RESUMO
TP73 belongs to the TP53 family of transcription factors and has therefore been well studied in cancer research. Studies in mice, however, have revealed non-oncogenic activities related to multiciliogenesis. Utilizing whole-exome sequencing analysis in a cohort of individuals with a mucociliary clearance disorder and cortical malformation, we identified homozygous loss-of-function variants in TP73 in seven individuals from five unrelated families. All affected individuals exhibit a chronic airway disease as well as a brain malformation consistent with lissencephaly. We performed high-speed video microscopy, immunofluorescence analyses, and transmission electron microscopy in respiratory epithelial cells after spheroid or air liquid interface culture to analyze ciliary function, ciliary length, and number of multiciliated cells (MCCs). The respiratory epithelial cells studied display reduced ciliary length and basal bodies mislocalized within the cytoplasm. The number of MCCs is severely reduced, consistent with a reduced number of cells expressing the transcription factors crucial for multiciliogenesis (FOXJ1, RFX2). Our data demonstrate that autosomal-recessive deleterious variants in the TP53 family member TP73 cause a mucociliary clearance disorder due to a defect in MCC differentiation.
Assuntos
Lisencefalia/genética , Depuração Mucociliar/genética , Mucosa Respiratória/metabolismo , Proteína Tumoral p73/genética , Diferenciação Celular/genética , Células Cultivadas , Ciliopatias/genética , Genes Recessivos , Homozigoto , Humanos , Mutação com Perda de Função , Microscopia de Vídeo , Mucosa Respiratória/citologia , Mucosa Respiratória/ultraestrutura , Sequenciamento do ExomaRESUMO
Junctional epidermolysis bullosa (JEB) is a severe and often lethal genetic disease caused by mutations in genes encoding the basement membrane component laminin-332. Surviving patients with JEB develop chronic wounds to the skin and mucosa, which impair their quality of life and lead to skin cancer. Here we show that autologous transgenic keratinocyte cultures regenerated an entire, fully functional epidermis on a seven-year-old child suffering from a devastating, life-threatening form of JEB. The proviral integration pattern was maintained in vivo and epidermal renewal did not cause any clonal selection. Clonal tracing showed that the human epidermis is sustained not by equipotent progenitors, but by a limited number of long-lived stem cells, detected as holoclones, that can extensively self-renew in vitro and in vivo and produce progenitors that replenish terminally differentiated keratinocytes. This study provides a blueprint that can be applied to other stem cell-mediated combined ex vivo cell and gene therapies.
Assuntos
Células Epidérmicas , Epidermólise Bolhosa Juncional/terapia , Regeneração , Células-Tronco/citologia , Células-Tronco/metabolismo , Transgenes/genética , Moléculas de Adesão Celular/genética , Moléculas de Adesão Celular/metabolismo , Diferenciação Celular , Linhagem da Célula , Autorrenovação Celular , Rastreamento de Células , Criança , Células Clonais/citologia , Células Clonais/metabolismo , Derme/citologia , Derme/patologia , Epiderme/patologia , Epidermólise Bolhosa Juncional/genética , Epidermólise Bolhosa Juncional/metabolismo , Epidermólise Bolhosa Juncional/patologia , Humanos , Queratinócitos/citologia , Queratinócitos/metabolismo , Queratinócitos/transplante , Masculino , Provírus/genética , CalininaRESUMO
BACKGROUND: During pediatric general anesthesia (GA) and sedation, clinicians aim to maintain physiological parameters within normal ranges. Accordingly, regional cerebral oxygen saturation (rScO2) should not drop below preintervention baselines. Our study compared rScO2 desaturation events in children undergoing GA or chloral hydrate sedation (CHS). METHODS: Ninety-two children undergoing long auditory assessments were randomly assigned to two study arms: CHS (n = 40) and GA (n = 52). Data of 81 children (mean age 13.8 months, range 1-36 months) were analyzed. In the GA group, we followed a predefined 10 N concept (no fear, no pain, normovolemia, normotension, normocardia, normoxemia, normocapnia, normonatremia, normoglycemia, and normothermia). In this group, ENT surgeons performed minor interventions in 29 patients based on intraprocedural microscopic ear examinations. In the CHS group, recommendations for monitoring and treatment of children undergoing moderate sedation were met. Furthermore, children received a double-barreled nasal oxygen cannula to measure end-tidal carbon dioxide (etCO2) and allow oxygen administration. Chloral hydrate was administered in the parent's presence. Children had no intravenous access which is an advantage of sedation techniques. In both groups, recommendations for fasting were followed and an experienced anesthesiologist was present during the entire procedure. Adverse event (AE) was a decline in cerebral oxygenation to below 50% or below 20% from the baseline for ≥1 min. The primary endpoint was the number of children with AE across the study arms. Secondary variables were: fraction of inspired oxygen (FIO2), oxygen saturation (SpO2), etCO2, systolic and mean blood pressure (BP), and heart rate (HR); these variables were analyzed for their association with drop in rScO2 to below baseline (%drop_rScO2). RESULTS: The incidence of AE across groups was not different. The analysis of secondary endpoints showed evidence that %drop_rScO2 is more dependent on HR and FIO2 than on BP and etCO2. CONCLUSIONS: This study highlights the strong association between HR and rScO2 in children aged < 3 years, whereas previous studies had primarily discussed the role of BP and etCO2. Prompt HR correction may result in shorter periods of cerebral desaturation. TRIAL REGISTRATION: The study was retrospectively registered with the German Clinical Trials Registry (DRKS00024362, 04/02/2021).
