RESUMO
Hypoxic-ischemic encephalopathy (HIE) occurs in up to 7 out of 1000 births and accounts for almost a quarter of neonatal deaths worldwide. Despite the name, many newborns with HIE have little evidence of perinatal hypoxia. We hypothesized that some infants with HIE have genetic disorders that resemble encephalopathy. We reviewed genetic results for newborns with HIE undergoing exome or genome sequencing at a clinical laboratory (2014-2022). Neonates were included if they had a diagnosis of HIE and were delivered ≥35 weeks. Neonates were excluded for cardiopulmonary pathology resulting in hypoxemia or if neuroimaging suggested postnatal hypoxic-ischemic injury. Of 24 patients meeting inclusion criteria, six (25%) were diagnosed with a genetic condition. Four neonates had variants at loci linked to conditions with phenotypic features resembling HIE, including KIF1A, GBE1, ACTA1, and a 15q13.3 deletion. Two additional neonates had variants in genes not previously associated with encephalopathy, including DUOX2 and PTPN11. Of the six neonates with a molecular diagnosis, two had isolated HIE without apparent comorbidities to suggest a genetic disorder. Genetic diagnoses were identified among neonates with and without sentinel labor events, abnormal umbilical cord gasses, and low Apgar scores. These results suggest that genetic evaluation is clinically relevant for patients with perinatal HIE.
Assuntos
Sequenciamento do Exoma , Hipóxia-Isquemia Encefálica , Humanos , Hipóxia-Isquemia Encefálica/genética , Hipóxia-Isquemia Encefálica/diagnóstico , Hipóxia-Isquemia Encefálica/diagnóstico por imagem , Recém-Nascido , Feminino , Masculino , Estudos Retrospectivos , Predisposição Genética para Doença , Exoma/genética , Doenças Genéticas Inatas/genética , Doenças Genéticas Inatas/diagnósticoRESUMO
With an increasing incidence of twin gestations, understanding the inherent risks associated with these pregnancies is essential in modern obstetrics. The unique differences in placentation in monochorionic twins leads to unique complications, including twin-to-twin transfusion syndrome, the twin anemia-polycythemia sequence, and selective fetal growth restriction. Not only does the understanding of the monochorionic placenta lead to an understanding of the pathophysiology of the complications of monochorionic twins, but it also has led to the development of highly effective directed fetal therapy via fetoscopic laser coagulation used in twin-to-twin transfusion syndrome.
Assuntos
Transfusão Feto-Fetal , Policitemia , Gravidez , Feminino , Humanos , Transfusão Feto-Fetal/diagnóstico , Transfusão Feto-Fetal/cirurgia , Retardo do Crescimento Fetal/terapia , Policitemia/diagnóstico , Policitemia/etiologia , Policitemia/terapia , Placenta , Placentação , Gravidez de Gêmeos , Gêmeos MonozigóticosRESUMO
With the recent advances in gene editing with systems such as CRISPR-Cas9, precise genome editing in utero is on the horizon. Sickle cell disease is an excellent candidate for in utero fetal gene therapy, because the disease is monogenic, causes irreversible harm, and has life-limiting morbidity. Gene therapy has recently been proven to be effective in an adolescent patient. Several hurdles still impede the progress for fetal gene therapy in humans, including an incomplete understanding of the fetal immune system, unclear maternal immune responses to in utero gene therapy, risks of off-target effects from gene editing, gestational age constraints, and ethical questions surrounding fetal genetic intervention. However, none of these barriers appears insurmountable, and the journey to in utero gene therapy for sickle cell disease and other conditions should be well underway.
