Clinical exome sequencing uncovers genetic disorders in neonates with suspected hypoxic-ischemic encephalopathy: A retrospective analysis.

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.

Monochorionic Twins: TTTS, TAPS, and Selective Fetal Growth Restriction.

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.

Society for Maternal-Fetal Medicine Special Statement: Beyond the scalpel: in utero fetal gene therapy and curative medicine.

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.

Chromogranin A predicts survival for resected pancreatic neuroendocrine tumors.

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.

Complications of peripherally inserted central catheters in pregnancy: a systematic review and meta-analysis.

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.

Placental Anatomy and Function in Twin Gestations.

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.

Optimization of potent hepatitis C virus NS3 helicase inhibitors isolated from the yellow dyes thioflavine S and primuline.

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.