Assuntos
Hidrato de Cloral , Sedação Consciente , Criança , Humanos , Lactente , Pré-Escolar , Hidrato de Cloral/efeitos adversos , Sedação Consciente/efeitos adversos , Sedação Consciente/métodos , Anestesia Geral/efeitos adversos , Oxigênio , Troca Gasosa Pulmonar , Hipnóticos e Sedativos/efeitos adversosRESUMO
AIM: We explored whether subnormal forced expiratory volume within 1 s (FEV1 ) at 5-9 years of age was lower in children born preterm who received less invasive surfactant administration (LISA) rather than surfactant via an endotracheal tube. METHODS: The multi-centre, randomised Nonintubated Surfactant Application trial enrolled 211 preterm infants born at 23-26 weeks of gestation from 13 level III neonatal intensive care units from April 2009 to March 2012. They received surfactant via LISA (n = 107) or after conventional endotracheal intubation (n = 104). The follow-up assessments were carried out by a single team blinded to the group assignments. The main outcome was FEV1 < 80% of predicted values. RESULTS: Spirometry was successful in 102/121 children. The other children died or were lost to follow-up. Median FEV1 was 93% (interquartile range 80%-113%) of predicted values in the LISA group and 86% (interquartile range 77-102%) in the control group (p = 0.685). Rates of FEV1 < 80% were 11/57 (19%) and 15/45 (33%), respectively, which was an absolute risk reduction of 14% (95% confidence interval -3.1% to 31.2%, p = 0.235). There were no differences in other outcome measures. CONCLUSION: The proportion of children aged 5-9 years with subnormal FEV1 was not significantly different between the groups.
Assuntos
Surfactantes Pulmonares , Criança , Pré-Escolar , Humanos , Recém-Nascido Prematuro , Intubação Intratraqueal , Surfactantes Pulmonares/administração & dosagem , EspirometriaRESUMO
AIM: The aim of this study was to evaluate neurocognitive outcome at 24 months of corrected age after less invasive surfactant application (LISA) in preterm infants born at 23-26 weeks of gestational age. METHODS: Surviving participants of a LISA trial conducted in 13 German level III neonatal intensive care units were reviewed for assessment of developmental outcome, hearing and vision problems, growth and rehospitalisation days. Maternal depression, breastfeeding rates and socio-economic factors were evaluated as potentially confounding factors. RESULTS: In total, 156/182 infants took part in the study, 78 had received surfactant via LISA and 78 via endotracheal intubation. 22% of LISA infants compared to 42% of intubated infants had a psychomotor development index (PDI) <70 (0.012). A significant difference in mental development index (MDI) was observed in the stratum of more mature infants (25 and 26 weeks of GA). For this group, MDI < 70 was observed in 4% of LISA infants vs 21% of intubated infants (P = 0.008). CONCLUSION: At 24 months of age, the LISA-treated infants scored less often PDI < 70 and had similar results in MDI. Infants born at 25 and 26 weeks treated with LISA had lower rates of severe disability. LISA is safe and may be superior.
Assuntos
Lactente Extremamente Prematuro , Surfactantes Pulmonares , Humanos , Lactente , Recém-Nascido , Surfactantes Pulmonares/uso terapêutico , Respiração Artificial , Tensoativos , Resultado do TratamentoRESUMO
AIM: Providing less invasive surfactant administration (LISA) to spontaneously breathing preterm infants has been reported to reduce mechanical ventilation and bronchopulmonary dysplasia (BPD) in randomised controlled trials. This large cohort study compared these outcome measures between LISA-treated infants and controls. METHODS: Infants receiving LISA, who were born before 32 gestational weeks and enrolled in the German Neonatal Network, were matched to control infants by gestational age, umbilical cord pH, Apgar-score at 5 min, small for gestational age status, antenatal treatment with steroids, gender and highest supplemental oxygen during the first 12 h of life. Outcome data were compared with chi-square and Mann-Whitney U-tests and adjusted for multiple comparisons. RESULTS: Between 2009 and 2012, 1103 infants were treated with LISA at 37 centres. LISA infants had lower rates of mechanical ventilation (41% versus 62%, p < 0.001), postnatal dexamethasone treatment (2.5% versus 7%, p < 0.001), BPD (12% versus 18%, p = 0.001) and BPD or death (14% versus 21%, p < 0.001) than the controls. CONCLUSION: Surfactant treatment of spontaneously breathing infants was associated with lower rates of mechanical ventilation and BPD. Additional large-scale randomised controlled trials are needed to assess the possible long-term benefits of LISA.