Assuntos
Anemia Falciforme/terapia , Edição de Genes , Anemia Falciforme/embriologia , Feminino , Terapia Genética , Humanos , Obstetrícia , Perinatologia , Guias de Prática Clínica como Assunto , Gravidez , Cuidado Pré-Natal , Sociedades MédicasRESUMO
BACKGROUND: Currently, no serological prognostic marker exists for pancreatic neuroendocrine tumors (pNETs). Previous studies have suggested potential for chromogranin A (CgA); however, the prognostic capability of CgA remains controversial. Our purpose was to explore preoperative CgA levels in predicting outcomes in patients with resected pNETs. MATERIALS AND METHODS: Patients with preoperative CgA levels who underwent resection of a pancreatic neuroendocrine tumor between July 2002 and May 2013 were identified from a prospective database. An elevated preoperative CgA was defined as a CgA laboratory value above the normal limit of the assay. All patients had pathologically confirmed primary pancreatic tumors. Outcomes were compared between elevated and normal CgA groups. RESULTS: A total of 38 patients were identified that met inclusion criteria. Of these, 45% were male, and the median age was 57 y (range, 17-81 y). All underwent resection with curative intent. Elevated preoperative CgA was present in 16 patients (42%). There were no differences in node positivity or margin status between the normal CgA and elevated CgA groups on univariate analysis. However, tumor size and grade were significantly different between the two groups. Both disease-free survival (DFS; P = 0.006) and overall survival (P = 0.017) were negatively impacted by an elevated preoperative CgA (median follow-up; 40 mo). CONCLUSIONS: In patients with resected pNETs, an elevated preoperative CgA level was negatively associated with DFS and OS and was the only independent predictor of DFS. These results indicate that preoperative CgA may be a clinically useful prognostic marker for patients undergoing pancreatic neuroendocrine tumor resection.
Assuntos
Biomarcadores Tumorais/sangue , Cromogranina A/sangue , Tumores Neuroendócrinos/sangue , Neoplasias Pancreáticas/sangue , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Tumores Neuroendócrinos/mortalidade , Tumores Neuroendócrinos/cirurgia , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/cirurgia , Wisconsin/epidemiologia , Adulto JovemRESUMO
BACKGROUND: Omphalocele is a congenital midline abdominal wall defect resulting in herniation of viscera into a membrane-covered sac. Pulmonary complications, including pulmonary hypoplasia, pulmonary hypertension, and prolonged respiratory support are a leading cause of neonatal morbidity and mortality. OBJECTIVE(S): This study aimed to assess the role of fetal MRI-derived lung volumes and omphalocele defect size as clinical tools to prognosticate postnatal pulmonary morbidity and neonatal mortality in those with a prenatally diagnosed omphalocele (PDO). STUDY DESIGN: This was a retrospective cohort study of all pregnancies with PDO at our fetal center from 2007-2023. Pregnancies with aneuploidy or concurrent life-limiting fetal anomalies were excluded. Using fetal MRI, observed-to-expected total fetal lung volume (O/E TLV) ratios were determined by a previously published method. The transverse diameter of the abdominal defect was also measured. The O/E TLV ratios and abdominal defect measurements were compared with postnatal outcomes. The primary outcome was death at any time. Secondary outcomes included death in the first 30 days of life or before discharge from birth hospitalization, the requirement of respiratory support with intubation and mechanical ventilation, or development of pulmonary hypertension. RESULTS: Of 101 pregnancies with a PDO, 54 pregnancies (53.5%) with prenatally diagnosed omphalocele met inclusion criteria. There was a significant increase in the rate of death when compared between the three O/E TLV classifications: 1/36 (2.8%) in the O/E ≥ 50% group, 3/14 (21.4%) in the O/E 25 - 49.9% group, and 4/4 (100%) in the O/E < 25% group (p < 0.001). The rate of intubation increased with the severity of O/E TLV classification, with 27.8% in the O/E ≥ 50% group, 64.3% in the O/E 25 - 49.9% group, and 100% in the O/E < 25% group (pâ¯=â¯0.003). The rate of pulmonary hypertension was also higher in the O/E 25 - 49.9% (50.0%) and the O/E < 25% (50.0%) groups compared to the O/E ≥ 50% group (8.3%, pâ¯=â¯0.002). There was no association between the transverse diameter of the abdominal wall defect and the primary outcome of death (ORâ¯=â¯1.08 95% CIâ¯=â¯[0.65-1.78], p=0.77). CONCLUSIONS: In our cohort of patients with PDO, O/E TLV <50% is associated with death, need for intubation, prolonged intubation, and pulmonary hypertension. In contrast, omphalocele size demonstrated no prognostic value for these outcomes. The strong association between low fetal lung volume on MRI and poor neonatal outcomes highlights the utility of fetal MRI for estimating postnatal prognosis. Clinicians can utilize fetal lung volumes to direct perinatal counseling and optimize the plan of care.
