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Congenital diaphragmatic hernia (CDH) is a severe congenital anomaly often accompanied by other structural anomalies and/or neurobehavioral manifestations. Rare de novo protein-coding variants and copy-number variations contribute to CDH in the population. However, most individuals with CDH remain genetically undiagnosed. Here, we perform integrated de novo and common-variant analyses using 1,469 CDH individuals, including 1,064 child-parent trios and 6,133 ancestry-matched, unaffected controls for the genome-wide association study. We identify candidate CDH variants in 15 genes, including eight novel genes, through deleterious de novo variants. We further identify two genomic loci contributing to CDH risk through common variants with similar effect sizes among Europeans and Latinx. Both loci are in putative transcriptional regulatory regions of developmental patterning genes. Estimated heritability in common variants is â¼19%. Strikingly, there is no significant difference in estimated polygenic risk scores between isolated and complex CDH or between individuals harboring deleterious de novo variants and individuals without these variants. The data support a polygenic model as part of the CDH genetic architecture.
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BACKGROUND: By March, 2023, 54 countries, areas, and territories (hereafter CAT) in the WHO European Region had reported more than 2·2 million COVID-19-related deaths to the WHO Regional Office for Europe. Here, we estimated how many lives were directly saved by vaccinating adults in the WHO European Region from December, 2020, to March, 2023. METHODS: In this retrospective surveillance study, we estimated the number of lives directly saved by age group, vaccine dose, and circulating variant-of-concern (VOC) period, regionally and nationally, using weekly data on COVID-19 mortality and infection, COVID-19 vaccination uptake, and SARS-CoV-2 virus characterisations by lineage downloaded from The European Surveillance System on June 11, 2023, as well as vaccine effectiveness data from the literature. We included data for six age groups (25-49 years, 50-59 years, ≥60 years, 60-69 years, 70-79 years, and ≥80 years). To be included in the analysis, CAT needed to have reported both COVID-19 vaccination and mortality data for at least one of the four older age groups. Only CAT that reported weekly data for both COVID-19 vaccination and mortality by age group for 90% of study weeks or more in the full study period were included. We calculated the percentage reduction in the number of expected and reported deaths. FINDINGS: Between December, 2020, and March, 2023, in 34 of 54 CAT included in the analysis, COVID-19 vaccines reduced deaths by 59% overall (CAT range 17-82%), representing approximately 1·6 million lives saved (range 1·5-1·7 million) in those aged 25 years or older: 96% of lives saved were aged 60 years or older and 52% were aged 80 years or older; first boosters saved 51% of lives, and 60% were saved during the Omicron period. INTERPRETATION: Over nearly 2·5 years, most lives saved by COVID-19 vaccination were in older adults by first booster dose and during the Omicron period, reinforcing the importance of up-to-date vaccination among the most at-risk individuals. Further modelling work should evaluate indirect effects of vaccination and public health and social measures. FUNDING: US Centers for Disease Control and Prevention.
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Vacunas contra la COVID-19 , COVID-19 , SARS-CoV-2 , Humanos , COVID-19/prevención & control , COVID-19/mortalidad , COVID-19/epidemiología , Estudios Retrospectivos , Persona de Mediana Edad , Anciano , Vacunas contra la COVID-19/administración & dosificación , Adulto , Europa (Continente)/epidemiología , Anciano de 80 o más Años , SARS-CoV-2/inmunología , Programas de Inmunización/estadística & datos numéricos , Organización Mundial de la Salud , Masculino , FemeninoRESUMEN
During the summer of 2023, the European Region experienced a limited resurgence of mpox cases following the substantial outbreak in 2022. This increase was characterised by asynchronous and bimodal increases, with countries experiencing peaks at different times. The demographic profile of cases during the resurgence was largely consistent with those reported previously. All available sequences from the European Region belonged to clade IIb. Sustained efforts are crucial to control and eventually eliminate mpox in the European Region.