Assuntos
Surfactantes Pulmonares/administração & dosagem , Síndrome do Desconforto Respiratório do Recém-Nascido/prevenção & controle , Displasia Broncopulmonar/etiologia , Displasia Broncopulmonar/prevenção & controle , Feminino , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Masculino , Análise por Pareamento , Estudos Prospectivos , Surfactantes Pulmonares/uso terapêutico , Respiração , Respiração Artificial/estatística & dados numéricos , Síndrome do Desconforto Respiratório do Recém-Nascido/complicações , Resultado do TratamentoRESUMO
BACKGROUND: Vitamin A plays a key role in lung development, but there is no consensus regarding the optimal vitamin A dose and administration route in extremely low birthweight (ELBW) infants. We aimed to assess whether early postnatal additional high-dose fat-soluble enteral vitamin A supplementation versus placebo would lower the rate of moderate or severe bronchopulmonary dysplasia or death in ELBW infants receiving recommended basic enteral vitamin A supplementation. METHODS: This prospective, multicentre, randomised, parallel-group, double-blind, placebo-controlled, investigator-initiated phase 3 trial conducted at 29 neonatal intensive care units in Austria and Germany assessed early high-dose enteral vitamin A supplementation (5000 international units [IU]/kg per day) or placebo (peanut oil) for 28 days in ELBW infants. Eligible infants had a birthweight of more than 400 g and less than 1000 g; gestational age at birth of 32+0 weeks postmenstrual age or younger; and the need for mechanical ventilation, non-invasive respiratory support, or supplemental oxygen within the first 72 h of postnatal age after admission to the neonatal intensive care unit. Participants were randomly assigned by block randomisation with variable block sizes (two and four). All participants received basic vitamin A supplementation (1000 IU/kg per day). The composite primary endpoint was moderate or severe bronchopulmonary dysplasia or death at 36 weeks postmenstrual age, analysed in the intention-to-treat population. This trial was registered with EudraCT, 2013-001998-24. FINDINGS: Between March 2, 2015, and Feb 27, 2022, 3066 infants were screened for eligibility at the participating centres. 915 infants were included and randomly assigned to the high-dose vitamin A group (n=449) or the control group (n=466). Mean gestational age was 26·5 weeks (SD 2·0) and mean birthweight was 765 g (162). Moderate or severe bronchopulmonary dysplasia or death occurred in 171 (38%) of 449 infants in the high-dose vitamin A group versus 178 (38%) of 466 infants in the control group (adjusted odds ratio 0·99, 95% CI 0·73-1·55). The number of participants with at least one adverse event was similar between groups (256 [57%] of 449 in the high-dose vitamin A group and 281 [60%] of 466 in the control group). Serum retinol concentrations at baseline, at the end of intervention, and at 36 weeks postmenstrual age were similar in the two groups. INTERPRETATION: Early postnatal high-dose fat-soluble enteral vitamin A supplementation in ELBW infants was safe, but did not change the rate of moderate or severe bronchopulmonary dysplasia or death and did not substantially increase serum retinol concentrations. FUNDING: Deutsche Forschungsgemeinschaft and European Clinical Research Infrastructures Network (ECRIN).
Assuntos
Displasia Broncopulmonar , Recém-Nascido de Peso Extremamente Baixo ao Nascer , Vitamina A , Humanos , Displasia Broncopulmonar/prevenção & controle , Displasia Broncopulmonar/mortalidade , Vitamina A/administração & dosagem , Método Duplo-Cego , Recém-Nascido , Masculino , Feminino , Estudos Prospectivos , Áustria , Suplementos Nutricionais , Alemanha , Unidades de Terapia Intensiva Neonatal , Idade Gestacional , Vitaminas/administração & dosagem , Lactente , Resultado do TratamentoRESUMO
Importance: The effects of probiotic interventions on colonization with resistant bacteria and early microbiome development in preterm infants remain to be clarified. Objective: To examine the efficacy of Bifidobacterium longum subsp infantis, Bifidobacterium animalis subsp lactis (BB-12), and Lactobacillus acidophilus (La-5) probiotics to prevent colonization with multidrug-resistant organisms or highly epidemic bacteria (MDRO+) and to shape the microbiome of preterm infants toward the eubiotic state of healthy full-term infants. Design, Setting, and Participants: The multicenter, double-blinded, placebo-controlled, group sequential, phase 3 Priming Immunity at the Beginning of Life (PRIMAL) randomized clinical trial, conducted from April 2018 to June 2020, included infants with gestational age of 28 to 32 weeks at 18 German neonatal units. Data analyses were conducted from March 2020 to August 2023. Intervention: A total of 28 days of multistrain probiotics diluted in human milk/formula starting within the first 72 hours of life. Main Outcomes and Measures: Colonization with MDRO+ at day 30 of life (primary end point), late-onset sepsis and severe gastrointestinal complication (safety end points), and gut dysbiosis, ie, deviations from the microbiome of healthy, term infants (eubiosis score) based on 16-subunit ribosomal RNA and metagenomic sequencing. Results: Among the 643 infants randomized until the stop of recruitment based on interim results, 618 (median [IQR] gestational age, 31.0 [29.7-32.1] weeks; 333 male [53.9%]; mean [SD] birth weight, 1502 [369] g) had follow-up at day 30. The interim analysis with all available data from 219 infants revealed MDRO+ colonization in 43 of 115 infants (37.4%) in the probiotics group and in 39 of 104 infants (37.5%) in the control group (adjusted risk ratio, 0.99; 95% CI, 0.54-1.81; P = .97). Safety outcomes were similar in both groups, ie, late-onset sepsis (probiotics group: 8 of 316 infants [2.5%]; control group: 12 of 322 infants [3.7%]) and severe gastrointestinal complications (probiotics group: 6 of 316 infants [1.9%]; control group: 7 of 322 infants [2.2%]). The probiotics group had higher eubiosis scores than the control group at the genus level (254 vs 258 infants; median scores, 0.47 vs 0.41; odds ratio [OR], 1.07; 95% CI, 1.02-1.13) and species level (96 vs 83 infants; median scores, 0.87 vs 0.59; OR, 1.28; 95% CI, 1.19-1.38). Environmental uptake of the B infantis probiotic strain in the control group was common (41 of 84 [49%]), which was highly variable across sites and particularly occurred in infants with a sibling who was treated with probiotics. Conclusions and Relevance: Multistrain probiotics did not reduce the incidence of MDRO+ colonization at day 30 of life in preterm infants but modulated their microbiome toward eubiosis. Trial Registration: German Clinical Trials Register: DRKS00013197.
