parameters were incidence of VCAC and EFE among different anatomical subgroups of HLH and hospital survival (30âd). RESULTS: 72 fetuses were included in this series. The incidence of VCAC was 11.1â% (8 cases) and EFE occurred in 33.3â% (24 cases). 5 fetuses with VCAC occurred in the subgroup of mitral valve stenosis/aortic valve atresia (MS/AA, 62.5â%) and 2 fetuses with VCAC occurred in the group of mitral atresia/aortic valve atresia (MA/AA, 25â%). Further classification was not possible in one case with VCAC (12.5â%). EFE predominantly occurred in the subgroup of MS/AA, MA/AA and in those cases with aortic valve stenosis and evolving HLH. The overall hospital survival on an intention-to-treat basis was 91.2â% (52/57 newborns). Hospital survival was 91â% for the subgroup of cases with MS/AA and for all other anatomical subgroups. CONCLUSION: The presence of VCAC in HLH can be diagnosed by fetal echocardiography predominantly occurring in cases with obstructed outflow and to some extent patent mitral valve. EFE is a frequent coexisting finding. Hospital survival was comparable among different anatomical subgroups and in cases with VCAC. The presence of VCAC in HLH did not limit the results of surgical palliation within the observation period of 30 days.
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Anomalías de los Vasos Coronarios/diagnóstico por imagen , Ecocardiografía Doppler en Color , Ecocardiografía , Fibroelastosis Endocárdica/diagnóstico por imagen , Ventrículos Cardíacos/anomalías , Ventrículos Cardíacos/diagnóstico por imagen , Síndrome del Corazón Izquierdo Hipoplásico/diagnóstico por imagen , Ultrasonografía Prenatal , Válvula Aórtica/anomalías , Válvula Aórtica/diagnóstico por imagen , Fibroelastosis Endocárdica/mortalidad , Femenino , Mortalidad Hospitalaria , Humanos , Síndrome del Corazón Izquierdo Hipoplásico/mortalidad , Recién Nacido , Embarazo , Pronóstico , Tasa de SupervivenciaRESUMEN
Minimally invasive fetoscopic surgery for spina bifida has been developed to improve the postnatal neurological function of affected fetuses and to achieve a reduced maternal trauma compared to open fetal surgery. This article gives an overview on the peri- and postoperative management of such cases at our centre.
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Enfermedades Fetales/cirugía , Fetoscopía/métodos , Cuidados Intraoperatorios/métodos , Procedimientos Quirúrgicos Mínimamente Invasivos/métodos , Cuidados Posoperatorios/métodos , Disrafia Espinal/cirugía , Enfermedades Fetales/patología , Humanos , Disrafia Espinal/patología , Resultado del TratamientoRESUMEN
Congenital diaphragmatic hernia is a malformation presenting with varying degrees of severity. An accurate prediction of outcome is crucial for parental counselling and therapeutic planning. In selected cases, foetal endoscopic tracheal occlusion (FETO) can improve foetal outcome. Timely referral to a highly specialised centre is important when the requirement for extracorporeal membrane oxygenation (ECMO) is expected.
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Oxigenación por Membrana Extracorpórea/métodos , Fetoscopía/métodos , Hernias Diafragmáticas Congénitas , Herniorrafia/métodos , Herniorrafia/rehabilitación , Ultrasonografía Prenatal/métodos , Terapia Combinada , Hernia Diafragmática/diagnóstico , Humanos , Recién Nacido , Pronóstico , Medición de RiesgoRESUMEN
The aetiology of urinary tract obstructions (LUTO) is heterogeneous. The most common entities are isolated posterior urethral valves or urethral atresia in male foetuses. In female foetuses LUTO is frequently a part of complex malformations. The natural history of LUTO is characterised by high morbidity and mortality due to the development of severe pulmonary hypoplasia caused by oligo- or anhydramnios affecting the cannalicular phase (16-24 weeks of gestation) of pulmonary development. The degree of renal damage is variable and ranges from mild renal impairment in infancy to end-stage renal insufficiency, necessitating dialysis and transplantation. Foetal interventions in order to bypass the obstruction are biologically plausible and technically feasible. Vesico-amniotic shunting as well as (currently less frequent) foetoscopic cystoscopy and laser ablation of posterior urethral valves are minimally invasive treatment options. Previous reports indicate that prenatal therapy is suitable to reduce perinatal mortality but does not improve postnatal renal function. Selection of foetuses who may profit from prenatal intervention is aggravated by the lack of reliable prognostic criteria for the prediction of postnatal renal function in both ultrasound and foetal urine analysis. Furthermore, there is no randomised trial available at the time of writing. Because of a relevant complication rate and still no clear evidence for foetal benefit, interventions should be performed in specialised centres. Further studies are necessary to improve case selection of affected foetuses and to evaluate the impact of interventions in earlier gestational weeks. The data from the PLUTO trial (percutaneous shunting in lower urinary tract obstruction) conducted by the University of Birmingham may help to answer these questions. In the meantime selection of foetuses for prenatal intervention puts high requirements on interdisciplinary counselling in every case. A general treatment algorithm for foetal therapy is not available at the moment.