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Brotes de Enfermedades , Filogenia , Humanos , Europa (Continente)/epidemiología , Masculino , Femenino , Adulto , Persona de Mediana Edad , Adolescente , Adulto Joven , Niño , Anciano , Vigilancia de la Población , Preescolar , IncidenciaRESUMEN
Gonorrhoea cases increased steeply in women aged 20 to 24 years across 15 EU/EEA countries in July to December 2022 and January to June 2023 with, respectively, 73% and 89% more cases reported than expected, based on historical data from 2015 to 2019. Smaller increases among men due to heterosexual transmission were observed in nine EU/EEA countries. Interventions to raise awareness among young people about sexually transmitted infection risks are needed, emphasising the benefit of safe sexual practices and testing.
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Gonorrea , Enfermedades de Transmisión Sexual , Masculino , Humanos , Femenino , Adolescente , Gonorrea/epidemiología , Enfermedades de Transmisión Sexual/epidemiología , Conducta Sexual , HeterosexualidadRESUMEN
Background: The emergence of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) in early 2020 and subsequent implementation of public health and social measures (PHSM) disrupted the epidemiology of respiratory viruses. This work describes the epidemiology of respiratory syncytial virus (RSV) observed during two winter seasons (weeks 40-20) and inter-seasonal periods (weeks 21-39) during the pandemic between October 2020 and September 2022. Methods: Using data submitted to The European Surveillance System (TESSy) by countries or territories in the World Health Organization (WHO) European Region between weeks 40/2020 and 39/2022, we aggregated country-specific weekly RSV counts of sentinel, non-sentinel and Severe Acute Respiratory Infection (SARI) surveillance specimens and calculated percentage positivity. Results for both 2020/21 and 2021/22 seasons and inter-seasons were compared with pre-pandemic 2016/17 to 2019/20 seasons and inter-seasons. Results: Although more specimens were tested than in pre-COVID-19 pandemic seasons, very few RSV detections were reported during the 2020/21 season in all surveillance systems. During the 2021 inter-season, a gradual increase in detections was observed in all systems. In 2021/22, all systems saw early peaks of RSV infection, and during the 2022 inter-seasonal period, patterns of detections were closer to those seen before the COVID-19 pandemic. Conclusion: RSV surveillance continued throughout the COVID-19 pandemic, with an initial reduction in transmission, followed by very high and out-of-season RSV circulation (summer 2021) and then an early start of the 2021/22 season. As of the 2022/23 season, RSV circulation had not yet normalised.
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COVID-19 , Infecciones por Virus Sincitial Respiratorio , Virus Sincitial Respiratorio Humano , Humanos , Estaciones del Año , Pandemias , Vigilancia de la Población , COVID-19/epidemiología , SARS-CoV-2 , Infecciones por Virus Sincitial Respiratorio/epidemiologíaRESUMEN
BACKGROUND: Extensive measures to control spread of SARS-CoV-2 have led to limited access to education for millions of children and adolescents during the COVID-19 pandemic. Education and access to schools is vital for children and adolescents' learning, health, and wellbeing. Based on high vaccine uptake and low incidence levels, the Nordic countries (Denmark, Finland, Iceland, Norway and Sweden) decided to start the academic year 2021/22 with schools open for in-person teaching and moderate mitigation measures. We describe trends in SARS-CoV-2 infections and vaccination coverage among students during the first 12 weeks of the fall semester. METHODS: In this multinational, retrospective, observational study, we have used surveillance and registry data from each of the Nordic countries to describe vaccine uptake (≥12 years), infection incidence (whole population) and transmission of SARS-CoV-2 among students. The study period, week 30 to 41 (Jul 26th - Oct 17th), represents the autumn semester from immediately before school started until fall break. In addition, we collected information on mitigation measures applied by the respective countries. RESULTS: There were slight variations between the countries regarding existing infection prevention and control (IPC) measures, testing strategies and vaccination start-up among adolescents. All countries had high vaccine uptake in the adult population, while uptake varied more in the younger age groups. Incidence in the school-aged population differed between countries and seemed to be influenced by both vaccine uptake and test activity. Infection clusters among school-aged children were described for Denmark and Norway, and the number of clusters per week reflected the incidence trend of the country. Most events consisted of only 1-2 cases. Larger clusters appeared more frequently in the higher grades in Norway and in lower grades in Denmark. CONCLUSION: Data from the Nordic countries indicate that vaccination of adults and adolescents, in addition to mitigation measures, enabled full in-person learning. As SARS-CoV-2 infection does not represent a severe medical risk for most children as previously thought, measures targeting this group should be carefully adjusted and kept at a minimum. Our data add to the evidence on incidence and transmission of SARS-CoV-2 among students in schools open for in-person teaching, and may be valuable for decision makers worldwide.