RESUMO
BACKGROUND: Although severe COVID-19 in children is rare, those with certain pre-existing health conditions are more prone to severe disease. Monoclonal antibodies (mAbs) against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are potent antiviral agents that reduce adverse clinical outcomes in adults, but are commonly not approved for use in pediatric patients. METHODS: We retrospectively evaluated mAb treatment in children <12 years of age or <40kg with SARS-CoV-2 infection between January 1, 2021, and March 7, 2022, in 12 tertiary care centers in 3 European countries. RESULTS: We received data from 53 patients from Austria, Denmark and Germany. Median age was 5.4 years [0-13.8, interquartile range (IQR) = 6.2], and median body weight was 20 kg (3-50.1, IQR = 13). The most frequent SARS-CoV-2 variant in this study, if known, was Omicron, followed by Delta and Alpha. Pre-existing conditions included immunodeficiency, malignancy, hematologic disease, cardiac disease, chronic lung disease, chronic liver disease, kidney disease and diabetes. Forty-two patients received sotrovimab (79%), 9 casirivimab/imdevimab (17%) and 2 bamlanivimab (4%). All but 1 patient survived. Median duration of hospital stay was 3 days (0-56, IQR = 6). Seven patients required treatment in an intensive care unit, and 5 required high-flow nasal cannula treatment. Potential side effects included neutropenia (6/53, 11%), lymphopenia (3/53, 6%), nausea or vomiting (2/53, 4%), rise of alanine transaminase (1/53, 2%) and hypotonia (1/53, 2%). CONCLUSIONS: MAb treatment was well tolerated by children in this cohort.
Assuntos
COVID-19 , Leucopenia , Adulto , Humanos , Criança , Lactente , Pré-Escolar , Estudos Retrospectivos , SARS-CoV-2 , Anticorpos Monoclonais/uso terapêutico , Anticorpos Neutralizantes , Anticorpos Antivirais , Doença CrônicaRESUMO
OBJECTIVE: To test whether chronic bronchial inflammation may be a contributing risk factor for persistent airflow limitation in children born before 32 weeks of gestation in later life. STUDY DESIGN: Thirty-six of 160 children born before 32 completed weeks of gestation who were born between 1988 and 1992 were recruited at a median age of 11 years. Eighteen age-matched children born at term were controls; 47% of the premature infants and 61% of the term born children produced sputum of sufficient quality for interleukin (IL)-8, cell numbers, and differential counts. RESULTS: Compared with term born children, sputum from the premature group had a higher proportion of neutrophils (62% vs 3.8%; P < .001) and higher IL-8/protein values (1.93 µg/g vs 0.64 µg/g; P = .008). Forced expiratory flow 25%-75% and forced expiratory volume in 1 second/vital capacity were significantly lower (73.4 % vs 116% predicted, P = .002 and 97% vs 101%, P = .012, respectively). Lung function values and sputum indices did not correlate. IL-8/protein and neutrophil percentages correlated significantly with decreasing gestational age (Spearman rank coefficient = -0.58, P = .020 and -.70, P =.03 respectively). CONCLUSION: A significant proportion of school children born very preterm demonstrate persistent peripheral airway obstruction that is accompanied by neutrophilic lower airway inflammation.
Assuntos
Obstrução das Vias Respiratórias/fisiopatologia , Bronquite Crônica/fisiopatologia , Doenças do Prematuro/fisiopatologia , Interleucina-8/metabolismo , Neutrófilos/metabolismo , Escarro/metabolismo , Obstrução das Vias Respiratórias/diagnóstico , Obstrução das Vias Respiratórias/metabolismo , Biomarcadores/metabolismo , Bronquite Crônica/diagnóstico , Bronquite Crônica/metabolismo , Estudos de Casos e Controles , Criança , Estudos Transversais , Feminino , Fluxo Expiratório Forçado , Volume Expiratório Forçado , Idade Gestacional , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Doenças do Prematuro/diagnóstico , Doenças do Prematuro/metabolismo , Modelos Logísticos , Masculino , Inquéritos e Questionários , Capacidade VitalRESUMO
AIM: ATP-binding cassette member A 3 (ABCA3) plays a critical role for the transport of surfactant phospholipids into the lamellar bodies of type II alveolar epithelial cells. Term infants carrying the E292V missense mutation of the gene encoding ABCA3 are likely to develop respiratory distress syndrome, and the mutation has also been linked to interstitial lung disease in paediatric patients. The aim of this study was to investigate the association of the E292V genotype with pulmonary morbidity in a large cohort of very-low-birth-weight (VLBW) infants. METHODS: We performed a genetic association study with a prospective, population-based multi-centre cohort of 3177 VLBW infants born in 16 German study centres between 2003 and 2009 (German Neonatal Network). The ABCA3 genotype was determined by restriction fragment length polymorphism-PCR in genomic DNA samples derived from buccal swabs. RESULTS: In a large cohort of 3177 VLBW infants, 11 individuals were found to be heterozygote for the E292V mutation (0.34%). After stratification according to ABCA3 genotype, no differences were noted for clinical characteristics, necessary treatments and neonatal pulmonary outcomes. CONCLUSIONS: Within the size limits of our study cohort, the ABCA3 missense mutation E292V had no remarkable effect on pulmonary outcome in VLBW infants. Present results do not rule out the possibility that E292V phenotype is associated with minor difference in the morbidity.
Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Recém-Nascido de muito Baixo Peso , Doenças Pulmonares Intersticiais/genética , Síndrome do Desconforto Respiratório do Recém-Nascido/genética , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Alemanha/epidemiologia , Humanos , Recém-Nascido , Doenças Pulmonares Intersticiais/epidemiologia , Masculino , Morbidade , Mutação de Sentido Incorreto , Estudos Prospectivos , Síndrome do Desconforto Respiratório do Recém-Nascido/epidemiologiaRESUMO
OBJECTIVES: To determine whether the tumor necrosis factor-α -308 G/A polymorphism is associated with blood culture-proven sepsis in two large cohorts of very-low-birth-weight infants. DESIGN: Genetic association studies. SETTING: Prospective, population-based, multicentered cohort of 1944 very-low-birth-weight infants born in 14 German study centers between 2003 and 2008 and 976 mothers, and a second prospective cohort of 926 very-low-birth-weight infants born in 2009 (German Neonatal Network). MEASUREMENTS AND MAIN RESULTS: In cohort I, 344 of 1944 (18.2%) very-low-birth-weight infants had at least one episode of blood culture-proven sepsis develop. The sepsis incidence stratified to genotype was 19.3% for G/G, 15.8% for G/A, 10.0% for A/A genotype (Cochrane-Armitage trend test: G/G vs. G/A: odds ratio, 1.32; 95% confidence interval, 1.03-1.71; G/G vs. A/A: odds ratio, 1.74; 95% confidence interval, 1.06-2.91; p = .03). There was a trend for association of tumor necrosis factor-α -308 A/G genotype with late-onset sepsis episodes (incidence: 17.2% for G/G, 12.5% for G/A, 10.0% for A/A genotype; Cochrane-Armitage trend test: G/G vs. G/A: odds ratio, 1.43; 95% confidence interval, 1.09-1.9; G/G vs. A/A: odds ratio, 2.05; 95% confidence interval, 1.19-3.56; p = .009). However, after adjustment for multiple testing, no significant associations were found. Furthermore, the genotype of the investigated 976 mothers had no impact on sepsis risk for their very-low-birth-weight infants. We additionally studied a second prospective cohort of 926 very-low-birth-weight infants and found no associations with sepsis risk. CONCLUSIONS: No association was found between the tumor necrosis factor-α -308 G/A polymorphism blood culture-proven sepsis in two large cohorts of very-low-birth-weight infants. A recent meta-analysis demonstrated that the tumor necrosis factor-α -308 A allele is associated with higher sepsis risk in adult cohorts. Thus, potential differences between adults and infants need to be incorporated in future study designs evaluating risk profiles for sepsis.
Assuntos
Doenças do Recém-Nascido/genética , Recém-Nascido de muito Baixo Peso , Polimorfismo Genético , Sepse/genética , Fator de Necrose Tumoral alfa/genética , Estudos de Coortes , Intervalos de Confiança , Suscetibilidade a Doenças , Ensaio de Imunoadsorção Enzimática , Feminino , Citometria de Fluxo , Alemanha , Mortalidade Hospitalar/tendências , Humanos , Recém-Nascido , Doenças do Recém-Nascido/sangue , Doenças do Recém-Nascido/mortalidade , Unidades de Terapia Intensiva Neonatal , Masculino , Razão de Chances , Prognóstico , Regiões Promotoras Genéticas/genética , Estudos Prospectivos , Medição de Risco , Sepse/sangue , Sepse/mortalidade , Análise de Sobrevida , Fator de Necrose Tumoral alfa/metabolismoRESUMO
The majority of congenital cytomegalovirus (cCMV) infections are asymptomatic at birth and therefore not diagnosed. Approximately 10-15% of these infants develop late-onset hearing loss and other developmental disorders. Implementation of a universal screening approach at birth may allow early initiation of symptomatic interventions due to a closer follow-up of infants at risk and offers the opportunity to consider treatment of late-onset disease. Real-time PCR assays for the detection of CMV DNA in buccal swab samples demonstrated feasibility and good clinical sensitivity in comparison to a rapid culture screening assay. Because most cCMV infections remain asymptomatic, a universal screening assay that stratifies CMV infected infants according to low and high risk of late-onset cCMV disease could limit the parental anxiety and reduce follow-up costs. We therefore developed and characterized a screening algorithm based on a highly-sensitive quantitative real-time PCR assay that is compatible with centralized testing of samples from universal screening and allows to determine CMV DNA load of saliva samples either as International Units (IU)/ml saliva or IU/105 cell equivalents. 18 of 34 saliva samples of newborns that tested positively by the screening algorithm were confirmed by detection of CMV DNA in blood and/or urine samples obtained during the first weeks of life. All screening samples that could not be confirmed had viral loads of <2.3x105 IU/ml saliva (median: 6.8x103) or 1.3x105 IU/105 cell equivalents (median: 4.0x102). The viral load of screening samples with confirmed cCMV infection ranged from 7.5x102 to 8.2x109 IU/ml saliva (median: 9.3x107) or 1.5x102 to 5.6x1010 IU/105 cell equivalents (median: 3.5x106). Clinical follow-up of these newborns with confirmed cCMV infection should reveal whether the risk of late-onset cCMV disease correlates with CMV DNA load in early life saliva samples and whether a cut-off can be defined identifying cCMV infected infants with or without risk for late-onset cCMV disease.