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Cistoscopía/métodos , Fetoscopía/métodos , Síntomas del Sistema Urinario Inferior/diagnóstico , Síntomas del Sistema Urinario Inferior/cirugía , Ultrasonografía Prenatal/métodos , Obstrucción del Cuello de la Vejiga Urinaria/diagnóstico , Obstrucción del Cuello de la Vejiga Urinaria/cirugía , Femenino , Humanos , Terapia por Láser/métodos , Síntomas del Sistema Urinario Inferior/congénito , Masculino , Obstrucción del Cuello de la Vejiga Urinaria/congénitoRESUMEN
Down syndrome (DS), the genetic condition caused by trisomy 21 (T21), is characterized by delayed neurodevelopment, accelerated aging, and increased risk of many co-occurring conditions. Hypoxemia and dysregulated hematopoiesis have been documented in DS, but the underlying mechanisms and clinical consequences remain ill defined. We report an integrative multi-omic analysis of â¼400 research participants showing that people with DS display transcriptomic signatures indicative of elevated heme metabolism and increased hypoxic signaling across the lifespan, along with chronic overproduction of erythropoietin, elevated biomarkers of tissue-specific hypoxia, and hallmarks of stress erythropoiesis. Elevated heme metabolism, transcriptional signatures of hypoxia, and stress erythropoiesis are conserved in a mouse model of DS and associated with overexpression of select triplicated genes. These alterations are independent of the hyperactive interferon signaling characteristic of DS. These results reveal lifelong dysregulation of key oxygen-related processes that could contribute to the developmental and clinical hallmarks of DS.
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PURPOSE: Preferential streaming of the ductus venosus (DV) toward the right atrium has been observed in fetuses with left diaphragmatic hernia (LDH). The purpose of this retrospective study was to compare survival rates to discharge between a group with preferential streaming of the DV toward the right heart and a group in which this abnormal flow pattern was not present. MATERIALS AND METHODS: We retrospectively searched our patient records for fetuses with LDH in whom liver position, DV streaming and postnatal outcome information was available. 55 cases were found and divided into two groups: Group I fetuses exhibited abnormal DV streaming toward the right side of the heart; group II fetuses did not. Various prognostic and outcome parameters were compared. RESULTS: 62â% of group I fetuses and 88â% of group II fetuses survived to discharge (pâ=â0.032). Fetoscopic tracheal balloon occlusion (FETO) was performed in 66â% of group I fetuses and 23â% of group II fetuses (pâ=â0.003). Postnatal ECMO therapy was performed in 55â% of group I fetuses and 23â% of group II infants (pâ=â0.025). Moderate to severe chronic lung disease in survivors was observed in 56â% of the survivors of group I and 9â% of the survivors of group II (pâ=â0.002). CONCLUSION: Preferential streaming of the DV toward the right heart in human fetuses with left-sided diaphragmatic hernia was associated with a poorer postnatal outcome despite a higher rate of invasive pre- and postnatal procedures compared to fetuses without this flow abnormality. Specifically, abnormal DV streaming was found to be an independent predictor for FETO.
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Ecocardiografía Doppler en Color , Atrios Cardíacos/anomalías , Atrios Cardíacos/diagnóstico por imagen , Cardiopatías Congénitas/diagnóstico por imagen , Cardiopatías Congénitas/embriología , Hernia Diafragmática/diagnóstico por imagen , Hernia Diafragmática/embriología , Síndrome de Circulación Fetal Persistente/diagnóstico por imagen , Síndrome de Circulación Fetal Persistente/embriología , Ultrasonografía Prenatal , Venas Umbilicales/diagnóstico por imagen , Vena Cava Inferior/diagnóstico por imagen , Oxigenación por Membrana Extracorpórea , Femenino , Edad Gestacional , Cardiopatías Congénitas/mortalidad , Cardiopatías Congénitas/terapia , Hernia Diafragmática/mortalidad , Hernia Diafragmática/terapia , Humanos , Recién Nacido , Síndrome de Circulación Fetal Persistente/mortalidad , Síndrome de Circulación Fetal Persistente/terapia , Embarazo , Pronóstico , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
This review focuses on the prenatal management and outcome of echogenic lung lesions and isolated hydrothorax of the fetus. We give an overview of the most common forms of echogenic lung lesions like cystic adenomatoid malformation of the lung and bronchopulmonary sequestration as well as of congenital high airway obstruction sequence. We review the occurrence, appearance, pathophysiology and natural history of these lesions. Furthermore we discuss selection criteria for intrauterine treatment and algorithms for prenatal surveillance of affected fetuses.