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COVID-19 , Adolescente , Adulto , Niño , Humanos , COVID-19/epidemiología , COVID-19/prevención & control , Pandemias/prevención & control , Estudios Retrospectivos , SARS-CoV-2 , Instituciones AcadémicasRESUMEN
Following the report of a non-travel-associated cluster of monkeypox cases by the United Kingdom in May 2022, 41 countries across the WHO European Region have reported 21,098 cases and two deaths by 23 August 2022. Nowcasting suggests a plateauing in case notifications. Most cases (97%) are MSM, with atypical rash-illness presentation. Spread is mainly through close contact during sexual activities. Few cases are reported among women and children. Targeted interventions of at-risk groups are needed to stop further transmission.
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Exantema , Mpox , Animales , Niño , Brotes de Enfermedades , Femenino , Humanos , Mpox/diagnóstico , Mpox/epidemiología , Monkeypox virus , Organización Mundial de la SaludRESUMEN
BACKGROUND/PURPOSE: As survival rates for patients with congenital diaphragmatic hernia (CDH) increase, long-term sequelae become increasingly prevalent. We present the outcomes of patients who underwent CDH repair at our institution and discuss standardization of follow-up care in our long-term multidisciplinary follow-up clinic. METHODS: A retrospective review of patients followed in multidisciplinary clinic after CDH repair at our institution from January 1, 2005 to December 1, 2020. RESULTS: A total of 193 patients met inclusion criteria, 73 females (37.8%) and 120 males (62.2%). Left-sided defects were most common (75.7%), followed by right-sided defects (20.7%). Median age at repair was 4 days (IQR 3-6) and 59.6% of all defects required patch repair. Median length of stay was 29 days (IQR 16.8-50.0). Median length of follow up was 49 months (IQR 17.8-95.3) with 25 patients followed for more than 12 years. Long-term outcomes included gastroesophageal reflux disease (42.0%), diaphragmatic hernia recurrence (10.9%), asthma (23.6%), neurodevelopmental delay (28.6%), attention deficit hyperactivity disorder (7.3%), autism (1.6%), chest wall deformity (15.5%), scoliosis (11.4%), and inguinal hernia (6.7%). CONCLUSION: As survival of patients with CDH improves, long-term care must be continuously studied and fine-tuned to ensure appropriate surveillance and optimization of long-term outcomes.
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Hernias Diafragmáticas Congénitas , Escoliosis , Pared Torácica , Femenino , Hernias Diafragmáticas Congénitas/complicaciones , Hernias Diafragmáticas Congénitas/cirugía , Herniorrafia , Humanos , Masculino , Estudios Retrospectivos , Escoliosis/complicaciones , Pared Torácica/anomalías , Resultado del TratamientoRESUMEN
Congenital diaphragmatic hernia (CDH) is a severe congenital anomaly that is often accompanied by other anomalies. Although the role of genetics in the pathogenesis of CDH has been established, only a small number of disease-associated genes have been identified. To further investigate the genetics of CDH, we analyzed de novo coding variants in 827 proband-parent trios and confirmed an overall significant enrichment of damaging de novo variants, especially in constrained genes. We identified LONP1 (lon peptidase 1, mitochondrial) and ALYREF (Aly/REF export factor) as candidate CDH-associated genes on the basis of de novo variants at a false discovery rate below 0.05. We also performed ultra-rare variant association analyses in 748 affected individuals and 11,220 ancestry-matched population control individuals and identified LONP1 as a risk gene contributing to CDH through both de novo and ultra-rare inherited largely heterozygous variants clustered in the core of the domains and segregating with CDH in affected familial individuals. Approximately 3% of our CDH cohort who are heterozygous with ultra-rare predicted damaging variants in LONP1 have a range of clinical phenotypes, including other anomalies in some individuals and higher mortality and requirement for extracorporeal membrane oxygenation. Mice with lung epithelium-specific deletion of Lonp1 die immediately after birth, most likely because of the observed severe reduction of lung growth, a known contributor to the high mortality in humans. Our findings of both de novo and inherited rare variants in the same gene may have implications in the design and analysis for other genetic studies of congenital anomalies.