Assuntos
Infecções por Citomegalovirus/diagnóstico , Citomegalovirus/genética , Doenças do Recém-Nascido/diagnóstico , Reação em Cadeia da Polimerase Multiplex/métodos , Triagem Neonatal/métodos , Reação em Cadeia da Polimerase em Tempo Real/métodos , Infecções por Citomegalovirus/virologia , DNA Viral/genética , Feminino , Humanos , Recém-Nascido , Doenças do Recém-Nascido/sangue , Doenças do Recém-Nascido/urina , Masculino , Saliva/virologia , Urina/virologia , Carga Viral , Viremia/diagnósticoRESUMO
OBJECTIVE: To determine if survival rates of preterm infants receiving active perinatal care improve over time. DESIGN: The German Neonatal Network is a cohort study of preterm infants with birth weight <1500 g. All eligible infants receiving active perinatal care are registered. We analysed data of patients discharged between 2011 and 2016. SETTING: 43 German level III neonatal intensive care units (NICUs). PATIENTS: 8222 preterm infants with a gestational age between 22/0 and 28/6 weeks who received active perinatal care. INTERVENTIONS: Participating NICUs were grouped according to their specific survival rate from 2011 to 2013 to high (percentile >P75), intermediate (P25-P75) and low (Assuntos
Lactente Extremamente Prematuro
, Unidades de Terapia Intensiva Neonatal/estatística & dados numéricos
, Assistência Perinatal/métodos
, Assistência Perinatal/estatística & dados numéricos
, Mortalidade Perinatal/tendências
, Causas de Morte
, Comorbidade
, Feminino
, Idade Gestacional
, Nível de Saúde
, Humanos
, Lactente
, Recém-Nascido
, Recém-Nascido de muito Baixo Peso
, Masculino
, Estudos Prospectivos
, Melhoria de Qualidade
, Fatores de Risco
, Fatores Sexuais
, Centros de Atenção Terciária
RESUMO
BACKGROUND AND OBJECTIVES: Controversy exists regarding the optimal enteral feeding regimen of very low birth weight infants (VLBW). Rapid advancement of enteral feeding has been associated with an increased rate of necrotizing enterocolitis. In contrast, delaying enteral feeding may have unfavorable effects on nutrition, growth, and neurodevelopment. The aim is to compare the short-term outcomes of VLBW infants in tertiary care centers according to their enteral feeding advancement. PATIENTS AND METHODS: We prospectively studied the influence of center-specific enteral feeding advancement in 1430 VLBW infants recruited from 13 tertiary neonatal intensive care units in Germany on short-term outcome parameters. The centers were post hoc stratified to "rapid advancement to full enteral feeds" (median duration of advancement to full enteral feeds < or =12.5 days; 6 centers), that is, rapid advancement (RA), or "slow advancement to full enteral feeds" (median duration of advancement to full enteral feeds >12.5 days; 7 centers), that is, slow advancement (SA). RESULTS: VLBW infants born in centers with SA (n = 713) had a significantly higher rate of sepsis compared with VLBW infants born in centers with RA (n = 717), which was particularly evident for late-onset sepsis (14.0% vs 20.4%; P = 0.002). Furthermore, more central venous lines (48.6% vs 31.1%, P < 0.001) and antibiotics (92.4% vs 77.7%, P < 0.001) were used in centers with SA. CONCLUSIONS: Center differences in enteral feeding advancement occur and may have a significant impact on short-term outcomes such as nosocomial sepsis. Large, multicenter, prospective trials are required to further elucidate the optimal feeding strategy for VLBW infants.
