Early Clinical Outcomes in Infants with Prenatally Diagnosed Perimembranous and Muscular Ventricular Septal Defects (VSDs).

Isolated ventricular septal defect (VSD) is often associated with good clinical outcomes. However, infants prenatally diagnosed with VSD are often recommended for delivery at tertiary care centers. The aim of our study was to determine the odds of neonatal intensive care unit (NICU) admission in infants with persistent isolated VSD and complicated VSD, where an infant is affected by VSD and other genetic/structural abnormalities. We performed a retrospective cohort study, with data collected from a single academic institution from June 2018 to March 2023. Individuals with prenatally diagnosed VSD, in the absence of any other heart defects, were included in this study. The primary outcome was admission to the NICU. Multivariable logistic regression was used to assess associations. The association between persistence of VSD and NICU admission was adjusted for maternal age, fetal genetic abnormalities, fetal extracardiac abnormalities, and gestational age at the time of delivery. The association between complicated VSD and NICU admission was adjusted for maternal age and gestational age of the infant at the time of delivery. The odds of NICU admission were similar in infants with persistent isolated VSD and VSD that closed in utero (adjusted OR 1.31, 95% CI 0.30-5.61). However, infants with complicated VSD were at increased risk of NICU admission (adjusted OR 15.52, 95% CI 2.90-82.92). The risk of NICU admission was only increased in infants whose VSD was complicated by another genetic/major structural abnormalities. Therefore, women whose infants are prenatally diagnosed with VSD alone may not require delivery at tertiary care centers.

Prepregnancy Roux-en-Y gastric bypass vs sleeve gastrectomy: a systematic review, pairwise, and network meta-analysis of obstetrical and neonatal outcomes.

OBJECTIVE: This study aimed to systematically investigate a wide range of obstetrical and neonatal outcomes with respect to 2 types of prepregnancy bariatric surgery, Roux-en-Y gastric bypass and sleeve gastrectomy, through: (1) providing a meta-analysis of the effect of bariatric surgery (Roux-en-Y gastric bypass vs no surgery and, separately, sleeve gastrectomy vs no surgery) on adverse obstetrical and neonatal outcomes, and (2) comparing the relative benefit of Roux-en-Y gastric bypass vs sleeve gastrectomy using both conventional and network meta-analysis. DATA SOURCES: We searched PubMed, Scopus, and Embase systematically from inception up to April 30, 2021. ELIGIBILITY CRITERIA: Studies reporting on pregnancies' obstetrical and neonatal outcomes with respect to 2 types of prepregnancy bariatric surgery-Roux-en-Y gastric bypass and sleeve gastrectomy-were included. The included studies either indirectly compared between the procedure and controls or directly compared between the 2 procedures. METHODS: We performed a systematic review followed by pairwise and network meta-analysis in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. In the pairwise analysis, multiple obstetrical and neonatal outcomes were tabulated and compared between 3 groups: (1) Roux-en-Y gastric bypass vs controls, (2) sleeve gastrectomy vs controls, and (3) Roux-en-Y gastric bypass vs sleeve gastrectomy. Primary outcomes included small for gestational age, large for gestational age, gestational hypertension/preeclampsia, and gestational diabetes mellitus. Secondary outcomes included preterm birth, anemia, cesarean delivery, and biochemical profile. The random-effects model was used to pool the mean differences or odds ratios and the corresponding 95% confidence intervals. Heterogeneity was assessed using the I2 value. The Newcastle-Ottawa scale was used to assess individual study quality. To resolve inconclusive findings and to rank current treatments, network meta-analysis was conducted for the primary outcomes. Quality of evidence was assessed with the Confidence in Network Meta-Analysis approach and the GRADE (Grading of Recommendations, Assessment, Development, and Evaluations) tool within the summary of findings table. RESULTS: A total of 20 studies were included, reporting on 40,108 pregnancies, of which 5194 underwent Roux-en-Y gastric bypass, 405 underwent sleeve gastrectomy, and 34,509 were controls. Compared with controls, Roux-en-Y gastric bypass increased the risk of small for gestational age infants (odds ratio, 2.56; 95% confidence interval, 1.77-3.70; I2, 29.1%; P<.00001), decreased the risk of large for gestational age infants (odds ratio, 0.25; 95% confidence interval, 0.18-0.35; I2, 0%; P<.00001), decreased gestational hypertension/preeclampsia (odds ratio, 0.54; 95% confidence interval, 0.30-0.97; I2, 26.8%; P=.04), decreased gestational diabetes mellitus (odds ratio, 0.43; 95% confidence interval, 0.23-0.81; I2, 32%; P=.008), increased maternal anemia (odds ratio, 2.70; 95% confidence interval, 1.53-4.79; I2, 40.5%; P<.001), increased neonatal intensive care unit admission (odds ratio, 1.36; 95% confidence interval, 1.04-1.77; I2, 0%; P=.02), and decreased mean gestational weight gain (mean difference, -3.37 kg; 95% confidence interval, -5.62 to -1.11; I2, 65.3%; P=.003). Only 3 studies compared sleeve gastrectomy with controls, and found no significant differences in primary outcomes or in mean gestational weight gain. The network meta-analysis showed that Roux-en-Y gastric bypass (malabsorptive procedure) resulted in greater decrease of large for gestational age, gestational hypertension/preeclampsia, and gestational diabetes mellitus, and a greater increase in small for gestational age infants when compared with sleeve gastrectomy (restrictive procedure). However, the small number of studies, small number of sleeve gastrectomy patients, limited outcomes, and data heterogeneity resulted in low-to-moderate network GRADE of evidence. CONCLUSION: This network meta-analysis showed that Roux-en-Y gastric bypass, compared with sleeve gastrectomy, resulted in greater decrease in large for gestational age, gestational hypertension/preeclampsia, and gestational diabetes mellitus, but in greater increase in small for gestational age infants. Certainty of evidence in the network meta-analysis was of a low-to-moderate GRADE. Evidence is still lacking for periconception biochemical profile, congenital malformations, and reproductive health outcomes for both interventions; thus, future well-designed prospective studies are needed to further characterize these outcomes.