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Proteasas ATP-Dependientes/genética , Proteasas ATP-Dependientes/fisiología , Anomalías Craneofaciales/genética , Variaciones en el Número de Copia de ADN , Anomalías del Ojo/genética , Trastornos del Crecimiento/genética , Hernias Diafragmáticas Congénitas/genética , Luxación Congénita de la Cadera/genética , Proteínas Mitocondriales/genética , Proteínas Mitocondriales/fisiología , Mutación Missense , Osteocondrodisplasias/genética , Anomalías Dentarias/genética , Animales , Estudios de Casos y Controles , Estudios de Cohortes , Anomalías Craneofaciales/patología , Anomalías del Ojo/patología , Femenino , Trastornos del Crecimiento/patología , Hernias Diafragmáticas Congénitas/patología , Luxación Congénita de la Cadera/patología , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Osteocondrodisplasias/patología , Linaje , Anomalías Dentarias/patologíaRESUMEN
Since the introduction of non-pharmacological interventions to control COVID-19, respiratory syncytial virus (RSV) activity in Europe has been limited. Surveillance data for 17 countries showed delayed RSV epidemics in France (≥â¯12 w) and Iceland (≥â¯4 w) during the 2020/21 season. RSV cases (predominantly small children) in France and Iceland were older compared with previous seasons. We hypothesise that future RSV epidemic(s) could start outside the usual autumn/winter season and be larger than expected. Year-round surveillance of RSV is of critical importance.
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COVID-19 , Infecciones por Virus Sincitial Respiratorio , Virus Sincitial Respiratorio Humano , Niño , Europa (Continente)/epidemiología , Francia/epidemiología , Humanos , Islandia/epidemiología , Lactante , Infecciones por Virus Sincitial Respiratorio/epidemiología , Infecciones por Virus Sincitial Respiratorio/prevención & control , SARS-CoV-2 , Estaciones del AñoRESUMEN
The diaphragm is critical for respiration and separation of the thoracic and abdominal cavities, and defects in diaphragm development are the cause of congenital diaphragmatic hernias (CDH), a common and often lethal birth defect. The genetic etiology of CDH is complex. Single-nucleotide variants (SNVs), insertions/deletions (indels), and structural variants (SVs) in more than 150 genes have been associated with CDH, although few genes are recurrently mutated in multiple individuals and mutated genes are incompletely penetrant. This suggests that multiple genetic variants in combination, other not-yet-investigated classes of variants, and/or nongenetic factors contribute to CDH etiology. However, no studies have comprehensively investigated in affected individuals the contribution of all possible classes of variants throughout the genome to CDH etiology. In our study, we used a unique cohort of four individuals with isolated CDH with samples from blood, skin, and diaphragm connective tissue and parental blood and deep whole-genome sequencing to assess germline and somatic de novo and inherited SNVs, indels, and SVs. In each individual we found a different mutational landscape that included germline de novo and inherited SNVs and indels in multiple genes. We also found in two individuals a 343 bp deletion interrupting an annotated enhancer of the CDH-associated gene GATA4, and we hypothesize that this common SV (found in 1%-2% of the population) acts as a sensitizing allele for CDH. Overall, our comprehensive reconstruction of the genetic architecture of four CDH individuals demonstrates that the etiology of CDH is heterogeneous and multifactorial.