Assuntos
Nutrição Enteral/métodos , Recém-Nascido Prematuro , Recém-Nascido de muito Baixo Peso , Antibacterianos/uso terapêutico , Nutrição Enteral/efeitos adversos , Feminino , Humanos , Recém-Nascido , Unidades de Terapia Intensiva Neonatal , Gravidez , Estudos Prospectivos , Sepse/etiologia , Sepse/prevenção & controle , Fatores de Tempo , Resultado do TratamentoRESUMO
Laminin 332-deficient junctional epidermolysis bullosa (JEB) is a severe genetic skin disease. JEB is marked by epidermal stem cell depletion, the origin of which is unknown. We show that dysregulation of the YAP and TAZ pathway underpins such stem cell depletion. Laminin 332-mediated YAP activity sustains human epidermal stem cells, detected as holoclones. Ablation of YAP selectively depletes holoclones, while enforced YAP blocks conversion of stem cells into progenitors and indefinitely extends the keratinocyte lifespan. YAP is dramatically decreased in JEB keratinocytes, which contain only phosphorylated, inactive YAP. In normal keratinocytes, laminin 332 and α6ß4 ablation abolish YAP activity and recapitulate the JEB phenotype. In JEB keratinocytes, laminin 332-gene therapy rescues YAP activity and epidermal stem cells in vitro and in vivo. In JEB cells, enforced YAP recapitulates laminin 332-gene therapy, thus uncoupling adhesion from proliferation in epidermal stem cells. This work has important clinical implication for ex vivo gene therapy of JEB.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Moléculas de Adesão Celular , Epiderme/metabolismo , Epidermólise Bolhosa , Terapia Genética , Células-Tronco/metabolismo , Fatores de Transcrição/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Adesão Celular , Moléculas de Adesão Celular/biossíntese , Moléculas de Adesão Celular/genética , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular , Epiderme/patologia , Epidermólise Bolhosa/genética , Epidermólise Bolhosa/metabolismo , Epidermólise Bolhosa/patologia , Epidermólise Bolhosa/terapia , Humanos , Queratinócitos/metabolismo , Queratinócitos/patologia , Camundongos , Células-Tronco/patologia , Fatores de Transcrição/genética , Proteínas de Sinalização YAP , CalininaRESUMO
BACKGROUND: Levels or fluctuations in the partial pressure of CO2 (PCO2) may affect outcomes for extremely low birth weight infants. OBJECTIVES: In an exploratory analysis of a randomized trial, we hypothesized that the PCO2 values achieved could be related to significant outcomes. METHODS: On each treatment day, infants were divided into 4 groups: relative hypocapnia, normocapnia, hypercapnia, or fluctuating PCO2. Ultimate assignment to a group for the purpose of this analysis was made according to the group in which an infant spent the most days. Statistical analyses were performed with analysis of variance (ANOVA), the Kruskal-Wallis test, the χ2 test, and the Fisher exact test as well as by multiple logistic regression. RESULTS: Of the 359 infants, 57 were classified as hypocapnic, 230 as normocapnic, 70 as hypercapnic, and 2 as fluctuating PCO2. Hypercapnic infants had a higher average product of mean airway pressure and fraction of inspired oxygen (MAP × FiO2). For this group, mortality was higher, as was the likelihood of having moderate/severe bronchopulmonary dysplasia (BPD), necrotizing enterocolitis (NEC), and poorer neurodevelopment. Multiple logistic regression analyses showed an increased risk for BPD or death associated with birth weight (p < 0.001) and MAP × FiO2 (p < 0.01). The incidence of adverse neurodevelopment was associated with birth weight (p < 0.001) and intraventricular hemorrhage (IVH; p < 0.01). CONCLUSIONS: Birth weight and respiratory morbidity, as measured by MAP × FiO2, were the most predictive of death or BPD and NEC, whereas poor neurodevelopmental outcome was associated with low birth weight and IVH. Univariate models also identified PCO2. Thus, hypercapnia seems to reflect greater disease severity, a likely contributor to differences in outcomes.
Assuntos
Dióxido de Carbono/sangue , Desenvolvimento Infantil , Recém-Nascido de Peso Extremamente Baixo ao Nascer , Lactente Extremamente Prematuro , Respiração Artificial , Peso ao Nascer , Displasia Broncopulmonar/epidemiologia , Hemorragia Cerebral/epidemiologia , Enterocolite Necrosante/epidemiologia , Feminino , Alemanha/epidemiologia , Idade Gestacional , Humanos , Hipercapnia/epidemiologia , Lactente , Recém-Nascido , Modelos Logísticos , Masculino , Testes Neuropsicológicos , Valor Preditivo dos Testes , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
BACKGROUND: Treatment of severe diffuse congenital hyperinsulinism (CHI) without sufficient response to diazoxide is complicated by the lack of approved drugs. Therefore, patients are often hospitalized long-term or have to undergo pancreatic surgery if episodes of severe hypoglycaemia cannot be prevented. A long-acting somatostatin analogue, octreotide, has been reported to be an effective treatment option that prevents severe hypoglycaemia in children with CHI, and its off-label use is common in CHI. However, octreotide requires continuous i.v. or s.c. infusion or multiple daily injections. Here, we report our experiences with the use of a monthly application of a long-acting somatostatin analogue, lanreotide autogel® (LAN-ATG), in early infancy. RESULTS: The mean blood glucose concentration within 7 days before the first LAN-ATG administration were compared to 7 days after the first LAN-ATG administration and increased by 0.75 mmol/L (range 0.39-1.19 mmol/L). In the following weeks intravenous glucose infusions, octreotide, and glucagon treatment could be successfully stopped in all patients 3-20 days after the first LAN-ATG injection without substantial worsening of the hypoglycaemia rate. Increased carbohydrate requirements could be normalized with an average reduction in the carbohydrate-intake of 7 g/kg body weight/d (range 1.75-12.8 g/kg body weight/d). Over a total of 52 treatment months, no serious adverse effects occurred. CONCLUSION: Long-term LAN-ATG treatment improved blood glucose concentrations, lowered the frequency of hypoglycaemia or allowed for normalization of oral carbohydrate intake in infants with CHI younger than 6 months of age. No severe side effects were observed. LAN-ATG might be an alternative treatment option in infants with severe CHI who lack risk factors for necrotizing enterocolitis and are not responding to current treatment regimens as an alternative to surgery after careful individual evaluation.
