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.

Obstetrical Challenges in Robinow Syndrome.

Robinow syndrome is a genetically heterogenous syndrome that exhibits great pleiotropy, involving skeletal genital, cardiac, and craniofacial developmental anomalies. Fertility is not always compromised, and many individuals may be able to have a healthy pregnancy. Similar to other more common skeletal dysplasias and growth disorders such as achondroplasia, there are several challenges to be addressed in managing physiologic differences that occur in the context of pregnancy, and published literature centers on pregnant people with achondroplasia. We present a patient with Robinow syndrome (ROR2 variant), follow her clinical course through three of her pregnancies (one 20-week loss followed by two preterm cesarean deliveries at 36-week gestation), and highlight the major obstetrical considerations in her individualized care.

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.

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.

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.

Operative Vaginal Delivery Is a Safe Option in Women Undergoing a Trial of Labor after Cesarean.

Objective To compare outcomes of operative intervention in the second stage of labor during trial of labor after cesarean (TOLAC). Study Design A secondary analysis of the Maternal-Fetal Medicine Units Network cesarean section registry was conducted. Analysis was by first attempted mode of delivery. Results A total of 1,837 met inclusion criteria. Subjects in the operative vaginal groups (OVDs) were more likely to have a prior vaginal delivery (vacuum 34.2%; forceps 34.3%) than the repeat cesarean delivery (RCD) group (22.6%; p < 0.0001). Most OVD attempts were successful (forceps 90.4%; vacuum 92.6%). Neonatal morbidity was not different (12.1% forceps vs. 14.6% vacuum; 14.8% RCD). Maternal morbidity was highest among forceps deliveries (32.3 vs. 24.3% vacuum; 22.0% RCD, p = 0.0001). RCD was associated with surgical injury (2.7 vs. 0.7% forceps; 0% vacuum; p < 0.0001), endometritis (8.4 vs. 3.2% forceps, 1.2% vacuum; p < 0.0001), and wound complications (1.9 vs. 0.4% forceps; 0.3% vacuum; p = 0.006). OVD was associated with anal sphincter laceration (22.7% forceps, 15.5% vacuum; 0% RCD; p = 0.01). Conclusion The success rate of OVD is high in TOLAC with similar outcomes to RCD. Maternal composite outcomes were highest with forceps-assisted vaginal deliveries. However, considering overall morbidity, OVD in the second stage of labor in TOLAC is a reasonable, safe option in selected cases.

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.

Nonlinear bifurcations of psychological stress negotiation: new properties of a formal dynamical model.

Dynamical systems analysis is applied to a nonlinear model of stress and coping (Neufeld, 1999). The model is composed of 6 order parameters and 11 control parameters, and integrates core constructs of the topic domain, including variants of cognitive appraisal, differential stress susceptibility, stress activation, and coping propensity. In part owing to recent advances in Competitive Modes Theory (Yao, Yu & Essex, 2002), previously intractable but substantively significant dynamical properties of the 6-dimensional model are identified. They include stable and unstable fixed-point equilibria (higher-dimensional saddle-node bifurcation), oscillatory patterns attending fixed-point de-stabilization, and chaotic behaviors. Examination of the nature of system fixed-point de-stabilization, in relation to its control parameters, unveils mechanisms of re-stabilization, and dynamic stability control. All identified dynamics emerge naturally from a system whose construction guideposts are lodged in the addressed content domain. Dynamical complexities therefore may be intrinsic to the present content domain, possibly no less so than in other disciplines where the presence of such attributes has been established.

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.

Coping with stress through decisional control: quantification of negotiating the environment.

Coping with stress through 'decisional control' - positioning oneself in a multifaceted stressing situation so as to minimize the likelihood of an untoward event - is modelled within a tree-structure scenario, whose architecture hierarchically nests elements of varying threat. Analytic and simulation platforms quantify the game-like interplay of cognitive demands and threat reduction. When elements of uncertainty enter the theoretical structure, specifically at more subordinate levels of the hierarchy, the mathematical expectation of threat is particularly exacerbated. As quantified in this model, the exercise of decisional control is demonstrably related to reduction in expected threat (the minimum correlation across comprehensive parameter settings being .55). Disclosure of otherwise intractable stress-coping subtleties, endowed by the quantitative translation of verbal premises, is underscored. Formalization of decisional stress control is seen to usher in linkages to augmenting formal developments from fields of cognitive science, preference and choice modelling, and nonlinear dynamical systems theory. Model-prescribed empirical consequences are stipulated.