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PURPOSE: Congenital diaphragmatic hernia (CDH) is associated with significant mortality and long-term morbidity in some but not all individuals. We hypothesize monogenic factors that cause CDH are likely to have pleiotropic effects and be associated with worse clinical outcomes. METHODS: We enrolled and prospectively followed 647 newborns with CDH and performed genomic sequencing on 462 trios to identify de novo variants. We grouped cases into those with and without likely damaging (LD) variants and systematically assessed CDH clinical outcomes between the genetic groups. RESULTS: Complex cases with additional congenital anomalies had higher mortality than isolated cases (P = 8 × 10-6). Isolated cases with LD variants had similar mortality to complex cases and much higher mortality than isolated cases without LD (P = 3 × 10-3). The trend was similar with pulmonary hypertension at 1 month. Cases with LD variants had an estimated 12-17 points lower scores on neurodevelopmental assessments at 2 years compared with cases without LD variants, and this difference is similar in isolated and complex cases. CONCLUSION: We found that the LD genetic variants are associated with higher mortality, worse pulmonary hypertension, and worse neurodevelopment outcomes compared with non-LD variants. Our results have important implications for prognosis, potential intervention and long-term follow up for children with CDH.
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Hernias Diafragmáticas Congénitas , Niño , Hernias Diafragmáticas Congénitas/genética , Humanos , Recién Nacido , Estudios RetrospectivosRESUMEN
BACKGROUND: Current practice patterns and opinions regarding subspecialization within pediatric surgery are not well known. We aimed to characterize the prevalence of and attitudes surrounding subspecialization within pediatric surgery. METHODS: An anonymous survey regarding subspecialization was distributed to all nonresident members of the American Pediatric Surgical Association. RESULTS: Of 1118 surveys, we received 458 responses (41%). A majority of respondents labeled themselves 'general pediatric surgeons' (63%), while 34% considered themselves general surgeons with a specific clinical focus, and 3% reported practicing solely within a specific niche. Subspecialists commonly serve as consultants for relevant cases (52%). Common niches included oncology (10%) and anorectal malformations (9%). Subspecialists felt to be necessary included transplant (79%) and fetal (78%) surgeons. Opinions about subspecialization were variable: 41% felt subspecialization improves patient care while 39% believe it is detrimental to surgeon well-roundedness. Only 10% felt subspecialists should practice solely within their subspecialty. Practicing at an academic hospital or fellowship program correlated with subspecialization, while length of time in practice did not. CONCLUSION: While pediatric surgeons report that subspecialization may benefit patient care, concerns exist regarding the unfavorable effect it may have on the individual surgeon. A better understanding of how subspecialization affects quality and outcomes would help clarify its utility. TYPE OF STUDY: Review article. LEVEL OF EVIDENCE: Level V.
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Pediatras/estadística & datos numéricos , Cirujanos/estadística & datos numéricos , Humanos , Pediatras/organización & administración , Cirujanos/organización & administración , Encuestas y Cuestionarios , Estados UnidosRESUMEN
BACKGROUND: The impact of social, racial, and economic inequities on health and surgical outcomes for children is poorly described. METHODS: A systematic review using search terms related to disparities in care of pediatric appendicitis identified 20 titles and narrowed to 11 full texts. Nine retrospective studies were analyzed, representing 350,408 cases treated across the United States from 1983 to 2010. Outcomes included length of stay (LOS), appendiceal perforation rate (AP), laparoscopic versus open approach, and rate of misdiagnosis. RESULTS: The most frequently reported outcomes were LOS (six of nine studies) and AP (six of nine studies). AP was higher for young children (48% for <6 versus 25% for >10), those in rural settings (42% versus 26% in urban settings), and patients receiving care at children's hospitals (35% versus 22% at nonchildren's hospitals). Longer LOS was associated with young age in three studies (2-5 d for age <10 y versus 1-3 d for age >11 y), race in four studies (1.5-3 d for African American children versus 1-2 d for other races), and lower family income in two studies (2-4 d versus 1-3 d for highest income). Inequitable use of laparoscopy, time to surgery, and rates of misdiagnosis were also reported to be associated with age and race. CONCLUSIONS: Although limited, the existing literature suggests that social, racial, and economic inequalities impact management and outcomes in pediatric appendicitis. More studies are needed to better describe and mitigate disparities in the surgical care of children.