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Quilotórax/congénito , Enfermedades Fetales/diagnóstico , Enfermedades Fetales/terapia , Anomalías del Sistema Respiratorio/diagnóstico , Anomalías del Sistema Respiratorio/terapia , Quilotórax/diagnóstico , Quilotórax/terapia , Medicina Basada en la Evidencia , Humanos , Pulmón/anomalías , Pulmón/diagnóstico por imagen , Resultado del Tratamiento , Ultrasonografía Prenatal/métodosRESUMEN
Individuals with Down syndrome (DS) display chronic hyperactivation of interferon signaling. However, the clinical impacts of interferon hyperactivity in DS are ill-defined. Here, we describe a multiomics investigation of interferon signaling in hundreds of individuals with DS. Using interferon scores derived from the whole blood transcriptome, we defined the proteomic, immune, metabolic, and clinical features associated with interferon hyperactivity in DS. Interferon hyperactivity associates with a distinct proinflammatory phenotype and dysregulation of major growth signaling and morphogenic pathways. Individuals with the highest interferon activity display the strongest remodeling of the peripheral immune system, including increased cytotoxic T cells, B cell depletion, and monocyte activation. Interferon hyperactivity accompanies key metabolic changes, most prominently dysregulated tryptophan catabolism. High interferon signaling stratifies a subpopulation with elevated rates of congenital heart disease and autoimmunity. Last, a longitudinal case study demonstrated that JAK inhibition normalizes interferon signatures with therapeutic benefit in DS. Together, these results justify the testing of immune-modulatory therapies in DS.
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Síndrome de Down , Humanos , Síndrome de Down/tratamiento farmacológico , Síndrome de Down/complicaciones , Síndrome de Down/genética , Proteómica , Interferones/metabolismo , Autoinmunidad , Transducción de Señal/genéticaRESUMEN
Down syndrome (DS), the genetic condition caused by trisomy 21, is characterized by variable cognitive impairment, immune dysregulation, dysmorphogenesis and increased prevalence of diverse co-occurring conditions. The mechanisms by which trisomy 21 causes these effects remain largely unknown. We demonstrate that triplication of the interferon receptor (IFNR) gene cluster on chromosome 21 is necessary for multiple phenotypes in a mouse model of DS. Whole-blood transcriptome analysis demonstrated that IFNR overexpression associates with chronic interferon hyperactivity and inflammation in people with DS. To define the contribution of this locus to DS phenotypes, we used genome editing to correct its copy number in a mouse model of DS, which normalized antiviral responses, prevented heart malformations, ameliorated developmental delays, improved cognition and attenuated craniofacial anomalies. Triplication of the Ifnr locus modulates hallmarks of DS in mice, suggesting that trisomy 21 elicits an interferonopathy potentially amenable to therapeutic intervention.
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Síndrome de Down , Cardiopatías Congénitas , Animales , Ratones , Síndrome de Down/genética , Receptores de Interferón/genética , Interferones , Fenotipo , Modelos Animales de EnfermedadRESUMEN
PURPOSE: Hypoplastic left heart (HLH) is one of the most common forms of cardiac abnormality detectable during gestation by fetal echocardiography. Antenatal diagnosis allows for appropriate counseling and time to consider treatment options. We report the actual outcome data after fetal diagnosis of HLH. MATERIALS AND METHODS: Retrospective analysis of the outcome in all cases with HLH from 1994â-â2011 presenting in fetal life at two tertiary referral centers for prenatal diagnosis and pediatric cardiology. RESULTS: 105 cases were included and the overall survival is 40.9â% (43/105) after prenatal diagnosis. There was an 81.1â% survival rate in infants undergoing surgery and a 64.1â% survival rate from an intention-to-treat position. Two neonates died due to tamponade and cardiac arrest following balloon septostomy and one neonate from sepsis before surgery. Extracardiac anomalies occurred in three fetuses, and karyotype anomalies in seven fetuses (18.9â%). In 4 of 5 babies born with additional extracradiac or karyotype anomalies, parents opted for compassionate care. The first had trisomy 13, the second had trisomy 18, the third neonate presented with spina bifida, and the fourth presented with hydronephrosis and pulmonary atresia. Termination of pregnancy took place in 17 cases (16.1â%). CONCLUSION: Thorough antenatal evaluation should include karyotyping, detailed extracardiac and intracardiac assessment to accurately predict the risks of surgery. Prenatal counseling might be modified after the exclusion of additional anomalies. These data provide up-to-date information for parental counseling.