Endothelial Rbpj Is Required for Cerebellar Morphogenesis and Motor Control in the Early Postnatal Mouse Brain.

Intercellular influences are necessary for coordinated development and function of vascular and neural components in the brain. In the early postnatal period after birth, the mammalian cerebellum undergoes extensive morphogenesis - developing its characteristic lobules, organizing its diverse cell types into defined cellular layers, and establishing neural circuits that support cerebellar function, such as coordinated movement. In parallel, the cerebellar vasculature undergoes extensive postnatal growth and maturation, keeping pace with the expanding neural compartment. Endothelial deletion of Rbpj leads to neurovascular abnormalities in mice, including arteriovenous (AV) shunts that supplant capillaries and instead direct high-pressure/high-flow arterial blood directly to veins. Gross and histopathological cerebellar abnormalities, associated with these Rbpj-mediated brain AV malformations (AVMs), led to our hypothesis that early postnatal morphogenesis and lamination of cerebellum was perturbed in mice harboring endothelial Rbpj deficiency from birth. Here, we show that endothelial Rbpj-mutant mice developed enlarged vascular malformations on the cerebellar surface, by 2-week post-Rbpj deletion. In addition, outgrowth of cerebellar lobules was impaired through decreased cell proliferation, but not increased apoptosis, in the external granule layer. Molecular layer thickness was reduced, and the Purkinje layer was affected, by decreased Purkinje cell number, primary dendrite length, and dendritic arbor density. Endothelial deletion of Rbpj also led to impaired motor behaviors, consistent with abnormal cerebellar morphogenesis and lamination. Thus, our data suggest that Rbpj is required, in early postnatal vascular endothelium, to ensure proper cerebellar outgrowth, morphogenesis, and function in mice.

Pathological pericyte expansion and impaired endothelial cell-pericyte communication in endothelial Rbpj deficient brain arteriovenous malformation.

Pericytes, like vascular smooth muscle cells, are perivascular cells closely associated with blood vessels throughout the body. Pericytes are necessary for vascular development and homeostasis, with particularly critical roles in the brain, where they are involved in regulating cerebral blood flow and establishing the blood-brain barrier. A role for pericytes during neurovascular disease pathogenesis is less clear-while some studies associate decreased pericyte coverage with select neurovascular diseases, others suggest increased pericyte infiltration in response to hypoxia or traumatic brain injury. Here, we used an endothelial loss-of-function Recombination signal binding protein for immunoglobulin kappa J region (Rbpj)/Notch mediated mouse model of brain arteriovenous malformation (AVM) to investigate effects on pericytes during neurovascular disease pathogenesis. We tested the hypothesis that pericyte expansion, via morphological changes, and Platelet-derived growth factor B/Platelet-derived growth factor receptor ß (Pdgf-B/Pdgfrß)-dependent endothelial cell-pericyte communication are affected, during the pathogenesis of Rbpj mediated brain AVM in mice. Our data show that pericyte coverage of vascular endothelium expanded pathologically, to maintain coverage of vascular abnormalities in brain and retina, following endothelial deletion of Rbpj. In Rbpj-mutant brain, pericyte expansion was likely attributed to cytoplasmic process extension and not to increased pericyte proliferation. Despite expanding overall area of vessel coverage, pericytes from Rbpj-mutant brains showed decreased expression of Pdgfrß, Neural (N)-cadherin, and cluster of differentiation (CD)146, as compared to controls, which likely affected Pdgf-B/Pdgfrß-dependent communication and appositional associations between endothelial cells and pericytes in Rbpj-mutant brain microvessels. By contrast, and perhaps by compensatory mechanism, endothelial cells showed increased expression of N-cadherin. Our data identify cellular and molecular effects on brain pericytes, following endothelial deletion of Rbpj, and suggest pericytes as potential therapeutic targets for Rbpj/Notch related brain AVM.