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Apendicectomía/estadística & datos numéricos , Apendicitis/cirugía , Disparidades en Atención de Salud/estadística & datos numéricos , Perforación Intestinal/epidemiología , Laparoscopía/estadística & datos numéricos , Negro o Afroamericano/estadística & datos numéricos , Factores de Edad , Apendicitis/complicaciones , Apendicitis/diagnóstico , Niño , Errores Diagnósticos/estadística & datos numéricos , Hospitales Pediátricos/estadística & datos numéricos , Humanos , Perforación Intestinal/etiología , Tiempo de Internación/estadística & datos numéricos , Población Rural/estadística & datos numéricos , Factores Socioeconómicos , Tiempo de Tratamiento/estadística & datos numéricosRESUMEN
BACKGROUND: Congenital diaphragmatic hernia (CDH) occurs in 1 out of 2500-3000 live births. Right-sided CDHs (R-CDHs) comprise 25% of all CDH cases, and data are conflicting on outcomes of these patients. The aim of our study was to compare outcomes in patients with right versus left CDH (L-CDH). METHODS: We analyzed a multicenter prospectively enrolled database to compare baseline characteristics and outcomes of neonates enrolled from January 2005 to January 2019 with R-CDH vs. L-CDH. RESULTS: A total of 588, 495 L-CDH, and 93 R-CDH patients with CDH were analyzed. L-CDHs were more frequently diagnosed prenatally (p=0.011). Lung-to-head ratio was similar in both cohorts. R-CDHs had a lower frequency of primary repair (p=0.022) and a higher frequency of need for oxygen at discharge (p=0.013). However, in a multivariate analysis, need for oxygen at discharge was no longer significantly different. There were no differences in long-term neurodevelopmental outcomes assessed at two year follow up. There was no difference in mortality, need for ECMO, pulmonary hypertension, or hernia recurrence. CONCLUSION: In this large series comparing R to L-CDH patients, we found no significant difference in mortality, use of ECMO, or pulmonary complications. Our study supports prior studies that R-CDHs are relatively larger and more often require a patch or muscle flap for repair. TYPE OF STUDY: Prognosis study LEVEL OF EVIDENCE: Level II.
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Hernias Diafragmáticas Congénitas , Oxigenación por Membrana Extracorpórea , Hernias Diafragmáticas Congénitas/complicaciones , Hernias Diafragmáticas Congénitas/epidemiología , Hernias Diafragmáticas Congénitas/mortalidad , Hernias Diafragmáticas Congénitas/terapia , Humanos , Hipertensión Pulmonar , Recién Nacido , Estudios RetrospectivosRESUMEN
Choledochal cysts (CDCs) and biliary atresia (BA) are rare pediatric hepatobiliary anomalies that require surgical intervention due to increased risk of malignancy and liver failure, respectively. The underlying disease and operative procedures place patients at risk for long-term complications, which may continue to affect them into adulthood. Lack of a transitional care model in the health-care system potentiates the challenges they will face following aging out of their pediatric providers' care. We sought to elucidate the long-term complications and challenges patients with CDCs and BA face, review the current literature regarding transitioning care, and propose guidelines aiding adult providers in continued care and surveillance of these patients. A literature review was performed to assess short-term and long-term complications after surgery and the current standards for transitioning care in patients with a history of CDCs and BA. While transitional programs exist for patients with other gastrointestinal diseases, there are few that focus on CDCs or BA. Generally, authors encourage medical record transmission from pediatric to adult providers, ensuring accuracy of information and compliance with treatment plans. Patients with CDCs are at risk for developing biliary malignancies, cholangitis, and anastomotic strictures after resection. Patients with BA develop progressive liver failure, necessitating transplantation. There are no consensus guidelines regarding timing of follow up for these patients. Based on the best available evidence, we propose a schema for long-term surveillance.