RESUMO
INTRODUCTION: Complication rates associated with peripherally inserted central catheters (PICCs) in the general population are variable, and rates specific to pregnant women are unclear. We conducted a systematic review and meta-analysis to estimate the rate of PICC-associated complications in pregnant women. METHODS: We searched published literature for records discussing PICC use in pregnant or postpartum women. We included studies with primary data regarding rates of maternal complications from PICC use. The primary outcomes were maternal infection (cellulitis, sepsis), venous thromboembolism (VTE), or combined major complication rate. Secondary outcomes were superficial thrombophlebitis or mechanical failure. Meta-analysis was performed using STATA 12 with the METAN and METAPROP software routines. Pooled estimates with 95%CI were calculated using random-effects models. RESULTS: After the removal of duplicates, the primary search yielded 318 articles, with 5 being included for final analysis. The pooled rate of combined infectious and thromboembolic complications was 26% (95%CI = 6-53%). For secondary outcomes the pooled rate of infectious complications was 18% (95%CI = 4-39%), VTE 6% (95%CI = 0-18%), mechanical failure 7% (95%CI = 3-12%), and superficial thrombophlebitis 1% (95%CI = 0-3%). There was significant statistical heterogeneity between studies for all outcomes calculated. CONCLUSION: There are limited data regarding complication rates due to PICC use in pregnancy, with a high level of heterogeneity among existing studies. The risk of VTE appears comparable to PICC-associated VTE in the non-pregnant hospitalized population. The risk of infection associated with PICC use was the most variable, with rates ranging from 4% to 37%. This suggests that infection risk may be modifiable and further studies are needed to assess interventions that may lower this risk.
Assuntos
Infecções Relacionadas a Cateter , Cateterismo Venoso Central , Cateterismo Periférico , Cateteres Venosos Centrais , Sepse , Tromboembolia Venosa , Infecções Relacionadas a Cateter/epidemiologia , Infecções Relacionadas a Cateter/etiologia , Cateterismo Venoso Central/efeitos adversos , Cateterismo Periférico/efeitos adversos , Catéteres/efeitos adversos , Cateteres Venosos Centrais/efeitos adversos , Feminino , Humanos , Gravidez , Estudos Retrospectivos , Fatores de Risco , Tromboembolia Venosa/complicações , Tromboembolia Venosa/etiologiaRESUMO
With an increasing incidence of twin gestations, understanding the inherent risks associated with these pregnancies is essential in modern obstetrics. The unique differences in placentation in twins contribute to the increased risks. Monochorionic twins are susceptible to complications because of their unique placental architecture, including twin-to-twin transfusion syndrome, the twin anemia-polycythemia sequence, selective intrauterine growth restriction, and the twin reversed arterial perfusion sequence. Knowing the clinical correlations of placental anatomy in these gestations helps perinatal pathologists perform a more informed placental evaluation, allowing for better care for the mother and her children.
Assuntos
Transfusão Feto-Fetal/diagnóstico , Placenta/diagnóstico por imagem , Gravidez de Gêmeos , Gêmeos Monozigóticos , Feminino , Humanos , Gravidez , Ultrassonografia Pré-Natal/métodosRESUMO
A screen for hepatitis C virus (HCV) NS3 helicase inhibitors revealed that the commercial dye thioflavine S was the most potent inhibitor of NS3-catalyzed DNA and RNA unwinding in the 827-compound National Cancer Institute Mechanistic Set. Thioflavine S and the related dye primuline were separated here into their pure components, all of which were oligomers of substituted benzothiazoles. The most potent compound (P4), a benzothiazole tetramer, inhibited unwinding >50% at 2 ± 1 µM, inhibited the subgenomic HCV replicon at 10 µM, and was not toxic at 100 µM. Because P4 also interacted with DNA, more specific analogues were synthesized from the abundant dimeric component of primuline. Some of the 32 analogues prepared retained ability to inhibit HCV helicase but did not appear to interact with DNA. The most potent of these specific helicase inhibitors (compound 17) was active against the replicon and inhibited the helicase more than 50% at 2.6 ± 1 µM.