Is a Low-Cost Drill Cover System Noninferior to Conventional Surgical Drills for Skeletal Traction Pin Placement?

SUMMARY: The Drill Cover system was developed as a low-cost alternative to conventional surgical drills with specific applicability to low- and middle-income countries. However, the system may also be useful for the sterile placement of traction pins in the emergency department of high-income country hospitals. In September 2019, a US-based Level-1 trauma center began using the Drill Cover system to apply skeletal traction pins in patients with femoral shaft fractures. With these data, we performed a retrospective interrupted time series study to determine if the Drill Cover system was noninferior to conventional surgical drills in terms of infections at the traction pin site. The study included 205 adult patients with femoral shaft fractures initially placed in skeletal traction using a conventional surgical drill (n = 150, preintervention group) or the Drill Cover system (n = 55, postintervention group). The primary outcome was an infection at the site of skeletal traction pin placement that required surgery or antibiotics, which was compared between groups using a noninferiority test with a 1-sided alpha of 0.05 and a noninferiority margin of 3%. No infections at the site of skeletal traction pin placement were found in either the preintervention or the postintervention group (difference, 0%; 95% confidence interval: 0.0%-1.4%; noninferiority P value < 0.01). The results suggest that the Drill Cover system was noninferior to conventional surgical drills regarding infections at the site of skeletal traction pins. The Drill Cover system may be a safe alternative to the more expensive surgical drills for skeletal traction pin placement in the emergency room environment.

The Small RNA Teg41 Regulates Expression of the Alpha Phenol-Soluble Modulins and Is Required for Virulence in Staphylococcus aureus.

Small RNAs (sRNAs) remain an understudied class of regulatory molecules in bacteria in general and in Gram-positive bacteria in particular. In the major human pathogen Staphylococcus aureus, hundreds of sRNAs have been identified; however, only a few have been characterized in detail. In this study, we investigate the role of the sRNA Teg41 in S. aureus virulence. We demonstrate that Teg41, an sRNA divergently transcribed from the locus that encodes the cytolytic alpha phenol-soluble modulin (αPSM) peptides, plays a critical role in αPSM production. Overproduction of Teg41 leads to an increase in αPSM levels and a corresponding increase in hemolytic activity from S. aureus cells and cell-free culture supernatants. To identify regions of Teg41 important for its function, we performed an in silico RNA-RNA interaction analysis which predicted an interaction between the 3' end of Teg41 and the αPSM transcript. Deleting a 24-nucleotide region from the S. aureus genome, corresponding to the 3' end of Teg41, led to a 10-fold reduction in αPSM-dependent hemolytic activity and attenuation of virulence in a murine abscess model of infection. Restoration of hemolytic activity in the Teg41Δ3' strain was possible by expressing full-length Teg41 in trans Restoration of hemolytic activity was also possible by expressing the 3' end of Teg41, suggesting that this region of Teg41 is necessary and sufficient for αPSM-dependent hemolysis. Our results show that Teg41 is positively influencing αPSM production, demonstrating for the first time regulation of the αPSM peptides by an sRNA in S. aureusIMPORTANCE The alpha phenol-soluble modulins (αPSMs) are among the most potent toxins produced by Staphylococcus aureus Their biological role during infection has been studied in detail; however, the way they are produced by the bacterial cell is not well understood. In this work, we identify a small RNA molecule called Teg41 that plays an important role in αPSM production by S. aureus Teg41 positively influences αPSM production. The importance of Teg41 is highlighted by the fact that a strain containing a deletion in the 3' end of Teg41 produces significantly less αPSMs and is attenuated for virulence in a mouse abscess model of infection. As the search for new therapeutic strategies to combat S. aureus infection proceeds, Teg41 may represent a novel target.