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Atresia Biliar/terapia , Quiste del Colédoco/terapia , Cuidado de Transición , Adolescente , Adulto , Atresia Biliar/complicaciones , Neoplasias del Sistema Biliar/etiología , Niño , Quiste del Colédoco/complicaciones , Humanos , Fallo Hepático/etiología , Guías de Práctica Clínica como Asunto , Riesgo , Cuidado de Transición/normas , Adulto JovenRESUMEN
Congenital diaphragmatic hernia (CDH) is a severe birth defect that is often accompanied by other congenital anomalies. Previous exome sequencing studies for CDH have supported a role of de novo damaging variants but did not identify any recurrently mutated genes. To investigate further the genetics of CDH, we analyzed de novo coding variants in 362 proband-parent trios including 271 new trios reported in this study. We identified four unrelated individuals with damaging de novo variants in MYRF (P = 5.3x10(-8)), including one likely gene-disrupting (LGD) and three deleterious missense (D-mis) variants. Eight additional individuals with de novo LGD or missense variants were identified from our other genetic studies or from the literature. Common phenotypes of MYRF de novo variant carriers include CDH, congenital heart disease and genitourinary abnormalities, suggesting that it represents a novel syndrome. MYRF is a membrane associated transcriptional factor highly expressed in developing diaphragm and is depleted of LGD variants in the general population. All de novo missense variants aggregated in two functional protein domains. Analyzing the transcriptome of patient-derived diaphragm fibroblast cells suggest that disease associated variants abolish the transcription factor activity. Furthermore, we showed that the remaining genes with damaging variants in CDH significantly overlap with genes implicated in other developmental disorders. Gene expression patterns and patient phenotypes support pleiotropic effects of damaging variants in these genes on CDH and other developmental disorders. Finally, functional enrichment analysis implicates the disruption of regulation of gene expression, kinase activities, intra-cellular signaling, and cytoskeleton organization as pathogenic mechanisms in CDH.
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Variación Genética , Hernias Diafragmáticas Congénitas/genética , Proteínas de la Membrana/genética , Mutación , Factores de Transcripción/genética , Preescolar , Variaciones en el Número de Copia de ADN , Discapacidades del Desarrollo/genética , Femenino , Cardiopatías Congénitas/genética , Hernias Diafragmáticas Congénitas/metabolismo , Humanos , Recién Nacido , Estudios Longitudinales , Masculino , Proteínas de la Membrana/metabolismo , Mutación Missense , Fenotipo , Análisis de Secuencia de ARN , Síndrome , Factores de Transcripción/metabolismo , Secuenciación del Exoma , Secuenciación Completa del GenomaRESUMEN
BACKGROUND: Congenital diaphragmatic hernia (CDH) is a prevalent major congenital anomaly with significant morbidity and mortality. Thirty to 40% mortality in CDH is largely attributed to pulmonary hypoplasia and pulmonary hypertension (PH). We hypothesized that the underlying genetic risk factors for hereditary PH are shared with CDH associated PH. METHODS: Participants were recruited as part of the Diaphragmatic Hernia Research & Exploration; Advancing Molecular Science (DHREAMS) study, a prospective cohort of neonates with a diaphragmatic defect enrolled from 2005 to 2012. PH affected patients with available DNA for sequencing had one of the following: moderate or severe PH on echocardiography at 3months of age; moderate of severe PH at 1month of age with death occurring prior to the 3month echocardiogram; or on PH medications at 1month of age. We sequenced the coding regions of the hereditary PH genes bone morphogenetic protein receptor type II (BMPR2), caveolin 1 (CAV1) and potassium channel subfamily K, member 3 (KCNK3) to screen for mutations. RESULTS: There were 29 CDH patients with PH including 16 males and 13 females. Sequencing of BMPR2, CAV1, and KCNK3 coding regions did not identify any pathogenic variants in these genes. TYPE OF STUDY: Prognosis study LEVEL OF EVIDENCE: Level IV.