Assuntos
Hiperinsulinismo Congênito/tratamento farmacológico , Peptídeos Cíclicos/administração & dosagem , Peptídeos Cíclicos/uso terapêutico , Somatostatina/análogos & derivados , Diazóxido/uso terapêutico , Feminino , Géis/administração & dosagem , Humanos , Lactente , Recém-Nascido , Masculino , Somatostatina/administração & dosagem , Somatostatina/uso terapêuticoRESUMO
BACKGROUND: Tolerating higher partial pressures of carbon dioxide (PCO2) in mechanically ventilated extremely low birthweight infants to reduce ventilator-induced lung injury may have long-term neurodevelopmental side effects. This study analyses the results of neurodevelopmental follow-up of infants enrolled in a randomised multicentre trial. METHODS: Infants (n=359) between 400 and 1000â g birth weight and 23 0/7-28 6/7â weeks gestational age who required endotracheal intubation and mechanical ventilation within 24â hours of birth were randomly assigned to high PCO2 or to a control group with mildly elevated PCO2 targets. Neurodevelopmental follow-up examinations were available for 85% of enrolled infants using the Bayley Scales of Infant Development II, the Gross Motor Function Classification System (GMFCS) and the Child Development Inventory (CDI). RESULTS: There were no differences in body weight, length and head circumference between the two PCO2 target groups. Median Mental Developmental Index (MDI) values were 82 (60-96, high target) and 84 (58-96, p=0.79). Psychomotor Developmental Index (PDI) values were 84 (57-100) and 84 (65-96, p=0.73), respectively. Moreover, there was no difference in the number of infants with MDI or PDI <70 or <85 and the number of infants with a combined outcome of death or MDI<70 and death or PDI<70. No differences were found between results for GMFCS and CDI. The risk factors for MDI<70 or PDI<70 were intracranial haemorrhage, bronchopulmonary dysplasia, periventricular leukomalacia, necrotising enterocolitis and hydrocortisone treatment. CONCLUSIONS: A higher PCO2 target did not influence neurodevelopmental outcomes in mechanically ventilated extremely preterm infants. Adjusting PCO2 targets to optimise short-term outcomes is a safe option. TRIAL REGISTRATION NUMBER: ISRCTN56143743.
Assuntos
Dióxido de Carbono/sangue , Desenvolvimento Infantil , Recém-Nascido de Peso Extremamente Baixo ao Nascer , Lactente Extremamente Prematuro , Respiração Artificial , Anti-Inflamatórios/efeitos adversos , Displasia Broncopulmonar/epidemiologia , Paralisia Cerebral/epidemiologia , Enterocolite Necrosante/epidemiologia , Feminino , Humanos , Hidrocortisona/efeitos adversos , Lactente , Recém-Nascido , Hemorragias Intracranianas/epidemiologia , Intubação Intratraqueal , Leucomalácia Periventricular/epidemiologia , Masculino , Testes NeuropsicológicosRESUMO
IMPORTANCE: Treatment of respiratory distress syndrome in premature infants with continuous positive airway pressure (CPAP) preserves surfactant and keeps the lung open but is insufficient in severe surfactant deficiency. Traditional surfactant administration is related to short periods of positive pressure ventilation and implies the risk of lung injury. CPAP with surfactant but without any positive pressure ventilation may work synergistically. This randomized trial investigated a less invasive surfactant application protocol (LISA). OBJECTIVE: To test the hypothesis that LISA increases survival without bronchopulmonary dysplasia (BPD) at 36 weeks' gestational age in extremely preterm infants. DESIGN, SETTING, AND PARTICIPANTS: The Nonintubated Surfactant Application trial was a multicenter, randomized, clinical, parallel-group study conducted between April 15, 2009, and March 25, 2012, in 13 level III neonatal intensive care units in Germany. The final follow-up date was June 21, 2012. Participants included 211 of 558 eligible (37.8%) spontaneously breathing preterm infants born between 23.0 and 26.8 weeks' gestational age with signs of respiratory distress syndrome. In an intention-to-treat design, infants were randomly assigned to receive surfactant either via a thin endotracheal catheter during CPAP-assisted spontaneous breathing (intervention group) or after conventional endotracheal intubation during mechanical ventilation (control group). Analysis was conducted from September 6, 2012, to June 20, 2013. INTERVENTION: LISA via a thin catheter. MAIN OUTCOMES AND MEASURES: Survival without BPD at 36 weeks' gestational age. RESULTS: Of 211 infants who were randomized, 104 were randomized to the control group and 107 to the LISA group. Of the infants who received LISA, 72 (67.3%) survived without BPD compared with 61 (58.7%) of those in the control group. The reduction in absolute risk was 8.6% (95% CI, -5.0% to 21.9%; P = .20). Intervention group infants were less frequently intubated (80 infants [74.8%] vs 103 [99.0%]; P < .001) and required fewer days of mechanical ventilation. Significant reductions were seen in pneumothorax (5 of 105 intervention group infants [4.8%] vs 13 of 103 12.6%]; P = .04) and severe intraventricular hemorrhage (11 infants [10.3%] vs 23 [22.1%]; P = .02), and the combined survival without severe adverse events was increased in the intervention group (54 infants [50.5%] vs 37 [35.6%]; P = .02; absolute risk reduction, 14.9; 95% CI, 1.4 to 28.2). CONCLUSIONS AND RELEVANCE: LISA did not increase survival without BPD but was associated with increased survival without major complications. Because major complications are related to lifelong disabilities, LISA may be a promising therapy for extremely preterm infants. TRIAL REGISTRATION: isrctn.org Identifier: ISRCTN64011614.