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Receptores de Proteínas Morfogenéticas Óseas de Tipo II/genética , Caveolina 1/genética , Hernias Diafragmáticas Congénitas/genética , Hipertensión Pulmonar/genética , Mutación , Proteínas del Tejido Nervioso/genética , Canales de Potasio de Dominio Poro en Tándem/genética , Ecocardiografía , Femenino , Predisposición Genética a la Enfermedad , Hernias Diafragmáticas Congénitas/complicaciones , Humanos , Hipertensión Pulmonar/complicaciones , Hipertensión Pulmonar/diagnóstico por imagen , Recién Nacido , Masculino , Estudios Prospectivos , Factores de RiesgoRESUMEN
Ventilation practices have changed significantly since the initial reports in the mid 1980 of successful use of permissive hypercapnia and spontaneous ventilation [often called gentle ventilation (GV)] in infants with congenital diaphragmatic hernia (CDH). However, there has been little standardization of these practices or of the physiologic limits that define GV. We sought to ascertain among Diaphragmatic Hernia Research and Exploration; Advancing Molecular Science (DHREAMS) centers' GV practices in the neonatal management of CDH. Pediatric surgeons and neonatologists from DHREAMS centers completed an online survey on GV practices in infants with CDH. The survey gathered data on how individuals defined GV including ventilator settings, blood gas parameters and other factors of respiratory management. A total of 87 respondents, from 12 DHREAMS centers completed the survey for an individual response rate of 53% and a 92% center response rate. Approximately 99% of the respondents defined GV as accepting higher carbon dioxide (PCO2) and 60% of the respondents also defined GV as accepting a lower pH. There was less consensus about the use of sedation and neuromuscular blocking agents in GV, both within and across the centers. Acceptable pH and PCO2 levels are broader than the goal ranges. Despite a lack of formal standardization, the results suggest that GV practice is consistently defined as the use of permissive hypercapnia with mild respiratory acidosis and less consistently with the use of sedation and neuromuscular blocking agents. GV is the reported practice of surveyed neonatologists and pediatric surgeons in the respiratory management of infants with CDH.
Asunto(s)
Hernias Diafragmáticas Congénitas/terapia , Respiración Artificial/normas , Humanos , Recién Nacido , Neonatólogos/estadística & datos numéricos , Respiración Artificial/estadística & datos numéricos , Encuestas y CuestionariosRESUMEN
Lower-extremity ischemia is a significant complication in children on femoral venoarterial extracorporeal membrane oxygenation (VA ECMO). Our institution currently routinely uses distal perfusion catheters (DPCs) in all femoral arterial cannulations in attempts to reduce ischemia. We performed a single-center, retrospective review of pediatric patients supported with femoral VA ECMO from January 2005 to November 2015. The outcomes of patients with prophylactic DPC placement at cannulation (prophylactic DPC) were compared to a historical group with DPCs placed in response only to clinically evident ischemic changes (reactive DPC). Ischemic complication requiring invasive intervention (fasciotomy or amputation) was the primary outcome. Twenty-nine patients underwent a total of 31 femoral arterial cannulations, 17 with prophylactic DPC and 14 with reactive DPC. Ischemic complications requiring invasive intervention developed in 2 of 17 (12%) prophylactic DPC patients versus 4 of 14 (29%) reactive DPC. In the reactive DPC group, 7 of 14 (50%) had ischemic changes postcannulation, six underwent DPC placement, and three out of six of these patients still required invasive intervention. One of the seven patients had ischemic changes, did not undergo DPC, and required amputation. While a greater percentage of patients in the prophylactic group was cannulated during extracorporeal cardiopulmonary resuscitation (ECPR), statistical significance was not otherwise demonstrated. We demonstrate feasibility of superficial femoral artery (SFA) access in pediatric patients. We note fewer ischemic complications with prophylactic DPC placement, and observe that salvaging a limb with a reactive DPC was only successful 50% of the time. Although there was no statistical difference in the primary outcome between the two groups, limitations and confounding factors include small sample size and a greater percentage of patients in the prophylactic DPC group cannulated with ECPR in progress.